Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications [1 ed.] 9781617283345, 9781616689919

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

CHEMICAL ENGINEERING METHODS AND TECHNOLOGY

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

GADOLINIUM: COMPOUNDS, PRODUCTION AND APPLICATIONS

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Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

CHEMICAL ENGINEERING METHODS AND TECHNOLOGY

GADOLINIUM: COMPOUNDS, PRODUCTION AND APPLICATIONS

CADEN C. THOMPSON

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EDITOR

New York

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Gadolinium : compounds, production, and applications / editor, Caden C. Thompson. p. cm. Includes index.

ISBN:  (eBook) 1. Gadolinium. QD181.G4G33 2009 546'.416--dc22 2010014107

Published by Nova Science Publishers, Inc. † New York

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

CONTENTS Preface Chapter 1

Chapter 2

Chapter 3

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Chapter 4

Chapter 5

Chapter 6

Chapter 7

vii Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes: Synthesis, Crystal Structures and Magnetic Properties Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo and Catalina Ruiz-Pérez

1

Application of the Gadolinium Foils as a Converters of Thermal Neutrons in Detectors of Nuclear Radiation D. A. Abdushukurov

53

Toxicities Associated with Gadolinium Contrast in Patients with Kidney Disease Mark A. Perazella

143

Electron Microscopic Studies of the Role of Gadolinium in Human Fibrosing Diseases J.A. Schroeder, E. Goffin, Ch Weingart, B. Banas, T. Vogt, F. Hofstaedter and B.K. Krämer Novel Nanovectors as the Liver Target Molecular: MRI Contrast Agents Na Zhang and Zhijin Chen Application of Gadolinium Based Contrast Agents in Abdominal Magnetic Resonance Imaging: Important Considerations Rafael O.P. de Campos, Vasco Herédia, Miguel Ramalho, Ersan Altun and Richard C. Semelka Use of Gadolinium-Based Contrast Agents in Cardio-Vascular Magnetic Resonance Imaging- A Review Cheryl Zvaigzne, Matthias G. Friedrich and Oliver Strohm

Chapter 8

The Use of Gadolinium for ESR Dosimetry M. Marrale, M. Brai and A. Longo

Chapter 9

Gadolinium as an Additive to Magnesium Alloys and Its Role in Environmental Issues

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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193

217

245 265

301

vi

Contents Masaki Sumida and Satoshi Kajino

Chapter 10

Chapter 11

Chapter 12

Ex-Vivo Application of Gadolinium: Its Utilisation to Certify the Viability of Marginal Organs during their Perfusion of Reanimation. Experimental Study Jean-Bernard Buchs, François Lazeyras, Raphael Ruttimann, Antonio Nastasi and Philippe Morel Gadolinium Compounds and MRI in Daily Practice: How to Reduce Inappropriate Ordering and Improve Communication between Radiologists and Referring Physicians Sergio Lopes Viana Rare Earth Gadolinium Nanoparticles for Hydrogen Induced Switching, Sensing and Storage Devices B. R. Mehta, I. Aruna and L. K. Malhotra

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Index

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335

341 351

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PREFACE Gadolinium is a silvery-white, malleable and ductile rare-earth metal. It has exceptionally high absorption of neutrons and therefore is used for shielding in neutron radiography and in nuclear reactors. Because of its paramagnetic properties, solutions of organic gadolinium complexes and gadolinium compounds are the most popular intravenous MRI contrast agents in medical magnetic resonance imaging. This new book presents and discusses research on the application of gadolinium-based contrast agents in abdominal MRIs; a review of GBC agents as causes of acute kidney injury and triggers of nephrogenic systemic fibrosis and others. Chapter 1 - Magneto-structural studies on polynuclear complexes, aimed at understanding the structural and chemical factors that govern the exchange coupling between paramagnetic centers, are of continuing interest. One of the best illustrative examples corresponds to the di--hydroxo-dicopper(II) complexes where the angle at the hydroxo bridge is the main factor governing the nature and magnitude of the intramolecular magnetic coupling. The large number of magneto-structural studies on polynuclear complexes with first-row transition metal ions has provided a relatively good comprehension of the magnetic coupling in this family; however, the situation with the lanthanide-containing metal complexes is much less advanced. The focus lies on the synthesis of compounds with paramagnetic centres which can interact with each other to afford large spin systems. This is why the natural choice seems to be compounds containing lanthanide cations because of the large spin values that these cations may present. In these systems, the mostly weak values of the magnetic coupling together with the influence of the ligand field which is hard to predict and that can easily be misinterpreted as an antiferromagnetic interaction, are problematic. Having in mind these difficulties, the magnetic studies with the gadolinium(III) is a convenient choice because it has a 8S7/2 ground state and the next excited state is well separated in energy (ca. 104 cm-1), so that its eff can be approximated with the spin-only formalism. The first magnetic studies concerning dinuclear gadolinium(III) complexes having the di--oxo bridging skeleton showed the occurrence of weak but significant intramolecular antiferromagnetic interactions. Interestingly, a few years later several reports have also revealed the presence of ferromagnetic interactions in this type of complexes. The interpretation of these results in the case of dinuclear gadolinium(III) compounds with a di-oxo(carboxylate) bridge, has allowed to establish a relationship between the nature of the magnetic coupling and the type of bridge involved.[4] At this respect, it deserves to be noted that magneto-structural data for polynuclear gadolinium(III) compounds are still scarce and

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Caden C. Thompson

consequently, more examples are needed to have a solid basis to analyze all the factors involved and then to establish a definitive magneto-structural correlation.[5] Given the ability of the carboxylate groups to lead to di--oxo (carboxylate) digadolinium(III) units where the magnetic coupling is either ferro- or antiferromagnetic, the authors have undertaken a systematic study of complex formation between gadolinium(III) and carboxylate-containing ligands aiming at investigating the factors that govern the magnetic coupling in the digadolinium(III) units. Chapter 2 - Converters of neutron radiation play a determining role in the development of detectors of these radiations. They determine the basic characteristics of detectors: the efficiency of registration, energy, time and spatial resolution. Among solid-state converters on the basis of gadolinium and it 157 isotopes are especially allocated, possessing is abnormal high cross section of interaction with thermal neutrons. In this article, theoretical bases of registration of neutron radiation by converters from gadolinium are considered. The efficiency of converters is the product of three variables. These are the following: Probabilities of capture of thermal neutrons by nucleus; Probabilities of creation of the secondary charged particles, in the authors‘ case of internal conversion and Auger electrons; Probabilities of escape created electrons from the material of the converter. Model calculations of registration efficiency of thermal neutrons by the foil converters made from natural gadolinium and its 157 isotope described. Processes of neutron absorption in the material of a converter and the probability of secondary electron escapes examined. Calculation made for converters with the various thicknesses, and other parameters of converters. It was chosen the most optimal converter thicknesses. The contribution low-energy Auger electrons radiated from L- subshell with the energy 4.84 keV and M-subsell with the energy 0.97 keV on efficiency of converters are lead. These electrons have rather small free path length in gadolinium; these are 0.3 microns (4.84 keV) and 0.04 microns (0.97 keV). But their contribution to become essential at use of converters from 157 gadolinium isotopes as the length of free path of neutrons in them does not exceed 2-3 microns and this length to become comparable with length of path electrons. The estimation of contribution of X-ray and low-energy gamma-quanta absorbed directly in the converter and resulting in occurrence of secondary electrons. In case of the account of the contribution of electrons formed by X-ray quanta the efficiency is increased a little, but their contribution is no more, than by 1%. Calculations of complex converters representing a set thin gadolinium foil located on the both sides of supporting kapton foils and calculations of complex converters representing a set thin drilled with the fine step foils located one over other in a gas volume are lead. Examples of development of detectors of neutrons based on gadolinium converters are described. Chapter 3 - Gadolinium-based contrast (GBC) agents have garnered intense interest from several groups including physicians across numerous specialties, patients and lawyers. These image-enhancing agents are widely employed as contrast for magnetic resonance imaging (MRI) and have been generally considered safe. Early studies, in particular phase III trials and small studies in low risk patients suggested a benign renal profile. These data led to the widespread use of these agents for imaging in patients with kidney disease as a safe alternative to iodinated radiocontrast. More recent studies raise the possibility of nephrotoxicity. However; GBC agents clearly do not approach the incidence of nephropathy

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Preface

ix

associated with iodinated radiocontrast, but high doses in at risk patients can cause acute kidney injury. Another complication of GBC agents came to light in 2006. Reports of a rare systemic fibrosing condition entitled nephrogenic systemic fibrosis (NSF) were recently linked to exposure of patients with advanced kidney disease to GBC-agents. Analysis of the data suggests that certain GBC agents are more likely to be associated with NSF. Also, not all patients with kidney disease are at risk to develop NSF, only those with advanced acute or chronic kidney disease. When appropriate, avoidance of GBC exposure is the best approach for high-risk patients. At times when GBC agents are required to obtain optimal images, use of low doses of more stable macrocyclic agents is safer and preferred. This chapter will review the status of GBC agents as causes of acute kidney injury and triggers of NSF, while also providing an opinion on how to use these agents in patients with underlying kidney disease. Chapter 4 - Gadolinium (chemical symbol Gd) is a rare earth metal with the atomic number 64 placed in the IIIA group elements or lanthanides of the periodic system, its name is derived from Johan Gadolin - a Finnish chemist and mineralogist. Previously found and mined in Sweden, the main mining areas are now in China, the United States, Brazil, India, and Australia with a cumulative production of approximately 400t pure Gadolinium per year to meet the requirements of industry and medical applications. One can observe a growing demand for this rare element in the computer and multimedia industry (screens, media-CD, lamps, TV sets, cellular phones, etc.) and, as a consequence, a non-controllable global dissemination of Gadolinium as ecological waste in the free natural environment (5). This in turn can contaminate the food chain and harm life because free Gadolinium as a trivalent (Gd+3) ion is highly toxic for living cells as reported in a number of laboratory animal experiments; it has no known metabolic function in the body. Chapter 5 - Accurate diagnosis in early stage is vital for the treatment of hepatocellular carcinoma(HCC). Contrast material–enhanced dynamic magnetic resonance imaging (MRI) performed with extracellular contrast agents such as gadolinium chelates is considered useful for detecting and characterizing focal liver lesions. However, the sensitivity and specificity of conventional MRI contrast agents are far from satisfaction for the detection and characterization of benign and malignant focal liver lesions in early stage. The novel molecular contrast agents special for liver with relatively longer metabolic time and stable contrast effect in liver tissue are highly desired. The developing nanotechnology provides an unprecedented opportunity for the diagnostic detection rate of HCC, and cell-surface receptor-targeted nanotenology provide improving specificity of the detection of focal liver lesions. In order to maximize lesion detection and characterization, novel gadolinium chelates loaded nanovectors include the solid lipid nanoparticles, nanocomplexes and polymeric nanoparticles has been used as biocompatible molecular MRI contrast agent. In this chapter, the authors would discuss the preparation, characterization and the advantages/ disadvantages of these novel nanovectors using as molecular MRI contrast agents. Furthermore, liver target nanovectors aimed at improving the diagnostic accuracy of liver MRI by targeting additional features of focal liver lesions would be highlighted. Chapter 6 - The chelation of gadolinium to organic ligands is necessary for the atom to be used as an in vivo contrast agent in humans. There are several formulations available with different ligands, constituting the gadolinium based contrast agents (GBCAs). They are the most widely used MR contrast agents. GBCAs induce T1-shortening resulting in marked

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elevation of signal on T1-weighted images. GBCA enhancement is crucial in the detection and characterization of abdominal diseases. There are important aspects for the achievement of high-quality GBCA enhanced abdominal images. The first critical aspect is the reduction of artifacts. It is imperative to obtain motion-free images. Respiration is the most important and most troubling source of artifacts in abdominal MR imaging. Current ―state-of-the-art‖ MR systems can generate high-quality diagnostic MR images in the great majority of patients, using breathing-independent sequences and breath-hold sequences. It is also essential to recognize the importance of timing of data acquisition in order to maximize the information available regarding the dynamic handling of contrast by the vascular and extracellular spaces of various organs, tissues, and disease processes. An efficient study should include three passes following GBCA administration: hepatic arterial dominant phase (HADP), early hepatic venous phase and interstitial phase. The exact timing is more critical in the HADP. The magnetic field strength (1.5T versus 3.0T) also influences significantly the quality of post-contrast abdominal MR studies, with advantages of imaging at 3.0T. There is a greater enhancement induced by GBCAs at 3.0T compared to 1.5T. There are also important considerations regarding the type of GBCA that can be used. High thermodynamic stability constants and lower dissociation rates (greater affinity of ligands for gadolinium ions) are important qualities of a GBCA, in order to minimize risks of nephrogenic systemic fibrosis, which is the major current concern following GBCA exposure. Chapter 7 - Cardiovascular magnetic resonance (CMR) imaging has emerged as an extremely advantageous and non-invasive imaging technique. Gadolinium-based contrast agents (GBCA) further increase its utility for the assessment of tissue characterization, perfusion, and myocardial viability in various cardiac diseases. Many pathological processes of the myocardium can be detected more accurately with an increased contrast-to-noise ratio. Gadolinium will wash in and out through normal tissue, areas of inflammation, ischemia, or scar at identifiable rates according to perfusion, endothelial permeability and extracellular volume of distribution. CMR image acquisition within the first minutes after gadolinium administration (Early Gadolinium Enhancement) is useful for detecting myocardial inflammation. Hyperemia and increased capillary permeability will increase the volume of distribution during this time and inflammatory tissue will have a higher signal relative to normal tissue. T1-weighted image acquisition ten minutes or later after GBCA injection, also referred to as Late Gadolinium Enhancement imaging, is considered the non-invasive gold standard for detecting non-viable myocardium. In necrotic and fibrotic tissues, Gadolinium shows a delayed washout due to distribution in the large extravascular volume, and these areas will have a higher signal relative to other areas. These characteristics allow specific imaging of tissue pathology and diagnosis of a variety of cardiovascular diseases. In this review article, the authors describe the utility of gadolinium-based contrast agents for CMR of coronary artery disease, myocarditis cardiomyopathies, vasculitis, and storage diseases. Chapter 8 – The application of gadolinium to sensitize Electron Spin Resonance (ESR) dosimeters is reviewed. This nucleus is chosen because it has very good features in interacting with ionizing radiations. In particular, it has a very high capture cross section for thermal neutrons which favors the interactions of these particles within the detector; moreover, the charged secondary particles released after neutron interactions (mainly Auger and internal conversion electrons) are able to release their energy close the gadolinium site and, therefore, inside the sensitive volume of the detector. Consequently, the addition of gadolinium inside ESR dosimeters produces a significant enhancement of thermal neutron

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Preface

xi

sensitivity. Furthermore, the presence of gadolinium can improve the sensitivity to photons because its high atomic number (ZGd=64) increases the effective cross photon section of the detectors. However, it must be taken into account for medical dosimetric application of Gdadded dosimeters that the tissue equivalence is heavily reduced. In this work, the response of ESR dosimeters added with gadolinium after irradiation to various radiation beams (such as 60 Co gamma photons, thermal neutrons, protons) is described. Monte Carlo simulations able to theoretically model the effects of gadolinium on the ESR dosimeter sensitivity are reported along with the comparison of these computational results with the experimental ones. Chapter 9 - In this chapter, the effects of the addition of gadolinium (Gd) on the material properties of magnesium (Mg) alloys are discussed. Mg alloys are widely utilized in industrial products as structural components for automobiles, aircraft and electronics due to their lightweight characteristics. However, new Mg alloys with integrated mechanical, thermal and other properties are required to expand the field of application. Here, solidified samples with nominal composition of AZ91D - 0 to 10 mass%Gd were prepared via a precision casting technique, with AZ91D being the most widely used alloy in the casting industry. Characterization of the samples identified that the Gd addition improves the solidified microstructure and tensile properties of AZ91D. By 10mass%Gd, the ultimate tensile strength and elongation were increased by 16% and 143%, respectively, while the 0.2% yield strength decreased by 6%. These results are explained in relation to the solidified microstructure. The combustion behavior during heating at 10°C/min in an air atmosphere was also investigated. The ignition temperature (Tig) was measured by direct observation for samples with a different amount of Gd addition. For AZ91D, Tig=703°C was obtained, whereas a minimum temperature of Tig=626°C was found for AZ91D-15mass%Gd and a temperature of Tig=798°C for AZ91D-25mass%Gd. These experimental results indicate that Gd is a beneficial additive for integration of the AZ91D and possibly other Mg alloys. Firstly, the current research on the effects of addition of Gd along with other conventional alloying elements to Mg alloys is reviewed before describing the results of the present work. Finally, the importance and potential benefit of Gd for development of new high-performance Mg alloys, and their possible contribution to environmental issues are discussed. Chapter 10 – The scarcity of organs for transplantation imposes on us the need to use marginal organs. The author group uses NMR tests to evaluate marginal organs‘ viability. NMR tests including Gd-Perfusion let us obtain information about intra renal redistribution of flow due to ischemic lesions. Moreover, Gd-Perfusion helps in the visualisation of the vascularisation of the organs. Marginal kidneys are tested after 8 hours of perfusion for their reanimation. The aim is the realization of a score allowing us to distinguish viable and not viable kidneys, the Intensive Magnetic Resonance Diagnosis (IMRD). The authors have developed a perfusion machine (O2 + HPP) compatible with the Magnetic Resonance technology, because perfusion must continue during the NMR examination. Chapter 11 - Inappropriate ordering of gadolinium for magnetic resonance imaging has been rarely addressed in the literature. Errors commonly seen in daily practice include indiscriminate solicitation of contrast-enhanced exams or, on the contrary, failure to request the administration of gadolinium when the clinical scenario so demands. The main causes for such errors from referring physicians seem to be deficient medical formation and lack of knowledge due to neglected continued medical education, while radiologists fail to cooperate with their colleagues aiming to clarify inadequately ordered tests. The sole most important

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factor, however, comes from both sides, consisting of a dangerous and unacceptable failure of communication based upon selfishness and egocentrism. Improved communication between MRI professionals and referring physicians in association with better medical training and continued medical education are the key points to disseminate knowledge and avoid such errors. As long as radiologists turn out to be better communicators and ordering doctors become open to hear and to learn from them, misuse of gadolinium compounds tends to be less frequent, so that better care can be offered to the authors‘ patients at a lesser cost. Chapter 12 - Recently, ‗nanoparticle route‘ has been successfully used to fabricate RE nanoparticle switchable mirrors to improve the color neutrality without adversely affecting the response time, optical contrast, reversibility, and stability of RE based switchable mirrors. It is well known that the optical band gap of the semiconductor nanoparticles shifts towards lower wavelength side as compared to the bulk and polycrystalline films due to the quantum confinement of charge carriers at nanodimensions. In addition, nanoparticles are known to be more reactive to the gaseous species due to the enhanced surface area at nanodimensions. The important nanoparticle characteristics of size-induced blue shift in the optical band gap and enhanced surface area at nanodimensions have been successfully utilized to achieve better color neutrality, faster response time, good optical contrast, and enhanced stability in gadolinium (Gd) nanoparticle films based switchable mirrors. This review presents the effect of nanoparticles size on the switchable mirror and hydrogen storage applications.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.1-52 © 2010 Nova Science Publishers, Inc.

Chapter 1

MAGNETIC INTERACTIONS IN OXO-CARBOXYLATE BRIDGED GADOLINIUM(III) COMPLEXES: SYNTHESIS, CRYSTAL STRUCTURES AND MAGNETIC PROPERTIES Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo and Catalina Ruiz-Pérez Universidad de La, Laguna, La Laguna, Spain

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ABSTRACT Magneto-structural studies on polynuclear complexes, aimed at understanding the structural and chemical factors that govern the exchange coupling between paramagnetic centers, are of continuing interest. One of the best illustrative examples corresponds to the di--hydroxo-dicopper(II) complexes where the angle at the hydroxo bridge is the main factor governing the nature and magnitude of the intramolecular magnetic coupling.[1] The large number of magneto-structural studies on polynuclear complexes with first-row transition metal ions has provided a relatively good comprehension of the magnetic coupling in this family; however, the situation with the lanthanide-containing metal complexes is much less advanced. The focus lies on the synthesis of compounds with paramagnetic centres which can interact with each other to afford large spin systems. This is why the natural choice seems to be compounds containing lanthanide cations because of the large spin values that these cations may present. In these systems, the mostly weak values of the magnetic coupling together with the influence of the ligand field which is hard to predict and that can easily be misinterpreted as an antiferromagnetic interaction, are problematic. Having in mind these difficulties, the magnetic studies with the gadolinium(III) is a convenient choice because it has a 8S7/2 ground state and the next excited state is well separated in energy (ca. 104 cm-1), so that its eff can be approximated with the spin-only formalism. The first magnetic studies concerning dinuclear gadolinium(III) complexes having the di--oxo bridging skeleton showed the occurrence of weak but significant intramolecular antiferromagnetic interactions.[2] Interestingly, a few years later several reports have also revealed the presence of ferromagnetic interactions in this type of complexes.[3] The interpretation of

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

2

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. these results in the case of dinuclear gadolinium(III) compounds with a di-oxo(carboxylate) bridge, has allowed to establish a relationship between the nature of the magnetic coupling and the type of bridge involved.[4] At this respect, it deserves to be noted that magneto-structural data for polynuclear gadolinium(III) compounds are still scarce and consequently, more examples are needed to have a solid basis to analyze all the factors involved and then to establish a definitive magneto-structural correlation.[5] Given the ability of the carboxylate groups to lead to di--oxo (carboxylate) digadolinium(III) units where the magnetic coupling is either ferro- or antiferromagnetic, we have undertaken a systematic study of complex formation between gadolinium(III) and carboxylate-containing ligands aiming at investigating the factors that govern the magnetic coupling in the digadolinium(III) units.

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INTRODUCTION The creation of metal-organic frameworks (MOFs) through coordination of metal ions by means of multifunctional organic ligands is a field of increasing interest. This premise is based on the potential technological applications such as opto-electronics or magnetic devices, microporous materials for shape- and size- selective separations and catalysis that can present molecular-based coordination polymers. These MOFs can be designed to allow a wide choice to perform multifunctional materials since specific electronic or structural characteristics of the metal ion can be adopted by the bulk properties for solid state compounds. Specifically the lanthanide owing to their similar structural properties but different physical properties from one to the other could lead to materials exhibiting tuneable properties via the choice of the rare earth ion. Nowadays there are numerous publications which describe structure and properties of several transition ions containing coordination polymers. However the situation with lanthanide complexes is quite different. Although it is possible to design coordination polymers with tuneable physical properties with an adequate choice of the lanthanide ion, the relatively high cost of these ions makes their study less attractive. The fact is, the synthesis of an expensive material must to be compensated with very interesting properties different from those economical complexes, since if this complex can be designed with transition metals, which are cheaper, and it could present the same properties, the use of lanthanide complex will not be attractive. However luminescent materials,[6] light converters,[7] nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) reagents,[8] and organic and biological catalysts[9] have been developed from lanthanide-complexes, and successfully employed in the fields of chemistry, biology, medicine and materials science. Lanthanide ions present characteristic 4f open-shell configurations and exhibit interesting variability across the series. This variety promotes the selection of the most suitable one to use it in the tailor-made synthesis of multifunctional materials. As an example of their special characteristics, the effective ionic radii of the members of this series decrease slightly as the atomic number increases. As the charge on the nucleus increases across the rare earth series, all electrons are pulled in closer to the nucleus so that the radii of the rare-earth ions decrease as the compounds go across the series. This reduction is known as the lanthanide contraction. This effect makes the atoms to become closer, since the radius is shorter, and it could be seen especially in isomorphous complexes.

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

3

Magnetic properties are one of the main points in the field of lanthanide coordination polymers. Unfortunately the inner character of the magnetic orbital of the rare earth ions leads to very poor overlap in terms of magnetic exchange coupling. However, this field of research remains active and interesting because the mechanisms of the 4f-4f and 4f-3d interactions are still misunderstood.

MAGNETIC ASPECTS To deal with the objective of this chapter we are going to explain some features about magnetism, particularly these parts concerning the gadolinium(III) ion, starting from the magnetic susceptibility. The magnetic susceptibility ( is the quantitative measure of the response of a material to an applied magnetic field. Some substances are slightly repealed by such a field (diamagnets), and on the contrary, others are attracted into this applied field (paramagnets). These forces produce changes on the weigh of the substances within the applied field and this provides one of the classical methods for the measurement of magnetic susceptibilities, the Gouy method. Experimentally the Gouy method involves measuring the force on the sample by a magnetic field and is dependent on the tendency of a sample to concentrate a magnetic field within itself. The definition of the magnetic susceptibility is:

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M = H

[1]

where M is the magnetic dipole moment per unit of volume, or magnetization, and H is the magnetic field strength. Both magnitudes measured in amperes per meter. Although the magnetic susceptibility is dimensionless, it is expressed in emu/cm3. If it is considered M as the magnetic moment per mol then, the molar susceptibility N is the magnetic susceptibility multiplied by the molar volume, and it is expressed in cm3/mol. When a sample is situated within an external magnetic field H, the field in the material generally changes, respect to the outer field. In this situation could happen that the density of the magnetic lines of force is reduced respect to the free external magnetic field, case in which we have a diamagnetic material, or that where the lines of the force are concentrated within the sample, which is the case of a paramagnetic sample. In all materials, the external field alters the orbital velocity of electrons around their nuclei, thus changing the magnetic dipole moment in the direction opposing H. Then diamagnetism is a property which is present in all matter. Molar susceptibility, in this case, is negative, and much smaller than the paramagnetic susceptibility, being of the order of -1 to -100 x 10-6 cm3/mol. Diamagnetic susceptibilities are independent of temperature and of the strength of the external field. They are characteristics of each atom or molecule, and present additive character. Because of these features, diamagnetic susceptibility of any sample can be estimated through Pascal‘s constants which provide an empirical method to perform this. Paramagnetism is a property which presents substances which concentrate the lines of force supplied by the external field, which results in a measurable gain of weight of the sample. Paramagnetic susceptibilities depend on the temperature of the sample, and frequently they become large at low temperatures. Usually the correction due to

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

4

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

diamagnetism of the sample at these temperatures is not necessary. The Curie law gives a first approximation of the magnetic susceptibility at low temperatures: 

=C/T

[2]

where C is the Curie constant and T is the absolute temperature. But sometimes because of a not negligible increase of the population of some energy levels in the temperature range of the measurement, this law is not strictly followed. The Curie-Weiss law introduces a small modification in terms of an the intercept with the abscissa is not at the origin: 

=C/(T-)

[3]

Where the correction term  present units of temperature, but a negative value must not be interpreted as negative temperatures. On the contrary, when is negative is indicative of an antiferromagnetic behaviour of the sample, and when it is positive points to the presence of ferromagnetic interactions. Antiferromagnetism, is a property which exhibits those samples where their magnetic moments of atoms or molecules, form an ordered array with neighbouring spins pointing in opposite directions. Ferromagnetism is a property, like antiferromagnetism at the atomic level, which causes the unpaired electron spins to align parallel to their neighbouring spins. Both properties are manifestations of ordered magnetism in the sample. Another term used to describe magnetic interactions is the effective magnetic moment, eff, which is defined as:

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

eff = (3k/N)1/2(T)1/2 = [g2s(s+1)]1/2B

[4]

where k is the Boltzman constant, 1.38 x 10-23 JK-1, N is Avogadro‘s number, 6.022 x 1023, g is the Landé factor, and B is the Bohr magneton which is described as: 

B = |e| ћ/2mc = 9.27 x 10-24 JT-1

[5]

where all the parameters have their usual meaning. The effective magnetic moment is a convenient measure of the magnetic properties because it is independent of temperature as well as external field strength for diamagnetic and paramagnetic materials. To describe the state of the system it is necessary to define the hamiltonian of it. Thus our hamiltonian must comprises at least the following spin only contribution, spin-orbit coupling, crystal field contribution and Zeeman term: H = HSS + HSO + HCF + HZE These terms will depend on the studied system, and sometimes can be neglected, as in the case of our gadolinium systems which will be explained further on.

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

5

If the energy levels of a system are known, and in the magnetic field range where the M versus H plot is linear, the magnetic susceptibility can be calculated through Van Vleck’s equation.10

M 

N  ( E n(1) 2 ) exp(  E n( 0 ) / kT ) n

kT  exp(  E n( 0 ) / kT )

[6]

n

This equation is based on quantum theory for the molar paramagnetism of a magnetically susceptible material. Following we are going to see where the origins of this formula are. In classical mechanics, when a sample is involved by an external magnetic field, its magnetization can be described as: M  E / H

[7]

In quantum mechanics we consider a molecule with energy levels En (n = 1, 2, ...). When an external magnetic field H is applied, each energy level presents a microscopic magnetization n as  n  En / H

[8]

According to these, microscopic magnetization M is obtained by adding the microscopic magnetizations of each energy level following the Boltzmann distribution law:

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M 

N

 (E / H ) exp(  E  exp(  E / kT ) n

n

n

n

/ kT )

n

[9]

Van Vleck proposed a simplification of [8] making some approximations. One of them is to develop the energies En following to the increasing powers of H: En  En(0)  En(1) H  En( 2) H 2  

[10]

where En(0) is the energy of level n in zero field. En(1) and En(2) are the first- and second-order Zeemann coefficients, respectively. With it n could be expressed as:

n  En(1)  2En( 2) H  

[11]

Another approximation is that H/kT is small enough respect to unity. Then the exponential term in [9] could be transformed in: exp En kT   exp En(0) kT 1  En(1) H kT 

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

[12]

6

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. From these two approximations, the magnetization may be expressed as: M

N

 ( E  2E H )(1  E H / kT ) exp( E  (1  E H / kT ) exp( E / kT ) (1) n

n

( 2) n

(1) n

(1) n

n

(0) n

/ kT )

(0) n

[13]

Taking into account zero field

E

(1) n

n





exp  En(0) kT  0

[14]

And substituting [13] into [12] and retaining only terms linear in H results in M 



  

NH  n En(1) 2 kT  2 En( 2 ) exp  En( 0 ) kT



n exp  En(0) kT



[15]

Then the susceptibility becomes: 

N

 (E n

(1) 2 n

/ kT  2 En( 2 ) ) exp(  En( 0 ) / kT )

 exp( E n

(0) n

/ kT )

[16]

When the eigenvalues En(0) and eigenfunctions n of the Hamiltonian in zero-field are known, the Van Vleck‘s formula may be employed. En(1) and En(2) are then expressed as

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

En(1)  n H ZE n

En( 2)  

mn

[17]

n | H ZE | m

2

( En( 0)  Em( 0) )

[18]

where HZE is the Zeeman operator:





H ZE   i I i  gsi  H

[19]

where Ii is the orbital momentum of electron i and si is the spin momentum of the same electron. When all energies En are linear in H, the second-order Zeeman coefficients En(2) vanish, then we arrive to the Van Vleck‘s equation [6].

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

7

GADOLINIUM(III): MAGNETIC PROPERTIES The gadolinium ion is the only lanthanide whose magnetic properties are because of exclusively spin only contribution. This is due to that the first excited state is sufficiently separated in energy (ca. 104 cm-1) from the ground state, therefore the ion reflects the properties of this latter state alone [see scheme 1]. With a half-filled 4f shell, gadolinium(III) present a 8S7/2 ground state. Subsequently, in the hamiltonian which describes the magnetic state of the system the orbital contribution is almost entirely quenched. The study of magnetic interactions within gadolinium(III) compounds can be carried out through Van Vleck‘s equation, if the interaction appears between two gadolinium(III) ions (dimer), or through the Fisher equation if the interaction take place through a chain of gadolinium(III) ions. In the case of two interacting gadolinium(III) ions which presents S = 7/2 in their ground states the Van Vleck‘s equation may be deduced as follows. For an S=7/2 the quantum number ms may present the following values:  7  2  5   ms   2 3   2  1  2

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with S = S1 + S2 = Ms, the subsequent wave functions will be |S, Ms>:  7  6  6  5  5  4   4   3  5   4     3   S  4; M s   2  9  4 S  5 ; M   11  S  6 ; M   13  3 s  S  7; M s    15 s 1  2  2  3    1   2  0   1    0    1 0 0 

 3  2  2  1   S  0; M s  0  1 S  2 ; M    1  5 S  1; M s   0  3 S  3; M s    7 s  0  1   0

The magnetic hamiltonian if we suppose it isotropic can be described as: H = -JS1S2

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

8

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. Having in mind that:

Energy (103 cm-1)

S  S1  S 2  S 2  S12  S 22  2S1 S 2 38 37 36 35 34 33 32 22 21 20 19 18 17 16 6 5 4 3 2 1 0

6

I17/2 I9/2 6 I7/2

6

6

P3/2 P5/2 6 P7/2 6

5

D2 5

5

5

D4

D1

D0

7

F0 F1 F2 7 F3

7 7

F6

7

F5

7

F4

7

7

F4

7 7

F3 F2 7 F1 7 F0

F5

7

Eu(III)

8

S7/2

Gd(III)

7

F6

Tb(III)

Scheme 1. Energy levels of Eu(III), Gd(III) and Tb(III) ions, where it may be appreciated the high gap between the ground energy level and the first excited state in the Gd(III) ion

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The hamiltonian takes the value:  JS1S 2  



J 2 S  S12  S 22 2



with H S , M s  S 2 S , M s  S ( S  1) S , M s S12 S , M s  S1 ( S1  1) S , M s S 22 S , M s  S 2 ( S 2  1) S , M s J S, M s H S , M s   0   S ( S  1)  S1 ( S1  1)  S 2 ( S 2  1)  2 

J S (S  1) J cte 2 2

cte

The energy levels will be then:

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

9

J S  7;  0   56  cte 2 S  6;  0  

J 42  cte 2

J S  5;  0   30  cte 2 J S  4;  0   20  cte 2

J S  3;  0   12  cte 2 J S  2;  0   6  cte 2 J S  1;  0   2  cte 2 S  0;  0  cte

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If we assume that the zero energy value is at S=0 state, we can translate it in the following scheme, where it could be seen the energy between consecutive states. J 2J

S=0 S=1 S=2

3J S=3 4J S=4 5J S=5 6J S=6 7J S=7

Considering first order interaction when we introduce the Zeeman hamiltonian where it accounts for a magnetic field applied parallel to the z axis:

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

-15 J

-10 J

10

S=5

S=4

-4g -4g -2g  g-5g  -5g -3g 0   -6g +4g -4g  -g   -7g +3g -5g  -2g +2g -6g -3g g  +6g +5g  +7g -4g  0 +5g +4g -5g +6g -g  +4g  +3g +4g -2g  +5g +3g  +2g +3g  +4g -3g +2g g  +2g  +3g -4g g0 g+2g   0+3g -g 0g   +2g -g  -2g -g0 g  -2g -3g  -2g 0-g  -3g -4g  -3g -2g -g -4g  -5g  -4g -2g  -3g -5g  +4g  +3g -4g -3g -6g +3g  +2g  -5g  +2g +5g  +2g g-6g   g+g  +4g  0-7g 0 0  +3g -g -g  -g  +2g -2g -2g  +6g -2g g  -3g  +5g 0+g -3g 0 +2g  +4g -4g -g   -g +g +3g -2g +3g  +7g  0  +2g -3g  +2g -g +6g 0  g -4g g-2g   +5g  -5g 0 0  +g +4g +4g -g-g  B 0  +3g -2g +3g -2g  -g B  +2g -3g +2g -3g  g g-4g  +2g B 00  -5g  0  +g -gB -g-6g 0-2g  -2g  +5g -g  B  -3g  +4g -3g -2g B -4g -4g  +3g +g   -5g  B +3g 0+2g -6g   +2g -gg -7g B 0 g B 00-g  +6g -2g -g  B  B +5g -2g -3g +4g -4g -3g B +3g -5g +2g  +4g  +2g +g  B +3g g  B 0 0  +2g B -g -g g B -2g -2g 0  +g  +7g -g B -3g 0  +6g -2g  -4g -g  B +5g  -5g -3g B +4g -6g -4g B 0 +3g  +3g +5g B +2g  +2g +4g   g B g+3g   0 B 0 +2g -g B -g g  -2gB -2g 0  -3g  -3g -g  B -4g  -2g B +2g -5g  -3g B +g  -6g  -4g B 0  -7g -5g B -g  +4g -2g  +6g  +3g +g B +5g B +2g 0 +4g B g  -g +3g B 0  +2g -g0 B g-2g B 0  -3g -g  B -4g -2g  +3g  B -3g  +2g  B -4g  B g -5g  B 0 -6g B -g

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. -15 J -21 J -10 J -28 J -6 J

S=5 S=6 S=4 S=7 S=3

HZE = gSH

S, M s HZE S , M s  g B M s H -6 J

SS== 32 S=4

-10-3JJ levels, because of the external magnetic field is showed in the The splitting of the energy following scheme: S=5 S=1 -15 J -J

-3 J 0 -21 -6 JJ -J

-28 J0J -10 -3 J

-J

-15 J -6 J0

-3 J -21 J

-10 J -J 0 -28 -6 JJ

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-15 J

-3 J

-J -10 J 0 -21 J

-6 J

S=2 S=0 SS==36 S=1 SS S== =047 S=2

S=1

S=5 SS == 03

S=2 S=6

S=4 S=1 S=0 S S= = 73

S=5

S=2

S=1 S=4 S=0 S=6

S=3

+5g -2g  +7g B +4g B +6g -3g +3g +5g  B +2g  +2g +4g B +g  S=2 g  +3g 0 B S=5 0  -15 J +2g B -g g-g B  -2g S=7 -2g  0 -28 J +g  S=1 -3g -g0 B -J -4g -2g B -g  -5g  -3g  B S=0 +4g  -4g 0 B 0 +3g -5g B -6g  +2g B g  -7g B S=4 0 -10 J -g  +6g  -2g  +5g  -3g  +4g  Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden-4g C. Thompson, Nova Science +3g  +3g  +2g  +2g  g S=6 g0  S=3 -21 J 0  -6 J -g -g  -2g  -2g  -3g  -3g -4g   +2g -5g  +g  -6g S=2 0  -3 J +5g -g  +4g 

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

11

Then we will have: S  0;  ( 1 ) 2  0

S  1;  ( 1 ) 2  2 g 2  B

S  3;  ( 1 ) 2  28g 2  B

S  4;  ( 1 ) 2  60g 2  B

2

S  6;  ( 1 )2  182g 2 B

S  2;  ( 1 ) 2  10g 2  B

2

S  5;  ( 1 ) 2  110g 2  B

2

S  7;  ( 1 ) 2  280g 2  B

2

2 2

2

Substituying in Van Vleck‘s equation [6]:

M

J    3J    6J    10J    15J    21J    28J  2 Ng 2  B 0  2 exp   10 exp   28 exp   60 exp   110exp   182exp   280exp   kT   kT   kT   kT   kT   kT   kT     J    3J    6J    10J    15J    21J    28J  kT 1exp0  3 exp   5 exp   7 exp   9 exp   11exp   13exp   15 exp   kT   kT   kT   kT   kT   kT   kT  

[20]

with x   J kT

M 

2 2 N B g 2  exp( x)  5 exp(3x)  14 exp(6 x)  30 exp(10x)  55 exp(15x)  91exp( 21x)  140 exp( 28x)  1  3 exp( x)  5 exp(3x)  7 exp(6 x)  9 exp(10x)  11exp(15x)  13 exp( 21x)  15 exp( 28x)  kT  

[21]

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This equation will be used to fit the experimental values obtained in the magnetic measurements when the structure present direct interactions between two gadolinium(III) ions. But what happens if the interaction takes place among three or more ions? Theoretical explicit laws must be used in each specific case. Fortunately, Michael E. Fisher in 196311 carried out the theoretical study when the interaction takes place through a chain of metal ions. Based on the hamiltonian: N

N





N

H   J ij S iz S jz  J ij ( S ix S jx  S iy S jy )  g  S ij i 1 j 1

||



[22]

i 1

where Six, Siy and Siz are the components of spin vector Si of the ith atom, the Fisher equation gives a susceptibility value of: 

N 2 g 2 1 u S ( S  1) 3kT 1 u

[23] kT  JS ( S  1)    kT  JS ( S  1)

In this expression, u is the Langevin function defined as u  coth

with N, , k and g having their usual meanings, J being the exchange coupling parameter between adjacent spins, and in the specific case of gadolinium(III) ions S takes the value 7/2.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

12

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

METAL ORGANIC FRAMEWORKS

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Metal-organic frameworks (MOFs), also known as coordination polymers, are compounds that via covalent metal-ligand bonding, may combine the specific characteristics of the metal and of the ligand, and translate them to the bulk properties for solid state compounds. This combination gives rise to multifunctional materials. The ligand is an organic bridging group capable to bond two or more metal ions to form multidimensional networks. The design or selection of a suitable ligand containing certain features, such as flexibility, versatile binding modes, and ability to form hydrogen bonds, is crucial in the building of polymeric complexes. In particular, multicarboxylate ligands are frequently used in the architectures of the lanthanide polymeric complexes, since lanthanides present high affinity towards oxygen atoms which improve the coordination using these ligands. Carboxylate ligands, which are characterized by a COOH terminal group [see figure 1], present several interesting characteristics: (a) after partial or full deprotonation, can coordinate to the metal ions in a wide variety of coordination modes leading to high-dimensional structures [see figure 2]; (b) they can act not only as hydrogen-bond acceptors but also as a hydrogen-bond donor, depending upon the number of deprotonated carboxylic groups; (c) their carboxylic groups may not lie in the plane of the ligand upon complexation to metal ions owing to geometrical constraints, and thus, they may connect metal ions in different directions; (d) high symmetry that they may exhibit could be helpful for the crystal growing of the product formed; (e) the lanthanide ions may be directly bonded via carboxylate oxygen atoms, which may give rise to magnetic exchange between them. Taking into account their great diversity, carboxylate ligands seem to be a good election for constructing novel materials with interesting properties such as porosity, chirality or magnetism.

R

R

COO-

COOH

Figure 1. Protonated (left) and de protonated (right) terminal group of the carboxylate ligands

a)

Monodentate

b)

c)

Bidentate

d)

Bismonodentate

Monodentate/bidentate

Figure 2. Frequently encountered coordination modes presented by the carboxylato groups Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

13

 

Scheme 2. Schematic view of the O(x);O(x)O(y) type of bridge

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To deal with the study of magnetic interactions between gadolinium centres, it is necessary to measure the magnetic properties of crystal structures that present a direct interaction between gadolinium ions. That means that they have to be linked via, at least, one oxygen bond. This type of bridge is named -oxo carboxylate.[12] In the majority of the cases this type of bridge appears within the carboxylate structures through a monodentate/bidentate coordination mode of the ligand [see figure 2] and the nomenclature used is O(x);O(x)O(y), where O(x) designate the direct bridge that through O(x) oxygen atom links both lanthanide ions, and O(x)O(y) appoint the carboxylate bridge that chelate the Gd(III) ion through O(x) and O(y) oxygen atoms [see scheme 2].

Acid + base => specific pH + gel

Adding the Gadolinium salt

Single crystals suitable for X-ray analysis appear after a few days

Scheme 3. Schematic view of the synthesis procedure to obtain single crystals by means of gel techniques

Picture 1. View of the fast precipitation (~35 seconds in this case) of the coordination polymer when an aqueous solution of gadolinium salt is added to an aqueous solution of the carboxylate ligand Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

14

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

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Synthetic Routes Gadolinium carboxylate containing complexes have previously been achieved, leading to ferro- or antiferromagnetic behaviour. Probably because of the crystal growth difficulties and because the mechanism of the 4f-4f and 4f-3d interactions are still misunderstood, the systematic study of these complexes present several complications. It deserves to be pointed out that the number of polynuclear gadolinium(III) compounds for which structural and magnetic data are available is quite low. Thus to deal with this study it is necessary to achieve to the obtaining of a high quantity of gadolinium complexes which present the desired bridge between gadolinium(III) ions and perform their magnetic studies. With this objective in mind and in order to design lanthanide-containing coordination polymers, we have improved synthetic routes based on the Henish[13] procedures in crystal growth in gel medium [see scheme 3], and based on Byrappa[14] hydrothermal procedures in crystal growth. They both deserve to be briefly described and highlight their respective advantages and drawbacks. The first method of synthesis is the slow diffusion of the reactants through a gel medium. This slow diffusion is necessary because of the high affinity of gadolinium(III) ions with the carboxylate-oxygen atoms which is translated into a very fast precipitation of the coordination polymers [see picture 1]. Typically the gel is poured in the bottom of an I-, H- or U-shaped tube. To deal with it, an appropriate ligand is selected and a base is added to achieve a pH of around 4. Sometimes we can use a gelificant that deprotonate the base as sodium metasilicate. In this case is not necessary to add any other reactant to obtain the gel medium, in the other cases we add a gelificant in an appropriate percentage. The pH of the final solution and the percentage in volume of the gelificant added are the factors that will govern the size of the pores within the gel matrix. The velocity of the reaction to obtain the coordination polymer will depend on this size and again of the pH of the final solution. Then solutions of the reactants are poured into the vertical parts of the respectively tube and allowed to slowly diffuse at room temperature and ambient pressure, taking care to do not damage the surface of the gel. Any damage on it may give rise to a nucleation point, which could contribute to nonreproducible conditions of synthesis. This technique presents great advantages as long as single crystals of metastable phases are needed. The obvious main disadvantage of this method is the separation of the products from the gel. Indeed, it is sometimes difficult to isolate the desired product from the gel medium. Some gels as pluronic or agarose may be converted into liquid when we decrease or increase the temperature, respectively. But these thermal treatments may produce serious problems in the obtained crystals. The problem with the gel medium can be solved when we are able to obtain the desired crystal phase by direct precipitation. In such cases, the gel methods are only used for structural characterization purposes and the availability of the material is ensured. The second method is the synthesis under hydrothermal conditions. There is an increasing interest for this technique. This interest is essentially due to inherent advantages such as a high reactivity of reactants, an easy control of solution or interface reactions, or the formation of metastable and original condensed phases. Typically, the synthetic procedure consists of preparing the coordination polymers in a stainless steel reactor with a teflon-liner [see photograph 2] under relatively high temperatures (typically between 150ºC and 250ºC) and elevated pressure (autogenous pressure). As far as lanthanide coordination polymers are concerned, this synthetic method seems to lead to materials exhibiting high dimensionality

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

15

and low hydration rate. That is why these methods have been up to now extensively used in order to obtain molecular precursors for three-dimensional microporous materials. The main drawback of this method is the difficult separation of the targeted product(s) from the resulting powder that may sometimes also contain remaining reactants and more than one phase of products.

1 mm

Photograph 2. View of the stainless steel reactor with a teflon-liner to carry on the hydrothermal synthesis

8 7 6 5 4 3 2

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

0

1996

1

1995

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Photograph 1. Crystals obtained by means of direct precipitation

Graphic 1. Evolution of the number of publications related with the magneto-structural study on Gd(III)-carboxylate complexes.1

1

Data obtained through Cambridge Crystallographic Data Center (CCDC 2009) and ISI Web of Knowledge.

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

 = 102.5º d = 4.035Å

 d

Figure 3. View of an isolated dinuclear unit in 1, showing the values of the distance Ce···Ce and the angle Ce-O-Ce

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State of the Art To the best of our knowledge, nowadays about 35 gadolinium-carboxylate compounds with the desired bridge linking two or more gadolinium ions, have been published with their magnetic properties studied and fitted. The first of all [1]2 has been published in 1995 by A. Panangiatopoulos, et al.[2.b] The structure of this compound consists of isolated dinuclear gadolinium(III) units where the gadolinium(III) ions are connected via a double oxocarboxylate bridge and double carboxylate bridge in syn-syn conformation. But these authors have measured the single crystal structure of an isomorphous complex with cerium(III), thus the distances and angles of this bridge are influenced by the lanthanide contraction, then we have to take into account that they are approximated. The main characteristics of this bridge are showed in figure 3. The gadolinium compound is a polycrystalline sample, and X-ray powder diffraction confirms that it is isomorphous with the cerium(III) complex. The magnetic measurements where performed using the hamiltonian H = -JS1S2 and the Van Vleck‘s equation, showing antiferromagnetic interactions between both gadolinium(III) ions in the dinuclear unit [J = -0.053]. Following a chronological review, in 2002 three new complexes where published: J.-P. Costes, et al. [2],[3.a] S. Y. Niu et al. [3][15] and D. Sun et al. [4].[16] Compounds 2[3] and 3[4] present 0-dimensional structures, while complex 4[5] show a three-dimensional network. Complexes 2 and 3 present very similar structure to 1, since they consist in dinuclear isolated units of gadolinium(III) surrounded by six salicylate ligands in 2 and two phenanthroline and four benzoate ligands in 3. In both structures gadolinium(III) ions are connected through the same exchange pathways as in 1: a double oxo-carboxylate bridge and double carboxylate bridge in syn-syn coconformation [see figure 4]. Once more in compound 2 the authors have measured the structure of an isomorphous complex. In this case the [Gd2(CO2CH3)6(phen)2] with phen ≡ o-phenanthroline [Gd2L6(H2O)2] with HL ≡ salicylic acid 4 [Gd2(C12H8N2)2(C6H5COO)6] with C12H8N2 ≡ phenanthroline; C6H5COO ≡ benzoate 5 [Gd(Hbtec)] with H4btec ≡ 1,2,4,5-benzenetetracarboxylic acid 2 3

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

17

compound measured contains Er(III) instead of Gd(III), thus the distances and angles of the bridge in the dinuclear units are approximated. These complexes have been magnetically studied using the spin-spin hamiltonian, with best fit results of J equal to +0.05 and -0.43 for 2 and 3 respectively. This last value of -0.43 seems to be very high antiferromagnetic contribution compared to the reported J values as we will see. Compound 4 presents a three dimensional network where the gadolinium(III) ions are connected through a double oxo-carboxylate bridge along the b axis. These chains are connected to their eight neighbouring chains via 1,2,4,5-benzenetetracarboxylate ligands in the ac plane [see figure 5]. Although magnetic measurement of this compound has been done, the authors were not able to model the experimental data through a Fisher law, thus the M data of 4 were fitted to a modified Curie–Weiss law  = 0 + C/(T + ). The calculated value of C is 7.137 and the Weiss temperature  = -0.834 K. The negative Weiss temperature indicates the presence of antiferromagnetic Gd(III)–Gd(III) interaction.

 = 116.12º d = 4.25Å  = 101.47º d = 4.053Å 

 d

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d

Figure 4. View of the isolated dinuclear units in 2 (left) and 3 (right), showing the values of the distance Ln···Ln and the angle Ln-O-Ln, where Ln = Er, Gd in 2 and 3 respectively



a)  = 113.46º d = 4.15Å

b)

c)

d

Figure 5. View of the asymetric unit in 4, showing the values of the distance Gd···Gd and the angle GdO-Gd [a)]; Gadolinium(III) chains which runs along the b axis[b)]; View of the three-dimensional structure along the b axis [c)]

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

a)

b)  = 104.94º d = 3.937Å

 = 115.48º d = 4.206Å

 d

 d

c)  = 112.03º d1 = 4.148Å  = 105.44º d2 = 3.928Å

 d1

d2



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Figure 6. View of the dinuclear units in 5, 9 and 8 [a), b) and c), respectively] showing the values of the distance Gd···Gd and the angle Gd-O-Gd

The year 2003 was fruitful in the publication of this type of compounds. Six complexes where measured and studied by S.T. Hascher, et al. [5],[3.d] M. Hernández-Molina, et al. [6],[3.b] J.-P. Costes, et al. [7],[3.c] A. Rizzi, et al. [8 and 9][17] and A. W.-H. Lam, et al. [10].[18] Three of them, compounds 56, 87 and 98, present cero dimensional structures where the gadolinium(III) ions are in dinuclear units connected by different bridges [see figure 6]. Compound 5 is an acetate-gadolinium(III) complex where the Gd(III) atoms are connected through a double oxo-carboxylate bridge, as occurs in 4. The authors used the acetate compound whose structure was published in 1980 by M. C. Favas,[19] to measure its magnetic behaviour which was actually unexpected, since it was studied using the Van Vleck‘s equation, giving the best fit results of J = +0.06 cm-1 which is one of the largest ferromagnetic interaction value obtained in this type of compounds. Compound 8 is obtained using trans-2-butenoic acid, and where it could be distinguished two different dinuclear units in terms of the type of bridge between the Gd(III) ions. On one side they are connected through a double oxo-carboxylate bridge, like compounds 4 or 5, and by the other side they are connected via a bridge like the present in compounds 1, 2 and 3, a double -oxocarboxylate and a double carboxylate bridge in syn-syn conformation. The magnetic measurements of this compound reveal that there is no interaction between metallic centres. 6 7 8

[{Gd(OAc)3(H2O)2}2]·4H2O with Ac ≡ acetate [Gd2(O2CCH=CHCH3)6(H2O)4]·2H2O with H(O2CCH=CHCH3) ≡ trans-2-butenoic acid [Gd2(O2CCH=CHCH3)6(phen)2]·2H2O with H(O2CCH=CHCH3) ≡ trans-2-butenoic acid; phen ≡ 1,10-phenanthroline

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

19

The magnetic susceptibility was analysed through a simple Curie law (M = C/T) with C = 14.63(2) emu K mol-1. The authors used the compound 8 to synthesize compound 9 adding a solution of 1,10-phenanthroline in water ethanol. The dinuclear Gd(III) units in 9 are constructed by double -oxo-carboxylate and a double carboxylate bridge in syn-syn conformation. The magnetic measurements reveal weak antiferromagnetic interactions which the authors has been fitted through a Curie Weiss law (M = C/(T-)) with C = 7.45(1) emu K mol-1 and  = -0.28(8) K. Compound 69 present a three-dimensional structure where two malonate ligands crystallographically independents bridge dinuclear units of gadolinium(III) ions through the c axis and the ab plane [see figure 7]. The Gd(III) ions in the dinuclear units are linked through a double -oxo-carboxylate, as in several compounds mentioned, and the magnetic interaction between them has been fitted, through the Van Vleck‘s equation, giving a value of the exchange coupling of J = +0.046 cm-1. Although compounds 710 and 1011 present unidimensional structures, the gadolinium(III) ions are bridged through oxo-carboxylate bridges forming chains and dinuclear units respectively. To synthesize 7 the authors have used acetylsalicylic acid, where the gadolinium(III) ions in the chain are bonded through two monoatomic, one triatomic and one pentaatomic bridges, as it could be seen in figure 8.a. As the pentaatomic bridge is too large and the magnetic interactions between gadolinium(III)ions are quite weak this bridge may be consider as a double oxo-carboxylate bridge with a carboxylate bridge in syn-syn conformation. This bridge is different to the others showed in all compounds studied until now. The main feature is that this last do not present an inversion centre in the middle of the bridge, thus the two angles Gd-O-Gd are different. Ferromagnetic interactions have been revealed through magnetic measurements with best fit value of J = +0.037 cm-1. In 10 the Gd(III) ions are connected through benzoate ligands forming a chain array where two types of bridges are alternated: a double carboxylate bridge in syn-syn conformation, and a double oxo-carboxylate with a double carboxylate in the syn-syn conformation bridge [see figure 8]. The authors have studied the magnetic properties of this compound using the Van Vleck‘s equation considering interactions through each pair of Gd(III) ions. These studies have shown antiferromagnetic interactions, with best fit value of the magnetic exchange equal to J = 0.097. In 2004 only one paper was published with the desired features. Two new compounds where synthesized and measured by A. M. Atria, et al. [11 and 12].[20] Both complexes have been synthesized with trans-2-butenoic acid, and present cero-dimensional structures. The Gd(III) ions on them are forming dinuclear entities, and in both cases the bridge between them is a double oxo-carboxylate bridge with a double-carboxylate in syn-syn conformation. In 1112 the dinuclear entities are constructed by only six trans-2-butenoate ligands and four coordinated water molecules, but also there are di(2-pyridyl)amine in the structure. Compound 1213 presents dinuclear entities with six trans-2-butenoate ligands, and in this case in the position of the coordinated water molecules in 11, appears two coordinated 2,2‘bipyridine [see figure 9]. Magnetic measurements reveal weak antiferromagnetic interactions [Gd(H2L)(HL)(L)·H2O] with H2L ≡ salicylic acid [Gd2(mal)3(H2O)6] with H2mal ≡ 1,3-propanedioic acid 11 [Gd(Bz)3(DMF)] with HBz ≡ benzoic acid; DMF ≡ dimethylformamide 12 [Gd2(crot)6(H2O)4] · 4(bpa) with bpa ≡ di(2-pyridyl)amine; crot ≡ crotonato or trans-2-butenoate 13 [Gd2(crot)6(bipy)2] with bipy ≡ 2,2‘-bipyridine; crot ≡ crotonato or trans-2-butenoate 9

10

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

in both compounds. Their 1/M plots obey the Curie–Weiss law (M = C / T - ) all through the investigated temperature range. The best fit for 11 yields parameters C = 21.8 cm3 mol-1 K,  = -0.97 K, and complex 12 present the values C = 15.33 cm3 mol-1 K and  = -0.4 K.

a)

b)  = 104.94º d = 3.937Å

 = 115.48º d = 4.206Å

 d

 d

c)

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 = 112.03º d1 = 4.148Å  = 105.44º d2 = 3.928Å

 d1

d2



Figure 7. Dinuclear units in 6 showing the values of the distance Gd···Gd and the angle Gd-O-Gd [left]; View of the three-dimensional structure along the b axis [right]

 = 116.70º d = 4.276Å

 d

Figure 8. Dinuclear units in 7 [a)] and 10 [c)] showing the values of the distance Gd···Gd and the angle Gd-O-Gd; View of the one-dimensional structures along the b axis in 7 [b)] and through the c axis in 10 [d)] Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

b)

a)

 = 114.31º  = 111.85º d = 4.1871Å

21

d

 

c)

d)

 d

 = 105.80º d = 3.914Å

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Figure 9. Dinuclear units in 11 [left] and 12 [right] showing the values of the distance Gd···Gd and the angle Gd-O-Gd

Within the next year, in 2005, two 0-dimensional structures [1321 and 1422] and two onedimensional networks [154 and 1623] with the desired features where published. D. John and W. Urland synthesized and studied the magnetic properties of compounds 1314 and 1415. Both complexes consist of gadolinium(III) dinuclear units formed by chloroacetate and 2,2‘bipyridyl, in 13, and by difluoroacetate and 1,10-phenanthroline, in 14 [see figure 10]. The dinuclear units are very similar and the bridge that links the gadolinium(III) ions within them, is a double oxo-carboxylate together with a double carboxylate in syn-syn conformation. They where studied through Van Vleck‘s equation and the best fit parameters obtained are J = -0.040 cm-1 and J = -0.032 cm-1, for 13 and 14 respectively, indicating that there are weak antiferromagnetic interactions in the structures. Compound 1516 is a citrate-gadolinium(III) complex in which the Gd(III) atoms are arranged in dinuclear entities bonded by means of the citrate ligand along the a axis constructing the final one-dimensional architecture. The Gd(III) ions in the dinuclear units are bonded via a double oxo-carboxylate bridge. Compound 1617 contains dichloroacetate as coordinating ligand, and methylammonium as counterion. It presents a one-dimensional network, with dinuclear units of gadolinium(III) ions which are bridged along the a crystallographic axis through four carboxylate bridges in syn-syn conformation. These [Gd2(ClH2CCOO)6(bipy)2] with H(ClH2CCOO) ≡ chloroacetic acid; bipy ≡2,2‘-bipyridyl [Gd(CF2HCOO)3(phen)] with H(CF2HCOO) ≡ difluoroacetic acid; phen ≡ 1,10-phenanthroline 16 [Gd(C6H5O7)(H2O)2·H2O] with C6H5O7 ≡ citrate 17 [NH3CH3][Gd(Cl2HCCOO)4] with NH3CH3 ≡ methylammonium; Cl2HCCOO ≡ dichloroacetate 14 15

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

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lanthanide atoms in the dinuclear units are linked through the same bridge as 15: a double oxo-carboxylate bridge [see figure 11]. Magnetic measurements in 15 and 16 reveals weak ferromagnetic interactions with a value of the magnetic exchange of J = +0.039 cm-1 and J = +0.046 cm-1 for 15 and 16 respectively. In these two last years, the change in the magnetic behaviour in gadolinium(III) complexes, start to has potential interest for a considerable group of researchers. Because of this, they use to present in their articles a review table which summarize the features of the published gadolinium(III) compounds, trying to find an structure-property relation. This new interest makes that in 2006 there was a really important increase of the number of published articles. Eight new compounds were synthesized and studied by A. Rohde, et al. [17, 18],[24, 25[ S.C. Manna, et al. [19],[26] Z.-H. Zhang, et al. [20],[27] D. John, et al. [21],[28] H.-L. Gao, et al. [22],29 another one by the group S. C. Manna, et al. [23],30 and the last by L. Cañadillas-Delgado, et al. [24].31 Compounds 1718 and 2119 present 0-dimensional structures where exist dinuclear entities of Gd(III) ions which are bonded through double oxo-carboxylate and double carboxylate in syn-syn conformation bridges. On one side, compound 17 was synthesized with trichloroacetic acid, which forms the bridges between Gd(III) ions, and with methylamonium chloride, which fill the pores of the structure in the form of methylamonium molecules. On the other side, compound 21 was synthesized using gadolinium dichloroacetate adding 4hydroxypyridine, which chelates the gadolinium (III) ions as it could be seen in figure 12. Both complexes present weak antiferromagnetic interactions with very similar values of the magnetic exchange coupling obtained through Van Vleck‘s equation [J = -0.0212 cm-1 and 0.022 cm-1 for 17 and 21, respectively].

 d

 = 106.58º d = 3.99Å

 d

 = 106.92º d = 4.034Å

Figure 10. View of the isolated dinuclear units in 13 (up) and 14 (down), showing the values of the distance Gd···Gd and the angle Gd-O-Gd 18

19

[(CH3NH3)2[Gd2(CCl3COO)6(H2O)6](CCl3COO)2·2CCl3COOH] with H(CCl3COO) ≡ trichloroacetic acid; CH3NH3 ≡ methylamonium [Gd2(Cl2HCCOO)6(H2O)2(hypy)2] with Cl2HCCOO ≡ dichloroacetate; hypy ≡ 4-hydroxypyridine

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

23



 = 118.49º d = 4.321Å

d

 = 114.07º d = 4.184Å



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d

Figure 11. Dinuclear units and view of the one dimensional arrangements in 15 [top] and 16 [bottom] showing the values of the distance Gd···Gd and the angle Gd-O-Gd

 = 107.64º d = 4.051Å



d

 d

 = 104.4º d = 4.20Å

Figure 12. Dinuclear units in 17 [left] and 21 [right] showing the values of the distance Gd···Gd and the angle Gd-O-Gd

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Compound 1820 presents a one-dimensional structure where dinuclear units of Gd(III) are linked through four carboxylate bridge in syn-syn conformation along the a direction, as occur in 16 [see figure 13]. Within the dinuclear entities the Gd(III) ions are bonded through double oxo-carboxylate bridge, where the oxygen atoms belong to dichloroacetate ligands. The pores of the structure are filled by ethylamonium. The magnetic studies of this complex reveal a weak ferromagnetic behaviour. The authors of this complex have propose a modification of the Van Valeck‘s equation to consider the interaction through the double oxo-carboxylate bridge [Jintra] and through the four carboxylate bridges in syn-syn conformation [Jinter].  N B 2 g 2 exp( 2 x)  5 exp(6 x)  14 exp(12x)  30 exp( 20x)  55 exp(30x)  91exp( 42x)  140 exp(56x)  ·   kT 1  3 exp( 2 x)  5 exp(6 x)  7 exp(12x)  9 exp( 20x)  11exp(30x)  13 exp( 42x)  15 exp(56x) 

1  mol 

1



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With x  J int ra and   2 zJ int er with z = 2 (number of neighbors). 2 kT N B g 2 As it could be seen they use the Hamiltonian H = -2JS1S2, then to compare with the other complexes we multiply by two their Jintra value. With that the magnetic exchange coupling is J = +0.058 cm-1. Compounds 1921, 2022, 2223 and 2324 present three-dimensional structures, where the gadolinium(III) ions are arranged forming dinuclear entities in 19 and 22, and chains in 20 and 23, through different bridges. Compound 19 is a gadolinium-fumarate complex where the dinuclear entities are bonded through carboxylate bridges in the [1 0 -1] direction and through fumarate ligands in the [1 0 1] and [0 1 0] directions leading to the final three-dimensional network, as it could be seen in figure 14. The gadolinium(III) ions inside the dinuclear units are linked through a double oxo-carboxylate bridge and by a carboxylate bridge in syn-syn conformation, as occurs in 7.

 = 113.50º d = 4.181Å

 d

Figure 13. View of the dinuclear entities in 18, showing the values of the distance Gd···Gd and the angle Gd-O-Gd [left], and the one-dimensional structure, along the a direction [right]

[NH3C2H5][Gd(Cl2HCCOO)4] with Cl2HCCOO ≡ dichloroacetate; NH3C2H5 ≡ ethylamonium [Gd2(fum)3(H2O)4]·2H2O with fum ≡ fumarate 22 [Gd(bta)(H2O)·1.39H2O] with H3bta ≡ 1,3,5-benzenetriacetic acid 23 [Gd2(PDA)3(H2O)3]·H2O with PDA ≡ pyridine-2,6-dicarboxylate 24 [Gd2(suc)3(H2O)2]·0.5H2O with suc ≡ succinate dianion 20 21

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

25

a)  = 111.84º  = 109.68º d = 4.1565Å

b)

 d 

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c)

Figure 14. View of the dinuclear entities in 19, showing the values of the distance Gd···Gd and the angle Gd-O-Gd [a)]; one-dimensional array where the dinuclear entities are bonded through carboxylate bridges in the [1 0 -1] direction [b)]; and view along the a direction of the three-dimensional network of 19 [c)].

Compound 20 has been synthesized with 1,3,5-benzenetriacetic acid, and present onedimensional arrays of gadolinium(III) ions along the a crystallographic axis where two different types of bridge, which bond the Gd(III) ions, are alternated. This alternation remains these observed in compound 10. One type is a double oxo-carboxylate bridge, while the other one is a double oxo-carboxylate bridge with a double carboxylate in syn-syn conformation [see figure 15]. The magnetic behaviour of complex 20 has been studied through a CurieWeiss law, as it could be seen later. In compound 23 the gadolinium(III) ions are bonded through a double oxo-carboxylate bridge and a carboxylate bridge in syn-syn conformation, like the bridges in 19, along the b direction. In this compound the Gd(III)-chains are linked in the a and c directions through succinate ligands to achieve the three-dimensional network [see figure 16]. Magnetic measurements of complex 23 reveal weak ferromagnetic behaviour, as it could be seen later.

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

a)

 d1

b )

 d2

 = 114.54º d1 = 4.1835Å  = 107.71º d2 = 3.9781Å

c)

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Figure 15. Detail of the values of the distances Gd···Gd and angles Gd-O-Gd in the Gd(III) chain in 20, where it could be seen the two types of bridge [a)]; view of the one-dimensional array which runs along the a axis [b)]; and view along the a direction of the three-dimensional network [c)].

 d



 = 109.96º  = 112.24º d = 4.0585Å

Figure 16. Detail of the bridge between consecutive Gd(III) ions in the chain in 23 [left]; and view along the b direction of the three-dimensional network [right]

Complex 22 was synthesized with pyridine-2,6-dicarboxylic acid, and present two gadolinium(III) ions crystallographically independent [Gd(1) and Gd(2)]. Gd(1) form dinuclear entities, where the lanthanides are bonded through a double oxo-carboxylate bridge, but in this occasion only one of the oxygen atoms of the carboxylate coordinates to a Gd(III) ion, as it could be seen in figure 17. These units are linked by means of four Gd(2) to other two dinuclear units, forming chains along the a direction. These Gd(2) ions are bridged in the c direction, bonding at the same time the one-dimensional arrays along b axis. Complexes 19, 20 and 22 present antiferromagnetic interactions, while compound 23 shows a weak

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

27

ferromagnetic behaviour. Compounds 20 and 22 have been studied through a Curie-Weiss law with best fit results  = -0.79 K and -3.07 K, respectively. Complex 19 has been studied through a Fisher law, since the authors have assumed that there is magnetic exchange through the carboxylate bridges, that links along the [1 0 -1] direction the dinuclear entities. With this statement, the magnetic exchange coupling presents a value of J = -0.0076 cm-1. Authors of compound 23 have made the magnetic studies through several models: DFT calculus, CurieWeiss law and Fisher law. Through the Curie-Weiss law they have obtained a value of  = 0.593 K, and by means of the Fisher law J = 0.019cm-1. The DFT calculations will be discussed further within this chapter.

 d



 = 109.96º  = 112.24º d = 4.0585Å

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Figure 17. Dinuclear units in 22 [a)] showing the values of the distance Gd···Gd and the angle Gd-OGd; View of the one-dimensional array which runs along the crystallographic a axis where the dinuclear entities are showed with the Gd(III) ions in yellow, while the Gd(2) atom which links the dimmers is coloured in green [b)]; View of the of the three-dimensional network of 22 along the a direction [c)]

 d  = 140.1º d = 4.9369Å

Figure 18. Detail of the values of the distance Gd···Gd and the angle Gd-O-Gd in the Gd(III) chain in 24 [left]; View of the sheet-like structure in the ab plane, where orange, blue and pink colours denote the different malonate ligands which are present in 24 [right] Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

28

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

Complex 2425 has been the first two-dimensional gadolinium(III) compound, that can be added to this magneto-structural study. It has been synthesized with malonic acid which links through a simple oxo-carboxylate bridge the Gd(III) ions along the a axis. This was also the first time that this type of bridge with only one oxygen atom as bridge, has been study in this context. Moreover these Gd(III) chains are bonded through a crystallographically different malonate ligand along the b direction, achieving the final two-dimensional architecture [see figure 18]. This compound has been studied using the Fisher law with best fit result of J = +0.0074 cm-1, which indicates very weak ferromagnetic interactions in the structure. In the following years there was an important decay in the number of publications related to this study. Maybe because of there were different theoretical and empirical studies published in 2006. To our knowledge, two compounds were published in 2007 by Y.-G. Huang, et al. [25]32 and D. Weng, et al. [26].33

 = 102.39º  = 101.97º d = 3.908Å 

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

d

Figure 19. One-dimensional array of Gd(2) atoms which runs along the crystallographic c axis in 25 showing the values of the distance Gd(2)···Gd(2) and the angles Gd(2)-O-Gd(2) [top]; View of the three-dimensional structure along the c direction where the Gd(2) atoms are displayed in yellow, while the Gd(1) atoms are coloured in green [bottom]

25

[Gd2(mal)3(H2O)5]·2H2O with mal ≡ malonate

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ... a)

29

 = 107.97º d = 4.2138Å

d 

b)

c)

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Figure 20. Detail of the values of the distances Gd···Gd and angles Gd-O-Gd in the Gd(III) dinuclear units in 26 [a)]; view of the three-dimensional network along the a [b)] and b [c)] axes.

Complex 2526 presents a three-dimensional network where there exist two crystallographically independent gadolinium(III) ions [Gd(1) and Gd(2)]. Gd(2) atoms are bonded by means of a double oxo-carboxylate bridge, in the same manner as compound 22, along the c direction. The main difference between the bridge in 25 and the same in 22 is that 25 do not present an inversion centre between the oxygen atoms that form the bridge, thus they are crystallographically independent. These chains are linked through Gd(1) atoms along the a and b axes, achieving the final three-dimensional network. The bridge between Gd(1) and Gd(2) ions is an hydroxo bridge [see figure 19]. The authors of this compound reject the interaction between Gd(1) and Gd(2) and consider just the Gd(2)···Gd(2) magnetic interaction, since the distance Gd(1)···Gd(2) is 4.446Å while Gd(2)···Gd(2) is 3.908Å. They are based on the empirical Bloch‘s law, which estimate that J ~ d-10, which means that a slightly increase of the distance between two interacting atoms will be translated in a considerable decrease in J. With these arguments the authors have used the Fisher law and found a best fit value of J = -0.03 cm-1. Complex 2627 presents a three-dimensional network where the gadolinium (III) ions are arranged forming dinuclear entities where the lanthanide ions are bonded through a double oxo-carboxylate bridge. Moreover these units are linked in the b and c directions through carboxylate bridges in syn-syn and anti-syn conformations. Finally, by means of the whole ligand of the complex, which is 3,3‘,4,4‘-biphenyltetracarboxylate ligand, these layers parallels to the bc plane are bonded in the a crystallographic direction to obtain the three26 27

[Gd3(-OH)4(2,5-pydc)(2,5-Hpydc)3(H2O)4] with 2,5-pydc ≡ pyridine-2,5-dicarboxylate [Gd(Hbptc)(H2O)] with H4bptc ≡ 3,3‘,4,4‘-biphenyltetracarboxylic acid

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30

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

dimensional network [see figure 20]. The authors have used the Curie-Weiss law as: M = C/(T-) + 0, where 0 is the background susceptibility, to perform the magnetic studies. They have obtained the values: C = 8.03 cm3mol-1K,  = -0.0039 K and 0 = -191 x 10-6 cm3mol-1. In 2008, although there were published several articles of Gd(III) compounds with the desired bridge between two or more Gd(III) ions and also magnetic measurements, there were, to our knowledge, three compounds with studies of the magnetic measurements which can be useful in this magneto-structural study: Y.-F. Han, et al. [27],34 N. Xu, et al. [28]35 and R. Calvo, et al. [29].36 a) b)

 d

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 = 123.6º d = 4.4885Å

c)  = 117.5º d = 4.233Å  = 109.2º d = 4.278Å  d

 d

Figure 21. Detail of the bridge between consecutive Gd(III) ions in the chain in 27 [a)]; View along the b direction of the three-dimensional network in 27 [b)]; View of the Gd(III)···Gd(III) bridges in the onedimensional structure of 28

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

31

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Compound 2728 present a three-dimensional structure with the Gd(III) ions bridged along the b crystallographic direction. In these chains the gadolinium(III) ions are bonded through simple oxo-carboxylate bridges and double carboxylate bridges in syn-syn conformation. Furthermore, these chains are bonded along the c and [1 0 1] directions through 4,4‘biphenyldicarboxylate ligands, to construct the three-dimensional architecture. Moreover in this structure there are molecules of formic acid coordinated to the Gd(III) ions. Compound 2829 present a one-dimensional structure, where the lanthanide ions are bonded through double oxo-carboxylate bridges, forming chains along the a direction. This compound contains 2-hydroxynicotinate ligands which links the Gd(III) ions, and coordinated sulphate molecules [see figure 21]. Both compounds, 27 and 28, have been studied magnetically by means of the Fisher law, giving best fit results of J = -0.0055 cm-1 and J = +0.03 cm-1, for 27 and 28 respectively. Compound 2930 presents a one-dimensional structure, as 28. However in this case the Gd(III) ions are grouped in dinuclear entities, where the Gd(III) ions are bonded by means of a double oxo-carboxylate bridge (Gd···Gd distance of 4.203Å), and linked to other dinuclear Gd(III) entities through Cu(II) ions along the a direction. These bridge do not present an inversion centre in the middle of the Gd(III) ions, thus the angles in this bridge are different. The Cu(II) ions are arranged also in dinuclear entitites, where the cupper(II) ions are bonded through four carboxylate bridges in syn-syn conformation (Cu···Cu distance of 2.645Å), as it could be seen in figure 22. The inclusion of cupper(II) ions changes the way in that the magnetic studies must to be done. In this occasion the authors have changed the hamiltonian used to perform these studies and have included different terms that represents the Cu(II)··Cu(II), Gd(III)···Gd(III) and Cu(II)···Gd(III) interactions, since the approximation of noninteracting Cu2 and Gd2 dinuclear units did not explain their magnetic results. Thus they used the method of Bonner and Fisher37 to treating numerically the magnetic properties of this compound. With this they considered weakly interacting tetranuclear Gd-Cu-Cu-Gd blocks, with a spin hamiltonian: H 0   J CuCu S Cu1 ·S Cu 2  J CuGd ( S Cu 2 ·S Gd 1  S Gd 2 ·S Cu1 )  g Cu  B ( S Cu1  S Cu 2 )·B  g Gd  B ( S Gd 1  S Gd 2 )·B

And where the neighbouring blocks in a chain coupled by the Gd···Gd exchange interaction giving rise the spin chain:

H '   J Gd Gd S Gd 1 ·S Gd 2 With these equations the authors have obtained the best fit results of JCu-Gd = +13.0 cm-1 and JGd-Gd = +0.25 cm-1. This is, to our knowledge, the largest ferromagnetic value of Gd···Gd interaction, in this type of complexes.

28 29 30

[Gd2(bpdc)3(HCOOH)2] with H2bpdc ≡ 4,4‘-biphenyldicarboxylate; HCOOH ≡ formic acid [Gd(Hnica)(H2O)2SO4] with Hnica ≡ 2-hydroxynicotinic acid [Cu2Gd2L10(H2O)4·3H2O] with HL ≡ trans-2-butenoic acid

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

 = 110.65º  = 114.46º d = 4.203Å



 d

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Figure 22. Detail of the bridges between metal ions in 29, showing the values of the distance Gd···Gd and the angles Gd-O-Gd [left]; View along the a direction of the one-dimensional network [right]

In 2009 at least five new complexes were reported, trying to give some light to this study. They were published by G.-X. Liu, et al. [30],38 by C. A. Black, et al [31],39 and the other three complexes [32, 33 and 34]40 by L. Cañadillas-Delgado, et al. all them quite different. Complex 3031 has been synthesized with pyridine-3,5-dicarboxylic acid, with gadolinium oxide and silver nitrate. It presents a three-dimensional network where the gadolinium(III) ions are bonded through one of the carboxylate groups of the ligand forming a double oxocarboxylate bridge, to generate infinite chains which runs along the b direction. Within these chains there are two different types of bridge, which bonds the Gd(III) ions in an alternated way. Moreover, these chains are linked through the ligand along the c direction to yield a two-dimensional array parallel to the bc plane. Finally, silver centres are bridged to the nitrogen atoms of the ligand of different layers to achieve the final three-dimensional architecture [see figure 23]. Since the Gd(III) ions are bonded through carboxylate-oxygen atoms forming infinite chains, the authors have used a uniform chain model to study the magnetic measurements. This model provides best fit result J = -0.0608 cm-1, indicating antiferromagnetic interactions in the structure. C. A. Black, et al have recently published the magnetic studies of compound 3132, while the crystal structure of this complex was published on 2008.41 This present also a threedimensional network, the Gd(III) ions are bonded through double oxo-carboxylate bridges and at the same time by double carboxylate bridges in syn-syn conformation, forming dinuclear entities. This dinuclear entities are linked by three crystallographically independent 2-amino-1,4-benzenedicarboxylate ligands, in the a, b and [1 1 1] crystallographic directions. Moreover, exists coordinated N,N′-dimethylformamide in this structure [see figure 24]. The authors not only have studied the magnetic interactions through a simple Curie-Weiss law [ = C/(T-); giving best fit results of C = 16.07cm3Kmol-1 and  = -0.18K], but also by means 31 32

[AgGd(PDC)2]·2H2O with H2PDC ≡ pyridine-3,5-dicarboxylic acid [Gd2(N-BDC)3(DMF)4] with N-H2BDC ≡ 2-amino-1,4-benzenedicarboxylic acid; DMF ≡ N,N′-dimethylformamide

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

33

of a modification of the Van Vleck‘s equation, adding a temperature independent paramagnetism (TIP) term. This term is introduced since the magnetic measurements reveal a gradual decay of MT from 16.12cm3Kmol-1 at RT to 15.90cm3Kmol-1 at 30K, which authors consider that could be due to temperature independent paramagnetism. With these last considerations the authors have obtained best fit results of J = -0.019 cm-1 and TIP = 6.1 x 104 cm3Kmol-1.

a)

b)

 = 108.19º  = 106.29º d1 = 3.988Å d2 = 3.987Å

 d1

 d2

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Figure 23. Detail of the values of the distances Gd···Gd and angles Gd-O-Gd in the Gd(III) chains in 30 [a)]; view of the three-dimensional network along the b [c)] axis  = 105.0º d = 4.032Å

 d

Figure 24. Dinuclear units in 31 showing the values of the distance Gd···Gd and the angle Gd-O-Gd [left]; View of the one-dimensional structures along the c axis [right]

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34

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. a)

b)

 d

 d

 = 115.47º d = 4.1589Å

 = 105.9º d = 3.8659Å

c)

d)

 = 119.12º d = 4.582Å

 d

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

e)

f)

Figure 25. Dinuclear units in 32, 33 and 34 showing the values of the distance Gd···Gd and the angle Gd-O-Gd [a), b) and d) respectively]; View of the two-dimensional structure of 33 along the [011] axis [c)]; View of the Gd(III) chains in 34, which run along [111] [e)], and the three-dimensional structure of 34, through [110] direction

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

35

 = 113.16º d = 4.1215Å  d

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Figure 26. Detail of the values of the distances Gd···Gd and angles Gd-O-Gd in the Gd(III) dinuclear entities in 35

Compounds 3233, 3334 and 3435 present different architectures, showing 0-, two- and three-dimensional structures, respectively. Complex 32 is a gadolinium-acetate compound, where the Gd(III) ions are arranged in dinuclear isolated entities, as the similar compound 5, bonded through double oxo-carboxylate bridges. The structure of complex 33 consists of digadolinium(III) units similar to those of 32, but where the Gd(III) ions are linked through double oxo-carboxylate bridges, from acetate ligands, together with double carboxylate bridges in syn-syn conformation, from fumarate ligands. These units are linked via two crystallographically independent fumarate ligands along the [110] and [101] directions to form a two-dimensional network. Finally compound 34 can be described as chains of gadolinium(III) atoms linked through double oxo-carboxylate bridges from fumarate ligands, that run along the [110] direction, which are interlinked by fumarate ligands along the a axis, and connected through oxalate ligands along the c axis giving rise to the final threedimensional network [see figure 25]. Compounds 32 and 33 where magnetically studied by means of Van Vleck‘s equation with best fit results of J = +0.03cm-1 and -0.076cm-1, respectively. With the premise of that the exchange pathway through O-C-O bridges is too long compared with the direct interaction through oxo bridges, we considered this pathway the only one to be taken into consideration to model the magnetic data of 34, using the Fisher law [best fit results of J = +0.019cm-1]. To validate this approach, we have analyzed the magnetic data of 34 by considering the possibility of a nonnegligible magnetic coupling through the oxalate ligand. We have performed a series of Monte Carlo simulations based on the classical approach, where the ratio between the exchange coupling constants has been changed, since there is no an analytical law to simulate the magnetic behaviour of this particular architecture. The best-fit parameters found shows that the value of J is the same than those in the previous fit and that J2, which is the exchange coupling constant through the new pathway considered, is practically zero, which support the validity of the simpler approach to an uniform chain behaviour, made through the Fisher law. Our research is not finish and several new complexes are being studied. As an example we have obtained recently a new gadolinium-valerate compound [35],42 which is to our [Gd2(ac)6(H2O)4]·2H2O with ac ≡ acetate [Gd2(ac)2(fum)2(H2O)4] with ac ≡ acetate; fum ≡ fumarate 35 [Gd2(ox)(fum)2(H2O)4] ·4H2O with ox ≡ oxalate; fum ≡ fumarate 33 34

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Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

knowledge the first lanthanide-valerate complex reported. The structure of 3536 consists of neutral centrosymmetric digadolinium(III) units with six valerate groups and four water molecules as ligands. Two of the six chelating carboxylate groups are responsible of the link between gadolinium ions in the dinuclear units constructing a double oxo-carboxylate bridge [see figure 26]. The magnetic measurements reveal a weak antiferromagnetic interaction in this complex, which has been analyzed through the Van Vleck‘s equation, giving a J value of -0.031 cm-1. All the principal features, concerning this study, of these complexes, are summarized in the following table [Table 1].

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Table 1.

36

 (K)

Compound

º

d (Å)

Bridge#

Oligomer

1

102.5*

4.035*

B

-0.053

-

2

101.47*

4.053*

B

Dinuclear units Dinuclear units

+0.05

3

116.12

4.25

B

4 5

113.46 115.48

4.15 4.206

A A

Dinuclear units Chains Dinuclear units

6

116.70

4.276

A

7

114.31 111.85

4.1871

C

8 9

112.03 105.44 104.94

4.148 3.928 3.937

A B B

10

105.80

3.914

B

11

105.64

3.9917

B

12

106.08

3.9363

B

13

106.58

3.99

B

14

106.92

4.034

B

15

118.49

4.321

A

16

114.07

4.184

A

17

104.4

4.20

B

18

113.50

4.181

A

J (cm-1)

C (cm3 K mol-1)

Magnetic interaction

Ref.

-

AFM

2.b

-

-

FM

3.a

-0.43

-

-

AFM

15

+0.06

-0.834 -

7.137 -

AFM FM

16 3.d,1 9

Dinuclear units Chains

+0.046

-

-

FM

3.b

+0.037

-

-

FM

3.c

Dinuclear units

-

-

14.63

No interaction

17

Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units Dinuclear units

-

-0.28

7.45

AFM

17

-0.097

-

-

AFM

18

-

-0.97

21.8

AFM

20

-

-0.4

15.33

AFM

20

-0.040

-

-

AFM

21

-0.032

-

-

AFM

22

+0.039

-

-

FM

4

+0.046

-

-

FM

23

-0.0212

-

-

AFM

24

+0.058

-

-

FM

25

[Gd2(pac)6(H2O)4] with Hpac ≡ pentanoic acid or valeric acid

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

37

Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ... Table 1. (Continued) º

d (Å)

Bridge#

19

4.1565

C

Chain

-0.0076

-

4.1835 3.9781 4.051

A B B

Chain

-

-0.79

21

111.84 109.68 114.54 107.71 107.64

C (cm3 K mol-1) -

Dinuclear units

-0.022

22

115.53

4.263

D

23

109.96 112.24

4.0585

C

Dinuclear units Chains

24 25

140.1 102.39 101.97 107.97

4.9369 3.908

E D**

4.2138

A

123.6 117.5 109.2 110.65 114.46

4.4885 4.233 4.278 4.203

F A A A**

31

108.19 106.29 105.0

3.988 3.987 4.032

A A B

32

115.47

4.1589

A

33

105.9

3.8659

B

34

119.12

4.582

A

35

113.16

4.1215

A

20

26 27 28 29 30

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 (K)

Compound

Oligomer

Chains Chains Dinuclear units Chains Chains Dinuclear units Chains Dinuclear units Dinuclear units Dinuclear units Chains Dinuclear units

J (cm-1)

Magnetic interaction AFM

Ref. 26

16.07

AFM

27

-

-

AFM

28

-

-3.07

15.755

AFM

29

0.019

0.593

7.58

FM

30

+0.0074 -0.03

-

-

FM AFM

31 32

-

-0.0039

8.03

AFM

33

-0.0055 +0.03

-

-

AFM FM

34 35

+0.25

-

-

FM

36

-0.0608

-

-

AFM

38

-0.019

-

-

AFM

39

+0.03

-

-

FM

40

-0.076

-

-

AFM

40

+0.019

-

-

FM

40

-0.031

-

-

AFM

42

* These values are approximated since they are from an isostructural complex. ** These type of bridge is almost equal to the A or D type of bridges, but these do not present an inversion centre in the middle of the Gd(III) ions. # The types of bridge are represented in scheme 4.

A

D

B

E

C

F

Scheme 4. Type of bridges presented by the 35 complexes studied

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38

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al.

16 14 12 10 8 6 4 2 0 A

B

C

D

E

F

Magnetic interactions

FM 37.1% (13 comp.)

AFM 60% (21 comp.)

No inter. 2.9% (1 comp.)

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Graphic 2. Representation of the number of complexes studied which show each type of bridge [left], and of the proportion of the complexes with different magnetic behaviour [right]

Type of Bridge A This type of bridge is present in 15 studied complexes [43% of the studied compounds]; 5 of them in chain arrangements and the other 10 in dinuclear entities. It presents a double oxocarboxylate bridge where at the same time the carboxylate branches chelate both gadolinium(III) ions. It present an inversion centre between both Gd(III) ions, in almost all cases with the exception of complex 29. This change implies different values in the Gd-O-Gd angles of the bridge. Looking at the geometry of this bridge it could be seen that the average value of the Gd···Gd distance here is ca. 4.20Å and the Gd-O-Gd angle ca. 113.3º. These values are larger than the mean values for all the complexes [mean values without considering compounds 1 and 2, since the gadolinium(III) compounds have not been measured: around 4.15Å and 111.5º]. Concerning at the magnetic interactions around the 60% of the complexes [9 compounds] which present this bridge show ferromagnetic interactions, while almost 33.3% of them [5 compounds] present antiferromagnetic interactions, and in only one compound [8] which present two different types of bridge within its structure [A and B] it has been assumed that do not present any dominant magnetic interaction. It has to been remarked that complex 29, which present values of distance d and angle  which do not differ so much

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from the mean d and  values for this bridge, shows a J value [+0.25cm-1] which is far away of the normal values, which show very weak interactions.

Type of Bridge B This bridge is the most popular bridge present in the studied compounds. 15 compounds show it in their structures which represent the 43% percent of the total. In this case the mean values of the geometrical parameters d and  are diminished [mean values around 4.01Å and 106.8º, without considering the values of complex 1 and 2, because of the d and  values displayed in the table 1 are from isoestructural complexes with Ce(III) and Er(III), respectively, but no from the Gd(III) one] due to the inclusion of the double carboxylate bridge in syn-syn conformation. It is present in the majority of the structures which present dinuclear gadolinium entities, which could indicate that the reduction in the Gd···Gd distance promotes this type of arrangement. Only one compound of the fifteen, present this type of bridge as part of a chain arrangement, and it is alternated with the A type of bridge. Complex 3 present the d and  values farthest from the mean values [4.25Å and 116.12º], and at the same time shows the highest antiferromagnetic interactions of all the complexes studied with a J value of -0.43cm-1. Almost all of these fifteen complexes present antiferromagnetic interactions while only compound 2 present dominant ferromagnetic interactions.

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Type of Bridge C Only three complexes present C type of bridge in their structures as part of Gd(III) chains. This type of bridge does not present any inversion centre since it has one carboxylate at the same time as two oxo bridges. With this, there are two  different values for each bridge. The mean values of d and  are 4.134Å and 111.65º, respectively, values that are between those of the A and B type of bridges. Within the magnetic aspect, two of the complexes present ferromagnetic interactions while the third one shows interactions with dominant antiferromagnetic behaviour.

Type of Bridge D This bridge is quite similar to A bridge. In this occasion only one oxygen atom of the carboxylate branches coordinates to the gadolinium(III) ions. Two complexes of our study present this type of bridge, one with an inversion centre in the middle of the Gd(III) ions and the other one without it. The one with inversion centre is present in the structure linking Gd(III) ions forming dinuclear entities, while the other complex present this bridge within Gd(III)-chains. Curiously, the d distance is shorter in the complex with Gd(III)-chains (3.908Å) than the other (4.263Å). Both complexes present dominant antiferromagnetic interactions.

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Type of Bridge E Only one complex (24) present this bridge, which is principally the half of the A type of bridge, with only one oxo-carboxylate bridge. Probably because of there is only one pathway through the Gd(III) ions the d distance (4.9369Å) and  (140.1º) angle are the largest of all the complexes, and these values could have promote the arrangement in chains of the Gd(III) ions. This complex present very weak ferromagnetic interactions in its structure, maybe due to the large exchange pathway between two consecutive gadolinium(III) ions.

Type of Bridge F This last type of bridge is present in just one complex of the studied ones. It presents only one oxo-carboxylate bridge together with two carboxylate bridges in syn-syn conformation. In complex 27, the d distance (4.4885Å) and  angle (123.6º) are two of the largest values of the bulk of the studied compounds, and like in complex 24 the E type of bridge, this bridge is part of Gd(III)-chains in the structure. Furthermore it shows also very weak magnetic interactions, but in this case with antiferromagnetic character.

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PUBLISHED EMPIRICAL STUDIES The magnetic interaction between two gadolinium(III) ions within a polycarboxylate complex, have awaken the interest in several scientific groups. One of them, the group of R. Baggio, et al. in Argentina, showed in 2005 this interest publishing a first empirical study about gadolinium complexes.4 In this publication they suggest that on one hand, compounds with A type of bridge [see scheme 4] present ferromagnetic contributions which dominates in the compounds, because of an small value of the overlap integral along the Gd-O-Gd exchange pathway. On another hand, due to the inclusion of two carboxylate bridges in synsyn conformation, compounds with a B type of bridge diminish their Gd···Gd distance and Gd-O-Gd angles, which increase the value of the overlap integral, making dominant the antiferromagnetic contribution in the complexes. Finally, before this study only compound 7 was published with a C type of bridge, thus the authors suggest that those complexes with this type of bridge, where the Gd···Gd distance and Gd-O-Gd angles are between those with A type of bridge and B type of bridge, these compounds could present ferromagnetic or antiferromagnetic dominant interactions depending on these structural values. However on 2005 the number of complexes studied available were so few (only 9 complexes were present on their study, not all with carboxylate bridges), and the authors conclude that it was not possible to make a quantitative correlation between the structural parameters and the magnitude of the magnetic exchange interactions, although the cases studied in this article follow this interpretation. Nowadays, almost the 35 compounds follow this theory but with a few exceptions. Complexes 4, 26, 30 and 35 present an A type of bridge in their structures but their magnetic measurements reveal dominant weak antiferromagnetic interactions, while complexes 2, which present B type of bridges in their structure, shows ferromagnetic interactions.

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THEORETICAL STUDIES In the last decade, theoretical calculations on the electronic structure have been widely used to understand, to interpret and to predict physical properties of molecular and periodical systems.43 Among of them, magnetic properties have been usually correlated to the electronic distribution and to the molecular geometries. Thus, the theoretical methods based on the density functional theory (DFT) have been very useful in the progress of the molecular magnetism field, which is shown in the large number of publications about these subjects in the last years.44 However, these studies have usually been limited to complexes with first-row metal transitions. This lack of studies with other transition metals becomes more pronounced in the complexes with rare earth metal ions and, specially, in those where other kind of metal ions are not present. There exist several reasons to explain this fact: i) the rare earth metal complexes are scarce, ii) the coordination sphere of these metal ions is more diverse since they can increase its coordination index, iii) the magnetic couplings between these metal ions are very weak which makes difficult the evaluation of the magnetic coupling constants (J) from theoretical calculations, iv) except for gadolinium(III) ion, in the rest of trivalent rare earth ions, an important spin-orbit coupling and also the effect of the weak ligand field are also observed in the magnetic measurements at higher and lower temperatures, respectively, that turns its study into a complex task, and v) the lanthanide ions are very heavy and nontrivial relativistic effects must be included to study any property related to its electronic structure. However, few studies on the electronic structure and on how it is related to the magnetic properties of rare earth metal ions have been reported,5, 30, 45 specially in systems with gadolinium(III) and other metal ions, usually copper(II) ions,46 where the spin-orbit coupling there is not and the magnetic couplings are less weak than those where only gadolinium(III) ions are present. Before to start any discussion or exposure our results, it is important to supply readers with basic details about the theoretical calculations that can be completed with the provided references. Calculations were done with the Gaussian code using the hybrid B3LYP functional.47, 48, 49 A triple- basis set proposed by Ahlrichs et al. for the copper atom and an all electron basis set with a contraction pattern (10 64322111/8442211/6421/411) obtained from an uncontracted basis set proposed by Nakajima were used.50, 51 A double- basis set proposed by Ditchfield et al. were used for the rest of atoms.52 In some cases, a scalar relativistic treatment has been used by inclusion of a relativistic scheme of eliminating small components (RESC).53 Calculations have been done on dinuclear fragments of experimental molecular geometries and on idealized dinuclear models. Energies for the S = 7 and S = 0 have been evaluated. For it, the broken-symmetry approach has been used for the singlet state. According to a previous description of this methodology done by Ruiz et al.,1.d, 54 the magnetic coupling constant in our system must be obtained from the equation J   E S  7  E BS  28 . The SIESTA program (Spanish Initiative for Electronic Simulations with Thousands of Atoms)55 was employed with the GGA exchange-correlation functional proposed by Perdew, Burke and Erzernhof (PBE).56 We have selected values of 50 meV for the energy shift and 200 Ry for mesh cutoff that provide a good compromise between accuracy and computer time needed to calculate the exchange coupling constants.57 Only external electrons are included in the calculations, the cores being replaced by normconserving scalar relativistic pseudopotentials factorized in the Kleinman-Bylander form.58

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These pseudopotentials are generated following the approach proposed by Trouiller and Martins59 from the ground state atomic configurations for all the atoms. The core radii for the s, p and d and f components of the Ni atoms are 2.00, 3.019, 4.17 and 7.00, respectively. The cutoff radii were 1.14 for oxygen, nitrogen and hydrogen atoms and 1.25 for carbon atoms, respectively. Firstly, a sample from several real systems that is representative of all results experimentally observed has been selected to calibrate the achievement of the chosen methodology. Thus, different magnitudes and natures of the magnetic coupling can be found in the selected set. To verify the adequation of our model, where we do not take into account the whole carboxlate pathway, we have chosen two systems in which the oxygen-bridge atom does not belongs to a carboxylate ligand [[Gd(AmPh)]22.a and [{Gd(Hsabhea)(NO3)}2]2.c]. The calculations reported in table 2 have been done with different approaches and several conclusions can be extracted from them: (i) Despite of the J constants to evaluate are very small, a good agreement is found between the theoretical results where relativistic effects have been included and the experimental data, allowing predict the nature but also the magnitude of the magnetic coupling. (ii) A better compliance is found in the systems that show antiferromagnetic couplings. (iii) When the relativistic effects are excluded, qualitatively similar results are obtained and only an increase of the magnetic coupling is observed independently of its nature, what it leads to an improvement of the agreement with the experimental data in the cases displaying ferromagnetic couplings. (iv) Even though correct values of the magnetic couplings for the complexes of the first transition metals are found when they are evaluated with SIESTA package, poor results have been obtained in gadolinium(III) complexes that points out that new pseudopotentials and basis sets for the gadolinium(II) ions must be built to improve the results. In fact values too larges are obtained and even an incorrect nature of the magnitude is predicted in some cases. Table 2. Main structural parameters and magnetic coupling constants (in cm-1) obtained for several real systems from experimental measurements or from DF calculations including (RESC) or excluding relativistic effects Compound

32 18 6 35 [Gd(AmPh)]2 {Gd(Hsabhea) (NO3)}2 a

Gd…Gda

Gd-OGdb

Gd…Oa

Jexp

J (RESC)

J (nonRESC)

J (SIESTA)

Ref.

4.159 4.181 4.276 4.121 3.984 3.764

115.47 113.50 116.70 113.13 113.12 107.61

2.539/2.378 2.571/2.433 2.597/2.426 2.543/2.394 2.392/2.383 2.341/2.324

+0.030 +0.058 +0.046 -0.03 -0.045 -0.198

+0.045 +0.038 +0.031 +0.019 -0.042 -0.279

+0.063 +0.076 +0.035 +0.053 -0.081 -0.365

-0.476 -0.106 +0.023 -0.578 -0.843 -1.211

40 25 3.b 42 2.a 2.c

in angstroms, b in degrees

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In summary, we can conclude that the chosen methodology is adequate to study the magnetic properties of this kind of compounds and allows analyze and establish magnetostructural correlations, which is the goal for this section. From now on, relativistic effects are considered in all shown results. In precedent sections, it has been established a magneto-structural correlation that connects the nature and magnitude of the magnetic coupling with the Gd-O-Gd angle () in gadolinium(III) complexes where carboxylate groups act as bridging ligands in a -OCO coordination, i.e , only an oxygen atom of the carboxylate group is involved in the exchange pathway. To carry out a theoretical study on this correlation and to deal other questions about this kind of complexes we have built some models shown in the next scheme.

Scheme 5. Schematic view of the models employed in the theoretical calculations

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Table 3. Magnetic coupling constant (in cm-1), absolute value of nAnBJ (in cm-1) and atomic spin densities (, in electrons) on the metal ions and oxygen(methoxo) atom for model A in a different Gd/Cu ratio MM‘

J

|nAnBJ|

(M)

(M‘)

GdGd GdCu CuCu

+0.05 -11.0 -1138.5

2.5 77.0 1138.5

6.98 6.99 0.59

6.98 0.60 0.59

(O) 0.004 0.093 0.155

Scheme 6. Perspective views of the calculated spin density distribution the ferromagnetic state for the GdGd and CuCu molecular models. Yellow and blue contours represent positive and negative spin densities, respectively. The isodensity surface corresponds to a value of 0.002 e bohr –3 Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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In these models, carboxylate groups have been replaced by a methoxo group, coordination index equal to six and eight have been considered and fluoride and ammonia groups have been used as peripheral ligands. However, to avoid strong interaction between closest ligands, ammonia molecules have been only used in the first model. In a lot of cases, the carboxylate bridging ligand also coordinates through the second oxygen atom (monodentate/bidentate in figure 2.d) or there are another carboxylate groups in a classical coordination way (bismonodentate, -CO2, in figure 2.c), which adds a new exchange pathway (OCO) in the transmission of the magnetic coupling. But, it is observed from the literature that in compounds where only carboxylate groups act as bridging ligands in a bismonodentate coordination way the J constant is less than 0.01 cm-1 [see ref. 40]. This fact is also observed when the oxalate ligand connects the rare earth metal ions. Thus, we can conclude that the carboxylate ligand in this coordination way doesn‘t constitute an efficient transmitter of the magnetic coupling between the gadolinium(III) ions, which validates the chosen model. Both manganese(II) and gadolinium(III) ions have half full valence shell, but they are d and f orbitals, respectively. However, whereas first-row metal complexes display moderate or strong magnetic couplings, very weak interactions are observed in rare-earth metal complexes. Which is the reason for this fact? It is well known that the magnetic coupling strongly depends on the interaction between the magnetic orbitals of the metal fragment and the appropriate orbitals of the transmitter group (ligand fragment) that in our model is a methoxo group. This interaction is tuned by the overlapping between orbitals of these fragments and by the energy closeness of them. The schematic diagram done from the DF calculations shown that the 4f orbitals of the gadolinium(III) ion are deeper enough than the first-row transition metal as copper(II) 3d orbitals and, in consequence, more distant from ligand orbitals. On the other hand, and more important, in gadolinium(III) ion there are not electron on 5d and 6s orbitals to shield efficiently the 4f electrons and therefore they are strongly attracted by the large nuclear charge that provides an strong decrease of diffusiveness of 4f orbitals that are radially compacted. Thus, if gadolinium(III) ions are systematically replaced by copper(II) ions in model A keeping a square planar coordination sphere for the last ones and fixing the M-O-M‘ angle at 120 degrees, the obtained J values show that, in agreement with the previous discussion, the magnetic coupling between metal ions decrease when the presence of gadolinium(III) ions is larger. In fact, the correct comparison must be done with the nAnBJ values, where nA and nB corresponds to the number of unpaired electrons on each paramagnetic center, but similar conclusions are reached. The same conclusion is reached from the visualization of the single occupied molecular orbitals (SOMOs) or from the atomic spin densities on the exchange pathway and on the metal ions that show that whereas a very weak delocalization on the bridging ligand from the gadolinium(III) ion this one is very important from the copper(II) ion [see table 3 and scheme 6]. Since the butterfly distortion in the complexes that we are interested is not important and such as it was already proposed by L. E. Roy et al.,5 the Gd-O-Gd () and Gd-O-R () angles can be charged on the tuning of the magnetic coupling. However, we prefer define the second angle as Gd-O-R () angle that is fully independently of the  angle [see scheme 7]. A dependence of J constant with the  angle with  = 180º is shown in graphic 3 for models A and B with ammonia, fluorine or any groups as peripheral ligands. For the model B only the

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case with fluorine groups is displayed. Several conclusions can be obtained from these results: i)

ii)

iii)

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iv)

v)

For model A, a dependence of the magnetic coupling with the nature of the peripheral ligand is observed, such as it was already established by Cano et al.60 Thus, more electronegative donor atoms in the peripheral ligand leads to a larger antiferromagnetic contribution that, in this case, is manifested in a delay at larger  values in the conversion to ferromagnetic interactions in the model with ammonia peripheral ligands. An increase in the coordination index of the metal ions that implies a change from octahedral to the square antiprism coordination sphere leads to a decrease in the antiferromagnetic contribution. This fact clearly shows that the kind of metal environment modifies significantly the magnetic coupling. Similar conclusions that in precedent point can be extrapolated when peripheral ligands are obviated. Even, independently of the nature, a significant increase of the magnetic coupling is observed in this model, the same qualitative dependence with the  angle that in previous models is observed. That is why to choice of this model is preferable in order to simplify the explanation of the molecular orbital diagram, we have chosen this model in the discussion of the results. Three magnetic gadolinium 4f orbitals interact by a -way with the oxygen pz orbital to transmit the magnetic coupling. The z3 orbital do it by means of the electronic densities on the two rings and, therefore, the overlapping between the metal and ligand orbitals is not dependent on the  angle [see scheme 8]. On the other hand, the overlapping between orbitals xyz and z(x2-y2) and the pz oxygen orbital depends on the  angle, but when it increases for a gadolinium orbital, it decreases for the other one so that both effects are counterbalanced [see scheme 8]. Moreover, as these three gadolinium orbitals interact with the same bridging ligand orbital, an energetic effect is not expected. In summary, the global contribution of these three magnetic 4f orbitals must be constant. The four remaining 4f magnetic orbitals interact by -way with the px and s oxygen methoxo orbital. In fact, this situation is the same that occurs in the bis-hydroxo and bis-alkoxo copper(II) complexes, where a compensation between the metal-ligand interaction in antisymmetric and symmetric SOMOs leads to a accidental orthogonality situation that favours ferromagnetic couplings for a certains values.1.d, 61 However, in the last cases, and in opposite to the suited systems studied here, the antiferromagnetic couplings are observed for the larger  angles. But, in our case is more difficult to predict the position of the ―magical angle‖, that shows the point when the nature of the magnetic coupling is changed, because a larger number of magnetic orbitals and their special spatial geometries [see scheme 8].

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Scheme 7. Mainly geometrical parameters involved in the magneto-structural correlation in the complexes showing a [Gd2(OR)2] core

Graphic 3. Dependence of J constant with the  angle with  = 180º for model A with ammonia (squares), fluoride (circles) or any groups as peripheral ligands (triangles) and for model B with fluoride as peripheral ligand (black circles)

Finally, we have evaluated the influence of the  angle on the magnetic coupling in model A with fluoride as peripheral ligands and without they ones. Since similar results are obtained in the two models, we show our results on the simplest model in graphic 4. Qualitatively same results are found for the range the  values studied and only small quantitative differences are detected. Thus, even the ―magical angle‖ is the same for all  values (close to 114 degrees), an intensification of the magnetic coupling is suggested for lower  value independently of the nature of the magnetic interaction. However, from graphic 4 we can conclude that the  angle will be the main responsible of the observed magnitude and nature of the magnetic coupling.

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ...

Scheme 8. Magnetic orbitals of the gadolinium(III) ion and qualitative scheme of their overlapping (interaction) with the adequate orbitals of the methoxo bridging

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Graphic 4. Angular dependence (, in degrees) of the magnetic coupling constant (J, in cm-1) for  (in degrees) equal to 180 (circles), 175 (black circles), 170 (squares), 165 (blsck circles) and 160 (rhombus)

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CONCLUSION Many few complexes, which contains at least one oxo-carboxylate bridge between two Gd(III) ions, have been thoroughly investigated from a magnetic point of view. These studies have shed some light on the comprehension of the change of the weak magnetic character of these complexes. In this increase has played an important role the develop of several synthetic routes, as well as the design of new ligands which contemplate specific features, lead to the model of the type of bridge between consecutive gadolinium(III) ions, in the final complexes, which permits at the same time the predisposition of one or another magnetic character in the sample. It could be seen, making a brief empirical analysis through the complexes presented in this chapter, that around a value of the  angle of 111º appears to be a change in the magnetic character of the complexes from antiferromagnetic at lower angles, to ferromagnetic at higher angles. The same phenomena appears if we pay attention to the distances Gd···Gd around 4.2Å. These values are close to the mean values of  and d of all complexes (4.15Å and 111.5º). These  values are slightly smaller than those obtained from the theoretical analysis, using model A which is around 114º, but closer to those obtained using model B which is almost 112º, as it could be seen in graphic 4. These change in the value of the angle  at which the complex change its magnetic character from model A to model B indicates that an increase in the coordination index of the metal ions, that implies a change from octahedral to the square antiprism coordination sphere, leads to a decrease in the antiferromagnetic contribution. This fact clearly shows that the kind of metal environment modifies significantly the magnetic coupling. However, in our case is difficult to predict the position of the angle that constitute the point when the nature of the magnetic coupling is changed, because of a larger number of magnetic orbitals and their special spatial geometries in the interaction of the gadolinium(III) ions. This last statement is the cause of the discrepancy

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between the results obtained from the empirical model used in the magnetic measurements, and the theoretical one. Furthermore, from the theoretical results it could be seen that the carboxylate bridge in syn-syn conformation represents an interaction bridge that does not constitute an efficient transmitter of the magnetic coupling between the gadolinium(III) ions. This has been crucial in the selection of an adequate theoretical model which permits us the simplification of the calculations that have been made. This has been our little contribution to the magnetic-structure correlation study of the Gd(III) complexes, but much more experiments are in develop, to arrive to a solid conclusion based on our recent results.

ACKNOWLEDGMENT We gratefully acknowledge the contributions of our co-workers and colleagues whose names appear in the references.

REFERENCES

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[1]

[2]

[3]

[4] [5] [6]

(a) Crawford, VH; Richardson, HW; Wasson, JR; Hodgson, DJ; Hatfield, WE. Inorg Chem 1976, 15, 2107-2110; (b) Willett, RD; Gatteschi, D; Kahn, O. MagnetoStructural Correlations in Exchange Coupled Systems; W. E. Hatfield Inc. Eds; NATO ASI Series 140; Reidel: Dordrecht, The Netherlands, 1985, 555 and references therein; (c) De Munno, G; Julve, M; Lloret, F; Faus, J; Verdaguer, M; Caneschi, A. Inorg Chem 1995, 34, 157-165; (d) Ruiz, E; Alemany, P; Alvarez, S; Cano, J. J Am Chem Soc, 1997, 119, 1297-1303. See for example: (a) Liu, S; Gelmini, L; Rettig, SJ; Thompson, RC; Orvig, C. J Am Chem Soc, 1992, 114, 6081-6087, (b) Panagiotopoulos, A; Zafiropoulos, TF; Perlepes, SP; Bakalbassis, E; Masson-Ramade, I; Kahn, O; Terzis, A; Raptopoulou, CP. Inorg Chem 1995, 34, 4918-4920; (c) Plass, W; Fries, G. Z Anorg Allg Chem, 1997, 623, 1205-1207. See for example: (a) Costes, JP; Clemente-Juan, JM; Dahan, F; Nicodéme, F; Verelst, M. Angew Chem Int Edit, 2002, 41, 323-325; (b) Hernández-Molina, M; Ruiz-Pérez, C; López, T; Lloret, F; Julve, M. Inorg Chem, 2003, 42, 5456-5458; (c) Costes, JP; Clemente-Juan, JM; Dahan, F; Nicodéme, F. Dalton Trans, 2003, 1272-1275, (d) Hastcher, ST; Urland, W. Angew Chem Int Edit, 2003, 42, 2862-2864. Baggio, R; Calvo, R; Garland, MT; Peña, O; Perec, M; Rizzi, A. Inorg Chem, 2005, 44, 8979-8987. Roy, LE; Hughbanks, T. J Am Chem Soc, 2006, 128(2), 568-575. See for example: (a) Binnemans, K. Chem Rev 2009, 109(9), 4283-4374, (b) SoaresSantos, PCR; Nogueira, HIS; Félix, V; Drew, MGB; Sá Ferreira, RA; Carlos, LD; Trindade, T. Chem Mater 2003, 15(1), 100-108; (c) Sun, LN; Zhang, HJ; Meng, QG; Liu, FY; Fu, LS; Peng, CY; Yu, JB; Zheng, GL; Wang, SB. J Phys Chem B, 2005, 109(13), 6174-6182; (d) Bakkera, BH; Goesa, M; Hoebea, N; van Ramesdonka, HJ;

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[7]

[8]

[9]

[10]

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[11] [12]

[13] [14]

[15] [16] [17] [18] [19] [20] [21]

Laura Cañadillas-Delgado, Joan Cano, Óscar Fabelo et al. Verhoeven, JW; Wertsa, MHV; Hofstraat, JW. Coordin Chem Rev, 2000, 208(1), 3-16, (e) Escribano, P; Julián-López, B; Planelles-Aragó, J; Cordoncillo, E; Viana, B; Sanchez, C. J Mater Chem, 2008, 18, 23-40. See for example: (a) Bünzlia, JCG; Piguet, C. Encyclopedia of Materials: Science and Technology; Elsevier Ltd., 2001, Vol. 11, 4465-4476 ISBN-13: 978-0-08-043152-9; (b) Gelamosa, JP; Laranjaa, ML; Lombardi Alvinoa, KC; Camachoa, SA; Pires, AM. J Lumin [Special Issue based on The 15th International Conference on Luminescence and Optical Spectroscopy of Condensed Matter (ICL'08)] 2009, 129(12), 1726-1730; (c) Parker, D. Coordin Chem Rev, 2000, 205, 109-130; (e) Kuriki, K; Koike, Y; Okamoto, Y. Chem Rev, 2002, 102, 2347-2356. See for example: (a) Pintacuda, G; John, M; Su, XC; Otting, G. Accounts Chem Res 2007, 40(3), 206-212; (b) Parker, D; Dickins, RS; Puschmann, H; Crossland, C; Howard, JAK. Chem Rev, 2002, 102(6), 1977-2010; Zhang, S; Merritt, M; Woessner, DE; Lenkinski, RE; Sherry, AD. Account Chem Res, 2003, 36(10), 783-790; (c) Caravan, P. Chem Soc Rev, 2006, 35, 512-523, (d) Polasek, M; Hermann, P; Peters, J. A; Geraldes, CFGC; Lukes, I. Bioconjugate Chem, 2009, 20(11), 2142-2153. See for example: (a) Nojiri, A; Kumagai, N; Shibasaki, M. J Am Chem Soc, 2009, 131(10), 3779-3784; (b) Kaboudin, B; Sorbiun, M. Tetrahedron Lett, 2007, 48(51), 9015-9017; (c) Edelmann, FT. Chem Soc Rev, 2009, 38(8), 2253-68; (d) Kobayashi, S. SYNLETT, 1994, 9, 689-701, (e) Collin, J; Daran, JC; Jacquet, O; Schulz, E; Trifonov, A. Chem-Eur J, 2005, 11(11), 3455-3462; (f) Ma, L; Abney, C; Lin, W. Chem Soc Rev, 2009, 38(5), 1248-1256. Van Vleck, JH. Electric and Magnetic susceptibilities. Oxford. University Press, London. 1932. Fisher, ME. Am J Phys, 1964, 32, 343-346. Connelly, NG; Hartshorn, RM; Damhus, T; Hutton, AT. Nomenclature of Inorganic Chemistry. IUPAC Recommendations 2005; Published for the International Union of Pure and Applied Chemistry by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK, 2005. Henisch, HK. Crystal Growth in Gels, The Pennsylvania State Univ. Press, Pittsburgh, 1970. Byrappa, K; Yoshimura, M. Handbook of Hydrothermal Technology: Technology for Crystal Growth and Materials Processing, William Andrew Inc. Norwich, NY 13815, 2001. Niu, SY; Jin, J; Jin, XL; Yang, ZZ. Solid State Sci, 2002, 4, 1103-1106. Sun, D; Cao, R; Liang, Y; Shi, Q; Hong, M. J Chem Soc, Dalton Trans, 2002, 18471851. Rizzi, A; Baggio, R; Garland, MT; Peña, O; Perec, M. Inorg Chim Acta, 2003, 353, 315-319. Lam, AWH; Wong, WT; Gao, S; Wen, G; Zhang, XX. Eur J Inorg Chem, 2003, 149163. Favas, MC; Kepert, DL; Skelton, BW; White, AH. J Chem Soc, Dalton Trans, 1980, 454-458. Atria, AM; Baggio, R; Garland, MT; Muñoz, JC; Peña, O. Inorg Chim Acta, 2004, 357, 1997-2006. John, D; Urland, W. Eur J Inorg Chem, 2005, 4486-4489.

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Magnetic Interactions in Oxo-Carboxylate Bridged Gadolinium(III) Complexes ... [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]

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[39] [40] [41] [42] [43] [44] [45] [46]

[47] [48] [49] [50] [51] [52] [53]

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John, D; Urland, W. Z Anorg Allg Chem, 2005, 631, 2635-2637. Rohde, A; Urland, W. Z Anorg Allg Chem, 2005, 631, 417-420. Rohde, A; Urland, W. Dalton Trans, 2006, 24, 2974-2978. Rohde, A; Urland, W. J Alloy Compd, 2006, 408-412, 618-621. Manna, SC; Zangrando, E; Ribas, J; Chaudhuri, NR. Polyhedron, 2006, 25, 1779-1786. Zhang, ZH; Liu, GX; Okamura, TA; Sun, WY; Ueyama, N. Struct Chem, 2006, 17, 311. John, D; Urland, W. Eur J Inorg Chem, 2006, 3503-3509. Gao, HL; Yi, L; Zhao, B; Zhao, XQ; Cheng, P; Liao, DZ; Yan, SP. Inorg Chem, 2006, 45, 5980-5988. Manna, SC; Zangrando, E; Bencini, A; Benelli, C; Chaudhuri, NR. Inorg Chem, 2006, 45, 9114-9122. Cañadillas-Delgado, L; Pasán, J; Fabelo, O; Hernández-Molina, M; Lloret, F; Julve, M; Ruiz-Pérez, C. Inorg Chem, 2006, 45, 10585-10594. Huang, YG; Wu, BL; Yuan, DQ; Xu, YQ; Jiang, FL; Hong, MC. Inorg Chem, 2007, 46, 1171-1176. Weng, D; Zheng, X; Li, L; Yang, W; Ji, L. Dalton Trans, 2007, 4822-4828. Han, YF; Zhou, XH; Zheng, YX; Shen, Z; Song, Y; You, XZ. CrystEng Comm, 2008, 10, 1237-1242. Xu, N; Shi, W; Liao, DZ; Yan, SP; Cheng, P. Inorg Chem, 2008, 47, 8748-8756. Calvo, R; Rapp, RE; Chagas, E; Sartoris, RP; Baggio, R; Garland, MT; Perec, M. Inorg Chem, 2008, 47, 10389-10397. Bonner; JC; Fisher, ME. Phys Rev, 1964, 135A, 640-657. Liu, GX; Ren, XM; Xu, H; Nishihara, S; Huang, RY. Inorg Chem Commun, 2009, 12, 895-897. Black, CA; Sánchez Costa, J; Fu, WT; Massera, C; Roubeau, O; Teat, SJ; Aromí, G; Gamez, P; Reedijk, J. Inorg Chem, 2009, 48, 1062-1068. Cañadillas-Delgado, L; Fabelo, O; Cano, J; Pasán, J; Delgado, FS; Lloret, F; Julve, M; Ruiz-Pérez, C. CrystEng Comm, 2009, 11, 2131-2142. Costa, JS; Gamez, P; Black, CA; Roubeau, O; Teat, SJ; Reedijk, J. Eur J Inorg Chem, 2008, 1551-1554. Cañadillas-Delgado, L; Fabelo, O; Pasán, J; Delgado, FS; Lloret, F; Julve, M; RuizPérez, C. sended to Dalton Trans. Gosh, A. Coord Chem Rev, 2009, 253(5-6), 523-525. Ruiz, E. Struct Bonding, 2004, 113, 71-102 and references therein. Zhu, L; Yao, KL; Liu, ZL. Phys. Rev. B, 2007, 76, 134409/1-134413/5. (a) Cirera, J; Ruiz, EC. R. Chimie, 2008, 11, 1227-1234; (b) Yan, F; Chen, Z. J Phys Chem, A 2000, 104, 6295-6300; (c) Paulovic, J; Cimpoesu, F; Ferbinteanu, M; Hirao, K. J Am Chem Soc, 2004, 126, 3321-3331. Becke, AD. Phys Rev A, 1988, 38, 3098-3100. Lee, C; Yang, W; Parr, RG. Phys Rev B, 1988, 37, 785-789. Becke, AD. J Chem Phys, 1993, 98, 5648-5652. Schafer, A; Huber, C; Ahlrichs, R. J Chem Phys, 1994, 100, 5829-5835. Nakajima, T; Hirao, K. J Chem Phys, 2002, 116, 8270-8275. Ditchfield, R; Hehre, WJ; Pople, JA. J Chem Phys, 1971, 54, 724-728. Nakajima, T; Hirao, K. Chem Phys Lett, 1999, 302, 383-391.

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[54] (a) Ruiz, E; Alvarez, S; Cano, J; Polo, V. J Chem Phys, 2005, 123, 164110/1164110/7; (b) Ruiz, E; Rodríguez-Fortea, S; Cano, J; Alvarez, S; Alemany, P. J Comput Chem, 2003, 24, 982-989. [55] (a) Artacho, E; Gale, JD; García, A; Junquera, J; Martin, RM; Ordejón, P; SánchezPortal, D; Soler, J. M. SIESTA 1.3, 2001. [56] Perdew, J; Burke, K; Ernzerhof, M., Phys Rev Lett, 1996, 77, 3865-3868. [57] (a) Massobrio, C; Ruiz, E. Monatsh Chem, 2003, 134, 317-326; (b) Ruiz, E; RodríguezFortea, A; Tercero, J; Cauchy, T; Massobrio, C. J Chem Phys, 2005, 123, 074102/1074102/10. [58] Kleinman, L; Bylander, DM. Phys Rev Lett, 1982, 48, 1425-1428. [59] Trouiller, N; Martins, JL. Phys Rev, B 1991, 43, 1993-2006. [60] Román, P; Guzmán-Miralles, C; Luque, A; Beitia, JI; Cano, J; Lloret, F; Julve, M; Alvarez, S. Inorg Chem, 1996, 35, 3741-3751. [61] Ruiz, E; Alemany, P; Alvarez, S; Cano, J. Inorg Chem, 1997, 36, 3683-3688.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.53-141 © 2010 Nova Science Publishers, Inc.

Chapter 2

APPLICATION OF GADOLINIUM FOILS AS CONVERTERS OF THERMAL NEUTRONS IN DETECTORS OF NUCLEAR RADIATION D. A. Abdushukurov* Physical-Technical Institute of the Academy of Sciences of the Republic of Tajikistan, 299/1, Aini Ave, Dushanbe, Republic of Tajikistan

ABSTRACT

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Converters of neutron radiation play a determining role in the development of detectors of these radiations. They determine the basic characteristics of detectors: the efficiency of registration, energy, time and spatial resolution. Among solid-state converters, those on the basis of gadolinium and its 157 isotopes are especially set apart, as they possess an abnormally high cross section of interaction with thermal neutrons. In this article, theoretical bases of registration of neutron radiation by converters from gadolinium are considered. The efficiency of converters is the product of three variables. They are the following: Probabilities of capture of thermal neutrons by the nucleus; Probabilities of creation of the secondary charged particles, in our case of internal conversion and Auger electrons; Probabilities of escape created electrons from the material of the converter. Model calculations of registration efficiency of thermal neutrons by the foil converters made from natural gadolinium and its 157 isotopes are described. Processes of neutron absorption in the material of a converter and the probability of secondary electron escapes are examined. Calculations are made for converters with various thicknesses, as well as other parameters of the converters. The most optimal converter thicknesses were chosen. The contributions of low-energy Auger electrons radiated from L- subshell with the energy 4.84 keV and M-subsell with the energy 0.97 keV on efficiency of converters aregiven. These electrons have a rather small free path length in gadolinium; these are 0.3 microns (4.84 keV) and 0.04 microns (0.97 keV). But their contribution becomes *

Corresponding author: E-mail: [email protected]

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D. A. Abdushukurov essential in the use of converters from 157 gadolinium isotopes as the length of the free path of neutrons in them does not exceed 2–3 microns and this length becomes comparable with the length of path electrons. The estimation is made of the contribution of X-ray and low-energy gamma-quanta absorbed directly in the converter and resulting in occurrence of secondary electrons. In the case of the account of the contribution of electrons formed by X-ray quanta, the efficiency is increased a little, but their contribution is no more than 1%. Calculations of complex converters representing a set thin gadolinium foil located on both sides of supporting kapton foils and calculations of complex converters representing a set thin drilled with the fine step foils located one over other in a gas volume are given. Examples of development of detectors of neutrons based on gadolinium converters are described.

1. INTRODUCTION Mechanisms for detecting neutrons in matter are based on indirect methods. Neutrons are neutral, they do not interact directly with the electrons in matter. The neutrons can cause a nuclear reaction. The process of neutron detection begins when neutrons, interacting with various nuclei, initiate the release of one or more charged particles. The products from these reactions, such as protons, alpha particles, gamma rays, electrons and fission fragments, can initiate the detection process. For detection of neutrally charged neutrons, it is necessary to use converters of neutron radiation. These converters will converse radiations of neutrons to the charged radiation, which can be further detected with manifold detectors. For an optimal choice of the converter foil material, the following properties should be considered:

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  



A large neutron-capture cross section is needed in order to achieve high detection efficiency with minimum foil thickness. The range of the neutron-induced charged primary particles should be large compared with the convertor foil thickness. The converter material should possess a small cross-section of activation. Daughter isotopes occurring as a result of activation should not create the significant background. The γ-ray sensitivity of the material should be low.

At the present time gaseous and solid-state converters are used. Thus, several kinds of nuclear reactions are used in these converters. The most widely known are 3He and 10BF3 based converters [1]. Gaseous converters are used in the wide class of gas detectors. Solidstate converters are applied in gaseous, semiconductor and in scintillation detectors. In the development of gaseous detectors of thermal neutrons, the highest efficiency of registration up to 80% has been reached with the use of gas mixes on the basis of Helium - 3 (3He) at pressure up to 15 atm. The use of the high pressure is necessary in order to increase the efficiency of registration and improvement of the spatial resolution. The increase of pressure dictates the additional requirements for the mechanical designs and first of all to the thickness of the entrance window. At the same time, the high price of the gas and fluidity of 3 He results in a sharp rise in price of detectors and their operation.

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Converters of neutron radiation play a determining role in designing detectors of neutron radiation. They define the key parameters of detectors, such as the efficiency, the spatial resolution and so on. Among the solid-state converters of thermal neutrons the highest efficiency of registration has been achieved using the gadolinium based converters, and especially, its 157 isotope. As a result of radiating capture of thermal neutrons by nucleus of gadolinium, electrons of internal conversion and Auger electrons are radiated. Another solidstate converter is rarely used in detectors of neutrons, which is first of all connected with the low efficiency of registration. Therefore, the efficiency of registration of detectors based on 10 В and 6Li usually do not exceed 3–4% and 1%, respectively [2,3]. The idea of using thin foils to convert neutron radiation into charged particles and count the conversion products in a solid-state detector was originally proposed by Feigl and Rauch [4,5]. They employed natural Gd and pure l57Gd convertor foils and measured the escape probabilities and the energy distributions of the escaping electrons with Si surface barrier detectors. In the paper A.P.Jeavons et al. [6], the efficiency of registration of thermal neutrons by the converters constructed based on gadolinium foils has been simulated. The following conditions were considered at the modeling: the neutron beam (2 fixed energies) perpendicularly fell on to the converting foils of various thicknesses; the output of the secondary electrons has been calculated both in lobby and back hemispheres. As the result the detector on the basis of the multiwire proportional chamber with the gadolinium converter has been developed. Nevertheless such a detector did not have enough good spatial resolution, about 10 mm. In order to improve the spatial resolution the same authors have offered to use the converter - collimator, which was the sandwich created from lead foils with the fiberglass layers and drilled with the fine step (Jeavons converter). This converter was nestled to the gadolinium foil and thus limited electron runs in the gas, simultaneously serving as the emitter of the secondary electrons. It has helped to improve the spatial resolution up to 2 mm, but the spatial resolution turned to module with step of apertures, besides the efficiency of registration has sharply fallen. Further, in the G.Charpak group [7], by the development of multistep avalanche chambers with gadolinium converters, they managed to improve sharply the spatial resolution of detectors (up to 1 mm) without use of Jeavons converter [8]. In the paper D.A.Abdushukurov et al. [9], modeling of the efficiency of registration of thermal neutrons by the gadolinium foils has been conducted. In contrast to earlier works the incidence angle of neutron beam was not a constant value (90 degrees) and varied from 1 up to 90 degrees. As the result the conclusion about the increase of efficiency of registration of neutrons at the small angles (up to 10 degrees) between the converter and beam of incidence neutrons has been done. It is connected with the increase of neutron path length in the body of the converter at conserving of effective thickness of material for the output of secondary electrons. At the disposition of two detectors on the different sides of the converter, the efficiency of registration of thermal neutrons can increase up to 60%. In the carried out calculations, we took into account only electrons with the energies higher than 29 keV. Thus only electrons of internal conversion and Auger electrons, radiated from K-shell, with the energy 34.9 keV were taken into account [10]. The minimal free path length of electrons with energy 29 keV in gadolinium makes 4.7 microns. The similar choice of energies of electrons was made not only us, but also by other researchers.

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Recently calculations of influence of low-energy secondary electrons radiated from gadolinium foils during radiating capture of thermal neutrons were carried out. These are Auger electrons radiated from a L-subshell with the energy 4.84 keV and electrons from Msubshell with energy 0.97 keV. These electrons have rather small free path length in gadolinium; these are 0.3 microns (4.84 keV) and 0.04 microns (0.97 keV), thus accordingly make average free path length of these electrons 0,1 and 0,015 microns. During calculations it was found out, that their contribution becomes essential at use of converters made from 157 isotope of gadolinium as the length of free path of neutrons in them does not exceed 2-3 microns and this length becomes comparable with the free path length of electrons. Results of modeling calculations within the limits of errors have coincided with the experimental data and published in [11]. The good consent of the calculated data with the experimental ones testifies to correctness of the chosen models and theoretical preconditions. In the literature and the tabulated data there are no data for the free path length of electrons with the energy less than 10 keV. All available data for electrons in various materials received from the Bethe-Bloch theory. The lower border of applicability of this theory is the energy of 10 keV. The theory constructed on the assumption, that the charged particles have continuous losses of energy at their motion in materials by two mechanisms. These are losses of energy on irradiations and direct collisions. For electron energies less than 10 keV the new mechanism added, it is the probability of capture of free electrons by the atom subshells having vacancies. Also practically, there are no data on the quantity of lowenergy Auger electrons. Available data differs with an error more than 100%. During realization of calculations, it is necessary to compare received results with the experimental data. It will allow estimating the correctness of theoretical preconditions and modeling representations. The thin layer converters will allow creating new types of detectors of thermal neutrons having the improved characteristics. Therefore, it will be possible to create detectors with pico-second time resolution for time-resolved experiments, also it an improvement of the spatial resolution can expected due to the reduction of thickness and parallax of detectors. It is possible to specify separately an opportunity of miniaturization of detectors that claimed for many applications. Computer modeling allows to prospect, without special material inputs of the most suitable configuration of converters, to carry out search of optimum geometrical ratio. It in turn allows refusing realization of superfluous development and researches. In present time to position - sensitive detection of thermal neutron radiation widely applied various detectors with solid-state converters such as normal-pressure multistep avalanche chambers (MSAC), low-pressure multistep avalanche chambers (LMSAC), microchannel plates, thin layer scintillators. New types of detectors are offered and developed such as hybrid low-pressure micro-strip gas chamber (MSGC), position sensitive silicon detectors (Gd Si PD), resistive plate chambers (RPCs), imaging plate neutron detectors (IPNDs), liquid scintillator into a capillary plate and so on.

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2. MATHEMATICAL MODELING OF CONVERTER PERFOMANCES 2.1. Theoretical Bases In the current chapter influence of various parameters of converters on their efficiency are viewed. Efficiency in our understanding is the ration of the electrons which have departed from converters, to total number of falling neutrons on the converter. The efficiency of converters is the product of three variables. These are the following: 

 

Probabilities of thermal neutrons capture by nucleus of the converter, which depends on its thickness, and the cross-section of interaction. The cross-section of interaction in turn depends on isotope composition of the converter and energy or wavelength of neutron. Probabilities of creation of the secondary charged particles, in our case of internal conversion and Auger electrons. Probabilities of escape of the created electrons from the material of the converter, which depends on, free path length of electrons in a converter material and geometry of emission.

Energies of the secondary electrons are discrete values and are formed with the certain probability. At calculation of probability of escape it is necessary to take into account emission of each electron with its characteristic energy and its weight factor (probability of formation). In that specific case efficiency can be described by the following expression

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Ei = Pn(σLj) * De (EiNi) * He(ReiΘi)

(1)

where Ei is the efficiency of registration of the absorbed with the probability Pn(σLj) neutrons, which caused formation of electrons De(EiNi) with the discrete energies and probability of formation, probability of escape of electrons from a material of converter He(ReiΘi) in view of the maximal free path length of electrons in a material of the converter and angle of their emission. Generally probabilities are necessary for summarizing, so calculations are made for 446 discrete energies of electrons with the energies in the range from 0.9 up to 1000 keV. ΣE = ΣPn(σLj) * ΣDe (EiNi) * ΣHe(ReiΘi)

(2)

2.1.1. Probability of neutrons absorption The attenuation of the narrow collimated neutron beam in thin layer materials is governed by the exponential law [12] Fx= F0 exp (-NA σ X)

(3)

where Fx and F0 are the neutron flux density after and before its passage through the layer of the material with the thickness X, correspondingly, NA is the number of nucleus in the volume of 1 cm3, σ- is full microscopic cross-section of neutron interaction with the nuclei of material.

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D. A. Abdushukurov

One can simplify the formulae for the neutron flux density on the distance R (cm or g/cm2) from the dot isotropic neutron source, emitting I0, neglecting the exponential correction on attenuation when

 

R [13] FR = I0 / 4



R2

(4)

In our calculations we use four fixed neutron energies. These are neutrons with wavelengths of 1, 1.8, 3 and 4 A0. In the table 1 their wavelengths, corresponding energies (eV) and velocities (m/s) are shown. Natural gadolinium is a mixture of isotopes that could participate in the (n,) nuclear reaction. The basic characteristics of the most widespread isotopes gadolinium including cross section of interaction with neutrons, daughter isotopes, and a half-life period of unstable daughter isotopes, are presented in table 2 [14,15]. As one can see in this table, the most interesting for our calculations are natural Gd and its 155 and 157 isotopes, which have abnormally high cross sections of interaction with neutrons. Other isotopes give an insignificant contribution to the interaction with neutrons. In the figure 1 the dependence of cross-section (barn) on the energy of incident neutrons (eV), for natural gadolinium and the same dependence for its 157 isotope are shown. Arrows indicate energy of neutrons for which we will carry out our calculations. As one can see, with the reduction of energy of neutrons the cross-section of interaction strongly increases. Especially it increases in the region of cold and ultra cold neutrons. Table 1.

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Wavelength AO

Energy of neutrons (eV)

Velocity of neutrons (m/c)

0.081894 0.025276 0.0090993 0.0051184

3955 2197.2 1318.3 988.76

1 1.8 3 4

Capture Cross Section (barns) for Nat Gd 13 563.56 48 149.41 70 597.77 89 066.84

Capture Cross Section (barns) for 157 Gd 75 323.47 253 778.40 367 842.60 464 373.40

Table 2. Isotope nat

Gd Gd 154 Gd 155 Gd 156 Gd 157 Gd 158 Gd 160 Gd 152

Abundance (%)

Cross section (b)

100 0.2 2.2 14.7 20.6 15.68 24.9 21.9

48890 1100 90 61000 2.0 255000 2.4 0.8

Daughter isotope 153 Gd 155 Gd 156 Gd 157 Gd 158 Gd 159 Gd 161 Gd

T1/2 241.6 d Stable Stable Stable Stable 18.6 h 3.66 min

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Figure 1. Cross-section of thermal neutrons capture, for the reaction (n,), depending on energy of neutrons for natural gadolinium and its 157 isotope [16]

2.1.2. Probability of gamma quanta’s formation In the reaction of 157Gd neutron capture, 7937.33 keV energy is emitted. In total 390 lines with energy ranges from 79.5 up to 7857.670 keV with line intensity of 2×10-8 up to 139 gamma-quanta on 100 captured neutrons are emitted. In the table 3 the most intensive, lowenergy gamma-lines having high coefficient of internal conversion are presented [17]. In the figure 2 the histogram showing dependence of gamma quantum intensity on the energy is presented.

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D. A. Abdushukurov

Table 3. Isotope

Eγ [kev] 79.510 135.26 181.931 212.97 218.225 230.23 255.654 277.544 365 780.14 944.09 960 975

Cross section [b] (error) 4010(100) 38(4) 7200(300) 10.8(7) 55(4) 20.0(11) 350(19) 493(12) 59(5) 1010(22) 3090(70) 2050(130) 1440(21)

Iγ [1/100 n] (error) 77.3(19) 0.73(8) 139(6) 0.21(13) 1.06(8) 0.385(21) 6.7(4) 9.50(23) 1.14(10) 19.5(4) 59.5(13) 39.5(25) 27.8(4)

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157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd 157-Gd

Daughter isotope 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd 158-Gd

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Figure 2. Histogram of dependence of intensity of gamma-quanta on energy for the reaction of 157Gd (n, γ) 158Gd (by 100 neutrons)

2.1.3. Probability of internal conversion electrons formation As there are the low-energy quanta at the spectrum during their emission electrons from an atomic subshells (so-called internal conversion electrons) are radiated with a high probability. The nuclear removes its excitation by radiating a gamma-quantum, but also there a close located electron can be irradiated. Usually K-electron (electron from К-subshell) is emitted, but also electrons from the higher subshells (like L, M, N and so on) can be emitted. Vacancy of electrons (an electronic hole), formed as a result of this process, is filled by another electron from a higher level. This process is accompanied by radiation of X-ray quantum, or radiation of Auger-electron. The probability of formation of internal conversion electrons can consider as follows. An electromagnetic decay of the atomic nucleus can proceed by competing modes: electromagnetic radiation (γ), production of electron-positron pairs (e+e-) or emission of orbital electrons (e-) that is, internal conversion. The conversion coefficient α is the ratio of the electron emission rate (Te) to the gamma emission rate (Tγ),

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α= Te / Tγ

(5)

The values of α are depend on four parameters: (l) the charge of the decaying nucleus, (2) the energy of the nuclear transition, (3) the atomic subshell out of which the orbital electron is ejected and, finally, (4) the multi-polarity and parity of the nuclear transition. The knowledge of the coefficients is one of the most important tools for the determination of parity and multipolarity of electromagnetic nuclear transitions and the construction of nuclear decay schemes, but other applications exist as well. The emission of nuclear gamma rays is accompanied by the emission of orbital electrons. Their branching ratio is the conversion coefficient α. The discovery of this process and its naming as a "conversion of the γ-radiation" is due to Hahn and Meitner [18]. The first correct theoretical description is due to Hulme in 1932. A review of the theory was given recently by Pauli, Alder, and Steffen [19]. In the lowest, non-trivial order of perturbation theory the conversion coefficient for a transition of pure electric multipole order L is given by

(6) The index σ refers to the atomic orbital (subshell) out of which the electron is ejected. The quantities in big parentheses are 3-j symbols. The total conversion coefficient is given by (7) and the total electromagnetic decay rate by (8)

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for transition energies ω < 2mec2. The relativistic angular-momentum quantum number is related to the total angular momentum j by j =│k│-1/2. An index zero refers to the initial bound state. A subshell σ is represented in addition by n0, the principal quantum number, i.e. σ=(n0, k0). The so-called dynamic radial matrix elements Tkko contain nuclear transition currents and charges, (9) For later reference we introduce a few other quantities. The bound energy of the bound electron with energy W0 is given by (10) The kinetic energy of the free electron is given by E=W-1

(11)

The transition energy ω is related to the latter two by (12) For a full subshell, the occupation probability has the value ωσ= 2j + 1. For a broken subshell ωσ has a smaller value caused either by a smaller number of valence electrons or by punching holes into a subshell. For the neutral atom, of course

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(13) The effect of internal conversion is accompanied by the significant X-ray radiation, which could positively affect on the use of scintillation detectors with the fine-dispersed gadolinium. We will only consider electrons with the energies higher than 20 keV. Data on coefficients of internal conversion are different in various sources [20,21] that lead to the divergences in quantity of the secondary electrons. In our last modeling, we based on the last data presented in the database [22]. The most intensive lines electrons are allocated in the table In table 4 data on the most intensive lines of electrons with the probability of emission higher than 0.03/100 neutrons, for the energies of primary gamma quantum less than 1 MeV. Data on Auger electrons which are formed during the K-shell filling are presented as well. In our calculations, totally 446 discrete electron energies with the output probability of more than 10-5 on 100 incidence neutrons were considered. On figure 3 the histogram is presented, which shows the dependence of the most intensive lines of electron intensity on their energy.

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Table 4.

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Electron Energies (keV) 29.3 34.9 71.7 78 131.7 174.1 180.4 205.4 227.3 729.9 893.85 911.8 926.8

Electron output 1/100 n 35,58 13 5,57 1,2 6,96 0,99 0,21 0,14 0,16 0,03 0,06 0,04 0,03

Electron path in Gadolinium (µm) 4,7 6,29 20,7 23,78 55,70 86,27 91,23 111,47 130,27 649,38 830,05 849,83 866,35

Energy of primary gamma quantum 79.51 79.51 79.51 181.93 181.93 181.93 255.66 277.54 780.14 944.09 960 975.4

Comment, level K K-Auger L M K L M K K K K K K

Figure 3. Intensity of internal conversion electrons emitted in the reaction 157Gd (n,γ) 158Gd depending on their energy (by 100 neutrons)

2.1.3. Intensity of Auger electrons Energy of emitted electrons defined by the energy of outcoming gamma quantum and the bound energy of electrons on the atom subshells

Ee  E  Ebi Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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D. A. Abdushukurov Table 5.

E

K

L1

L2

L3

M1

M2

M3

M4

M5

N1

N2

O1

O2

64Gd

50.24

8.38

7.93

7.24

1.89

1.69

1.55

1.22

1.19

0.38

0.27

0.04

0.03

where, Ee is the energy of outcoming electron, Eγ – energy of gamma quantum, Ebi- bound energy of electrons on the atom shells. In the table 5 given bound energy of electrons on different gadolinium atom shells [15] By knocking out electrons, an electron hole (vacancy) is formed, which is filled by electrons from higher levels. During vacancy filling X-ray radiation, with the energy equal to the difference of bound energies at corresponding levels, is radiated

Ex  Ebi  Ebj

(15)

where Ex is the energy of X-ray radiation, Ebi and Ebj are bound energies of electrons at the corresponding atomic levels. Energy of excitation of atom can be removed also by the emission of Auger electrons. These electrons are emitted instead of X-ray quantum and possess energy equal to the energy of X-ray quantum minus bound energy of electron at the corresponding level

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Eea  E x  Ebi

(16)

where Eea– energy of Auger electron. In table 6 the most intensive X-ray lines and their relative outputs [23] are represented. Data are normalized to the intensity of line Ka1, whose intensity is chosen as 100%. Also, Augur electron data are represented, irradiation of them results in reduction of X-ray radiation output. The effect of internal conversion is accompanied by the significant X-ray radiation, which could positively affect on the use of scintillation detectors with fine-dispersed gadolinium. Table 6. X-ray radiation X-ray energy IX (%) Comment (average) (keV) 6.06 42.6 L 42.31 55.6 Ka2 (KL2) 42.9962 100 Ka1 (KL3) 48.7 30.8 Kb1 (KM(tot)) 50.0 8.9 Kb2 (KNO(tot))

Auger electrons Electron Energy Ie (%) Comment (keV) 4.84 201 L- Auger 34.9 14.2 K- Auger

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Probability of formation of Auger electrons have been derived from the theoretical emission probabilities through the relationship

,

(17)

where PK-XY is the theoretical emission probability of a K-XY Auger electron, from Chen, et al. [24], ωk is the K fluorescence yield, from Krause [25], and the summation is over all Auger electrons which are energetically possible. Approximate Auger-electron energies can be calculated by the empirical Dillman quotation [26]. The average energy for a K-LiX Auger transition is given by (18) and for higher atomic shells by (19)

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Eli is the bound energy of the Li atomic shell for the element, EK and EM3 are the corresponding bound energies of the K and M3 atomic shells, EM3+ is the bound energy of the M3 atomic subshell for the next higher element, and X and Y are designations for the higher atomic subshells. More precise Auger electron energies, one is referred to the publication of Larkins [27].

2.1.6. Passage of electrons through a substance The probability of escape of electrons from a material of the converter can be considered on the basis of Bloch theory. For realization of calculations it is important to have exact data on brake ability of various substances for the charged particles. Brake ability is average speed of lose of energy by charged particles in any point along their tracks. For electrons and positrons full brake ability usually is divided on two components: a the brake ability caused by collisions ("collision stopping power"), - average losses of energy on the unit of length of path due to non-elastic Coulomb collisions with the bound electrons of the environment, resulting in ionization and excitation; b - radiating brake ability ("radiative stopping power") - average losses of energy on the unit of length of path due to emission of brake radiation in the electric field of atomic nucleus and atomic electrons. Division of brake ability into two components is expediently for two reasons. First, methods of their determining are completely various. Second, the energy going on ionization and excitation of atoms, is absorbed by the environment rather close to the track of a particle, while the basic part of energy lost in the form of brake radiation, leaves far from a track before to be swallowed up. This distinction is important, when the attention is accented to the energy "transferred locally" to environment along a track, in distinction to the energy lost by an incident particle. Actually, the part of energy lost in ionization impacts, turns to kinetic energy of secondary electrons and is transferred thus to some distance from a track of an initial particle.

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In order to receive a rough estimation of locally transferred energy, it is expedient to enter the limited brake ability caused by collisions ("restricted collision stopping power") and to determine it as average losses of energy on the unit of length of the path due to events of excitation and ionization, in which the energy transmitted to secondary electrons, less than the chosen threshold. Though brake abilities and path of electrons are widely used, they are seldom measured and turn out from the theory of energy losses. All data brought in tables contain the brake ability of electrons caused by collisions at the energies higher 10 keV, which is calculated according to Be the theory (1930, 1932, 1933). Energy in 10 keV usually consider as the bottom limit of applicability of the theory. Basically, the non-trivial value describing properties of the substance in Bethe formula for brake ability is mean excitation energy, representing geometrical average of energies of excitation (atoms) of the substance, weighed in view of the appropriate oscillator forces. Except for the elements with very small nuclear number mean excitation energies are approximately equal to 10Z eV, where Z is the nuclear number. Exact calculations ab initio of mean excitation energies are possible now only for simple atomic gases. For the majority of substances the mean excitation energy could be determined from experimental data. Other important value in the formula for the brake ability, not contained in original Bethe theory, is correction on the density effect, reducing brake ability at polarization of substance by the relativistic charged particles [28]. Also at calculations it is necessary to take into account corrections on density effect by the Sternheimer method (1952) [29]. The linear brake ability caused by collisions with the dimension energy/length, is designated as — (dE/dx)co1 or Sсо1. It is frequently more convenient to consider the appropriate mass brake ability caused by collisions, Sco1/ρ, where ρ is the substance density. Transition from the linear to the mass brake ability caused by collisions, substantially removes dependence on the density except for residual dependence due to the correction on density effect. If Sco1 is expressed in MeV • cm-1 and ρ – in g•cm3 Sco1/ρ is expressed in MeV • cm2• g-1. The brake ability caused by collisions is realized due to the energy transmitted by a incidence particle to connected nuclear electrons. We shall designate by dσ/dW differential cross section (on a atom electron) of non-elastic impacts with the energy transfer W. Then the mass brake ability caused by collisions is (20) where N is the number of atoms by 1 g of substance; Z is the nuclear number; N= NA/MA = (uA)-1, where NA = 6,022045 x 1023 mol-1 – Avogadro number; МА is molar weight, g x mol1 ; A is the relative weight of atom (sometimes designated Аr) and u = 1.6605655 • 10-24 g is nuclear mass unit (1/12 weights of nuclide atom 12С). Following formalism of Uehling (1954)[30], Bethe discuss results of estimation of the equation of brake ability [expression (20)]. These results are applicable to electrons and positrons, mesons, protons, α-particles and the heavy ions, completely deprived electrons. Energy W transferred to nuclear electrons in non-elastic impacts, divides on two classes depending on those, is W less or more than some threshold Wc which should satisfy to two conditions: a) Wc should be big in comparison with bond energy of nuclear electrons of the braking substance; b) the parameters of impact

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appropriate to losses of energy, smaller than Wc, should be big in comparison with the sizes of atoms. Then the mass brake ability caused by collisions could be represented as the sum two components: (21) The basic result of Bethe theory with reference to electrons and the heavy charged particles could be expressed by the formula

,

(22)

where re is the classical radius of electron; mc2 is the rest energy of electron; β is the speed of incidence particles in terms of speed of light; z is an initial charge of a particle in terms of a charge of electron and I- is average energy of excitation of atoms of the substance. Using numerical values Cohen and Taylor (1973) [31] for various physical constants, we receive, that

.

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(23) Expression (23) is fair when the speed of incident particles is greater than speed of nuclear electrons. With reference to electrons K-shell, it means that the condition (Z/137β) < 1 is satisfied. Component of brake ability owing to close collisions it is estimated in approximation of free and bond electrons

,

(24)

where dσ/dW now is the differential cross-section of the energy transfer W in the collision with the free electron, and

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D. A. Abdushukurov

is the greatest possible energy transfer; τ is the attitude of kinetic energy the incidence particles to their rest energy of rest; m/М is the ratio of weight of an electron to the weight of incidence particles. For electrons the big transfers of energy to nuclear electrons, which are considered as free, are characterized by cross section (Moller (1932)) [32].

,

(26)

where τ=T/mc2 is the ratio of kinetic energy of an incidence electron to its rest energy. In the cross section Moller takes into account both relativistic and spin effects, and exchange effects due to in-distinguish-ability of incident electrons and electrons of a target. Conventionally the brake ability caused by collisions is calculated for fastest of the electrons formed in impact. The greatest possible transfer of energy Wm equal to Т according to expression (2.37), in this case should be equal to T/2. Using in expressions (20), (21) and (22) the Miller section, we receive the following formula for the mass brake ability of electrons caused by collisions (Rohrlich and Carlson, 1953; Uehling, 1954г.) [33, 30]:

,

(27)

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where

(28)

Corrections to Bethe theory, similar to corrections on shell-effect for brake ability, were discussed by Inokuti (1971) [34] concerning cross section of excitation. He marks, that these corrections contain the additional member proportional to the ratio m/М of electron mass to the mass of incident particles. Thus, one can expect, that in the case of electrons, for which M = m, corrections will be much more, than for protons. Probably the same happens concerning corrections of brake ability on shell-effect. From measurements of brake ability (Sсо1/ρ)ехр it is possible to determine the mean excitation energy:

.

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Where (30)

is the full correction uniting the corrections on shell-effect and the density effect, correction of Barkas and the Bloch correction. Let ∆Sco1 is the error of the measured value Sco1, and ∆х is the error of a correction term х. We assume, that ∆х and Sco1 are independent and could be incorporated quadratialy then the total error of estimated value I makes

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∆ ↑2↑12 ,

(31)

where Lехр is experimentally determined brake number [last term in the expression (31)], and ∆Lехр is the appropriate error. When in order to determine the values I one uses the data on run, the analysis of errors is more complicated and should take into account both the error of experimental value of run, and the error of the correction term х at all energies down to initial energy of incidence particles. The full correction C on the shell effect is the sum of components СK, CL... for various nuclear shells. It is supposed, that the error owing to application of hydrogen-like wave functions is rather small for K-shell, is more essential to L-shell (especially for nuclear numbers Z < 30) and, probably, it is even more for the M - environment. Extending of calculations on farther shells is possible by application of more perfect wave functions, but could be very toilful. Bichsel [35] instead of this method applied semiempirical numerical approach with the parameters determined from experimental data on the brake ability. He has accepted, that up to factor dependences СM on speed of a particle shell effect are similar, and this assumption is extended also to farther shells. For L-shell with eight functions Walske [36] has received the function CL(θL ηL), which depends on potential of ionization of L - shell through the parameter θL and on the energy of particle via the value

,

(32)

where Z* = Z — 4,15 is effective nuclear charge for L-shell. The correction for the M – shell are calculated by the following ratio:

,

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D. A. Abdushukurov

where VM = 1/8 of numbers of electrons on the M-shell, and НM is adjustment parameter. The similar scale ratios were used for N-shell and for the combined O-P-shell. On Figure 4 and 5 dependence of size of free path length electrons in gadolinium (g/sm2) and (µm) from their energy [37] is presented. Size Re can be defined by energy of electron and size specific ionization losses. The absorption coefficient F0 characterizes probability of absorption of electrons in the substance. If Х is the thickness of the converter, Re is the electron path in the material of the converter, then F0(X)=1–X* ρ / Re ,

(34)

where ρ is the density of the converter. For the gadolinium it is ρ =7,9 g/cm3. Re is defined both by the electron energy and by the specific ionization loss value E

Re   dE(dE / dX )

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0

Figure 4. Dependence of the free path length of electrons on their energies in gadolinium (g/cm2)

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Figure 5. Dependence of the free path length of electrons on their energies in gadolinium (μm)

2.2.1. Model representation and calculation Modeling was realized by examining the simplest targets, namely the plane-parallel foils. The calculations for thermal neutrons with the fixed energies, which correspond to the neutron wavelength of 1, 1.8, 3 and 4 A0 were carried out; also both the thickness of converters from 1 µm to 40 µm, and isotopic composition of converter (for natural Gd and 157 Gd) were varied. In the calculation all electrons (appeared as a result of neutron capture act) are taken into account which are able to escape an infinite plane-parallel plate of the converter. The ratio of the number of electrons escaped from the foil to that of the number of incident neutrons is referred to as the efficiency of the converter. Conventionally we divide the thickness of a foil into more thin components. For each elementary layer we count the probability of neutrons absorption with the fixed energy. Efficiency of the converter will be determined by the sum of probabilities of neutron absorption and probability of the electron escape from the converter. In order to calculate the electron escape we have chosen a simple model, namely, geometrical. The choice of the model is made from the following assumptions: all electron emissions are isotropic, the length of path for any fixed energy of electrons (Rei) is constant (fluctuation of power losses in the end of path is neglected). Then the density of probability to find electrons in the material forms a sphere with the radius equal to Rei (for each fixed energy). If the center of the sphere is crossed by the plane, two identical hemispheres are formed, which correspond to the electron escape to the forward and backward hemisphere, thus the area of hemispheres

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could be considered as the probability of an electron output. In this case total probability is 100%, and escape to the one of hemispheres is 50%. If we begin to cross a sphere with a step much less than Rei, segments will be formed whose area will be equal to probability of the electron escape. The step of iterations should be at least 100 times less than Rei, and then the electron absorption under the big angles could be neglected. The area of a segment and accordingly probability of the electron escape becomes equal to zero in the intersection of a sphere by the plane at the distance Rei. The sum of probabilities of electron escapes for all energies, taking into account their weight contribution will determine the total electron escape probability.

Figure 6. Probability of yield of isotropic emitting secondary electrons from gadolinium foils of various thickness, in view of their intensity and a spatial angle

Separated energies of electrons could be divided into 4 groups (Figure 4). In the first group the least energetic and therefore having small ranges in the substance, and in the fourth one the most energetic electrons are placed. Calculations of escape probability of isotropic emitting electrons for gadolinium are conducted. In figure 6 one can see contributions of electrons of different energetic groups. Calculations were made for conditionally fixed point of conversion of neutrons having coordinate (X=0, Y=0). The contribution of 4 groups of electrons with different energies is well seen. In calculations, the probability of neutron absorption for each elementary layer, as a result of reaction of inelastic interaction (n,), is determined, using database for fixed neutron

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energies. The probability of electron emission and their escape probability from the body of the converter were calculated.

Figure 7. Curve uptakes of neutrons for lengths of waves 1, 1.8, 3 and 4 А0 for natural gadolinium and it 157 isotopes

Table 7. Calculated data on efficiency and optimal thicknesses for natural gadolinium converter foils λ(A0) 1

Efficiency E and optimal thickness T Forward backward 0.044 (18) 0.064 (40)

(µm) total 0.10 (24)

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D. A. Abdushukurov 1.8 3 4

0.096 (5) 0.122 (4) 0.138 (4)

0.135 (30) 0.164 (25) 0.182 (20)

0.208 (7) 0.261 (5) 0.295 (4)

Table 8. Calculated data on efficiency and optimal thicknesses for 157Gd converter foils (A0)

Efficiency E and optimal thickness

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Forward

backward

T (µm) total

1

0.126 (4)

0.169 (18)

0.270 (5)

1.8

0.208 (3)

0.258 (12)

0.448 (4)

3

0.232 (2)

0.277 (7)

0.489 (3)

4

0.241 (2)

0.287 (5)

0.516 (2)

Results of calculations of neutron absorption in converters made from natural gadolinium and its 157 isotope are shown in the figure 7. Figure shows that at 30 microns thickness of the natural gadolinium converter the neutrons with the wave length above 1.8 A0 are absorbed completely. For its 157 isotope for neutrons with the wave lengths >1.8 A0 the same absorption happens at 8 microns thickness of the converter. In order to detect thermal neutrons by the 157Gd converters we could limit ourselves by the thickness of 5 microns of the converter, if there no technological restrictions. It should be taken into account that the majority of electrons emitted in the reaction of radiating capture of neutrons have ranges less than 5 microns. When using natural gadolinium the situation is more complex, since low absorption requires converter to be thicker than 20-40 micron. Obtained data on efficiency and optimal thicknesses of converters for natural gadolinium and its 157 isotopes; see table 7 and table 8, respectively. Figure 8 and Figure 9 shows the dependence of registration efficiency on converter thickness for neutrons with the different energies. Obtained results of calculations are compared with the experimental data presented in the paper [38], which data were received in the reactors of Atominstitut in Vienna (ATI) and the ILL Grenoble. In this paper experimental data on the detection efficiency was measured in backward direction for six different energies and compared to a calibrated 3He counter. In this work converter made from natural gadolinium and enriched up to 90.5% 157Gd converter were used. The effect of comparison is shown in figure 10 for natural gadolinium a curve of calculations lie a little below experimental data. Errors of calculations are caused both by the precision of determining of gamma-quanta output and by determining of neutron crosssection. For the converter made from 157 isotope the experimental curve is little bit higher (at the account of electrons with energy more than 29 keV) that testifies to necessity of the account of more thin effects.

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Figure 8. The dependence of the neutron registration efficiency of the natural gadolinium converter on its thickness. Curve 1 and 2 correspond to emission of electrons into the front and back hemisphere, respectively, curve 3 is their sum

Figure 9. The dependence of the neutron registration efficiency of the 157 isotope of gadolinium converter on its thickness. Curve 1 and 2 correspond to emission of electrons into the front and back hemisphere, respectively, curve 3 is their sum

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Figure 10. Comparison of our calculated data with the experimental data for backward escape geometry. Experimental data are obtained in Atominstitut in Vienna (ATI) and the ILL Grenoble [38]

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2.2.2. Probability of converters activation Deficiency of detectors with natural gadolinium converters is possible activation of converters, which is accompanied by radiation of retarding gamma quanta and electrons which, in turn can spot a background level. The basic contribution is carried out long-lived isotopes (table 1). The activity A(t) (particles s−1) at a time t seconds after the removal of a thin foil from a neutron flux having an energy spectrum Φ(E) in which the foil has been irradiated for T seconds is given by [39]

,

(36)

where V, ρ and A are the volume, density and atomic weight of the foil material respectively, NA is Avogadro's constant, λ (s−1) is the decay constant of the radioactive species produced by the irradiation and σact(E) is the activation cross-section of the material. Values of σact averaged over the thermal and fission energy regions are given in the table together with the activation resonance integral. Calculations of possible activation of converters from natural gadolinium have been fulfilled, and a background (noise level) which will accompany decay of the activated isotopes. At calculations of level of the directed background emitted electrons have been considered only. On Figure 11 effects of calculations for foils with a thickness 1, 3 and 10 microns (curves 1, 2 and 3) are presented. Calculations have been satisfied for a requirement that quantity of a neutron stream makes 1n/sm2s and irradiation time of 30 hours. In it cases maximum noise 3 microns of converters occurring as a result of activation will not exceed 4 х 10-5 Bk on an individual neutron. In too time vessel activation can be considered at post processing of the data.

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Figure 11. The background level of converters from natural gadolinium with thickness 1, 3 and 10 microns (accordingly curves 3, 2 and 1) at exposure on a bundle of neutrons intensity 1n/sm2s and irradiation time of 30 hours [9]

Figure 12. Dependence of efficiency of registration of neutrons with a wavelength 1.8 A from an angle of neutrons failing, for 157Gd for thickness of converters 1 and 3 microns. A curve 1 and 2 accordingly an escaping of electrons in forward and back hemispheres, the curve 3 their sum Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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2.2.3. Modeling for a case of neutrons flow under various angles In the process of calculation we varied the angle of incidence of neutron flow onto the foil. Under the small angle of fall we can increase neutron path in the material of the converter, yield path for the output of the secondary electrons will be small and constant. The most ideal case would be a direction of a bunch of neutrons along the converter of small thickness. This case cannot be realized in the practice, but yet it is possible to estimate theoretical or maximum possible efficiency. On the Figure 12 the dependence of efficiency on the incidence angle of neutrons for 157 Gd for two various thicknesses of converters (1 and 3 microns) are cited. From figure it can be seen, that at small thickness of the converter (1 micron and less) difference of electron outputs in frontward and backward of hemisphere is not so significant. The probability of an output of electrons makes approximately 32 and 35% respectively for an output of electrons in frontward and backward of hemispheres. Total efficiency reaches 64% [9, 40], which can be considered as the greatest possible efficiency for gadolinium converters. The difference becomes more substantial when thickness of converters is increased.

Figure 13. Dependence of efficiency of registration of neutrons with a wavelength 1.8 A0 from an angle of neutrons failing, for natGd for thickness of converters 1 and 3 microns. A curve 1 and 2 accordingly an escaping of electrons in forward and back hemispheres, the curve 3 their sum

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Similar calculations are made as well for converters from natGd. From figure 13 it is clear that at extremely small angles of neutron incidence (2-3о), converters from natural gadolinium can compete with the converters from 157Gd. The calculations made for a case of neutron incidence under angle of 10 о for various thicknesses of converters for length of a wave of neutrons 1,8о, for two types of converters natural gadolinium and its 157 isotope. Using converters from 157Gd, at a thickness of 1 micron it is possible to reach efficiency of 64% which is a theoretical limit. Obtained as a result of modeling calculations data, allows looking with optimism at possibility of making of effective position-sensitive detectors of thermal neutrons with solidstate converters from the natural gadolinium which efficiency of registration becomes comparable with efficiency of detectors filled 3He, in too time these detectors will be much more low-cost and are more easy-to-work.

Figure 14. Dependence of efficiency of registration of thermal neutrons with a wave length 1,8 A0 from a thickness of the converter at an angle 100 of flowing neutrons

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Figure 15. Schematic view of the detector, where MWPC- multiwire proportional chamber, T-transfer gap, PA- preamplification gap, Gd-gadolinium converter

Table 9.

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Sensitive area Efficiency of registrations λ=1 А λ=1.8 А λ=3 А λ=4 А Spatial resolution Time resolutions (on anode) Gas mixture Producing pressure

(200-350) х 10 мм2 35% 55% 58% 59% 0.4 мм 1-3 х10-9 с. Izo-butane 5-20 torr

For example on Figure 15 the simplified plan of the one-co-ordinate detector of thermal neutrons on the basis of two multistep avalanche chambers with a natural gadolinium converter is presented. The detector will be oriented at an angle 100 to an axis of slope of a neutron beam. In table 9 detector key parameters [9] are given. The detector will possess small sensitivity to gamma – irradiation and high counting rate which will be depend by a used method of removal of the information. Efficiency of registration of the detector will be comparable with detectors on a base of 3Не convertor at much best space resolution.

2.2.4. Contribution of low-energetic electrons to general efficiency of converters In our earlier calculations we have taken into account only those electrons, which have energy higher than 29 keV. These energies of electrons have been chosen not only in our calculations, but also by other authors. Thus there were not taken into account the lowenergetic Auger electrons, i.e. Auger electrons from the L-shell with the energy of 4.84 keV and Auger electrons from the M-shell with the energy of 0.97 keV. These electrons have rather small free path length in gadolinium; these are 0.3 microns (4.84 keV) and 0.04 microns (0.97 keV). They bring a small contribution to the general efficiency at use of converters made from natural gadolinium as the free path length of neutrons in natural

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gadolinium makes tens micron. At the same time their contribution becomes rather essential at use of converters made from 157 isotope of gadolinium as the free path length of neutrons in them does not exceed 2-3 microns and this length becomes comparable with the length of free path length of electrons.

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Figure 16. Curve of dependence of electron runs in gadolinium depending on their energy, for a lowenergy range

In the literature and databases there is none data on free path length of electrons in various materials with energy less than 10 keV. All data begins with this energy. All tabular data is made on the basis of the theory Bette - Bloch and energy 10 keV is lower limit of usability of the yielded theory. For calculation of free path length of electrons of Auger in gadoliniums we had to extrapolate available data to almost zero-point energy. Effects of extrapolation are given in drawing 16. From figure it is visible that the maximum free path length of electrons with energy 4,84 keV can makes 0,3 microns, and for electrons with energy 0,97 keV can makes 0,04 microns. Similar free path length are rather small, especially in comparison with run of neutrons in natural gadolinium. In too time for converters from 157 isotopes of gadolinium run in 0,3 microns makes more than 10% from a free path length of neutrons and it can increase efficiency of converters essentially. There are different data on the quantity of Auger electrons in the literature, so the quantity of electrons from the K-shell makes from 10 up to 14% [14, 23], these data are normalized to the intensity of X-ray radiation Ka1 (KL3) which intensity is chosen for 100%. The data on the quantity of electrons from the L-shell even more differ, from 150 up to 200 [14, 23]. There are no data for electrons from the M-shell at all. At the choice of quantity of electrons from the M-subshell we started with the assumption that the quantity of Auger electrons grows at distance from a nucleus. So the quantity of electrons grows approximately 15 times at the transition from the K-subshell to L-subshell. This tendency is kept further too, i.e. from L to M-subshell and further, N and O. At the Auger effect the external electronic shells are peeled from the electrons practically completely. All data on the quantity of electrons are usually normalized to Ka1 (KL3) of Xray line, which is the most intensive one. At radiating capture of neutrons by gadolinium

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nuclei radiations of electrons of internal conversion occurs. The probability of emission of electrons of internal conversion makes approximately 60%. Auger electrons accompany emission of electrons of internal conversion as at radiation of electrons of internal conversion there vacancies on electronic shells which are filled by the electrons from the higher shells are formed. This process is accompanied by X-ray radiation and Auger electrons. In our calculations, at normalization to the quantity of neutrons, at calculation of the quantity of Auger electrons it is necessary to normalize not to Ka1 (KL3) X-ray line, but to the quantity of electrons of internal conversion, i.e., the quantity of electrons depends on factor of internal conversion. In table 10 the most intensive lines of electrons emitted during the process of radiating capture of thermal neutrons by gadolinium nuclei are presented. The data on Auger electrons L-Auger and M-Auger are added to the Table. Converters made from 157 isotope of gadolinium have an abnormal high cross-section of interaction with thermal neutrons so the cross-section makes 253778.40 barns for neutrons with the wavelength of 1.8А0. The cross-section strongly grows with the increase of neutron wavelength. Converters with the thickness of 2.5 microns absorb more than 80% of neutrons with the wavelength of 1.8А0 and more than 90% of neutrons with the wavelengths more than 3А0, see Figure 7. Another situation takes place at use of converters made from natural gadolinium. So the section of interaction makes 48149.41 barns for neutrons with the length of wave 1.8 A0. 80% of attenuation of a neutron beam (1.8А0) happens at the thickness more than 12 microns. The analysis of curves shows, that at use 157 isotope of gadolinium, the small run of Auger electrons (< 0.3 microns) can increase the general efficiency of converters essentially.

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Table 10. Electron energy (keV) 0.97 4.84 29.3 34.9 71.7 78 131.7 174.1 180.4 205.4 227.3 729.9 893.85 911.8 926.8

Electron output 1/100 n (error) >200 97(33) 35.58 7.9(4) 5.57 1.2 6.96 0.99 0.21 0.14 0.16 0.03 0.06 0.04 0.03

Electron path in gadoliniummicrons 0.04 0.3 4.7 6.29 20.7 23.78 55.70 86.27 91.23 111.47 130.27 649.38 830.05 849.83 866.35

Energy of initial gamma-quantum

79.51 79.51 79.51 181.93 181.93 181.93 255.66 277.54 780.14 944.09 960 975.4

Comments, level M-Auger L-Auger K K- Auger L M K L M K K K K K K

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Figure 17. Curves describing the efficiency of converters made from natural gadolinium depending on the thickness of the converter, taking into account the low-energy Auger electrons. The curve 1 characterizes electron emission in a direct, the curve 2 - in back hemispheres. The curve 3 is their sum

Figure 18. Curves describing the efficiency of converters made from 157 isotope of gadolinium depending on the thickness of the converter, taking into account the low-energy Auger electrons. The curve 1 characterizes electron emission in a lobby, a curve 2 - in back hemispheres. The curve 3 is their sum. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Calculations of the efficiency of gadolinium foils are carried out, at use of natural gadolinium and its 157 isotope, for four fixed wavelengths of neutrons depending on the thickness of converters. In figures 13 and 14 shows the results of calculations without taking into account of the influence of low-energy Auger electrons. In the figures, 17 and 18 show the results of similar calculations, but here the low-energy electrons taken into account. One can see from figures that with the increase of neutron wavelength the difference in the efficiencies is increased. Especially the difference is well visible at use of 157 isotope of gadolinium. So for neutrons with the wavelength of 4А0 the total efficiency grows practically by 10%. Comparison of result of calculations for a case of recording of electrons with energy is more 29 keV and more than 0.93 keV are given in the table 11. Table 11. Wave length (A)

Forward

Backward

Total

Wave length (A)

Nat

1 1.8 3 4

Backward

Total

157

0.107 0.2324 0.2854 0.3195

1 1.8 3 4

0.107 0.2527 0.3127 0.352

1 1.8 3 4

Gd (E> 29 keV) 0.1262 0.1686 0.2098 0.258 0.2319 0.2772 0.2443 0.2865 157 Gd (E> 0.93 keV) 0.1402 0.1851 0.2342 0.3103 0.2633 0.3501 0.2848 0.3756

0.2948 0.4678 0.5091 0.5308 0.3253 0.5445 0.6134 0.63

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1 1.8 3 4

Gd (E> 29 keV) 0.0435 0.0635 0.0967 0.1357 0.1218 0.1636 0.1379 0.1816 Nat Gd (E> 0.93 keV) 0.0462 0.068 0.1063 0.1464 0.1335 0.1792 0.1509 0.2011

Forward

Figure 19 Comparison of the results of our calculations with the experimental data presented in the paper [38]. Calculations are conducted for two boundary energies of taken into account electrons; higher than 29 keV and higher than 0,93 keV. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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The received data were compared with the experimental data given in the paper[38]. In this work the experimental data on the efficiency of detecting of neutrons emitting in a back hemisphere for 6 various energies and their comparisons with the calibrated 3He counter are received. In this work converters made from natural gadolinium and enriched up to 90,5% 157 Gd were used. The work was carried out on the reactors of Atominstitut in Vienna (ATI) and the ILL Grenoble (Figure 19). One can see from the figure that in the case of the account of the contribution of lowenergy Auger electrons (electrons with the energy > 0.93 keV) the results of our calculations well coincide with the experimental data. This concurrence is well visible for the converters made from 157 isotope of gadolinium. If we do not take into account the low-energy electrons the curve lays much below experimental data.

2.2.5. Contribution of X-rays and soft gamma radiations on general efficiency of converters At calculations of the efficiency of converters it is necessary to take into account all secondary electrons. Earlier we took into account only internal conversion electrons and Auger electrons. But in the process also secondary electrons appearing during absorption of X-ray radiation and gamma-quanta can participate. These are photoelectrons, Compton electrons, electron-positron pairs. During radiation of electrons of internal conversion vacancies on electronic shells which are filled by electrons from higher shells are formed. At their filling X-ray quanta or Auger electrons are radiated. We have estimated the contribution of X-ray and low-energy gamma-quanta absorbed directly in the material of the converter and resulting in occurrence of secondary electrons. At practical calculations absorption of quanta in materials of detectors also should be taken into account. At such calculation total efficiency can appear higher, as the part of electrons can be formed from quanta in a material of the detector. In the calculations we take into account only an escape of electrons from a material of the converter. Internal conversion coefficient is defined as follows:

 ik 

I I

,

(37)

where Ie is the intensity of conversion electron, and Iγ is the intensity of gamma radiation. Iγ is well known (table 3). Energy of emitted electrons defined by energy of outcoming gamma quantum and bound energy of electrons on the atom subshells

Ee  E  Ebi

,

(38)

where, Ee is the energy of outcoming electron, Eγ – energy of gamma quantum, Ebi- bound energy of electrons on the atom shells. By knocking out electrons, an electron hole (vacancy) is formed, which is filled by electrons from higher levels. During vacancy filling X-ray radiation, with the energy equal to the difference of bound energies at corresponding levels, is radiated

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E x  Ebi  Ebj

,

(39)

where Ex is the energy of X-ray radiation, Ebi and Ebj are bound energies of electrons at the corresponding atomic levels. Energy of excitation of atom can be removed, also due to the emission of Auger electrons. These electrons are emitted instead of X-ray quantum and possess energy equal to the energy of X-ray quantum minus bound energy of electron at the corresponding level

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Table 12. X-Ray Energy (keV) 181.931 79.510 42,996 42,309 41,864 48,695 49,959 48,551 50,099 49,038 50,219 6,058 6,026 6,713 7,102 6,832 6,687 7,243 6,867 7,79 8,087 8,105 7,93 6,049 5,362

Shell Comments

Intensity (1/100 Vacancies)

Gamma Gamma Kα1 Kα2 Kα3 Kβ1 Kβ2 Kβ3 Kβ4 Kβ5 KO2,3 Lα1 Lα2 Lβ1 Lβ2,15 Lβ3 Lβ4 Lβ5 Lβ6 Lγ1 Lγ2 Lγ3 Lγ6 Lη L1

47,5 26,6 0,00824 9,3 3,11 4,81 0,038 0,146 0,45 6,3 0,7 3,9 1,32 0,126 0,077 0,0108 0,063 0,67 0,024 0,034 0,0055 0,092 0,266

Intensity [1/100 neutrons] 139(6) 77.3(19) 28,5 15,96 0,004944 5,58 1,866 2,886 0,0228 0,0876 0,27 3,78 0,42 2,34 0,792 0,0756 0,0462 0,00648 0,0378 0,402 0,0144 0,0204 0,0033 0,0552 0,1596

Eea  E x  Ebi where Eea– energy of Auger electron.

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(40)

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In table 12 are given both the most intensive X-ray and gamma-lines their relative escape on 100 formed vacancies [41]. We have made calculation of X-ray quanta on 100 captured neutrons (the data are presented in the table also). The output of X-ray quanta on 100 formed vacancies is represented in the figure 20. From figure one can see, that the most intensive are K-lines 42.3 and 43 keV. The most interesting are low-energy L-lines however their output is strongly suppressed by irradiated Auger electrons. During the passage of X-ray quanta through a material of the converter there absorption occurs. The degree of their absorption is described by the mass factor µ/ρ of attenuation of X-rays. A narrow beam of monoenergetic photons with an incident intensity Io, penetrating a layer of material with mass thickness x and density ρ, emerges with intensity I given by the exponential attenuation law

.

(41)

Equation (41) can be rewritten as

(42)

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from which µ/ρ can be obtained from measured values of Io, I and x.

Figure 20. Amount of X-ray photons depending on their energy, which formed, on 100 vacancies in electron subshell of Gadolinium.

Note that the mass thickness is defined as the mass per unit area, and is obtained by multiplying the thickness t by the density ρ, i.e., x = ρt. Present tabulations of µ/ρ rely heavily on theoretical values for the total cross section per atom, σtot, which is related to µ/ρ according to

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.

(43)

In (eq 3), u (= 1.660 540 2 × 10-24 g) [43] is the atomic mass unit (1/12 of the mass of an atom of the nuclide 12C), A is the relative atomic mass of the target element, and σtot is the total cross section for an interaction by the photon, frequently given in units of b/atom (barns/atom), where b = 10-24 cm2. The attenuation coefficient, photon interaction cross sections and related quantities are functions of the photon energy. Explicit indication of this functional dependence has been omitted to improve readability. The total cross section can written as the sum over contributions from the principal photon interactions,

,

(44)

where σpe is the atomic photoeffect cross section, σcoh and σincoh are the coherent (Rayleigh) and the incoherent (Compton) scattering cross sections, respectively, σpair and σtrip are the cross sections for electron-positron production in the fields of the nucleus and of the atomic electrons, respectively, and σph.n. is the photonuclear cross section. Accordingly µ/ρ can be represented as following

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.

(45)

Values of the mass attenuation coefficient, µ/ρ, for the mixtures and compounds (assumed homogeneous) were obtained according to simple additive:

,

(46)

where wi is the fraction by weight of the ith atomic constituent. The methods used to calculate the mass energy-absorption coefficient, µen/ρ, are described perhaps more clearly through the use of an intermediate quantity, the mass energytransfer coefficient, µtr/ρ. Mass factors of absorption of X-ray quanta for various materials are represented in the tabulated data [43]. On the Figure 21 the dependence of µ/ρ on energy of quanta is depicted. In figure peaks and edges of absorption of electronic subshells K, L, M are well visible. Absorption of quanta strongly depends on their energy. Low-energy quanta are absorbed most intensively, however formed secondary electrons are also the low-energy ones and have rather small run in a material of the converter. In the figures below, dependences of formation of secondary electrons on depth of penetration of quanta are given. Amounts of formed electrons are given without taking into account their absorption in a material of the converter (an integral one).

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Figure 21. Dependence of mass factor of absorption of quanta on their energy for gadolinium [43]

Figure 22. Dependence of number of formed electrons on thickness of the converter. For quanta with the energy range 6 up to 7 keV Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 23. Dependence of number of formed electrons on thickness of the converter. For quanta with the energy range from 7 up to 8 keV

In figure 24 the integrated characteristic of formation of secondary electrons is presented. The low-energy quanta form mainly photoelectrons, and gamma-quantum with the energy 181.9 forms Compton electron. The low energy quanta with the energy range from 5 and up to 9 keV form low-energy electrons, the maximal free length path of which in gadolinium are accordingly equal to 0.4 and 0.6 microns for quanta with the energy 5 and 8 keV. At calculation of electron escape the quanta formed in a layer, which is a little thicker, than a maximal free length path of electrons for the given energy, are taken into account only. In the table the new data, on electrons which are added by the data on secondary electrons formed as a result of X-ray and low-energy quanta absorption. These electrons are designated in the comment as X.

Figure 24. Dependence of the number of secondary electrons depending on energy of quanta

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The contribution of photoelectrons to a total sum of electrons for each value of energy does not exceed 2%. And their total amount does not exceed 0.97 electrons on 100 incident neutrons that is 1% less. Calculations of the contribution of photoelectrons in general efficiency of gadolinium converters are carried out. Results of calculations give on Figure 25. From the figure one can see that in the case of the account of the contribution of electrons formed by X-ray quanta, the efficiency is increased a little, but their contribution is insignificant. The increase occurs for no more than by 1%. It is rather possible, that X-ray quanta can essentially affect on the total efficiency at the account of their absorption in a material of detectors. So gas detectors with Argon filling can increase efficiency essentially. If the conversion of quanta will occur in a working body of the detector, therefore the full gathering of formed secondary electrons will take place. They can render even greater influences in the case of use of semi-conductor detectors. Table 13.

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Energy of electrons (keV) 0.97 4.84 5-8 29.3 29,3 34.9 34,9 71.7 78 78 131.7 131,7 174.1 180.4 205.4 227.3 729.9 893.85 911.8 926.8

Electron escape 1/100 n (error) >200 97(33) 0,2 35,58 0,18 7.9(4) 0,18 5,57 1,2 0,03 6,96 0,38 0,99 0,21 0,14 0,16 0,03 0,06 0,04 0,03

Electron run in gadolinium (µm)

0,04 0.3 0,4 - 0,6 4,7 4,7 6,29 6,29 20,7 23,78 23,78 55,70 55,70 86,27 91,23 111,47 130,27 649,38 830,05 849,83 866,35

Energy of initial gamma-quantum

79.51

79.51 79.51 181.93 181.93 181.93 255.66 277.54 780.14 944.09 960 975.4

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Remarks, level

M-Auger L-Auger X K X K- Auger X L M X K X L M K K K K K K

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Figure 25. Comparisons of our theoretical calculations with the experimental data give in the paper [38]. Calculations are carried out for two boundary energies taken into account electrons; more than 29 keV and more than 0.93 keV and in view of the contribution of secondary electrons formed by X-ray and low-energy gamma-quanta (a dashed line)

2.3.1. Modeling of converters representing sandwiches, from supporting films and converters Recently more often started to apply widely solid-state converters of thermal neutrons of complicated forms, such as bilateral converters made from thin gadolinium with supporting film made from kapton, neutron converters on the base of GEM-structures and others, which manufacturing techniques consist in drawing of thin gadolinium converters (0.5-5 microns) on the surfaces of film made from kapton with the thickness of 5-100 microns. Such converters allow manufacturing detectors of the big areas. Presence of supporting films results in additional reduction of secondary electron escapes, at the same time the use of bilateral converters allows to increase conversion of neutrons, at use of two detectors from both sides of the converter. Modeling of efficiency of registration of thermal neutrons by these kinds of converters is an interesting problem and during its development one can expect occurrence of new converters. Modeling of the efficiency of registration of thermal neutrons by the converters, which represent kapton film, serving for support of thin gadolinium layers is carried out. Layers can be settled down on one, or on both sides of supporting film. Calculations are made for natural gadolinium and its 157 isotope, for four fixed energies of neutrons. In calculations electrons with energy more than 29 keV were considered only. Attenuation of electron flux arising in the reaction of radiating capture of neutrons by gadolinium nucleus occurs both in the substance of the converter and in kapton film. On Figure 26 curves of probabilities of electron flux output for gadolinium and kapton are given. These curves characterize absorption of electrons in these substances.

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Figure 26. Probability of electron output, formed in the reaction of radiating capture of thermal neutrons by gadolinium nuclei, from kapton and gadolinium

Figure 27. Efficiency of complex converters made from thin gadolinium (1 micron) put on a substrate from kapton, depending on thickness of a substrate. Various curves characterize wavelengths of neutrons Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Contributions of various energies of electrons which are well visible it is conditionally possible to part on 4 groups. In first group the least energetic and having small run in substance in the fourth most energetic electrons, Figure 7. Calculations of efficiency of converters with the thickness of 1 micron made from natural gadolinium and its 157 isotope, for four fixed neutron wavelengths are carried out. Calculations were performed for the case, when only one thin converters were directly settled on the films made from kapton of various thicknesses, Figure 27. This kind of geometry is characteristic for a case of drawing of thin converting films (0.5-3 microns) on supporting substrates made from kapton. Thickness of supporting films as usual is chosen within the limits of 5-100 microns. Model calculations of converters like the developed and used in DETNI project in HahnMeitner-Institut (HMI) are carried out. The detector and the converter are described in the paper [44]. The detector‘s size is 285 х 285 мм2 and it is shown on the Figure 28. Each segment consists of centrally located converter consisting of 157Gd/CsI foil. Converters are located from both sides of supporting foil. Thicknesses of converters lay in the range from 0.5 - up to 1.5 microns of 157Gd. CsI is used for thermalization of electron energy as an emitter of secondary electrons, and has thickness less than 1 micron. Necessity of the use of secondary emitter CsI caused by the reason that there plane-parallel chambers of low pressure are used in the detector. Electrons escaping from the converter have enough big range in low pressure gases, which can result in appreciable deterioration of the spatial resolution.

Figure 28. The scheme of the detector used in article []. The converter consists of a supporting film executed of kapton film from which two sides of its two gadolinium converter were placed

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Calculations of efficiency of registration of neutrons by gadolinium foils in this kind of geometry are carried out. Calculations were carried out for converters made from natural gadolinium and its 157 isotope, for 4 fixed neutron wavelengths. Thickness of converters varied from 1 up to 3 microns. Possible efficiency of converters with emission of electrons in 4π geometry without taking into account attenuation in kapton was taken into account Calculations are made for electrons with energy more than 29 KeV. At calculations the secondary emitters of electrons executed on the basis of crystals CsI were not considered. In figure 31effects of calculations of efficiency of gadolinium foil in simple geometry are given. Calculations were made for one foil without supporting films. Efficiency for converters from natural gadolinium grows with enlargement of a thickness. At use converters from 157 isotopes of gadolinium efficiency for electrons departs in a back hemisphere not significant growth. For electrons departing for a forward hemisphere even efficiency decrease is observed

Figure 29. Efficiency of registration of neutrons with wavelengths 1, 1.8, 3 and 4 А0 for natGd and 157Gd for converters with the thickness 1, 2 and 3 microns without supporting films Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 30. Efficiency of the complex converter for a case of electron output to the forward and back hemispheres is given. Thickness of the converter from 157 Gd is 1, 2 and 3 microns, thickness of kapton is 10 microns. Wavelength of neutrons is 1.8 А0

Figure 31. Efficiency of the complex converter for a case of electron output to the forward and back hemispheres is given. Thickness of the converter from 157 Gd is 1, 2 and 3 microns, thickness of kapton is 50 microns. Wavelength of neutrons is 1.8 А0

For the this complicated converter, at an arrangement of the converters from both sides of supporting film, the part of neutrons will be converted in the first converter and a part in the second. From the first converter electrons emitting to the back hemisphere will be registered,

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they will be registered by the forward chamber. From the second converter electrons emitting to the forward hemisphere will be registered, and they will be registered correspondingly by the back chamber. These processes will be the primary. At the same time a part of high energy electrons can penetrate through the supporting film and will be registered by the next chamber. This process can increase total efficiency of registration a little. One can see from the Figure 30-31 that the optimal thickness for electron escape to a back hemisphere is the thickness of 2 microns for gadolinium-157 films. Up to 3 microns of thickness growth of efficiency is observed, however this converter is a lobby one and the further increase of its thickness will result in shielding the second converter. For the second converter (escape of electrons to the forward hemisphere) an optimum thickness is 2 microns, as the further increase of thickness does not result in increase of efficiency. Figure shows, that at use of 157 isotope of gadolinium the main absorption of neutrons occurs on the forward converter. The second converter is substantially shielded by the first converter. Similar calculations conducted also for converters made from natural gadolinium; results of these calculations presented in figures 32 and 33. Calculation of efficiency thin gadolinium converters is made in view of their attenuation in kapton. Thus thickness of the kapton film (from 10 up to 50 microns) and thickness of gadolinium (from 1 up to 3 microns) were varied. From the Figure 30 and 31 one can see, that the optimal thickness for an electron emission to the back hemisphere is gadolinium 157 thickness of 2 microns. Up to the thickness of 3 microns growth of efficiency is observed, however this converter is a lobby and the further increase of its thickness will result in shielding the second converter. For the second converter (electron emission to the forward hemisphere) an optimum thickness is 2 microns as the further increase of thickness does not result in increase of efficiency. The optimal thickness for a kapton film is the thickness of 10 microns. With the growth of thickness the secondary electron escape falls. Especially it has an effect at registration electrons emitted to the forward hemisphere. In table 14 contributions of each of 2 converters in the efficiency of the back (2 detector) detector, an electron emission in the forward hemisphere are shown. For a case of use of converters made from 157 gadolinium isotope. Neutron wave length is 1.8 А0. In table 15 contributions of each of 2 converters in the efficiency of the forward detector (1 detector), an electron emission to the back hemisphere are presented. For a case of use of converters made from 157 gadolinium isotope. Neutron wave length is 1.8 А0. In table 16 contributions of each of 2 converters in the efficiency of the back detector, an electron emission to the forward hemisphere are presented. For a case of use of converters made from natural gadolinium. Neutron wave length is 1.8 А0. In table 17 contributions of each of 2 converters in the efficiency of the forward detector, an electron emission to the back hemisphere are given. For a case of use of converters made from natural gadolinium. Neutron wave length is 1.8 А0. Calculations of efficiency of these kind converters are carried out in case of their cascading. Converters will be located the one above the other, thus each subsequent converter will be shielded by the previous converters. The case of use of 3 converters is considered. This kind of scheme is not applied in practice, since does not allow transferring electrons through converters to the detector. However the case is interesting for calculations because it allows estimating a degree of shielding of the subsequent converters.

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Figure 32. Efficiency of the complex converter for a case of electron output to the forward and back hemispheres is given. Thickness of the converter from nat Gd is 1, 2 and 3 microns, thickness kapton is 10 microns. Neutron wavelength is 1.8 А0.

Figure 33. Efficiency of the complex converter for a case of electron output to the forward and back hemispheres is given. Thickness of the converter from nat Gd is 1, 2 and 3 microns, thickness kapton is 50 microns. Neutron wavelength is 1.8 А0

In figures 34 and 36 the contribution of each converter for a thickness of the kapton film in 10, 20 and 50 microns is shown. One can see from these figures that at use of gadolinium157, the basic conversion of neutrons will occur on the first converter. The subsequent converters will be substantially shielded. In figures 35 and 37 total efficiency of similar converters is shown.

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Application of the Gadolinium Foils as a Converters of Thermal … Table 14. Kapton Thickness, microns

Geometry, microns

10

1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3

20

30

40

50

Contribution of converters in the efficiency (forward electron emission) 2 detector 1 layer Escape from the 1 layer in view 2 layer of attenuation 0.160 0.070 0.074 0.208 0.091 0.045 0.202 0.089 0.020 0.160 0.032 0.074 0.208 0.042 0.045 0.202 0.041 0.020 0.160 0.028 0.074 0.208 0.037 0.045 0.202 0.036 0.020 0.160 0.025 0.074 0.208 0.032 0.045 0.202 0.031 0.020 0.160 0.021 0.074 0.208 0.027 0.045 0.202 0.026 0.020

Total of both converters Total of both converters 0.144 0.136 0.109 0.106 0.087 0.061 0.102 0.082 0.056 0.099 0.077 0.051 0.095 0.072 0.046

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Table 15. Kapton Thickness, microns

Geometry, microns

10

1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3

20

30

40

50

Contribution of converters in the efficiency (back electron emission) 1 detector 1 layer 2 layer Escape from the 2 layer in view of attenuation 0.161 0.062 0.027 0.223 0.031 0.014 0.246 0.011 0.005 0.161 0.062 0.012 0.223 0.031 0.006 0.246 0.011 0.002 0.161 0.062 0.011 0.223 0.031 0.005 0.246 0.011 0.002 0.161 0.062 0.010 0.223 0.031 0.005 0.246 0.011 0.002 0.161 0.062 0.008 0.223 0.031 0.004 0.246 0.011 0.001

Total of both converters Total of both converters 0.188 0.237 0.251 0.173 0.229 0.248 0.172 0.228 0.248 0.171 0.228 0.248 0.169 0.227 0.247

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Kapton Geometry, Thickness, microns microns 10

20

30

40

50

1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3

Contribution of converters in the efficiency (forward electron emission) 2 detector 1 layer Escape from the 1 layer in view of 2 layer attenuation 0.041 0.018 0.035 0.069 0.030 0.052 0.087 0.038 0.056 0.041 0.008 0.035 0.069 0.014 0.052 0.087 0.017 0.056 0.041 0.007 0.035 0.069 0.012 0.052 0.087 0.015 0.056 0.041 0.006 0.035 0.069 0.011 0.052 0.087 0.013 0.056 0.041 0.005 0.035 0.069 0.009 0.052 0.087 0.011 0.056

Total of both converters Total of both converters 0.053 0.082 0.094 0.043 0.066 0.073 0.042 0.064 0.071 0.041 0.063 0.069 0.04 0.061 0.067

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Table 17. Kapton Thickness, microns

Geometry, microns

10

1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3 1+1 2 +2 3+3

20

30

40

50

Contribution of converters in the efficiency (back electron emission) 1 detector 1 layer Escape from the 2 layer in 2 layer view of attenuation 0.040 0.013 0.029 0.069 0.014 0.033 0.089 0.011 0.025 0.040 0.006 0.029 0.069 0.007 0.033 0.089 0.005 0.025 0.040 0.005 0.029 0.069 0.006 0.033 0.089 0.004 0.025 0.040 0.004 0.029 0.069 0.005 0.033 0.089 0.004 0.025 0.040 0.004 0.029 0.069 0.004 0.033 0.089 0.003 0.025

Total of both converters Total of both converters 0.053 0.083 0.1 0.046 0.076 0.094 0.045 0.075 0.093 0.044 0.074 0.093 0.044 0.073 0.092

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Figure 34. Efficiencies of each of the complex converters at their sequence cascading. For an application case of kapton thickness 10 micron

Figure 35. Summary efficiency of the complex converter at their sequence cascading. For an application case kapton a thickness 10 micron

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Figure 36. Efficiencies of each of the complete converters at their sequence cascading. For an application case of kapton thickness 50 micron

Figure 37. Summary efficiency of the complex converter at their sequence cascading. For an application case kapton a thickness 50 micron

2.2.6. Modeling of converters executed from a set of thin drilling converters The new solid-state converter of thermal neutrons is offered. The converter will consist of a set of thin gadolinium foils located one over other in a gas volume. Foils there will be drilled with the fine step (2 mm) with diameter of apertures 1 mm. These foils will have an optical transparency of 40%; correspondingly, gadolinium will fill 60% of a surface. Secondary electrons will emit for all sides, and in an electric field they will be entice up in

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holes and further drift in the direction of the detector. As a detector there a various gas detectors, such as the multi-wire proportional chamber, multi-step avalanche and multi-strip detectors, and so on, can be used. The schematic sketch of this kind of detector is shown on the Figure 38. On the Figure 39 the cross-section of the detector is shown. Technologically this kind of converter can made from foils with the thickness more than 5 microns. However, more thin foils are also of interest for calculations. The distance between the foils can be chosen in a range from 0.2 up to 2 mm. For avalanche detectors working at normal atmospheric pressure the distance of 0,2 mm will be enough for secondary electron formation. Secondary electrons, having small energy, will drift on the direction of electric field to the detector. Selecting an intensity of the electric field it is possible to achieve an effective transfer of electrons to the drift gap and further to the detector. This kind detector will have not so good spatial resolution, which will be modulated with the step of apertures (in this case 2 mm). For the series of tasks this resolution is sufficient. In order to improve the spatial resolution one should prepare foils with finer step, correspondingly, with the smaller diameter of apertures. Calculations of this kind collimator are carried out. In calculations only conversion and Auger electrons with the energy higher than 29 keV isotropic emitting to the all sides were considered. Efficiency for each foil and their sum were separately calculated. In the figures 40 and 42 results of calculations for the converters made from natGd with the thicknesses of 5 and 10 microns correspondingly, presented. Efficiency is calculated for each foil separately. At absorption of neutrons by lobby foils, a neutron flux to the subsequent foil falls. It results in shielding of foils. The greatest efficiency can be received for foils with the thickness in 1 micron. At use of a foil with the thickness more than 5 microns the efficiency decreases due to a loss in secondary electron escape. In figures 41, 43 total efficiency is shown. For calculations is in interest only converters from natural gadolinium as it can increment their total efficiency.

Figure 38. A schematic sketch of the detector consisting of the complex converter made from drilled by fine step foils located one over other in the same gas volume Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 39. Scheme of the complex detector

Figure 40. Efficiency of everyone of the subsequent drilled converter from 5 microns thickness natural gadolinium with an optical transparency of 40% Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 41. Summary efficiency of the converter consists from 10 drilled foilsг of natural gadolinium with a thickness of 5 micron

Figure 42. Efficiency of everyone of the subsequent drilled converter from10 microns thickness natural gadolinium with an optical transparency of 40% Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 43. Summary efficiency of the converter consists from 10 drilled foils of natural gadolinium with a thickness of 10 micron

3. POSITION SENSITIVE DETECTORS OF TERMAL NEUTRONS WITH GADOLINUM CONVERTERS The idea of using thin foils to convert neutrons radiation into charged particles and count the conversion products in a solid-state detector was originally proposed by Feigl and Rauch [4,5]. They employed natural Gd and pure l57Gd convertor foils and measured the escape probabilities and the energy distributions of the escaping electrons with Si surface barrier detectors. Jeavons et al. [6] applied a multiwire proportional chamber (MWPC) for the amplification and imaging of the secondary charged particles and discussed convertor materials other than Gd. To reduce the position broadening due to the large angular spread and finite range of the escaping fast electrons, a "high-density" drift space used as initial stage of the detector. This stage is essentially a multi-pinhole collimator where along each pinhole an electric field can established to drift the secondary ionization products towards the amplification and imaging stage. However, the finite size of the pinholes limits the position resolution and the comparably large mass of the collimator increases the γ-ray sensitivity and reduces detection efficiency. Melchart et al. [8] proposed a multistep avalanche chamber atmospheric pressure for imaging the electrons escaping from a Gd foil. The exponential avalanche growth in the

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parallel gap preamplification stage makes the detector more sensitive to charges produced near the entrance point of the particle track into the gas volume, thus ensuring a good localization of the neutron interaction in the thin convertor foil. Indeed, they achieved a position resolution better than 1 mm (FWHM). The resolution was therefore found to be pulse-height dependent and the best spatial resolution was obtained only by restricting the amplitude range and thus the detection efficiency of the detector. We also have developed and made normal pressure MSAC with converter of natural gadolinium. Thus in operations we have made detailed studying of performances MSAC. Possibilities stabilization of operation, influence of separate devices of detectors constructions on performances of detectors studied. As a result, it was possible to refine considerably performances of detectors and to obtain long-term stability in-process detectors. Breskin et al. [45] makes further step in development of multistep avalanche chambers they was development of low-pressure multistep avalanche chambers. In one of our publication, possibility of reception of a regime of a preamplification in the low-pressure multiwire proportional chambers also has shown at usage additional plain-parallel gap disposed on top the MWPC [46]. Dangendorf et al. [47] has offered for the first time low pressure MSAC with gadolinium converter. It thus offered to use developing techniques to increase the low-energy secondary electron emission of the convertor foil. Despite the exponential growth of the avalanche in the first multiplication stage, the localization resolution of neutron detectors based on lowpressure multistep avalanche chambers depends on the direction and range of the neutroninduced charged particles. Moreover, for weakly ionizing particles (like the conversion electrons from Gd) the detection efficiency depends on the probability of creating at least one slow ionization electron in the first few hundred micrometer thick gas layer of the preamplification gap. An increase in the number of charges produced close to the convertor surface would improve the localization resolution and the detection efficiency. Gebauer et al. [44] offered fast and high-resolution hybrid low-pressure micro-strip gas chamber (MSGC) detectors and being developed, which lend themselves for setting up largearea detector arrays. Abbrescia et al. [48] offered Resistive Plate Chambers (RPCs) wide spread, cheap, easyto-build and large size detectors. Here a technique, consisting in coating the inner surface of the bakelite electrodes with a mixture of linseed oil and Gd2O3 reported. This allows making RPCs sensitive also to thermal neutrons, making them suitable to employ for industrial, medical or de-mining applications. Thermal neutron-sensitive RPCs can operated at atmospheric pressure, are lightweighted, have low -ray sensitivity and are easy to handle even when large areas have to be covered. Takahashi et al. A new series of experimental imaging plate neutron detectors (IP-NDs) were made, where the composition of the respective IP-NDs, containing a photostimulable BaFBr:Eu2+ phosphor and a neutron converter material, Gd203 or 6LiF, were varied systematically [49]. The different conversion processes between natural abundant Gd and 6Li caused distinct imaging properties. The imaging steps and the factors governing the image quality are considered in the same way as X-ray radiography, and the quantum noise is estimated by the effective neutron absorption in these IP-NDs when they read by a BAS2000 image reader. Gunji et al. [50] have been developing a new type of neutron imaging detector with position resolution better than 10 micrometer by absorbing liquid scintillator for neutron

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capture into a capillary plate by capillary phenomena. Establishing the methods to absorb liquid scintillator to the capillary plate and attaching it into a photomultiplier, we irradiated the detector with neutrons and alpha particles. From the results of basic experiments, it recognized that the capillary plate absorbing liquid scintillator could operate as a neutron detector. Bruckner et al. [38] have been developing position sensitive silicon detectors and the corresponding electronics allow the construction of fast time response thermal neutron detectors. These detectors also exhibit excellent position resolution by combination of silicon detectors with thin Gd converter foils. Authors constructed several one- and two-dimensional prototype detectors. The position resolution and the detector efficiency for different converters at wavelengths from 1.1 to 3.3 A0 were determined at the TRIGA reactor in Vienna and at the ILL in Grenoble. Spatial resolutions of less than 100 μm and efficiencies up to 40% have achieved. These detectors can also used for phase topography experiments using perfect crystal neutron interferometers.

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3.1. Normal Presure Multistep Avalanche Chamber A multistep avalanche chambers (MSAC) consists of a conventional MWPC placed within a single gaseous volume with additional grid electrodes forming preamplification and drift spacing. Gadolinium converter settles down directly ahead of a preamplification grid. MSAC registers electrons escaping off in a back hemisphere. In the preamplification gap, there forms an electron-photon avalanche, which transferred to MWPC for terminal amplification and registration. Due to the exponential amplification in the preamplification gap there is implemented a tie of coordinates to the entrance point of particles to the detector volume. The spatial resolution of MSAC can be improved by the amplitude analysis and the consequent mathematical processing of events up to 0,2-0,3 µm. The gas amplification coefficient of MSAC is of the order 106-7, which provides registration of single electrons with practically zero energy. The registration efficiency of the MSAC-based detectors mainly defined of converter‘s characteristics. In the Physical Technical Institute of Academy of Sciences of Republic Tajikistan, the detector based on MSAC with natural Gadolinium converter is developed and created. Appearance of the detector showed in figure 45. The basic parameters of detectors are: sensitive volume - 200x200 mm, gaseous mixture Ar + (1,5%) of n-geptane, operation pressure - 1 atm, detection efficiency (at λ=1.8A0)-35%, spatial resolution- 104 rare spark disruptions in a preamplification gap observed. With magnification of an amplification values intensity of spark disruptions is incremented. At Gpr> 105 the continuous spark discharge localized under a radiation sources is observed.

Figure 47. Factor of preliminary amplification in dependence on high voltage on pre-amplification gap. A gas mix of argon with 1,6% of acetone (a curve 1) and 3% of acetone (a curve 2) Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Value of coefficient of preamplification gain can reach quantities 105, at registration γquanta with energy of 6 KeV. It is necessary to note that at quantities Gpr> 104 rare spark disruptions on the area in a preamplification gap observed. At definition of the full coefficient of preamplification gain in a gap, it is necessary to consider losses of electrons while transferring avalanches in the drift gap. For a relation of fields of the drift and preamplification gap 1/5 full value Gpr = 5*105 that corresponds to value of coefficient α = 4,4 mm-1. Common amplification gain of MSAC taking into account amplification in MWPC can reach values G = 106 -107. At Gpr > 106 the recurring operation, MSAC caused by a photon feedback observed. A part of the ultraviolet quanta formed in MWPC, can reach a Gd converter, causing occurrence of photoelectrons from materials, impulses from which observed through 1μs after the first occurrence. At Gpr> 107 avalanche develops into a streamer that comes to a spark disruption in MSAC. Examinations efficiency registration and the time resolution spent on a gas intermixture of argon with 2% of acetone. Extent of a plateau counting rates studied at registration γquanta 55Fe. On Figure 7 given extends of plateau counting rates of signals from anode MWPC at various values electric field strength of a preamplification gap depending on quantity electric voltage on the anode MWPC (Ua). The curve 1 on Figure 48 measure at low intensity of Epr, thus an avalanche did not develop and only transfer electrons from conversion to the drift gap, carried out. At Epr = 8- 10 kV/cm quantity Gpr essentially increases that considerably increments extent of a plateau counting rates (curves 2-4). It is visible that the plateau reaches quantities 800 V in at value Gpr 104. Efficiency of registration of charged particles with the minimum ionization losses was explored with β - particles 90St (Emax = 0,53 MeV). On Figure 49(A) observed dates depending on quantity of anode voltage MWPC for the various field gradients in a preamplification gap presented. Measuring spent in the absence of a conversion gap. At enough high values of Epr with efficiency ~ 98% register the detector β - particles, quantity of a plateau makes 300 V.

Figure 48. Counting characteristics of the detector at registration γ-quanta 55Fe on dependence on high voltage on MWPC. Value Еpr is equal 2 kV/cm (1); 8,3 kV/cm (2); 9,0 kV/cm (3) and 9,7 kV/cm (4)

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Figure 49. Efficiency of the detector at registration β- radiations depending on voltage on MWPC. Value Еpr is equal 8,3 kV/cm (1); 9,0 kV/cm (2); 9,7 kV/cm (3); 10 kV/cm (4). A - the detector without conversion gap; B - size of gap АВ = 1 mm

As it told above, quantity Gpr for the electrons of secondary ionization formed in different points on a thickness of a preamplification gap is various. Introduction of a conversion gap by quantity of 1 mm leads to magnification of a plateau of efficiency of the detector and allows reducing value of necessary anode voltages.

3.1.3. Spatial resolution of the multistep avalanche chambers Multistep avalanche chambers (MSACs), as well as plane-parallel avalanche detectors, surpass of the ordinary multiwire proportional chambers (MWPCs), their high accuracy in determining coordinates along both the X – and Y- axes, the presence of the so-called ―focusing effect‖ (i.e., the coordinates of the point at which a particle hits the detector‘s sensitive volume are measured) and a high gas amplification coefficient. An electron–photon avalanche that develops in the preamplification gap transferred through the drift gap to the MWPC for further amplification and detection. Coordinate data read out of the MWPC cathodes via delay lines, and the anode signal can used for amplitude selection of events. The path of photoelectrons, Auger electrons, and fluorescent quanta limit the spatial resolution of gas-filled position-sensitive detectors (GFPSD) for a narrow collimated γ-ray beam. For example, 5.9-keV γ-rays are converted in argon, mainly on its K subshell with a 3.2-keV ionization potential escaping photoelectrons with an energy of 2.7 keV have a range of 30 μg/cm2 (i.e., 250 μm of argon at normal pressure and temperature). A fluorescent

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quantum is produced in 88% of events; its energy is 3.2 keV and its mean free path in argon is ~40 mm. Absorption of a fluorescent quantum inside the detector results in emission of an electron with an energy of 3 keV and a range of 250 μm. Let us consider the effect that the photoelectron range exerts on the spatial resolution of a GFPSD. Conversion of γ- rays assumed to occur at one point, and detection efficiency for fluorescent quanta thought to be low and can ignored. Photoelectrons escaping from the conversion point in all directions form a spherical cloud of secondary electrons with radius Re equal to the photoelectron range. The full width at half-maximum (FWHM) of the projection of this cloud onto the plane of the detector is 3/2 Re. The dependence of the spatial resolution on the electron energy can also found from the empirical formula in [51]: σ (μm) = a Ee n/ρ,

(51)

Where Ee [keV] is the electron energy; ρ [mg/cm2] is the specific density of the detecting medium; and the coefficients have the following values:

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a= 30, n= 1.30 for Ee= 1–5 keV and a= 17, n= 1.64 for Ee= 5–20 keV. Apart from the photoelectron range, the spatial resolution is dependent on other factors too, particularly on the resolutions of the delay line and the data acquisition electronics. The spatial resolution of the MSAC investigated by using a highly collimated (slit width, 50 μm) 55Fe source, which was moved over the detector surface. The experimental results presented in Figure 50. The FWHM was 400 μm. Taking into account the contributions of Re and the collimator, the intrinsic resolution of the detector was 260 μm (FWHM) [52]. When MWPC detects charged particles from an isotropic emitter, such as Gd converters, its spatial resolution is rather poor. This explained by the fact that, in the case of oblique incidence, secondary electrons produced along the track of electrons form an extended cloud of charges that collected onto the MWPC anode plane and the center of this cloud is displaced from the particle‘s hit point through a significant distance. As distinct from the conventional MWPC, gas amplification in the pre-amplification gap of the MSAC obeys the exponential law; therefore, the first electrons produced in the upper layer of the gap were responsible for ~80% of the whole signal amplitude. This improves substantially the spatial resolution of the MSAC for isotropic radiation and gives rise to the so-called ―collimating‖ effect characteristic of the MSAC.

Figure 50. Spatial resolution of the MSAC. The highly collimated 55Fe source moved with a step of 5, 4, 3, 2 and 1 mm Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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In the first operations on studying of performances, MSAC with gadolinium converter [8] dependence of the space resolution on amplitude of displayed signals has detected. The amplitude of a signal is in turn out to an angle of an escaping of electrons from a converter material. The spatial resolution can improve by using amplitude selection of events in electron detection [52]. With this aim in mind, we used two radiation sources (14C) with approximately equal activities, shaped as spots ~1mm in diameter and spaced 1 mm apart (the spacing between the boundaries of these spots). The sources placed on the entrance window of the detector. Anode signals used for amplitude selection of events by differential amplitude discriminator. The gating signal for data acquisition generated by the discriminator and arrived at the control input of the time-to-amplitude converter. Information acquired with a multichannel amplitude analyzer. The amplitude spectrum of the anode signals from the detector irradiated by β-particles of an uncollimated source (14C) shown in Figure 51. Particles incident on the surface of the chamber at small angles travel a significant distance in the upper layers of the pre-amplification gap, giving rise to additional avalanches due to secondary electrons along primary particle tracks. These particles are associated with higher-amplitude signals. As a result, as the angle of incidence decreases, the signal amplitude increases, the electron cloud grows in size, and its centroid displaced toward the direction of the primary particle. A small bend on the right of the spectrum can be attributed to the presence of a 0.5-mm-wide conversion gap and represented by the superposition of two spectra, one of which is formed by particles that suffered interaction in the conversion gap and generated secondary electrons and the other of which is due to particles that passed the conversion gap without interaction. The coordinate resolution obtained when all events were detected (segment AD of the curve in Figure 51) shown in Figure 52 (curve 1). The ratio of the depth of the dip between the peaks to their height is 0.25. It is possible to improve the spatial resolution by selecting (using the differential discriminator) events corresponding to the portion of the anode signal spectrum from A to B (Figure 51). Incidentally, the ratio of the depth of the dip to the peak height is 0.4 (curve 2 in Figure 52). In this case, the spatial resolution limited by the own resolution of the detector system. Which is dependent both, on the delay time per unit length of the delay line, and on the accuracy of the electronic channels. When the coordinate information obtained from events with high signal amplitudes (segment CD in Figure 51), the spots cannot be resolved (curve 3 in Figure 52).

Figure 51. Amplitude spectrum of β particles from the 14C source

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Figure 52. Spatial resolution of two radioactive zones of 14C isotope, each 1 mm in diameter, located with 1-mm spacing between the boundaries

The spatial resolution of the MSACs has investigated. The intrinsic spatial resolution is 260 μm (FWHM) or 100 μm (σ). The spatial resolution of the detector under exposure to soft γ-rays of the 55Fe source is 400 μm (FWHM). The spatial resolution of the MSACs is dependent on the angle of incidence of conversion electrons. The high signal amplitudes due to particles incident on the surface of the chamber at small angles (25% of all events) considerably impair the spatial resolution. By analyzing the signal amplitude and selectively measuring the coordinates, or by estimating the signal amplitude and its contribution to the reconstructed image, it will be possible to raise the spatial resolution when electrons escaping from solid-state neutron (Gd) or γ-ray converters detected.

3.1.4. Influence of gas mixes on characteristic MSAC Researches of influence on concentration of the additive on characteristics MSAC brought on a gas mix argon + acetone. Acetone as the additive has chosen from - that allowed changing in a wide range concentration of the additive in a mix. On Figure 53 values of dependence of factor of preliminary amplification (Gpr) from value of an applied voltage (Upr) for various values of concentration of acetone are brought. From figure, it is visible, that with increase in concentration of acetone at fixed Upr the factor of preliminary amplification decreases. Thus, Gpr can increase at corresponding increase Upr. Reduction of factor Gpr is connected with reduction of average energy drifting electrons as dominating process becomes interaction electrons with molecules of the additive. This interaction leads to sharp loss of energy electrons. Excitation of molecules removed without radiation because of rotary and oscillatory transitions. Dependence of amplification on concentration of the additive at the fixed voltage on a preamplifying gap well described by following expression [53];

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G (p) = 10-(n · pi),

(52)

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where: рi - concentration of the additive in%: n - the factor depending from рi and for a range 0,5 ÷ 3% is equal 2. So change рi within the limits of  0,5% cause change G in  10 times. The dotted curve designates border sparking in a pre-amplification gap. Optimum for achievement of the maximal factor of amplification are concentration 1,5÷ 2%.

Figure 53. Dependence of factor of preliminary amplification MSAC on a high voltage on a preamplification gap for various values of concentration of acetone in argon

Figure 54. Dependence of time resolution of MSAC on concentration of acetone in a gas mix. A curve 1 - FWHM, a curve 2 - width at a level of 97% of the registered events (FWTM)

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Figure 55. Extent of a plateau counting characteristics of MSAC for various concentration of acetone in a mixture. Curves 1 and 2 accordingly, the beginning and the end of a plateau for a source 55Fe

Influence of concentration of the additive on time characteristics MSAC investigated by 90 St. Measurements were spent at fixed values G and Gpr. On Figure 54 dependences of the time resolution of the detector for a mix argon + acetone are resulted at various concentration of acetone. The curve 1 shows FWMH, a curve of distribution of 2 widths at a level of 97% of the registered events FWTH. From figure it is visible, that with increase in concentration of the additive time resolution of MSAC which for concentration of 4% makes 21 nanoseconds (FWMH) and 60 nanoseconds at a level of 97% of the registered events improves. Researches of influence of acetone concentration on plateau length of counting characteristics carried out. Researches were spent at fixed factors Gpr. The curve 1 on Figure 55 shows voltage on anode MWPC, corresponding to the beginning of a plateau for a source 55 Fe. The curve 2 shows voltage MWPC corresponding to the end of a plateau counting characteristic. From figure it is visible, that with increase in concentration of the additive extent of a plateau, this increase, basically increases, occurs due to displacement of the end of a plateau. Therefore, extent of a plateau makes 900 V for the concentration of acetone equal of 4%.

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 - a source

3.1.5. Ways of stabilization of operating modes for work MSAC Proceeding from above the characteristic show, that the highest factor of amplification, can be reached for a mix of argon with 1,5 ÷ 2,5% of the additive. At the same time, the factor of amplification strongly depends on variation of concentration of the additive (in 10 times) at change of concentration of the additive on 0,5%. Other characteristics of MSAC depend strongly on the variation of concentration of the additive as well. In order to receive the long-term stable operating mode MSAC it is necessary to stabilize concentration of organic compound applied as additives. One of possible ways of stabilization of concentration of additives is thermostat control of flasks with a liquid through which gas passed. Thermo stating can carry out by means of thermostats, or at the temperature of a thawing ice. For maintenance of concentration of known additives within the limits of 1 ÷ 3% it is necessary to pass part of gas through a flask

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with a liquid. It dictates necessity of stabilization of gas speeds by means of highly stable reducers. However, even at use of similar reducers there is a necessity to expose and supervise carefully gas having blown on rotametrs. For the further increase of stability of work of MSAC it is necessary to use new gas mixes. The most convenient in operation are organic compounds with low-pressure saturated vapor, which at passage through them of all argon at temperature 0оС allow receiving concentration of the additive in a range 1 ÷ 3%. Such mixes are argon + Н-heptanes and argon + isopropyl spirit. At passage of all argon through Н-heptanes and isopropyl spirit at 0оС their concentration, accordingly makes 1.5 and 1.1%. Received data on these mixes are similar to the characteristics, received on mixes argon + acetone. Other interesting gas mixes for work MSAC are gas mixes on the basis of neon which emitted more vigorous (in comparison with argon) photons at transition in the basic condition. Energy of photons is sufficient for ionization of some organic additives, in particular methane. The gas mixes neon + methane is convenient at operation as allows preparing binary mixes in high-pressure tanks. Researcher of characteristics MSAC on this gas mix carried out. The mix allows to receive high enough factor of preliminary amplification Gpr =104. However, at the same time a neon + the methane mix does not allow receiving a wide plateau. At registration of relativistic particles, extent of a plateau is 100 V for concentration of 2.8% of methane. The plateau of efficiency of registration of relativistic particles can increased at addition of argon to the neon mixes. Therefore, extent of a plateau of efficiency increases by 100 V for gas mixes Ne + (10 ÷ 15%) Ar+ methane. Neon mixes has more higher (2 times) the time resolution in comparison with argon. So the time resolution for mix Ne ÷ of 2,2% of methane makes 15 nanoseconds (FWHM). Mixes based on neon can applied to detecting low vigorous electrons in conditions raised gamma – background, first in the neutron detectors with gadolinium convertors.

3.1.6. Detector testing Physically, each MSAC consists of a series of wire electrodes located one after the other in a common gas volume, thereby forming conversion, preamplification, and drift gaps and a MWPC. The schematic diagram of the MSAC it‘s shown in Figure 56. The conversion gap is formed by convertor window A, which is made from gadolinium foil and electrode B. The preamplification gap confined between grid electrodes B and C (these are commercially produced grids or grids composed of orthogonally wind wires). It should be noted that efficient transfer of an electron–photon avalanche from the preamplification gap to the drift gap can be obtained only when the grids have a high optical transparency. In [54], it noted that stable operation of the MSAC could obtain only when the grids made from thick wires (50–100µm in diameter). For grids composed of 20-µm diameter wires, sparking in the gap makes it impossible to achieve preamplification coefficients Epr> 10. Because drift electrode C begin playing the role of a quasi-anode and development of an electron–photon avalanche becomes a dominant process near the wires of this electrode, which increases significantly the probability of a spark breakdown in the preamplification gap.

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Figure 56. Schematic diagram of the MSAC

The wire pitch in the grid is governed by the requirement that the electrostatic field in the preamplification gap be uniform. The electrostatic field assumed uniform at distance L≥3λ, where λ is the grid period. Taking into account, that two grids (B and C) form the preamplification gap, it is desirable that the wire pitch selected be λ≤L/6, where L is the width of the preamplification gap. The width of a preamplification gap usually selected from a range of 3–8 mm. However, the operability of an MSAC with a 20-mm preamplification gap was demonstrated in [55]. The preamplification coefficient Gpr of the MSAC is exponentially dependent on distance (L) and the first Townsend coefficient (α), Gpr = (eαL – 1)/(1 –αL),

(53)

and increases with increasing gap width. However, in the case of inclined tracks, the preamplification gap width should reduce to achieve a high spatial resolution. Incidentally, the requirements for the parallelism of the gaps become more stringent. Stable operation of an MSAC can nevertheless achieved without using the drift gap. We investigated the characteristics of such a two-step structure. Two-step MSACs also exhibit high gas amplification coefficients, but are not free from some drawbacks. In the case of a spark breakdown, the spark short-circuits the cathode plane, which in turn may lead to a local breakdown of the delay lines and damage the amplifiers. Creation of the uniform electrostatic field in the preamplification gap is fraught with difficulties due to the cathode discontinuity. MSACs with the inductive readout permit the obtaining of equal spatial accuracies for both coordinates; however, for coordinates along the Y-axis parallel to the anode wires, this holds true if an electron avalanche covers several adjacent wires, forming cluster events. An avalanche expands in the preamplification gap in the process of its development and during its transfer through the drift gap in the MWPC.

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As a rule, the widths of the drift gap are 5–10 mm. The use of wider gaps requires that a higher voltage be applied to the drift and preamplification gaps and the detector have a larger gas volume. An MSAC usually comprises a standard MWPC composed of an anode plane and two orthogonal planes X and Y. The anode plane is formed by a gold-plated tungsten wire 20µm in diameter, positioning with a pitch of 2 mm. All the wires combined into a common busbar. The cathode planes formed by beryllium- bronze wires, 50–100 µm in diameter, positioning with a pitch of 1 mm and combine into the strips. Each strip comprises four wires and soldered to the delay line. The standard width of the anode-to-cathode gaps is 5 mm.

3.1.7. Effects of some constuctional elements on the MSAC characterisrics The uniformity of gas amplification coefficient G over the detector area is an important characteristic of an MSAC. A difference in the values of G can lead to nonuniformity of the detection efficiency. Figure 57 shows the distribution of G over the MSAC area [54]. Taking the logarithm of Eq. (53), one can obtain deviation of the preamplification gap width ∆L versus the relative variation in the MSAC amplification coefficient: ∆L= (1/α)/(ΔG/G) = (L/lnG)/(ΔG/G) ,

(54)

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where: G is the mean average of amplification coefficient over the chamber area. This formula helps estimate the deviations from the parallelism in the preamplification gap. The deviations of the gap width in the MSAC detector from an ideal plane (dashed lines), which calculated according to Eq. (3), shown in Figure 58. The deviations of mean amplification G are actually dependent both on the parallelism of the preamplification gap and on the spread of the MWPC amplification coefficient.

Figure 57. Spread of the amplification coefficient in the MSAC over its area [54]

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Figure 58. Deviations of the gap width in the MSAC from the ideal plane shown with dashed lines

Figure 59. Calculated deviations of the gas amplification coefficient ΔG vs. the spread of the gap with at Gpr = 103 and gap widths of 3, 5 and 7 mm (respectively curves 1,2 and 3).

Figure 59 presents calculated deviations of the gas amplification coefficient ∆G such as versus the deviations of gap width from its nominal value at a fixed value of amplification (Gpr= 103) and three values of the gap width (3, 5, and 7 mm). From Figure 4, it is apparent that a 100-µm spread of the gap width causes the value of G to vary by 10, 14 and 23% for 7-, 5-, and 3-mm-wide gaps, respectively. An increase in gas amplification coefficient Gpr to a value of 105 is followed by an increase in the fluctuations of the gas amplification versus the spread of the gap width. As a result, a 100-µm spread of the gap width causes G to vary by 16, 23, and 39% for 7-, 5-, and 3 -mm-wide gaps, respectively. As the preamplification gap width is reduced, more stringent requirements are specified for the accuracy with which the

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detector components should be produced. This fact is especially important for manufacture of large-area detectors.

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3.2. Thermal Neutron Imaging Detectors Combining Novel Composite Foil Convertors and Gaseous Electron Multipliers The potential of a thermal neutron imaging system based on a composite neutron convertor foil combined with a low-pressure, multistep avalanche chamber demonstrated in the work [47]. Neutron-induced charged particles from a primary convertor element induce multiple low-energy electrons escaping from a second thin film of high electron-emissive material. Authors investigated the performance of detectors with Gd- and Li-based primary convertors coated with CsI as a secondary electron emitter. It is shown, that the detector can be operated with high stability at a sufficiently high gain to detect all escaping particles, fast time resolution, low occupation time and high count rate A localization resolution of 0.4 mm (FWHM) was obtained. The good imaging performance, free of parallax errors in divergent neutron beams, capability, make this instrument an excellent tool for time-resolved neutron scattering experiments and for neutron radiography and tomography. Idea of original programmers therefore is to replace the single layer convertor with a composite convertor foil; such a foil consists of a traditional neutron convertor coated with a thin film of an efficient secondary electron emitter. Neutron-induced particles from the convertor induce the emission of multiple low-energy secondary electrons, which initiate a well localized avalanche close to the neutron impact location. To obtain the optimal imaging and timing performance it is important for the detector to be sensitive primarily to the slow ionization electrons in the vicinity of the convertor foil. These electrons originate either from gas ionization by the fast particle or from ionizations occurring in the foil, leading to the emission of slow secondary electrons into the gas. Assuming a mean energy of 50 keV for the primary electron escaping from the Gd into the CsI, authors should expect more than 10 secondary electrons emitted on the average from a few hundred μm thick CsI layer. This number is at least 5 times larger compared to the number of ionization electrons induced in the gas by the 50 keV electron, assuming a 2 mm gap filled with 10 hPa of isobutane. Moreover, due to the statistically distributed ionization processes in the gas and the exponential avalanche growth in the preamplification gap, the effective contribution of these electrons to the final avalanche is even smaller. Thus, the SEE from the CsI is the leading process and we expect an increase of about an order of magnitude in the pulse-height and detection efficiency close to 100% for fast electrons escaping from the neutron convertor foil.

3.2.1. The neutron convertor foil The convertor material was deposited on an aluminum disk, 5 mm thick and 75 mm in diameter. A 300 μm thick natural Gd foil was glued onto the Al disk. The Gd surface was coated with CsI layers of various thicknesses, deposited by standard vacuum evaporation. A low-density CsI film of spongy structure was produced by evaporation under 7.5 hPa of Ar. Under this evaporation condition it is known that the deposited layer has a porous structure and its average density is only a few percent of the bulk density of solid CsI. It is expected

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that this structure, with its large surface-to-volume ratio, leads to an enhanced secondary electron emission. Unfortunately, authors did not have any control over the effective mass of CsI deposited on Gd, since the thickness monitor did not function under these evaporation conditions.

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3.2.2. The Multistep avalanche chamber The preamplification gap is defined by the convertor foil and an 81% transmission grid made of stainless steel. The width of the gap is 2 mm and it is operated in a proportional amplification mode. After preamplification the avalanche electrons are transferred to the second multiplication region through a 20 mm long drift and diffusion gap, which improves the operation stability at high gains. The second amplification stage, a multiwire proportional counter, consists of a 1-mm spaced wire anode plane, 20 μm in diameter, placed between two 1-mm-spaced, 50 μm in diameter wire cathode planes. The localization of the center of the avalanche corresponding to the neutron-capture location in the convertor foil is obtained by analysing the induced signals on the cathode wires, applying the well-known delay-line readout technique. 3.2.3. Detector characteristics To obtain maximum neutron detection efficiency with Gd-based convertors, the avalanche chamber must be capable of detecting events originating from a small number of slow electrons, often-single ones, produced in the vicinity of the convertor surface. To achieve a count rate plateau, the chamber must therefore operate at a high gas amplification of several times 106. To determine the gain capability of the detector the neutron convertor foil was replaced by a polished Al photocathode and irradiated with UV light from a Hg lamp. The avalanches were thus initiated by single primary electrons from the photocathode. Close to 100% of the signals clearly separated from the noise. At high gain of about 4x 106, the detector operates in a stable way over long periods, even in the neutron beam. For all convertors investigated the pulse-height distributions and the total detection efficiencies for neutrons at a wavelength of 0.115 nm were measured at various gas pressures and voltages. Although the detector with the pure Gd convertor was operated at significantly higher gain, the pulse-height spectrum obtained with the composite convertor shows a significant increase in the number of events with medium pulse-heights. This reflects the expected increase in the number of slow electrons deposited in the preamplification gap by SEE from the CsI. The detector with CsI-coated convertors reaches count-rate saturation at significantly lower voltages, which is important for its long-term operation stability. The efficiency values are about 8%, which is in good agreement with the theoretical value for a thick natural Gd foil under backscattering conditions. The detection efficiencies at 40 hPa seem to exceed the theoretical predictions. However, at this pressure the maximum attainable gain in the preamplification gap is lower by more than a factor of 10 as compared to the value reached at lower pressures. Therefore the MWPC contribution to the total gain dominates and the detector becomes susceptible to all charges produced somewhere in the gas, making the detector very sensitive to all kinds of background radiation. For example γ-rays originating from the reactor or from the Gd foil may be Compton-scattered in the detector wall, the emitted electrons may enter the sensitive gas volume and be multiplied and registered. This is

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an additional argument in favor of the low-pressure operation of avalanche chambers in this application. Furthermore, it should noted that for CsI-coated converters the total conversion efficiency is almost independent of the gas pressure, even at the lowest applied pressures where the probability of producing secondary electrons in the first layers of the gas is negligible. This clearly demonstrates the effectiveness of the CsI secondary electron emission. A spatial resolution of 0.4 mm (FWHM) was obtained. In the work, authors present a novel neutron-imaging system based on a composite foil convertor combined with a low-pressure gaseous electron amplification device. The system has many attractive features:     

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

The concept based on comparatively simple and inexpensive technologies. The detector is practically not limited in size or geometry. A position resolution of better than 0.5 mm (FWHM) can be achieved. In divergent neutron beams the position determination is free of parallax errors. Due to the thin conversion layer (below 100 μm thickness) the arrival time of thermal neutrons can be determined with an uncertainty of less than 100 ns. This excellent time resolution enables time-of-flight and coincidence measurements. An operation at very high count rates (> 10-6 s-1 mm-2) is possible with adequate read-out and acquisition electronics.

The main drawback of the method is the relatively low detection efficiency compared with 3He or scintillation detectors. The efficiency of the detector was found to be in good agreement with the theoretical predictions of the particle conversion and escape probabilities. It is expected that the application of isotopic pure convertor materials will result in detection efficiencies of 36% and 52% for neutrons with wavelengths of 0.1 nm and 0.2 nm with l57Gd convertors. This can be further improved by a multi-foil system, where n foils are read out by n + 1 multistep avalanche chambers, recording electrons emitted from both surfaces of each foil.

3.3. Hybrid Low-Pressure (MSGC) Neutron Detectors 3.3.1. The detector principle A detector scheme with four full size detector segments of 285 x 285 mm2 size is shown in Figure 60. Each segment comprises a central composite 157Gd/CsI converter foil and either side of the converter in 0.25 mm distance extraction grids embedded in 4.5 mm deep lowpressure gas multiplication gaps. The gaps are closed by two-dimensional position-sensitive MSGC plates, which are fabricated by multi-layer deposition on glass plates [44]. The optimal is for thermal neutron detection, whereas for cold neutrons 1–3 μm thick 157 Gd converters deliver higher efficiency. The Gd is coated with columnar CsI secondary electron (SE) emitter (SEE) layers delivering a detectable cluster of slow (eV) SEs into the gas volume from a well-defined locus ( μm) on the converter surface where the fast CE penetrates. The CsI layers have thickness of smaller than 1 μm in order to keep the sensitivity to energetic γ and X-ray background in the beam low. On the other hand, if photons emitted

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after neutron capture from 157Gd should emit a cluster of SEs triggering an avalanche above threshold, this signal is as valid and as localized as a CE signal due to the thin converter. Between the converter and the extraction grid a high field strength of E=5–10 kV/cm is applied for enhancing the SE extraction from the columnar CsI surface. The extraction gap works in addition as a pre-amplification gap with short mean free path for ionization λi in the three-stage gas avalanche multiplication mode used for SE amplification. In this exponential gas amplification mode only avalanches starting at the converter surface achieve the full gain, whereas avalanches triggered elsewhere in the gas volume remain below the detection threshold. Therefore, the sensitivity to weakly ionizing Xrays and γ- rays will be significantly reduced. Due to low-pressure operation at p 20 mbar in the very good, quench gas isobutane very high reduced field strengths E/p and thus exponential gas avalanche multiplication can be achieved over three amplification stages: In the 0.25mm deep pre-amplification gap between converter and extraction grid E/p is as high as 50–500 V/(cm mbar) resulting in λi 53 μm and thus very good time localization of the SE avalanches. Due to the short λi the sensitive detector volume is restricted to the converter surfaces, parallax is avoided and avalanches released from other parts of the detector volume remain below threshold.

Figure 60. Schematic diagram of a four-segment low-pressure MSGC neutron detector, comprising in each segment (i) a composite 157Gd/ CsI converter foil with extraction grids; (ii) two adjacent lowpressure (p 20 mbar) gas gaps on either side of the converter with high constant reduced electrical field strengths E/p; (iii) two fourfold subdivided MSGC detector planes, which function as amplification and readout elements. The diagram indicates the gas amplification mode at low gas pressures (left inset), the composite converter foil (top), the micro-strip planes either side of the converter (bottom), some coarse details of the micro-strip plate multi-layer design (right) and the layouts (bottom right) of the micro-strip plane (metal 2), with parallel anode and cathode strips, and of the ‗Second Coordinate Pad (SCP)‘ plane with SCP and return current strips (metal 1, magenta)

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In the subsequent constant field region extending from the grid to 0.5 mm distance from the MSGC plate the lower E/p of 100 V/(cm mbar) is still more than sufficient for parallel plate avalanche multiplication. However, only a fraction of 50% of the electrons of the pre-amplification gap can reach this lower-field region by diffusion/scattering through the grid holes. This is enhanced due to the high electron temperature in the high E/p of the preamplification gap and due to the only 20μm thick stainless steel extraction grid with doublesided etched holes of 40 μm diameter and 60 μm pitch. This grid reduces further the UV photon feedback from the end of the avalanche to the converter and thus secondary avalanches. In the high altenating fields between the micro-strip (MS) anodes and cathodes microstrip amplification sets in with rising E/p when the electron avalanches approach the anodes. Due to strong diffusion extending from the pre-amplification gap over the full trajectory length, the avalanche heads are broadened, and charge is induced on 3–4 anode–cathode pairs although with Δx= 255 μm a pitch of 635 μm is chosen. Thus, with readout methods determining the center of gravity of the induced charge and with the very good signal-to-noise ratio of the three-stage gas multiplication a position resolution corresponding to a fraction of the MS pitch is achievable. Due to the higher E/p and shorter drift times the count rate capability of low-pressure MSGCs is even higher than that one of normal pressure MSGCs, which exceeds 106 cps/mm2, since most of the positive ions are set free in the gas avalanche close to the anode micro-strips and are drifting over a short distance to the cathode strips.

3.3.2. Converter fabrication For fabrication of 1-3 μm thick Gd converters at HMI two half as thick Gd layers were RF sputter-deposited either side on a 6 μm thick Aramid plastic support foil on thin Al barrier layers. Great attention was paid to prepare very uniformly stretched Aramid foils because of the high compressive stresses appearing in the thick Gd layers during deposition. In order to avoid thermal deformation of the Aramid foil, for Gd sputtering a two-inch sputter source was operated with low power of 50-100 W. In addition, the rear side of the foil was Peltier-cooled via a polished copper plate. For achieving with the small source a homogeneous layer deposition on full-size plates the substrate must be moved across the source in x and y directions. This is possible in the new chamber but not in the old setup. Therefore, so far converters for prototype size detectors with 101 x 101 mm2 inner frame opening were made. As depicted in Figure 61, columnar CsI layers of ~ 1 μm thickness and with ~ 4-5 times smaller column base width were made by thermal evaporation in an Ar atmosphere of 10-3 mbar base pressure, again on thin Al sub-layers.

3.4. Resistive Plate Chambers with Gd-Coated Electrodes as Thermal Neutron Detectors Resistive Plate Chambers (RPCs) basically consist of two bakelite plates kept at a 2 mm distance by a grid of plastic spacers [48]. An appropriate gas mixture is circulated in between and a 4–5 kV/mm electric field is applied. When an ionizing particle crosses the gas gap, subsequent avalanche or streamer processes induce a detectable signal on external readout strips.

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Figure 61. Scanning electron micrograph of a 1mm thick columnar CsI layer deposited as described in the text.

Figure 62. Appearance of the detector.

Even if this device has been mainly employed to reveal ionizing particles, its possible use to detect neutrons could lead to interesting practical applications like, for instance, the spotting of explosive materials contained in anti-personnel and antitank mines underground. A possible detection technique, accurately studied in the context of the DIAMINE project, uses a 252Cf source placed near the mined ground, which, undergoing fission processes, emits neutrons ranging in energy from about 1 to 4 MeV. Going through the layer of soil overhanging the mine and hitting materials compounding it (mainly H and N), neutrons lose energy in multiple scatterings till termination. The goal is to reveal the backscattered thermal neutrons directing upwards, since an intense enhancement in their number is a precise signature of the presence of the mine. RPCs are very good candidates to fulfill the requirements of an ‗‗on-field‘‘ application of this technique because they are cheap and mechanically robust. Neutron detection can only be achieved after interaction with a suitable material, called converter, which has the role of generating ionizing particles. Two gadolinium isotopes, namely Gd and 157Gd, present in absolute, have the largest cross-section to thermal neutrons (of the order of 105 barn). Cross-section for these converters follows the same typical behaviour, decreasing with 1/v, where v is the velocity of the incoming neutron; in the case of Gd the cross-section slope

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is much steeper, starting from an energy around 40 meV to become comparable to others for Ek 1 eV. This means that Gd can be particularly suited to produce detectors specifically designed to reveal thermal neutrons (and not fast neutrons); this is an advantage, since fast neutrons coming directly from the 252Cf source could constitute a sort of undesirable background. In the work, natural Gd, which is composed of a mixture of many isotopes, of which 157 Gd and 155Gd constitute about 30% of the natural composition, has been chosen. This material was actually used in the form of Gd-oxide (Gd2O3), which presents itself as a white inert powder, with granules 1-3 mm in diameter. This is inert, very easy to handle, poses no problem of gas contamination and is very cheap (100$/kg). Gd-oxide powder was put in suspension inside the linseed oil normally coated on the inner surface of the bakelite electrodes, so that the usual method for its polymerisation allows to trap the granules of converter in a solid layer. Since Gd-oxide is not conductive the electric properties of the electrodes are not altered. To estimate the possible performance of this kind of detector, suitable calculations have been carried out. In particular, a Monte Carlo program has been developed, taking into account the basic interesting processes, i.e., the interaction of the incident thermal neutron, the emission of the secondary electron with the correct energy spectrum, its travel in a Gdoxide sheet up to its surface and the eventual entering into the detector active volume. Total detection efficiency rapidly reaches a maximum of around 10–15μm thickness of about 35%, and after that it decreases slowly. When the Gd-oxide thickness is lower than 10 μm, the probability of an electron stopping inside the Gd sheet is negligible, and the fast rise in efficiency reflects the increasing number of neutron interactions as the Gd thickness increases. When Gd thickness becomes comparable with electron range, one has to take into consideration the fact that neutron flux decreases exponentially inside Gd-oxide; this means that only a surface layer of Gd mostly contributes to the conversion processes. Once produced, ‗‗forward‘‘ electrons have to cross more and more Gd-oxide to exit the sheet, as Gd thickness increases, while ‗‗backward‘‘ electrons have just a, more or less, fixed thickness to cross. This causes two different behaviours for the curves representing the contributions to the total detection efficiency. In this configuration, one can choose to reveal ‗‗forward‘‘ or ‗‗backward‘‘ electrons, depending where the detector active volume is located. Revealing ‗‗backward‘‘ electrons, one has not to worry much about the layer thickness, which may be difficult to control, provided it is greater than 10 μm. This new technique was applied to build three RPCs, 10 x 10 cm2 in dimension, of which one without Gd2O3 and the others coated, on the inner surface of one of the two electrodes, with different Gd2O3 concentrations.

3.5. The Neutron Sensitivy Image Plates Imaging plates (IPs), two dimensional detectors for ionizing radiations such as X-, β-, γray, ultraviolet light, etc. utilizing photostimulated luminescence (PSL), are used in many fields of applications, such as medical and industrial radiography, autoradiography, X-ray diffraction experiments, and transmission electron microscopy. In each case, the inherent imaging principle is the same explained as follows: after the radiographic image is transferred

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to an IP, it is scanned point-by-point by a laser beam in an image reader. A series of the PSL emissions corresponding to the scanned pixels is detected by a photomultiplier tube through a high-efficiency light guide to be converted into the electric signals as a function of time. These analog signals are logarithmically amplified and converted into digital signals. By processing these signals through a computer, the computed radiograph can be reconstructed. Moreover, these digital signals can be easily analyzed, stored, and communicated. Authors have succeeded in experimentally developing an imaging plate neutron detector (IP-ND) [49]. The intrinsic part of the IP-ND is composed of a fine mixture of a PSL phosphor, BaF(Br,I):Eu2+, and a neutron converter material, Gd203 or LiF. The nuclear reactions of Gd with neutrons produce γ-ray of 0.3, 0.4, 1.2 MeV and other energies and internal conversion electrons with an average energy of about 70 keV, and those of 6Li produce a particles of 2.05 MeV and tritium of 2.74 MeV. These charged particles emitted from the converter can excite the PSL phosphor in the IP-ND, where the ranges of these particles in the phosphor layer are calculated to be less than a few tens of micro-meters, excepting effective penetration length of the γ-ray . BaFBr:Eu2+ is used as a PSL material, and Gd203 with natural abundance of Gd or 6LiF is used as a converter material. The average diameters of these powders are 5.0 μm and 3.3 μm or 3.5 μm, respectively. In each IP-ND, 250 μm and 6 μm thick polyethylene telephthalate (PET) films are used as a support and a protection layer, respectively. The size of these IPNDs is 20 cm X 25 cm or 20 cm X 40 cm. Exposure to neutrons of 2.3 A0 wavelength was carried out in JRR-2 of Japan Atomic Energy Research Institute (JAERI) and the BAS2000, a bio-imaging analyzer system (manufactured by Fuji Photo Film Co., Ltd.), was used for reading the IP-NDs. The pixel size of the BAS2000 can chosen between 100μ m X 100 μm and 200 μm X 200 μm. The latter was used here. Image formation process and the image quality factors by means of the IP-NDs, which is similar to the case of X-ray imaging except for the excitation process through the converter. This consideration is essential for neutron radiography as well, in order to design or utilize the system properly. FCR7000 is an image reader system used in medical diagnostics (manufactured by Fuji Photo Film Co., Ltd.), where a pixel size of 100 μm X 100 μm was used. The result indicated that the ratio of an X-ray photon noise to a light photon noise was about 8:1 at a spatial frequency of 1 cycle/mm. This means that the light photon noise is a minor component of the quantum noises in this system, which is to say that the number of light quanta detected for a single absorbed X-ray photon is sufficiently larger than unity. As for BAS2000, the relative situation among the quantum noises are not different because the laser energy for a unit area and the efficiency of collecting emitted light are almost equal to those of FCR7000. In neutron imaging with the IP-NDs, the energies of secondary particles from Gd and 6Li converters are higher than the average X-ray photon energy of about 40 keV, which corresponds to the exposure tube voltage of 80 kV mentioned above. The number of light quanta detected for a single absorbed-neutron is expected to be sufficiently larger than unity, since the number of light quanta emitted for a single absorbed X-ray photon or neutron can be determined by the energy of the X-ray photon or the secondary particles. Therefore, the light photon noise in the system of BAS2000 and the IP-NDs is estimated to be a minor component of the quantum noises, and the neutron absorption efficiency of the IP-NDs governs the image quality.

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Figure 63. Layout showing the ―backward‖ configuration

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The IP-ND has a severe problem in that it is also sensitive to γ-ray since the PSL phosphor is sensitive to X-rays. To solve this problem, an image processing to subtract γ-ray image from the neutron plus γ-ray image was tried. Since Li emits secondary particles of a much higher energy than Gd, the Li-IPs are not so influenced by γ-ray as the Gd-IPs. It is expected that the Li-IPs are more suited to the imaging where there are higher y-ray to neutron ratios than Gd-IPs. The PSL is maximized at about 50 mol% of Gd to Ba ratio in the Gd-IPs, while it is not saturated up to 90 mol% of 6Li to Ba ratio in the Li-IPs. In case of the same neutron absorption efficiency, both of the Gd-IPs and the Li-IPs show higher PSL under lower converter concentration. It has been shown that most important factor governing the image quality is effective neutron absorption in both of the Gd-IPs and the Li-IPs. For the most part, the Gd-IPs can absorb neutrons more efficiently than Li-IPs. However, the amplification rate in the conversion and excitation process of the Gd-IPs is about 30 times lower. Therefore, the Li-IPs are expected to be more suited to the imaging where there are higher γ-ray to neutron ratios than Gd-IPs.

Figure 64. The left figure is the schematic view of the capillary plate. The capillary plate consists of a bundle of fine glass capillaries. The middle figure is the schematic view of one glass capillary. The length and the diameter are about 800 µm and from 6 µm to 100 µm, respectively. Liquid scintillator for neutron capture is absorbed into each capillary. The lights emitted via neutron capture are reflected on the inner surface of each capillary and then are led to a optical device. The right figure is the schematic view of the neutron detector coupled with optical position sensitive device

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3.5. Neutron Imaging Detector Using Capillary Phenomena and Liquid Scintillator Neutron beam and the imaging detectors are useful to investigate the inner feature of human body. So, several imaging detectors for neutrons such as an Imaging Plate or scintillating-fiber were developed. In general, three important characteristics are required for neutron imaging detectors. These are fine position resolution, timing resolution, and low background. Though the Neutron Imaging Plate has good position resolution of 25 μm and has high detection efficiency for neutrons, it can not obtain timing information. In particular, the capillaries filled with liquid scintillator will be good candidate for neutron detector with both fine position resolution and good timing resolution [49]. It is because bundle of capillaries with the diameter of 6 μm can be manufactured at present and the liquid scintillator with Gadolinium (Gd) or Boron (Gd) has high detection efficiency for neutrons. So authors have been developing the neutron detector which consists of liquid scintillator with Gd or B and a capillary plate commercially manufactured by Hamamatsu Photonics Inc. Figure 64 shows the schematic view of the capillary plate and the neutron detector under development. The capillary plate consists of a bundle of fine glass capillaries with uniform length. The diameter and the length of each capillary are 6-100 μm and 800 μm, respectively. Though the effective area of the typical plate is 20 mm in diameter, it is possible to manufacture the capillary plate with larger diameter. Because the plate is thin, it does not have high detection efficiency for gamma rays which are background for neutron detectors. On the other hand it has good detection efficiency for thermal neutrons in spite of the thinness because Gd or B has high detection efficiency for thermal neutrons. Under the capillary plate absorbing liquid scintillator, optical detector with fine position resolution such as IICCD (Image Intensified CCD camera) or EBCCD (Electron Bombered CCD camera) is attached. As the neutrons are captured by Gd or B, electrons or alpha particles are emitted. They run in the liquid scintillator and the scintillation lights are emitted. If the lights emitted from one capillary by neutron capture can be confined in the capillary and are led to the mounted optical device, the detector can obtain the position resolution of 6 µm. The key technologies to manufacture such neutron detector are as follows. 1) It is required to absorb the liquid scintillator into each capillary uniformly and to seal it. 2) It is necessary to obtain enough light output by the neutron capture to detect with the optical device. 3) It is required to confine the emitted lights by neutron capture in the capillary and to lead them to the optical device. To realize it, it is necessary to coat the inner surface of the capillaries with light reflector. So we challenged to establish the first technology using capillary phenomena. Then by irradiation with neutrons we investigated the light output from the capillary plate attaching a photomultiplier. Finally, we carried out irradiation experiment of alpha particles attaching the capillary plate with a position sensitive photomultiplier. In this paper, we will report in detail the methods to absorb the liquid scintillator into the capillary plate and results for the basic experiments of neutron and alpha particle irradiation. Five kinds of liquid were used for these tests. These are water, ethanol, benzene, xylene, and liquid scintillator (BC525) of 2% Gd doped. Authors used two kinds of capillary plates with the diameters of 100 µm and 6 µm, which the side surface inside each capillary is not coated. Though liquid can not be uniformly absorbed into capillary plates by the method of

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Type (A) for any combination, we succeeded in absorbing any liquid into capillary plates by the method of Type (B). Authors have been developing the neutron detector with fine position resolution by absorbing liquid scintillator with Gd or B and to the capillary plate by capillary phenomena. They have established the methods to uniformly absorb the liquid scintillator to each capillary and to seal both sides. Injecting neutrons to the capillary plate attached on the PMT, the basic characteristics have been investigated. From the results, it was confirmed that the capillary plate with the liquid scintillator of BC525 can operate as the neutron detector though the light output is not yet enough. Moreover, injecting alpha particles to the capillary plate attached on the PSPMT, prototype position sensitive detector has been tested. However, the position resolution is not good yet because the lights emitted from the capillary are not confined in the capillary. In near future, will try to manufacture the capillary plate with the liquid scintillator of Boron doped and will establish the method to plate the inner surface of capillaries with light metal for the light reflector.

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3.6. Position Sensitive Detection of Thermal Neutrons with Solid State Detectors (Gd Si Planar Detectors) The central concept of these new detectors is to combine position sensitive Si planar sensors with external Gd converter foils [38]. The thermal neutrons are absorbed in the Gd foil and the resulting conversion electrons detected in the silicon devices. Figure 65 shows a schematic drawing of a Gd-Si neutron detector consisting of one Gd converter foil and two Si detectors. A position sensitive Si planar detector consists of an array of many p+n-diodes on one single substrate. Each p + n-junction works as a detector for ionizing particles. The position of the detected particle is given by the individual address of the diode that collects the charge. Each diode is equipped with an individual amplifier chain to ensure real time readout. Typical wafers have a diameter of 4-6 in. and a thickness of about 300 μm. The single structures can be as small as 10 μm and are limited in their extent only by the size of the wafer. A position resolution of less than 10 μm has been achieved with these devices, as well as the construction of large detectors with areas up to m2, for several high-energy physics experiments. Considering only one converter layer (no sandwich detectors), the (n, γ) reaction in Gd, which produces also a reasonable number of conversion electrons, is the only suitable one for high detector efficiency. The proton, α-particle and triton from the 6Li and 10B reactions have a very short range. Therefore, these converters can only be used in situations, which require low detection efficiency, e.g. beam monitors, or for the detection of cold or ultra cold neutrons. One can also think of doping the Si detectors with Li, but the usual doping concentrations of about 1016/cm3 are much too low for efficient absorption of thermal neutrons. The (n,γ) reaction in Gd produces a quite complex conversion electron spectra with significant energy lines between 29 and about 200 keV. Due to the high absorption, cross section of Gd the converter can be made very thin, so that the range of the conversion electrons is sufficient to reach the Si-detector. The band-gap in Si of 1.11 eV results in an average energy of about 3.6 keV for the electron hole creation. Therefore, the device must be

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capable to measure a charge of less than 5000 e- to detect the low-energy conversion electrons, which have already lost part of their energy when escaping the converter foil. The detectors are made of high resistivity silicon in planar technology and operated in fully depleted mode. For a typical detector less than 100 V applied to the p + n-junction ensures, that the whole detector works as one large depletion region. This mode decreases the detector noise, because it reduces the capacity between strip and backplane, and the thermally generated leakage currents. In addition, it guarantees that the entrance window on the rear side is as thin as the one on the front side and that there are no dead sections between the strips. While CCDs are made of only partly sensitive shift registers and contain inefficient channel stops to separate the columns, Si planar detectors are continuously efficient devices. Another important distinction between these detectors and CCDs concerns their readout. CCDs are integrating devices with charge transfer that means serial readout. Therefore, highresolution time information is very difficult to obtain. Contrary Si detectors constructed to measure single events with parallel readout electronics. Provided the lower level discriminator is set sufficiently high, the energy distribution of the conversion electrons does not effect the detector response, as in the case when the spectra would be detected by an integrating device such as film or CCD. The theoretical time resolution of the Gd Si detector given by the charge collection time in Si, the transit time of the thermal neutrons through the converter foil and the lifetime of the excited Gd atoms after the neutron capture. None of these intervals is longer than some nanoseconds, which allows the construction of a very fast detector.

Figure 65. Schematic of a 4% Gd-Si-neutron detector consisting of one converter foil and two Sidetectors with corresponding electronics.

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For parallel readout, it is necessary to equip each detector diode with the full amplification and readout electronics (more sophisticated readout techniques can reduce the number of channels). For many channels and/or a high position resolution, this can only do by the use of very large-scale integrated electronics. Although the technique used for the detector fabrication from a general point of view similar to the one used for electronic circuits, it differs in some essential aspects, which prevent so far the construction of detector and electronics on the same wafer.

3.6.1. Characteristics of detector For every stopped neutron the probability, that an electron will be emitted is given by the conversion factors of the corresponding (n, γ) reaction. As the decay pattern of Gd is quite complex some simplifications have to be made for the calculations of the detector efficiency. Taking the values of the dominant isotopes 155Gd and 157Gd from the nuclear data sheets, we used only the lowest energy levels which have the highest conversion factors, Ey (keV) = 88.97, 199.21, 296.53, 263.58 for 156Gd and Ey (keV) = 79.51, 181.93, 277.54, 255.66 for 158Gd. The energy distribution of the conversion electrons was calculated, by subtracting the binding energies of the K, L and M shells. Although each conversion electron is accompanied by several γ-rays as well as X-rays and Auger electrons, which follow the ionization of the atom, only the conversion electrons, and the Auger electrons with an energy of more than 20 keV have been taken into account. For all electrons, which enter the Si detector with a remaining energy of at least 15 keV, the efficiency of the Si detector can be assumed to be 100%. The efficiency, defined as the number of registered neutrons divided by the number of incident neutrons, was measured in backward direction for six different wavelengths in comparison to a calibrated 3He counter. The results for natural Gd and an enriched (90.5%) 157 Gd converter are shown in Figure 11. For thermal neutrons, authors can conclude an efficiency of more than 35% for the enriched 157Gd converter and about half of this value for natural Gd. One can clearly see the increase towards higher wavelengths. The measured values are constantly higher than the calculated ones. This is caused by Xrays and γ-rays following the neutron capture, which are partly detected. The X-ray lines is more dominant for natural Gd. Conversion electrons, γ-rays and X-rays are emitted simultaneously compared to the time resolution of the amplifier of about 1 μs, therefore, one captured neutron can cause only one signal in the detector. Nevertheless, the electromagnetic radiation can increase the overall efficiency in the case when the electron not detected. Otherwise, the detection of γ-rays and X-rays causes only a spread of the energy spectra. With the first measurements about three years ago, authors could demonstrate that a onedimensional neutron detector can be constructed from a single-sided strip detector. The position resolution achieved with this early system is compared with the results of a pad detector and the latest measurements with a double-sided strip detector. As for the previous setup the position resolution was determined by measuring the detector response to an edge. An Lorentzian edge spread function was fitted to the data near the edge, which gives a position resolution of FWHM= 210 μm. The measurements confirmed that the distance between Gd converter foil and detector is the critical parameter for the position resolution. To take advantage of the extremely high resolution of the strip detector, the Gd converter has to be placed onto the detector surface or deposited directly on the Si wafer.

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CONCLUSIONS Theoretical bases of conversion electrons formation are considered at reaction of radiating capture of neutrons; the value of α depends on four parameters: (l) on the charge of radiating nucleus, (2) on the energy of nuclear transitions, (3) on the nuclear shell from which an orbital electron was emitted and, finally, (4) on multipolity and parity of nuclear transitions. Based on Bloch theory brake ability of electrons is considered. For electrons full brake ability usually is divided into two components: a - the brake ability caused by collisions ("collision stopping power"), - mean energy losses by the unit of length of path due to nonelastic Coulomb collisions with the bond electrons of the substance, resulting in ionization and excitation; b - radiating brake ability ("radiative stopping power") - average losses of energy on the unit of length of path due to emission of brake radiation in the electric field of nuclear nucleus and nuclear electrons. Division of brake ability into two components is expedient for two reasons. First, methods of their determination are completely different. Second, the energy going on in ionization and excitation of atoms, is absorbed in the substance rather close to a track of a particle, while the basic part of energy lost in the form of brake radiation, leaves far from a track before being swallowed up. This distinction is important, when the attention to the energy "transferred locally" to substance along a track accented, in contrast to the energy lost by an incident particle. Actually, the share of energy lost in ionization impacts, turns to kinetic energy of secondary electrons and is transferred thus to some distance from a track of an initial particle Model calculations of efficiency of registration of thermal neutrons by the foil converters made from natural gadolinium and its 157 isotope were carried out. Processes of neutron absorption in the material of a converter and the probability of secondary electron escapes were examined. Calculation was made for converters with various thicknesses. We have chosen the most optimal converter thicknesses, both from natural gadolinium and from its 157 isotope. While using converters from natural gadolinium it is possible to obtain total efficiency of 10, 21, 26, 30%, correspondingly for the neutrons with wavelengths of 1, 1.8, 3 and 4 A0 with converter thickness of 24, 7, 5, 4 microns. For the converters with 157 isotopes it is possible to reach total efficiency of registration up to 27, 45, 49, 52% for the neutrons with the wavelengths 1, 1.8, 3 and 4 A0 with the thickness of converter 5, 3, 2, 2 microns. In earlier calculations, we took into account only electrons with energy higher than 29 keV. Thus not taken into account were the low-energy Auger electrons; these are the Auger electrons from L-shell with the energy 4.84 keV and Auger electrons of M-sell with the energy 0.97 keV. These electrons have rather small free path length in gadolinium; these are 0.3 microns (4.84 keV) and 0.04 microns (0.97 keV). They bring the small contribution to the general efficiency at use of converters made from natural gadolinium as the length of free path of neutrons in natural gadolinium is tens of microns. At the same time, their contribution becomes essential at use of converters made from 157 isotope of gadolinium as the free path length of neutrons in them does not exceed 2–3 microns and this length becomes comparable with length of electron paths. Calculations of the efficiency of registration of thermal neutrons by the foils made from natural gadolinium and its 157 isotope were carried out. In calculations, the low-energy

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electrons were taken into account. The received results are in a good agreement with the experimental data. We have estimated the contribution of X-ray and low-energy gamma-quanta absorbed directly in a material of the converter and resulting in occurrence of secondary electrons. At practical calculations, it is also necessary to take into account the absorption of quanta in materials of detectors. At such calculation, total efficiency can appear higher, as the part of electrons can be formed from quanta in a material of the detector. In our calculations, we take into account only an output of electrons from a material of the converter. In the case of the account of the contribution of electrons formed by X-ray quanta, the efficiency increased a little, but their contribution is insignificant. The occurred increase is no more than 1%. It is rather possible that X-ray quanta can affect essentially the total efficiency at the account of their absorption in a material of detectors. Therefore, gas detectors with Argon filling can increase the efficiency essentially. If the conversion of quanta will occur in a working body of the detector, then the full gathering of formed secondary electrons will take place. They can render even greater influences in the case of use of semi-conductor detectors. Calculations of complex converters representing a set of thin gadolinium foils located on both sides of supporting kapton foils were carried out. These calculations are of interest from the point of view of calculation of GEM structures. They have the similar geometry, but only contain apertures in 300 microns diameter and with 300 microns step. Thickness of the kapton foil considerably influences the efficiency of neutron registration. With the increase of thickness of a film, the probability of the secondary electron escape decreases. These kinds of converters could give a good result at application of natural gadolinium. The new solid-state converter of thermal neutrons is offered. The converter will consist of a set of thin gadolinium foils located one over another in a gas volume. Foils there will be drilled with the fine step (2 mm) with diameter of apertures 1 mm. These foils will have an optical transparency of 40%; correspondingly, gadolinium will fill 60% of a surface. Secondary electrons will emit for all sides, and in an electric field, they will be soaked up in apertures and further drift in the direction of the detector. As for a detector, there a various gas detectors, such as the multi-wire proportional chamber, multi-step avalanche and multistrip detectors, and so on, that can used. Calculations made for this complex converter representing a set of thin gadolinium foils located one over another in a gas volume were made. Similar converters can give good result at application of foils from natural gadolinium. Technologically, foil thickness should be more than 5 microns. Thinner films are difficult to drill. In this article, position - sensitive detector of thermal neutron radiation is described. These detectors use the solid-state converters such as normal-pressure multistep avalanche chambers (MSAC), low-pressure multistep avalanche chambers (LMSAC), microchannel plates, thin layer scintillators. New types of detectors are offered and developed such as hybrid low-pressure micro-strip gas chamber (MSGC), position sensitive silicon detectors (Gd Si PD), resistive plate chambers (RPCs), imaging plate neutron detectors (IP-NDs), liquid scintillator into a capillary plate and so on. Basic characteristics of MSAC were described. The factor of preliminary amplification of MSAC can reach the value 105. However, for reception of a stable mode without sparking it is necessary to choose it 106 registration of individual photoelectrons is possible. Extent of a plateau counting characteristic at registration gamma-quantums with energy 6 keV makes 800 V.

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MSAC extent of a plateau by efficiency 300 V possesses efficiency of registration of relativistic particles close to 100%. The energy resolution at registration gamma - quantums from a source 55Fe is equal to 18%. The time resolution at use of mixes based on argon 20 ÷ 30 nanoseconds (FWHM) and 15 nanoseconds (FWHM) at use of neon mixes. When measured, the spatial resolution of the detector was equal to 260 microns (FWHM) and 100 microns (σ). Spatial resolution MSAC at registration gamma - quantums with energy 6 keV was about 400 microns (FWHM). The opportunity of improvement of spatial sanction MSAC in case of registration non-collimated charged radiation by peak selection of events is shown. Thus on amplitude of signals it is possible to judge in the indirect images angle of an input of particles in the volume of the chamber. Application of the given way - "electronic collimation " - allows us to improve twice approximately the spatial resolution. The way can be as is applied at registration conversion electrons, let out by converters at registration of neutron and gamma - radiations. Dependence of characteristics of MSAC on concentration of molecular additives was investigated. So change of concentration of additives on ± 0,5% causes change G in ± 10 times. Extent of a plateau strongly depends on change of concentration of the additive as counting characteristics and time resolution MSAC. Ways of stabilization of operating mode MSAC, which at use of the above-stated mixes allow reaching long-term stability of work of the detector, are developed. Mathematical modeling of this work has been accomplished under the Project T-1157 of the International Science and Technology Center. I would like to thank Prof. H.Rauch and Dr. V.Dangendorf for interest in our works.

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REFERENCES P; Convert, JB. Forsyth, (eds.), Position-sensitive detection of thermal neutrons, Academic Press, London, 1983. Meardon, BH; Salter, DC. A Survey of Position Sensitive Detectors and Multi-Counter Arrays with Particular Reference to Thermal Neutron Scattering, 1972, RHEL-R-262, 91. Crane, TW; Baker, MP. Chapter 13, ―Neutron Detectors,‖ in Passive Nondestructive Assay of Nuclear Materials, edited by TD; Reilly, N; Ensslin, HA. Smith, US Nuclear Regulatory Commission NUREG/CR-5550, March 1991. Rauch, H; Grass, F; Feigl, B. Ein neuartiger fur langsame neutronen, Nuclear Instruments and Methods in Physics Research, 1967, 46, 150-153. Feigl, B; Rauch, H. Der Gd-neutronenzahler, Nuclear Instruments and Methods in Physics Research, 1968, 61, 349-356. Jeavons, AP; Ford, NL; Lindberg, B; Sachot, R. A new position-sensitive detector for thermal and epithermal neutrons, IEEE Transaction on Nuclear. Science, 1978, Vol.NS-25, No 1, 553-556. Charpak, G; Sauli, F. The multistep avalanche chamber: a new high-rate, high-accuracy gaseous detector, Phys. Letters, 1978, v. 78B, № 4, 523.

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Melchart, G; Charpak, G; Sauli, F. The multistep avalanche chamber as a detector for thermal neutrons, Nuclear Instruments and Methods in Physics Research, 1981, 186, 613. Abdushukurov, DA; Djuraev, AA; Evteeva, SS; et al., ―Model Calculation of GadoliniumBased Converters of Thermal Neutrons‖. Nuclear Instruments and Methods in Physics Research, 1994, v. B 84, 400. Abdushukurov, DA; Abduvokhidov, MA; Bondarenko, DV; et al., ―Modeling the registration efficiency of thermal neutrons by gadolinium foils‖, J. of Instrumentation, 2007, JINST, 2, PO4001, 1-13, Archives of Los Alamos National Laboratory USA, 2007, 1-19. http://arxiv.org/ftp/physics Abdushukurov, DA; Bondarenko, DV; Muminov, Kh.Kh; Chistyakov, DYu. ―Contribution of nano-scale effects to the total efficiency of converters of thermal neutrons on the basis of gadolinium foils‖. Archives of Los Alamos National Laboratory USA, 2008, 19. http://xxx.lanl.gov/ftp/arxiv/papers/0802/0802.0401.pdf. Gusev, NG; Dmitriev, PP. Quantum radiation of radioactive nuclear, Moscow, Energoatomizdat, 1977. Kozlov, VF. Manual for Radiation Safety, Moscow, Energoatomizdat, 1987. WWW Table of Radioactive Isotopes, Radiochemistry society, http://www.radiochemistry.org/periodictable/frames/isotopes Under edition I.K.Kikoin, The table of physical parameters, Moscow, Energoatomizdat, 1976. Evaluated Nuclear Data File (ENDF), IAEA-NDS, http://www.nndc.bnl.gov/ exfor3/endf00.htm. Thermal neutron Capture Gammas by Target, NDS, IAEA, http://www-nds.iaea.org/ oldwallet/tnc/ngtblcontentbyn.shtml. Hahn, O; Meitner, L. Z. Phys., 1924, 29, 169. Pauli, HC; Alder, K; Steffen, RM. ―The Theory of Internal Conversion‖ in The Electromagnetic Interaction in Nuclear Spectroscopy, edited by D. Hamilton, NorthHolland, Amsterdam, 1975, Chap.10 Rosel, F; Fries, HM; Alder, K; Pauli, HC. ―Internal Conversion Coefficients for all Atomic Shells‖, Atomic Data and Nuclear Data Tables, 1978, vol. 21, 91, Lee, MA; Nuclear data sheets for A=158, Nuclear Data Sheets, 1989, 56, 158. Bricc 2.0a. Band-Raman International Conversion Coefficients, BNL, http://www.nndc.bnl.gov/bricc/ Lederer, CM; Shirley, VS. Table of Isotopes, 7-th Edition, Wiley, New York, 1978. Chen, MH; Crasemann, B; Mark, H. Atomic Data and Nucl. Data Tables, 1979, vol. 24, 13. Krause, MO. J. Phys. Chem., Ref. Data, 1979, vol.8, 307. Dillman, LT. EDISTR - A Computer Program to Obtain a Nuclear Decay Data Base for Radiation Dosimetry,, Oak Ridge National Lab. Report ORNL/TM-6689, 1980. Larkins, FB. Atomic Data and Nucl. Data Tables, 1977, vol. 20, 313. Bethe, HA; Ashkin, J. ―Passage of radiations through matter‖, Experimental Nuclear Physics, Wiley, New York., 1953, vol.1, 166. Sternheimer, RM. ―The density effect for the ionization loss in various materials‖, Phys.Rev., 88, 851, 1952. Uehling, EA. ―Penetration of heavy charged particles in matter‖, Annual Rev. Nucl. Sci., 1954, No 4, 315.

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140

D. A. Abdushukurov

Conen, ER; Taylor, BN. ―The 1973 least-squares adjustment of the fundamental constants‖, J. Phys. Chem. Ref. Data, 1973, No 2, 663. Moller, C. ―Zur Theorie des Durchgangs schneller Elektronen durch Materiie‖, Ann. Phys., 1932, vol. 14, 568. Rohrlich, F; Carlson, BC. ―Positron-electron differences in energy loss and multiple scattering‖, Phys. Rev., 1953, vol. 93, 38. Inokuti, M. Inelastic collisions of fast charged particles with atoms and molecules- the Bethe theory revisited, Rev. Mod. Phys., 1971, vol.43, 297. Bichsel, H. Passage of charged particles through matter, in American Institute of Physics Handbook, 3rd Edition, D.E.Gray ed., New-York, 1972, 8. Walske, MC. Stopping power of L-electrons, Phys. Rev., 1956, vol. 101, 940. International Commision on Radiation Units and Measurements, Stopping Powers for Electrons and Positrons, 1984, ICRU Re 37. Bruckner, G; Czermak, A; Rauch, H; Welhammer, P. Position sensitive detection of thermal neutrons with solid state detectors (Gd Si planar detectors), Nuclear Instruments and Methods in Physics Research, 1999, A 424, 183. Murin, AN. Physics Principal of Radiochemistry, Moscow, Higher School, 1971. Abdushukurov, DA; Bondarenko, DV; Muminov, Kh.Kh; Chistyakov, DYu. ―Calculations of the Efficiency of Registration of Thermal Neutrons by Complex Converters Constructed on the Basis of Gadolinium Foils‖, Archives of Los Alamos National Laboratory USA, 2007, 1-22. http://xxx.lanl.gov/ftp/arxiv/papers/0711/0711.1282.pdf X-RAY DATA BOOKLET, Center for X-ray Optics and Advanced Light Source, LBNL, USA, http://ie.lbl.gov/ atomic/ x2.pdf/ Cohen, ER; Taylor, BN. The 1986 Adjustment of the Fundamental Physical Constants, CODATA Bulletin 63 (values republished most recently in Physics Today, August 1997, BG7-BG11). 1986. X-Ray Mass Attenuation Coefficients http:// physics. nist. gov/ PhysRefData/ XrayMassCoef/tab3.html Gebauer, B; Alimov, SS; Klimov, A.Yu. et al., Development of hybrid low-pressure MSGC neutron detectors, Nuclear Instruments and Methods in Physics Research, 2004, A 529, 358-364. Breskin, A; Charpak, G; Majewski, S. On the low pressure operation of multistep avalanche chambers, Nuclear Instruments and Methods in Physics Research, 1984, 220, 349. Abdushukurov, DA; Zanevsky, Yu.V; Movchan, SA; et al. "Multiwire Low Pressure Chamber with a High Gas Amplification Coefficient". Instruments and Experimental Techniques, 1983, v. 26, 1287. Dangendorf, A; Demian, H; Friedrich, et al., Thermal neutron imaging detectors combining novel composite foil convertors and gaseous electron multipliers, Nuclear Instruments and Methods in Physics Research, 1994, A 350, 503-510. Abbrescia, M; Iaselli, G; Mongelli, T; et al., Resistive Plate Chambers with Gd-coated electrodes as thermal neutron detectors, Nuclear Instruments and Methods in Physics Research, 2004, A 533, 149-153. Kenji Takahashi, Seiji Tazaki, Junji Miyaharaa, et al., Imaging performance of imaging plate neutron detectors, Nuclear Instruments and Methods in Physics Research, 1996, A 377, 119-122.

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Gunji, S; Yamashita, Y; Sakurai, H; et al., Development of Neutron Imaging Detector Using Capillary Phenomena and Liquid Scintillator, 2005, IEEE Nuclear Science Symposium Conference Record, 2899-2902. Gilvin, PJ; Matheison, E; Smith, GC. Position resolution in Multiwire Chamber with Graded-Density Cathodes, IEEE Trans., Nucl. Sci., 1981, v. NS-28, No 1, 835. Abdushukurov, DA; Abduvokhidov, MA; Bondarenko, DV. «Spatial Resolution of the Multistep Avalanche Chambers», Instruments and Experimental Techniques, 2007, Vol. 50, No. 3, 333-335. Abdushukurov, DA; Zanevskii, Yu.V; Peshekhonov, VD. ―Effect of gas-mixture composition on characteristics of multistage cascade chambers‖, Instruments and experimental techniques, 1989,Vol. 32, No 1, pt 1, 78-81. Abdushukurov, DA; Abduvaliev, AA; Abduvokhidov, MA; Muminov, Kh.Kh. ―Structural Features of the Multistep Avalanche Chambers‖, Instruments and Experimental Techniques, 2007, Vol. 50, No. 1, 37-40. Breskin, A; Charpak, G; Sauli, F. A Multistep Parallax Free Imaging Counter, CERNEP/81/106, CERN, 1981.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.143-165 © 2010 Nova Science Publishers, Inc.

Chapter 3

TOXICITIES ASSOCIATED WITH GADOLINIUM CONTRAST IN PATIENTS WITH KIDNEY DISEASE Mark A. Perazella* Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8029

ABSTRACT

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Gadolinium-based contrast (GBC) agents have garnered intense interest from several groups including physicians across numerous specialties, patients and lawyers. These image-enhancing agents are widely employed as contrast for magnetic resonance imaging (MRI) and have been generally considered safe. Early studies, in particular phase III trials and small studies in low risk patients suggested a benign renal profile. These data led to the widespread use of these agents for imaging in patients with kidney disease as a safe alternative to iodinated radiocontrast. More recent studies raise the possibility of nephrotoxicity. However; GBC agents clearly do not approach the incidence of nephropathy associated with iodinated radiocontrast, but high doses in at risk patients can cause acute kidney injury. Another complication of GBC agents came to light in 2006. Reports of a rare systemic fibrosing condition entitled nephrogenic systemic fibrosis (NSF) were recently linked to exposure of patients with advanced kidney disease to GBC-agents. Analysis of the data suggests that certain GBC agents are more likely to be associated with NSF. Also, not all patients with kidney disease are at risk to develop NSF, only those with advanced acute or chronic kidney disease. When appropriate, avoidance of GBC exposure is the best approach for high-risk patients. At times when GBC agents are required to obtain optimal images, use of low doses of more stable macrocyclic agents is safer and preferred. This chapter will review the status of GBC agents as causes of acute kidney injury and triggers of NSF, while also providing an opinion on how to use these agents in patients with underlying kidney disease.

*

Corresponding author: Tel 203-785-4184, Fax 203-785-7068, Email: [email protected]

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Keywords: gadolinium, toxicity, acute kidney injury, nephrogenic systemic fibrosis, chronic kidney disease, end stage kidney disease, magnetic resonance imaging, radiocontrastinduced nephropathy, osmolality, viscosity.

INTRODUCTION

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The end of 1980s brought a new form of imaging--magnetic resonance imaging (MRI) into clinical practice. This technology has been employed to image numerous organ systems including the central nervous system, hepatic structures, and the vasculature. MR images are significantly enhanced by use of gadolinium-based contrast (GBC) agents, which often provide images that are superior to those obtained with computed tomography (CT) scan. They also have the advantage of avoiding iodinated radiocontrast agents which have more overall toxicity (allergic and non-allergic reactions). Thus, imaging with GBC agents has been considered a relatively safe alternative to CT scan in situations where a radiocontrast agent is thought required for enhanced image attainment. However, two complications of gadolinium-based contrast agents have come to light in recent times. First, concern for GBC agent-induced acute kidney injury (AKI) has been raised as a potential problem based on several studies in patients with underlying kidney disease and other co-morbidities over the past decade. GBC agents are similar to iodinated radiocontrast in that they are hyperosmolar and completely eliminated from the body the kidneys (glomerular filtration). Second, and potentially more concerning is the recognition that GBC agent exposure in patients with advanced kidney disease may trigger the development of nephrogenic systemic fibrosis (NSF), a debilitating and often devastating systemic fibrosing condition (1-12). This chapter will focus on the status of these clinically important complications of GBC agents in patients with underlying kidney disease.

Gadolinium-Based Contrast Agents General properties Gadolinium (Gd) is a lanthanide metal with atomic number 64 on element chart, which has paramagnetic properties that disturb relaxation of water protons and by shortening relaxation times, increases signal intensity. This physical quality makes this metal an excellent intravenous and/or intra-arterial contrast agent to improve imaging of various tissues and organs. As it is a metal, it must be in an ionic form to be soluble in water and allow it to be injected as a contrast agent that distributes throughout the body. However, gadolinium in this free ionic form (Gd3+) is highly toxic. Gadolinium obstructs passage of calcium through ion channels of muscle cells and nerve tissue cells thereby reducing neuromuscular transmission, and interferes with intracellular enzymes and cell membranes. The toxic effects of gadolinium are circumvented by sequestration of the metal by a nontoxic substance, in this case a "chelate" (13). Chelates are large organic molecules that form a stable complex with Gd3+, do not readily dissociate in vivo, and make the ion biochemically inert (13,14). The GBC agents are classified into four main categories based on their biochemical structure (linear versus macrocyclic) and their charge (ionic versus non-ionic)

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(Figure 1). Macrocyclic chelates bind Gd3+ more tightly than linear chelates, tend to be more stable both in vitro and in vivo, and possess lower dissociation rates (15). The different properties of the chelates have implications for possible toxicity and the risk for liberation of free Gd3+ from its chelate, a process known as transmetallation. The phenomenon of transmetallation entails release of free Gd3+ from its chelate ligand, which then binds with another endogenous metal such as zinc or copper, allowing free Gd3+ to bind an endogenous ligand such as phosphorus. The characteristics of the commonly employed Food and Administration Drug (FDA) approved GBC agents and iodinated radiocontrast agents are noted in Table 1.

Pharmacokinetics Following intravenous or intra-arterial injection, GBC agents are rapidly distributed into the extracellular space, quickly equilibrating between the plasma and interstitial compartments. They are restricted to the extracellular space, have limited protein binding, and do not undergo biotransformation. These agents have small volumes of distribution, approximately 0.26 - 0.28 L/kg body weight, due to their exclusion from the intracellular compartment. They are eliminated unchanged by the kidneys via glomerular filtration without any contribution from tubular secretion. Renal clearance of GBC agents ranges from 1.1 to 1.6 ml/min/kg in individuals with normal renal function, approximating creatinine clearance (CrCl) and maintain a mean terminal half-life (T1/2) of approximately 1.3 - 1.6 hours. Over 95% of an injected dose is eliminated within 24 hours with less than 3% being eliminated in the feces (13,14,16). Hence, kidney function is important in overall terminal half-life. Table 1. FDA approved contrast agents

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GBC Formulation

Molecular Structure/Charge

Gadodiamide Linear Non-ionic (Omniscan) Gadopentetate Linear Ionic (Magnevist) Gadoversetamide Linear Non-ionic (OptiMARK) Gadobenate Linear Ionic (MultiHance) Gadoteridol Cyclic Non-ionic (Prohance) Iodinated Radiocontrast Diatrizoate Monomer Ionic Iopamidal, Monomer Iohexol Non-ionic Iodixanol Dimer Non-ionic Iosmenol Dimer Non-ionic

Osmolality (mosm/l)

Viscosity* (mPa.S)

Stability Constant

900

1.4

1014.9

Excess Chelate (mg/ml) 12

1960

2.9

1018.1

0.4

1110

2.0

1015

28.4

1970

5.3

1018.4

0.1

630

1.3

1017.1

0.23

1980 600-1000

6.0 5-10.0

N/A N/A

N/A N/A

280 280

11.0 7.0

N/A N/A

N/A N/A

Abbreviations: GBC, gadolinium-based contrast. * Contrast Media Industry Guide data.

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Figure 1. Structures of gadolinium-based contrast agents, which vary on the basis of linear vs. macrocyclic structure and ionic vs. non-ionic charge

As noted in pharmacokinetic studies, the volume of distribution for intravenous GBC agents is similar for patients with moderate (CrCl, 31 - 60 ml/min; n = 15) and severe (CrCl, 15 - 30 ml/min; n = 17) kidney disease when compared with healthy subjects. However, the mean blood and renal clearances are both much lower in moderate (56 ml/min; 47 ml/min) and severe (31 ml/min; 22 ml/min) kidney disease than in normal subjects (183 ml/min; 118 ml/min). The mean terminal T1/2 is prolonged in moderate (5.6 hours) and severe (9.2 hours) kidney disease as compared with healthy subjects (1.3-1.6 hours). Comparable pharmacokinetics of GBC agents in patients with underlying kidney disease have been reported in other studies (17,18). The relatively small molecular weight (500 Daltons), small volume of distribution (0.28 L/kg), and negligible protein binding characteristics of GBC agents predicts that they can be removed by hemodialysis. In one study, the T1/2 of GBC agents of non-dialyzed CKD stage V (CrCl = 2 - 10 ml/min) patients was prolonged at 34.3 hours but decreased significantly to 2.6 hours following hemodialysis (19). Another study noted that the average GBC agent serum elimination using hemodialysis was approximately 74% with one treatment, 92% with 2 treatments and 99% after the 3rd treatment (20,21). In contrast, peritoneal dialysis was an ineffective method of GBC agent removal (T1/2 of approximately 53 hours) (19). It is important to recognize that this study suffers by the use of what is now considered an inadequate peritoneal dialysis prescription (2.0 liter volumes for 4 exchanges over a 24 hour period). It is possible that a more aggressive prescription might enhance peritoneal clearances of the GBC agent, but this is currently untested.

Nephrotoxicity of Gadolinium-Based Contrast Agents Iodinated radiocontrast-media induced AKI is well described and quite common in at risk populations. It is a particularly vexing problem in patients with underlying kidney disease, the elderly, patients with diabetes mellitus, and in the setting of other co-morbidities.

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Radiocontrast-induced nephrotoxicity (RCIN) is associated with significant morbidity, increased hospital length of stay, and increased in-hospital, 1 year and 5 year mortality. However, the issue of GBC agent-induced nephrotoxicity is somewhat controversial. Since GBC agents have characteristics very similar to those of iodinated radiocontrast (Table 1), in particular hyperosmolality and renal clearance entirely dependent upon glomerular filtration, nephrotoxicity was an obvious initial concern of both manufacturers and physicians. However, as GBC agents have significantly lower viscosity and are used at significantly lower volumes (4 - 11 times less) than radiocontrast, these characteristics may make them potentially less nephrotoxic. For example, a typical body CT scan uses 150 ml of radiocontrast whereas a typical MRI study (0.1 - 0.3 mmol/kg) uses 14 - 42 ml of GBC. Thus, it is possible that GBC agents could be similarly nephrotoxic as radiocontrast, minimally nephrotoxic or completely free of nephrotoxicity. The nephrotoxicity of GBC agents will be compared with that of iodinated radiocontrast agents will be employed as a frame of reference for the reader.

Experimental studies The potential nephrotoxicity of GBC agents was initially examined in experimental animals. Studies utilizing multiple different animals (mice, rats, rabbits, pigs, dogs) were undertaken using a range of doses (0.6 - 3.0 mmol/kg). As a reference, FDA approved GBC agent doses are 0.1 mmol/kg, while doses of 0.3 mmol/kg are utilized off label for some imaging studies of the vasculature, particularly angiograms. When compared with human doses, those employed in experimental animals ranged from large (0.6 - 1.0 mmol/kg) to massive (1.0 - 3.0 mmol/kg) (22). Serum and urinary markers of renal injury were studied. In general, no or mild increases in blood urea nitrogen and serum creatinine concentrations were noted, while mild elevations in urinary tubular cell enzymes occurred. When nephrotoxicity, albeit mild, actually developed the gadolinium-based contrast agent was administered in very high doses, generally greater than 1.0 mmol/kg, to animals with normal kidney function (22). Histopathology demonstrated vacuolization and necrosis of cortical tubular epithelial cells. These data suggest limited nephrotoxicity, however, high risk animals with underlying kidney disease were not examined in these experiments. Human studies Initial phase III trials examined the potential adverse renal effects of GBC agents. Early studies in normal healthy subjects as well as small groups of patients with mild to moderate levels of underlying kidney disease suggested a relatively favorable renal safety profile (23, 24). Based on this limited data, the GBC agents were considered relatively safe for use in patients with underlying kidney disease, even with the high doses required for vascular imaging. This led to the frequent use of GBC agent exposure where most other imaging techniques were not sufficiently diagnostic (renal scans and ultrasonography) or were considered too risky (CT angiograms with iodinated radiocontrast). The importance of this issue deserves emphasis as numerous patients considered at high risk for radiocontrastinduced nephropathy (RCIN) from an iodinated radiocontrast study were exposed to a GBC agents as a "kidney safe" alternative. Critical review of the literature on this subject is undertaken and some of the pertinent studies published on this subject will be reviewed.

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Literature supporting renal safety of gadolinium-based contrast agents Several studies are available suggesting that GBC agents lack significant kidney toxicity (Table 2). A phase III trial examining the renal safety of GBC agents was published in 1993. A large number of patients (n = 1171) were exposed to a 0.1 mmol/kg dose of high osmolar (1960 mOsm/L)/low viscosity (2.9 mPa.S) gadopentetate (23). Patients were grouped according to serum creatinine concentration (< 1.3, 1.3 - 1.4, > 1.4 mg/dl) and change in serum creatinine 24 hours following GBC agent exposure was examined. No significant change in serum creatinine concentration developed in the 3 groups. Two small subgroups of high-risk patients with more severe kidney disease (GFR 20 - 40 ml/min; n = 10 and GFR < 20 ml/min; n = 5) were also evaluated. These groups developed a mean increase in serum creatinine concentration of 0.25 mg/dl at 5 days. Table 2. Gadolinium-based contrast agent renal safety Author Year Niendorf23 1993

Arsenault25 1996

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Prince26 1996 Swan16 1999 Hammer27 1999 Spinosa28 2000

Spinosa29 2001 Sancak30 2001 Rieger31 2002

Study

Contrast Agent Gadopentetate

Dose (mmol/kg) 0.1

Renal function ([Cr] in mg/dl) [Cr] < 1.3, [Cr] >1.3-1.4, [Cr] > 1.4

Retrospective, N = 136 N = 90 with pre/post [Cr] at 3 days Retrospective, N=64 [Cr] 2d pre and 2d post, CIN ≥ 0.5 mg/dL Prospective, double blind random, 32 pts (2:1), CIN > 0.5 mg/dL N = 31, 34 DSAs, Mean age 53.1 CIN > 0.5 mg/dL N = 40, LE angiograms 42 procedures RC- 15, GBC- 20 CIN ≥ 0.5 mg/dL at 48 hr Consecutive patients treated with GBC + CO2, CIN > 0.5 mg/dL at 48 hr N = 16, IV GBC for upper extremity or SVC

Gadopentetate

0.1

[Cr] > 2.0, mean [Cr] = 2.5

Gadopentetate Gadodiamide Gadoteridol Gabobenate dimeglumine

0.2 - 0.4

Gadopentetate

0.4

[Cr] > 1.5, Mean [Cr] = 2.0±1.4 CrCl 10-30, CrCl 31-60, 24 hr urine [Cr] > 1.5

Gadodiamide

up to 0.4

Gadodiamide

< 0.3

Gadodiamide

0.3

Prospective, N = 29, 32 procedures (IA & IV) CIN > 0.5 mg/dL at 72 hr

Gadopentetate

0.34 ± 0.06

Phase III Trial, N = 1171 [Cr] at 24 hours, subgroup with [Cr] at 5 days

0.2

Result No change in [Cr], Subgroup of pts: GFR 20-40: [Cr]  0.25 GFR < 20: [Cr]  0.25 No change in [Cr] Baseline: 2.5 to day 3: 2.3 CIN: RC- 11/64 (17%) GBC- 0/64 (0%) No CIN

CIN: 1/34 (3%)

[Cr] > 1.5, Mean [Cr] = 2.2, Range [Cr] = 1.63.6 [Cr] > 1.5,

RC- 6/15 (40%) GBC- 1/20 (5%)

Mean [Cr] = 1.5, Range [Cr] = 1.21.8 [Cr] > 1.5 Mean [Cr] = 3.6

Largest increase in [Cr] = 0.2 mg/dL 1/29 (atheroemboli)

CIN: 3/95 (3%)

Abbreviations: GBC, gadolinium-based contrast; RC, iodinated radiocontrast; GFR, glomerular filtration rate; CrCl, creatinine clearance; [Cr], serum creatinine concentration; CIN, contrastinduced nephropathy; ref, reference; DSA, digital subtraction angiogram; LE, lower extremity; SVC, superior vena cava; IV, intravenous; IA, intra-arterial.

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Two retrospective studies published in 1996 also demonstrated a fairly safe renal profile for the GBC agents. Arsenault and colleagues reviewed 90 of 136 patients with a mean serum creatinine concentration of 2.5 mg/dl (stage III/IV CKD utilizing back calculation) who were exposed to 0.1 mmol/kg of gadopentetate and had pre/post serum creatinine measurements (25). Day 3 serum creatinine concentrations were unchanged (2.5 to 2.3 mg/dl), suggesting absence of nephrotoxicity. In another study, a cohort of 64 patients with mild CKD as defined by baseline serum creatinine concentration of 2.0  1.4 mg/dl were examined (26). All patients received both GBC agent and iodinated radiocontrast at separate times, thus serving as their own control. The rate of contrast-induced nephrotoxicity, as defined by a rise in serum creatinine concentration of 0.5 mg/dl following each exposure, was compared between the 2 different exposures. The dose of GBC agents administered during the study ranged from 0.2 - 0.4 mmol/kg. No patient receiving the GBC agents developed AKI as compared with 17% of patients receiving iodinated radiocontrast. A prospective study of 32 patients with moderate (CrCl, 31-60 ml/min; n = 15) and severe (CrCl, 10-30 ml/min; n = 17) kidney disease was undertaken to examine GBC agent pharmacokinetics and renal safety (16). Patients received 0.2 mmol/kg of intravenous gadobenate, which has an osmolality of 1970 mosm/L and viscosity of 5.3 mPa.S. Twentyhour urine CrCl before and at days 1, 2, 3, 5, and 7 following gadobenate exposure was measured. There was no significant change in CrCl at any time point in the study, supporting the absence of any clinically important nephrotoxicity. Patients with kidney disease (serum creatinine concentration greater than 1.5 mg/dl) were studied using gadopentetate (0.4 mmol/kg dose) as an alternative imaging agent in patients who were allergic to iodinated radiocontrast (27). Thirty-one patients underwent 34 digital subtraction angiographies with this hyperosmolar (1960 mosm/L) but low viscosity agent (2.9 mPa.S). Only one out of 34 exposures was complicated by AKI, which was defined as an increase in serum creatinine concentration greater than 0.5 mg/dl. A study in patients with CKD (mean serum creatinine concentration of 2.2 mg/dl; range, 1.6 - 3.6 mg/dl) and peripheral vascular disease was undertaken to compare nephrotoxicity of nonionic radiocontrast with CO2 supplemented with either GBC agent (up to 0.4 mmol/kg of gadodiamide) or nonionic radiocontrast (28). Forty patients underwent 42 lower extremity angiograms using one of the following contrast protocols: radiocontrast (n = 15), gadodiamide (n = 20), and CO2 (n = 7). All received 300-500 ml of normal saline prior to contrast exposure as prophylaxis. Contrast-induced nephropathy was defined as an increase in serum creatinine concentration greater than 0.5 mg/dl at 48 hours post procedure. Contrastinduced nephropathy developed in 6 out of 15 (40%) iodinated radiocontrast studies but only 1 out of 20 gadodiamide exposures (5%). The same authors subsequently published another study which again supported GBC agent safety in patients with CKD and ischemic nephropathy (29). One hundred forty-six consecutive patients with a serum creatinine concentration greater than 1.5 mg/dl underwent renal angiography using a combination of CO2 and gadodiamide (osmolality, 800 mOsm/L; viscosity, 1.4 mPa.S). Contrast-induced nephropathy was defined as an increase in serum creatinine concentration greater than 1.5 mg/dl at 48 hours; 95 patients had data available for study. Three patients (3.2%) developed AKI. The absence of a control group makes it difficult to draw firm conclusions, however, this incidence is less than what is commonly seen in similar patients exposed to iodinated radiocontrast.

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In 2001, 16 patients with mild CKD (mean serum creatinine concentration equal 1.5 mg/dl; range = 1.2-1.8 mg/dl) underwent intravenous studies with gadodiamide at a dose of 0.3 mmol/kg (30). No patient developed clinically significant kidney dysfunction. The largest increase in serum creatinine concentration was 0.2 mg/dl. Lastly, a study published in 2002 prospectively examined 29 patients with chronic kidney disease stage IV (mean serum creatinine concentration of 3.6 mg/dl; range, 1.6 - 7.0 mg/dl) that received 0.34 mmol/kg of gadopentetate (31). In contrast to other studies, intravenous saline was employed as prophylaxis. A total of 32 procedures were performed on these patients. None of the patients developed GBC agent-induced AKI as defined as an increase in serum creatinine concentration greater than 0.5 mg/dl, over a 3 day period of observation. There was no change from baseline mean serum creatinine concentration at 24 and 72 hours (3.6  3.5  3.6 mg/dl). One patient developed AKI; however, this was attributed to renal atheroemboli rather than GBC agent injury. Table 2 summarizes the studies. It is notable that GBC agent-associated AKI developed in 0 to 5% of patients, which was less than iodinated radiocontrast (17 and 40%). The mean baseline serum creatinine in the group was approximately 2.8 mg/dl (range 1.5 - 3.6 mg/dl) and the mean dose of GBC agent was 0.21 mmol/kg (range 0.1 - 0.4 mmol/kg). Predominantly intravenous injection of GBC agents was employed in these studies.

Literature supporting nephrotoxicity with gadolinium-based contrast agents In contrast to the prior reports supporting renal safety, a number of studies suggest that GBC agents exhibit variable degrees of nephrotoxicity (Table 3). In 2003, a retrospective study was published that examined the effect of both intra-arterial (n = 42) and intravenous (n = 153) gadopentetate (1960 mOsm/L; 2.9 mPa.S) on kidney function in 260 patients, of which 195 had underlying CKD (32). The average dose of high osmolality/low viscosity gadopenetate was 0.28 mmol/kg and no contrast prophylaxis was provided. CKD patients who received intravenous and intra-arterial gadopentetate had mean baseline serum creatinine concentrations of 2.1 mg/dl (estimated CrCl = 61 ml/min) and 2.6 mg/dl (estimated CrCl = 40 ml/min), respectively. Contrast-induced AKI, defined as an increase in serum creatinine concentration greater than 1.0 mg/dl within 48 hours developed in 3.5% (7/195) of the entire population: 1.9% (3/153) with intravenous and 9.5% (4/42) with intra-arterial administration. In the 7 patients who developed nephrotoxicity, the average baseline serum creatinine concentration was 2.5 mg/dl; 4 had diabetes and 5 had hypertension. In patients that did not suffer from nephrotoxicity, the average baseline serum creatinine concentration was 2.2 mg/dl. Also of note was the difference in GBC agent dose in each group (AKI patients, 0.37 mmol/kg; non-AKI patients, 0.27 mmol/kg). Although this study was retrospective and did not have a control group, the high rate of AKI seen in this population was evidence for GBC nephrotoxicity. Not surprisingly, more advanced kidney disease, diabetes and hypertension, and higher GBC agent dose were risk factors for AKI. In a prospective study, 21 CKD patients with a serum creatinine concentration greater than 1.5 mg/dl (eGFR < 50 ml/min/m2) were randomized to either high dose gadobutrol (0.34 - 0.90 mmol/kg) or iohexol for digital subtraction angiography (33). Ten patients receiving gadobutrol had a baseline eGFR of 34 ml/min and 60% had diabetes mellitus while the iohexol group (n = 11) had an eGFR of 29 ml/min with 36% of the patients having diabetes mellitus. Both groups received intravenous fluids prior to contrast. Contrast-induced AKI,

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which was defined as a 50% decrease in eGFR within 48 hours, developed in 45% of iohexol patients and 50% of gadobutrol patients; none of which required renal replacement therapy. A retrospective study examined 91 patients with stage III (n = 50) and IV (n = 41) CKD for nephrotoxicity (increase in serum creatinine concentration of 0.5 mg/dl within 24 - 72 hours) following GBC agent exposure (34). The patients received one of three different GBC preparations at a dose of 0.2 mmol/kg without any form of prophylaxis. Approximately 20% of patients had diabetes mellitus and 80% hypertension. Eleven patients (12.1%) developed RCIN, again suggesting that GBC agents can be nephrotoxic. Six of these patients had diabetes mellitus and 9 had stage IV CKD. No patient required renal replacement therapy for AKI. A prospective study in 25 patients with CKD (mean serum creatinine concentration of 2.3 mg/dl) and a matched historical control (n = 32) examined the nephrotoxicity of 2 different GBC agents administered during cardiac catheterization (35). Contrast prophylaxis with 0.45% saline and N-acetylcysteine was provided to all patients. In the GBC agent group, a contrast mixture that contained 0.6 mmol/kg of GBC agent and 0.4 ml/kg of iso-osmolar nonionic radiocontrast was compared with the same iso-osmolar radiocontrast agent alone in the historical control group. The 2 contrast protocols were considered equivalent based on the concept of "x-ray attenuating doses", a term accepted by radiologists. In the GBC/iso-osmolar contrast group, 28% of patients developed an increase in serum creatinine concentration of 0.5 mg/dl within 48 hours as compared with 6.5% in the radiocontrast alone historical control group. It is hard to compare the 2 groups as mixtures of GBC agent and iodinated contrast were utilized and a historical control was the comparison group. Finally, a recently published retrospective study in 163 CKD patients undergoing percutaneous renal angiogram for resistant hypertension or ischemic nephropathy compared the rates of contrast-induced AKI between GBC agent, a mixture of GBC and iodinated radiocontrast and iodinated radiocontrast alone (36). The majority of patients had stage IV CKD (81%), while 15% had stage III and 4% had stage V CKD. Contrast-induced AKI was defined as an increase in serum creatinine concentration of 0.5 mg/dl within 7 days of the procedure. The groups were well matched with respect to age, diabetes mellitus, and hypertension. The baseline estimated creatinine clearance was significantly (p < 0.02) lower in the GBC agent groups (23.1 ml/min) as compared with the radiocontrast alone group (27.5 ml/min). All groups received similar rates of intravenous fluid prophylaxis, while the GBC agent group was exposed to a significantly (p = 0.01) lower dose of GBC (76 ml) as compared with radiocontrast alone group (102 ml). Acute kidney injury developed in 5.3% of GBC agent exposed patients compared with 10.5% in the GBC/radiocontrast group and 20.6% in the radiocontrast alone group (p < 0.01). Table 3 summarizes the studies. It is notable that GBC agent associated nephrotoxicity developed in 3.6 to 50% of patients, which was equal to or greater than the rate seen with iodinated radiocontrast (6.5 to 45%). The mean baseline serum creatinine concentration in the GBC agent group was approximately 3.3 mg/dl (range 2.5 - 4.0 mg/dl) and the mean dose of GBC agent was 0.42 mmol/kg (range 0.2 - 0.6 mmol/kg). In addition, the majority of studies utilized arterial injection of GBC agent. Compare these data to the studies where only 0 to 5% of patients developed nephrotoxicity post GBC agent exposure: mean baseline serum creatinine concentration approximately 2.8 mg/dl (range 1.5 - 3.6 mg/dl), mean GBC agent dose approximately 0.21 mmol/kg (range 0.1 - 0.4 mmol/kg), and primarily intravenous injection of GBC agent.

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Mark A. Perazella Table 3. Gadolinium-based contrast agent renal toxicity

Author Year Sam32 2003

Erley33 2004

Briguori35 2006

Ergun34 2006

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Kane36 2008

Study

Contrast Agent Gadopentetate

Dose (mmol/kg) 0.28

Renal function ([Cr] in mg/dl) CrCl < 80 ml/min, CG = 38.2±16 ml/min

Randomized prospective N = 21 CIN >50% decrease in GFR Retrospective, N = 25, (historical controls, N = 32) CIN ≥ 0.5 mg/dL within 48 hr or dialysis within 5 days Retrospective, N = 91 [Cr] measured pre-GBC, days 1, 3, and 7, and 1 mo, CIN ≥ 0.5 mg/dL within 72 hr

Gadobutrol = 10 Iohexol = 11

0.57±0.17

[Cr] > 1.5 or CrCl < 50 ml/min/1.73m2

Gadodiamide = 8 Gadobutrol = 17 3:1 mixture with RC

0.6±0.3 0.28-1.23

[Cr] > 2 mg/dL or CrCl < 40 ml/min

Gadopentetate Gadodiamide Gadoterate

0.2

Stage III & IV CKD Mean [Cr] = 33 ml/min Range CrCl = 15-58

CIN: 11/91 (12.1%) CKD Stage IV: 9/11 with CIN

Retrospective, N = 163 [Cr] measured pre-GBC and within 7 days, CIN ≥ 0.5 mg/dL within 7 days

GBC agent, GBC + RC mixture, RC alone

GBC-76 ml, GBC + RC mixture55 + 37 ml, RC-102 ml

Stage III-V CKD GBC [Cr] = 2.77 GBC+RC [Cr] = 2.63 RC [Cr] = 2.48

CIN: GBC: 5.3% GBC + RC: 10.5% RC: 20.6%

N = 195 with CKD No control group CIN > 1.0 mg/d at 48 hr with oligoanuria

Result CIN: 7/195 MRA: 3/153 (1.9%) DSA: 4/42 (9.5%) CIN: GBC: 5/10 (50%) RC: 5/11 (45%) CIN: GBC: 7/25 (28%) RC: 2/32 (6.5%)

Abbreviations: CKD, chronic kidney disease; GBC, gadolinium-based contrast; RC, iodinated radiocontrast; CIN, contrast-induced nephropathy; [Cr], serum creatinine concentration; MRA, magnetic resonance angiography; DSA, digital subtraction angiography; CrCl, creatinine clearance; mo, month; hr, hours; GFR, glomerular filtration rate.

Gadolinium-based contrast nephrotoxicity: What should we conclude? Drawing a conclusion from the information reviewed above is somewhat difficult. Data from the studies are hampered by the use variable designs, small numbers of patients, wide ranges of GBC agent dose, non-uniform measures of kidney function, patients with varying levels of kidney function, erratic use of contrast prophylaxis, and poor controls or lack of control groups altogether. In general, the majority of studies suggest renal safety, but clearly GBC agent-induced nephrotoxicity can develop. On balance, it appears that GBC agents are less nephrotoxic than iodinated radiocontrast. One can speculate that this is due to the lower viscosity of these agents as well as the much lower dose (volume) of GBC agent required to achieve imaging. That being said, there appears to be adequate data to suggest that GBC agents have enough of a nephrotoxic potential that caution should be exercised with their use in patients with advanced (stage IV/V) CKD, and possibly even more caution in patients with concurrent CKD, diabetes mellitus and hypertension. Higher doses of GBC agents and intraarterial injection also are likely risk factors for development of AKI in at risk patients. It is impossible to know if "contrast prophylaxis" is useful in the prevention of RCIN. Thus, it is prudent to employ the lowest dose of GBC agent possible to achieve adequate image quality in higher-risk patients.

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Gadolinium-Based Contrast and Nephrogenic Systemic Fibrosis

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Nephrogenic systemic fibrosis: A new disease A previously unrecognized fibrosing disorder of the skin that was histologically similar to scleromyxedema was noted in nine renal transplant recipients with failed allografts requiring chronic dialysis, five ESRD patients on chronic dialysis, and one AKI patient (7). Following a publication describing the cases, the disease was initially called a "scleromyxedema-like disorder of renal dialysis patients". In a subsequent publication, the entity was descriptively coined "nephrogenic fibrosing dermopathy" (NFD) after detailed examination of the clinical and histopathologic data of 14 cases (7). Despite evaluation by the Centers for Disease Control and Prevention (CDC) and California Department of Health, a specific etiology or trigger was not identified, but advanced kidney dysfunction was a common thread. The subsequent recognition that fibrosis also occurred in systemic organs, led to a new name for the disease "nephrogenic systemic fibrosis" (NSF). Briefly, this process symmetrically affects the extremities (lower >upper) more so than the trunk, the face is always spared. Initial symptoms and signs include sharp pain and burning associated with redness and swelling of the skin. Rash, papules, plaques and other skin lesions may develop and progress over a matter of weeks to months to extensive dermal fibrosis, often producing marked joint contractures and severe limitations in mobility. A wheelchair dependent or bed bound state may ensue (6). Systemic organs involvement (liver, heart, lungs, diaphragm, esophagus, kidneys, brain and skeletal muscle) has also been reported and may be associated with fatal consequences (6,7). Gadolinium-based contrast agents: The NSF trigger After the initial report of cases, the NSF literature consisted predominantly of case reports/case series with the cause being ascribed to any of a number of potential agents or associations. However, no unifying agent or risk factor except for underlying kidney disease was identified. In 2006, a major breakthrough occurred when Grobner reported the development of NSF in 5 ESRD patients exposed to gadodiamide in the setting of metabolic acidosis (2). Subsequently, several centers have confirmed this association. Marckmann and colleagues described 13 patients (ESRD and stage V CKD) in Denmark who developed symptoms of NSF within 2 to 75 days post exposure to gadodiamide (3). A case control study noted NSF in 3 patients exposed to gadolinium contrast (2 gadodiamide, 1 gadopentetate) demonstrating an incidence of 4.3 cases per 1000 patient years (37). This was associated with an absolute risk of 3.4% for development of NSF in an exposed patient. Another 12 patients with either AKI or ESRD on dialysis were noted to develop NSF following gadodiamide exposure (2-11 weeks), with an odds ratio of 22.3 (4). Six patients with variable levels of kidney disease were also described to develop NSF following gadodiamide (5). The onset of symptoms ranged form 19 days to 2 months. The CDC published the results of a case control study of 19 patients with either ESRD or dialysis-requiring AKI with confirmed NSF (38). The type and dose of GBC was subsequently identified as gadodiamide (except for 3 exposures with gadoversetamide). Thirteen cases of NSF following gadodiamide administration in ESRD or AKI patients were published (39). They also confirmed the high mortality (31%) associated with this disease state. Most recently, a case control study of 19 ESRD/CKD patients exposed to a high cumulative gadodiamide developed NSF (40). It is

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notable that NSF has been reported in most European countries including Denmark, United Kingdom, Austria, Belgium, the Netherlands, Norway, Sweden, and Switzerland (1,41). The odds ratio for developing NSF in exposed versus unexposed patients with ESRD/CKD from 4 case control studies (37,40,42,43) are all greater than 20 for occurrence of NSF following GBC agent exposure. These data are supported by systematic review and meta-analysis, which notes an odds ratio of 26.7 for development of NSF following GBC agent exposure (44).

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Evidence to incriminate gadolinium-based contrast agents in NSF Further evidence of the importance of GBC agents as a trigger for NSF was provided by documentation of Gd3+ within the tissues of patients with NSF using scanning electron microscopy and energy dispersive x-ray spectroscopy (45,46). In addition to this qualitative evidence, High and coworkers quantified the concentration of Gd3+ in tissues of the NSF patients previously examined (47). They found that the NSF tissues contained 35-150 fold higher amounts (5-106 parts per million [ppm]) than the tissues of healthy subjects (0.4771.77 ppm) exposed to GBC. The authors speculate that phagocytosis of Gd3+ retained in tissues by macrophages results in production of profibrotic cytokines that eventuate in dermal and/or systemic fibrosis. Others have confirmed these findings with even more sensitive techniques. Schroeder and colleagues demonstrated deposition of Gd3+ in tissues of NSF patients that were associated with iron deposits and located in the perivascular area (48). Certain gadolinium-based contrast agents are more likely to cause NSF A complete review of the published literature on the association of GBC agents with NSF put the risk of NSF with certain GBC agents into perspective (49). A total of 190 cases of biopsy-proven NSF were identified using PubMed/MEDLINE. Gadodiamide was the culprit GBC agent in 157 cases whereas gadopentetate (n = 8), and gadoversetamide (n = 3) were the others noted. In the remaining cases, 18 were unspecified, 4 were confounded, and 5 cases of NSF are purported to have no GBC agent exposure. If one includes NSF cases made by clinical diagnosis only, an additional 3 cases of gadodiamide and 20 cases of gadopentetate are noted. The author appropriately notes that biased reporting from academic centers more likely to use certain types of GBC agents may explain the current reports. Also, while gadodiamide and gadopentetate claim 81% of the market share for these agents, (2006 per the Contrast Media Industry Guide report), gadopentetate is utilized twice as much as gadodiamide but is associated with NSF at a much smaller rate. Another source of data on the association of NSF with type of GBC agent use is the Yale University NSF registry, which was created in 2001 to collect data on all cases of NSF (7). As of May 2007, greater than 95% of 239 cases of NSF (where data are available) have been linked to exposure to gadolinium (7). Gadodiamide has been implicated in approximately 85% of these cases, gadopentetate in 15%, and less than 5% have no identifiable GBC exposure. Most cases had either large GBC dose exposures or multiple GBC agent exposures. A recently published retrospective study examined the relationship of GBC exposure and biopsy-proven NSF at 4 U.S. academic medical centers (50). They collected data on type and cumulative dose of GBC administered and calculated a benchmark incidence at the medical centers. Two centers used only gadodiamide, while the other 2 centers used only gadopentetate. They found that predominantly stage V CKD patients developed NSF

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following large cumulative doses of GBC agents. The benchmark incidence of NSF was 1 in 44,224 with gadopentetate and 1 in 2913 with gadodiamide. This calculates to an odds ratio of 13 for developing NSF with gadodiamide compared with gadopentetate. In a recent publication examining the FDA MedWatch reporting system data as of 10/07, numerous cases of NSF associated with exposure to GBC agents have been reported (51). This publication noted the type and number of GBC agent exposures as well as patient demographics. Gadodiamide was noted in 283 cases (246 alone), gadopentetate with 125 (96 alone), gadoversetamide with 20 (8 alone), gadobenate with 10 (2 alone) and gadoteridol with 9 (1 alone). It must be remembered that these data are not confirmed or peer reviewed. However, the numbers of NSF cases associated with gadodiamide and gadopentetate reflect the published literature. It is interesting that gadoteridol, which has the 3rd greatest market share has the least number of reported NSF cases, with only one case noted with exposure to gadoteridol alone. An important retrospective study that sheds light on the different risk potential of the different GBC agents was published by Reilly at the North Dallas VA medical center (51). The VA electronic medical records, dermatology records, pathology reports and discharge summaries were queried to examine for cases of NSF in ESRD patients on hemodialysis. During this time, 141 ESRD patients had 198 gadoteridol (macrocyclic non-ionic chelate) exposures over a 7-year period (2000-2007). The majority of exposures were single (n = 104), but several were 2 or greater (n = 37). No cases of NSF were noted during this period, clearly less than the 2-18% prevalence described with gadodiamide exposure. These data support the possibility that different GBC agent chelate characteristics influence the risk of NSF post exposure. A couple of studies shed light on the different risk potential of the different GBC agents. The prevalence of NSF following gadopentetate was extremely low in a retrospective study conducted in a large HMO population in California over a 40-month period (52). Despite significant gadopentetate exposure in 530 ESRD patients and 2862 stage IV/V CKD patients, only 1 definite case of NSF was noted. Nine centers in France examined the prevalence of NSF over a year (7/05-7/06) in CKD patients (53). 232 patients received GBC, of which ~75% had stage IV/V CKD. The majority received the macrocyclic-chelate gadoterate (~76%), while the rest received gadopentetate (~20%), gadodiamide (~3%), and gadobenate (~1%). No cases of NSF were noted. These data support the notion that different GBC agent chelate characteristics influence the risk of NSF post-exposure, with nonionic-linear-chelates having the greatest risk, ionic-linear-chelates having moderate risk, and macrocyclic-chelates having the lowest risk.

Animal studies on GBC agents and NSF Development of an animal model to examine a new human disease, test causative agents (various GBC agents), and evaluate potential therapies is logical. Forty-two rats with normal kidney function were exposed to various types of high dose (2.5mmol/kg) GBC agents or saline control daily for 28 days (54). The dose chosen was based on pharmacokinetic studies designed to mimic GBC dosing in the setting of renal insufficiency. Rats exposed to gadodiamide developed NSF-like skin lesions at 5 days, whereas the rest of the animals did not. On histopathology, dermal thickening, collagen deposition, and fibrosis were only noted in the gadodiamide exposed animals. In addition, hypercellularity and increased numbers of CD34-positive cells were noted. Gadolinium concentrations were also measured in tissues;

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they were highest with gadodiamide followed by gadoversetamide, and gadopentetate. Although gadolinium was present in the 3 other animal groups (gadobenate, gadobutrol, gadoterate), the gadolinium concentrations were approximately 30-fold lower. This experiment suggests that gadodiamide, perhaps due to the process of transmetallation with release of gadolinium, is more likely to cause NSF than the other GBC agents, at least in rats. Interestingly, gadoversetamide, a GBC agent similar to gadodiamide did not cause clinical or histological evidence of NSF, although gadolinium tissue concentrations were second highest (albeit much lower) in these animals. It may be that the excess free chelate provided in the formulation (2x > gadodiamide formulation), binds released Gd3+ and prevents tissue exposure. Two similarly performed animal studies are worth noting. Rodents exposed to various GBC agents demonstrated long-term retention of linear GBC agents within the skin, whereas 3 different macrocyclic GBC agents were similar to saline control (55). Another study exposing rats (naïve and partially nephrectomized) to various GBC agents (no macrocyclic agents) noted significant Gd3+ concentrations in various tissues as compared with saline and chelate-only controls (56). Interestingly, the animals developed skin lesions similar to NSF, but histology did not demonstrate fibrotic changes. A renal failure rat model (5/6 nephrectomy) was utilized to examine the different Gd3+ skin concentrations associated with linear and macrocyclic-based GBC agents (57). Rats exposed to 5 daily high doses of various GBC agents had skin concentrations measured up to 168 days after the last injection. Skin concentrations (day 168) were highest with nonioniclinear-chelates (gadodiamide>gadoversetamide), mid-range with gadopentetate (ionic-linear) and lowest (~ 500 times less) with gadovist (macrocyclic). Three of 12 gadodiamide exposed animals developed macroscopic NSF lesions, whereas none of the others did so. All of these studies suggest that GBC agents have different abilities to enter tissues (linear >> macrocyclic), but one (55) did not confirm that NSF develops histologically in these animals. Obviously, these models are not ideal, but they do provide some insight into the potential role of GBC agents in causing NSF.

Gadodiamide is more frequently associated with NSF If gadodiamide is more likely to cause NSF than the other GBC agents, what factors make it unique in this regard? One theory relates to its stability, defined as the ability of the chelate to bind to and sequester Gd+3. Gadodiamide has the lowest stability constant and highest dissociation rate of the five GBC preparations available in the United States (Table 1). Because of this decreased stability, the Gd+3 ion of gadodiamide is more likely to dissociate from its stabilizing chelate moiety then other GBC agents. Reduced kidney function significantly increases the T1/2 of GBC agents as they are slowly excreted by the kidneys in the setting of a reduced GFR. Thus, significant renal impairment is associated with increased time for transmetallation (Figure 2) and prolonged tissue exposure, which may promote deposition of toxic Gd3+ leading to fibrosis. To deal with the dissociation issue, excess chelate (12 mg/ml of sodium calcium diamide) is added to the commercial formulations of gadodiamide in an attempt to diminish freely circulating Gd3+ (14,15). The stability constant of gadoversetamide is essentially the same as gadodiamide, however the excess chelate in this preparation is even greater at 28.4 mg/ml (sodium calcium versetamide), and is tempting to use this as an explanation for the decreased

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Figure 2. Transmetallation of gadolinium-based contrast. A non-ionic linear chelate GBC agent binds Gd3+ less tightly than other chelates, allowing endogenous cations such as Cu 2+, Fe3+, Zn2+, and Ca2+ to compete with Gd3+ for chelate binding. This allows free Gd3+ to be release into the circulation where it may bind other anions such as phosphate. Gd3+, gadolinium; Cu2+, copper; Fe3+, iron; Zn2+, zinc and Ca2+, calcium

cases of NSF associated with gadoversetamide as compared with gadodiamide. It is also possible that the extremely small market share of gadoversetamide explains the low association rate with NSF. The stability constant of gadopentetate is much greater than either gadodiamide or gadoversetamide, yet this agent is now the second most common GBC associated with NSF. This may relate to its more widespread use, but suggests that the dissociation rate and the process of transmetallation have a threshold level that must be crossed. The data currently available on the extremely low association of gadoteridol with NSF suggests that the macrocyclic chelates are more stable. This is supported by the observation that NSF has not occurred in Europe following the switch to a macrocyclic ionic chelate-based product (gadoterate), despite use in relatively high-risk patients.

Patients with advanced kidney disease are at highest risk to develop NSF following GBC exposure The published literature and Yale NSF registry clearly documents that patients with advanced kidney disease, including ESRD on dialysis, stage V CKD and AKI are at highest risk to develop NSF following GBC agent exposure. Some publications suggest that patients on peritoneal dialysis without significant residual renal function may be at higher risk than those on hemodialysis, perhaps due to the poor GBC clearance associated with peritoneal dialysis. Nearly 80% of patients have ESRD on dialysis, whereas the rest are primarily stage V CKD and AKI (many dialysis requiring). A small number of patients have been described

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with stage IV CKD (n ~ 5). It is important to note that no cases of stages I-III have been reported in the published literature. In fact, several studies that include patients with stages IIV CKD exposed to GBC agents have not noted NSF as a complication (43,58,59). In the HALT and CRISP studies, ADPKD patients with stages I-III CKD underwent 1,111 GBC agent exposures with no cases of NSF developing (59). Patients with stages III-IV CKD (n = 592) exposed to GBC also did not develop NSF (43). Finally, patients with stages I-IV CKD (n = 88) who underwent 94 GBC agent exposures, including 38 patients with stage IV CKD did not develop NSF (58). Thus, it appears that patients with advanced kidney disease with very low levels of GFR are at the highest risk. Based on the literature, stage IV CKD seems to be at very low risk and this should be considered when weighing the risks and benefits of the GBC agent exposure required to image the patient.

Figure 3. Speculated mechanism of NSF. In the setting of advanced kidney disease, linear GBCA exposure is associated with an increased half-life, whereupon the retained GBCA undergoes transmetallation with endogenous cations (Fe3+, Ca2+), allowing free Gd3+ or Gd3+ bound to phosphate (PO43-) to enter tissues. Underlying inflammation and vascular endothelial injury enhance leakage of Gd3+ entry into tissues. Once in tissues, Gd3+ may be engulfed by macrophages, which produce local and systemic cytokines. Those mediators and high-dose ESA stimulate circulating fibrocytes to enter the tissues. The fibrocytes transform into spindle cells, which promote tissue fibrosis through the production of various pro-fibrotic factors. GBCA, gadolinium-based contrast agent; ESA, erythropoietin stimulatory agents

Other purported risk factors for NSF following GBC agent exposure Compared with other conditions that affect patients with underlying kidney disease, NSF is relatively rare. Once must speculate that other patient-related factors must be required to allow NSF to develop; as GBC exposure and advanced kidney disease are necessary but not sufficient. A number of putative co-factors are described in the literature (60). Increased

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serum phosphate and calcium concentrations, iron mobilization (or intravenous iron therapy) and high dose erythropoietin are possibilities (60). Excess serum phosphate may bind free Gd3+ that is released by the process of transmetallation, allowing the Gd3+-phosphate complex to deposit in tissues. In fact, Gd3+-phosphate complexes within cells are demonstrated in some NSF tissues (61). Increased serum calcium concentration might promote Gd3+ transmetallation by competing with Gd3+ for its chelate (60,62). Although no link to intravenous iron therapy has been noted, it is possible that this metal may also compete with Gd3+ for its chelate and similarly induce transmetallation. High dose erythropoietin may increase tissue fibrosis through effects as a growth factor and mobilization of bone marrow derived fibroblast precursors, which deposit in tissue containing Gd3+. Alternatively, high doses of exogenous erythropoietin may be a marker of an inflamed, erythropoietin-resistant state, which itself may increase risk for NSF following GBC exposure. Underlying vascular injury and a pro-inflammatory state may also be important risk factors for NSF to develop. Various forms of vascular injury and pro-inflammatory states (infection, major surgery, connective tissue disorders) are present in NSF patients (39,61-64). Certain GBC agents have also been shown to induce inflammation, perhaps contributing further to patient risk (65,66). Gadopentetate (linear-chelate) but not gadobutrol (macrocyclicchelate) increased C-reactive protein in dialysis patients, suggesting this pro-inflammatory effect may increase NSF risk in those exposed to the linear agents (66). In support of this, the nonionic-linear–chelate gadodiamide increased a number of pro-inflammatory cytokines in animals that developed clinical/histologic NSF (67). Vascular injury and inflammation may increase risk for NSF by two mechanisms. First, leaky, damaged vasculature allows dissociated Gd3+to enter the interstitial space and tissues more readily. Second, underlying inflammation may facilitate pro-fibrotic cytokine and chemokine synthesis. These substances would attract circulating fibrocytes (other bone-marrow-derived cells) to tissues containing Gd3+, and increase collagen production by deposited fibrocytes and other local cells involved in tissue fibrosis. Figure 3 represents a hypothesis of the mechanism and various factors involved in NSF.

Gadolinium-based contrast and NSF: What should we conclude? Based on the current published literature, a couple of conclusions can be drawn. First, patients at highest risk to develop NSF following GBC agent exposure are those with ESRD (peritoneal dialysis > hemodialysis), stage V CKD and those with AKI, especially associated with rising serum creatinine and liver disease. Patients with stage IV CKD maintain some risk, but it is likely much lower than the above-named group. There appears to be little or no risk for patients with stages I-III CKD, but patients with advanced stage III CKD (eGFR < 40 ml/min/m2) should be monitored closely. Clearly, patients with normal kidney function have no risk. The risk associated with the various GBC agents is likely different as well. Gadodiamide, the linear non-ionic chelate-based formulation maintains the highest risk based on epidemiological data and animal studies. It is probable that gadoversetamide also has the same risk as it has the same characteristics as gadodiamide (except for twice as much free chelate in the formulation). Gadopentetate, the linear ionic chelate-based product probably has a medium risk, less than the linear nonionic chelates but more than the macrocyclic chelates. Gadoteridol, the only FDA approved macrocyclic chelate, maintains less risk and has only been described in one MedWatch case. Clearly high doses and large cumulative

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doses of these agents will increase risk for NSF. It is likely that other factors (co-factors) play a role along with GBC agent exposure in patients with advanced acute or chronic kidney disease.

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Approach to Gadolinium-Based Contrast Agent use in Kidney Disease As there is currently no effective therapy for NSF, avoidance of exposure by using alternative imaging modalities is the best option. This would entail identifying the high-risk groups as previously outlined. Options for non-GBC agent enhanced imaging of patients with advanced kidney disease are becoming increasingly more available. These include ultrasonography, CT scanners with improved imaging technology, USPIOs for MRI contrast enhancement, and newer MRI machines that provide excellent images of the vasculature without any enhancing agent. However, if an imaging test using a GBC agent is required to provide the necessary diagnostic information, then a discussion with the health care providers and patient should ensue to discuss the risks and benefits. Once informed consent is obtained and documented, I would recommend the following approach: First, a macrocyclic chelatebased agent is preferred, avoiding linear chelates. Second, the lowest dose of GBC agents required to achieve the image should be utilized, while also avoiding repeat exposures with GBC agents. Finally, consider performing hemodialysis on the same day of the exposure (and the next 2 days) in patients who are already maintained on hemodialysis recognizing that there are no data that support prevention of NSF with this modality. The recommendation is based on the pharmacokinetics of GBC agents and the theoretical benefit of removing it with hemodialysis. Two currently published studies provide conflicting data on the benefit of hemodialysis following GBC agent exposure; however, this may be partly explained by the different timing of dialysis in the studies. Placing a dual lumen hemodialysis catheter purely for the purpose of removing GBC material is not recommended in patients on peritoneal dialysis and those with advanced CKD not yet on chronic maintenance dialysis.

CONCLUSION It is no longer acceptable to consider gadolinium-based contrast as safe as they have traditionally been considered when administered to patients with underlying kidney disease. Although the toxicity profile of the GBC agents may be narrower than that associated with iodinated radiocontrast agents, they are clearly not entirely benign. Nephrotoxicity can occur in high-risk patients (stage IV/V CKD) who receive a large dose (> 0.3 - 0.4 mmol/kg) and intra-arterial injection of GBC agent. NSF can be a catastrophic complication of GBC agent exposure and a concerted effort should be made to avoid this dreaded condition. There is strong evidence that NSF is related to a tissue response to the toxic effects of gadolinium. Avoidance of GBC agent exposure in high-risk patients, when possible, is the best measure to prevent the disease. If GBC agent exposure is required, using the smallest dose of a macrocyclic chelate is the next best option. Hemodialysis should be considered after GBC agent exposure in patients who are already on this modality.

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REFERENCES [1] [2]

[3]

[4]

[5]

[6] [7] [8]

[9]

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[10]

[11]

[12] [13] [14] [15] [16]

[17] [18]

Perazella, MA; Rodby, RA. Gadolinium use in patients with kidney disease: A cause for concern. Semin Dial, 2007, 20, 179-184. Grobner, T. Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant, 2006, 21, 1104-1108. Marckmann, P; Skov, L; Rossen, et al. Nephrogenic systemic fibrosis: suspected etiological role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol, 2006, 17, 2359-2362. Broome, DR; Girguis, MS; Baron, PW; et al. Gadodiamide-associated nephrogenic systemic fibrosis: Why radiologists should be concerned. Amer J Roent, 2007, 188(2), 586-92. Khurana, A; Runge, VM; Narayanan, M; et al. Nephrogenic systemic fibrosis: A review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol, 2007, 42, 139-145. Galan, A; Cowper, SE; Bucala, R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol, 2006, 18(6), 614-617. Cowper, SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org Accessed 6/1/2007. Thomsen, HS; Morcos, SK; Dawson, P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis. Clin Radiol, 2006, 61, 905-906. Thomsen, HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol, 2006, 16, 2619-2621. Food and Drug Administration (2006) Public Health Advisory: Gadolinium-containing contrast agents for magnetic resonance imaging (MRI). http://www.fda.gov/cder/drug/advisory/gadolinium. Food and Drug Administration (2006) Public Health Advisory: Gadolinium-containing contrast agents for magnetic resonance imaging (MRI). http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm. Perazella, MA. Nephrogenic systemic fibrosis, gadolinium, and chronic kidney disease: Is there a link? Clin J Am Soc Nephrol, 2007, 2, 200-202. Bellin, MF. MR contrast agents, the old and the new. Eur J Radiol, 2006, 60, 314-323. Lorusso, V; Pascolo, L; Fernetti, C; et al. Magnetic resonance contrast agents: from the bench to the patient. Curr Pharm Design, 2005, 11, 4079-4098. Runge, VM. Safety of magnetic resonance contrast media. Topics Magn Res Imaging, 2001, 12(4), 309-314. Swan, SK, Lambrecht, LJ; Townsend, R; et al. Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment. Invest Radiol, 1999, 34(7), 443-455. Reinton, V; Berg, KJ; Svaland, MG; et al. Pharmacokinetics of gadodiamide injection in patients with moderately impaired renal function. Acta Radiol, 1994, 1, 56-61. Schuhmann-Giampieri, G; Krestin, G. Pharmacokinetics of Gd-DTPA in patients with chronic renal failure. Invest Radiol, 1991, 11, 975-979.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

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[19] Joffe, P; Thomsen, HS; Meusel, M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acta Radiol, 1998, 5, 491-502. [20] Saitoh, T; Hayasaka, K; Tanaka, Y; et al. Dialyzability of gadodiamide in hemodialysis patients. Radiat Med, 2006, 24, 445-451. [21] Okada, S; Katagirir, K; Kumazaki, T; et al. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol, 2001, 42, 339-341. [22] Wible, JH; Troup, CM; Hynes, MR; et al. Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging. Invest Radiol, 2001, 36, 401-412. [23] Niendorf, HP; Alhassan, A; Haustein, J; Clauss, W; Cornelius, I. Safety and risk of gadolinium-DTPA: extended clinical experience after more than 5,000,000 applications. Adv MRI Contrast, 1993, 2, 12-19. [24] Bellin, MF; Deray, G; Assogba, U; et al. Gd-DOTA: evaluation of its renal tolerance in patients with chronic renal failure. Magn Reson Imaging, 1992, 10, 115-118. [25] Arsenault, TM Systemic gadolinium toxicity in patients with renal insufficiency and renal failure: retrospective analysis of an initial experience. Mayo Clin Proc., 1996, 71(12), 1150-4. [26] Prince, MR; Arnoldus, C; Friscoli, JK. Nephrotoxicity of high-dose gadolinium compared with iodinated contrast. J Magn Reson Imaging, 1996, 6 (1), 162-166. [27] Hammer, FD; Goffette, PP; Malaise, J; Mathurin, P. Gadolinium dimeglumine: An alternative contrast agent for digital subtraction angiography. Eur Radiol, 1999, 9(1), 128-136. [28] Spinosa, DJ; Angle, JF; Hagspiel, KD; et al. Lower extremity arteriography with use of iodinated contrast material or gadodiamide to supplement CO2 angiography in patients with renal insufficiency. J Vasc Interv Radiol, 2000, 11(1), 35-43. [29] Spinosa, DJ; Matsumoto, AH; Angle, JF; et al. Safety of CO2- and gadodiamideenhanced angiography for the evaluation and percutanwous treatment of renal artery stenosis in patients with chronic renal insufficiency. Am J Roentgenol, 2001, 176(5), 1305-11. [30] Sancak, T; Bilgic, S; Sanldilek, U. Gadodiamide as an alternative contrast agent in intravenous digital subtraction angiography and interventional procedures of the upper extremity veins. Cardiovasc Intervent Radiol, 2002, 25(1), 49-52. [31] Reiger, J; Sitter, T; Toepfer, M; Linsenmaier, U; Pfeofer, KJ; Schiffl, H. Gadolinium as an alternative contrast agent for diagnostic and interventional angiographic procedures in patients with impaired renal function. Nephrol Dial Transplant, 2002, 17, 824-828. [32] Sam, AD; Morasch, MD; Collins, J; et al. Safety of gadolinium contrast angiography in patients with chronic renal insufficiency. J Vasc Surg, 2003, 38, 313-318. [33] Erley, CM; Bader, BD; Berger, ED. Gadolinium-based contrast media compared with iodinated media for digital subtraction angiography in azotemic patients. Nephrol Dial Transplant, 2004, 19, 2526-2531. [34] Ergun, I; Keven, K; Uruc, I; Ekmekci, Y; Canbakan, B; Erden, I; Karatan, O. The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrol Dial Transplant, 21, 697-700.

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[35] Briguori, C; Colombo, A; Airoldi, F; et al. Gadolinium-based contrast agents and nephrotoxicity in patients undergoing coronary artery procedures. Cath Cardiovasc Intervent, 2006, 67, 175-180. [36] Kane, GC; Stanson, AW; Kalnicka, D; Rosenthal, DW; Lee, CU; Textor, SC; Garovic, VD. Comparison between gadolinium and iodine contrast for percutaneous intervention in atherosclerotic renal artery stenosis: clinical outcomes. Nephrol Dial Transplant., 2008, 23(4), 1233-40. [37] Deo, A; Fogel, M; Cowper, SE. Nephrogenic systemic fibrosis: A population study eaxmining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol, 2007, 2, 264-267. [38] Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents-St. Louis, Missouri, 2002-2006. Morbid Mortal Weekly Report, 2007, 56(7), 137-141. [39] Sadowski, EA, Bennett, LK; Chan, MR; et al. Nephrogenic systemic fibrosis: Risk factors and incidence estimation. Radiology, 2007, 243, 148-157. [40] Marckmann, P; Skov, L; Rossen, K; Heaf, J; Thomsen, HS. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant, 2007, 22(11), 3174-8. [41] Personal communication, Henrik, S. Thomsen, Department of Diagnostic Radiology, Copenhagen University, Denmark. [42] Collidge, TA; Thomson Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology., 2007, 245(1), 168-75. [43] Othersen, JB; Maize, JC; Woolson, RF Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant., 2007, 22(11), 317985. [44] Agarwal, R; Brunelli, SM; Williams, K; Mitchell, MD; Feldman, HI; Umscheid, CA. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant., 2009, 24(7), 856-63. [45] High, WA; Ayers, RA; Chandler, J; et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol, 2007, 56, 21-26. [46] Boyd, AC; Zic, JA; Abraham, JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol, 2007, 56, 27-30. [47] High, WA; Eng, M; Ayers, RA; Cowper, SE. Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol, 2007, 56, 12. [48] Schroeder, JA; Weingart, C; Coras, B; Hausser, I; Reinhold, S; Mack, M; et al. Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and end-stage renal disease. Clin J Am Soc Nephrol, 2008, 3, 968-975. [49] Broome, DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol., 2008, 66(2), 2304. [50] Wertman, R; Altun, E; Martin, DR; Mitchell, DG; Leyendecker, JR; O'Malley, RB; et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology, 2008, 248(3), 799-806.

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[51] Reilly, RF Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol., 2008, 3(3), 74751. [52] Hope, TA; Herfkens, RJ; Denianke, KS; et al. Nephrogenic systemic fibrosis in patients with chronic kidney disease who received gadopentetate dimeglumine. Invest Radiol, 44, 2009 Jan 15; [Epub ahead of print] PMID: 19151610. [53] Janus, N; Launay-Vacher, V; Karie, S; et al. Prevalence of nephrogenic systemic fibrosis in renal insufficiency patients: Results of the FINEST study. Eur J Radiol, 2009, 13(2), 97-102. [54] Sieber, MA; Lengsfeld, P; Frenzel, T; Golfier, S; Schmitt-Willich, H; Siegmund, F; et al. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol, 2008, 18, 2164-73. [55] Pietsch, H; Lengsfeld, P; Jost, G; et al. Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents. Eur Radiol Jan, 24, 2009 Feb 26, [Epub ahead of print] PMID: 19252439. [56] Grant, D; Johnsen, H; Juelsrud, A; Lovhaug, D. Effects of gadolinium contrast agents in naïve and nephrectomized rats: Relevance to nephrogenic systemic fibrosis. Acta Radiol, 2009, 50(2), 156-69. [57] Pietsch, H; Lengsfeld, P; Steger-Hartmann, T; et al. Impact of renal impairment on long-term retention of gadolinium in the rodent skin following the administration of gadolinium-based contrast agents. Invest Radiol, 2009, 44, 226-33. [58] Chapman, A; Grantham, JJ; Guay-Woodford, LM; Braun, W; Rahbari-Oskovi, F; Kelleher, C; et al. Absence of NSF following gadolinium exposure in ADPKD individuals with stable CKD. ASN Abstract, 2007. [59] Rydahl, C; Thomsen, HS; Marckmann, P. High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadoliniumcontaining magnetic resonance contrast agent. Invest Radiol., 2008, 43(2), 141-4. [60] Perazella, MA. Tissue deposition of gadolinium and development of NSF: a convergence of factors. Sem Dial, 2008, 21(2), 150-4. [61] Boyd, AC; Zic, JA; Abraham, JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol, 2007, 56, 27-30. [62] Prince, MR; Zhang, H; Morris, M; et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology, 2008, 248, 807-816. [63] Perez-Rodriguez, J; Lai, S; Ehst, BD; et al. Nephrogenic systemic fibrosis: Incidence, associations, and effect of risk factor assessment-Report of 33 cases. Radiology , 2009, 250, 371-377. [64] Kuo, PH. NSF-active and NSF-inert species of gadolinium: mechanistic and clinical implications. AJR, 2008, 191, 1861-1863. [65] Steen, H; Giannitsis, E; Sommerer, C; et al. Acute phase reaction to gadoliniumDTPA in dialysis patients. Nephrol Dial Transplant, 2008, 24(4), 1274-7. [66] Schieren, G; Tokmak, F; Lefringhausen, L; et al. C-reactive protein levels and clinical symptoms following gadolinium administration in hemodialysis patients. Am J Kidney Dis, 2008, 51(6), 976-986.

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[67] Steger-Hartmann, T; Raschke, M; Riefke, B; et al. The involvement of proinflammatory cytokines in nephrogenic systemic fibrosis- A mechanistic hypothesis based on preclinical results from a rat model with gadodiamide. Experimental Toxicol Path 2009 Jan 6; [Epub ahead of print] PMID: 19131226.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.167-192 © 2010 Nova Science Publishers, Inc.

Chapter 4

ELECTRON MICROSCOPIC STUDIES OF THE ROLE OF GADOLINIUM IN HUMAN FIBROSING DISEASES J.A. Schroeder*1, E. Goffin2, Ch Weingart1, B. Banas1, T. Vogt1, F. Hofstaedter1 and B.K. Krämer3 1

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Departments of Pathology, Nephrology, and Dermatology, University Medical Center, Regensburg, Germany 2 Department of Nephrology, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium 3 Medical Clinic V., University Medical Center Mannheim, University of Heidelberg, Germany

INTRODUCTION When you google or search in PubMed database for references concerning Gadolinium and its association with an enigmatic human fibrotic disease, you will realize by the spectrum of displayed journals, that this issue is highly relevant to three medical disciplines: Radiology (search Mar.15, 2010 = 236 hits), nephrology (271), and dermatology (211). Furthermore, one can note an environmental aspect (313) of this rare earth element and its potential adverse impact on human health in conjunction with products of the multimedia industry and evolving nanotechnology (14). With the help of electron microscopic (1-3) investigations – a visualisation method, which aids the scientist eye with an outstanding nanoscale resolution power – we try in this chapter to shed some light in understanding of the interaction of Gadolinium with the human tissue in clinical terms of two rare diseases. Gadolinium (chemical symbol Gd) is a rare earth metal with the atomic number 64 placed in the IIIA group elements or lanthanides of the periodic system, its name is derived from Johan Gadolin - a Finnish chemist and mineralogist. Previously found and mined in Sweden,

* Corresponding author: Josef A. Schroeder, Department of Pathology, Central EM-Laboratory, University Medical Center, F-J-Strauss-Allee 11, 93053 REGENSBURG, Germany, Phone: 0049 941 944 6636, Fax:0049 941 944 6602, Email: [email protected] Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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the main mining areas are now in China, the United States, Brazil, India, and Australia with a cumulative production of approximately 400t pure Gadolinium per year to meet the requirements of industry and medical applications (4). One can observe a growing demand for this rare element in the computer and multimedia industry (screens, media-CD, lamps, TV sets, cellular phones, etc.) and, as a consequence, a non-controllable global dissemination of Gadolinium as ecological waste in the free natural environment (5). This in turn can contaminate the food chain and harm life because free Gadolinium as a trivalent (Gd+3) ion is highly toxic for living cells as reported in a number of laboratory animal experiments; it has no known metabolic function in the body (6-12).

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DIRECT TOXIC EFFECTS OF GADOLINIUM Ionized Gd has been shown to interact with biomembranes (13) and a variety of known ion-channels, especially different Ca-channels, Na-channels and K-channels (6, 14, 12). Accordingly, infusions of GdCl can cause severe cardiovascular effects in animals, especially disorders of the cardiac conduction system, ventricular fibrillation and even complete cardiac failure. These effects are thought to be caused mainly by the Gd-induced blocking of ion channels (15). Infusion of larger quantities of Gd induces severe pulmonary failure in animals, most likely through formation of microemboli in the pulmonary vessels. Ionic Gadolinium (applied as GdCl) has been shown to form such mineral emboli throughout the circulation forming insoluble colloid and deposits in a variety of tissues. In rats, those colloid particle are partially taken up by phagocytotic cells (16, 17, 10) and may even be thereafter found in the nucleus of some cells. Larger quantities lead to macrophage dysfunction and cell death (18). However, the presence of Gd-deposits in bile ducts indicate, that excretion of Gdcomplexes may also occur. These data on direct toxic effects resulted from experiments in animals, some of them performed more than 50 years ago. In contrast there has been no or only little data on toxicity of ionic Gadolinium in humans.

THE MEDICAL CAREER OF GADOLINIUM Nonetheless, this dangerous potential was not a hindrance for Gd remarkable career in the field of diagnostic medicine as a contrast agent for magnetic resonance imaging (MRI). This is owing to Gadolinium‘s atom-specific electron configuration which makes it paramagnetic (it behaves as a magnet when entering a magnetic field). This is due to the seven unpaired electrons in the 4f orbital, which can influence surrounding water molecules in the body fluids to quickly relax, providing notable contrast enhancement in MRI images of a body (19, 20). Depending on the different tissue or organs that have been scanned, contrast agents usually display diseased tissue brighter or darker than the surrounding tissue. Even more, the unpaired electrons are shielded by electrons of the higher orbitals also in an ionizated atom or bounded with other ligands without loss of the paramagnetic attributes – this pointed the way to toxicity reduction of free Gadolinium (21, 22). Gadolinium was approved as a contrast agent in 1988 with an anorganic linear ligand as gadopentetate dimeglumine chelate (brand name ―Magnevist©‖) for central nervous system

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applications in Japan, Germany, and the United States (Figure 1). A number of other linear (Omniscan©, Optimark©) and macrocyclic chelates (Dotarem©, Gadovist©; ProHance©) followed, one can divide them into ionic (Magnevist©, Dotarem©) and charge neutral (Omniscan©, Gadovist©, Optimark©, ProHance©) compounds. They were developed for intravenous injection as extracellular fluid (ECF) agents, which means, that the compounds distribute equally in the extracellular compartment of the body and are excreted almost exclusively by the kidney. Later, compounds were designed for liver imaging and angiography as well as agents administered orally for gastrointestinal MRI scans (21). The chelate ―caged‖ and detoxified Gadolinium ion become part of highly efficacious, safety approved, and now for over 20 years widely used MRI contrast agents; especially the cyclic chelates showed a higher complex stability in the body. For better contrast imaging, it has not been uncommon to use higher dosage and interchangeable administration of the different Gadolinium based contrast agents (23).

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Figure 1. Example of a Gadolinium compound applicated as MRI contrast agent (Gadopentetate, linear and ionic Gd chelate formulation).

AN ENIGMATIC DISEASE EMERGED The universally applicable Gadolinium based MRI contrast agents were thought to be safe even in renal failure patients because there was no known toxicity of both the chelates and metabolites of these agents. Furthermore, iodinated contrast agents are increasingly avoided in patients with renal failure due to their well known nephrotoxicity. The introduction of MR-based angiography techniques nearly replaced –where available – conventional angiographies in patients with renal impairment. In 1997 however, a number of dialysis patients in southern California attracted attention because of the appearance of remarkable browny-coloured indurated plaques on the skin of their extremities never seen before and that resembled scleromyxoedema. This observation was published in 2000 as a dialysis associated disease by a dermatopathologist from San Francisco – S.E. Cowper (24). Two years later these dermal fibrotic lesions with a distinct evidence of CD34-positive fibrocytes and CD68positive histiocytic cells between the hypertrophic bundles of collagen were related to renal dysfunction and characterized as nephrogenic fibrosing dermopathy (25, 26). The growing number of clinical and autopsy data in the following years suggested a systemic fibrogenic process that involves many other tissues (e.g. joint contractures) and various internal organs,

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such as muscles, myocardium, testes, lungs, dura and other; so that, in consequence the name of the disease was modified to ―Nephrogenic Systemic Fibrosis‖ (NSF) (27-36). The intense sought for an epidemiologic evidence of a trigger of this disorder such as infectious agents, drugs or toxins lasted for nearly 9 years and was preliminary culminated by T. Grobner, a nephrologist from Vienna. He first realized that all known NSF cases in his ward had a history of exposure to Gadolinium based contrast agents. He proposed a toxic effect of Gadolinium as a possible cause for NSF (37). After a number of confirmatory articles and warnings published in 2006/7 from the US Food and Drug Administration as well as different national health authorities, the policy of Gadolinium based contrast agents use was revised to minimize the risk of NSF for patients with renal insufficiency (38-48). The adapted treatment regimens (applicability restriction only to patients with a glomerular filtration rate (GFR) > 30 ml/min) and awareness in the medical diagnostic practices and hospitals of the potential risk of the previously as believed safe Gadolinium compounds, has induced a significant drop in the reported number of new NSF cases (49, 50, 23). Today, compiling all the data available from NSF cases, one can notice that it is a rare disorder affecting about 500 cases reported in the literature out of esteemed globally 200 million administrations of Gadolinium based contrast agents (23). However, not every case has been diagnosed yet and presumably a large number of cases will never be reported to the NSF registry (51). The typical NSF patient is a patient on dialysis (peritoneal dialysis or haemodialysis) with a history of exposition to at least one dose of a Gd-containing contrast agent. The most oftenly reported substance has been Gadodiamide, which is related to more than 90% of all cases worldwide. Onset after exposure seems to be variable between 2 and 30 weeks (52). However, symptoms may be subtle in the beginning and may be ignored by the patient as well as by the physician. There may be subclinical courses as well. Although NSF has been shown to be a systemic disorder, the road to diagnosis is a typical alteration of the skin, usually of the proximal extremities. The skin gets increasingly thick and compact in affected areas, reducing the flexibility of the joints, especially of elbows and knees. (Figure 2 and 3). These changes may dramatically influence the patient‘s condition, eventually leading to inability to walk or even sit. Involvement of internal organs additionally causes symptoms of cardiac insufficiency in case of cardiac, or dyspnea in case of pulmonary involvements, respectively. Most patients show a progressive worsening of symptoms and, to our knowledge; a large number dies in the following months. However, epidemiologic data on survival rates do not exist. There is no known therapeutic intervention that has been shown to effectively delay the development or the progressive worsening of the symptoms. Data on improvement in some patients, for example after renal transplantation, are anecdotic. Other therapeutic interventions with immunosuppressive agents have been reported, but none showed any significant benefit. Intensive physical therapy may alleviate symptoms and preserve some mobility. Given the fact that there is no effective therapy by the time the symptoms of the disorder have commenced, the best strategy seems to be prevention according to the recent warning of different health authorities worldwide. Gd-containing contrast agents should be avoided whenever possible in patients with reduced renal function. However, there may be lifethreatening conditions, when no alternative contrast agent is applicable. In such cases it may be useful to use a macrocyclic formula that is thought to be chemically more stable than the linear agents. Acidosis should be corrected in these patients, but the most important procedure

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is to perform a haemodialysis session shortly after Gd exposure. This latter recommendation is deduced from theoretical considerations and data on the removal of Gd-chelates by haemodialysis, which is quite effective (99% removal within 3 haemodialysis procedures) (53).

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Figure 2. Lower extremities of a patient with NSF. Progressive thickening of the skin leads to contractures of both knees and subsequently to an inability to walk.

Figure3. Macroscopic aspect of a skin area of the lateral thigh of the same patient suffering from NSF. Note the scattered hyperpigmented spots. The skin appears glossy and compact. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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PATHOPHYSIOLOGICAL CONSIDERATIONS NSF is observed exclusively in patients with severe renal impairment in whom the glomerular filtration rate is lower than 30 mL/min/1.73m2 at the time of exposure and of course in end-stage renal disease (ESRD), but also affected patients with acute kidney injury have also been reported. As mentioned previously, the Gadolinium chelates distribute equally in the extracellular tissue compartment and are excreted almost completely by the kidney; therefore, their half-life time increases dramatically when kidney function deteriorates. In healthy humans, half-life of Gadolinium chelates is approximately 1.3h, whereas in patients with ESRD it is prolonged to approximately 120h (42, 43, 52). Furthermore, the likelihood to induce NSF is higher after multiple Gadolinium administrations - particularly when large doses are given during a single exam, but a single dose has also been reported to be harmful (39, 23). Rareness of the disorder leads to a search for additional conditions or risk factors that could further promote NSF development. A number of such risk factors were suggested: edema, systemic inflammation, metabolic acidosis, thrombotic events, recent surgery, high dose erythropoietin (EPO) or concomitant iron administration (54-57). The mechanisms linking Gd-containing contrast agents and NSF remain to be eludicated but there is strong evidence that toxic effects of Gadolinium play a pivotal role. Although Gadolinium chelates have been shown to be stable depending on their chemical nature and at physiologic pH (7.4), there is a relevant potential for significant release of free Gd3+ ions or transmetallation reactions with other competing ions, such as iron, calcium, or magnesium, especially in case of a prolonged status of metabolic acidosis – a frequent condition in seriously renal compromised patients. Finally, free toxic Gd3+ ions induce the fibrotic process; however, the exact pathogenesis and the contribution of the mentioned various risk factors is still a matter of debate (58, 59, 10, 60, 55, 61, 62, 47, 63, 64, 57). Indeed, we need to face the fact, that the great fraction of renal ―high risk‖ patients does not develop NSF despite a documented exposure to Gadolinium based contrast agents – which remains an open question. On the other hand, the applied policy of prevention of renal compromised patients to Gadolinium exposure resulted in a fast decline in the number of reported new NSF cases (49, 50, 23).

NSF DIAGNOSIS AND EVIDENCE OF GADOLINIUM IN THE SKIN TISSUE Currently, the diagnosis of NSF is confirmed histopathologically by a deep dermal biopsy from affected skin areas showing marked fibrosis and specific histopathologic features such as identification of CD34+/procollagen positive spindle cells (which are believed to be bone marrow – derived fibrocytes). Frequently also diffusely dispersed CD68 positive histiocytic cells and macrophages, edema, and mucin between the abundant collagen bundles are present, the inflammatory reaction is usually perivascular located and of low grade (40, 52, 36, 47). Direct demonstration of Gadolinium presence in cutaneous biopsies of NSF patients was reported by two groups applying scanning electron microscopy/energy dispersive x-ray (38, 65-68, 63, 69) and inductively coupled plasma mass spectroscopy (70). The element

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visualization in tissue paraffin sections was done by backscattered electrons with the best possible resolution of approximately 250 nm. We used an alternative approach for direct Gadolinium evidence by Energy Filtered Transmission Electron Microscopy (EFTEM) analysis on ultrathin resin tissue sections. This method provides a much higher structural resolution (0.1 nm) (71) and sensitivity for element detection and localization (72-79, 36, 80). The EFTEM technique is based on the phenomenon that primary beam electrons passing through a sample interact with target atoms of the specimen. By exciting the inner shell (K-, L-, M-shell) electrons of the specimen atoms, the transmitted beam electrons loose a defined, element-specific, amount of energy (―inelastic scattering‖). The energy loss of the beam electrons is analysed by an in-column integrated energy filter (spectrometer), which works analogous to an optical prism and separates the electrons scattered through the sample according to their energy content. A special slit-aperture at the spectrometer egress, selects electrons at the element-specific energy-loss level for imaging the elemental distribution in the sample. In biological specimens two modes of EFTEM are widely used: Electron Energy-Loss Spectroscopy (EELS) records the whole energy-loss range (0-2,500 eV) as a complete energy spectrum, where ―edges‖ at characteristic energy levels provide information about the chemical composition of the sample. The spatial distribution of elements present in the sample can be mapped by Electron Spectroscopic Imaging (ESI) using inelastically scattered electrons with the element specific energy loss (81-86, 78, 87-89, 36). In human tissue, elemental micro-analysis is performed on very thin resin sections (about 40 nm) to minimize multiple electrons scattering in the sample, collected on foil-uncoated copper grids without any heavy metal post-staining. Conventional electron microscopy is required to search for suspect electron-dense deposits, that can be further evaluated with specific elemental energy loss spectra (EELS) of these small specimen regions as described above. The latter were acquired in the spot mode of the parallel EELS method with the ―iTEM‖ software (OSIS/Germany). All our investigations were performed with the LEO912AB electron microscope (ZEISS/Germany) operated at 120kV acceleration and equipped with a sidemounted 1kx1k pixel CCD digital camera (TRS/Germany).

Case Description and Examination Results A 76–year-old patient was presented in our vascular surgery department in September 2006 due to peripheral artery disease, which had led to an ulcerous lesion underneath his left great toe (36). His medical history at this time included arterial hypertension, diabetes mellitus for several years, coronary artery disease and stenosis of both carotid arteries (surgically revascularizated 4 years earlier). Renal function at presentation was already reduced to a GFR of 18 ml/min. Awareness of impaired renal function contributed to the decision of performing MRT scans to avoid renal toxicity of conventional iodinated contrast agents. Within two weeks the patient underwent three MRT scans in total, thereof two MRangiographies, and receiving in total 49.5 mmol Gadopentetate (Figure 1). Haemodialysis had to be started because of progressive renal failure two days after surgery. In February 2007, four months after initiation of haemodialysis, the patient complained of worsening mobility of his lower extremities. Furthermore, the femoral skin had increasingly thickened during the

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weeks before, which contributed to a significant decrease of mobility. To confirm the suspected diagnosis of nephrogenic systemic fibrosis a deep punch biopsy of the skin of the medial right thigh was performed (July 2007). Differential diagnoses, e.g. autoimmune disorders like scleroderma and pseudosclerodermia caused by paraproteinemia, were ruled out by dedicated specified laboratory tests as well as protein electrophoresis were performed (tested negative). The disease showed a progressive course, and in July 2008 - approximately 2 years after the disease onset, the patient died. At autopsy, advanced fibrosis in many organs were present, biopsy sample of the skin lesion were obtained for microscopic examinations.

Histopathology and Conventional Electron Microscopy

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The skin biopsy material was formalin fixed, paraffin-embedded, and sections for light microscopy histopathologic examination were prepared; representative histological changes of the skin and the subcutaneous tissue are shown in Figure 4. While the epidermis displayed no noticeable changes, the corium and the subcutis showed pronounced fibrosis with only discrete perivascular inflammatory infiltrates. Immunohistochemistry staining for CD34 identified multiple positive spindle-shaped cells as fibrocytes, whereas scattered histiocytes were CD68-positive, confirming the diagnosis of NSF. The histopathology of the postmortem skin biopsy revealed similar results.

Figure 4. Deep skin biopsy (sampled July 2007): (A) H&E stain showing dense dermal fibrosis with spindle cells and slight perivascular cellular infiltrate, (B) CD34 positive spindle cells between collagen bands, (C) Area with numerous CD68 positive histiocytic cells, (D) Double toluidine blue/fuchsin stained semithin resin section showing a fragment of the wax reprocessed tissue containing a blood vessel selected for EM study. Bar 100 µm.

For electron microscopy examination the paraffin-embedded material was reprocessed. This routine automated sample deparaffinization and reembedding in epon resin blocks is a well established procedure in our lab, and apart from the known extraction artefacts related to the processing method, the deparaffinized material still allowed the recognition of cellular membranous structures, desmosomes, cytoskeleton filaments, and inclusions/deposits.

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Figure 5. Conventional electron microscopy of deparaffinized skin tissue (primarily formalin –fixed): (A) Low magnification overview of the dermis displaying bundles of collagen (C) with clefts, profile of a small blood vessel (V), histiocytes (H), fibroblastic (F), and inflammatory cells, bar 10 µm, (B) Closer view at a higher differentiated elongated cell presenting myofibroblastic hallmarks including attachment plaques (arrow) and bundles of intermediate filaments (asterix and insert), bar 2 µm (insert bar 500 nm), (C) Overview showing a blood vessel with empty lumen (L) and numerous tiny deposits (arrow heads) at the external side of the basal lamina, bar 10 µm, (D) Features noted at higher magnification of the irregular shaped deposits with fine-granular texture mostly adhering to the basal membrane (BM), bar 500 nm.

In this case, the electron microscopic examination of the routinely heavy metal stained ultrathin sections revealed a dermis with abundant tortuous collagen bundles and elastic fibers, numerous spindle-shaped and elongated fibrocytes, scattered histiocytic cells, and a minimal, mostly perivascular inflammatory infiltrate; all structures exhibited a compromised ultrastructure preservation adequate for deparaffinized tissue (Figure 5a). In the peripheral cytoplasm of some of the elongated cells with a cigar-shaped nucleus, bundles of parallel intermediate filaments (5-8 nm in thickness) and numerous subplasmalemmal attachment plaques were observed (Figure 5b), indicating myofibroblastic differentiation. A diligent examination of the blood vessel wall revealed tiny, moderately electron-dense, material spots at the outer site of the basal lamina and irregularly disseminated between collagen fibers in the adjacent connective tissue. These pleomorphic spots showed a fine granular texture and

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had a size range between 100 and 400 nm, several reached approx. 1,000 nm in diameter. These inclusions were consistent with anorganic material deposits like calcium, magnesium, and phosphate salts, but the question whether they also contain gadolinium remained open (Figure 5c, d).

Figure 6. Electron Spectroscopic Imaging (ESI), overview of images taken from an unstained skin section showing the perivascular region of a blood vessel using inelastic scattered electrons: (A) Background image at 1,164 eV energy loss, (B) Image taken at the maximum of the Gd specific signal at 1,193 eV energy loss, (C) Structure-sensitive image (HCI) taken at the 250 eV energy loss before the carbon specific signal, note the darkfield-like structure visualisation, (D) Net Gd signal calculated by subtracting the extrapolated background image from the Gd specific signal. The obtained image reflects the Gd distribution and is displayed in red color, yellow color is attributed to more intense element signal. Original magnification = x2, 100.

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Figure 7. ESI and parallel EELS: (A) Gadolinium mapping in the skin lesion at low magnification. The net Gd signal image is superimposed on the inverted HCI-image showing the precise localization of the signals as red spots on the tissue structures. Note the dispersed Gd aggregates in the perivascular zone of the blood vessel and only singular deposits in the adjacent tissue. (B) Higher magnification of portion of (A) showing detailed features of the Gd deposits and their multifocal association with the blood vessel basal lamina, cell profiles, and collagen fibrils. In the dark lysosomal structure Gd signal is only visible at the periphery. (C) Parallel EELS-spectrum. The confirmation of a particular element is demonstrated by its defined energy-loss edge at the energy level necessary for atom inner shell ionization. Record of the measured (spot mode) Gd signal (red) displaying the typical ―white line‖ peaks characteristic for Gd. For comparison note the reference Gd spectrum from the element atlas (blue). (D) Simultaneous Gd and iron mapping in deep dermis. Both net Gd (red) and iron (green) signal were combined with the original HCI-image. Note the iron signal co-localization in the Gd deposits (orange dots) and their periphery as well as small iron aggregates in the adjacent tissue. Bar 2 µm (all images).

Electron Spectroscopic Imaging of Gadolinium EFTEM micro-analysis was performed on the unstained 40 nm ultrathin resin sections, and to get a topological overview information, the structure contrast in the image was enhanced using only inelastically scattered electrons of carbon atoms in the sample with the defined energy loss of ∆E = 250 eV (High Contrast Imaging, HCI). The resulting inelastic

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darkfield images displayed the dermal structures and facilitated the search for the deposits in question (Figure 5c). After selection of adequate specimen areas, the ESI-image series for detection of gadolinium, iron, calcium, and magnesium were acquired and the net element image calculated, respectively (Figure 6d). A superimposition of the net Gadolinium image on the corresponding electronically inverted HCI-image shows the element mapping in the specimen: the Gadolinium signal was visible mainly perivascular as deposits multifocally associated with the outer site of the blood vessel basal lamina, profiles of cell bodies and processes, and collagen fibers in the deep dermis (Figure 7a). Some electron-dense deposits or inclusions were only partially containing Gadolinium, in some areas the Gadolinium seemed to be localized intracytoplasmatically (Figure 7b). A characteristic parallel EELSspectrum obtained from a Gadolinium containing perivascular deposit presenting the typical GdM4, 5 ―white line‖ shape is shown in Figure 7c. In a subsequently performed iron elemental mapping at the iron ionisation L-edge (FeL2, 3 = 708 eV) traces of iron signal were demonstrated in singular Gadolinium positive deposits and in very small inclusions (measured range of 40 – 150 µm) in the adjacent connective tissue (Figure 7d). The respective parallel EELS-spectra revealed a rather weak iron signal peak, calcium and magnesium were not detected. The autoptic samples were fixed in Karnovsky-fixative, postosmicated, and routinelly embedded in epon resin. Ultrastructurally, a similar but scanty gadolinium deposition was found in the deep dermis as described above: Figure 8 displays the focal pericollagenous gadolinium localisation in the fibrotic lesion, Figure 9 show the recorded corresponding EELS-spectrum from the same deposit confirming its gadolinium content.

Figure 8. Conventional electron microscopy of autopsy skin biopsy (primarily Karnovsky-fixed). Fragment of a cross-sectioned collagen bundle of the deep dermis. Note the scanty focal gadolinium distribution visible as electron-dense pericollagenous fiber deposition with a fine texture in a routine ultrathin section post-stained with lead and uranyl salts. Bar 1 µm (original microscopic magnification = x10,000).

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Figure 9. Parallel EELS spectrum of the Gd deposit shown in figure 8 recorded from the same heavy metal stained ultrathin section. The low element content is masked by the staining but produce a ―white line‖ edge profil typical for gadolinium (red line, Gd-M5=1,193 eV electron energy loss, spot mode). To fit the measured spectrum for comparison with the atlas Gd reference spectrum (blue line), the background was subtracted and adjusted to the diagram scale (in consequence the recorded Gd-white line edges are dwarfed, compare with figure 7C).

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ENCAPSULATING PERITONEAL SCLEROSIS - ANOTHER FIBROSING DISEASE AND GADOLINIUM Irrespective of the NSF story described above, another fibrosing disease has also been increasingly recognized in ESRD patients treated by long-term peritoneal dialysis (PD): Encapsulating Peritoneal Sclerosis (EPS). This disorder is characterised by the development of an extensive fibrosis of the peritoneal membrane forming an ―abdominal cocoon‖ that may eventually lead to life-threatening intestinal constriction, because of persistent, intermittent or recurrent bowel obstruction (Figure 10), sometimes associated with bloody ascites. Weight loss and malnutrition usually ensue. Mortality associated with this condition is high (90-92). The cause of EPS still remains elusive, though multiple triggering factors have been incriminated (long-term exposure of the peritoneal membrane to poorly biocompatible peritoneal dialysates, repeated peritoneal infections, genetic predispositions…) (91, 93). An increased incidence of EPS following renal transplantation in patients previously treated by peritoneal dialysis has been suspected in the last 2-3 years (94-96). Gadolinium is poorly removed by conventional peritoneal dialysis (97) and NSF has initially been described in this patient group (98, 34, 99). Because numerous PD patients had a history of Gd-based contrast agent injection for MR-imaging, and because Gd deposits have been found in numerous tissues, including the liver, heart, and muscles, it was tempting to speculate that the etiopathogenesis of EPS could be similar to that of NSF, involving thus intraperitoneal Gadolinium deposits.

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Figure 10. Abdominal CT Scan of patient #1 showing encasement of small-bowel loops and thickening of the intestinal wall (arrows). R: right.

In a recently published study (100), we therefore tested the hypothesis of the presence of Gadolinium deposits within the peritoneal tissue of peritoneal dialysed patients with EPS, representing thus a localised form of NSF - confined to the peritoneal membrane. This hypothesis could have explained the recently observed increased incidence of post-renal transplant EPS. We performed light and electron microscopic examinations of peritoneal membrane samples of 2 EPS (with no clinical signs of NSF) and of 2 control patients, with similar PD duration, to look for indirect signs of Gd exposure or of the presence of Gd deposits. Both EPS patients had been exposed to PD during 100 and 55 months, respectively. The biopsies were taken in all patients at the time of catheter removal, during renal transplantation. EPS patients had received Gd injections 9 and 20 months before renal transplantation, respectively. We looked for histopathologic signs of peritoneal fibrosis together with, at immunohistochemistry, the presence of fibrocytes and histiocytic cells expressing CD 34 (a marker of endothelial cells) and CD68 (a marker of macrophages) antigens, respectively, as mentioned above. Both markers are concerned specific of NSF in the skin. Conventional electron microscopic examinations as well as ESI and EELS analysis to detect tissular Gadolinium deposits were also used as described previously.

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Histopathologic and Electron Microscopic Observations

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Hematoxylin eosin-stained sections of the EPS peritoneal tissue showed a denuded mesothelium and a thickened, highly vascularized submesothelial fibrous band together with normal adjacent adipose tissue. The upper part of the submesothelial fibrous band had a fibrohyalin appearance with low inflammatory cellular infiltration (Figure 11). All those lesions are characteristic of EPS.

Figure 11. Parietal peritoneal biopsies of patient #1 with EPS (A-B-C) and Control 1 (D-E-F). (A) Denuded mesothelium and a thickened, highly vascularized submesothelial fibrous band together with normal adjacent adipose tissue. The upper part of the submesothelial fibrous band has a hypocellular fibrohyalin appearance (H&E. Obj. x 20). (B) Immunoperoxidase staining of the peritoneal wall showing arteriolar endothelial cells expressing CD34 (Obj. x 20). (C) Immunoperoxidase staining of the peritoneal wall showing several macrophages expressing CD68 (Obj. x 40). (D) Well-preserved peritoneal membrane (Obj. x 20). (E) Immunoperoxidase staining showing arteriolar endothelial cells expressing CD34 (Obj. x 20).(F) Immunoperoxidase staining showing numerous macrophages expressing CD68 (Obj. x 20).

We also found a similar strong expression of CD34 within the peritoneum of both EPS and control patients, not by fibrocytes as it can be seen in NSF patients, but by the numerous peritoneal capillaries. This latter observation reflects the neoangiogenesis process commonly associated with long-term PD (101). Likewise, a virtually not different strong expression of CD68 by numerous resident interstitial macrophages was found in both EPS and control peritoneal membranes, which is a common finding in the peritoneal membrane of long-term PD patients (102). Electron microscopy analysis of peritoneal tissues of EPS patients showed abundant collagen and scattered elastic fibres. There were also some electron-optic dark granular deposits recognised as mast cell granules and artificially condensed chromatin. In both

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patients, very tiny (0.1 – 2.0 m, mostly approximately 0.3 m diameter) singular/multiple electron-optically dark inclusions were found in cell protrusions (probable macrophages) disseminated in the connective tissue. The ESI and EELS spectral analysis of those inclusions was negative for Gd and calcium, but positive for iron in some of them (Figure 12). Peritoneal tissues from both controls only showed moderate fibrotic tissue with blood vessels.

Figure 12. ESI and parallel EELS. (A). Iron mapping on electron-opticaly dark inclusions found in cell protrusions (probable macrophages) disseminated in the peritoneal connective tissue, at high magnification (original magnification x10,000). The net iron signal image is superimposed on the inverted HCI image showing the precise localization of the signal as a red spot on the tissue structure. (B) Parallel EELS spectrum. Record of the measured gadolinium signal (red) does not correspond to the reference gadolinium spectrum (green) allowing to exclude the presence of gadolinium in the peritoneal tissue. (C) Parallel EELS spectrum. Record of the measured iron signal (red) corresponds to the reference iron spectrum (green) allowing to document the presence of iron deposits in the peritoneal tissue.

Altogether, the absence of clinical signs of NSF in both our EPS patients (despite the exposure to linear chelates of Gd, i.e. those with the highest risk of toxicity) (93, 103), together with the peritoneal biopsies examination that showed a highly fibrotic process without CD34 and CD68 immunostaining in peritoneal fibrocytes and the absence of electron microscopic demonstration of Gadolinium deposits, therefore argue against the implication of Gd in the EPS development of both our PD patients. A word of caution has however to be raised since some iron-positive signals have been found in the peritoneal tissues of both EPS patients; a finding that has also been seen in association with Gd deposits in other tissues (104, 105). Though a transmetallation phenomenon cannot be entirely ruled out (106, 103),

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iron load, due to multiple iv iron infusions to raise hemoglobin level, as frequently observed in dialysis patients, is more likely to explain this finding (107, 108). Also, the lag time between NSF development and Gd injection which is usually below 3 months, according to both Marckmann (45) and Swaminathan (105), while it was 9 and 20 months, respectively in both our EPS patients. It seems thus unlikely that Gd could have triggered the fibrotic process of EPS and have subsequently disappeared totally from the peritoneal tissues, given its high tissular affinity and long half-life. The present observation therefore innocents Gadolinium as the triggering factor for EPS and imply that a search for another aetio-pathogenic factor should be pursued in EPS following PD.

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CONSIDERATIONS OF THE GADOLINIUM EVIDENCE IN THE SKIN LESION Those data strongly suggest a causal relationship between exposition to Gadolinium and development of NSF in patients with severe renal insufficiency (38, 65, 70, 69). However, there may be additive triggers of the disorder, indicating that the pathogenesis of NSF requires a pattern of premises that facilitate and promote fibrosis (56, 57). Diagnosis of this disorder is still based on the detection of histopathologic signs of fibrosis in combination with significant amounts of CD34-positive fibrocytes (25), which is suggestive, but not exclusively specific, for NSF. Among the numerous poorly differentiated fibrocytes (without ultrastructural signs of excessive intracytoplasmic collagen production) seen in the haemodialysis patient described above, we also found a few higher differentiated fibrocytes. They phenotypically resembled myofibroblastic cells presenting classical bundles of intermediate filaments and attachment plaques in the peripheral cytoplasm (59). This finding is in line with the currently discussed aetiopathogenic role of free circulating fibrocytes in NSF (109) which are able to differentiate into contractile myofibroblasts, a finding that may be seen numerous in a fibrotic process (61, 62, 47). A high amount of myofibroblasts in progressing NSF skin lesions was also reported by Swartz (26), which found similarities to wound healing processes. Whereas the finding of myofibroblasts was not surprising, we also detected tiny deposits, primarily noticed only at the external basal lamina aspect of the blood vessels. These deposits were rated as anorganic deposits that could contain Gd. This point could be confirmed by applying EELS analytic and ESI-imaging technologies. Some Gd-signal-positive deposits showed the coexistence with scanty iron-positive signals and iron traces in the adjacent connective tissue. This finding substantiates previous detection of iron deposits (65, 68). A contamination of our samples by an iron-containing microtome blade could be excluded using a diamond knife at ultramicrotomy and avoiding any contact of our samples with ironcontaining surfaces. The quantitative data of other authors (38, 65, 70, 68, 69) report intralesional Gd amounts in 5-106 ppm range. Actually these deposits still persisted 3 years after the last Gd administration. Our ESI images display that Gd is distributed in small irregular deposits or aggregates of 100 to 1,000 nm arranged in a perivascular zone of approximately 5 µm width. Showing such a distinct perivascular distribution of Gd with a high resolution allowing to discriminate even

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small-sized particles, our observations refine and extend the previous reports detecting Gd deposits in the skin by other lower resolving methods (38, 65, 68, 69, 110) and give us a better spatial illustration of the Gd distribution in the skin lesions. This was particularly well demonstrable in the primarily Karnovsky-fixed post-mortem samples displaying focal fine pericollagenous fiber localization of gadolinium deposits. The colocalization of Gd and iron signals in the same deposits advocates the transmetallation hypothesis of Gd chelates, which is probably one important trigger or at least a cofactor of the disorder (37, 42, 43, 45, 47, 58). To our knowledge, this is the first study demonstrating Gd deposits at high EM resolution and sensitivity of the EELS technique. The EFTEM technology is an established method and has been applied in a number of life science studies (86, 77, 80) generating substantial information, i.e. concerning the non-pinocytotic interaction of exogenous particles with cells (81, 87) or elucidating the role of different elements in pathologic lesions (82-84, 78, 88, 89). Probably because of the wax sample reprocessing and compromised ultrastructure preservation in autoptic material, we were not able to show signs of cytotoxicity caused by Gd as described by Mizgerd on dermal cells and macrophages in vitro (10). Additionally he reported Gd located in lysosomes and nuclei as well as signs of apoptosis. In our material we could not find any intranuclear Gd signal. Although we were able to detect a predominantly perivascular element dispersion, we could not obtain further any information about possible vasculopathic signs or possible blood vessel wall leakage, as reported by Mendoza (32).

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CONCLUSIONS AND PERSPECTIVES The ultrastructural examination and EFTEM element analysis of skin lesions of a patient with ESRD and histopathologically confirmed NSF revealed data displaying a mainly perivascular and multifocal pericollagenous dispersed Gadolinium deposition. Additionally colocalization of iron can be seen. A number of the probably infiltrating fibrocytes show distinct signs of myofibroblastic differentiation. Our results clarify that Gadolinium, and possibly iron, may play a pivotal role in the development of fibrotic disorders like NSF. By contrast, we failed to demonstrate Gadolinium involvement in EPS affected patients with previous Gadolinium exposure history, but confirmed some iron presence in the tissue – this is in line with the Gadolinium transmetallation hypothesis. The evidenced distinct pericollagenous deposition of Gadolinium issues a number of questions, e.g. which collagen fiber components (proteoglycans?) are the binding partner for gadolinium and how stable there are. High resolution examinations of future in-vivo and in-vitro models should provide more insight into the interaction of Gd within the affected tissue. To address this particular question analysis of the near edge fine structure of the EELS spectra (ELNES methodology) should be used (75, 111). This technique has the potential to provide insight into the chemical bonding characteristics between Gd and other elements or compounds in situ (e.g. in cryosections of hydrated tissue (76, 77)) opening the door for new explanation (60), so that, the proposal of some authors to once again rename the disease in ―Gadolinium-Associated Systemic Fibrosis‖ (GASF), will be able to endure (48). Based on the NSF example, it is interesting to notice how modern medicine has induced and now try to cope a new man-made human disease emerged at the beginning of this

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millennium (23). It is to be hoped, that we will also learn from this lesson, that the now exploding nanotechnology applications introduced in nearby all life, food, global industry, and environmental aspects, including medical diagnostic and therapeutic fields (112), can be deleterious. In this context the use of gadolinium loaded nanotubes or nanohorns with embedded Gd labels as advanced MRI contrast agents (113, 114) will have to be closely monitored. A lot of new insight will be necessary to correctly understand the nanoparticle modified interactions of gadolinium with the human body for an optimal diagnostic benefit and in order to avoid potential harmful disease induction.

ACKNOWLEDGMENTS The authors gratefully acknowledge the exellent technical assistance of Beate Voll and Heiko I. Siegmund (Central EM-Lab, Regensburg). The permission to reproduce figures 4 to 9 was kindly granted by the Clin JASN/American Society of Nephrology, and figures 10 to 12 by the NDT/Oxford University Press journals publishers.

REFERENCES

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[1]

Bozzola, JJ & Russell, LD: Electron microscopy : Principles and techniques for biologists, Boston, Jones and Bartlett Publishers 1992. [2] Ghadially, FN: Ultrastructural Pathology of the cell and matrix 4. Ed., Boston, Butterworth-Heinemann 1997. [3] Maunsbach, AB & Afzelius, B: Biomedical electron microscopy : Illustrated methods and interpretations, San Diego, Calif., Academic Press 1999. [4] Gadolinium Production. 2010 pp Available at: http://en.wikipedia.org/wiki/Gadolinium. [5] Ahlem, A, Samira, M, Ali el, H, Pierre, G & Leila, T: Ultrastructural study of the intracellular behavior of four mineral elements in the lactating mammary gland cells: study using conventional transmission electron microscopy. Microsc Res Tech, 71: 84955, 2008. [6] Adding, LC, Bannenberg, GL & Gustafsson, LE: Basic experimental studies and clinical aspects of gadolinium salts and chelates. Cardiovasc Drug Rev, 19: 41-56, 2001. [7] Ahlem, A, Ali el, H & Leila, T: Lysosomes of the liver and the duodenal enterocytes, a site of handling of two rare earths. Ultrastructural and microanalytical study. Biol Trace Elem Res, 124: 40-51, 2008. [8] 8. Ishii, C & Kawabata, Z: Ecological evaluation of gadolinium toxicity compared with other heavy metals using an aquatic microcosm. Bull Environ Contam Toxicol, 66: 2318, 2001. [9] Hirano, S & Suzuki, KT: Exposure, metabolism, and toxicity of rare earths and related compounds. Environ Health Perspect, 104 Suppl 1: 85-95, 1996. [10] Mizgerd, JP, Molina, RM, Stearns, RC, Brain, JD & Warner, AE: Gadolinium induces macrophage apoptosis. J Leukoc Biol, 59: 189-95, 1996.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

186

J.A. Schroeder, E. Goffin, Ch Weingart et al.

[11] Mogilevskaya, OY, Roshchina, P. A.: Toxicity of the oxides of rare-earth elements gadolinium and dysprosium. In: Powder Metallurgy and Metal Ceramics. New York, Springer, 1965, pp 256-258. [12] Sieber, MA, Steger-Hartmann, T, Lengsfeld, P & Pietsch, H: Gadolinium-based contrast agents and NSF: evidence from animal experience. J Magn Reson Imaging, 30: 1268-76, 2009. [13] Sabin, J, Prieto, G, Sennato, S, Ruso, JM, Angelini, R, Bordi, F & Sarmiento, F: Effect of Gd3+ on the colloidal stability of liposomes. Phys Rev E Stat Nonlin Soft Matter Phys, 74: 031913, 2006. [14] Kakigi, A, Nishimura, M, Takeda, T, Okada, T, Murata, Y & Ogawa, Y: Effects of gadolinium injected into the middle ear on the stria vascularis. Acta Otolaryngol, 128: 841-5, 2008. [15] Haley, TJ, Raymond, K, Komesu, N & Upham, HC: Toxicological and pharmacological effects of gadolinium and samarium chlorides. Br J Pharmacol Chemother, 17: 526-32, 1961. [16] Bannenberg, GL & Gustafsson, LE: Stretch-induced stimulation of lower airway nitric oxide formation in the guinea-pig: inhibition by gadolinium chloride. Pharmacol Toxicol, 81: 13-8, 1997. [17] Hardonk, MJ, Dijkhuis, FW, Hulstaert, CE & Koudstaal, J: Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol, 52: 296-302, 1992. [18] Husztik, E, Lazar, G & Parducz, A: Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol, 61: 624-30, 1980. [19] Evans, C: Biochemistry of the lanthanoides, London, Plenum Press 1990. [20] Tweedle, MF, Eaton, SM, Eckelman, WC, Gaughan, GT, Hagan, JJ, Wedeking, PW & Yost, FJ: Comparative chemical structure and pharmacokinetics of MRI contrast agents. Invest Radiol, 23 Suppl 1: S236-9, 1988. [21] Aime, S & Caravan, P: Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging, 30: 1259-67, 2009. [22] Caravan, P: Contrast agents: basic principles, Philadelphia, Saunders 2005. [23] Weinreb, JC & Abu-Alfa, AK: Gadolinium-based contrast agents and nephrogenic systemic fibrosis: why did it happen and what have we learned? J Magn Reson Imaging, 30: 1236-9, 2009. [24] Cowper, SE, Robin, HS, Steinberg, SM, Su, LD, Gupta, S & LeBoit, PE: Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet, 356: 10001, 2000. [25] Cowper, SE, Su, LD, Bhawan, J, Robin, HS & LeBoit, PE: Nephrogenic fibrosing dermopathy. Am J Dermatopathol, 23: 383-93, 2001. [26] 26. Swartz, RD, Crofford, LJ, Phan, SH, Ike, RW & Su, LD: Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med, 114: 563-72, 2003. [27] 27. Nephrogenic fibrosing dermopathy associated with exposure to gadoliniumcontaining contrast agents--St. Louis, Missouri, 2002-2006. MMWR Morb Mortal Wkly Rep, 56: 137-41, 2007.

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Electron Microscopic Studies of the Role of Gadolinium in Human ...

187

[28] Gambichler, T, Paech, V, Kreuter, A, Wilmert, M, Altmeyer, P & Stucker, M: Nephrogenic fibrosing dermopathy. Clin Exp Dermatol, 29: 258-60, 2004. [29] Gibson, SE, Farver, CF & Prayson, RA: Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med, 130: 209-12, 2006. [30] Hauser, C, Kaya, G & Chizzolini, C: Nephrogenic fibrosing dermopathy in a renal transplant recipient with tubulointerstitial nephritis and uveitis. Dermatology, 209: 502, 2004. [31] 31. Levine, JM, Taylor, RA, Elman, LB, Bird, SJ, Lavi, E, Stolzenberg, ED, McGarvey, ML, Asbury, AK & Jimenez, SA: Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve, 30: 569-77, 2004. [32] Mendoza, FA, Artlett, CM, Sandorfi, N, Latinis, K, Piera-Velazquez, S & Jimenez, SA: Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum, 35: 238-49, 2006. [33] Najafian, B, Franklin, DB & Fogo, AB: Acute renal failure and myalgia in a transplant patient. J Am Soc Nephrol, 18: 2870-4, 2007. [34] Othersen, JB, Maize, JC, Woolson, RF & Budisavljevic, MN: Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant, 22: 3179-85, 2007. [35] Plamondon, I, Samson, C, Watters, AK, Begin, LR, Cote, J, Deziel, C & Querin, S: [Nephrogenic systemic fibrosis: more hard times for renal failure patients]. Nephrol Ther, 3: 152-6, 2007. [36] Schroeder, JA, Weingart, C, Coras, B, Hausser, I, Reinhold, S, Mack, M, Seybold, V, Vogt, T, Banas, B, Hofstaedter, F & Kramer, BK: Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and end-stage renal disease. Clin J Am Soc Nephrol, 3: 968-75, 2008. [37] Grobner, T: Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant, 21: 1104-8, 2006. [38] Boyd, AS, Zic, JA & Abraham, JL: Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol, 56: 27-30, 2007. [39] Caccetta, T & Chan, JJ: Nephrogenic systemic fibrosis associated with liver transplantation, renal failure and gadolinium. Australas J Dermatol, 49: 48-51, 2008. [40] Cowper, SE, Bucala, R & Leboit, PE: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis--setting the record straight. Semin Arthritis Rheum, 35: 208-10, 2006. [41] Galan, A, Cowper, SE & Bucala, R: Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol, 18: 614-7, 2006. [42] Grobner, T & Prischl, FC: Gadolinium and nephrogenic systemic fibrosis. Kidney Int, 72: 260-4, 2007. [43] Heinrich, M & Uder, M: [Nephrogenic systemic fibrosis after application of gadolinium-based contrast agents--a status paper]. Rofo, 179: 613-7, 2007. [44] Lim, YL, Lee, HY, Low, SC, Chan, LP, Goh, NS & Pang, SM: Possible role of gadolinium in nephrogenic systemic fibrosis: report of two cases and review of the literature. Clin Exp Dermatol, 32: 353-8, 2007.

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188

J.A. Schroeder, E. Goffin, Ch Weingart et al.

[45] Marckmann, P, Skov, L, Rossen, K, Dupont, A, Damholt, MB, Heaf, JG & Thomsen, HS: Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol, 17: 2359-62, 2006. [46] Partain, CL: Focus on contrast-associated nephrogenic systemic fibrosis. J Magn Reson Imaging, 30: 1231-2, 2009. [47] Swaminathan, S & Shah, SV: New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol, 18: 2636-43, 2007. [48] Todd, DJ, Kagan, A, Chibnik, LB & Kay, J: Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum, 56: 3433-41, 2007. [49] Leiner, T & Kucharczyk, W: Special issue: nephrogenic systemic fibrosis. J Magn Reson Imaging, 30: 1233-5, 2009. [50] Roditi, G, Maki, JH, Oliveira, G & Michaely, HJ: Renovascular imaging in the NSF Era. J Magn Reson Imaging, 30: 1323-34, 2009. [51] Cowper, SE: Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007 pp Available at http://icnfdr.org. [52] Mayr, M, Burkhalter, F & Bongartz, G: Nephrogenic systemic fibrosis: clinical spectrum of disease. J Magn Reson Imaging, 30: 1289-97, 2009. [53] Silberzweig, JI & Chung, M: Removal of gadolinium by dialysis: review of different strategies and techniques. J Magn Reson Imaging, 30: 1347-9, 2009. [54] Mazhar, SM, Shiehmorteza, M, Kohl, CA, Middleton, MS & Sirlin, CB: Nephrogenic systemic fibrosis in liver disease: a systematic review. J Magn Reson Imaging, 30: 1313-22, 2009. [55] Peak, AS & Sheller, A: Risk factors for developing gadolinium-induced nephrogenic systemic fibrosis. Ann Pharmacother, 41: 1481-5, 2007. [56] Prince, MR, Zhang, HL, Roditi, GH, Leiner, T & Kucharczyk, W: Risk factors for NSF: a literature review. J Magn Reson Imaging, 30: 1298-308, 2009. [57] Wahba, IM, Simpson, EL & White, K: Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant, 7: 2425-32, 2007. [58] Cowper, SE, Kuo, PH & Bucala, R: Nephrogenic systemic fibrosis and gadolinium exposure: Association and lessons for idiopathic fibrosing disorders. Arthritis Rheum, 56: 3173-5, 2007. [59] Eyden, B: The myofibroblast: a study of normal, reactive and neoplastic tissues with an emphasis on ultrastructure, Siena, Nuova Immagine Editrice 2007. [60] Newton, BB & Jimenez, SA: Mechanism of NSF: New evidence challenging the prevailing theory. J Magn Reson Imaging, 30: 1277-83, 2009. [61] Quan, TE, Cowper, S, Wu, SP, Bockenstedt, LK & Bucala, R: Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol, 36: 598-606, 2004. [62] 62. Schmidt, M, Sun, G, Stacey, MA, Mori, L & Mattoli, S: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol, 171: 380-9, 2003. [63] Thakral, C & Abraham, JL: Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis. J Cutan Pathol, 36: 1244-54, 2009.

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189

[64] Vakil, V, Sung, JJ, Piecychna, M, Crawford, JR, Kuo, P, Abu-Alfa, AK, Cowper, SE, Bucala, R & Gomer, RH: Gadolinium-containing magnetic resonance image contrast agent promotes fibrocyte differentiation. J Magn Reson Imaging, 30: 1284-8, 2009. [65] High, WA, Ayers, RA, Chandler, J, Zito, G & Cowper, SE: Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol, 56: 21-6, 2007. [66] Kalb, RE, Helm, TN, Sperry, H, Thakral, C, Abraham, JL & Kanal, E: Gadoliniuminduced nephrogenic systemic fibrosis in a patient with an acute and transient kidney injury. Br J Dermatol, 158: 607-10, 2008. [67] Singh, M, Davenport, A, Clatworthy, I, Lewin, J, Deroide, F, Hubbard, V & Rustin, MH: A follow-up of four cases of nephrogenic systemic fibrosis: is gadolinium the specific trigger? Br J Dermatol, 158: 1358-62, 2008. [68] Thakral, C & Abraham, JL: Automated Scanning Electron Microscopy and X-Ray Microanalysis for in situ Quantification of Gadolinium Deposits in Skin. J Electron Microsc (Tokyo), 56: 181-7, 2007. [69] Thakral, C, Alhariri, J & Abraham, JL: Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging, 2: 199-205, 2007. [70] High, WA, Ayers, RA & Cowper, SE: Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol, 56: 710-2, 2007. [71] Reimer, L, Deininger, C, Egerton, RF, Hofer, F, Jouffrey, B, Krahl, D, Leapman, RD, Mayer, J, Rose, H, Schattschneider, P & Spence, JCH: Electron-Filtering Transmission Electron Microscopy, Berlin, Springer 1995. [72] Egerton, RF: Electron Energy-Loss Spectroscopy in the Electron Microscope, New York, Plenum Press 1996. [73] Egerton, RF: New techniques in electron energy-loss spectroscopy and energy-filtered imaging. Micron, 34: 127-39, 2003. [74] Egerton, RF: Limits to the spatial, energy and momentum resolution of electron energyloss spectroscopy. Ultramicroscopy, 107: 575-86, 2007. [75] Jouffrey, B, Schattschneider, P & Hebert, C: Ionization Edges: Some Underlying Physics and Their Use in Electron Microscopy. In: Advances in Imaging and Electron Physics. edited by HAWKES, P. W., San Diego, Academic Press, Elsevier Science, 2002, pp 413-450. [76] Keast, VJ & Bosman, M: New developments in electron energy loss spectroscopy. Microsc Res Tech, 70: 211-9, 2007. [77] Leapman, RD, Sun, SQ, Hunt, JA & Andrews, SB: Biological electron energy loss spectroscopy in the field-emission scanning transmission electron microscope. Scanning Microsc Suppl, 8: 245-58; discussion 258-9, 1994. [78] Mayr, M, Kim, MJ, Wanner, D, Helmut, H, Schroeder, J & Mihatsch, MJ: Argyria and decreased kidney function: are silver compounds toxic to the kidney? Am J Kidney Dis, 53: 890-4, 2009. [79] Reimer, L, Zedke, U, Moesch, J, Schulze-Hillert, ST, Ross-Messemer, M, Probst, W & Weimer, E: EELS-Spectroscopy: A Reference Handbook of Standard Data for the Identification and Interpretation of Electron Energy Loss Spectra and for Generation of Electron Spectra Images., Oberkochen, Carl Zeiss electron optic division Ed 1992.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

190

J.A. Schroeder, E. Goffin, Ch Weingart et al.

[80] Simon, GT & Heng, YM: Electron energy loss spectroscopic imaging in biology. Scanning Microsc, 2: 257-66, 1988. [81] Geiser, M, Rothen-Rutishauser, B, Kapp, N, Schurch, S, Kreyling, W, Schulz, H, Semmler, M, Im Hof, V, Heyder, J & Gehr, P: Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect, 113: 1555-60, 2005. [82] Hirai, K, Pan, J, Shimada, H, Izuhara, T, Kurihara, T & Moriguchi, K: Cytochemical energy-filtering transmission electron microscopy of mitochondrial free radical formation in paraquat cytotoxicity. J Electron Microsc (Tokyo), 48: 289-96, 1999. [83] Jonas, L, Baguhl, F, Wilken, HP, Haas, HJ & Nizze, H: Copper accumulation in actinomyces druses during endometritis after long-term use of an intrauterine contraceptive device. Ultrastruct Pathol, 26: 323-9, 2002. [84] Jonas, L, Fulda, G, Kroning, G, Merkord, J & Nizze, H: Electron microscopic detection of tin accumulation in biliopancreatic concrements after induction of chronic pancreatitis in rats by di-n-butyltin dichloride. Ultrastruct Pathol, 26: 89-98, 2002. [85] Kapp, N, Kreyling, W, Schulz, H, Im Hof, V, Gehr, P, Semmler, M & Geiser, M: Electron energy loss spectroscopy for analysis of inhaled ultrafine particles in rat lungs. Microsc Res Tech, 63: 298-305, 2004. [86] Kapp, N, Studer, D, Gehr, P & Geiser, M: Electron Energy-Loss Spectroscopy as a Tool for Elemental Analysis in Biological Specimens. In: Electron Microscopy, Methods and Protocols, Second Edition. second edition ed. edited by JOHN, K., Totowa, New Jersey Humana Press Inc., 2007, pp 431-447. [87] Rothen-Rutishauser, BM, Schurch, S, Haenni, B, Kapp, N & Gehr, P: Interaction of fine particles and nanoparticles with red blood cells visualized with advanced microscopic techniques. Environ Sci Technol, 40: 4353-9, 2006. [88] Rouelle-Rossier, VB, Biggiogera, M & Fakan, S: Ultrastructural detection of calcium and magnesium in the chromatoid body of mouse spermatids by electron spectroscopic imaging and electron energy loss spectroscopy. J Histochem Cytochem, 41: 1155-62, 1993. [89] Schlotzer-Schrehardt, U, Kortje, KH & Erb, C: Energy-filtering transmission electron microscopy (EFTEM) in the elemental analysis of pseudoexfoliative material. Curr Eye Res, 22: 154-62, 2001. [90] Balasubramaniam, G, Brown, EA, Davenport, A, Cairns, H, Cooper, B, Fan, SL, Farrington, K, Gallagher, H, Harnett, P, Krausze, S & Steddon, S: The Pan-Thames EPS study: treatment and outcomes of encapsulating peritoneal sclerosis. Nephrol Dial Transplant, 24: 3209-15, 2009. [91] Chin, AI & Yeun, JY: Encapsulating peritoneal sclerosis: an unpredictable and devastating complication of peritoneal dialysis. Am J Kidney Dis, 47: 697-712, 2006. [92] Summers, AM, Clancy, MJ, Syed, F, Harwood, N, Brenchley, PE, Augustine, T, Riad, H, Hutchison, AJ, Taylor, P, Pearson, R & Gokal, R: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end-stage renal failure. Kidney Int, 68: 2381-8, 2005. [93] Perazella, MA: Current status of gadolinium toxicity in patients with kidney disease. Clin J Am Soc Nephrol, 4: 461-9, 2009. [94] Fieren, MW, Betjes, MG, Korte, MR & Boer, WH: Posttransplant encapsulating peritoneal sclerosis: a worrying new trend? Perit Dial Int, 27: 619-24, 2007.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Electron Microscopic Studies of the Role of Gadolinium in Human ...

191

[95] Goffin E., DP: Does the incidence of encapsulating peritoneal sclerosis increase after renal transplantation? Perit Dial Int. 2008 pp 28: S5. [96] Korte, MR, Yo, M, Betjes, MG, Fieren, MW, van Saase, JC, Boer, WH, Weimar, W & Zietse, R: Increasing incidence of severe encapsulating peritoneal sclerosis after kidney transplantation. Nephrol Dial Transplant, 22: 2412-4, 2007. [97] Murashima, M, Drott, HR, Carlow, D, Shaw, LM, Milone, M, Bachman, M, Tsai, DE, Yang, SL & Bloom, RD: Removal of gadolinium by peritoneal dialysis. Clin Nephrol, 69: 368-72, 2008. [98] Marckmann, P, Skov, L, Rossen, K, Heaf, JG & Thomsen, HS: Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant, 2007. [99] Tsai, CW, Chao, CC, Wu, VC, Hsiao, CH & Chen, YM: Nephrogenic fibrosing dermopathy in a peritoneal dialysis patient. Kidney Int, 72: 1294, 2007. [100] Goffin, E, Schroeder, JA, Weingart, C, Decleire, PY & Cosyns, JP: Absence of gadolinium deposits in the peritoneal membrane of patients with encapsulating peritoneal sclerosis. Nephrol Dial Transplant, 25: 1334-9, 2009. [101] Combet, S, Miyata, T, Moulin, P, Pouthier, D, Goffin, E & Devuyst, O: Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis. J Am Soc Nephrol, 11: 717-28, 2000. [102] Di Paolo, N & Sacchi, G: Atlas of peritoneal histology. Perit Dial Int, 20 Suppl 3: S596, 2000. [103] Prchal, D, Holmes, DT & Levin, A: Nephrogenic systemic fibrosis: the story unfolds. Kidney Int, 73: 1335-7, 2008. [104] Sadowski, EA, Bennett, LK, Chan, MR, Wentland, AL, Garrett, AL, Garrett, RW & Djamali, A: Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology, 243: 148-57, 2007. [105] Swaminathan, S, High, WA, Ranville, J, Horn, TD, Hiatt, K, Thomas, M, Brown, HH & Shah, SV: Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis. Kidney Int, 73: 1413-8, 2008. [106] Idee, JM, Port, M, Raynal, I, Schaefer, M, Le Greneur, S & Corot, C: Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol, 20: 563-76, 2006. [107] Kovesdy, CP: Iron and clinical outcomes in dialysis and non-dialysis-dependent chronic kidney disease patients. Adv Chronic Kidney Dis, 16: 109-16, 2009. [108] Wish, JB: Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol, 1 Suppl 1: S4-8, 2006. [109] Bucala, R: Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol, 5: 36-9, 2008. [110] Thakral, C & Abraham, JL: Automated scanning electron microscopy and x-ray microanalysis for in situ quantification of Gadolinium deposits in skin. J Electron Microsc (Tokyo), 156: 181-7, 2007. [111] Stoeger, M: ELNES - energy loss near edge structure [The EELS Group / Institute for Solid State Physics Website]. 2002 pp Available at http://tem.atp.tuwien.ac.at/EELS/ELNES.htm.

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J.A. Schroeder, E. Goffin, Ch Weingart et al.

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[112] Sarin, H, Kanevsky, AS, Wu, H, Sousa, AA, Wilson, CM, Aronova, MA, Griffiths, GL, Leapman, RD & Vo, HQ: Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors. J Transl Med, 7: 51, 2009. [113] Li, JX, Liu, JC, Wang, K & Yang, XG: Gadolinium-containing bioparticles as an active entity to promote cell cycle progression in mouse embryo fibroblast NIH3T3 cells. J Biol Inorg Chem. [114] Miyawaki, J, Matsumura, S, Yuge, R, Murakami, T, Sato, S, Tomida, A, Tsuruo, T, Ichihashi, T, Fujinami, T, Irie, H, Tsuchida, K, Iijima, S, Shiba, K & Yudasaka, M: Biodistribution and ultrastructural localization of single-walled carbon nanohorns determined in vivo with embedded Gd2O3 labels. ACS Nano, 3: 1399-406, 2009.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.193-215 © 2010 Nova Science Publishers, Inc.

Chapter 5

NOVEL NANOVECTORS AS THE LIVER TARGET MOLECULAR: MRI CONTRAST AGENTS Na Zhang* and Zhijin Chen School of Pharmaceutical Science, Shandong University, 44 Wenhua Xi Road, 250012 Ji‘nan, People‘s Republic of China

ABSTRACT

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Accurate diagnosis in early stage is vital for the treatment of hepatocellular carcinoma(HCC). Contrast material–enhanced dynamic magnetic resonance imaging (MRI) performed with extracellular contrast agents such as gadolinium chelates is considered useful for detecting and characterizing focal liver lesions. However, the sensitivity and specificity of conventional MRI contrast agents are far from satisfaction for the detection and characterization of benign and malignant focal liver lesions in early stage. The novel molecular contrast agents special for liver with relatively longer metabolic time and stable contrast effect in liver tissue are highly desired. The developing nanotechnology provides an unprecedented opportunity for the diagnostic detection rate of HCC, and cell-surface receptor-targeted nanotenology provide improving specificity of the detection of focal liver lesions. In order to maximize lesion detection and characterization, novel gadolinium chelates loaded nanovectors include the solid lipid nanoparticles, nanocomplexes and polymeric nanoparticles has been used as biocompatible molecular MRI contrast agent. In this chapter, we would discuss the preparation, characterization and the advantages/ disadvantages of these novel nanovectors using as molecular MRI contrast agents. Furthermore, liver target nanovectors aimed at improving the diagnostic accuracy of liver MRI by targeting additional features of focal liver lesions would be highlighted.

*

Corresponding author: E-mail: [email protected]

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1. INTRODUCTION The incidence of the hepatocellular carcinoma (HCC) is increasing recently and HCC has risen to become the 5th commonest malignancy worldwide and the third leading cause of cancer-related death, exceeded only by cancers of the lung and stomach[1]. Early diagnosis of HCC remains a key goal in improving the poor prognosis of HCC. Identifying HCC at early stage is often associated with better treatment options for patients with small, asymptomatic tumors[2]. Magnetic resonance imaging (MRI), the best available diagnostic technique, offers good contrast resolution and diagnostic sensitivity ranging from 33% to 77%. The main difficulty is not in diagnosing large tumors, but rather small tumors (60 min and resistant to washing out by buffer rinses. Ultrastructural analysis of the nanoparticles revealed the targeting groups at the nanoparticle surfaces and the distribution of the Gd chelates within the nanoparticles and enabled counts for use in determining relaxivity. The relaxivity values revealed were extremely high, accounting for the strong MR signals observed. Occasionally, nanoparticles larger than 100 nm were seen in close spatial association with disrupted regions of cell membrane or of collagen fibrils in the extracellular matrix. The data suggest that 100-nm nanoparticles generate adequate contrast for molecular MRI and cause least disruption to endothelial cell surfaces.

2.2.3. Chitosan nanoparticles Chitosan is a cationic copolymer of N-acetyl glucosamine and D-glucosamine, varying in composition, sequence and molecular chain length. This compound is nontoxic and biocompatible, thus offering powerful potential for biomedical applications such as drug and gene delivery, tissue engineering as well as wound healing. With the rise of nanotechnology, chitosan in conjunction with bioactive nanoparticles is fabricated into various bio-nanocomposites, providing alternatives to the new era of regenerative medicine, as drug delivery vehicles and possibly as contrast agent carriers for molecular imaging[35]. The accumulation of gadolinium loaded as gadopentetic acid (Gd-DTPA) in chitosan nanoparticles (Gd-nanoCPs), which were designed for gadolinium neutron-capture therapy (Gd-NCT) for cancer, was evaluated in vitro in cultured cells[36]. Using L929 fibroblast

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cells, the Gd accumulation for 12 h at 37℃ was investigated at Gd concentrations lower than 40 ppm. The accumulation leveled above 20 ppm and reached 18.0±2.7 (mean±S.D.) mg Gd/106 cells at 40 ppm. Furthermore, the corresponding accumulations in B16F10 melanoma cells and SCC-VII squamous cell carcinoma, which were used in the previous Gd-NCT trials in vivo, were 27.1±2.9 and 59.8±9.8 mg Gd/106 cells, respectively, hence explaining the superior growth-suppression in the in vivo trials using SCC-VII cells. The accumulation of Gd-nanoCPs in these cells was 100-200 times higher in comparison to dimeglumine gadopentetate aqueous solution (Magnevist®), a magnetic resonance imaging contrast agent. The endocytic uptake of Gd-nanoCPs, strongly holding Gd-DTPA, was suggested from transmission electron microscopy and comparative studies at 48C and with the solution system. These findings indicated that Gd-nanoCPs had a high affinity to the cells, probably contributing to the long retention of Gd in tumor tissue and leading to the significant suppression of tumor growth in the in vivo studies. The expansive development and clinical application of Gd chelates for MRI applications has led to a rebirth of interest in the use of Gd as a radiosensitizer in neutron capture therapy (NCT). However, the poor selective tissue labeling and localization provided by conventional molecular Gd chelates has limited success in both MRI and NCT applications. Encapsulating Gd into nanoparticulate materials or conjugating on the exterior of the nanoparticles has been developed to overcome these limitations. Incorporating Gd chelates into nanovectors affords additional flexibility in engineering targeting and also provides a means to apply high tissuecentric concentrations of Gd-often critical for both imaging and therapeutic applications. The

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potential of Gd-NCT for cancer was evaluated using chitosan nanoparticles as a novel gadolinium device[37]. The nanoparticles, incorporating 1200 mg of natural gadolinium, were administered intratumorally twice in mice bearing subcutaneous B16F10 melanoma. The thermal neutron irradiation was performed for the tumor site, with the fluence of 6.32×1012 neutrons/cm2, 8 h after the second gadolinium administration. After the irradiation, the tumor growth in the nanoparticle-administered group was significantly suppressed compared to that in the gadopentetate solution-administered group, despite radioresistance of melanoma and the smaller Gd dose than that administered in past Gd-NCT trials. This study demonstrated the potential usefulness of Gd-NCT using gadolinium-loaded nanoparticles.

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2.3. Polymeric Nanocomplexes Through the adsorption to form the nanocomplexes contain gadolinium is one of the valuable ways to create the contrast agent carriers. Gd-DTPA could be adsorbed onto an oppositely charged spherical nanoparticle or polymeric micelles to formulate the nanocomplexes. For example, Gd ions was bounded to the anionic block copolymers (poly(ethylene glycol)-b-poly(aspartic acid) derivative), then coupled with the cationic polymeric micelles (polyallylamine or protamine) to form novel molecular imaging agent providing high contrasts in MRI by shortening the T1 longitudinal relaxation time of protons of water[38]. The Gd-binding block copolymer alone showed high relaxivity (T1-shortening ability) values from 10 to 11 mol−1s−1, while after couple with the cationic polymeric micelles, the novel nanocomplexes exhibited low relaxivity values from 2.1 to 3.6 mol−1s−1. These findings point out the feasibility of a novel MRI contrast agent that selectively provides high contrasts at solid tumor sites owing to a dissociation of the micelle structures, while selective delivery to the tumor sites is achieved in the polymeric micelle form. The polymeric nanocomplexes were usually formed by self assemble technology. The advantages of the Gadolinium carried on the exterior of the polymeric nanocarriers via self assemble technology include: i) ensure exposure the gadolinium on the surface of the carriers that can maintain the enhanced ability of the contrast agent; ii) it could absorb sufficient gadolinium on the carriers that can produce enough enhanced signal in vivo than the encapsulation method. Using poly lactic acid-polyethylene glycol/ gadolinium-diethylenetriamine- pentaacetic acid (PLA-PEG/Gd-DTPA) nanocomplexes as biocompatible molecular magnetic resonance imaging (MRI) contrast agent have been developed and evaluated in our group[39]. The PLAPEG/Gd-DTPA nanocomplexes were obtained using self-assembly nanotechnology by incubation of PLA-PEG nanoparticles and the commercial contrast agent (Gd-DTPA). The nanocomplexes had high plasma stability, better image contrast effect, and liver targeting property. The mean size of the PLA-PEG/Gd-DTPA nanocomplexes was 187.9 ± 2.30 nm, the polydispersity index was 0.108, and the zeta potential was -12.36 ± 3.58 mV. The results of MRI test confirmed that the PLA-PEG/Gd-DTPA nanocomplexes possessed the ability of MRI, and the direct correlation between the MRI imaging intensities and the nano-complex concentrations was observed (r = 0.987). The signal intensity was still stable within 2 h after incubation of the nanocomplexes in human plasma. The nanocomplexes gave much better image contrast effects and longer stagnation time than that of commercial contrast agent in rat

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liver. A dose of 0.04 mmol of gadolinium per kilogram of body weight was sufficient to increase the MRI imaging intensities in rat livers by five-fold compared with the commercial Gd-DTPA. These results indicated that the PLA-PEG/Gd-DTPA nanocomplexes might be potential as molecular targeted imaging contrast agent. A new nanoparticulate paramagnetic contrast agent with highGd3+ payload and high relaxivity was developed[40]. The loading of the Gd3+ derivatives into the nanocomplexes was performed by simply mixing β-CD aqueous solutions containing the Gd3+ derivatives with alkyl side chains (MD) solutions (Figure 4). These supramolecular assemblies with a mean diameter of about 200 nm resulted from the association of two water soluble polymers: (i) dextran grafted MD and (ii) polymer of beta cyclodextrin (β-CD). The cohesion of these stable structures is based upon a ―lock and key‖ mechanism; inclusion complexes are formed between the hydrophobic alkyl chains (lauryl) on MD and the molecular cavities contained in the β-CD[41]. Indeed, the mechanism of formation has been studied[42]. In these conditions, a payload of 1.8×105 units of Gd3+ per nanocomplexe and a relaxivity r1 of 48.4mM−1 s−1 at 20MHz and 37℃ were obtained. These results were particularly promising, placing these

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nanocomplexes as good candidates for MRI.

Figure 4. Schematic representation of the nanocomplexes of the gadolinium and the polymer[40]

Figure 5. Schematic representation of multifunctional micelle structure made of a diblock copolymer

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Small particulate gadolinium oxide (SPGO) has been used experimentally as prototype contrast agent for multimodality imaging. In this study[43], an initial attempt was made to obtain better solubilized SPGO, prevent particle aggregation, and investigate the physicochemical properties of dextran SPGO relevant to its use as a high-field magnetic resonance contrast agent in aqueous solution. Dextran SPGO was prepared by mixing a baseneutralized colloid solution containing 6 mL 0.5 M NaOH and 500 mg of gadolinium (III) oxide with 15 mL of a 20% solution of dextran previously prepared in deionized, distilled water. The solution was heated to 100℃ for 15 minutes with stirring followed by sonication at 30℃, 70 W/cm2 using a sonicator. The slurry solution was centrifuged at 2700 rpm 4℃ for 20 minutes, decanted, and washed twice by membrane dialysis at 4°C. Dextran SPGO demonstrates regular crystalline lattices and has a gadolinium oxide electron diffraction pattern consistent with that of published X-ray powder diffraction (XPD) patterns. The subtraction XPD pattern of dextran SPGO shows diffraction angles and intensities similar, but not identical, to that of published Gd2O3 diffraction patterns. High r2/r1 ratios and magnetic susceptibility studies indicate dextran SPGO can be classified as a superparamagnetic compound. Enhanced relaxivity is observed at high magnetic field strength; largely because of solubilization of SPGO via the surface adherent carbohydrate. Perhaps also contributing to the observed relaxivity enhancement is the ideal lattice structure of the central gadolinium oxide crystal and the effects of sonochemical preparation on nanoparticle physicochemical properties. It is anticipated that these studies will help provide a basis for the development of novel nanoparticulate contrast agent platforms capable of improving T1 and T2/T2 contrast for high-field magnetic resonance imaging and molecular imaging.

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2.4. Polymeric Micelles At present, polymer micelles combined with gadolinium are very promising because of their ability to provide positive contrast (i.e., T1-weighted images), robust structural features, and simple fabrication. In such a micelle assembly product, the rate of water exchange is similar to that observed in Gd-DTPA, because the Gd complex is exposed in the exterior shell layer of the micelle[44]. Polymeric micelles that composed by AB-type, ABA-type or BAB-type block copolymers have shown many therapeutic advantages such as small particle size and high stability in blood circulation. Polymeric micelles selectively accumulated at tumors through an enhancement of the vascular permeability of the tumor vasculature (enhanced permeability and retention effect: EPR effect[45]). Polymeric micelles are frequently created from the selfassembly of biocompatible amphiphilic block copolymers in aqueous environments. In water, the hydrophobic portion of the block copolymer self-associates into a semi-solid core, with the hydrophilic segment of the copolymer forming a coronal layer (Figure 5). Application of polymeric micelle drug carrier systems to delivery MRI contrast agent was with high successful potential[46]. A block copolymer, PEG-b-poly(L-lysine) (PEG-PLL), consisting of a polycationic PLL backbone whose end amino group was chemical linked with PEG chains, was used for conjugation of gadolinium ions through chelating moieties, DOTA. The DOTA moieties were successfully conjugated to all primary amine groups of the lysine residues. The obtained block copolymer, PEG-b-poly(L-lysine-DOTA), formed polymeric

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micelle. The polymeric micelle structure was maintained even after partial gadolinium (∼40%) chelated to the DOTA moieties. The prepared polymeric micelle MRI contrast agent was injected into a mouse tail vein at a dose of 0.05 mmol Gd/kg. The polymeric micellebased MRI contrast agent exhibited stable during the blood circulation. A considerable amount (6.1±0.3% of ID/g of the polymeric micelle) was found to accumulate at solid tumors 24 h after intravenous injection by means of the EPR effect. An MRI analysis revealed that the signal intensity of the tumor was enhanced 2.0-fold by the use of this contrast agent. These accumulation ratios were similar to those in case of doxorubicin-incorporated polymeric micelle, but better tumor/muscle ratios were obtained in this MRI contrast agent.

2.5. Polyersomes Polymersomes, are used as multifunctional polymer vesicles which self-assembled from a diverse array of synthetic amphiphilic block copolymers containing hydrophilic and hydrophobic blocks[47]. The use of nanovesicles with encapsulated Gd as MR contrast agents has largely been ignored due to the detrimental effects of the slow water exchange rate through the vesicle bilayer on the relaxivity of encapsulated Gd. The facile synthesis of a composite MR contrast platform is described[48]. It consists of dendrimer conjugates encapsulated in porous polymersomes. These nanovectors exhibit improved permeability to water flux and a large capacity to store chelated Gd within the aqueous lumen, resulting in

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enhanced longitudinal relaxivity. The porous polymersomes, ～130 nm in diameter, are produced through the aqueous assembly of the polymers, polyethylene oxide-b-polybutadiene (PBdEO), and polyethylene oxide-b-polycaprolactone (PEOCL). The inclusion of PEOCL within the polymersome membrane allowed for the facile formation of pores via acid hydrolysis of the polycaprolactone block[49]. Subsequent hydrolysis of the caprolactone (CL) block resulted in a highly permeable outer membrane. To prevent the leakage of small Gdchelate through the pores, Gd was conjugated to polyamidoamine (PAMAM) dendrimers via diethylenetriaminepentaacetic acid dianhydride (DTPA dianhydride) prior to encapsulation (Figure 6). As a result of the slower rotational correlation time of Gd-labeled dendrimers, the porous outer membrane of the nanovectors, and the high Gd payload, these functional nanovectors are found to exhibit a relaxivity (R1) of 292 109 mM-1 s-1 per particle. The polymersomes are also found to exhibit unique pharmacokinetics with a circulation half-life of >3.5 h and predominantly renal clearance.

2.6. Dendrimers Dendrimers are a class of highly branched synthetic spherical polymers consisting of a vast array of types, chemical structures, and functional groups[50]. Two types of dendrimers, the polyammidoamine (PAMAM) and the diaminobutane (DAB) dendrimers, are commercially available. They are highly soluble in aqueous solution and both have a unique surface topology of primary amino groups. The defined structure and large number of available surface amino groups of these dendrimers have led to their use as substrates for the attachment of large numbers of chelating agents. These dendrimers have enabled the

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synthesis of numerous MRI contrast agents that possess very similar chemical structures but also cover a wide range of molecular weights.

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Figure 6. Schematic diagram illustrating approach used to prepare paramagnetic porous vesicles. Nanovesicles were formed through the coassembly of diblock inert copolymer PBdEO and biodegradable copolymer PEOCL. Gd-DTPA-labeled generation 3 dendrimers were encapsulated within the aqueous interior during vesicle formation. Pores were subsequently formed in the polymersome bilayer by hydrolysis of the caprolactone block[48]

Figure 7. Structure of the dendrimers and probes[51] Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Gd(III)-containing dendrimers are promising contrast agents for MRI. In order to provide experimental information on this issue, the electron paramagnetic resonance (EPR) of a stable Gd(III) complex with DTPA in various PAMAM dendrimers was investigated as a function of dendrimer generation (G2, G4, and G6), dendrimer core (ethylenediamine: EDA, and cystamine: cys), and dendrimer surface functionality (NH2, 5-oxo-3-pyrrolidinecarboxylic acid methyl ester: pyr, and tris(hydroxymethyl) methylamine: tris)[51]. The dendrimer systems were investigated in the presence and absence of paramagnetic probes, that is, Cu(II) and nitroxide radicals (4-(trimethylammonium and dodecyl-dimethylammonium) 2,2,6,6tetramethyl- piperidine 1-oxyl bromide: CAT1 and CAT12, respectively). The analysis of the EPR spectra revealed anisotropic locations of Gd-DTPA inside the dendrimer (Figure 7). Computer analysis of the EPR spectra of the probes identified the interactions of the Gddendrimers with ions and organic molecules. The interaction between the probes and the dendrimer internal and external surface depends on the type of core, the composition of the external surface and the generation of the dendrimer. The negatively charged Gd-DTPA complex attracts the positively charged species and this provokes spin-spin interactions between Gd and the probes, which increases with a decrease in generation, mainly from G6 to G4, and with an increase in both the Gd-dendrimer concentration and the probe concentration. The cys core increases the internal volume and decreases the packing of the branches.

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2.6. Others Nanovectors In the study for a highly effective, non-toxic contrast agent, fullerene molecules have received much attention. Fullerenes (C60) are a family of carbon allotropes, molecules composed entirely of carbon, in the form of a hollow sphere, ellipsoid, tube, or plane[52]. Researchers have speculated that fullerenes might be used to safely encapsulate and carry medically useful metals to different parts of the body where they could then be used for diagnostic or therapeutic purposes. The fullerenol contrast agent was developed and used for cell imaging[53]. The studies were to test Tl enhancement of cells on MRI using a paramagnetic Gd@C82 fullerenol contrast agent. Proliferation, viability, and differentiation assays of mesenchymal stem cell (MSC) cultures; light and electron microscopy of MSC and macrophages; and MRI of MSC, macrophage, and HeLa cervical carcinoma cell cultures in vitro and in vivo were performed to evaluate the labeled cells. The results showed that culture with the protamine sulfate could increased the cell uptake efficacy of Gd@C82 fullerenols. Tl of labeled MSC at 7 T was reduced 71% compared with unlabeled cells. Therefore, cellular labeling with Gd@C82 is feasible and can produce Tl-enhanced cells on MRI. This study suggests that further investigation of Gd fullerenols for tracking studies of viable cells, including stem cells, is warranted.

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3. LIVER TARGET MOLECULAR MRI CONTRAST AGENT

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3.1. Passive Targeting of Liver Using Nanoparticles A key feature in using nanoparticles as targeted contrast agents is the ability of the particles to accumulate in or be directed to the area of interest. Such targeting may achieve via passive or active principle. The reticuloendothelial system (RES) organs, such as the liver, play a major role in clearing small foreign particles from blood, which might serve as a marker for the nanoparticles to be passively targeted to certain phagocytic cells. The size of particles plays a critical role in their uptake by the phagocytic cells. Particles greater than 150 nm may be passive to the liver[54]. The solid lipid nanoparticles encapsulated taspine (TaSLN), which the size of the Ta-SLN was 173.0 ± 62.8 nm, showed that can be target to the liver after administration. At all time points, taspine liver concentration was higher for TaSLN than for the free taspine preparation. Similarly, in the study of PLA-PEG/Gd-DTPA nanocomplexes as biocompatible molecular magnetic resonance imaging (MRI) contrast agent carried out in our group[39], nanocomplexes with mean diametersaround 190 nm could reach high liver targeting and the TEC of the liver was 4.98, which indicated that the nanocomplexes can effectively concentrate to the liver and enhance the signal intensity. Unique paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. A series of amphipathic gadolinium complexes, which mimic phospholipids, was incorporated into the lamella of small unilamellar liposomes such that they become an integral part of its surface. The amphipathic complexing agents consisted of DTPA reagents in which two stearyl chains are attached via amide, ester, and thioester linkages. The in vitro stability and the in vivo lifetimes of the new amphipathic agents were dependent on the method used to attach the long-chain alkyl groups[55]. The most effective rate enhancement and best physical stability were attained when the amphiphilic complex constituted one-third of the lipid content of the liposome. The T1 relaxation of the liver was enhanced by 110% when 13.5 μmol of lipid was injected. In order to determine the distribution and lifetime of the various GLL agents in vivo, biodistribution experiments were performed utilizing gadolinium-153 as the tracer element. The results demonstrated that the agents were rapidly cleared from the blood and accumulated in the liver and spleen. The result of live imaging also indicated the uptake patterns and kinetics of the polystyrene nanoparticles dependant on the size of the nanoparticls[56]. In general, particles of sizes > 250-300 nm in diameter do not exhibit long circulation times compared with smaller particles, and seem to accumulate to a great extent in the spleen[5759]. A negative charge on liposome was shown in several studies to activate the complement system due to electrostatic adsorption of complement proteins on the liposome surface that would shorten their circulation times[60]. Although passive targeting mechanisms will increase the accumulation of contrast agent in a tumor, however, they are unlikely to be sufficient to achieve the concentrations necessary for successful molecular magnetic resonance imaging. Furthermore, larger tumors show poor vascularization, especially inside necrotic areas, preventing the localisation of contrast agents in the tumor. Hence, improved targeting of molecular contrast agents to tumors is necessary.

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3.2. Active Targeting of Liver Using Nanoparticles

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In general, passive targeting can provide general micro anatomical information while, specific biochemical information requires active targeting strategies to provide molecular specificities. Active targeting strategies to the disease tissues involve conjugation of a specific moiety on the nanocarriers‘ surface that will be recognized by the specific cells present at the disease site. Molecular imaging of cells and cellular processes can be achieved by tagging intracellular targets such as receptors, enzymes, or mRNA. To achieve the active target contrast agent, target ligands were used as the target molecular to modify the nanocarriers. A wide variety of targeting moieties are utilized to decorate ligand-directed (―targeted‖) contrast agents to identify specific pathological tissues. The non-limiting examples of ligands used for targeting are : monoclonal antibodies (and Fab fragments), small molecule ligands (e.g. folic acid), peptidomimetics, aptamers, and polysaccharides (e.g. heparin)[61]. The active target ability of nanoparticles was dependant on the target cell antigen density and the target legend used in the contrast agent system.

3.2.1. Peptides Oligopeptides play multiple roles in nanomedicine. Some can serve as templates for nanoparticle formation, whereas others, especially homo-oligomers, are used as charged molecules for formation of nanoparticles[62]. Small peptides are frequently the drug payloads incorporated into nanoparticles. Many others are used as targeting groups, including the arginine-glycine-aspartic acid (RGD) peptide conjugated with the polymer PLA-PEG[63]. Seeking to visualize the presence-of specific mRNAs by MR imaging, peptide nucleic acids (PNA, antisense to mRNA of DsRed2 protein and nonsense with no natural counterpart) were coupled with gadolinium-based MR contrast agents for intracellular target imaging [64]. The conjugates were produced by continuous solid-phase synthesis followed by chelation with gadolinium. Their cellular uptake was confirmed by fluorescence microscopy and spectroscopy as well as by MR imaging of labeled cells. The cell-penetrating peptide D-Tat (57-49) was selected over two other derivatives of HIV-1 Tat peptide, based on its superior intracellular delivery of the gadolinium-based contrast agents. Significant enhancement in MR contrast was obtained in cells labeled with concentrations as low as 2.5 μM of these agents. Specific binding of the targeting PNA containing conjugate to its complementary oligonucleotide sequence was proven by in vitro cell-free assay. In contrast, a lack of specific enrichment was observed in transgenic cells containing the target due to nonspecific vesicular entrapment of contrast agents. Preliminary biodistribution studies showed conjugate-related fluorescence in several organs, especially the liver and bladder, indicating high mobility of the agent in spite of its high molecular weight. These results are encouraging, as they warrant further molecular optimization and consecutive specificity studies in vivo of this new generation of contrast agents. 3.2.2. Folic acid The folate receptor is a well-known tumor marker that binds vitamin folate and folatedrug conjugates with a high affinity and carries these bound molecules into the cells via receptor-mediated endocytosis[65].

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A target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor was synthesized using generation five (G5) of polyamidoamine (PAMAM dendrimer. Surface modified dendrimer was functionalized for targeting with folic acid (FA) and the remaining terminal primary amines of the dendrimer were conjugated with the bifunctional NCS-DOTA chelator that forms stable complexes with gadolinium (Gd III)[66]. Dendrimer-DOTA conjugates were then complexed with GdCl3, followed by ICP-OES as well as MRI measurement of their longitudinal relaxivity (T1 s(-1) mM(-1)) of water. In xenograft tumors established in immunodeficient (SCID) mice with KB human epithelial cancer cells expressing folate receptor (FAR), the 3D MRI results showed specific and statistically significant signal enhancement in tumors generated with targeted Gd(III)-DOTAG5-FA compared with signal generated by non-targeted Gd(III)-DOTA-G5 contrast nanoparticle. The targeted dendrimer contrast nanoparticles infiltrated tumor and were retained in tumor cells up to 48 hours post-injection. The presence of folic acid on the dendrimer resulted in specific delivery of the nanoparticle to tissues and xenograft tumor cells expressing folate receptor in vivo. The specific dendrimer nanoparticles for targeted cancer imaging possessed the prolonged clearance time compared with the current clinically approved gadodiamide (Omniscan(TM)) contrast agent simultaneity. Potential application of this approach may include determination of the folate receptor status of tumors and monitoring of drug therapy.

3.2.3. Monoclonal antibody Monoclonal antibodies labeled with paramagnetic atoms or superparamagnetic nanoparticles are believed to be the critical tumor-seeking resources. Though some monoclonal antibodies have also been used to develop targeted contrast agents[67, 68], there is no found described about the liver target contrast agent. One novel molecular nanoparticles contrast agent target to the liver through conjugated the antibody to the surface of the nanoparticles was under developing by our group. The biocompatible polymer PLA-PEGNH2 was employed to establish the nanoparticles. The gadolinium was first conjugated with the PLA-PEG-NH2 through the DTPA, and one part of the PLA-PEG-NH2 was biotinylated. The nanoparticles were prepared by the nanoprecipitation method. The antibody (anti-alphafetoprotein, anti-AFP) was directly immobilized onto the formed nanoparticles by modifying the amino-modified nanoparticles with glutaraldehyde. Then the FITC conjugated with the nanoparticles through biotin-avidin system (Figure 8). The target effect was evaluated in the HepG2 cell. HepG2 cells (2 × 104 cells/mL) were seeded in a 25-T flask of DMEM medium with 10% fetal bovine serum (FBS) in a humidified atmosphere of 5% CO2 at 37℃. After the HepG2 cells had been incubated in a logarithmic growth phase, samples of co-culturing were added for 2 h, 4h at 4 °C. HepG2 cells were thrice washed by PBS solution, and analyzed by fluorescence microscopy for intracellular delivery of the nanoparticles. The primary result showed that the nanoparticles could be targeted to the HepG2 cell effectively than the nontarget nanoparticles (Figure 9).

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Figure 8. The scheme of the antibody target molecular contrast agent

Figure 9. Result of the target effect of the nanoparticles showed that the cell uptake was a time dependant: A, the cells that did not treat with any nanoparticls; B1, treated with antibody target nanoparticles, and B2 with non-target nanoparticles at 2h; C1, treated with antibody target nanoparticles, and C2 with non-target nanoparticles at 4h

4. CONCLUSION It is very obvious that the future of liver MRI will benefit from the development of new paramagnetic and superparamagnetic substances. The expectations for new tumor-, pathology- or receptor-specific agents are pretty high. Peptide or monoclonal antibodies labeled with nanocerriers that carried the paramagnetic atoms or superparamagnetic are believed to be the tumor-seeking target molecular MRI contrast agents. Investigations in small animals revealed that it is possible to achieve a distinct concentration of the magnetic label at the target. And the multifunctional nanoparticles should play key role in the novel diagnostic model. Using multifunctional nanoparticles, it may be possible to achieve (1) improved delivery of poorly water-soluble contrast agent; (2) targeted delivery of contrast agents in a cell- or tissue-specific manner; (3) real-time read on the in vivo efficacy of a

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therapeutic agent; and (4) visualization of sites of drug delivery by combining therapeutic agents with imaging modalities: theragnostics. Theragnostics is a treatment strategy that combines therapeutics with diagnostics. It associates both a diagnostic test that identifies patients most likely to be helped or harmed by a new medication, and targeted drug therapy based on the test results. However, the introduction of theragnostic tests into routine health care requires both a demonstration of cost-effectiveness and the availability of appropriate accessible testing systems. Gadolinium chelates have been widely applied to enhance the imagery of anatomical tissues via MRI. And recently it was demonstrated that Gd@C82(OH)22 nanoparticles could inhibit tumor growth more efficiently than prevailing chemotherapy drugs. Gd@C82(OH)22 nanoparticles are more effective in inhibiting tumor growth in mice than some clinical anticancer drugs but have negligible side effects. To be brief, the development of the nanovector carried the gadolinium provide more suitable modes for the molecular MRI and NCT, thus combine therapeutics with diagnostics pretty well and may accelerate the development of the theragnostics. However, there are some questions need to be speculated. An important issue in the effectiveness and the toxicity of a Gd(III) based MRI contrast agent is knowledge of the relative locations and concentrations of Gd(III) in target tissue. Therefore, the target multifunctional nanovectors molecular MRI contrast agent that combined with the therapeutic agent should play more important role in the future in the nanomedicine.

REFERENCES

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[1] [2] [3] [4]

[5]

[6] [7]

[8]

Organization, WH. Mortality database. Available URL: http://www.who.int/whosis/en. Befeler, AS; Di Bisceglie, AM. Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology, 2002, 122 (6), 1609-1619. Taouli, B; Losada, M; Holland, A; Krinsky, G. Magnetic resonance imaging of hepatocellular carcinoma. Gastroenterology, 2004, 127(5), S144-S152. Nakamura, E; Makino, K; Okano, T; Yamamoto, T; Yokoyama, M. A polymeric micelle MRI contrast agent with changeable relaxivity. Journal of Controlled Release, 2006, 114 (3), 325-333. Kozlowska, D; Foran, P; MacMahon, P; Shelly, MJ; Eustace, S; O'Kennedy, R. Molecular and magnetic resonance imaging: The value of immunoliposomes. Advanced Drug Delivery Reviews, 2009, 61 (15), 1402-1411. Jaffer, FA; Libby, P; Weissleder, R. Molecular and cellular imaging of atherosclerosis: emerging applications. J Am Coll Cardiol, 2006, 47(7), 1328-38. Wang, S; Jarrett, BR; Kauzlarich, SM; Louie, AY. Core/shell quantum dots with high relaxivity and photoluminescence for multimodality imaging. J Am Chem Soc, 2007, 129 (13), 3848-56. Saul, JM; Annapragada, AV; Bellamkonda, RV. A dual-ligand approach for enhancing targeting selectivity of therapeutic nanocarriers. Journal of Controlled Release, 2006, 114 (3), 277-287.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

212 [9]

[10]

[11]

[12]

[13]

[14]

[15]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[16]

[17]

[18]

[19] [20]

[21]

[22]

[23]

Na Zhang and Zhijin Chen Mikhaylova, M; Stasinopoulos, I; Kato, Y; Artemov, D; Bhujwalla, ZM. Imaging of cationic multifunctional liposome-mediated delivery of COX-2 siRNA. Cancer Gene Ther, 2009, 16 (3), 217-26. Dierling, AM; Sloat, BR; Cui, Z. Gadolinium incorporated reconstituted chylomicron emulsion for potential application in tumor neutron capture therapy. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 62, 275-281. Lu, J; Ma, S; Sun, J; Xia, C; Liu, C; Wang, Z; Zhao, X; Gao, F; Gong, Q; Song, B; Shuai, X; Ai, H; Gu, Z. Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging. Biomaterials, 2009, 30 (15), 2919-28. Yu, G; Yamashita, M; Aoshima, K; Takahashi, M; Oshikawa, T; Takayanagi, H; Laurent, S; Burtea, C; Vander Elst, L; Muller, RN. A glycosylated complex of gadolinium, a new potential contrast agent for magnetic resonance angiography? Bioorg Med Chem Lett, 2007, 17 (8), 2246-9. Mikawa, M; Kato, H; Okumura, M; Narazaki, M; Kanazawa, Y; Miwa, N; Shinohara, H. Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents. Bioconjug Chem, 2001, 12 (4), 510-4. Podesta, JE; Al-Jamal, KT; Herrero, MA; Tian, B; Ali-Boucetta, H; Hegde, V; Bianco, A; Prato, M; Kostarelos, K. Antitumor activity and prolonged survival by carbonnanotube-mediated therapeutic siRNA silencing in a human lung xenograft model. Small, 2009, 5 (10), 1176-85. Bakalova, R; Zhelev, Z; Aoki, I; Masamoto, K; Mileva, M; Obata, T; Higuchi, M; Gadjeva, V; Kanno, I. Multimodal silica-shelled quantum dots: direct intracellular delivery, photosensitization, toxic, and microcirculation effects. Bioconjug Chem, 2008, 19 (6), 1135-42. Li, F; Son, DI; Kim, TW; Ryu, E; Kim, SW. Carrier transport mechanisms of bistable memory devices fabricated utilizing core-shell CdSe/ZnSe quantum-dot/multi-walled carbon nanotube hybrid nanocomposites. Nanotechnology, 2009, 20(8), 85202. Sun, WT; Zhang, N; Li, AG; Zou, WW; Xu, WF. Preparation and evaluation of N-3-Otoluyl-fluorouracil-loaded liposomes. International Journal of Pharmaceutics, 2008, 353 (1-2), 243-250. Bai, F; Liu, C; Dai, L; Liu, L; Zhang, N. Preparation and pharmacokinetics in mice of N3-O-toluyl-flulorouracil solid lipid nanoparticles. Chinese Journal of New Drugs and Clinical Remedies, 2009, 28 (3), 185-190. Torchilin, VP. Recent advances with liposomes as pharmaceutical carriers. Nature Reviews Drug Discovery, 2005, 4 (2), 145-160. Kabalka, G; Buonocore, E; Hubner, K; Moss, T; Norley, N; Huang, L. Gadoliniumlabeled liposomes: targeted MR contrast agents for the liver and spleen. Radiology, 1987, 163 (1), 255-8. Devoisselle, JM; Vion-Dury, J; Galons, JP; Confort-Gouny, S; Coustaut, D; Canioni, P; Cozzone, PJ. Entrapment of gadolinium-DTPA in liposomes. Characterization of vesicles by P-31 NMR spectroscopy. Invest Radiol, 1988, 23 (10), 719-24. Lokling, KE; Fossheim, SL; Skurtveit, R; Bjornerud, A; Klaveness, J. pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies. Magn. Reson. Imaging, 2001, 19 (5), 731-738. Hak, S; Sanders, HM; Agrawal, P; Langereis, S; Grull, H; Keizer, HM; Arena, F; Terreno, E; Strijkers, GJ; Nicolay, K. A high relaxivity Gd(III)DOTA-DSPE-based

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Novel Nanovectors as the Liver Target Molecular: MRI Contrast Agents

[24]

[25]

[26]

[27]

[28] [29]

[30]

[31]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[32] [33]

[34]

[35] [36]

[37]

213

liposomal contrast agent for magnetic resonance imaging. Eur J Pharm Biopharm, 2009, 72(2), 397-404. Pardeike, J; Hommoss, A; Muller, RH. Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. International Journal of Pharmaceutics, 2009, 366 (1-2), 170-184. Jenning, V; Lippacher, A; Gohla, SH. Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization. J Microencapsul, 2002, 19(1), 1-10. Lu, B; Xiong, SB; Yang, H; Yin, XD; Chao, RB. Solid lipid nanoparticles of mitoxantrone for local injection against breast cancer and its lymph node metastases. Eur J Pharm Sci, 2006, 28(1-2), 86-95. Yu, W; Liu, C; Ye, J; Zou, W; Zhang, N; Xu, W. Novel cationic SLN containing a synthesized single-tailed lipid as a modifier for gene delivery. Nanotechnology, 2009, 20(21), 215102. Subedi, RK; Kang, KW; Choi, HK. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. Eur J Pharm Sci, 2009, 37 (3-4), 508-13. Chen, YJ; Jin, RX; Zhou, YQ; Zeng, J; Zhang, H; Feng, QR. [Preparation of solid lipid nanoparticles loaded with Xionggui powder-supercritical carbon dioxide fluid extraction and their evaluation in vitro release]. Zhongguo Zhong Yao Za Zhi, 2006, 31 (5), 376-9. Morel, S; Terreno, E; Ugazio, E; Aime, S; Gasco, MR. NMR relaxometric investigations of solid lipid nanoparticles (SLN) containing gadolinium(III) complexes. Eur. J. Pharm. Biopharm., 1998, 45 (2), 157-163. Chen, ZJ; Zhang, N. Preliminary studies on cationic solid lipid nanoparticles/Gd-DTPA complex as molecular imaging agent. Chinese Journal of New Drugs, 2009, 18 (15), 1443-1447. Vauthier, C; Bouchemal, K. Methods for the preparation and manufacture of polymeric nanoparticles. Pharm Res, 2009, 26(5), 1025-58. Amber LD; Kimberly AH; Stanislav E; Brannon-Peppas, L. Poly(Lactic-co-Glycolic) Acid as a Carrier for Imaging Contrast Agents. Pharmaceutical Research, 2009, 26(3), 674-682. Paschkunova-Martic, I; Kremser, C; Mistlberger, K; Shcherbakova, N; Dietrich, H; Talasz, H; Zou, Y; Hugl, B; Galanski, M; Solder, E; Pfaller, K; Holiner, I; Buchberger, W; Keppler, B; Debbage, P. Design, synthesis, physical and chemical characterisation, and biological interactions of lectin-targeted latex nanoparticles bearing Gd-DTPA chelates: an exploration of magnetic resonance molecular imaging (MRMI). Histochem Cell Biol, 2005, 123 (3), 283-301. Agrawal, P; Strijkers, GJ; Nicolay, K. Chitosan-based systems for molecular imaging. Adv Drug Deliv Rev, 2009. Shikata, F; Tokumitsu, H; Ichikawa, H; Fukumori, Y. In vitro cellular accumulation of gadolinium incorporated into chitosan nanoparticles designed for neutron-capture therapy of cancer. Eur J Pharm Biopharm, 2002, 53 (1), 57-63. Tokumitsu, H; Hiratsuka, J; Sakurai, Y; Kobayashi, T; Ichikawa, H; Fukumori, Y. Gadolinium neutron-capture therapy using novel gadopentetic acid-chitosan complex nanoparticles: in vivo growth suppression of experimental melanoma solid tumor. Cancer Lett, 2000, 150(2), 177-82.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

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Na Zhang and Zhijin Chen

[38] Nakamura, E; Makino, K; Okano, T; Yamamoto, T; Yokoyama, M. A polymeric micelle MRI contrast agent with changeable relaxivity. J Control Release, 2006, 114 (3), 325-33. [39] Chen, ZJ; Yu, DX; Wang, SJ; Zhang, N; Ma, CH; Lu, ZJ. Biocompatible Nanocomplexes for Molecular Targeted MRI Contrast Agent. Nanoscale Research Letters, 2009, 4 (7), 618-626. [40] Battistini, E; Gianolio, E; Gref, R; Couvreur, P; Fuzerova, S; Othman, M; Aime, S; Badet, B; Durand, P. High-relaxivity magnetic resonance imaging (MRI) contrast agent based on supramolecular assembly between a gadolinium chelate, a modified dextran, and poly-beta-cyclodextrin. Chemistry, 2008, 14 (15), 4551-61. [41] Gref, R; Amiel, C; Molinard, K; Daoud-Mahammed, S; Sebille, B; Gillet, B; Beloeil, J. C; Ringard, C; Rosilio, V; Poupaert, J; Couvreur, P. New self-assembled nanogels based on host-guest interactions: characterization and drug loading. J Control Release, 2006, 111 (3), 316-24. [42] Othman, M; Bouchemal, K; Couvreur, P; Gref, R. Microcalorimetric investigation on the formation of supramolecular nanoassemblies of associative polymers loaded with gadolinium chelate derivatives. Int J Pharm, 2009, 379 (2), 218-25. [43] McDonald, MA; Watkin, KL. Investigations into the physicochemical properties of dextran small particulate gadolinium oxide nanoparticles. Acad Radiol, 2006, 13(4), 421-7. [44] André, JP; Tóth, É; Fischer, H; Seelig, A; Mäcke, HR; Merbach, AE. High Relaxivity for Monomeric Gd(DOTA)-Based MRI Contrast Agents, Thanks to Micellar SelfOrganization. Chemistry - A European Journal, 1999, 5(10), 2977-2983. [45] Maeda, H; Bharate, GY; Daruwalla, J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur. J. Pharm. Biopharm., 2009, 71, 409-419. [46] Shiraishi, K; Kawano, K; Minowa, T; Maitani, Y; Yokoyama, M. Preparation and in vivo imaging of PEG-poly(L-lysine)-based polymeric micelle MRI contrast agents. J Control Release, 2009, 136(1), 14-20. [47] Discher, DE; Eisenberg, A. Polymer vesicles. Science, 2002, 297 (5583), 967-73. [48] Cheng, Z; Thorek, DLJ; Tsourkas, A. Porous Polymersomes with Encapsulated GdLabeled Dendrimers as Highly Efficient MRI Contrast Agents. Advanced Functional Materials, 19(23), 3753 - 3759. [49] Shum, HC; Kim, JW; Weitz, DA. Microfluidic fabrication of monodisperse biocompatible and biodegradable polymersomes with controlled permeability. J Am Chem Soc, 2008, 130(29), 9543-9. [50] Kobayashi, H; Brechbiel, MW. Dendrimer-based nanosized MRI contrast agents. Curr Pharm Biotechnol, 2004, 5(6), 539-49. [51] Lei, XG; Jockusch, S; Turro, NJ; Tomalia, DA; Ottaviani, MF. EPR characterization of gadolinium(III)-containing-PAMAM-dendrimers in the absence and in the presence of paramagnetic probes. J Colloid Interface Sci, 2008, 322(2), 457-64. [52] Miyamoto, A; Okimoto, H; Shinohara, H; Shibamoto, Y. Development of water-soluble metallofullerenes as X-ray contrast media. Eur Radiol, 2006, 16(5), 1050-3. [53] SA, A; KK, L; JA, F. Gadolinium-fullerenol as a paramagnetic contrast agent for cellular imaging. Investigative radiology, 2006, 41 (0020-9996), 332-338.

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Novel Nanovectors as the Liver Target Molecular: MRI Contrast Agents

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[54] Lu, W; He, LC; Wang, CH; Li, YH; Zhang, SQ. The use of solid lipid nanoparticles to target a lipophilic molecule to the liver after intravenous administration to mice. Int. J. Biol. Macromol., 2008, 43 (3), 320-324. [55] Kabalka, GW; Davis, MA; Moss, TH; Buonocore, E; Hubner, K; Holmberg, E; Maruyama, K; Huang, L. Gadolinium-labeled liposomes containing various amphiphilic Gd-DTPA derivatives: Targeted MRI contrast enhancement agents for the liver. Magn. Reson., Imaging 1990, 13(1), 31-37. [56] Clift, MJ; Rothen-Rutishauser, B; Brown, DM; Duffin, R; Donaldson, K; Proudfoot, L; Guy, K; Stone, V. The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line. Toxicol Appl Pharmacol, 2008, 232(3), 418-27. [57] Klausner, MA; Hirsch, LJ; Leblond, PF; Chamberlain, JK; Klemperer, MR; Segel, GB. Contrasting splenic mechanisms in the blood clearance of red blood cells and colloidal particles. Blood, 1975, 46 (6), 965-76. [58] Moghimi, SM; Hunter, AC; Murray, JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev, 2001, 53 (2), 283-318. [59] Moghimi, SM; Porter, CJ; Muir, IS; Illum, L; Davis, SS. Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem Biophys Res Commun, 1991, 177 (2), 861-6. [60] Sofou, S; Sgouros, G. Antibody-targeted liposomes in cancer therapy and imaging. Expert Opin Drug Deliv, 2008, 5(2), 189-204. [61] Pan, D; Lanza, GM; Wickline, SA; Caruthers, SD. Nanomedicine: perspective and promises with ligand-directed molecular imaging. Eur J Radiol, 2009, 70(2), 274-85. [62] Kish, PE; Tsume, Y; Kijek, P; Lanigan, TM; Hilfinger, JM; Roessler, BJ. Bile acidoligopeptide conjugates interact with DNA and facilitate transfection. Mol Pharm, 2007, 4(1), 95-103. [63] Hu, Z; Luo, F; Pan, Y; Hou, C; Ren, L; Chen, J; Wang, J; Zhang, Y. Arg-Gly-Asp (RGD) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery. J Biomed Mater Res A, 2008, 85(3), 797-807. [64] Mishra, R; Su, W; Pohmann, R; Pfeuffer, J; Sauer, MG; Ugurbil, K; Engelmann, J. Cell-Penetrating Peptides and Peptide Nucleic Acid-Coupled MRI Contrast Agents: Evaluation of Cellular Delivery and Target Binding. Bioconjugate Chemistry, 2009, 20 (10), 1860-1868. [65] Leamon, CP; Reddy, JA. Folate-targeted chemotherapy. Advanced Drug Delivery Reviews, 2004, 56 (8), 1127-1141. [66] Swanson, SD; Kukowska-Latallo, JF; Patri, AK; Chen, CY; Ge, S; Cao, ZY; Kotlyar, A; East, AT; Baker, JR. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement. International Journal of Nanomedicine, 2008, 3(2), 201-210. [67] Sofou, S; Sgouros, G. Anti body-targeted liposomes in cancer therapy and imaging. Expert Opinion on Drug Delivery, 2008, 5 (2), 189-204. [68] Erdogan, S; Roby, A; Sawant, R; Hurley, J; Torchilin, VP. Gadolinium-loaded polychelating polymer-containing cancer cell-specific immunoliposomes. J Liposome Res, 2006, 16(1), 45-55.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.217-243 © 2010 Nova Science Publishers, Inc.

Chapter 6

APPLICATION OF GADOLINIUM BASED CONTRAST AGENTS IN ABDOMINAL MAGNETIC RESONANCE IMAGING: IMPORTANT CONSIDERATIONS Rafael O.P. de Campos, Vasco Herédia, Miguel Ramalho, Ersan Altun and Richard C. Semelka* Department of Radiology University of North Carolina Hospitals, Chapel Hill, NC, USA

ABSTRACT Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

The chelation of gadolinium to organic ligands is necessary for the atom to be used as an in vivo contrast agent in humans. There are several formulations available with different ligands, constituting the gadolinium based contrast agents (GBCAs). They are the most widely used MR contrast agents. GBCAs induce T1-shortening resulting in marked elevation of signal on T1-weighted images. GBCA enhancement is crucial in the detection and characterization of abdominal diseases. There are important aspects for the achievement of high-quality GBCA enhanced abdominal images. The first critical aspect is the reduction of artifacts. It is imperative to obtain motion-free images. Respiration is the most important and most troubling source of artifacts in abdominal MR imaging. Current ―state-of-the-art‖ MR systems can generate high-quality diagnostic MR images in the great majority of patients, using breathing-independent sequences and breath-hold sequences. It is also essential to recognize the importance of timing of data acquisition in order to maximize the information available regarding the dynamic handling of contrast by the vascular and extracellular spaces of various organs, tissues, and disease processes. An efficient study should include three passes following GBCA administration: hepatic arterial dominant phase (HADP), early hepatic venous phase and interstitial phase. The exact timing is more critical in the HADP. The magnetic field strength (1.5T versus 3.0T) also influences significantly the quality of post-contrast abdominal MR studies, with advantages of imaging at 3.0T. There is a greater enhancement induced by GBCAs at 3.0T compared to 1.5T. There are also important considerations regarding the type of *

Corresponding author: Department of Radiology, UNC at Chapel Hill, CB 7510 – 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510, Phone: (919) 966-9676, Fax: (919) 843-7147, E-mail: [email protected]

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Rafael O.P. de Campos, Vasco Herédia, Miguel Ramalho et al. GBCA that can be used. High thermodynamic stability constants and lower dissociation rates (greater affinity of ligands for gadolinium ions) are important qualities of a GBCA, in order to minimize risks of nephrogenic systemic fibrosis, which is the major current concern following GBCA exposure.

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INTRODUCTION Free gadolinium is toxic in vivo and the chelation of gadolinium to organic ligands (chelate complex) is necessary for the atom to be used as an in vivo contrast agent in humans. There are several formulations available with different ligands, constituting the gadolinium based contrast agents (GBCAs) [1]. This class of contrast agents is overwhelmingly the most commonly used among all MR contrast agents. Since 1988, when the first GBCA was approved for clinical use by the FDA, it is estimated that approximately 150 million MR studies have been performed using a GBCA [2]. These agents shorten the T1 (spin-lattice) relaxation times of adjacent water protons, resulting in marked elevation of signal on T1weighted (T1W) images [1-2]. GBCA injection has become an indispensable part of clinical studies of the neural system, vascular system, and mainly for body applications. GBCA enhancement is crucial in the detection and characterization of abdominal diseases [2-4]. It provides at least two additional imaging properties that facilitate diagnosis: the pattern of blood delivery (i.e., capillary enhancement) and the size and/or rapidity of drainage of the interstitial space (i.e., interstitial enhancement) [2, 5]. Unenhanced MR imaging protocols alone are relatively inaccurate for evaluation of the abdomen [6]. For example characterization of a focal liver or pancreatic lesion is rarely possible on the basis of unenhanced imaging alone. To maximize the benefits rendered by the GBCAs is important to obtain high-quality MR images. This chapter describes important aspects for the achievement of high-quality GBCA enhanced images, such as motion-free imaging, timing, magnetic field strength (1.5 T versus 3.0 T) and type of GBCA used. In addition, we discuss critical issues related to optimized use of GBCAs, emphasizing the reduction of the possibility of nephrogenic systemic fibrosis (NSF), which is the major current concern following GBCA exposure.

MOTION-FREE IMAGE QUALITY The first important aspect to an efficient application of GBCAs in abdominal MR imaging is the acquisition of high quality and reproducible MR studies. In keeping with this, we need motion-free images, devoid of substantial artifacts, especially those due to motion. Respiration is the most important and most troubling source of artifacts in abdominal MR imaging [2, 7]. Control of these artifacts is most critical in GBCA enhanced studies in which dynamic T1W imaging is employed. We routinely acquire three set of images following GBCA injection and a small but significant percentage of patients have difficulty to suspend respiration for the entire acquisition, resulting in varying degrees of motion artifact. These artifacts can simulate GBCA enhancement or obscure it [7-8] (Figure 1). Motion also impairs the comparison between the different phases of post-contrast imaging and pre-contrast T1W

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images, which is essential for analyzing GBCA enhancement. Furthermore, motion can adversely affect fat suppression, reducing difference in signal intensities between enhanced tissue and background tissue. However, using breathing-independent sequences and breathhold sequences we can obtain high-quality diagnostic MR images in the great majority of patients. For evaluation of GBCA enhancement, we obtain T1W gradient echo sequences (instead of spin-echo sequences): spoiled gradient echo (2D-SGE) or three dimensional gradient echo (3D-GE). Current ―state-of-the-art‖ MR systems use 3D-GE as the primary technique for dynamic contrast-enhanced imaging of the abdomen. The addition of parallel imaging technique, especially with multi-channel coils, can significantly shorten imaging times, rendering improved comfort and as a result compliance for patients on breath-hold sequences [9].

Figure 1. Importance of breath holding. Two acquisitions in a cirrhotic patient obtained on separate days at 1.5T. Transverse T1-weighted post-gadolinium fat-suppressed hepatic arterial dominant phase (HADP) (a, c) and interstitial phase (b, d) 3D-GE images. The initial exam (a, b) shows the impact of motion on both phases of enhancement, in which no lesion is visible. This examination was considered unsatisfactory and on a subsequent scanning (13 days apart) (c, d), with proper breath holding, it is clearly demonstrated a small hypervascular liver lesion, which shows washout on the interstitial-phase (white arrow c, d). These findings are consistent with a small hepatocellular carcinoma

The use of a technique named magnetization-prepared rapid-acquisition gradient echo (MPRAGE), which is a single shot sequence with image acquisition duration of 1 to 2 seconds, has made possible good MR studies in noncooperative patients. The ultra-short time of this sequence renders it relatively breathing independent [8] (Figure 2 and 3). Adequate quality MPRAGE sequences (with 180° non-slice selective technique, which is required for dynamic GBCA-enhanced acquisitions) are currently available only in ―state-of-the-art‖ MR systems. In this regard, the higher intrinsic signal to noise of 3T system allow for good quality image with MPRAGE especially when water excitation is employed [8] (Figure 4).

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Figure 2. SGE vs MPRAGE. Transverse T1-weighted pre-contrast in-phase (a) and out-of-phase (c) SGE images, and in-phase (b) and out-of-phase (d) MPRAGE images. In-phase (IP) and out-of-phase (OP) T1-weighted SGE image shows mild motion artifacts due to respiration. MPRAGE sequences display IP (b) and OP properties (d) with good image quality. The presence of a black rim phase cancellation artifact surrounding abdominal organs in the OP images (c, d) and its absence in the IP (a, b) images is considered the surrogate for adequacy of OP and IP image quality. MPRAGE is a singleshot sequence with motion resistant properties adequate for noncooperative patients

Figure 3. Application of magnetization-prepared rapid-acquisition gradient echo (MPRAGE) technique. When patient non-cooperation is extreme, a water-excitation MPRAGE (WE-MPRAGE) can be utilized, as shown in the depiction of a renal cyst at 3.0T. On the conventional breath-held T1-weighted post-gadolinium fat-suppressed 3D-GE (a) there are significant artifacts with poor imaging of the cyst. On the post-gadolinium WE-MPRAGE (b) there are no significant motion artifacts, clearly demonstrating a left renal cyst

CORRECT SUBPHASE OF ENHANCEMENT Correct timing is also essential for an efficient application of GBCAs in abdominal MR imaging. Following GBCA injection we routinely obtain three phases to evaluate tissue perfusion (hepatic arterial dominant phase), blood pool venous withdrawal (early hepatic venous phase), and interstitial space size (interstitial phase) (Figure 5).

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Figure 4. Water excitation magnetization-prepared rapid-acquisition gradient echo (WE-MPRAGE) technique at 3.0T. Patients unable to hold their breath may be satisfactorily imaged and have a diagnostic MR study using this technique, mainly on a 3.0T system. Note in this case the high-quality images acquired: (a) transverse pre-contrast WE-MPRAGE, (b) transverse post-gadolinium WEMPRAGE and (c) coronal post-gadolinium WE-MPRAGE

Figure 5. Phases of enhancement. T1-weighted fat-suppressed hepatic arterial dominant phase (HADP) (a, b), early hepatic venous phase (EHVP) (c) and interstitial phase (d) 3D-GE images at 1.5T. Note that on the HADP (a, b) the contrast is present in the arteries (hepatic, renal, splenic and superior mesenteric); and renal, splenic, portal and superior mesenteric veins but not in the hepatic veins (black arrows a, b). The renal cortex demonstrates intense enhancement and the spleen, pancreas and liver demonstrate moderate enhancement. The moderate enhancement of the normal pancreas (white arrows b) reflects the adequate timing of enhancement of HADP. EHVP (c) shows enhancement of the entire vascular system of the liver and maximal enhancement of its parenchyma

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The most important set of images are those obtained in the hepatic arterial dominant phase (HADP), in which the contrast must be present in the hepatic arteries and portal veins prior to appearing in the hepatic veins [2-4, 10-11] (Figure 5). There is a relatively short time window for this and correct timing is critical. Three different techniques including empirical timing, test bolus and bolus tracking methods have been employed [12]. It has been reported that arterial-phase bolus-track liver examination (ABLE) technique is a successful method for the acquisition of hepatic arterial dominant phase [13]. A bolus track sequence, which produces an image approximately every second, is used to detect the arrival of GBCA to the level of celiac axis. After 8 seconds, the liver is scanned with standard ordered k space for a 16-20 second sequence. During the 8 second-period, the patient is given breathing instructions. This is also the technique that we routinely use at our institution. All these techniques depend on the empirical estimation of circulation time of the contrast material from the site of injection or abdominal aorta to the liver [10, 12]. Because the circulation time of the contrast material to the liver shows variations depending on various factors, different subphases of enhancement, other than the HADP, may be detected in the ―early post-contrast hepatic imaging‖, based on the vessel enhancement patterns as well as the enhancement of abdominal parenchymal organs [10]. A recent report of our group on this subject, employing an 18-s set time-delay empiric timing scheme for the initiation of scanning allowed us to observe five subphases of early contrast enhancement of the liver: (a) early hepatic arterial phase (EHAP), (b) mid-hepatic arterial phase (MHAP), (c) late hepatic arterial phase (LHAP), (d) splenic vein only HADP (SVHADP) and (e) HADP [10] (Table 1).

a

c

b

d

Figure 6. Early subphases of enhancement. The early hepatic arterial phase (EHAP) was observed on transverse T1-weighted 2D-GE images (a, b) acquired at 1.5T. The mid hepatic arterial phase (MHAP) was observed on transverse 3D-GE images (c, d) acquired at 3.0T. The contrast enhancement is seen in the aorta, renal arteries and superior mesenteric artery, but there is no contrast enhancement in the veins on both EHAP and MHAP. The renal cortex, spleen, pancreas and liver demonstrate minimal enhancement on EHAP. The renal cortex, spleen and pancreas show mild enhancement and the liver shows slight enhancement on MHAP. The mild enhancement of the normal pancreas (arrow d) reflects the too early acquisition of data in these subphases

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On the EHAP, the renal cortex, spleen, pancreas and liver similarly demonstrated no or slight enhancement, which significantly increased on the MHAP. The enhancement of the pancreas on two first subphases was significantly lower, both qualitatively and quantitatively, compared to the other later phases (LHAP, SVHADP and HADP), where it was not significantly different. The liver demonstrated significantly higher enhancement on HADP and SVHADP compared to LHAP. Our results suggest that it is too early to evaluate liver enhancement during EHAP and MHAP (Figure 6). In addition, EHAP is essentially identical to non-contrast images in demonstrating liver lesions, which is thus unable to provide distinctive enhancement of focal liver lesions. The LHAP, SVHADP and HADP can be used to evaluate liver lesion enhancement and may be considered as the optimal range of phases of enhancement. Pancreatic capillary blush can be a useful surrogate for optimal timing to evaluate liver disease (Figure 5 and 7). These impressions are also supported by previous reported findings in the literature [2-3, 11, 14-16]. The enhancement of renal veins can help to determine the adequacy of liver enhancement, since we consider an important finding of true LHAP is contrast in these veins, in addition to visual pancreatic enhancement (Figure 5-7). On the subsequent SVHAD phase there is also the enhancement of suprarenal IVC, splenic vein and portal vein. On HADP, contrast is also present in the superior mesenteric vein (Table 1)

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Table 1. The vessel and organ enhancement patterns according to subphases*.

Vessel enhancement All predetermined arteries Renal veins Portal vein Splenic vein Superior mesenteric vein Suprarenal IVC Hepatic vein

EHAP

MHAP

LHAP

SVHADP

HADP

+ − − − − − −

+ − − − − − −

+ + − − − ± −

+ + + + − + −

+ + + + + + −

Organ enhancement Renal cortex

No or Mild or Moderate Moderate Moderate slight moderate to intense to intense to intense Spleen No or Mild or Moderate Moderate Moderate slight moderate to intense to intense to intense Pancreas No or Slight or moderate Moderate Moderate slight mild Liver No or Slight or Slight or Mild Moderate slight mild mild *Reprinted with permission from reference 10. EHAP= early hepatic arterial phase; MHAP= mid-hepatic arterial phase; LHAP= late hepatic arterial phase; SVHADP= splenic vein only hepatic arterial dominant phase; HADP= hepatic arterial dominant phase.

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Figure 7. Late hepatic arterial phase of enhancement (LHAP). MR study acquired on 3.0T in a 55-yearold man evaluated for possible hepatocellular carcinoma (a - c). The LHAP was observed on transverse T1-weighted fat-suppressed 3D-GE images. The contrast enhancement is seen in the aorta, celiac trunk, common hepatic artery and its branches, splenic, renal and superior mesenteric arteries; and renal veins. The renal cortex demonstrates intense enhancement, pancreas and spleen demonstrate moderate enhancement and the liver shows mild enhancement on LHAP. The moderate enhancement of the normal pancreas reflects the adequate timing of enhancement of LHAP. Contour irregularity of the liver, splenomegaly, patchy and nodular enhancement of the liver are also detected. Patchy enhancement of the liver is most pronounced in the left lobe (b - c) and consistent with acute-onchronic hepatitis. Small nodular enhancement (arrow, c) is consistent with a dysplastic nodule.

The combination of these vessel enhancement patterns with the enhancement patterns of the renal cortex and spleen may also serve as adequate surrogates and a guide for the optimal phase of enhancement in the case of chronic pancreatitis or other pancreatic diseases, where pancreatic enhancement may be minimal [10]. Using these landmarks, we can determine with confidence if the ―first pass‖ or capillary bed enhancement of tissues has been captured. Optimal timing of contrast enhancement is essential not only for the detection of liver lesions, especially hypervascular tumors such as hepatocellular carcinomas (HCC), hypervascular metastases and benign hepatocellular tumors, but also for evaluation of response to treatment (Figure 8 and 9) [3-4, 10-11, 14-17]. The vascularity of tumors, as evidenced by extent of early enhancement, has been shown to predict the likelihood of response to certain treatment methods [16]. Other abdominal organs, such as the pancreas, can also present hypervascular tumors which are better displayed on images obtained in a correct phase of enhancement [18-19] (Figure 10). In addition, an optimal timing is very important when considering non focal mass lesions of the abdominal parenchymal organs. For instance, too little pancreatic enhancement is consistent with pancreatic fibrosis or chronic pancreatitis, and too little enhancement of renal cortex may imply ischemic nephropathy or acute cortical necrosis. This can be reliably judged on HADP images, based on the fixed vessels landmarks cited above. In the EHAP, minimal enhancement of pancreas or renal cortex may reflect an early image acquisition rather than disease process (Figure 5 and 6).

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Figure 8. Optimal timing of contrast enhancement. Cirrhotic patient evaluated for possible HCC (a – c) and a patient evaluated for indeterminate liver mass (d – f). The hepatic arterial dominant phase (HADP) (a, d), early hepatic venous phase (EHVP) (b, e) and interstitial phase (c, f) were observed on transverse T1-weighted fat-suppressed 3D-GE images acquired at 3.0 T. The first patient displayed a lesion (white arrow a - c) with central diffuse enhancement on HADP, with rapid washout and peripheral capsular enhancement developing on EHVP and interstitial phase (corresponding to a pseudocapsule). These MR imaging features are characteristic of HCC. Prominent varices are also observed (thin black arrow a – c). The second patient displayed three lesions (black arrows d – f) with discontinuous peripheral nodular enhancement on HADP and progressive centripetal enhancement on subsequent phases. These MR imaging features are characteristic of hemangioma. The greatest lesion occupies a large portion of left lobe and shows persistence of a central scar on interstitial phase imaging, consistent with a type 3 hemangioma.

The early hepatic venous phase images are obtained between 45 and 90 seconds postcontrast injection and can be recognized by the presence of GBCAs in portal and hepatic veins (Figure 5). Thus, the time window is relatively wide and timing is not so critical. This phase shows maximal enhancement of the hepatic parenchyma and is especially useful for the detection of hypo/isovascular HCC and hypovascular metastases, as well as other hypovascular lesions (cysts and scar tissue) (Figure 11). It is also important in lesion characterization, including hypervascular lesions such as focal nodular hyperplasia, which shows fading and HCC which shows washout in this phase [3-4, 15-17] (Figure 12). Patency or thromboses of hepatic vessels are also best shown in this phase (Figure 13).

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Figure 9. Optimal timing of contrast enhancement rendering diagnostic MR imaging. Patient one (a – c) and two (d – f) were evaluated for follow-up of a hepatic nodular lesion. Both patients do not present clinical history of chronic hepatic disease or neoplasm. Pre-contrast T1-weighted fat-suppressed 3D-GE (a), pre-contrast T1-weighted 2D-GE (d), hepatic arterial dominant phase (HADP) (b, e) and interstitial phase (c, f) T1weighted fat-suppressed 3D-GE images were obtained. The first patient displayed a lesion (white arrow on b and c) with diffuse enhancement on HADP (b), with rapid fading on hepatic venous phase (not shown) and minimal central washout on the interstitial phase (c). MR findings in this clinical set suggest a hepatocellular adenoma. The second patient displayed a lobular lesion (white arrow on e and f) that is mildly hypointense on the pre-contrast T1W image (d), demonstrating an intense and almost diffuse enhancement in the HADP (e), and fades to near isointensity in the interstitial phase (f). There is also a central scar. The findings are consistent with a focal nodular hyperplasia (FNH). Notice that in both cases the detection and characterization of the lesions would not be possible without these optimal timed HADP images.

Figure 10. Pancreatic islet cell tumor. Two level transverse T1-weighted fat-suppressed postgadolinium 3D-GE hepatic arterial dominant phase (HADP) images at 1.5T (a, b). One hypervascular solid lesion is identified in the ventral aspect of the pancreas (asterisk on image a) proximal to the tail of the organ. This lesion represents an islet cell tumor. HADP is also appropriate to detect hepatic metastases (arrows).

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Figure 11. Importance of the early hepatic venous phase images (EHVP). Patient with multiple biliary hamartomas. Transverse pre-contrast T1-weighted (T1W) 2D-GE image (a), post-contrast T1W fatsuppressed 3D-GE image in the hepatic arterial dominant phase (HADP) (b) and in the EHVP (c) images are shown. There are multiple well defined lesions (most < 1cm) scattered throughout the liver. They have high signal intensity on T2 (not shown) and low signal intensity on T1W images. There is a thin perilesional rim enhancement on post-contrast images (b,c). Note that the lesions are better delimitated on the EHVP (c), in which the hepatic parenchymal enhancement is maximal. The thin perilesional rim enhancement is also better demonstrated on the EHVP (c).

Figure 12. Hepatocellular carcinoma. Post-liver transplant MR imaging in a patient with a liver mass. Fat-suppressed T2-weighted SS-ETSE (a), T1-weighted fat-suppressed 3D-GE image pre-contrast (b), and post-contrast in the hepatic arterial dominant phase (HADP) (c) and in the early hepatic venous phase (EHVP) (d). There is a mass in the right hepatic lobe, demonstrating well-defined margins, increased signal intensity on T2 (a), moderately decreased signal intensity on T1 (b), intense heterogeneous enhancement in the HADP (c), and washout with enhancement of a pseudocapsule in the EHVP (d). These findings are consistent with a large hypervascular HCC.

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Figure 13. Chronic portal vein thrombosis. Transverse T1-weighted fat-suppressed post-gadolinium late hepatic arterial phase (LHAP) (a) and early hepatic venous phase (EHVF) (b) 3D-GE images. Geographic hyper-enhancement is noted in segment VII of the liver on the LHAP (a) that fades to homogeneity with background liver on the EHVP. Absence of enhancement of the posterior right portal branch is noted (arrow, b). These finding are consistent with perfusional abnormality caused by portal vein chronic thrombosis. Vessel conspicuity is higher in the EHVP (b).

Figure 14. Hepatocellular carcinoma. Cirrhotic patient evaluated for possible HCC. Fat-suppressed T2weighted SS-ETSE (a), T1-weighted fat-suppressed 3D-GE image pre-contrast (b), and post-contrast in the hepatic arterial dominant phase (HADP) (c) and interstitial phase (d). There is a well-defined nodular lesion in the liver (arrows). This lesion demonstrates slightly increased signal intensity on T2 (a), moderately decreased signal intensity on T1 (b), intense homogeneous enhancement on the HADP (c), and washout with enhancement of a pseudocapsule on the interstitial phase (d). These findings are consistent with a hypervascular HCC. Note the importance of the interstitial phase for the diagnosis. The washout and pseudocapsule enhancement are clearly demonstrated in this phase, making possible a confident diagnosis of HCC.

The Late hepatic-venous or interstitial phase has a broad time range, which is from approximately 90 seconds to 5 minutes after initiation of contrast injection, with no exact timing requirement. During this phase, hepatic parenchymal enhancement persists (Figure 5).

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This phase also provides additional information to characterize focal hepatic lesions, by demonstrating their late-phase temporal handling of contrast. Hemangiomas reveal progressive enhancement, persistent enhancement is observed in small-sized hemangiomas, and washout of hypervascular metastases and HCC is also apparent during this phase [3-4, 15-17] (Figure 8 and 14). This phase is also important to diagnose diseases that are superficially spreading or inflammatory in nature. Concomitant use of fat suppression improves the conspicuity of disease processes characterized by increased enhancement on interstitial phase images including: peritoneal metastases, cholangiocarcinoma, ascending cholangitis, inflammatory bowel disease and abscesses [2, 4] (Figure 15).

Figure 15. Peritoneal Carcinomatosis. MR study acquired for post treatment evaluation of a patient with an ovarian neoplasm. Post-contrast T1-weighted fat-suppressed 3D-GE images acquired in the interstitial phase at 1.5T: (a, b) transverse, (c) coronal and (d) sagital image. There is a large volume ascitis, associated with diffuse linear thickening and enhancement of the peritoneal surfaces. There are also regions of nodular peritoneal thickening (thin white arrows). These findings are better shown in the interstitial phase of enhancement and hardly depicted in the arterial phase (not shown), and are consistent with peritoneal carcinomatosis.

FIELD STRENGTH The current worldwide proliferation of 3.0T MR imaging systems beyond academic and research centers has added other important consideration to the routine clinical practice, especially regarding GBCA-enhanced images: 3.0T versus 1.5T. The major advantage of MR imaging at 3T compared to 1.5T is the theoretical twofold increase in signal-to-noise ratio (SNR), which can be translated into higher spatial resolution and/or temporal resolution, particularly with the use of parallel imaging techniques [8, 20-25]. At 3.0T, post-gadolinium T1W 3D-GE sequence can be obtained with higher quality than at

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1.5T, primarily because of the thinner section acquisition. It is also relatively resistant to the drawbacks of 3.0T MRI including specific absorption rate constraints, prolonged T1 relaxation times and the increase in imaging artifacts [8, 20-25]. The ability of GBCAs to reduce T1 (known as the relaxivity) is slightly lower at 3T (5% to 10%) compared to 1.5T. However, the T1 relaxation times of the tissues are prolonged on the order of 40% or more at 3.0T compared to 1.5T. Therefore, an equivalent dose of GBCA at 3.0T causes an increased contrast difference compared to 1.5T [20-26]. This increased effect of GBCAs contributes to better SNR and contrast-to-noise ratio at 3.0T. Corroborating this and supporting previous descriptions in the literature, one recent report of our group has demonstrated consistent differences in the extent of enhancement of abdominal organs between 1.5T and 3.0T on the subphases of hepatic arterial enhancement, with achievement of higher relative enhancement at 3.0T [22]. The benefits of this higher extent of enhancement at 3.0T may potentially translate into better detection of lesions that have a blood supply greater or lesser than background abdominal organs. This is particularly important to detect hypervascular lesions in the cirrhotic liver, such as HCC (Figure 16), and hypervascular metastases [17, 20-22, 25].

Figure 16. Small hepatocellular carcinoma at 3.0T. Two MR examinations of a cirrhotic patient obtained on separate days at 3.0T. All images are T1-weighted fat-suppressed 3D-GE: (a, d) Precontrast; (b, e) hepatic arterial dominant phase (HADP), (c, f) early hepatic venous phase (EHVP). A small hypervascular lesion (arrow, b) was observed in the first exam (a – c), showing washout in the EHVP (c), features that are consistent with a HCC. At the follow-up exam two months later (d – f), the lesion has increased, displaying a clear washout, confirming the diagnosis and progression of the HCC. Notice also that there are some small liver hypovascular lesions consistent with cysts.

The addition of the newly available 32-channel coil to MRI systems will permit significant improvement in parallel imaging, which will accelerate 3D-GE and aid in achieving ultra-short, high-quality, dynamic 3D imaging following bolus contrast administration.

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The differences between post-contrast dynamic 3D imaging of the abdomen using 1.5T and 3.0T, may render an improved detection of lesions at 3.0T, with important implications for the follow-up of lesions studied with different MR systems. For example, a follow-up exam of a probably high-grade dysplastic nodule versus small HCC in a cirrhotic patient or a post-treatment control of small liver metastases in a breast cancer patient both obtained at a 3.0T MR system. The lesions may be better seen at the follow-up study and be more enhanced in the HADP post-contrast imaging, when compared to the previous exam obtained at 1.5T. This raises the question of whether these differences result from better lesions display at 3.0T when compared to 1.5T or from progression of the disease.

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TYPES OF GBCAS The chelation of gadolinium to organic ligands (chelate complex) is necessary for the atom to be used as an in vivo contrast agent in humans [1-2, 5-6, 27]. There are several formulations available with different ligands, constituting the GBCAs (Table 2). Depending on the ligand, GBCAs are classified into linear or macrocyclic (according to the backbone structure of their amine group) and may be further subclassified according to their charges as ionic or non-ionic. Depending on these characteristics, GBCAs dissociate to varying extent in solution. Following intravenous injection, it is possible to detect gadolinium-chelate complexes, free gadolinium ions and free chelates in human tissues. This dissociation can be defined by the thermodynamic stability constant and dissociation constant [1-2, 28-29]. Thermodynamic stability constant determines the concentration at which gadolinium ions will dissociate from gadolinium-chelate complexes. The rate of this dissociation reaction is dependent on the dissociation constant. Taken together, these two constants define the affinity of ligands for gadolinium ions at the physiological pH [1-2, 28-29]. Each GBCA has a different thermodynamic stability constant and dissociation rate. Macrocyclic GBCAs create tighter bonds with gadolinium and therefore have higher thermodynamic stability constants and lower dissociation rates [2, 28-29]. The electrostatic charges present in ionic GBCAs render tighter bonding than nonionic GBCAs, and therefore ionic GBCAs are more stable than non-ionic GBCAs [2, 28-29]. These latter pharmacological characteristics have become relevant in the radiological literature since 2006, when it was recognized a strong association between the administration of GBCAs and the development of a debilitating and potentially life-threatening disease in patients with severe renal impairment, termed nephrogenic systemic fibrosis (NSF) [30-31]. The risk of NSF depends on the type and the dose of GBCA used [28-29, 31-37]. High thermodynamic stability constants and lower dissociation rates (greater affinity of ligands for gadolinium ions) are important qualities of a GBCA to minimize risks of NSF [28-29, 31-37]. Current literature and NSF databases show that the types of GBCAs associated with the development of NSF are the least stable, in the following order: 1) Omniscan [gadodiamide (GE Healthcare, Buckinghamshire, United Kingdom)], 2) Optimark [gadoversetamide (Mallinckrodt, St Louis, MO, USA)] and 3) Magnevist [gadopentetate dimeglumine (Bayer Schering Pharma AG, Germany)] [2, 28-29, 32-40]. All these three gadolinium agents have linear amine structure [28]. Omniscan, which has one of the lowest thermodynamic stability constants and the highest dissociation rates, shows the highest degree of association with NSF development among these three GBCAs [28, 32-34].

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Therefore, it is very important to consider the pharmacological characteristics when deciding which type of GBCA to use.

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Nonspecific Extracellular Contrast Agents GBCAs are also classified into three types according to their distribution in the body: extracellular agents, combined extracellular and intracellular agents and blood pool agents. The great majority of the GBCAs in clinical use are nonspecific extracellular contrast agents, sharing similar pharmacokinetics with iodinated contrasts in the abdomen and throughout the body. After intravenous injection, they follow the route of blood circulation and in the abdomen first reach the aorta and its branches; enter the splanchnic and splenic circulation by the celiac axis, superior and inferior mesenteric arteries, and then into their companion veins and subsequently into the portal vein. Contrast agents enter the venous system after the passage through the sinusoids in the liver, and after passing the capillaries in the peripheral circulation. They are freely redistributed from the vascular to the interstitial space [1-2, 5-6, 27]. Whereas the iodine molecule is directly imaged at computed tomography (CT), in MR imaging it is the effect of gadolinium that is evaluated rather than the agent itself. Gadolinium exhibits an amplification effect, in which many adjacent water protons are relaxed by a single gadolinium atom, shortening T1 of the tissues (effect known as relaxivity). As a result, MR imaging is more sensitive to the effect of gadolinium than is CT to the effect of iodine [5, 27]. The recommended dose of the extracellular contrast agents is 0.1 mmol/kg of body weight. The recommended injection rate is 2-3 ml/sec. All extracellular agents are eliminated by the kidneys and are not excreted by the hepatobiliary system in patients with normal renal function. They do not exhibit protein binding [1-2, 27, 31] (Table 2). Extracellular agents can be used for the acquisition of hepatic arterial dominant, early hepatic venous and interstitial phases of standard gadolinium-enhanced MRI studies. Contrast agents with greater T1-relaxivity may show better enhancement effects. In this regard, Gadovist [gadobutrol (Bayer Schering Pharma AG, Germany)], which is a nonionic macrocylic GBCA, has higher T1 relaxivity and can be theoretically administered in a lower dose to achieve the same imaging effect. Due to its macrocylic structure Gadovist has higher stability in solution and there are no cases of NSF related to its use [2, 29, 33, 39-40]. Dotarem [gadoterate meglumine (Guerbet, Aulnay-sous-Bois, France)] is an ionic macrocylic agent, and therefore combines both the predominant stability factor of macrocyclic design with the ancillary factor of ionicity. Hence, from a theoretical standpoint of stability, Dotarem should be one of the best of all the GBCAs. Until the present time, there are no cases of NSF related to its use [2, 29, 33, 39-40]. Prohance [gadoteridol (Bracco Diagnostics, Princeton, NJ, USA)] is the other macrocyclic nonspecific extracellular contrast agent that is currently manufactured and is in clinical use in the world. It is a nonionic agent which, in addition, has a low viscosity. The lower viscosity translates into easier and more rapid injection when administered by hand injection compared to other agents. This may be both advantageous, for example when only a small vein is cannulated this facilitates adequate injection, or potentially disadvantageous, for example more of a perceived ―contrast rush‖ due to rapid injection [2, 29, 33, 39-40]. Regarding NSF, there are no reports related to Prohance use alone.

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Combined Extracellular and Intracellular Contrast Agents This class of GBCAs is distributed into the extracellular space including vascular and interstitial spaces, and intracellular spaces of hepatocytes (hepatocyte phase). Therefore, these agents can also be termed as combined extracellular and hepatocyte specific agents. They can be used for the acquisition of the hepatic arterial dominant, early hepatic venous, interstitial and hepatocyte phases of GBCA-enhanced MR studies. These agents are Multihance [gadobenate dimeglumine (Bracco Diagnostics, Princeton, NJ, USA)] and Eovist [gadoxetic acid (Bayer HealthCare Pharmaceuticals, Wayne, NJ, USA), in the US] / Primovist [gadoxetic acid (Bayer Schering Pharma AG, Germany), outside the US]. They are taken up by hepatocytes and excreted into bile ducts. Consequently, they have dual elimination including both renal and biliary eliminations (Table 2). This is an important pathway of elimination if kidneys are poorly functioning, helping to decrease the gadolinium burden in the body [2, 33, 41]. The hepatocyte phase is useful to characterize lesions with biliary structures, especially focal nodular hyperplasia (FNH) [27, 41-42]. This phase is particularly helpful for the differentiation of FNH from adenoma. FNH contains hepatocytes and biliary canaliculi; therefore, hepatocyte specific agents can be uptaken and excreted into the bile ducts in FNH. However, hepatic adenomas do not contain normal hepatocytes and biliary canaliculi; hence, hepatocyte specific agents do not show uptake. Thus, while FNH enhances on the hepatocyte phase, hepatic adenomas do not [27, 41-42] (Figure 17 and 18). The hepatocyte phase is also helpful for the detection of lesions which do not contain hepatocytes, as signal intensity difference is expanded between enhanced liver parenchyma and non-enhanced lesions. This includes metastases or poorly differentiated hepatocellular carcinomas [41]. Since these agents are excreted into bile ducts in later phases, they can induce good enhancement of the biliary tree, which is useful in the detection of biliary diseases [41, 43] (Figure 19). Multihance has been used in Europe for several years. In the United States, it was approved for use in December 2004 [2, 27, 33, 41]. The agent has shown good patient tolerance, and to date with over three million doses administered, no cases of NSF have been associated with its use alone [33]. It demonstrates weak and transient binding with serum albumin, remaining in the intravascular space for a longer time than do other gadolinium chelates. In addition, its protein-binding characteristic results in increased T1 relaxivity compared with that achieved with other GBCAs. Increased T1 shortening results in increased signal intensity, which is useful for MR angiography and may yield improvements in tumor imaging [41-42, 44-45]. Serial contrast-enhanced liver imaging can be performed with the use of Multihance after bolus injection, in the same fashion as with other nonspecific extracellular contrast agents [2, 5-6, 41-42, 44]. The results are comparable with other conventional extracellular contrast agents, particularly for the improved visualization of hypervascular lesions [2, 5-6, 41-42, 44]. Multihance is approved for use at 0.1 mmol/kg; however, it has been shown that 0.05 mmol/kg (half-dose) of this agent has diagnostic efficacy compared to the full-dose of standard extracellular GBCAs [44-46]. We therefore routinely use half-dose Multihance. One of our major considerations is to minimize the administered volume of GBCA, which is in accordance with the policy advocated by the American College of Radiology (ACR) [40], in order to reduce the risk of NSF [29, 33, 36-37, 39-40]. A recent research at our institution (data not published yet) showed that Multihance can be used in a

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dose as low as 0.025mmol/kg (quarter-standard dose) for abdominal MR imaging at 3.0T (Figure 20). The enhancement was quantitatively and qualitatively inferior to half-dose (0.05 mmol/kg), but was still considered diagnostic. Therefore, patients considered at risk for NSF may have a satisfactory abdominal MR study with this very low dose (Figure 20).

Figure 17. Focal nodular hyperplasia (FNH). Transverse T2-weighted fat-suppressed SS-ETSE (a), T1weighted (T1W) out-of-phase 2D-SGE (b), and post-Gadobenate dimeglumine (Multihance) fatsuppressed late hepatic arterial phase (LHAP) (c), interstitial phase (d) and 1.5 hour delay (e) T1W 3DGE images. No lesion is clearly appreciated on the T2W (a) or T1W out-of-phase (b) images. There is a lesion in segment VI that demonstrates uniform blush on the LHAP (c), rapidly fading to isointensity on the interstitial phase (d). On the hepatobiliary phase (1.5 hour delay) (image e), the lesion is isointense with the background liver, which is increased in signal intensity, reflecting hepatocyte uptake of Multihance. Enhancement of common bile duct (arrow, e) is observed reflecting biliary excretion. These findings are characteristic of FNH.

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Figure 18. Hepatic adenoma. Transverse T2-weighted fat-suppressed SS-ETSE (a), transverse T1weighted (T1W) out-of-phase 2D-SGE (b), and transverse post-Gadobenate dimeglumine (Multihance) fat-suppressed hepatic arterial dominant phase (HADP) (c), early hepatic venous phase (EHVF) (d) and 1.5 hour delay (e) T1W 3D-GE images. Within the pre-contrast images (a, b) one lesion is depicted in the segment VII of the liver only in the out-of-phase (b) sequence, with decrease in signal intensity when compared to in-phase images (not shown), given the presence of heterogeneous intralesional fat accumulation. There is diffuse blush on the HADP post-contrast T1W 3D-GE image (c), with heterogeneous fading and mild washout on the EHVP image (d). These features and the absence of enhancement on the hepatobiliary phase (1.5 hour delay) (image e) reflecting lack of biliary canaliculi, are consistent with hepatic adenoma.

Eovist/Primovist has greater degree of protein binding than Multihance and a much greater proportion of biliary excretion (Table 2) [6, 41, 43]. Consequently, the hepatocyte phase is earlier, occurring at about 20 minutes (lasting till about 4 h). This permits ready acquisition of an entire post-contrast study, including hepatic arterial dominant, early hepatic venous, and interstitial phases, with hepatocyte-phase, in one imaging session. On the other hand, Multihance usually requires a separate imaging session for the hepatocyte-phase, because the hepatobiliary enhancement occurs at 60 to 120 minutes after its intravenous injection [6, 41, 43].

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Figure 19. Hepatobiliary phase of enhancement with gadoxetic acid (Eovist/Primovist). Coronal T1weighted fat-suppressed 3D-GE images obtained at 3.0T in two patients (a – d patient one; e, f patient two). Notice the clear enhancement of the common biliary duct in both patients (arrows).

Figure 20. MR imaging at 3.0T with quarter-dose (0.025mmol/kg) of gadobenate dimeglumine (MultiHance). This MR study was performed for staging of a renal carcinoma. This patient had poor renal function, although was not in dialysis. Transverse T1-weighted fat-suppressed 3D-GE images: pre-contrast (a), hepatic arterial dominant phase (HADP) (b, c), and interstitial phase (d). The patient was considered at risk for NSF due to the renal insufficiency. If the patient underwent a contrast enhanced CT, the risk of a contrast-induced nephropathy would be greater than the risk of developing NSF, even with injection of standard-dose of GBCA. Using a quarter-dose (0.025mmol/kg) of a stable agent like MultiHance, the risk of NSF is considered negligible. Notice that the patient could be satisfactorily imaged with this very low dose, with clear enhancement and delimitation of a left renal solid mass (arrow, b, d).

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Table 2. Gadolinium based contrast agents. Generic Name

Chemical abbreviation

Extracellular Agents GadoverGd-DTPAsetamide BMEA

Product name

Charge

Excretion

Protein binding

Standard Dosage

OptiMark (Mallinckrodt, St Louis, MO, USA) Omniscan (GE Healthcare, Buckinghamshire, United Kingdom) Magnevist (Bayer Schering Pharma AG, Germany) Gadovist (Bayer Schering Pharma AG, Germany)

Linear

Nonionic

Renal

None

0.1 mmol/kg

Linear

Nonionic

Renal

None

0.1 mmol/kg

Linear

Ionic

Renal

None

0.1 mmol/kg

Macrocyclic

Nonionic

Renal

None

0.1 mmol/kg*‡

Gadodiamide

Gd-DTPABMA

Gadopentetate dimeglumine Gadobutrol

Gd-DTPA

Gadoteridol

Gd-HPDO3A

ProHance (Bracco Diagnostics, Princeton, NJ, USA)

Macrocyclic

Nonionic

Renal

None

0.1 mmol/kg

Gadoterate meglumine

Gd-DOTA

Dotarem (Guerbet, Aulnaysous-Bois, France)

Macrocyclic

Ionic

Renal

None

0.1 mmol/kg

Linear

Ionic

Renal (%97), Biliary (%3)

25%, or >0.5 mg/ dL, within 72 hours of CT), which was irreversible in approximately half (4.8%) (defined as persistent serum creatinine increase over 45 days after CT). These fractions were lower in patients with normal renal function, but still considerable at 4.9% CIN incidence (3.2% irreversible) for iso-osmolar, and 3.1% (1.0% irreversible) for low-osmolar ICA. Comparing with the published data on NSF [2, 28-29, 32-40, 51], in patients with diminished renal function who are not on regular dialysis, the risk of CIN following the administration of iodinated contrast agent is considerably higher than the risk of NSF following the administration of the most unstable GBCA [29, 51].

CONCLUSION This chapter described the important characteristics of GBCA-enhanced MR imaging of the abdomen, emphasizing the importance of breath-holding and of understanding the significance of exact subphase of enhancement. We have also described 1.5T and 3T imaging and advantages of 3T. Finally, we have described a number of the agents in clinical use that we recommend using, stressing the reduction of the risk of NSF, which is the major current concern with these agents.

REFERENCES [1] [2] [3]

Lin, SP; Brown, JJ. MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging, 2007, 25, 884-99. Semelka, RC. Abdominal-Pelvic MRI. 3rd ed. New York: Wiley-Liss; 2010. Semelka, RC; Martin, DR; Balci, NC. Magnetic resonance imaging of the liver: how I do it. J Gastroenterol Hepatol, 2006, 21, 632-37.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

240 [4]

[5] [6] [7]

[8]

[9] [10]

[11]

[12]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[13]

[14]

[15] [16]

[17]

[18] [19]

Rafael O.P. de Campos, Vasco Herédia, Miguel Ramalho et al. Martin, DR; Semelka, RC. Magnetic resonance imaging of the liver: review of techniques and approach to common diseases. Semin Ultrasound CT MR, 2005, 26, 116-31. Semelka, RC; Helmberger, TK. Contrast agents for MR imaging of the liver. Radiology, 2001, 218, 27-38. Schneider, G; Reimer, P; Mamann, A, et al. Contrast agents in abdominal imaging: current and future directions. Top Magn Reson Imaging, 2005, 16, 107-24. Stadler, A; Schima, W; Ba-Ssalamah, A; Kettenbach, J; Eisenhuber, E. Artifacts in body MR imaging: their appearance and how to eliminate them. Eur Radiol, 2007, 17, 1242-55. Altun, E; Semelka, RC; Dale, BM; Elias, J, Jr. Water excitation MPRAGE: an alternative sequence for postcontrast imaging of the abdomen in noncooperative patients at 1.5 Tesla and 3.0 Tesla MRI. J Magn Reson Imaging, 2008, 27, 1146-54. Yang, RK; Roth, CG; Ward, RJ; deJesus, JO; Mitchell, DG. Optimizing abdominal MR imaging: approaches to common problems. RadioGraphics, 2010, 30, 185-99. Goncalves Neto, JA; Altun, E; Vaidean, G; et al. Early contrast enhancement of the liver: exact description of subphases using MRI. Magn Reson Imaging, 2009, 27, 792800. Kanematsu, M; Semelka, RC; Matsuo, M; et al. Gadolinium-enhanced MR imaging of the liver: optimizing imaging delay for hepatic arterial and portal venous phases--a prospective randomized study in patients with chronic liver damage. Radiology, 2002, 225, 407-15. Chu, LL; Joe, BN; Westphalen, AC; et al. Patient-specific time to peak abdominal organ enhancement varies with time to peak aortic enhancement at MR imaging. Radiology, 2007, 245, 779-87. Sharma, P; De Becker, J; Beck, GM; et al. Arterial-phase Bolus-track Liver Examination (ABLE): Optimization of Liver Arterial Phase Gadolinium Enhanced MRI Using Centric Re-ordered 3D Gradient Echo and Bolus Track Real-Time Imaging. Proc Intl Soc Mag Reson Med, 2006, 14, 3318. Mori, K; Yoshioka, H; Takahashi, N; et al. Triple arterial phase dynamic MRI with sensitivity encoding for hypervascular hepatocellular carcinoma: comparison of the diagnostic accuracy among the early, middle, late, and whole triple arterial phase imaging. AJR Am J Roentgenol, 2005, 184, 63-9. Danet, IM; Semelka, RC; Nagase, LL; et al. Liver metastases from pancreatic adenocarcinoma: MR imaging characteristics. J Magn Reson Imaging, 2003, 18, 181-8. Braga, L; Semelka, RC; Pietrobon, R; et al. Does hypervascularity of liver metastases as detected on MRI predict disease progression in breast cancer patients? AJR Am J Roentgenol, 2004, 182, 1207-13. Willatt, JM; Hussain, HK; Adusumilli, S; Marrero, JA. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology, 2008, 247, 311-30. Pamuklar, E; Semelka, RC. MR imaging of the pancreas. Magn Reson Imaging Clin N Am, 2005, 13, 313-30. Ku, YM; Shin, SS; Lee, CH; Semelka, RC. Magnetic resonance imaging of cystic and endocrine pancreatic neoplasms. Top Magn Reson Imaging, 2009, 20, 11-8.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Application of Gadolinium Based Contrast Agents in Abdominal Magnetic…

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[20] Ramalho, M; Altun, E; Heredia, V; Zapparoli, M; Semelka, R. Liver MR imaging: 1.5T versus 3T. Magn Reson Imaging Clin N Am, 2007, 15, 321-47, vi. [21] Ramalho, M; Heredia, V; Tsurusaki, M; Altun, E; Semelka, RC. Quantitative and qualitative comparison of 1.5 and 3.0 Tesla MRI in patients with chronic liver diseases. J Magn Reson Imaging, 2009, 29, 869-79. [22] Goncalves Neto, JA; Altun, E; Elazzazi, M; et al. Enhancement of abdominal organs on hepatic arterial phase: quantitative comparison between 1.5- and 3.0-T magnetic resonance imaging. Magn Reson Imaging, 2010, 28, 47-55. [23] Choi, JY; Kim, MJ; Chung, YE; et al. Abdominal applications of 3.0-T MR imaging: comparative review versus a 1.5-T system. RadioGraphics, 2008, 28, e30. [24] Merkle, EM; Dale, BM. Abdominal MRI at 3.0 T: the basics revisited. AJR Am J Roentgenol, 2006, 186, 1524-32. [25] Erturk, SM; Alberich-Bayarri, A; Herrmann, KA; Marti-Bonmati, L; Ros, PR. Use of 3.0-T MR Imaging for Evaluation of the Abdomen. RadioGraphics, 2009, 29, 1547-63. [26] Merkle, EM; Dale, BM; Barboriak, DP. Gain in signal-to-noise for first-pass contrastenhanced abdominal MR angiography at 3 Tesla over standard 1.5 Tesla: prediction with a computer model. Acad Radiol, 2007, 14, 795-803. [27] Gandhi, SN; Brown, MA; Wong, JG; Aguirre, DA; Sirlin, CB. MR contrast agents for liver imaging: what, when, how. RadioGraphics, 2006, 26, 1621-36. [28] Rofsky, NM; Sherry, AD; Lenkinski, RE. Nephrogenic systemic fibrosis: a chemical perspective. Radiology, 2008, 247, 608-12. [29] Altun, E; Semelka, RC; Cakit, C. Nephrogenic systemic fibrosis and management of high-risk patients. Acad Radiol, 2009, 16, 897-905. [30] Grobner, T. Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant, 2006, 21, 1104-8. [31] Penfield, JG; Reilly, RF; Jr. What nephrologists need to know about gadolinium. Nat Clin Pract Nephrol, 2007, 3, 654-68. [32] Wertman, R; Altun, E; Martin, DR; et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology, 2008, 248, 799-806. [33] Altun, E; Martin, DR; Wertman, R; et al. Nephrogenic Systemic Fibrosis: Change in Incidence Following a Switch in Gadolinium Agents and Adoption of a Gadolinium Policy--Report from Two U.S. Universities. Radiology, 2009, 253, 689-96. [34] Sadowski, EA; Bennett, LK; Chan, MR; et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology, 2007, 243, 148-57. [35] Perez-Rodriguez, J; Lai, S; Ehst, BD; Fine, DM; Bluemke, DA. Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases. Radiology, 2009, 250, 371-7. [36] Prince, MR; Zhang, HL; Prowda, JC; Grossman, ME; Silvers, DN. Nephrogenic Systemic Fibrosis and Its Impact on Abdominal Imaging. RadioGraphics, 2009, 29, 1565-74. [37] Juluru, K; Vogel-Claussen, J; Macura, KJ; et al. MR imaging in patients at risk for developing nephrogenic systemic fibrosis: protocols, practices, and imaging techniques to maximize patient safety. RadioGraphics, 2009, 29, 9-22.

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[38] Abujudeh, HH; Kaewlai, R; Kagan, A; et al. Nephrogenic systemic fibrosis after gadopentetate dimeglumine exposure: case series of 36 patients. Radiology, 2009, 253, 81-9. [39] Thomsen, HS. How to avoid nephrogenic systemic fibrosis: current guidelines in Europe and the United States. Radiol Clin North Am, 2009, 47, 871-5, vii. [40] Kanal, E; Barkovich, AJ; Bell, C; et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol, 2007, 188, 1447-74. [41] Seale, MK; Catalano, OA; Saini, S; Hahn, PF; Sahani, DV. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. RadioGraphics, 2009, 29, 1725-48. [42] Kuwatsuru, R; Kadoya, M; Ohtomo, K; et al. Comparison of gadobenate dimeglumine with gadopentetate dimeglumine for magnetic resonance imaging of liver tumors. Invest Radiol, 2001 36, 632-41. [43] Lee, NK; Kim, S; Lee, JW; et al. Biliary MR imaging with Gd-EOB-DTPA and its clinical applications. RadioGraphics, 2009, 29, 1707-24. [44] Schneider, G; Maas, R; Schultze Kool, L; et al. Low-dose gadobenate dimeglumine versus standard dose gadopentetate dimeglumine for contrast-enhanced magnetic resonance imaging of the liver: an intra-individual crossover comparison. Invest Radiol, 2003, 38, 85-94. [45] Schneider, G; Ballarati, C; Grazioli, L; et al. Gadobenate dimeglumine-enhanced MR angiography: Diagnostic performance of four doses for detection and grading of carotid, renal, and aorto-iliac stenoses compared to digital subtraction angiography. J Magn Reson Imaging, 2007, 26, 1020-32. [46] Nural, MS; Gokce, E; Danaci, M; Bayrak, IK; Diren, HB. Focal liver lesions: whether a standard dose (0.05 mmol/kg) gadobenate dimeglumine can provide the same diagnostic data as the 0.1 mmol/kg dose. Eur J Radiol, 2008, 66, 65-74. [47] Tamada, T; Ito, K; Sone, T; et al. Dynamic contrast-enhanced magnetic resonance imaging of abdominal solid organ and major vessel: comparison of enhancement effect between Gd-EOB-DTPA and Gd-DTPA. J Magn Reson Imaging, 2009, 29, 636-40. [48] Hartmann, M; Wiethoff, AJ; Hentrich, HR; Rohrer, M. Initial imaging recommendations for Vasovist angiography. Eur Radiol, 2006, 16 Suppl 2, B15-23. [49] Iezzi, R; Soulez, G; Thurnher, S; et al. Contrast-enhanced MRA of the renal and aortoiliac-femoral arteries: Comparison of gadobenate dimeglumine and gadofosveset trisodium. Eur J Radiol, 2009. [50] Maki, JH; Wang, M; Wilson, GJ; Shutske, MG; Leiner, T. Highly accelerated first-pass contrast-enhanced magnetic resonance angiography of the peripheral vasculature: comparison of gadofosveset trisodium with gadopentetate dimeglumine contrast agents. J Magn Reson Imaging, 2009, 30, 1085-92. [51] Martin, DR; Semelka, RC; Chapman, A; et al. Nephrogenic systemic fibrosis versus contrast-induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients. J Magn Reson Imaging, 2009, 30, 1350-6. [52] McCullough, PA; Adam, A; Becker, CR; et al. Risk prediction of contrast-induced nephropathy. Am J Cardiol, 2006, 98, 27K-36K. [53] Sandstede, JJ; Roth, A; Machann, W; Kaupert, C; Hahn, D. Evaluation of the nephrotoxicity of iodixanol in patients with predisposing factors to contrast medium

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induced nephropathy referred for contrast enhanced computed tomography. Eur J Radiol, 2007, 63, 120-3. [54] Heinrich, MC; Haberle, L; Muller, V; Bautz, W; Uder, M. Nephrotoxicity of isoosmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. Radiology, 2009, 250, 68-86. [55] Levy, EM; Viscoli, CM; Horwitz, RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA, 1996, 275, 1489-94. [56] Cheruvu, B; Henning, K; Mulligan, J; et al. Iodixanol: risk of subsequent contrast nephropathy in cancer patients with underlying renal insufficiency undergoing diagnostic computed tomography examinations. J Comput Assist Tomogr, 2007, 31, 493-8.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.245-263 © 2010 Nova Science Publishers, Inc.

Chapter 7

USE OF GADOLINIUM-BASED CONTRAST AGENTS IN CARDIO-VASCULAR MAGNETIC RESONANCE IMAGING- A REVIEW Cheryl Zvaigzne, Matthias G. Friedrich and Oliver Strohm* Stephenson Cardiovascular Magnetic Resonance Centre at the Libin Cardiovascular Institute of Alberta, Departments of Cardiac Sciences and Radiology, University of Calgary, Alberta, Canada

ABSTRACT Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Cardiovascular magnetic resonance (CMR) imaging has emerged as an extremely advantageous and non-invasive imaging technique. Gadolinium-based contrast agents (GBCA) further increase its utility for the assessment of tissue characterization, perfusion, and myocardial viability in various cardiac diseases. Many pathological processes of the myocardium can be detected more accurately with an increased contrastto-noise ratio. Gadolinium will wash in and out through normal tissue, areas of inflammation, ischemia, or scar at identifiable rates according to perfusion, endothelial permeability and extracellular volume of distribution. CMR image acquisition within the first minutes after gadolinium administration (Early Gadolinium Enhancement) is useful for detecting myocardial inflammation. Hyperemia and increased capillary permeability will increase the volume of distribution during this time and inflammatory tissue will have a higher signal relative to normal tissue. T 1-weighted image acquisition ten minutes or later after GBCA injection, also referred to as Late Gadolinium Enhancement imaging, is considered the non-invasive gold standard for detecting non-viable myocardium. In necrotic and fibrotic tissues, Gadolinium shows a delayed washout due to distribution in the large extravascular volume, and these areas will have a higher signal relative to other areas. These characteristics allow specific imaging of tissue pathology and diagnosis of a variety of cardiovascular diseases. In this review article, we describe the utility of *

Corresponding author: Stephenson Cardiovascular Magnetic Resonance Centre at the Libin Cardiovascular Institute of Alberta, Departments of Cardiac Sciences and Radiology, University of Calgary, 1403 29 th Street NW, FMC SSB Suite 0700Calgary, Alberta T2N 2T9, Canada, Telephone 1 (403) 944-8806, Fax 403 9448510, E-mail [email protected]

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Cheryl Zvaigzne, Matthias G. Friedrich and Oliver Strohm gadolinium-based contrast agents for CMR of coronary artery disease, myocarditis cardiomyopathies, vasculitis, and storage diseases.

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INTRODUCTION TO MAGNETIC RESONANCE IMAGING Magnetic Resonance Imaging (MRI) is a relatively new medical imaging technique that has been in clinical use since the 1980‘s, and has advanced significantly in the last decade. MRI scans are usually performed at magnetic field strengths of 1.5 to 3.0 Tesla. Such a magnetic field is at least 25,000 times stronger than that of the earth and is required to align and modify the behaviour of unevenly charged protons in the patient‘s body. Brief radio frequency pulses with specific properties are applied, which change the axis of rotation (precession) in the protons. The protons rapidly resume their original precession angle and emit a small signal, which is used to compute images. Importantly, the behaviour of resuming their previous state is strongly dependent on the molecular environment; in other words: different tissue composition creates different image contrasts. The main advantages of MRI techniques include their completely non-invasive nature, lack of any harmful radiation or radioactivity, and the lack of need for Iodine-based contrast agents. It is considered to be free of any harm to patients, but – since metal is affected in a magnetic field – it may not be performed if the patient carries certain magnetic material such as specific electronic devices or some metallic implants. The most commonly performed MRI scans are of the head, brain, spine, large joints and abdomen. Cardiac applications of MRI (Cardiovascular MR or CMR) have been applied since the late 1980‘s and have evolved into a robust, clinically valid application due to recent advances in both hardware and software. CMR provides a variety of valuable diagnostic information including anatomy and function of the heart, flow of blood, and perfusion and viability of the myocardium. Its most unique advantage is the ability to visualize tissue characteristics selectively based on molecular environments, adding a new and valuable piece of information to medical testing [1]. With state-of-the-art protocols, CMR can provide comprehensive information on heart size, morphology, function, perfusion and tissue characteristics such as viability with the same or better clinical robustness as transthoracic echocardiography, Computed Tomography (CT), and nuclear cardiology techniques. Due to its large, non-restricted field of view and its high spatial and temporal resolution, it is considered highly appropriate in multiple clinical settings [2].

Contrast Agents Image generation with MRI does not rely on absorption of radiation (as in CT), on reflection of sound waves (as in ultrasound) or on the emission of injected radionuclides (as in nuclear medicine). Instead, MRI uses tissue composition to generate images directly, rendering it an ideal soft-tissue imaging modality. However, identification of vascular structures, inflammatory changes or malignant tissue can be improved with the use of contrast agents that enhance specific body compartments and that can be followed over time.

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Furthermore, contrast agents allow for assessing pathologic changes of blood flow, for example in coronary artery disease (delayed inflow), inflammation (accelerated inflow), or scar (delayed washout). Two basic types of contrast agents are available to improve the visibility of structures: ―negative‖ and ―positive‖ contrast agents. ―Negative‖ contrast agents block the signal received from the tissues, resulting in a reduced signal intensity (SI) and leading to a darker impression of enhanced tissue. These include, for example, supermagnetic iron oxides. ―Positive‖ contrast agents intensify the received signal, thereby increasing the SI in enhanced tissue and leading to a brighter appearance of these tissues on the image. The most commonly used positive contrast agents are Gadolinium-based complexes that have paramagnetic properties. Gadolinium-based contrast agents (GBCA) are the largest group of contrast agents used in MRI imaging and are commonly used in clinical practice. Today, only about 5% of contrast use is for cardiac indication.

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Early and Late Gadolinium Enhancement Gadolinium (Gd) enables assessment of myocardium viability and perfusion imaging. Due to so-called paramagnetic properties, Gd accelerates proton relaxation and thus shortens the T1-relaxation time of tissues, increasing the local signal in T1-weighted CMR images [3]. Because of its toxicity in its free form, Gd is chelated to form a GBCA, such as Gadopentetic acid (Magnevist®) or Gadobutrol (Gadovist®). Typically, it is injected into a peripheral vein. Due to the SI increase, it is possible to track a bolus of the contrast agent on the CMR images as it circulates through the body, and to create a time-intensity curve to visualize perfusion, for example, in the myocardium. Gd can cross vascular membranes and therefore rapidly distributes in the extracellular fluid space. It will not enter cell membranes of viable cells; however, it will accumulate in cells if their membranes are dysfunctional as in necrosis. Therefore, based on various properties of the tissue, GBCA will accumulate in and wash out of different types of tissue at different rates. Analysis of SI shortly after Gd administration and comparison of myocardial and peripheral muscular enhancement is used to generate an ―Early Gd Enhancement‖ ratio or EGE; this is considered to reflect acute inflammatory changes, for example, in acute myocarditis. Imaging at a later time point after injection of Gd can be used to obtain ―Late Gd Enhancement‖ or LGE images, that reflect irreversibly damaged myocardium, as in myocardial infarction or in post-inflammatory fibrosis.

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Cheryl Zvaigzne, Matthias G. Friedrich and Oliver Strohm

Common uses of Gadolinium in CMR Coronary Artery Disease Myocardial Infarction

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Ischemia from a myocardial infarction (MI) can lead to diastolic dysfunction, systolic dysfunction, and wall-motion abnormalities, significantly reducing the left ventricular ejection fraction (LVEF). Ischemic cell death begins in the subendocardial layer of the myocardium and spreads toward the epicardium, as first described by Reimer and Jennings in 1977 [4]. In these necrotic and fibrotic cells, Gd is washed out more slowly than out of viable myocardium, becoming visible as LGE, a bright area relative to the surrounding myocardium. Therefore, LGE of ischemic origin always originates in the subendocardial layer and may progress to be transmural [5,6]. Using the 17-segment American Heart Association (AHA) model, the location and extent of LGE can be assigned to coronary artery territories; for example, a scar in the anteroseptal wall would indicate a problem in the left anterior descending (LAD) coronary artery. The location in the myocardium and the distribution of LGE allows the reader to distinguish ischemic from non-ischemic injuries. See Figure 1 for an example of an inferior infarction, where an MI occurred in the right coronary artery (RCA). LGE in CMR allows for a safe and easy identification of myocardial necrosis, thus allowing a tailored treatment approach for patients, regardless of functional impairment. In cases with capillary plugging after prolonged ischemia, a so-called ―no-reflow‖ phenomenon may leave a hypointense (= dark) subendocardial core within areas of LGE that needs to be identified as part of the irreversible tissue damage [7]. Figure 2 shows an example of an acute inferior infarction with a large no-reflow area.

Figure 1. Short axis view, LGE technique of an inferior myocardial infarction. Arrowheads denote subendocardial scar, arrow points to transmural part of infarction Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 2. Short axis view, LGE technique of an acute inferior myocardial infarction. Note large transmural scar (arrows) with dark core (arrowheads), indicating no-reflow here.

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LGE alone may not be able to identify the age of infarcts, but a combined protocol using T2-weighted sequences and LGE allows for this discrimination; acute injuries lead to an increased SI in T2-weighted images, whereas chronic injuries do not demonstrate this imaging feature [8]. See Figure 3 for an example of edema in an acute myocardial infarction.

Figure 3. Short axis view, T2-weighted STIR (short tau inversion recovery) of an acute anteroseptal myocardial infarction. Color map shows acute edema as dark blue pixels Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Myocardial Perfusion Deficits First-pass imaging of a Gd bolus, injected during vasodilatory stressor infusion (for example, adenosine or dipyridamole) allows for a visualization of hypoperfused myocardial segments, indicating obstructive stenosis in the supplying epicardial coronary artery (CA). As in LGE and EGE, the SI of normally perfused myocardium increases, thus a series of T1weighted fast gradient-recalled echo images, taken immediately after injection of the GBCA, can allow visualization of Gd travelling from the vein into the right heart, the pulmonary circulation, the left ventricle, and finally into the arteries and myocardium [9]. In comparing rest and stress images, an assessment of reduced myocardial perfusion is possible in a visual and semi-quantitative manner. Figure 4 shows an example of a stress-induced septal deficit. CMR perfusion has been demonstrated to have an excellent negative predictive value in patients with chest pain [10,11]. In recent years, Gd dosing regimens have been investigated and hardware- and software-specific protocols have been published for all major systems. Although CMR has a significantly higher resolution than either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) [12], diagnostic performances of first pass perfusion and SPECT are considered similar [13]. Mastouri and colleagues (2010) asserted that non-invasive tests for CAD including stress echocardiography, CMR, SPECT, and PET, each have their benefits and disadvantages, and that the most appropriate imaging technique appears to vary with each patient‘s case [14].

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Tissue Characterization In normal myocardial tissue, a GBCA will rapidly enter the extracellular space surrounding the densely packed myocytes, and will rapidly be washed out again [7]. At the first equilibrium state, or early Gd enhancement (EGE), the signal intensity (SI) in the normal myocardium will be increased; later, measured as LGE, the SI will be low due to efficient washout of the GBCA.

Figure 4. Short axis view, Adenosine ―stress‖ perfusion in a patient with known CAD and s/p CABG. Arrowheads denote large perfusion deficit in the anteroseptal region Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Early enhancement appears to be particularly useful for assessing inflammation. Due to a combination of hyperemia, one of the primary components of acute inflammation, and increased capillary permeability (due to myocyte injury), inflammatory tissue will have a higher than normal amount of GBCA at EGE, and thus will have a higher SI relative to normal tissue. In myocardial inflammation, hyperemia as defined by increased early Gd enhancement was found to be the best CMR predictor [15]. In areas of ischemia, flow into the myocardial tissue is significantly reduced. Therefore in EGE, the SI will be low. If the tissue is ischemic, but still viable, Gd washes out in a normal pattern, giving a low SI in LGE. Late enhancement is considered the non-invasive ―gold standard‖ for visualization of irreversible injured myocardium. In fibrotic tissue, a collagen matrix replaces the myocytes over time. Because of reduced blood supply, Gd enters these fibrotic tissues slowly, then gets trapped in the dense collagen matrix and therefore diffuses out of the tissue slowly. After approximately ten minutes, SI is higher in fibrotic tissue relative to normal tissue in sequences with myocardial suppression pre-pulses. LGE can also indicate the presence of necrotic myocytes. These cells have a disrupted cell membrane, allowing the accumulation of GBCA and delayed washout. At the time of LGE, GBCA will have washed out of all tissues other than fibrotic and necrotic tissue. Figure 5 illustrates the rates of GBCA perfusion, or contrast kinetics, in important myocardial tissue pathologies.

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Non-ischemic Cardiomyopathy The presence of LGE in patients with non-ischemic cardiomyopathy is correlated with a three-fold hazard ratio increase [16]. Patients with LGE also had an eight-fold increase in risk for sudden cardiac death, heart failure, and incidents of appropriate intracardiac device (ICD) firing during a 17-month follow-up period [17].

Figure 5. Simplified and schematic contrast kinetics in different myocardial pathologies. Green line = healthy myocardium, note fast recovery to nearly pre-peak SI. Red line = myocardial inflammation, note increased maximal SI and fast return to nearly pre-peak SI; note higher SI post-peak compared to healthy myocardium, explaining increased Early Gadolinium Enhancement ratio. Blue line = ischemic myocardium, e.g. during adenosine infusion, note reduced SI at peak and delayed peak compared to normal. Black line = scar tissue, note fast inflow and then reduced outflow.

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Myocarditis Myocarditis is typically understood as inflammation of the myocardium with variable degrees of myocyte injury that is not caused by coronary artery disease. It is most often caused by a viral infection or an autoimmune process. Until recently, myocarditis has been difficult to diagnose due to non-specific clinical presentations and suboptimal diagnostic tests. A commonly used diagnosis technique is endomyocardial biopsy, but this is an invasive procedure that suffers from low sensitivity and specificity. Using currently published methods (a combined protocol with functional assessment, T2-weighted techniques, EGE and LGE), CMR has evolved into a valuable clinical tool for the exclusion, or the diagnosis and follow-up of myocarditis [18,19].

EGE in Myocarditis

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Hyperemia and comprised myocytes are integral components of inflammation, and both contribute to a high SI in EGE. EGE was first described in patients with suspected myocarditis by Friedrich et al. in 1998 [20] and later proposed as a part of a comprehensive CMR protocol [21]. It was noted that myocardial inflammation is not always identified by EGE in cases where inflammation involves the skeletal muscle because the signal from the myocardium is compared to the signal from the skeletal muscle. This can result in a ‗pseudonormal‘ EGE [22]. EGE MRI allows visualization of inflammatory activity in the myocardium, and these parameters can be used in a follow-up visit to monitor resolution or chronification of the disease. See Figure 6 for an example of EGE imaging in acute myocarditis.

LGE in Myocarditis LGE was developed initially to visualize areas of myocardial infarction, but it has been demonstrated to be applicable in any type of necrosis or fibrosis [23]. The true frequency of LGE, indicating an irreversible injury, is not yet determined in myocarditis. Mahrholdt et al [24] reported an 88% incidence of LGE in the lateral free wall in myocarditis patients, while later reports found a lower incidence [15,21,25).

Figure 6. Short axis views in T1-weighted SE technique before (left) and after (right) 0.1 mmol/kg Gadolinium-based contrast agent in a young patient with acute myocarditis. Note diffuse uptake in the post-contrast image, indicating inflammation. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Contrary to ischemic cardiomyopathy, cell death in myocarditis does not have to begin in the subendocardial layer of the myocardium and does not follow the distribution areas of coronary arteries; most often, it is found in the epicardial layers of the lateral segments. Yilmaz et al [19] described separate distribution patterns of LGE in myocarditis, including intramural, rim-like or midwall distribution, patchy areas of enhancement in the lateral segments and some diffuse, even transmural uptake. See Figure 7 for an example of LGE in a patient with acute myocarditis. Some authors linked the underlying virus in acute myocarditis with a specific distribution pattern of LGE [26,27]. For example, Mahrholdt and colleagues found that patterns of LGE occurring in the lateral free wall to be strongly associated with parvovirus B19, while LGE predominantly in the midwall of the interventricular septum was associated with human Herpesvirus 6 [27]. Because the border between healthy and fibrotic myocardium is electrically unstable, it has been suggested that the presence of LGE in could indicate likeliness to develop arrhythmias. Mahrholdt and colleagues (2006) identified the presence of septal LGE and the extent of total LGE as strong predictors of chronic LV dysfunction and dilatation [27]. While LGE alone gives a 68% diagnostic accuracy of myocarditis, Friedrich et al. estimated that myocarditis could be diagnosed with 78% accuracy if the three CMR techniques (EGE, LGE and T2-weighted imaging) are combined [18]. These CMR methods have therefore been identified as currently the most sensitive, specific, and safe diagnostic evaluation of myocarditis [18,28].

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Systemic Vasculitis Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disorder that can affect the heart. CMR is useful in assessing myocardial involvement in SLE and may be used to individually adjust medical therapy in these cases.

Figure 7. Long axis view (4-chamber-view) in LGE technique in a patient with acute myocarditis. Arrowheads denote epicardial lateral uptake, arrow points to intra-myocardial uptake (midwall sign) Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Myocardial involvement has been reported in less than 10% of SLE patients based on conventional methods such as electrocardiography (ECG) or echocardiography [29], however autopsy-based studies reported up to 37% of SLE patients to have myocarditis [30]. Cardiac involvement of SLE may often be missed, as clinical manifestations may be subtle or nonspecific. Imaging findings in SLE patients are similar to viral myocarditis, with interstitial edema and focal fibrosis that is intramural, most often inferolateral and usually does not affect the subendocardium [31]. Mavrogeni et al. (2009) speculate that LGE in SLE represents secondary myocyte injury resulting from interstitial inflammation [32].

Dilated Cardiomyopathy

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Dilated cardiomyopathy (DCM) is defined as dilation and impairment of function in one or both ventricles. It is the most common non-ischemic cardiomyopathy. Presence and distribution of LGE in DCM is variable. If present, it has been described in a streaky or patchy pattern in the midwall of the left ventricle, typically in the basal and midseptum [12]. However, a small proportion of patients with heart failure yet not explained by coronary artery disease have scar patterns consistent with ischemic injury [6,33]. Figure 8 shows an example of LGE in DCM. Approximately 30-35% of DCM patients have LGE in the midwall, and these patients have a worse prognosis than those without LGE. DCM patients with LGE experience more hospitalizations for cardiac events, ventricular tachycardia, and deaths than those without LGE [16]. Furthermore, Choi et al (2009) have shown that DCM patients with midwall LGE have a higher ventricular stiffness and less efficient ventriculoarterial coupling than those DCM patients without midwall LGE [33].

Figure 8. Short axis view in LGE technique in a patient with DCM. Arrows denote large area of midwall-uptake, sparing the endocardial and the epicardial layers Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Nazarian and colleagues (2005) demonstrated that patients with DCM who had a transmural extent of LGE greater than 25% were at higher risk for ventricular arrhythmias [34]. Coelho-Filho et al demonstrated that LGE is a better predictor of VT, sudden death or primary all-cause mortality in comparison with ejection fraction [12]; therefore, LGE seems to be superior in the clinical decision-making process for anti-tachycardic devices such as ICD as compared to using ejection fraction only.

Hypertrophic Cardiomyopathy

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Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy that leads to regional or diffuse hypertrophy and reduced function of the left ventricle. LGE is a frequent finding in HCM patients. LGE in HCM is associated with fibrosis, and is due to either expansion of the interstitial space or myocardial disarray. [7,35] Different patterns of distribution have been reported. According to Coelho-Filho and colleagues (2009), Gd accumulates in the most hypertrophic areas. The distribution includes patchy patterns in the mid-wall of the septum, most commonly at the junctions of the septum and the right ventricle, the RV insertion points [7,35]. Refer to Figure 9 for an example of LGE in HCM. As in DCM, HCM patients with LGE have a lower left ventricular ejection fraction, and are more likely to develop ventricular tachycardia [35]. Rubinshtein et al (2009) found that LGE in HCM patients was not associated with symptoms such as angina and dyspnea, but they showed a strong correlation between presence of LGE and arrhythmias and sudden cardiac death [37].

Figure 9. Short axis view in LGE technique in a patient with HCM. Arrows denote non-ischemic uptake in the RV-insertion points.

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Myocardial Storage Diseases Amyloidosis

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In amyloidosis, fibrils of a pathological low-molecular weight protein, amyloid, is stored diffusely in the extracellular tissue. Cardiac involvement has been reported in up to 40% of patients diagnosed with systemic amyloidosis [12], and more than 50% of cardiac amyloid cases develop life-threatening arrhythmias [38]. An endomyocardial biopsy is usually required to confirm the diagnosis of cardiac involvement, but CMR has become a clinically useful tool to assess cardiac involvement and thus to determine the prognosis of these patients [39]. Deposition of amyloid fibrils causes interstitial expansion, which causes GBCA to accumulate in this space, affecting the rate at which gadolinium washes in and out. Therefore, unlike most other cardiomyopathies, presence of LGE in patients with amyloid does not visualize fibrotic areas within the myocardium. Importantly, the typical LGE protocol must be modified in cases of amyloidosis, as the contrast kinetics are dramatically changed; Gd washes out quickly from the blood pool, leaving a typical ―dark blood pool / dark ventricular cavities‖ at the usual timing of LGE imaging. In amyloidosis, LGE images should be acquired earlier, at approximately five minutes after injection of the bolus. Alternatively, the dose of Gd should be increased [40]. LGE visualization in amyloidosis may be global in the left ventricle, but the subendocardium is most often affected [7,38,41], as amyloid fibrils preferentially deposit there. Maceira et al (2005) also reported diffuse LGE, particularly in the basal endocardial segments of the left ventricle [40]. Diffuse LGE in the right ventricle and in the atria has also been reported [38). See Figure 10 for an example of LGE in a patient with amyloidosis.

Figure 10. Short axis view in LGE technique in a patient with known amyloidosis. Note extensive LV hypertrophy and diffuse, ring-like uptake in the myocardium Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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The presence of LGE in amyloid patients is associated with a fourfold reduction in survival compared to patients without LGE; mean survival time is only four months for these patients [42].

Anderson-Fabry Anderson-Fabry disease (AFD) is a lysosomal storage disease. A deficiency of the enzyme alpha galactosidase A causes a sphingolipid to accumulate in the patient‘s organs and blood vessels. Cardiac involvement occurs in up to 50% of Anderson-Fabry cases. These patients have concentric LV hypertrophy, which often leads to conduction defects, valvular dysfunction, arrhythmias, and heart failure. LGE findings have been reported in patients with AFD in the mid-myocardium in the basal inferolateral wall [43,44]. Moon et al (2006) performed an autopsy of a male AFD patient who had a previous CMR report of LGE in the basal inferolateral wall and demonstrated that LGE in AFD is caused by the deposition of collagen [45].

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Cardiac Sarcoidosis Sarcoidosis is a systemic inflammatory disease of unknown etiology, characterized by the formation of small inflammatory nodules throughout the body, and affecting multiple systems including the heart. The incidence of cardiac involvement is not exactly known, but appears to be high. Furthermore, of a number of sarcoidosis patients who had cardiac involvement proven by autopsy, it is estimated that 67% died by sudden cardiac death as a result of ventricular arrhythmias, while the remaining 23% died of congestive heart failure [46]. Despite these deaths, only 5% of patients with cardiac sarcoidosis have clinical symptoms [47,48]. Therefore, a non-invasive diagnostic test that can detect early cardiac involvement of sarcoidosis would have high clinical value. EGE and T2-weighted CMR have been reported as very useful in diagnosing myocardial involvement in sarcoidosis [49,50,51] and during follow-up [52]. A study by Cheong et al (2009) reported LGE, representing non-ischemic fibrosis or infiltration of inflammatory nodules, in 26% of 31 patients who had biopsy-proven systemic sarcoidosis with no previously known cardiac involvement [53]. Another study compared the ability of LGE CMR to detect cardiac involvement of sarcoidosis with the current consensus criteria: a standard cardiac evaluation comprising a 12-lead EKG and one other non-CMR study [54]. The authors concluded that LGE is twice as sensitive in detecting cardiac sarcoidosis as the current consensus criteria. In a similar study, Manins and colleagues found LGE CMR to be superior to the Japanese Ministry of Health and Welfare criteria [55]. Cheong et al (2009) observed LGE most frequently in the basal inferoseptum, and also commonly in the basal inferolateral wall. These patterns occurred primarily in the midwall and spread to the adjacent endo- or epicardium [53]. A study in Japan that observed LGE in ten of 11 patients with cardiac sarcoidosis, also identified LGE predominantly in the basal and subepicardial myocardium [56].

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It is evident that CMR is valuable in identifying early cardiac involvement in sarcoidosis, thereby is useful for guiding therapy on an individualized basis.

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Side Effects of Gadolinium-Based Contrast Agents – Nephrogenic System Fibrosis Nephrogenic Systemic Fibrosis (NSF) is a rare condition similar to scleromyxedema, but with some important clinical distinctions. Patients experience swelling, and thickening of the skin that acquires a woody texture, and development of papules with a ‗peau d‘orange‘ appearance, usually sparing the face and upper extremities. The disease may also affect the skeletal muscle, myocardium, lungs, kidneys, testes, and dura mater, and it becomes excruciating, debilitating, and is often fatal [57]. The earliest cases of NSF were described in 1997, around the time that Gd became widely used in imaging [58], and eight years after the first approval of use of a newer Gdbased contrast agent, gadopentetate. According to Prchal et al, (2008) NSF was recognized in 1997 but not described in the literature until 2000 [59]. This disease is still extremely rare, with only just over 335 cases identified globally so far. All patients who have developed NSF have acute or chronic renal insufficiency, and received intravenous administration of a high dose of a GBCA. There is no described risk of developing NSF in patients with normal renal function. In addition to renal insufficiency, factors that increase risk for development of NSF include a high lifetime total dose of Gd, and inflammatory factors such as recent surgery, sepsis, venous thrombosis and coagulopathy, or vascular injury. It is important to emphasize that almost all Gd compounds carry a lower overall risk than iodinated contrast agents used in other imaging modalities [60]. Furthermore, it is important to understand that NSF requires free Gd to cause tissue damage [61]. Gd, however, is not released fast enough to accumulate in any tissue, unless there is a delay of Gd clearance as in severe renal insufficiency and when Gd compounds have a short half-life. The half-life of non-ionic Gd compounds with open-chain structure can be reduced, especially at low pH levels. This, however, is extremely rare in all other agents and introduces a negligible risk for most of the contrast agents. In fact, in patients with renal insufficiency, the risk of NSF likely is up to 1000-fold higher with the non-ionic, open-chain agent Gadodiamide than with other MRI contrast agents [62]. Newer, especially macrocyclic chelates are considered as too stable for causing NSF. Recently published reports in more than 15,000 patients did not show any cases of NSF when using these agents [63,64]. The current FDA Guidelines state: ―Healthcare providers should avoid use of gadolinium in patients with acute or chronic severe renal insufficiency – where the glomerular filtration rate is less than 30 mL/min/1.73m2, or in any acute renal sufficiency due to the hepatorenal system or in the perioperative liver transplantation period‖ [65]. All patients receiving GBCA should be screened for renal dysfunction with a history and/or laboratory tests. These precautionary measures appear to have prevented further development of NSF, making gadolinium contrast-enhanced MRI completely harmless, as we know it.

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CONCLUSION CMR is advancing as one of the most valuable imaging modalities in medicine and will continue to grow in newer areas, such as cardiac and vascular imaging, not only because it is non-invasive, uses no ionizing radiation, and provides consistently high image quality and high spatial resolution, but especially because of its comprehensive approach to myocardial phenotyping including tissue characterization. In addition to native CMR, contrast agents allow for increased signal and assessment of regional blood distribution, which facilitates tissue characterization. Currently, the use of Gadolinium-based contrast agents represents an invaluable contribution to the application of MRI in the management of cardiovascular diseases.

REFERENCES [1]

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[2]

[3]

[4]

[5]

[6]

[7]

[8]

Friedrich, M. Tissue characterization of acute myocardial infarction and myocarditis by cardiac magnetic resonance. JACC 2008;1:652-662. Hendel, RC; Patel, MR; Kramer, CM; et al. ACCF/ACR/SCCT/ SCMR/ ASNC/ NASCI/SCAI/SIR 2006 Appropriateness Criteria for Cardiac Computed Tomography and Cardiac Magnetic Resonance Imaging - A Report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. Journal of the American College of Cardiology, 2006;48:1475-1497. Gore, TB; Rollings, RC; Gore, AW. The many facets of Cardiovascular Magnetic Resonance Imaging: Review of background, clinical utility, and increasing use in the community hospital. Southern Medical Journal, 2009, 102, 719-724. Reimer, KA; Lowe, JE; Rasmussen, MM; Jennings, RB. The wavefront phenomenon of ischemic cell death. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation, 1977, 56, 786-794. Wu, E; Judd, RM; Vargas, JD; et al. Visualisation of presence, location, and transmural extent of healed Q-wave and non-Q-wave myocardial infarction. Lancet, 2001, 357, 218. McCrohon, JA; Moon, JC; Prasad, SK; et al. Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation, 2003, 108, 54-9. Vohringer, M; Mahrholdt, H; Yilmaz, A; Sechtem, U. Significance of late gadolinium enhancement in cardiovascular magnetic resonance imaging (CMR). Herz, 2007, 32, 129-37. Abdel-Aty, H; Zagrosek, A; Schulz-Menger, J; et al. Delayed enhancement and T2weighted cardiovascular magnetic resonance imaging differentiate acute from chronic myocardial infarction. Circulation, 2004, 109, 2411-6.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

260 [9]

[10]

[11]

[12] [13]

[14]

[15]

[16] [17]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[18]

[19] [20]

[21]

[22] [23]

[24]

Cheryl Zvaigzne, Matthias G. Friedrich and Oliver Strohm Muehling, OM; Dickson, ME; Zenovich, A; et al. Quantitative magnetic resonance first-passs perfusion analysis: inter- and intraobserver agreement. J Cardiovasc Magn Reson, 2001, 3(3), 247-56. Ingkanisorn, WP; Kwong, RY; Bohme, NS; et al. Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain. J Am Coll Cardiol, 2006, 47(7), 1427-32. Jahnke, C; Nagel Eike, Gebker, R; et al. Prognostic Value of Cardiac Magnetic Resonance Stress Tests: Adenosine Stress Perfusion and Dobutamine Stress Wall Motion Imaging. Circulation, 2007, 115, 1769-1776. Coelho-Filho, OR; Nallamshetty, L; Kwong, RY. Risk stratification for therapeutic management and prognosis. Heart Failure Clin, 2009, 5, 437-455. Schwitter, J; Wacker, CM; van Rossum, AC; et al. MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur Heart J, 2008, 29(4), 480-9. Mastouri, R; Sawada, SG; Mahenthiran, J. Current noninvasive imaging techniques for detection of coronary artery disease. Expert Rev Cardiovasc Ther., 2010, Jan;8(1), 7791. Gutberlet, M; Spors, B; Thoma, T; et al. Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence. Radiology, 2008, 246, 401-9. Assomull, RG; Prasad, SK; Lyne, J; et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol, 2006, 48, 1977-85. Wu, KC; Weiss, RG; Thiemann, DR; et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in non-ischemic cardiomyopathy. J Am Coll Cardiol, 2008, 51(25), 2414-21. Friedrich, MG; Sechtem, U; Schulz-Menger, J; et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol., 2009, 53, 14751487. Yilmaz, A; Klingel, K; Kandolf, R; et al. Imaging in inflammatory heart disease: from the past to current clinical practice. Hellenic J Cardiol , 2009, 50, 449-460. Friedrich, MG; Strohm, O; Schulz-Menger, J; Marciniak, H; Luft, FC; Dietz, R. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation, 1998, 97, 1802-1809. Abdel-Aty, H; Boye, P; Zagrosek, A; et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparision of different approaches. J Am Coll Cardiol, 2005, 45, 1815-22. Laissy, JP; Messin, B; Varenne, O; et al. MRI of acute myocarditis: a comprehensive approach based on various imaging sequences. Chest, 2002, 122, 1638-48. Mahrholdt, H; Wagner, A; Judd, RM; et al. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischemic cardiomyopathies. Eur Heart J, 2005, 26, 1461-74. Marhrholdt, H; Goedecke, C; Wagner, A; et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation, 2004, 109(10), 1250-8.

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[25] Yilmaz, A; Mahrholdt, H; Athanasiadis, A; et al. Coronary vasospasms the underlying cause for chest pain in patients with PVB19- myocarditis. Heart, 2008, 94, 1456-63. [26] Bowles, NE; Ni, J; Kearney, DL; et al. Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiology, 2003, 42, 466-72. [27] Marhrholdt, H; Wagner, A; Deluigi, CC; et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation, 2006, 114(15), 1581-90. [28] Skouri, Dec, GW; Friedrich, MG; et al. Noninvasive Imaging in Myocarditis. Journal of the American College of Cardiology, 2006, 48, 2085-2093. [29] Wijetunga, M; Rockson, S. Myocarditis in systemic lupus erythematosus. Am J Med, 2002, 113, 419-423. [30] Panchal, L; Divate, S; Vaideeswar, P; et al. Cardiovascular involvement in systemic lupus erythematosus: an autopsy study of 27 patients in India. J Postgrad Med., 2006, Jan-Mar; 52(1), 5-10. [31] Abdel-Aty, H; Siegle, N; Natusch, A; et al. Myocardial tissue characterization in systemic lupus erythematosus: value of a comprehensive cardiovascular magnetic resonance approach. Lupus, 2008, 17, 561-67. [32] Mavrogeni, Spargias, K; Markussis, V; et al. Myocardial Inflammation in Autoimmune Diseases: Investigation by Cardiovascular Magnetic Resonance and Endomyocardial Biopsy. Inflammation & Allergy-Drug Targets, 2009, 8, 1-8. [33] Choi, EY; Choi, BW; Kim, SA; et al. Patterns of late gadolinium enhancement are associated with ventricular stiffness in patients with advanced non-ischemic dilated cardiomyopathy. Eur J Heart Fail, 2009, 11, 573-580. [34] Nazarian, S; Bluemke, DA; Lardo, AC; et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation, 2005, 112(18)2821-5. [35] Satoh, H; Matoh, F; Shiraki Katsunori, et al. Delayed enhancement on cardiac magnetic resonance and clinical, morphological, and electrocardiographical features in hypertrophic cardiomyopathy. Journal of Cardiac Failure, 2009, 15, 419-427. [36] Choudhury, L; Mahrholdt, H; Wagner, A; et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol, 2002, 40, 2156-64. [37] Rubinshtein, R; Glockner, JF; Ommen, SR; et al. Characteristics and clinical significance of late gadolinium enhancement by contrast-enhanced magnetic resonance imaging in patients with hypertrophic cardiomyopathy. Circ Heart Fail 2009; Oct 22 (Epub ahead of print). [38] O‘Hanlon, R; Pennell, DJ. Cardiovascular magnetic resonance in the evaluation of hypertrophic and infiltrative cardiomyopathies. Heart Failure Clin, 2009, 5, 369-387. [39] Selvanayagam, JB; Hawkins, PN; Paul, B; et al. Evaluation and Management of the Cardiac Amyloidosis. Journal of the American College of Cardiology 2007, 50(22), 2101-2110. [40] Maceira, AM; Joshi, J; Prasad, SK; et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation, 2005, 111(2), 186-93. [41] Perugini, E; Rapezzi, C; Piva, T; et al. Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance. Heart, 2005, 92, 343-349.

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[42] Falk, RH; Skinner, M. The systemic amyloidoses: an overview. Adv Intern Med, 2000, 45, 107-37. [43] Moon, JC; Sachdev, B; Elkington, AG; et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J, 2003, 24, 2141-5. [44] Gange, CA; Link, MS; Maron, MS. Utility of Cardiovascular magnetic resonance in the diagnosis of Anderson-Fabry disease. Circulation, 2009, 120, e96-e97. [45] Moon, JC; Sheppard, M; Reed, E; et al. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. Journal of Cardiovascular Magnetic Resonance, 2006, 8, 479-482. [46] Perry, A; Vuitch, F. Causes of death in patients with sarcoidosis. A morphologic study of 38 autopsies with clinicopathological correlations. Arch Pathol Lab Med, 1995, 119, 167-172. [47] Sharma, OP; Maheshwari, A; Thaker, K. Myocardial sarcoidosis. Chest, 1993, 103, 253-258. [48] Sharma, S. Cardiac imaging in myocardial sarcoidosis and other cardiomyopathies. Curr Opin Pulm Med, 2009, 15, 507-512. [49] Schulz-Menger, J; Strohm, O; Dietz, R; et al. Visualization of cardiac involvement in patients with systemic sarcoidosis applying contrast-enhanced magnetic resonance imaging. Magma, 2000, 11, 82-3. [50] Vignaux, O; Dhote, R; Duboc, D; et al. Detection of myocardial involvement in patients with sarcoidosis applying T2-weighted, contrast-enhanced, and cine magnetic resonance imaging: initial results of a prospective study. Journal of computer assisted tomography, 2002, 26, 762-7. [51] Schulz-Menge, J; Wassmuth, R; Abdel-Aty, H; et al. Patterns of myocardial inflammation and scarring in sarcoidosis as assessed by cardiovascular magnetic resonance. Heart, 2005, 92, 399-400. [52] Vignaux, O; Dhote, R; Duboc, D; et al. Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis: a 1-year follow-up study. Chest, 2002, 122(6), 1895-901. [53] Cheong, BY; Muthupillai, R; Nemeth, M; et al. The utility of delayed-enhancement magnetic resonance imaging for identifying nonischemic myocardial fibrosis in asymptomatic patients with biopsy-proven systemic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis., 2009, Jul;26(1), 39-46. [54] Patel, JR; Cawley, PJ; Hetner, JF; et al. Detection of myocardial damage in patients with sarcoidosis. Circulation, 2009, 120, 1969-1977. [55] Manins, V; Habersberger, J; Pfluger, H; Taylor, AJ. Cardiac magnetic resonance imaging in the evaluation of cardiac sarcoidosis: an Australian single-centre experience. Intern Med J, 2009, 39, 77-82. [56] Ichinose, A; Otani, H; Oikawa, M; et al. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. Am J Roentgenol, 2008, 91, 862-869. [57] Juluru, K; Vogel-Claussen, J; Macura, KJ; Kamel, IR; Steever, A; Bluemke, DA. MR Imaging in patients at risk for developing nephrogenic systemic fibrosis: protocols, practices, and imaging techniques to maximize patient safety. Radiographics, 2009, 29, 9-22.

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[58] Cowper, SE. Nephrogenic Fibrosing Dermopathy [ICNSFR Website]. 2001-2009. Available at http://www.icnsfr.org. Accessed 11/03/2009. [59] Prchal, D; Holmes, DT; Levin A. Nephrogenic systemic fibrosis: the story unfolds. Kidney International, 2008, 73, 1335-1337. [60] Altun, E; Semelka, RC; Cakit, C. Nephrogenic systemic fibrosis and management of high-risk patients. Acad Radiol, 2009, 16, 897-905. [61] High, WA; Ayers, RA; Chandler, J; Zito, G; Cowper, SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol., 2007, 56, 21-26. [62] Wertman, R; Altun, E; Martin, DR; et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology, 2008, 248, 799-806. [63] Forsting, M; Palkowitsch, P. Prevalence of acute adverse reactions to gadobutrol - A highly concentrated macrocyclic gadolinium chelate: Review of 14,299 patients from observational trials. European Journal of Radiology, 2009 doi:10.1016/j.ejrad. 2009, 06.005. [64] Altun, E; Martin, DR; Wertman, R; et al. Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy-report from two U.S. universities. Radiology, 2009, 253, 689-961. [65] Information for Healthcare Professionals: Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). Rockville, MD: US Food and Drug Administration, May 23, 2007. Available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation for Patients and Providers /ucm142884.htm

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.265-299 © 2010 Nova Science Publishers, Inc.

Chapter 8

T HE USE OF G ADOLINIUM FOR ESR D OSIMETRY M. Marrale1,2, ∗, M. Brai1,2 , A. Longo1 1 Dipartimento di Fisica e Tecnologie Relative, Universit`a di Palermo, Viale delle Scienze, Edificio 18, 90128 Palermo, Italy 2 Gruppo V Sezione INFN, Catania, Italy

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Abstract The application of gadolinium to sensitize Electron Spin Resonance (ESR) dosimeters is reviewed. This nucleus is chosen because it has very good features in interacting with ionizing radiations. In particular, it has a very high capture cross section for thermal neutrons which favors the interactions of these particles within the detector; moreover, the charged secondary particles released after neutron interactions (mainly Auger and internal conversion electrons) are able to release their energy close the gadolinium site and, therefore, inside the sensitive volume of the detector. Consequently, the addition of gadolinium inside ESR dosimeters produces a significant enhancement of thermal neutron sensitivity. Furthermore, the presence of gadolinium can improve the sensitivity to photons because its high atomic number (ZGd =64) increases the effective cross photon section of the detectors. However, it must be taken into account for medical dosimetric application of Gd-added dosimeters that the tissue equivalence is heavily reduced. In this work, the response of ESR dosimeters added with gadolinium after irradiation to various radiation beams (such as 60 Co gamma photons, thermal neutrons, protons) is described. Monte Carlo simulations able to theoretically model the effects of gadolinium on the ESR dosimeter sensitivity are reported along with the comparison of these computational results with the experimental ones.

PACS 87.53.Bn, 76.30.-v Key Words: ESR, dosimetry, organic compounds, gadolinium,60 Co-γ photons, thermal neutrons, protons

∗

E-mail address: [email protected]

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1. Introduction The passage of ionizing radiations through matter induces processes of ionizations and excitations of the medium atoms and molecules. These microscopic processes are the origin of macroscopic directly or indirectly measurable effects. The fundamental issue common to various scientific branches (such as solid state physics, radiobiology, medical diagnosis and therapy, genetic engineering, etc.) is to correlate the biological, physical and chemical effects to the physical features of the radiation field. Since these observed effects are correlated to the energy released by ionizing radiations, the knowledge of the energy absorbed by the unit mass of the exposed medium plays a fundamental role for the solution of the above-mentioned problem. The dosimetry has as primary target the measurement or the calculation of the dose absorbed by the irradiated matter. Any effect which causes the variation of a physical and/or chemical parameter as a function of the energy absorbed per unit mass of a medium could be exploited to carry out a measurement of the absorbed dose. The various measurement methods can be distinguished in absolute methods (such as calorimetric, chemical and ionometric methods) which allow to obtain the dose value directly from the measure of physical or chemical parameter and relative methods (such as photographic and thermoluminescence method) which need an inter-calibration with some absolute equipment. The EPR dosimetry, extensively treated in this work, is a relative method and is based on the detection of the free radicals in organic and inorganic compunds produced by ionizing radiation in passing through matter. The ESR technique is nowadays widely employed for dosimetric and dating applications [1]. This method shows various advantages such as the ability of providing a dose estimation with a simple and time saving procedure and the non-destructiveness of the radiation sensitive material used and therefore the possibility of preserving it for future inspection [2]. These properties are exploited for dose reconstruction in humans by tooth enamel and bone material analysis [3, 4], for identification of food irradiation [5–7] and for dating of geological and archaeological materials [8, 9]. Electron spin resonance (ESR) has been applied for dosimetric purposes since early works in 1960s-1970s [10–13]. A systematic analysis of the dosimetric properties of pellets of the amino acid L-α-alanine (+ H3 N − CH(CH3 ) − COO− ) was carried out by Regulla and Deffner in 1982 [14]. Many works have been performed on alanine afterwards. Nowadays, since alanine has good dosimetric features (such as wide linear dose range, tissue equivalence, high stability of the free radicals, independence of the response of dose rate and radiation energy), this amino acid is recognized by the IAEA (International Atomic Energy Agency) [15] as a routine, reference and transfer dosimeter for industrial applications in the high dose range (of the order of a few kGy). Furthermore, the alanine dosimeters are commonly adopted by several international calibration laboratories (such as IAEA (International Atomic Energy Agency, Vienna, Austria) [15–18], NIST (National Institute for Standards and Technology, USA) [19] and NPL (National Physical Laboratory, UK) [20]) for transfer dosimetry for high dose irradiation. However, very precise measurements in low dose range (about 1 Gy) involve use of alanine samples with great mass and volume with consequent low spatial dose resolution. Alanine signals are too weak for measuring doses below 1 Gy with high spatial resolution.

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This drawback has stimulated the development of ESR dosimeters with improved S/N ratio at low dose levels. In the last ten years, various research laboratories have studied new materials for ESR dosimetry [2]. Among the different materials tested, ammonium tartrate (AT) (H4 N+ − OOC − CH(OH) − CH(OH) − COO− + NH4 ) is one of the most studied. This substance is tissue equivalent and has a signal-to-noise ratio higher than that of alanine [21–24]. In the last years, the search of new materials for EPR dosimetry has payed attention to additive substances to improve the EPR sensitivity to low doses of various radiation type. The additive compounds must have suitable properties or must fulfill appropriate functions in increasing relaxation rates of free radicals produced by ionizing radiations and/or in radiation energy transfer and/or improving time stability of signal. In particular, in order to increase the relaxation rate in EPR organic compound such as lithium dithionates and lithium formates paramagnetic metal ion salts (nickel&rhodium and nickel, respectively) have been added [25, 26]. The additive nuclei are also chosen with the aim of enhancing the probability interaction of various ionizing radiation with the solid state matter. For instance, for photon beams the improvement of radiation energy transfer is achieved by adding nuclei with high atomic number Z. Indeed, the number of interacting photons and the amount of energy released in matter by them is a function of both photon energy and atomic number Z of the target elements. For the three main processes responsible for absorption of γ-rays (photoelectric absorption, Compton scattering and production of electron-positron pairs) the cross section per atom increases with the atomic number Z of the target atoms [27]. Therefore, to increase the sensitivity and the efficiency of a photon detector, atoms with high atomic number should be used [28]. However, it must be pointed out that the addition of high Z-nuclei reduce tissue equivalence and this is a drawback for application in radiation therapy for which it is preferable that the material has an atomic composition and density as close as possible to those of soft tissue [29]. For a given photon energy spectrum, the absorbed dose in compounds with high Z atomic number is different from that in soft tissue. The dose differences are larger for low energy photons. If the photon energy spectrum is someway known, it is possible to rescale measured dose in order to take into account the reduction of tissue equivalence due to the high Z-nuclei added. For thermal neutron beams the sensitivity of ESR dosimeters is quite low since the organic compounds usually chosen are constituted by nuclei with a relatively low neutron capture cross section. This involves a small energy release (and consequently a small number of free radicals) inside the pellets because a small number of neutron effectively interact inside the dosimeters. In this case it is prefered to add nuclei with a high neutron capture cross section that increase the interaction probability with neutrons. In literature works on the addition of 10 B nuclei for enhancing sensitivity of alanine to thermal neutrons have been carried out [30–33]. The heavy charged ions (Li ions and alpha particles) released after nuclear reactions induced by neutrons are high LET (linear energy transfer) particles and release a large amount of energy inside the dosimeter. Furthermore, the enrichment with the 6 Li nucleus, which gives rise to the 6 Li(n,α)3 H, has been used to render organic Li-compounds more sensitive to thermal neutron [34, 35]. In this work the research activities on the effects of gadolinium addition on the ESR response of alanine and ammonium tartrate pellets exposed to various radiation beams such as

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thermal neutrons, 60 Co γ-photons and 25 MeV protons have been reviewed. The gadolinium nucleus is mainly chosen as very good sensitizer for thermal neutron beams. In fact, gadolinium has two characteristic features which make it a valuable tool for detecting thermal neutrons: • high thermal neutron capture cross section: the effective natural Gd neutron capture cross section can be estimated to be about 50 000 barn; • the emitted particles after nuclear reaction must have high LET to release all their energy in the reaction site: the neutron capture by gadolinium triggers a complex reaction whose last products are internal-conversion electrons Auger electrons, together with emissions of soft X-ray and photon. The Auger electrons release their energy in several nanometers [36]. Moreover, gadolinium improves the sensitivity to photons because of its high atomic number (ZGd = 64). In the following the experimental results of ESR pellets are reported. Also Monte Carlo simulations aimed at getting insight on the energy deposition of the the various radiation beams into the dosimeters have been shown along with the comparison with the experimental data. These computational analysis furnishes valuable information information about the efficiency of the gadolinium in improving the sensitivity of ESR dosimeters to various radiation beams.

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2. Gadolinium interaction features with photons and neutrons Here a more detailed description of the properties of the interaction of gadolinium with indirectly ionizing radiations (e.g. photons and neutrons) is reported. In particular, the differences between gadolinium and the nuclei usually present in organic compounds are remarked. As above-mentioned, the presence of gadolinium improves the radiation energy transfer in case of photon beams because of its high atomin atomic number ZGd = 64. Indeed, the number of interacting photons and the consequent amount of energy released in matter is a function of both photon energy and atomic number Z of the target elements. The Figure 1 shows the trends of the mass energy absorption coefficients µen /̺ for various elements as a function of the photon energy. As can be seen from this plot, the probability of interaction (which is directly correlated to theµen /̺ coefficient) of photons is much larger in gadolinium than in the other low Z-elements (which are also the main elements present in soft tissue). The differences are more evident in the low energy range (below 1 MeV) than for high energies. This explains the choice of high Z nuclei for enhancing photon sensitivities of photon detectors. Another prominent feature is the presence of the absorption edges the energy range shown in figure 1. At the K shell binding energies of gadolinium (EK = 50.2 keV), the increase of the µen /̺ coefficient is a factor of about 5. They result from the fact that photoelectric absorption involving K shell electrons cannot occur if the photon energy is smaller than the K shell binding energy. L absorption edges also are seen at Egamma ∼ 7−8 keV for gadolinium. L and K absorption edges for the light elements occur at energies smaller than those shown in this graph.

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The use of Gadolinium for ESR Dosimetry

Hydrogen Carbon Nitrogen Oxygen Gadolinium

1000

H̐ΡLen Hcm2gL

269

10

0.1

0.001 0.001

0.01

0.1

1

10

E HMeVL Figure 1. Trend of the mass attenuation coefficient as a function of the incident photon energy for various

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elements [37].

The vacancy in an orbital electron shell produced after photoelectric interaction leads to the emission of characteristic X rays (of energies equal to the energy differences from outermost to innermost shells) or Auger electrons and these radiations are usually easily absorbed. On the one hand the gadolinium addition allows a better detection of γ photons improving ESR dosimeter sensitivity, on the other hand it reduce tissue equivalence of the pellets. However, the full knowledge of a photon beam permits to calculate the effective dose in Gd-added compounds. Regarding neutron interaction, gadolinium is the element with two stable isotopes (155 Gd and 157 Gd) with very high thermal neutron cross sections. Indeed, 157 Gd has the highest thermal neutron capture cross section (σth ≅ 250, 000 barn) of all stable nuclides in the Periodic Table. In particular, 155 Gd (σth ≅ 75, 000 barn) and 157 Gd have natural abundancies 0.148 and 0.156, respectively. This involves a thermal neutron cross section σth of natural gadolinium of about 50,000 barns. The comparison of the neutron cross section trends for these two Gd isotopes and for other elements (used in ESR dosimetry and not) is shown in Figure 2. It is evident that the cross section of Gd isotopes are much larger that those of the other nuclei below 0.1 eV. In the region between 1 eV and 1 keV shoes many resonance peaks and occur at neutron energies where reactions with nuclei are enhanced. In particular, the 157 Gd, when it encounters a thermal neutrons, brings about a 157 Gd(n,γ)158∗ Gd reaction which releases prompt γ photons. These photons, interacting with inner core electrons, give rise to internal conversion electrons and Auger electrons, to-

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1

Hydrogen Lithium 10 Boron 14 Nitrogen 16 Oxygen 155 Gadolinium 157 Gadolinium

1. ´ 106

6

ΣT HbarnL

10000

100

1

0.01 1. ´ 10-9

1. ´ 10-7

0.00001

0.001

0.1

10

E HMeVL

Figure 2. Trends of the neutron cross section of various nuclei. gether with soft X ray and photon emissions. A schematic representation of these processes is reported below.

157

Gd + nth −→158∗ Gd −→

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−→158 Gd + γ + 7.9 MeV ւ internal conversion electrons

(1)

ց Auger electrons

The average energy of the γ rays is ∼2.2 MeV and therefore unlikely they release their energy near the reaction site. The particles that release their energy in proximity of the gadolinium place are the internal conversion electrons and the low energy Auger electrons (whose paths have lengths of several millimiters and several nanometers, respectively ) [36]. For the sake of completeness the main reactions induced by thermal neutrons with the other nuclei which constitute the main molecules and additives used for the ESR dosimeters’preparation are here reported. • 1 H(nth ,γ)2 D reaction (σ 1 H (Enth ) ∼ 0.333 barns): in this reaction (called hydrogen capture gamma), a γ ray with an energy of 2.224 MeV is emitted, a fraction of which

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can escape from the medium: 1

•

H + nth → 2 D + γ.

(2)

14 N(n,p)14 C

reaction (σ 14 N (Enth ) ∼ 1.83 barns): the total energy released in this reaction is 0.62 MeV and is mainly carried by the proton and 0.04 MeV by 14 C. The 14 C isotope is radioactive and emits a β particle. 14

N + nth →

14

C + p.

(3)

• 6 Li(nth ,α)3 H reaction (σ 6 Li (Enth ) ∼ 940 barns): this nuclear reaction occurs when 6 Li absorbs thermal neutrons and gives rise to α particles and tritium nuclei [28]. The energies of the reaction products have been estimated as 2.73 MeV (tritium) and 2.05 MeV (α particle): 6 Li + nth → 3 H + 4 He (4) •

10 B(n,α)7 Li

reaction (σ 10 B (Enth ) ∼ 3840 barns): this reaction can be described by two parallel nuclear fission processes that occur (with different probabilities) on absorption of a thermal neutron. The excited 11 B nucleus splits producing two high energy ions, 4 He2 (α particle) and 7 Li3 [28]: 10

6%

B + nth → [11 B] −→ 4 He2 + 7 Li3 + 2.79 MeV 94% ↓ 4

(5) 7

He2 + Li3 + Eγ + 2.79 MeV

where Eγ = 0.48 MeV.

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3. EPR dosimetry In the last decades side by side with the increase of the practical application of radiation processing (such as the radiotherapy with various radiation beams — electrons, photons and, more recently, protons and neutrons —, the radiation sterilization of medical and pharmaceutical products for killing the pathogenic microorganisms, the radiation sterilization of foodstuffs for extending their shelf life) the dosimetric systems able to check and supervise the irradiation processes have been developed. Nowadays, among the different dosimetric methods for this purpose, the EPR technique shows various advantages such as the ability of providing a dose estimation with a simple and time saving procedure and the non-destructiveness of the radiation sensitive material used and therefore the possibility of preserving it for future inspection [2]. EPR dosimetry commonly uses solid organic compounds wherein the primary active particles (produced by ionizing radiations) originate free radicals and some final products of radiolysis [2]. The EPR dosimetry provides information about the absorbed dose of a medium through measuring the concentration of the paramagnetic centres produced by ionizing radiation. Up to now, there are three internationally recognized applications of the EPR technique [2]: alanine/EPR dosimetry [15–20], identification of irradiated foodstuffs containing cellulose [7] and bone material [4].

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Since the early works by Box and Freund in 1959 [10], Bradshaw et al. 1962 [11], Rotlab and Simmons in 1963 [12] and Bermann et al. in 1971 [13], the development of alanine/ESR dosimetry has reached a level that makes it competitive with classical methods of dosimetry such as thermoluminescence, chemical and ionization methods, at least in the higher dose range (above 10 Gy). Thus, they opened the possibility to use alanine as a dosimetric material. The work of Regulla and Deffner [14] has described the reliability of the EPR dosimetric system based on the microcrystalline L-α alanine delineating the procedures to be adopted for preparation, use and storage of alanine samples.

Figure 3. Schematic representation of the alanine molecule.

ESR signal Ha.u.L

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The EPR signal (see Figure 4) from X irradiated powders of alanine consists of components from at least three different radicalic species.

338.5

343.5

348.5 B HmTL

353.5

358.5

Figure 4. ESR spectrum of irradiated alanine. The main radical species is the product denoted R1 (also known as SAR, Stable Alanine Radical), formed by deamination from a protonated alanine radical anion [38–43]). The second species, R2 , is stabilized by net hydrogen abstraction from the central carbon atom, while R3 is probably another oxidation product [44–47]. The first two radical species R1 and R2 appear to occur in comparable relative amounts (55-60 and 30-35%, respectively),

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whereas the third species is a minority species (5-10%).

R1

R2

R3

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Figure 5. Radical species forms in alanine after photons irradiation. Up to now, alanine is considered a secondary reference and transfer dosimeter for high dose irradiation [2]. The alanine/EPR dosimetry has many advantages such as [2, 48]:the linearity of the EPR response from 10 up to 5×104 Gy, long term stability of the radiation induced free radicals (mainly R1 and R2 ); long shelf life and low background signal, ‘tissue-equivalence’ i.e. similarity of biological tissue in terms of radiation absorption properties, no sample treatment before EPR measurement of the signal, absence of dose rate dependence of response, sufficiently small size for use in mapping radiation dose distribution. Therefore, alanine/EPR dosimeters are very successfully used for estimation of γ-ray photons and electrons in the high dose region [1, 48]. In addition, some experiments have been realized to extend the possible applications of the alanine dosimeters for high-LET radiation such as fast neutrons, protons and various heavy charged particles [49–55]. However, large mass and volume of alanine sample are needed for precise measurements in low dose range (about 1 Gy) with consequent low spatial dose resolution. Nevertheless, as above mentioned, the ESR technique can be used to follow the entire radiotherapeutic treatment, often constituted by dose fractionation, and to provide an indication of the integrated absorbed dose. Therefore, many research laboratories have started investigations on new materials or new blends of organic and/or inorganic compounds in order to make the ESR method a realistic alternative to existing dosimetry systems, such as thermoluminescence or chemical dosimetry. In the last ten years, various strategies for finding new materials for ESR dosimeters have recently been proposed [56–58]. The criteria followed to select these materials are: a high efficiency of radiation-energy transfer, sharp spectral lines, fast relaxation rates and time stability of the radicals at room temperature [56, 57]. Among the new radiation sensitive materials, promising studies have been performed in these years on sugar [59–61], aminoacids [51, 58, 62], acetates, phosphates and lactates [56, 63], ammonium tartrate [21–24, 64–71], formates and dithionates [25, 26, 72–75], acids with sulfur [76, 77], barium sulphate [78], ferrous ammonium sulfate [79], vitamin C [80], etc. Other materials can be found in work [2]. Some of them have a sensitivity 2 - 3 times larger than alanine because of a more suitable EPR spectrum with narrow lines and small (or absent) hyperfine splitting [57]. Among the different materials tested, ammonium tartrate (AT) which has the following chemical formula is one of the most studied. Ammonium tartrate has a chemical composition similar to that of soft tissue and therefore it is almost tissue-equivalent from a dosimetric point of view [22].

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Figure 6. Schematic representation of the ammonium tartrate structure. This substance has a signal-to-noise ratio higher than that of alanine [21–24] (approximately double in its standard composition and approximately triple if the hydrogen atoms are replaced with deuterium [23]). The high sensitivity of ammonium tartrate is due to the narrow spectrum even though the radical yield is lower than that of alanine [57]. The main radical, called RTA1, produced by γ or X at room temperature, was found by Brustolon et al. [81] through nuclear double resonance (ENDOR) and electron spin echo envelope modulation (ESEEM) to be:

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Figure 7. Representation of the stable radical of ammonium tartrate. This radical shows an EPR spectrum with ESR width of ∼ 10 G, which is much narrower than that of many other irradiated organic crystals (such as alanine) (see Figure 8). The spectrum of AT is constituted by one main resolved line. Two other structures appear, symmetrically spaced at about 1.8 mT from the central line that are not relevant for dose evaluation. There is a drawback in using ammonium tartrate: the time variation of the ESR signal in the first hours after irradiations [21–24]. In particular it was found that the signal intensity of AT pellets exposed to 60 Co (50 Gy) increased by about 20% during the first 24 h after irradiation, reaching its maximum value after 6 days, and slowly decreasing afterwards [21]. This behavior suggests that more free radical species with different stability properties are produced [22], and that diffusion and recombination processes may be present. The less stable species could be found among the free radicals in the salt of the tartaric acid. Two AT radical species, obtainable from those reported in literature for the DL-tartaric acid after X irradiation, are [82–84] one formed by CO2 elimination to which an amminic group is linked (Figure 9 left side), and the radical obtained from the elimination of an amminic and an hydroxil groups (Figure 9 right side).

4. Influence of gadolinium on the ESR spectrum Before analyzing the effects of the gadolinium addition on the ESR sensitivity of the

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ESR signal Ha.u.L

The use of Gadolinium for ESR Dosimetry

344.5

346.5

348.5

350.5

352.5

B HmTL

Figure 8. ESR spectrum of irradiated ammonium tartrate.

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Figure 9. Representation of other two possible free radicals produced in ammonium tartrate. pellets exposed to various radiation beams, a study about the way the gadolinium presence influences the dependence of the ESR spectrum on the instrumental acquisition parameters of 60 Co photons irradiated pellets of alanine and ammonium tartrate has been carried out [65, 85]. All the results reported in the following sections have been obtained by adding gadolinium oxide (Gd2 O3 ) with natural isotope abundances. The spectrum of irradiated dosimeters of alanine is shown in Figure 10 (top) and is characterized by the above mentioned complex signal centered at g ∼2 (broad ∼15 mT). The ESR signal of dosimeters added with Gd2 O3 is also characterized by the presence of the ESR signal from Gd2 O3 . This signal is much broader (∼270 mT) than alanine signal with and it also centered at g ∼2 (Fig. 10 left side); furthermore, it is not dependent on dose. For the dose determination the Gd2 O3 background signal has been eliminated and the peak-to-peak amplitude hpp of the central line is commonly used as a measure of the signal intensity. Figure 10 (right side) shows the similarity of ESR spectra of samples of alanine and alanine with Gd2 O3 irradiated to 3 kGy after the baseline elimination. The spectrum of AT is constituted by one main resolved line, as above stated. Also in

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M. Marrale, M. Brai and A. Longo Figure 10.

a

ESR signal Ha.u.L

ESR signal Ha.u.L

Alanine

b

Gd2 O3 -Alanine

100

200

300

400 B HmTL

500

600

700

338.5

Wide-range ESR spectrum of a Gd2 O3 -added alanine dosimeters: (a) unirradiated; (b) γirradiated (3kGy)1 .

343.5

348.5 B HmTL

353.5

358.5

ESR spectra of the irradiated (3 kGy) alanine (top) and Gd2 O3 -alanine dosimeters after the baseline subtraction (bottom)1 . Adapted from original.

this case the large ESR Gd2 O3 signal is present, as shown in Fig. 11 (left side). Figure 11. a

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ESR signal Ha.u.L

ESR signal Ha.u.L

Ammonium tartrate

b

100

200

300

400 B HmTL

500

600

700

Wide-range ESR spectrum of a Gd2 O3 -added ammonium tartrate dosimeters: (a) unirradiated; (b) γ-irradiated (3kGy)2 .

Gd2 O3 -Ammonium tartrate

344.5

346.5

348.5

350.5

352.5

B HmTL

ESR spectra of the irradiated (3 kGy) ammonium tartrate (top) and Gd2 O3 -ammonium tartrate dosimeters after the baseline subtraction (bottom)2 .

1

Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, A. BARTOLOTTA, and M. C. D’OCA, ESR response to γ-rays of alanine pellets containing B(OH)3 or Gd2 O3 ., Appl. Radiat. Isot. 65, 435 (2007)” with permission from Elsevier. 2 Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, L. TRANCHINA, A. BARTOLOTTA, and M. C. D’OCA, ESR response to 60 Co-rays of alanine pellets using Gd2 O3 as additive., Radiat. Meas. 42, 225 (2007) ” with permission from Elsevier.

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The use of Gadolinium for ESR Dosimetry

277

As in the case of alanine (see Fig. 11 left side), the contribution of the Gd2 O3 signal can be eliminated by a linear baseline subtraction (Fig. 11 left side). After the Gd2 O3 signal elimination, also for AT the presence of gadolinium does not significantly modify the spectra pattern. In the following the analysis of the effects of gadolinium addition on ESR signal as a function of microwave power and modulation amplitude is reported. This study is aimed at finding the best recording acquisition parameters to obtain the highest S/N ratio, trying to avoid an exeessive signal distortion due to power saturation and to large modulation amplitude. Figure 12 shows the alanine peak-to-peak signal amplitude, hpp , as a function of the modulation amplitude (microwave power= 1 mW) and of microwave power (modulation amplitude=0.958 mT), on the left and right side respectively. Signal amplitude values are normalized to the maximum for the corresponding blend. Figure 13 shows the analogous trends for ammonium tartrate dosimeters. Figure 12. 0.0025

0.01

P HmWL 0.25 1

25

100

5

10

1 1

0.5 0.8

hppHa.u.L

hppHa.u.L

0.2 0.6 Alanine

0.4

0.1

0.05 Gd2 O3 -Alanine

Alanine Gd2 O3 -Alanine

0.2

0.05 0

0.5

1

1.5

2

0.1

2.5

Modulation amplitude HmTL

Signal amplitudes (hpp ) of alanine blends as functions of the modulation amplitude1 .

0.5

1

!!!! P HmW12L

Signal amplitudes (hpp ) of alanine blends as functions of microwave power1 . Adapted from original.

Figure 13. 0.0025

0.01

P HmWL 0.25 1

25

100

5

10

1

0.5

hppHa.u.L

0.8

hppHa.u.L

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

1

0.6 Ammonium tartrate

0.4

0.2

Ammonium tartrate Gd2 O3 -Ammonium tartrate

0.1

Gd2 O3 -Ammonium tartrate

0.2

0.05

0.05

0

0.5

1 1.5 Modulation amplitude HmTL

2

Signal amplitude (hpp ) of ammonium tartrate blends as functions of modulation amplitude2 .

2.5

0.1

0.5

1

!!!! P HmW12L

Signal amplitude (hpp ) of AT blends as functions of microwave power2 .

1

Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, A. BARTOLOTTA, and M. C. D’OCA, ESR response to γ-rays of alanine pellets containing B(OH)3 or Gd2 O3 ., Appl. Radiat. Isot. 65, 435 (2007)” with permission from Elsevier. 2 Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, L. TRANCHINA, A. BARTOLOTTA, and M. C. D’OCA, ESR response to 60 Co-rays of alanine pellets using Gd2 O3 as additive., Radiat. Meas. 42, 225 (2007) ” with permission from Elsevier.

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M. Marrale, M. Brai and A. Longo

For both alanine and ammonium tartrate, the trends between pure and Gd-added dosimeters are quite similar and, therefore, the presence of gadolinium is not influencing the dependece of ESR signal on microwave power and modulation amplitude.

5. Response to 60Co γ-ray photons The analyses of the effects of gadolinium on the response of ESR dosimeters exposed to 60 Co γ-rays are reported in the works [65, 85]. In both articles pellets of sensitive materials (alanine [85] and ammonium tartrate [65]) added with Gd2 O3 were realized by pressing a blend where the sensitive material and gadolinium oxide Gd2 O3 are present in equal proportion in weight. Figures 14 and 15 show the dose response of the alanine and ammonium tartrate blends 60 to Co irradiation in the 1-50 Gy range, respectively. These experimental data in the entire range were fitted with a linear function hγ = hγ0 + f γ Dγ .

(6)

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The dependencies of the responses on the dose are linear in this range, and Tables 1 and 2 list the characteristics of the regression.

Figure 14. Response curves of pure alanine and Gd2 O3 -alanine to 60 Co γ-photons1 . Adapted from original.

1

Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, A. BARTOLOTTA, and M. C. D’OCA, ESR response to γ-rays of alanine pellets containing B(OH)3 or Gd2 O3 ., Appl. Radiat. Isot. 65, 435 (2007)” with permission from Elsevier.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova

The use of Gadolinium for ESR Dosimetry Blend Alanine Gd2 O3 -alanine

Linear regression parameters hγ0 f γ (sensitivity) 0.22 ± 0.02 0.362 ± 0.004 0.47 ± 0.06 0.670 ± 0.009

279

R2

LDD (Gy)

0.99375 0.99985

2.89 0.80

Table 1. Parameters of the linear regression of the ESR signal amplitude of alanine vs absorbed dose and the lowest detectable doses1 .

20

hΓ Ha.u.L

15

10

Ammonium tartrate

5 Gd2 O3 -Ammonium tartrate

0 10

20

30

40

50

Absorbed dose in water DΓ HGyL

Figure 15. Response curves of ammonium tartrate and Gd2 O3 -ammonium tartrate to 60 Co γ-photons2

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Blend Ammonium tartrate Gd2 O3 -ammonium tartrate

Linear regression parameters hγ0 (a.u.) f γ (a.u.)

R2

LDD (Gy)

0.17 ± 0.03

0.403 ± 0.005

0.9923

2.9

0.62 ± 0.07

0.724 ± 0.009

0.9989

1.1

Table 2. Parameters of the linear regression of the ESR signal amplitude of alanine vs absorbed dose and the lowest detectable doses2 .

As can be seen from figures 14 and 15 and from tables 1 and 2, for all blends a linear response has been observed and the sensitivities (the slopes of the calibration lines) of the Gd2 O3 -added dosimeters have been found to be almost twice those of pure sensitive materials. This enhancement in sensitivity could be due to the relatively high atomic number (64) 1

Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, A. BARTOLOTTA, and M. C. D’OCA, ESR response to γ-rays of alanine pellets containing B(OH)3 or Gd2 O3 ., Appl. Radiat. Isot. 65, 435 (2007)” with permission from Elsevier. 2 Reproduced from the article ”M. BRAI, G. GENNARO, M. MARRALE, L. TRANCHINA, A. BARTOLOTTA, and M. C. D’OCA, ESR response to 60 Co-rays of alanine pellets using Gd2 O3 as additive., Radiat. Meas. 42, 225 (2007) ” with permission from Elsevier.

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M. Marrale, M. Brai and A. Longo

of the gadolinium, which increases the radiation interaction probability. Furthermore, the presence of gadolinium reduces the lowest detactable dose (LDD) (equal to the dose that produces an ESR signal equal to the mean value of the zero-dose signal plus three its standard deviations [86]), so improving the ability to detect low doses. Indeed, for alanine and ammonium tartrate the LDD values are reduced of about a factor 3 by means of gadolinium and are about 1 Gy. Moreover, the thickness of Gd2 O3 -added pellets is smaller than pure ones. This allows to achieve a better spatial dose resolution. However, the blends with gadolinium oxide are not tissue equivalent because of the high Gd content. Their use for dose measurements should therefore be limited to irradiation conditions identical or equivalent to those used in calibration or the knowledge of the photon energy is needed to correct for the difference in mass energy absorption properties.

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6. Response to neutron field Various works have been carried out about the effects of gadolinium addition on the thermal neutron sensitivity of ESR dosimeters of alanine and ammonium tartrate. In particular, the response to thermal neutrons of alanine and ammonium tartrate after the addition of gadolinium oxide (∼50% Gd2 O3 content) [66,87], the variations of the sensitivity enhancement to thermal neutrons as a function of the gadolinium amount inside the pellets [68, 69] and the Monte Carlo computations [69, 71] are reported. The first works [66, 87] have been aimed at investigating the ability to improve the sensitivity to thermal neutrons of ESR dosimeters of alanine and ammonium tartrate. For this analysis the pellets with an equal content of alanine (or ammonium tartrate) and Gd2 O3 have been used. In particular, also alanine with 10 B(OH)3 , which has been previously investigated [30–33], has been analyzed in order to have comparison with another additive nucleus used for enhancing neutron sensitivity. All dosimeters have been exposed to a mixed neutron-gamma field produced by a neutron reactor with fluences ranging from ∼ 3 × 1012 to ∼ 10 × 1012 nth cm−2 and gamma dose between 0.2 and 3.25 Gy. The gamma contribution has been eliminated by using the 60 Co calibration function of ESR dosimeters. The neutron irradiated dosimeters of alanine, alanine with boric acid and alanine with gadolinium show spectra similar each other and to those observed after gamma irradiations. Figures 16 and 17 show the response of the alanine and ammonium tartrate blends to thermal neutrons, respectively. Along with the experimental data the best fit curves according to the following linear function hn = hn0 + f n Φ, where Φ is the neutron fluence and f n is the neutron sensitivity of the blend, are reported. The results are shown in Tables 3 and 4.

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281

600 Alanine BHOHL3 -Alanine

500

Gd2 O3 -Alanine

hn Ha.u.L

400

300

200

100

0 0

10

20

30

40

Fluence H1012 nth cm-2L

Figure 16. Response curves of alanine, 10 B(OH)3 -alanine and Gd2 O3 -alanine as a function of the fluence3 .

800 Ammonium tartrate

700

Gd2 O3 -Ammonium tartrate

600

hnHa.u.L

500 400 300 200

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100 0 0

10

20

30

40

Fluence H1012 cm-2L

Figure 17. Trend of the hn amplitude of the ESR signal of dosimeters of ammonium tartrate and Gd2 O3 ammonium tartrate as a function of thermal neutron fluence. The best fit curves are also reported4 .

3

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. TRIOLO, A. BARTOLOTTA, M. C. D’OCA, and G. ROSI, Alanine blends for ESR measurements of thermal neutron uence in a mixed radiation eld, Radiat. Prot. Dosim. 126, 631 (2007) ” with permission from Oxford Press. 4 Reproduced from the article ”M. BRAI, M. MARRALE, G. GENNARO, A. BARTOLOTTA, M. C. D’OCA, and G. ROSI, Improvement of ESR dosimetry for thermal neutron beams through the addition of gadolinium, Phys. Med. Biol. 52, 5219 (2007) ” with permission from Institute Of Physics (IOP).

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282

M. Marrale, M. Brai and A. Longo Blend Alanine3 10 B(OH) -alanine3 3 Gd2 O3 -alanine4

Linear regression parameters hn0 f n (×10−13 ) −2 (6 ± 3)×10 (3.88 ± 0.04) (-2 ± 4)×10−1 (49.1 ± 0.9) (47 ± 3)×10−1 (147.9 ± 0.6)

R2 0.9976 0.9968 0.9984

LDF (1010 nth cm−2 ) 312 25 ∼1

Table 3. Results of the fitting procedure for the three blends of alanine. In the last column the LDF computed as discussed in the main text is reported.

Blend Ammonium tartrate Gd2 O3 -ammonium tartrate

Linear regression parameters hn0 f n (×10−13 )

R2

LDF (1010 nth cm−2 )

(8 ± 7)×10−2

(6.75 ± 0.17)

0.9951

189

(65 ± 7)×10−1

(178.0 ± 1.5)

0.9975

8

Table 4. Results of the fitting procedure for the two blends of ammonium tartrate. In the last column the

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lowest detactable dose (LDF) values are reported4 .

Figures 16 and 17 and Tables 3 and 4 show that after the addition of gadolinium oxide for both alanine and ammonium tartrate the dosimeters with Gd2 O3 present a remarkable sensitivity improvement (about a factor 30) with respect to the corresponding pure dosimeters. This is very interesting enhancement of ESR sensitivity and stimulates the use of these Gd-added materials for neutron dosimetry also for neutron capture therapy (NCT) applications. It must be underlined that the sensitivity of Gd2 O3 -alanine pellets is larger (about three times) than that of 10 B(OH)3 -alanine dosimeters, which in turn are ∼12 times more sensitive that pure alanine dosimeters. This can be explained by considering that the number of neutron captured is larger with Gd addition than 10 B addition since the effective thermal neutron reactions in natural Gd is about 13 times higher than in 10 B. However, the energy released in the dosimeter by Auger electrons and internal conversion electrons for each Gd neutron capture process is smaller than the energy released by the alpha particles and lithium ion produced in the 10 B neutron capture. The resulting effect of these two interaction features is a sensitivity ratio of about three. Also for dosimeters exposed to thermal neutron the detection limits have been examined. In particular, an estimation of the lowest detectable fluence (LDF) has been made (analogously to the LDD for gamma irradiations). The results of this analysis are reported in Tables 3 and 4. The lowest detectable fluences of Gd2 O3 -added dosimeters is two order of magnitude smaller that those of dosimeters without gadolinium. Furthermore, Gd2 O3 alanine has a LDF smaller than 10 B(OH)3 -alanine, which in turn has a dectection limit smaller than simple alanine. The addition of gadolinium therefore significantly improves the dosimetric properties of ESR dosimeters remarkably enhancing neutron sensitivity and considerebly reducing LDF. Both these effects are correlated to two features of neutron interaction with gadolinium: high Gd neutron capture cross section and high LET particles, 3

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. TRIOLO, A. BARTOLOTTA, M. C. D’OCA, and G. ROSI, Alanine blends for ESR measurements of thermal neutron uence in a mixed radiation eld, Radiat. Prot. Dosim. 126, 631 (2007) ” with permission from Oxford Press. 4 Reproduced from the article ”M. BRAI, M. MARRALE, G. GENNARO, A. BARTOLOTTA, M. C. D’OCA, and G. ROSI, Improvement of ESR dosimetry for thermal neutron beams through the addition of gadolinium, Phys. Med. Biol. 52, 5219 (2007) ” with permission from Institute Of Physics (IOP).

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The use of Gadolinium for ESR Dosimetry

283

produced in the nuclear reactions induced by thermal neutrons, which release the energy in the proximity of the Gd nuclei [36]. Furthermore, the possibility of realizing a dosimetric system able to discriminate the two components (photons and neutrons) of a mixed radiation field by means of Gd-added dosimeters was investigated. Since a pair of detectors with different sensitivities to photons and neutrons must be used, various dosimetric systems composed of 2 ESR dosimeters (added or not with Gd) have been analysed for the determination of neutron and photon components [66]. In particular, a blind test has been carried out on various samples. In Table 5 the results of this test are reported for various pair of dosimeters; ”A” stands for alanine, ”AT” for ammonium tartrate, ”AG” for Gd2 O3 -alanine and ”ATG” for Gd2 O3 ammonium tartrate. Dosimeter A A A AT AT

fA =

n fA γ fA

1.15 1.15 1.71 1.71

Dosimeter B AG ATG AG ATG

fB =

n fB γ fB

22.1 26.5 22.1 26.5

Φ (1012 cm−2 )

Dγ (Gy)

4.81 ± 0.14 4.7 ± 0.5 4.76 ± 0.15 4.6 ± 0.6

1.2 ± 0.4 1.3 ± 0.7 2.2 ± 1.2 2.4 ± 1.5

Table 5. Values of neutron fluence and photon dose ( ± 1 S.D.) obtained using various dosimeters pairs. In

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γ n the table, the values of the sensitivity ratio fA = fA /fA are also reported4 .

A good agreement between neutron fluence values reported in Table 5 and the nominal values of neutron fluence provided by the irradiation center are Φ = (4.80 ± 0.14)×1012 cm−2 . In particular, for two dosimeter pairs (alanine&Gd2 O3 -alanine and ammonium tartrate&Gd2 O3 -alanine), the relative uncertainty is about 3% and therefore suitable for application in the radiotherapeutic field. Gamma dose provide by the irradiation center is Dγ = 0.410 ± 0.012 Gy whereas all photon doses reported in Table 5 are consistent with the zero value. This is because this gamma dose is comparable to the detection limits of at least one dosimeter of the pair which is therefore unable to distinguish it from background signal.

6.1. Response to neutrons at various gadolinium concentrations In order to get deeper insight on the neutron sensitivity enhancement produced by the gadolinium addition studies have been performed with dosimeters at various gadolinium concentration [68, 69]. Indeed, the analysis of the ESR response of pellets of alanine and AT added with gadolinium and exposed to a mixed field (photons and thermal neutrons) is needed because, even though the neutron sensitivity increases with gadolinium content, the presence of Gd oxide inside the pellet significantly reduces the tissue equivalence. Therefore, it must be found a optimum compromise between maximization of neutron sensitivity and reduction of tissue equivalence. 4

Reproduced from the article ”M. BRAI, M. MARRALE, G. GENNARO, A. BARTOLOTTA, M. C. D’OCA, and G. ROSI, Improvement of ESR dosimetry for thermal neutron beams through the addition of gadolinium, Phys. Med. Biol. 52, 5219 (2007) ” with permission from Institute Of Physics (IOP).

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M. Marrale, M. Brai and A. Longo

284

Alanine and ammonium tartrate dosimeters with various Gd2 O3 concentrations (ranging from 0% to about 50% of the total weight of the pellets) were exposed to a mixed (n,γ) field at the neutron fluence of (18.8 ± 0.02)×1012 cm12 and the gamma dose values of (1.49 ± 0.02) Gy, respectively . In figure 18 the ESR spectra of Gd2 O3 -alanine and Gd2 O3 ammonium tartrate pellets at various gadolinium oxide concentrations are compared. The spectra were rescaled in order to have the same peak to peak amplitude and the factor by which each spectrum has been multiplied is reported on the left side. The baseline shift increasing with Gd2 O3 content inside the pellets is due to the ESR signal of gadolinium 18. This baseline is eliminated before peak-to-peak amplitude measurements. Figures 19 and 20 show the enhancement of the ESR signal amplitude due to only neutron component per alanine mass unit as a function of the gadolinium oxide content for alanine and ammonium tartrate dosimeters. Figure 18. ´ 18

Gd2 O3 mass percentage = 0%

´ 14

Gd2 O3 mass percentage = 0%

´ 2.5

Gd2 O3 mass percentage = 3%

´ 1.4

Gd2 O3 mass percentage = 3%

´ 1.2

Gd2 O3 mass percentage = 5%

´ 1.1

Gd2 O3 mass percentage = 5%

´ 1.0

Gd2 O3 mass percentage = 10%

´ 1.0

Gd2 O3 mass percentage = 10%

´ 1.0

Gd2 O3 mass percentage = 25%

´ 1.0

Gd2 O3 mass percentage = 25%

´ 1.5

´ 1.8

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Gd2 O3 mass percentage = 50%

341

345

349 B HmTL

353

357

344

Gd2 O3 mass percentage = 50%

346

348 B HmTL

350

352

ESR spectra of alanine pellets with various concentration of gadolinium oxide exposed to the mixed

ESR spectra of aamonium tartrate pellets with various concentration of gadolinium oxide exposed to

field5 .

the mixed field5 .

For low Gd2 O3 content the signal is found to be almost proportional to the gadolinium oxide amount inside the dosimeter. As the content of additive in the blend increases, the ESR signal reaches its maximum value and then decreases. In particular, a signal enhancement of more than 13 times for both alanine and ammonium tartrate is observed when the gadolinium mass percentage is about 5%. For both the organic compounds studied the 5

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. BARTOLOTTA, and M. C. D’OCA, Study of the effect of gadolinium on the ESR response of alanine and ammonium tartrate exposed to thermal neutrons., Radiat. Res. 169, 232 (2008)” with permission from Radiation Research.

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285

maximum value is reached when the mass percentage of gadolinium oxide is about 25% of the active material inside the dosimeter. The signal is enhanced about 30 times for alanine dosimeters and about 20 times for ammonium tartrate dosimeters. The trends of the ESR peak-to-peak amplitude, which present an increase up to a maximum value and then a decrease, can be explained by considering that on one hand the number of very sensitive targets per unit volume and the number of free radicals produced increase with gadolinium content; on the other hand, since all dosimeters have the same mass, an increase of gadolinium oxide mass involves a reduction of the amount of the sensitive compound (either alanine or ammonium tartrate) inside the pellets. Therefore, even though for high gadolinium concentrations the number of target is huge, the sensitivity of the pellets decreases because the total number of molecules able to produce free radicals is reduced, and the ESR signal decreases as a consequence. ALANINE 1 0.9 0.8 R ' n Ha.u.L

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

10

20 30 40 Gd2O3 mass percentage H%L

50

Figure 19. Trend of the ESR signal, due to the only neutron component for the mixed field, of Gd2 O3 -alanine Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

dosimeters as a function of gadolinium oxide content5 .

In order to evaluate the effects of the gadolinium presence on the photon tissue equivalence for various gadoliniumconcentrations an analysis of the effective photon mass  µen (E) of each blend has been carried out. The energy absorption coefficient ̺ ef f   µen (E) parameters, calculated as the weighted average values of the mass energy ̺ ef f   µen (E) of the elements constituting the blend and divided absorption coefficient ̺ elem   µen (E) of the soft tissue by the value of mass energy absorption coefficient ̺ sof t tissue reported by ICRU [29], at various concentrations of Gd2 O3 for alanine and ammonium 5

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. BARTOLOTTA, and M. C. D’OCA, Study of the effect of gadolinium on the ESR response of alanine and ammonium tartrate exposed to thermal neutrons., Radiat. Res. 169, 232 (2008)” with permission from Radiation Research.

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286

tartrate blends as a function of the photon energy are shown in figures 6.1. and 6.1., respectively. AMMONIUM TARTRATE 1 0.9 0.8 R ' n Ha.u.L

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

10

20 30 Gd2O3 mass percentage H%L

40

50

Figure 20. Trend of the ESR signal, due to the only neutron component for the mixed field, of Gd2 O3 ammonium tartrate dosimeters as a function of gadolinium oxide content5 .

ALANINE

50 Gd2 O3 mass percentage

50% 25% 10% 5% 3% 0%

HΜenΡLeff HΜenΡLsoft tissue

20

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

10 5

2 1

0.01

0.05

0.1

0.5 E HMeVL

1

5

10

Figure 21. Ratio of the mass energy absorption coefficient of the various blend constituted by alanine and gadolinium oxide to the mass energy absorption coefficient of the soft tissue as a function of the photon energy5 .

5

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. BARTOLOTTA, and M. C. D’OCA, Study of the effect of gadolinium on the ESR response of alanine and ammonium tartrate exposed to thermal neutrons., Radiat. Res. 169, 232 (2008)” with permission from Radiation Research.

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The use of Gadolinium for ESR Dosimetry

287

AMMONIUM TARTRATE

Gd2 O3 mass percentage

HΜenΡLeff HΜenΡLsoft tissue

100

50% 25% 10% 5% 3% 0%

50 20 10 5 2 1

0.01

0.05

0.1

0.5

1

5

10

E HMeVL

Figure 22. Ratio of the mass energy absorption coefficient of the various blend constituted by ammonium tartrate and gadolinium oxide to the mass energy absorption coefficient of the soft tissue as a function of the photon energy5 .

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

From these figures, it is evident that for photon energies above 1 MeV, the addition of the gadolinium does not modify significantly the response of the various blends to the photon beams, whereas for energies below 1 MeV the gadolinium presence largely influences the behavior of these dosimeters to the photon beams. Furthermore, the K absorption edges of the gadolinium are evident in the trends of Gd2 O3 -added pellets. The differences of the trends become less evident with decreasing gadolinium concentration. For low gadolinium content (3% and 5%) the mass energy absorption coefficient at low energy is only a few times larger than in dosimeters without gadolinium. Consequently, for these concentrations the tissue equivalence is not excessively reduced and a large neutron sensitivity (about a factor 13) increase can be achieved with a low Gd2 O3 content (e.g. 5%). Consequently, in order to realize a tissue equivalent ESR dosimeter with improved sensitivity to thermal neutrons, low concentration of gadolinium oxide (of the order of 5% of the total mass of the dosimeter) must be chosen.

6.2. Monte Carlo simulation The investigation about the enhacement produced by gadolinium addition is also aided by computational analyses. In particular, Monte Carlo simulations of the energy released by ionizing radiation in matter have been performed in order to give a calculated estimate of the neutron sensitivity improvement with Gd [69, 71]. The comparison of experimental results with MC simulations can provide information about the ability of the Monte Carlo technique to describe and eventually to predict the ESR response of ESR dosimeters with and without additive after the exposure to neutrons. The Monte Carlo simulations have been carried out by means of N-Particle-MCNP5 [88] radiation transport code. In the case of neutron irradiation of Gd2 O3 -alanine and Gd2 O3 -ammonium tartrate pellets with various gadolinium oxide concentrations, the ir5

Reproduced from the article ”M. MARRALE, M. BRAI, G. GENNARO, A. BARTOLOTTA, and M. C. D’OCA, Study of the effect of gadolinium on the ESR response of alanine and ammonium tartrate exposed to thermal neutrons., Radiat. Res. 169, 232 (2008)” with permission from Radiation Research.

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M. Marrale, M. Brai and A. Longo

radiation setup and neutron source geometry used for simulations is for Figure 23. The aim of this computation analysis is to accomplish information about the average amount of energy deposited per unit mass of the sensitive material.

Air Water Sensitive material Gadolinium oxide

Z-axis

Figure 23. Example of the irradiation and target geometry used for Monte Carlo simulation used in the case

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of single gadolinium layer. The beam direction is from top to bottom6 .

The system geometry has axial simmetry and conseqsuently the neutron source, the pellet and the pellet holder have cylindrical shapes and are coaxial (1 cm diameter) with different thicknesses. In particular, neutron source has negligible thickness. The beam in this case consist of 90% thermal and 10% epithermal and fast neutron component. The pellet parallel layers of various materials (sensitive material and gadolinium oxide) are supposed to be altenate. The thickness of the gadolinium oxide layers is set to be equal to the average size of gadolinium oxide microcrystals in the mixture (∼ 100 µm). The number of gadolinium layers increases with gadolinium content. The energy released per unit mass inside sensitive material is also due to the secondary particles (mainly Auger electrons and internal conversion electrons) which, even though produced in the Gd2 O3 layer, are able to deliver their energy inside the adjacent alanine layers. Plastic dosimeter holder has been simulated as composed of water. Also air layers have been taken into account in the irradiation setup in order to reproduce as accurately as possible the real irradiation process. The energy per mass unit in alanine or ammonium tartrate layers has been compared with the experimental ESR data. The comparisons of experimental and simulation results is reported in figure 24 and 25 as function of gadolinium oxide percentage content for alanine and ammonium tartrate dosimeters, respectively. 6 Reproduced from the article ”M. MARRALE, G. GENNARO, M. BRAI, S. BASILE, A. BARTOLOTTA, and M. C. D’OCA, Exposure of Gd2 O3 -alanine and Gd2 O3 -ammonium tartrate ESR dosimeters to thermal neutrons: experiments and Monte Carlo simulations. Radiat. Meas. 43, 471 (2008)” with permission from Elsevier.

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ALANINE

Normalized values Ha.u.L

1 0.8 0.6 Experimental data

0.4

Simulation

0.2

0

10

20

30

40

50

Gd2O3 mass percentage inside the dosimeter H%L

Figure 24. Experimental data (normalized to their maximum value) and Monte Carlo simulation for alanine exposed to neutrons6 .

AMMONIUM TARTRATE

Normalized values Ha.u.L

1 0.8 0.6 Experimental data

0.4

Simulation

0.2

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0

10

20

30

40

50

Gd2O3 mass percentage inside the dosimeter H%L

Figure 25. Experimental data (normalized to their maximum value) and Monte Carlo simulation for ammonium tartrate exposed to neutrons6 .

As can be seen from both figure, a good agreement is achieved, especially in the range of low gadolinium content. This is because a proportionality between ESR signal and amount of energy released inside the dosimeters subsists. For high gadolinium concentrations (e.g. ∼ 50%) the divergences between simulated and experimental values could be attributed to saturation or recombination effects in free radicals of the sensitive materials. Therefore, the above mentioned proportionality is not more valid and the number of free radicals produced is not proportional to the energy released inside alanine or ammonium tartrate. This 6 Reproduced from the article ”M. MARRALE, G. GENNARO, M. BRAI, S. BASILE, A. BARTOLOTTA, and M. C. D’OCA, Exposure of Gd2 O3 -alanine and Gd2 O3 -ammonium tartrate ESR dosimeters to thermal neutrons: experiments and Monte Carlo simulations. Radiat. Meas. 43, 471 (2008)” with permission from Elsevier.

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leads to a reduction of the ESR signal per unit mass with increasing gadolinium content inside the pellet. Since then Monte Carlo simulation does not account for these effects, the computational values do not agree with experimental ones. However, the Monte Carlo simulation are found to be able to quite accurately describe the ESR response of these organic compounds after the addition of suitable nuclei and therefore it could be used for predicting the enhancement of neutron sensitivity which could be achieved after the addition of gadolinium in case of different irradiation setups and different neutron spectra. This has been done in the work [71] where alanine and ammonium tartrate dosimeters added with gadolinium oxide are supposed to be exposed to neutron beams with composite energy spectra and under different irradiation setups. One of the aims of this work is to study the response of Gd2 O3 -added alanine and ammonium tartrate to neutron beams at various depths from the upper surface of dosimeter pellet. This was taken into account in the Monte Carlo simulation geometry by varying the thickness of the water layer above the dosimeter. These thickeness values are 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 10.0 cm. Three neutron spectra with different neutron energy distributions (one mainly made up of thermal neutrons, one mainly made up of epithermal neutrons, and one mainly made up of fast neutrons) have been employed (see Table 6). Energy range (eV) 0.0—0.1 0.1—0.4 0.4—104 104 —106

Spectrum 1 (%) 70 22 7 1

Spectrum 2 (%) 1 22 70 7

Spectrum 3 (%) 1 7 22 70

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Table 6. Energy neutron spectra7 . Figures 26 show the energy released per alanine mass unit for various thicknesses of the water layer above the dosimeter at three different neutron energy spectra (”Spectrum 1”, ”Spectrum 2”, and ”Spectrum 3” from top left to bottom right). As can be seen from Figure 26 (top left), the maximum absorbed dose (which is proportional to the energy released per mass unit in alanine) increases more than 20-fold. The sensitivity enhancement is larger for low gadolinium concentrations than for high ones. However, as above mentioned, only the values computed at low gadolinium concentrations (below 30-40% in weight) well agree with experimental data and these results can be considered for predicting the response enhancement for this neutron spectrum. The response of dosimeters at various dephts from the surface have been performed by choosing various thicknesses of the water layer above the pellet. For all neutron energy spectra the energy released decreases with increasing the thickness of the water layer as this attenuates the beam intensites. The presence of gadolinium involves a very high neutron sensitivity improvemnet for thermal neutron beams, whereas the enhancement is lower for 7

Reproduced from the article ”M. MARRALE, S. BASILE, M. BRAI, and A. LONGO, Monte Carlo simulation of the response of ESR dosimeters added with gadolinium exposed to thermal, epithermal and fast neutrons. App. Radiat. Isot. 67, S186 (2009)” with permission from Elsevier.

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Figure 26. Energy per unit mass released inside the alanine layers as a function of the gadolinium concentration for various thicknesses of the upper water layer. The neutron spectrum is mainly composed of: thermal Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

neutrons (top left), epithermal neutrons (top right), and fast neutrons (bottom left) . In each figure from top to bottom thicknesses are: 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0,and 10.0 cm7 .

epithermal and much lower for fast neutron beams. Indeed, the gadolinium is very sensitive to thermal and epithermal neutrons (as can be seen from figure 2) but it unlikely interacts with fast neutrons. This brings about a independence of the enhancement of fast neutron sensitivity from the gadolinium concentration. Therefore, gadolinium is not effective as sensitizer for fast neutron beams.

7

Reproduced from the article ”M. MARRALE, S. BASILE, M. BRAI, and A. LONGO, Monte Carlo simulation of the response of ESR dosimeters added with gadolinium exposed to thermal, epithermal and fast neutrons. App. Radiat. Isot. 67, S186 (2009)” with permission from Elsevier.

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7. Response to protons at various gadolinium concentrations In order to investigate the ability of the gadolinium to improve the sensitivity of the ESR dosimeters to various radiation beams, the signal of pellets exposed to 25 MeV protons has been analysed. For the analysis of the ESR response, alanine dosimeters with various concentration of gadolinium have been exposed to a proton beam at the Laboratori Nazionali del Sud (INFN) Catania. Figure 27 shows the dose response of Gd2 O3 -alanine pellets with four different concentrations of gadolinium oxide exposed to protons in the 1-35 Gy dose range. The error bars correspond to one standard deviation. These experimental data for all trends in the entire range were fitted with a linear function hprotons = hprotons 0 + f protons Dprotons .

(7)

The dependences of the responses on the dose are linear in this range, and Table 7 lists the characteristics of the regressions.

25 MeV proton irradiation 0% Gd

50

5% Gd

40

10% Gd

hpp Ha.u.L

30% Gd

30

20

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10

0 5

10

15 20 Absorbed dose in water D HGyL

25

30

Figure 27. Proton dose response curves for Gd2 O3 -alanine at four gadolinium oxide concentrations in the range 1-35 Gy.

Also in this case the LDD values following the procedure above described for 60 Co γ photons irradiations have been calculated. Figure 27 and Table 7 show that with increasing the gadolinium content inside the pellets the sensitivities of the dosimeters do not undergo improvements, but even a reduction of the ESR response is observed as the additive amount inside pellets increases. With the aim of better comprehending this result a simulation of the energy released in matter by a proton beam has been performed. For this simulation the TRIM (TRansport

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The use of Gadolinium for ESR Dosimetry Gd2 O3 content 0% 5% 10 % 30 %

R2

Linear regression parameters hprotons 0 f protons (sensitivity) 4.1 ± 0.9 1.40 ± 0.09 2±2 1.48 ± 0.15 5.1 ± 0.4 1.15 ± 0.04 6.8 ± 0.8 0.82 ± 0.07

0.97105 0.92884 0.99686 0.87521

293 LDD (Gy) 4.2 4.0 3.8 5.5

Table 7. Linear regression parameters ( ± 1. S.D.) of the dependencies of the Gd2 O3 -alanine dosimeters ESR signal amplitude on the proton dose and the lowest detectable doses.

of Ions in Matter) code has been used [89]. In this simulation software the user have to define accurately the composition of the target and the properties of the beam to obtain information on the energy released along the path not on total energy released inside the pellets. However, by summing the contributions of the energy released along the path by the various simulated particles it is possible to achieve the needed information on the total energy released inside the dosimeter. Figure 28 shows the experimental sensitivities compared to the simulated values of the energy released inside the dosimeters. In order to carry out this comparison the experimental and simulated values relative to 0% gadolinium concentration have been set equal to 1 and in agreement with this setting the other values have been rescaled. 25 MeV proton irradiation 50 Gy

1.75

Experimental sensitivity

1.5

Simulation

Intensity Ha.u.L

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1.25 1

0.75 0.5 0.25

0

5 10 15 20 25 Gd2O3 mass percentage inside the dosimeter H%L

30

Figure 28. Comparison of the proton sensitivities of alanine dosimeters with different gadolinium oxide concentrations.

As can be seen from this figure 28, the simulated energy released by protons very slightly depends on the amount of gadolinium inside the dosimeter. Therefore, according to these simulations it should be expected that the sensitivity would not change with gadolinium content. The reduction of sensitivity observed in experimental data is not re-

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lated to differences in the total energy released but should be correlated to other physical (such as reaction of protons with Gd) and/or chemical (migration of radicals also in the Gd2 O3 molecule) processes. Further studies should be performed to deeply investigate the reasons of this behaviour. However, the experimental data suggest that the addition of the gadolinium is not useful for enhancing the sensitivity of alanine to proton beam and therefore it must not be used for this kind of radiation.

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8. Conclusions In summary, the addition of gadolinium in ESR dosimeters of alanine and ammonium tartrate involves significant variations in sensitivity to photons and neutrons. In particular, for 60 Co photon beams a sensitivity increment (about a factor 2) and a reduction of the lowest detectable dose (LDD) have been observed. Moreover, the thickness of Gd2 O3 -added pellets is smaller (0.7 times) than pure ones, permitting to achieve a better spatial dose resolution. All these results could be correlated with the high atomic number of gadolinium (ZGd = 64). However, the gadolinium presence reduce tissue equivalence, and its use for dose measurements should therefore be limited to irradiation conditions identical or equivalent to those used in calibration. Regarding the neutron irradiation, the addition of gadolinium in ESR dosemeters of alanine and AT promisingly improves the dosimetric sensitivities to neutrons. This result is due to the high gadolinium cross section for neutron capture, that greatly increases the probability of thermal neutrons’ interaction, and also to the secondary particles and, in particular, the Auger electrons that release their energy entirely in the dosimeter. Furthermore, the gadolinium reduces the lowest detectable fluence. Since the gadolinium presence involves the reduction in or even the loss of tissue equivalence, a compromise should be found between maximization of neutron sensitivity and reduction of tissue equivalence. The results show that the ESR dosimetry by means of gadolinium could be applied for dosimetry in mixed (n,γ) fields, also for those employed in neutron capture therapy (NCT). Furthermore, Monte Carlo simulation reveal itself a valuable tool for describing the trend of the experimental data and for predicting the response enhancement achievable with use of suitable additive. The survey of the response of ESR pellets added with gadolinium exposed to neutrons beams could be completed by collecting data on Gd2 O3 blends irradiated with epithermal neutrons (usually chosen for NCT treatments of in-depth tumors — the neutrons thermalize in passing through the first tissue layers and afterwards interact with 10 B or 157 Gd in the cancer cells) and fast neutrons. Other nuclei and/or sensitive compounds (other than alanine and AT) could be used for further enhancing the sensitivity to neutron beam and to improve the ability of distinguishing the two components (neutrons and photons) in a mixed (n,γ) field. Furthermore, the response of Gd2 O3 -alanine dosimeters exposed to 25 MeV protons shows that no improvements have been involved after the gadolinium addition. To increase the knowledge on the effects of gadolinium on the sensitivity of ESR dosimetry compounds, also pellets added with gadolinium could be exposed to other radiation beams such as light ions, heavy ions, low energy X-ray, etc.

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Acknowledgments The research described in this paper was supported by the ”Universit`a di Palermo”, by the Gruppo V ”Instituto Nazionale di Fisica Nucleare” (INFN) and by Unit`a CNISM Palermo.

References [1] Regulla D. F. Appl. Radiat. Isot., 62:117–127, 2005. [2] Gancheva V. Yordanov N.D. Recent development of epr dosimetry. In EPR of free radicals in solids. Edited by Lund A., Shiotani M., 2003. [3] Ikeya M., Sumitomo H., Yamanaka C., Lloyd D.C., and Edwards A.A. Appl. Radiat. Isot., pages 1–5, 1996. [4] CEN Protocol EN 1786. Detection of irradiated food containing bone: analysis by electron paramagnetic resonance., 1997. [5] M. Desrosiers. Nature, 345:485, 1990. [6] Parlato A., Calderaro E., Bartolotta A., D’Oca M. C., Brai M., Marrale M., and Tranchina L. Radiat. Phys. Chem., 76:1466–1469, 2007. [7] CEN Protocol EN 1787. Determination of irradiated food containing cellulose: analysis by epr., 1997. [8] Skinner A.R. Appl. Radiat. Isot., 52:1311–1316, 2000. [9] Skinner A.F., Blackwell B.A.B., Chasteen N.D., and P. Brassard. Intern. Adv. ESR Appl., 18:77–82, 2002.

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[10] Box H.C. and Freund H.G. Nucleonics, 17:66–76, 1959. [11] Bradshaw W. W., Cadena D. G., Crawford E. W., and Spetzler H. A. Radiat. Res., 17:11–21, 1962. [12] Rotlab J. and Simmons J.A. Phys. Med. Biol., pages 489–497, 1963. [13] Bermann F., DeChoudens H., and Descours S. Application a` dosimetrie de la mesure par resonance paramagn´etique e´ lectronique des radicaus libre cr´ee´ s dans les acides amines. In Advances in Physical and Biological Radiation Detectors, STI/PUB/269 (Vienna: IAEA), pages 311–325. 1971. [14] Regulla D. F. and Deffner U. Int J. Appl. Radiat. Isot., 33:1101–1114, 1982. [15] Mehta K. Report of the second research co-ordination meeting (rcm) for the coordination research project (crp e2 40 06) on characterisation and evaluation of highdose dosimetry techniques for quality assurance in radiation prosessing. Technical report, SSDL Newsletter No. 39, IAEA, Vienna, 1998.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova

296

M. Marrale, M. Brai and A. Longo

[16] Mehta K. High-dose dosimetry programme of the iaea. In Techniques for high dose dosimetry in industry, agriculture and medicine, Extended Synopses of Symposium held in Vienna, November 2-5 1998, volume paper IAEA-SM-356/R2, 1998. [17] Mehta K. and Girzikowski R. Appl. Radiat. Isot., 47:1189, 1996. [18] Mehta K. and Girzikowski R. Iaea reference dosimeter: Alanine-esr. In Techniques for high dose dosimetry in industry, agriculture and medicine, Proc. Symp., IAEATECDOC-1070, page 299, 1999. [19] M. Desrosiers at al. Alanine dosimetry at the nist. In Book of Abstracts of Intl. Conf. Biodosimetry and 5th Intl. Sym. ESR Dosimetry and Applications, Moscow/Obninsk, Russia, page 149, June 22 1998. [20] Sharpe H. G. and Sephton J. P. Alanine dosimetry at npl - the development of a mailed reference dosimetry service at radiotherapy dose level. In Techniques for high dose dosimetry in industry, agriculture and medicine, Proc. Symp., IAEA-TECDOC-1070, page 299, 1999. [21] Bartolotta A., D’Oca M.C., Brai M., Caputo V., De Caro V., and Giannola L.I. Phys. Med. Biol., 46:461–471, 2001. [22] Olsson S., Bagherian S., Lund A., Carlsson G. A., and Lund E. Appl. Radiat. Isot., 50:955–965, 1999. [23] Olsson S., Lund E., and Lund A. Appl. Radiat. Isot., 52:1235–1241, 2000. [24] Yordanov N. D. and Gancheva V. Radiat. Phys. Chem., 69:249–256, 2004.

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[25] Gustafsson H., Danilczuk M., Sastry M. D., Lund A., and Lund E. Spectrochim. Acta Part A, 62:615–620, 2005. [26] Danilczuk M., Gustafsson H., Sastry M. D., and Lund E. Spectrochim. Acta Part A, 67:1370–1373, 2007. [27] Kaplan I. Nuclear Physics. Addison Wesley Publishing Company, Inc., 1963. [28] Knoll F.G. Radiation detection and measurement. John Wiley and Sons, Inc, 1978. [29] International Commission on Radiation Units and measurements. Tissue substitutes in radiation dosimetry and mesurements. Technical report, ICRU reports, 1989. [30] Bartolotta A., D’Oca M. C., Lo Giudice B., Brai M., Borio R., Forini N., Salvatori P., and Manera S. Radiat. Prot. Dosim., 110:627–630, 2004. [31] Galindo S. and Ure˜na-N´un˜ ez F. Radiat. Res., 133:335–337, 1993. [32] Ure˜na-N´un˜ ez F., Galindo S., and Azor´ın J. Appl. Radiat. Isot., 49:1657–1664, 1998. [33] Ure˜na-N´un˜ ez F., Galindo S., and Azor´ın J. Appl. Radiat. Isot., 50:763–767, 1999.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova

The use of Gadolinium for ESR Dosimetry

297

[34] Herrera E., Ure˜na-N´un˜ ez F., and Delf´ın Loya A. Appl. Radiat. Isot., 63:241–246, 2005. [35] Lund E., Gustafsson H., Danilczuk M., Sastry M. D., and Lund A. Spectrochim. Acta Part A, 60:1319–1326, 2004. [36] Salt C., Lennox A. J., Takagaki M., Maguire J., and Hosmanea S. Russ. Chem. Bull., 53:1871–1888, 2004. [37] http://physics.nist.gov/PhysRefData/XrayMassCoef/tab3.html. [38] Miyagawa I. and Gordy W. J. Chem. Phys., 32:255–263, 1960. [39] Morton J.R. and Horsefield A. J. Chem. Phys., 35:1142–1143, 1961. [40] Miyagawa I. and Itoh K. J. Chem. Phys., 36:2157–2163, 1962. [41] Sinclair J. and Hanna M.W. J. Chem. Phys., 50:2125–2129, 1969. [42] Friday E. and Miyagawa I. J. Chem. Phys., 55:3589–3594, 1971. [43] Kuroda S. and Miyagawa I. J. Chem. Phys., 76:3933–3944, 1982. [44] Sagstuen E., Hole E.O., Huagedal S.R., and Nelson W.H. J.Phys.Chem., 101:9763– 9772, 1997. [45] Heydari M.Z., Malinen E., Hole E.O., , and Sagstuen E. J.Phys.Chem., 106:8971– 8977, 2002. [46] Malinen E., Heydari M.Z., Sagstuen E., and Hole E.O. Radiat. Res., 159:23–32, 2003.

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[47] Malinen E., Hult E.A., Hole E.O., and Sagstuen E. Radiat. Res., 159:149–153, 2003. [48] McLaughlin W. L. Radiat. Prot. Dos., 47:255–262, 1993. [49] Hansen J. W., Olsen K. J., and Wille M. Radiat. Prot. Dosim., 19:43, 1987. [50] Katsumura Y., Tabata Y., Seguchi T., Hayakawa N., and Tamura N. Radiat. Phys. Chem., 26:211, 1985. [51] Simmons J. A. Radiat. Res., 111:374–377, 1987. [52] Onori S., D’Errico F., De Angelis, Egger E., Fattibene P., and Janovsky I. Med. Phys., 24(3):447–453, 1997. [53] Wielopolski L. and Ciesielski B. Radiat. Res., 140:105–111, 1994. [54] Ciesielski B., Stuglik Z., and Wielopolski L. Radiat. Res., 150:469–474, 1998. [55] Waligorski M. P. R., Danialy G., Loh K.S., and Katz R. Appl. Radiat. Isot., 40:923– 933, 1989.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova

298

M. Marrale, M. Brai and A. Longo

[56] Ikeya M., Hassan G. M., Sasaoka H., Kinoshita Y., Takaki S., and Yamanaka C. Appl. Radiat. Isot., 52:1209–1215, 2000. [57] Lund A., Olsson S., Bonora M., Lund. E., and Gustafsson H. Spectrochim. Acta Part A, 58:1301–1311, 2002. [58] Bartolotta A., Brai M., Caputo V., De Caro V., Giannola L. I., and Teri G. Rad. Prot. Dosim., 84:293–296, 1999. [59] Nakajima T. Health. Phys., 55:951, 1988. [60] Yordanov N. D. and Karakirova Y. Radiat. Meas., 42:347–351, 2007. [61] Yordanov N. D. and Karakirova Y. Radiat. Meas., 42:121–122, 2007. [62] Gancheva V., Sagstuen E., and Yordanov N. D. Radiat. Phys. Chem., 75:329–335, 2006. [63] Hassan G.M. and Ikeya M. Appl. Radiat. Isot., 52:1247–1254, 2000. [64] Marrale M., Bartolotta A., Brai M., Triolo A., and D’Oca M.C. Radiat. Res., 166:802– 809, 2006. [65] Brai M., Gennaro G., Marrale M., Tranchina L., Bartolotta A., and D’Oca M.C. Radiat. Meas., 42:225–231, 2007. [66] Brai M., Marrale M., Gennaro G., Bartolotta A., D’Oca M. C., and Rosi G. Phys. Med. Biol., 52:5219–5230, 2007.

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[67] Marrale M., Brai M., Gennaro G., Triolo A., and Bartolotta A. Radiat. Meas., 42:1217–1221, 2007. [68] Marrale M., Brai M., Gennaro G., Bartolotta A., and D’Oca M.C. Radiat. Res., 169:232–239, 2008. [69] Marrale M., Gennaro G., Brai M., Basile S., Bartolotta A., and D’Oca M. C. Radiat. Meas., 43:471–475, 2008. [70] Marrale M., Brai M., Barbon A., and Brustolon M. Radiat. Res., 171:349–359, 2009. [71] Marrale M., Basile S., Brai M., and Longo A. App. Radiat. Isot., 67:S186–S189, 2009. [72] Vestad T. A., Malinen E., Lund A., Hole E. O., and Sagstuen E. Appl. Radiat. Isot., 59:181–188, 2003. [73] Lund E., Gustafsson H., Danilczuk M., Sastry M.D., Lund A., Vestad T.A., Malinen E., Hole E.O., and Sagstuen E. Appl. Radiat. Isot., 62:317–324, 2005. [74] Vestad T.A., Malinen E., Olsen D. R., Hole E.O., and Sagstuen E. Phys. Med. Biol., 49:4701–4715, 2004.

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova

The use of Gadolinium for ESR Dosimetry

299

[75] Malinen E., Waldeland E., Hole E.O., and Sagstuen E. Phys. Med. Biol., 52:4361– 4369, 2007. [76] Maghraby A. and Tarek E. Radiat. Meas., 41:170–176, 2006. [77] Maghraby A. Nucl. Instrum. Meth. B., 262:46–50, 2007. [78] Sharaf M. A. and Hassan G. M. Nucl. Instrum. Meth. B., 225:521–527, 2004. [79] Juarez-Calder´on J. M., Negr´on-Mendoza A., and S. Ramos-Bernal. Radiat. Phys. Chem., 76:1829–1832, 2007. [80] Sato H. and Ikeya M. Appl. Radiat. Isot., 62:337–341, 2005. [81] Brustolon M., Maniero A.L., Jovine S., and Segre U. Res. Chem. Intermed., 22:359– 368, 1996. [82] Moulton G.C. and Cernansky B. J. Chem. Phys., 53(8):3022–3025, 1970. [83] Moulton G.C. and McDearmon G. J. Chem. Phys., 72(3):1665–1668, 1980. [84] Samskog P.O., Nilsson G., and Lund A. J. Chem. Phys., 68(11):4986–4991, 1978. [85] Brai M., Gennaro G., Marrale M., Bartolotta A., and D’Oca M.C. Appl. Radiat. Isot., 64:435–439, 2007. [86] Bartolotta A., Fattibene P., Onori S., Pantaloni M., and Potetti F. Appl. Radiat. Isot., 44:13–17, 1993. [87] Marrale M., Brai M., Gennaro G., Triolo A., Bartolotta A., D’Oca M.C., and Rosi G. Radiat. Prot. Dosim., 126:631–635, 2007.

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[88] Briesmeister J.F. (Ed.). Los alamos national laboratory report la-13709-m. Technical report, Los Alamos National Laboratory, 2000. [89] Biersack J. P. Nucl. Instr. and Meth. B, 182/183:199, 1981.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.301-316 © 2010 Nova Science Publishers, Inc.

Chapter 9

GADOLINIUM AS AN ADDITIVE TO MAGNESIUM ALLOYS AND ITS ROLE IN ENVIRONMENTAL ISSUES Masaki Sumida and Satoshi Kajino National Institute of Advanced Industrial Science and Technology Advanced Manufacturing Research Institute 1-2-1 Namiki, Tsukuba, Ibaraki 305-8564, Japan

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ABSTRACT In this chapter, the effects of the addition of gadolinium (Gd) on the material properties of magnesium (Mg) alloys are discussed. Mg alloys are widely utilized in industrial products as structural components for automobiles, aircraft and electronics due to their lightweight characteristics. However, new Mg alloys with integrated mechanical, thermal and other properties are required to expand the field of application. Here, solidified samples with nominal composition of AZ91D - 0 to 10 mass%Gd were prepared via a precision casting technique, with AZ91D being the most widely used alloy in the casting industry. Characterization of the samples identified that the Gd addition improves the solidified microstructure and tensile properties of AZ91D. By 10mass%Gd, the ultimate tensile strength and elongation were increased by 16% and 143%, respectively, while the 0.2% yield strength decreased by 6%. These results are explained in relation to the solidified microstructure. The combustion behavior during heating at 10°C/min in an air atmosphere was also investigated. The ignition temperature (Tig) was measured by direct observation for samples with a different amount of Gd addition. For AZ91D, Tig=703°C was obtained, whereas a minimum temperature of T ig=626°C was found for AZ91D-15mass%Gd and a temperature of T ig=798°C for AZ91D-25mass%Gd. These experimental results indicate that Gd is a beneficial additive for integration of the AZ91D and possibly other Mg alloys. Firstly, the current research on the effects of addition of Gd along with other conventional alloying elements to Mg alloys is reviewed before describing the results of the present work. Finally, the importance and potential benefit of Gd for development of new high-performance Mg alloys, and their possible contribution to environmental issues are discussed.

Keywords: Gadolinium, Magnesium alloy, New alloy design, Environmental issues. Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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1. INTRODUCTION 1.1. New Magnesium Alloy Design by Alloying

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In the last decades, gadolinium (Gd) and other rare earth (RE) metals have attracted a huge amount of attention from materials scientists due to their excellent benefits as additional elements to magnesium (Mg) alloys [1]. In this chapter, the application of Gd as an additive to improve the material properties of Mg alloys is described, and also its potential role in contributing to environmental issues is discussed. When Gd is added to Mg, Mg-Al, Mg-Zn and other Mg alloys, the mechanical, thermal, and other material properties are enhanced even when added in small amounts. In the recent years, much scientific and technical research has been carried out on such alloys. The density of pure Mg is 1.74g/cm3, which is the lowest density among common industrial metallic materials including Fe (7.87 g/cm3), Cu (8.92 g/cm3), Al (2.70 g/cm3) and Ti (4.51 g/cm3) alloys. Based on their specific characteristics of lightness and strength, Mg alloys have been used increasingly in industrial applications, for example, as casings, wheels, seat-frames and other structural components in automobiles. In terms of power train applications, creep resistance characteristics above 150°C are required. If such constraints can be realized, these alloys could offer new materials for components to replace conventional steels, Al alloys and organic plastics. However, the mechanical, thermal and other properties have to be improved and sufficiently examined to satisfy these requirements. Much progress is being made, with new Mg alloys with improved performance being developed and published one after another. Examples include their use in the outer body of mobile telephones, notebook-type computers, humanoid robots, numerical cameras, videos and other electronic products, and as structural parts in medical devices and biomaterials.

Figure 1. Schematic equilibrium phase diagram of Mg-Gd binary system [6]

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Conventional design techniques for new materials via solidification process are classified as alloying, microstructure refinement, solid-solutioning, precipitation and grain boundary control. Alloying is a conventional but effective technique to achieve them. Secondary elements are added for the purpose of increasing corrosion resistance, ductility, hardness, strength and thermal characteristics, and electric and magnetic properties. A variety of new Mg alloys with beneficial characteristics should be possible by the addition of appropriate amounts of elemental sources added singularly or in combination. Here, the effects of addition of Gd and other alloying elements related to Mg alloys are reviewed briefly [2,3].

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1.2. Effects of Gadolinium Addition to Magnesium Alloys RE elements, which include Gd, are effective in enhancing the material properties of Mg alloys [4,5]. Figure 1 shows the Mg-Gd binary phase diagram [6], which indicates that Mg and Gd form four intermetallics of Mg5Gd, Mg3Gd, Mg2Gd and MgGd, all of which are stoichiometric. On the Mg side, the Mg phase is stable up to 650C and the eutectic reaction of L = Mg+Mg5Gd occurs at TE = 548C, with the eutectic composition being Mg38.4mass%Gd. On the Gd side, Gd is stable up to 1313C and Gd is stable above 700C. The maximum solid solubility of Gd in Mg is 23.5 mass% Gd (4.5 mol%) at TE. This solubility limit is one of the largest among various Mg-RE and other binary alloys and indicates that a solid-solutioning effect should occur upon Gd addition. The solubility limit decreases to 3.8 mass%Gd at 200C and the solvus line of Mg/Mg+Mg5Gd has quite a low gradient below the eutectic temperature towards room temperature. This suggests that a subsequent ageing treatment would enhance the mechanical properties [7-9]. The efficiency of solid solution strengthening in binary Mg-Gd and ternary Mg-Gd-Y alloys has been reported by Gao et al. [10]. Single-phase specimens were prepared by melting and consequent solution treatments. The hardness increases with increasing Gd content between 3.11 to 19.6 mass%Gd. The 0.2% proof strength of Mg-Gd alloys increases in proportion to cn, where c is the solute atom concentration and n = 1/2 or 2/3. Comparing the solid solution strengthening effect of Gd and Y with that of Al and Zn, and with previous results on a binary Mg-Y alloy, they showed that Gd and Y are much more effective than Al and Zn, while Gd is slightly poorer than Y. The electrical resistivity of Mg-Gd alloys (up to 2.57 mol%Gd) was characterized at 293 and 77 K by Vostrý et al. [11]. The binary Mg-Gd alloys were prepared by squeeze casting and solution treatment was performed at 500C. Electrical resistivity was measured by means of the dc four-point method. The resistivity was found to increase with Gd content at both temperatures but was higher at 293 K than 77 K. A linear dependence on concentration was observed. Mg-Gd and Mg-Gd-Y alloys formed via melting and a hot extrusion process were characterized by Rohklin and Nikitina [12]. Extruded rods were subjected to solution treatment at 530–540°C for 2 h (T5) and ageing treatment at different temperatures for up to 200 h (T6). Mg-15 to 20 wt%Gd (T5) showed good strength properties with a UTS close to 400 MPa, but rather low elongation of only a few percent at room temperature. A Mg10mass%Gd-5mass%Y-0.5mass%Mn alloy rod extruded after homogenization at 490°C for 12 h and subsequent ageing at 200°C for 24 h showed a UTS of 400–435 MPa and a YS of

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345–385 MPa with 4.0% elongation at room temperature, and a UTS of 270–285MPa and a YS of 230MPa with 13–21% of elongation at 300°C. These values were significantly reduced at 350°C, however. Warm-extruded Mg96.5Zn1Gd2.5 (in mol%) was prepared for mechanical and microstructure characterizations by Yamazaki et al.[13]. As-cast ingots of nominal composition of the above alloy were subjected to heat treatment at 773 K over different times, and extruded at 623 K with an extrusion ratio of 10. The proof strength increased to 345 MPa with increasing heat treatment time, while the elongation decreased from the value of 6.9% for the as-cast sample. These results are attributed to refinement in the microstructure during extrusion along with fine 14H long-period-ordered structure precipitated during heat treatment. As another example, Mg-3.2Gd-0.5Zn-0.2Zr and Mg-3.2Gd-0.75Zn-0.2Zr (in mol%) showed remarkable age hardening due to precipitation of a bco structure phase [14]. The hardness values were HV = 138 for the former alloy and HV = 128 for the latter. Residual Mg3Gd particles were found at the grain boundary, which did not disappear after solution treatment but suppressed coarsening of the Mg grains. The tensile strength of the T6-treated alloys was 410 MPa at room temperature and 390 MPa at 473 K. Mg-1.8Gd-1.8Y-0.7Zn0.2Zr (in mol%) were consequently developed via ingot metallurgy, hot extrusion and ageing process [15]. The sample exhibited the ultimate tensile strength of 542MPa, proof stress of 473MPa and elongation to failure of 8.0%. These values are owing to precipitation of ‘ and  phases during ageing and they are superior to Al alloy T8-treated super Duralumin. Mg-12mass%Gd-4mass%Y-0.6mass%Zr was developed by the extrusion, the solution treatment and the ageing with aid of the calculated equilibrium phase diagram [16]. The binary sections of the Mg-Gd-Y-Zr system were calculated and drawn by the commercial software. These indicate the phase formation sequence of Zr, Mg, GdMg5, and Mg24Y5 phases. The calculated phase diagrams could also guide the recommended processing temperature conditions in regards to the phase equilibrium boundaries. The solution treatment and extrusion were conducted at temperatures below 564˚C and the ageing was done below 342˚C. An alloy with the ultimate tensile strength up to 462MPa at the room temperature was eventually developed. Mg-8Gd-2Y-Nd-0.3Zn(in mass%) alloy was prepared by the high pressure die-cast technique [17]. The mechanical properties in the temperature range from room temperature to 573˚C were obtained as the ultimate tensile strength of 302MPa, yield strength of 267MPa, the elongation of 0.85% and 38GPa of Young‘s modulus at the room temperature, while 199MPa, 151MPa, 6.92% and 27GPa respectively at 573˚C. From microstructure observation, these superior properties are attributed to small dendrite spacing, wide skin region, and some dispersed precipitates of Mg5RE and Mg3X along the dendrite boundaries formed under high cooling rate. Addition of 20 mass%Gd to AZ91D increases its thermal conductivity by a factor of 2.8 and its hardness by a factor of 1.6 [18,19]. This is attributed to the high reactivity of Al and Gd in the melt of Mg. That is, Al and Gd react to form globular particles of intermetallic Al2Gd dispersed in the microstructure. These particles form as the primary phase, crystallizing before the main Mg grains during solidification, and because of these particles, the purity of the Mg grains increases, thus increasing the thermal conductivity. The globular

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Al2Gd particles are mechanically hard with HV = 513-626, and as such the hardness of the microstructure is increased. Addition of Gd to AZ31 alloy is also effective in improving rolling capability and microstructure refinement [20]. Among the tested alloys from AZ31-0 to 3 mass%Gd, AZ312mass%Gd showed the finest microstructure and the best rolling capability. Addition of Gd also shortened the homogenization time required before rolling. The enhanced rolling capability is ascribed to microstructure refinement and a decrease in the Mg17Al12 phase. When a large amount of Gd is added, polygonal Al2Gd particles are formed in the microstructure. These particles retard the recrystallization process during rolling.

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1.3. Related Alloying Elements Besides our investigation of Gd, some of the conventionally utilized and important alloying elements are given in the following. The descriptions refer to cases in which these elements are added singularly to Mg. For addition of these elements to Mg along with Gd, naturally the chemical interaction with Gd has to be considered. This interaction sometimes dramatically dominates the physical properties of the alloys. That is, it can yield unknown intermetallics, change the solidification path, and as a result, it plays a critical role in determining the performance of alloys of new composition. While it can often enhance the material properties, in some cases it may lead to negative effects. Aluminium (Al) is perhaps the most important alloying element for Mg used to date. It strengthens Mg and enhances the fluidity of the melt, and the Mg17Al12 which precipitates at the grain boundary promotes corrosion resistance [2]. The Mg-Al binary phase diagram [21] shows that, on the Mg side, the eutectic reaction, L = Mg + Mg17Al12, is located at 437C. It also shows that with an increase in the Al content to 12.9 mass%, the liquidus temperature of Mg decreases and the solidification range increases. The eutectic point is located at 33 mass%Al. This element significantly reduces the thermal conductivity () with increasing addition [22]. For example, while the  of pure Mg is 160 W/mK that of Mg-9mass%Al is only 50 W/mk. The microstructure of Mg-Al binary alloys has been investigated by Dahle et al. [23]. As a rule of thumb, the alloys are composed of Mg grains with the eutectic Mg+Mg17Al12 forming at the grain boundaries, where the morphology and shape are dependent on the composition and solidification condition. When Gd is added to an Mg-Al system, Al and Gd readily form intermetallics in the Mg-Al-Gd melt, in which a globular Al2Gd phase forms primarily and secondarily. Zinc (Zn) is also widely used an alloying element in Mg alloys. The addition of a small amount of Zn improves the mechanical properties and castability, but excessive addition of Zn leads to the formation of micro- and macro-cracks during casting [2]. In addition, the low boiling point of Zn (902C) eases the formation of pores. Simultaneous addition of Zn and Gd is effective in enhancing the mechanical property of Mg, as mentioned in the preceding section. This combination precipitates the 14H long-period-ordered structure, which enhances the alloy strength. Silicon (Si) improves the castability when added in small amounts, and Mg2Si precipitated at the grain boundary improves the creep resistance characteristics. A small amount of manganese (Mn) improves corrosion resistance [2], while iron, nickel, copper, and

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chromium are known to degrade corrosion resistance. In the commercial Mg alloys, amounts of these elements are strictly regulated. Calcium (Ca) is an effective grain refiner for Mg alloys [24-27]. Upon addition of Ca, Al2Ca precipitates at the grain boundary, which acts to suppress grain boundary sliding thus enhancing the creep resistance. The optimum amount of Ca addition to improve the mechanical property of Mg-Al alloys has been found to be ~1 mass% [26,27], however, the simultaneous addition of Ca and Gd to Mg alloys has not been fully clarified. Zirconium (Zr) is also an effective grain refiner for Mg alloys that do not contain Al [2]. An amount in the order of 0.1 mass% Zr is widely used for this purpose, although its availability is limited due to its low economic performance. Addition of a small amount of titanium (Ti) to AZ31 can refine the microstructure, although Ti has no effect on the formation and distribution of secondary phases [28]. The AZ31-0.01mass%Ti alloy has significantly increased yield strength as compared with AZ31 due to grain refinement, but excess addition degrades the strength. The effect of grain refinement of magnesium alloys has also been reported for addition of carbon (C) [2]. Carbon forms Al4C3 in the Mg melt and acts as a heterogeneous nucleation site during crystallization. Addition of strontium (Sr) to Mg-Al alloy improves the creep resistance [24]. When the amount of Sr added is small, intermetallic Al4Sr forms in the microstructure while a ternary Mg-Al-Sr compound appears when amount of Sr is large.

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1.4. Research Objective In previous studies [18,19], Gd-added AZ91D was solidified, and a relation was identifed between the microstructure, solute partitioning, and material properties. Gd addition remarkably improved the thermal conductivity and Vickers hardness of the resulting alloy. These results and the many other previous reports imply great potential for use of Gd as an effective additive to Mg alloys. However, to confirm this potential it is necessary to accumulate more experimental data concerning the material properties of such alloys. The present research investigated the effects of addition of a small amount of Gd in terms of the tensile property of AZ91D precision castings. Different amounts of Gd up to 10mass%Gd were added to the AZ91D and cast for sample preparation. Tensile tests were performed and the results were examined in regards to the strength, ductility and formability of the material. Because of its technological importance, the combustion behavior of AZ91D with different amounts of Gd added was investigated. The ignition temperature of small pieces of Gd-added AZ91D was measured under a constant heating rate in an air atmosphere.

2. EXPERIMENTAL Precision casting using a gypsum mould was carried out for sample preparation. This casting technique is preferable in making experimental test samples along with trial products because it involves relatively facile mould design and construction, and yields a smooth castsurface as compared to the conventional sand- and die-casting. Due to the low thermal conductivity of gypsum (principally composed of CaSO4), the cooling rate is low as compared to sand-casting, leading to less shrinkage, but results in a coarser microstructure

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and lower strength for the cast products. The nominal compositions of the samples were chosen to be AZ91D-3, 5, and 10 mass%Gd. AZ91D with no Gd added was also cast for reference. The melt was made by mixing an appropriate amount of AZ91D with the AZ91D50mass%Gd mother alloys. Blocks of AZ91D and the mother alloys with a weight of 2.3 kg were heated and melted in a steel crucible 150 mm in inner diameter and 150 mm in height. A protection gas flow with Ar+9%SF6 was introduced into the electric furnace at a flow rate of ~110 ml/min during the process. The melt temperature was set at 685±10°C and the melt poured into the gypsum mould, which was preliminarily heated to 180°C. Mechanical stirring was performed with a steel rod for a minute before pouring to ensure a homogeneous melt. However, this stirring does not completely suppress gravity segregation of the high density Gd (=7.9 g/cm3) and Al2Gd (=5.7 g/cm3) that tend to sink to the bottom of the crucible during the stirring and pouring time. For casting, three rod-type specimens in the shape appropriate for conventional tensile tests were formed. These rods had dimensions of 14 mm in diameter and 60 mm in length for the parallel part, (No.4 type in [29]). Small pieces cut from the castings were obtained for microstructure observation. These were mounted into resin and their surface polished by emery papers finished off with buff polishing using 0.1 m diamond polishing powder. In this case, an oil lubricant was used, because Mg easily oxidizes when water-based lubricants are used. After ultrasonic cleaning in an ethanol bath, chemical etching was performed using a reagent composed of 4 g of picric acid, 5 ml of acetic acid, 66 ml of ethanol and 10 ml of pure water. The immersion time was a number of seconds usually but increased with increasing amounts of Gd added. Microstructure observations were made using a scanning electron microscopy with energy dispersive spectroscopy and electron backscatter diffraction (SEM-EDS, Jeol JSM-7400FEDAX). An acceleration voltage of 15 kV was needed for the SEM-EDS to distinguish between, and quantify, the spectra. The Mg K, Al K, Zn K and Gd L lines were used for quantitative analyses, wherein ZAF calibration was automatically done. Tensile property tests were carried out on the as-cast samples at room

temperature. These were done on a universal testing machine (Shimadzu Co. AG100KNIS) equipped with a non-contact elongation measurement system using CCD cameras to capture digital images of the markers at the ends of the gage length. The gage length was taken to be 50 mm within the parallel part. The strain rate was set at 110-4 s-1. The ultimate tensile strength (UTS), the 0.2% yield strength (YS), and the percentage total elongation at fracture (E) were estimated from their nominal stress-strain (ss) curves as mean values of three measurements for each composition. The combustion behavior was directly observed for small pieces of AZ91D with different amounts of Gd. This test was performed in view of the practical requirements of the casting industry, in which the melting and pouring temperatures, protection gas, flux and other casting conditions must be known. Pieces approximately 0.1 g and 10×10×2 mm in size were cut from the solidified blocks [18,19] and put on an alumina substrate. A K-type thermocouple was placed next to the sample at a distance of approximately 10 mm to measure its temperature. The sample piece on the substrate was set inside an alumina crucible 73 mm in outer diameter and 59 mm in height, and this assemblage was put inside a graphite crucible 147 mm in outer diameter and 182 mm in height. This double crucible structure was adopted for protection of the furnace. The entire assemblage was heated in an electric resistance furnace at a heating rate of 10˚C/min in an air atmosphere. The combustion behavior was

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directly observed and recorded by digital video recorder (DCR-SR100, Sony Co.). Three measurements were performed for each composition and the ignition temperature (Tig) was determined based on the heating curve measured by the thermocouple. When the sample ignites, the heating curve shows an abrupt increase in temperature. The starting point of the temperature increase is defined as Tig.

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3. RESULTS Figure 2 shows SEM micrographs of the cast samples for (a) AZ91D, (b) AZ91D3mass%Gd, (c) AZ91D-5mass%Gd and (d) AZ91D-10mass%Gd. In Figure 2(a), the microstructure of AZ91D shows the principal Mg grains with eutectic Mg+Mg17Al12 in light grey at the web-like grain boundary. Phase identification was made by EDS along with x-ray diffraction analyses [18,19]. Due to the slow cooling rate in the solidification range, the microstructure is quite coarse and the g grain size is on the order of hundreds of micrometers. Upon addition of Gd, grain refinement of Mg is not clearly observed, but the eutectic phase fraction at the grain boundary obviously decreases. With smaller amounts of residue at the grain boundaries, the g grains were more likely to be in contact with each other. For the high Gd samples, globular Al2Gd particles can be identified (white color) (Figure 2(b), (c) and (d)), and the amount of these particles increased with increasing Gd. Table 1 summarizes the results of the tensile tests. For AZ91D, values of UTS=127.0 MPa, YS=78.9 MPa and E=1.4% were obtained. These values are very consistent with traditional values. The table shows that UTS and E increase with increasing Gd, while the YS slightly decreases. For the AZ91D-10mass%Gd, for example, values of UTS=147.3 MPa, YS=74.1 MPa and E=3.4% were obtained, giving an increase in UTS by 16%, a decrease in YS by 6% and an increase in E by 143%. Typical s-s curves of the alloys are shown in Figure 3 for (a) AZ91D, (b) AZ91D-3mass%Gd, (c) AZ91D-5mass%Gd and (d) AZ91D10mass%Gd. These figures show clearly that the region of plasticity (nominal strain above 0.002) increased remarkably while that of elasticity (nominal strain from 0 to 0.002) reduced slightly with increasing Gd. Table 1. Results of tensile tests of Gd-added AZ91D alloys

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Figure 2. Scanning electron microscopic images of microstructure of (a) AZ91D, (b) AZ91D - 3 mass% Gd, (c) AZ91D - 5 mass% Gd, and (d) AZ91D - 10 mass% Gd

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Figure 3. Typical nominal stress-strain (s-s) curves of (a) AZ91D, (b) AZ91D - 3 mass% Gd, (c) AZ91D - 5 mass% Gd, and (d) AZ91D - 10 mass% Gd

Figure 4 shows sequential images of AZ91D taken during heating at (a) room temperature, (b) T=682.0C, (c) T=682.5C, (d) T=698.5C, (e) T=712.0C and (f) after combustion. On heating, a small bulge forms at the alloy surface on the right at T=682.0C (Figure 4(b)). This bulge expands at T=682.5C (Figure 4(c)) before a small explosion occurs at T=698.5C (Figure 4(d)). By T=712.0C, the entire volume had combusted (Figure 4(e)).

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After cooling to room temperature (f), it was noted that the shape and color had changed and transformed into oxides. Figure 5 shows the typical heating curve of AZ91D measured by thermocouples set next to the sample over time. The temperature increases at an almost constant rate until t=3670 s (T=707.0C). At this temperature, the gradient rises, signaling the combustion event that took place. This increase continued until t=3880 s (T=760C), at which point heating ceased and the sample started to cool down. The ignition temperature, (Tig), determined at the gradient rise, was measured for samples with different amounts of Gd up to 25 mass%, as shown in Figure 6. Tig=703C was obtained for AZ91D in this figure. A minimum ignition temperature of Tig=626C was found for AZ91D-15mass%Gd, while Tig=798C was found for AZ91D-25mass%Gd. This figure shows that a small amount of Gd reduces the Tig but in greater amounts leads increases the Tig.

Figure 4. Sequential images of the directly observed combustion behavior of the AZ91D sample at (a) room temperature, (b) T=682.0C, (c) T=682.5C, (d) T=698.5C, (e) T=712.0C, and (f) after combustion. A 0.1 g piece of AZ91D was heated at 10C/min in an air atmosphere. A K-type thermocouple (TC) was placed next to the sample at a distance of approximately 10 mm

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Figure 5. Typical heating curve of AZ91D sample over time measured by the K-type thermocouple

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4. DISCUSSION As shown in Table 1 and Figure 3, addition of Gd drastically changed the tensile properties of AZ91D. The strength and elongation of AZ91D were improved while only a slight decrease in YS was observed. This behavior is a result of the underlying microstructure of the alloy. Figure 2 showed that the amount of the eutectic Mg+Mg17Al12 decreased for the Gd-added AZ91D. This effect should act to strengthen the alloys, because connectivity of the Mg grains is enhanced. The residues act as the origin of crack propagation under tensile load. Globular Al2Gd particles dispersed in the microstructure can also influence the reinforcement, but it is still unclear whether their bonding at the interface between the Mg matrix is firm enough. A solid-solutioning effect of Gd in the Mg grains could be another reason for the increase in strength. Since the difference in atomic radii between Gd (188 pm) and Mg (150 pm) is large, replacement of a lattice position of Mg with Gd causes distortion of the crystal lattice of the hcp Mg. It may pin the motion of dislocations and strengthen the alloy. Addition of RE elements can also lead to increased randomization of the texture of the Mg alloys [30] during plastic deformation processes. This randomized texture then enhances the plastic formability. During plastic deformations, including forging and extrusion, the base (0001) planes of the hcp crystals and Mg grains are likely to be oriented close to the sheet planes. This is because this plane is the most facile to slippage. The texture randomization that occurs by RE addition is induced by a reduction in this orientation due to the lattice distortion, along with an enhancement in the solid nucleation frequency. Figure 4(a) shows the narrow plasticity region in an s-s curve of cast-AZ91D, indicating the low plastic formability. In Figure 4(b)-(d), widening of the plasticity region in the s-s curves and enhancement of the formability of AZ91D are observed upon Gd addition by the mechanism described.

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Figure 6. Dependence of ignition temperature (Tig) on amount of Gd in AZ91D alloy

Figure 6 shows the combustion temperature decreases up to 15 mass%Gd after which it increases. On heating, AZ91D begins to melt at Tms=420C, at which temperature a web-like eutectic phase located at the grain boundary starts to dissolve into the liquid. The solidus temperature is Tsol=470C, at which point Mg grains start to transform into the liquid. Between Tms and Tsol, the volume fraction of the liquid is small, but above Tsol, it increases. At the liquidus temperature, Tliq=596C, the entire volume has transformed into a liquid. During this process, the alloy pieces become enveloped by an oxide layer. The bulge observed in Figure 4(b) is considered to be caused by a gas bubble, which forms inside the volume of liquid by evaporation of the constituents. This bubble expands and moved to the surface of the sample. Upon breaking this, the oxide layer also breaks and the new melt surface is exposed to the air. This then leads to rapid oxidation and combustion (Figure 4(d)). This takes place in a large volume fraction of liquid, that is, above or nearby the liquidus temperature. For AZ91D, the Tig is above Tliq. For AZ91D-20mass%Gd, differential thermal analysis gives values of Tsol=463C, Tliq (for Mg)=636C and Tliq (for Al2Gd)=784C [18]. In Figure 6, Tig is between Tliq (for Mg) and Tliq (for Al2Gd), which means this alloy exits in a large volume fraction of liquid. However, precise investigation of the relation between the liquid volume fraction and Tig remains a subject for further study.

5. FUTURE OUTLOOK OF GADOLINIUM RESEARCH AS AN ADDITIVE TO MAGNESIUM ALLOYS Currently, the industrial applications of Gd are limited. Among its current uses are as a radiocontrast agent for image diagnostics, in magnetic materials, and in nuclear reactor control materials due to its very large neutron absorption cross-section. However, this newly investigated material has the potential to considerably expand its field of application. The present results clearly show that Gd dramatically changes the material properties of AZ91D. Taking into account that Gd both increases the thermal conductivity and Vickers hardness [18,19], it is clear that Gd is a beneficial additive for AZ91D. As has been mentioned, new

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Mg alloys with high performance offer great potential in a wide range of industrial applications. An important outlook for today is the sustainability of our industrial society and the natural environment. In this regard, production of industrial materials must also consider environmental issues, in which it is desired that the material extraction and production processes reduce energy consumption as well as emission of harmful by-products including CO2. Use of Mg alloys allows a reduction in the total weight and energy consumption for automobiles, and offers lower emissions. General consent indicates that 5-6% of fuel consumption can be saved by a weight reduction of 10% for automobiles, and thus exhaust gas can be reduced as well. Hence, development of new Mg alloys with high material performance is one of the key technologies for incorporation into automobiles, electronics, and medical devices. Mg alloys also show a low volumetric heat capacity, which is two third that of Al alloys, a high damping capacity, a shielding capability for electromagnetic radiation, and are non-toxic to humans. Around the world, primary magnesium production was 670 kilotonnes in 2005. This value has increased almost by a factor of two in the last ten years. Further experimental research into the benefits of Gd-added Mg alloys should accelerate research and development in this field generally and begin to focus on environmental issues. Equilibrium phase diagrams give useful and essential information for the design of new alloys. Although databases have been established for the binary phase diagrams including Mg-based and Gd-based alloys [31], those representing ternary and higher-order alloys have not been fully reported. Despite this, a phase relationship in the ternary Mg-Al-Gd system is cited. The liquidus surface of the Mg-Al-Gd [32,33] shows that the primary phase field of Mg is located near the Mg corner. The primary phase field of Al2Gd is broad and extends to that of Mg. This information can provide selection criteria for the composition and temperature conditions required to test unknown alloys [18]. To the best of knowledge, other important ternary and higher-order systems including Mg-Gd-Zn and Mg-Gd-Y have not been completely clarified. Thus in order to accelerate the design of new alloys, accurate equilibrium phase diagrams should be constructed for ternary and higher-order alloys. A number of review articles provide compiled knowledge on various fields relevant to the materials scientists. For example, the selection and application and corrosion resistance of industrial Mg alloys has been outlined in [34]. Polmear [35] have reviewed developments in light alloys including Al, Mg, Ti alloys. Research on developments in Mg alloy for power train applications has been reviewed by Pekguleryuz and Kaya [24] and Luo [36]. Intermetallic compounds, which are residual in the microstructure and essentially determine the material properties, have been summarized by Hort et al. [37]. Such reviews offer the distribution of much critical knowledge that will accelerate the research and development of such alloys.

CONCLUSION In this chapter, an application of Gd as an additive to Mg alloys was described. After a review of the current relevant research, the effects of 3–10 mass%Gd addition on the solidification microstructure, tensile properties of the AZ91D magnesium alloy were

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investigated. AZ91D and AZ91D with 3, 5 and 10 mass%Gd alloys were prepared by the precision-casting technique. Microstructure observations showed that the Gd-added alloys exhibited a microstructural change to an g matrix with less eutectic Mg+Mg17Al12 present at the grain boundaries. In the samples with higher amounts of Gd added, globular Al2Gd particles were found. The mechanical properties were measured at the room temperature at a strain rate of 1×10-4 s-1. The ultimate tensile strength (UTS), 0.2% yield strength (YS) and elongation (E) were estimated for the samples with different amounts of Gd added. The results show that UTS and E increased, while YS decreased slightly with increasing Gd. The combustion behavior of Gd-added AZ91D was also investigated by direct observation. These results were discussed briefly in relation to microstructure observations and quantitative analyses. Finally, we have presented a future outlook for this research field, highlighting the potential benefits of Gd as an additive to Mg alloys and its role in the environmental issues.

ACKNOWLEDGMENT The authors would like to acknowledge Hashiba Tire Mold Inc. for the aids in the precision-casting.

REFERENCES

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[1]

Sato, E. In Handbook of Advanced Magnesium Technology, Y; Kojima, Ed; Kallos publishing Co. Ltd. : Tokyo, JP, 2000, 71-104. [2] Kamado, S. In Handbook of Advanced Magnesium Technology, Y; Kojima, Ed; Kallos publishing Co. Ltd.: Tokyo, JP, 2000, 155-233 [3] Yang, Z; Li, JP; Zhang, JX; Lorimer, GW; Robson, J. Acta. Metall. Sin., 2008, 21, 5, 313-328. [4] Lu, Y; Wang, Q; Zeng, X; Ding, W; Zhai, C; Zhu, Y. Mater. Sci. Eng., 2000, A278, 6676. [5] Qudong, W; Yizhen, L; Xiaoqin, Z; Wenjiang, D; Yanping, Z; Qinghua, L; Jie, L. Mater. Sci. Eng., 1999, A271, 109-115. [6] In ASM Handbook; H; Baker, Ed; Alloy Phase Diagrams; ASM international: OH, 1992, vol.3, 2•220. [7] Vostrý, P; Smola, B; Stulíková, I; von.Buch, F; Mordike, BL. Phys. Stat. Sol. (a) 1999, 175, 491-500. [8] Cizek, J; Prochazka, I; Smola, B; Stulikova, I; Ocenasek, V J. Alloy. Compds., 2007, 430, 92-96. [9] Nishijima, M; Hiraga, K. Mater. Trans., 2007, 48, 1, 10-15. [10] Gao, L; Chen, RS; Han, EH. J. Alloys Compds, 2009, 481, 379-384. [11] Vostrý, P; Stulíková, I; Smola, B; Kiehn J. von Buch, F. Z.Metallkd. 1999, 90, 11 888891. [12] Rohklin, LL; Nikitina, NI. Z. Metallkd, 1994, 85, 12 819-823.

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[13] Yamazaki, M; Anan, T; Yoshimoto, S; Kawamura, Y. Script. Mater, 2009, 53, 799803. [14] Ozaki, T; Kuroki, Y; Yamada, K; Hoshikawa, H; Kamado S; Kojima, Y. Mater. Trans., 2008, 49, 10, 2185-2189. [15] Homma, T; Kunito, N; Kamado, S; Script. Mater, 2009, 61, 644-647. [16] Yongchun, G; Jianping, L; Jinshan, L; Zhong, Y; Juan, Z; Feng, X; Minxian, L; J. Alloys Compds, 2008, 450, 446-451. [17] Peng, Q; Wang, L; Wu, Y; Wang, L. J. Mater. Res., 2008, 23, 5, 1269-1275. [18] Sumida, M; Jung, SH; Okane, T. Mater. Trans., 2009, 50, 5, 1161-1168. [19] Sumida, M; Jung, SH; Okane, T. J. Alloys Compds, 2009, 475, 903-910. [20] Li, WP; Zhou, H; Li, ZF. J. Alloys Compds, 2009, 475, 227-232. [21] In ASM Handbook; Baker H. et al; Ed; Alloy Phase Diagrams; ASM international : OH, 1992, vol.3, 2•48. [22] Kojima, Y. In Handbook of Advanced Magnesium Technology, Y; Kojima, Ed; Kallos publishing Co. Ltd. Tokyo, JP, 2000, 55-70. [23] Dahle, AK; Lee, YC; Nave, MD; Schaffer, PL; StJohn, DH. J. Light Metals, 2001, 1, 61-72. [24] Pekguleryuz, MO; Kaya, AA. Adv. Eng. Mater, 2003, 5, 12, 866-878. [25] Pekguleryuz, MO; Baril, E. Mater. Trans., 2001, 42, 7, 1258-1267. [26] Wu, G; Fan, Y; Gao, H; Zhai, C; Zhu, YP. Mater. Sci. Eng., 2005, A408, 255-263. [27] Hirai, K; Somekawa, H; Takigawa, Y; Higashi, K. Mater. Sci. Eng., 2005, A403, 276280. [28] Wang, Y; Zeng, X; Ding, W; Luo, AA; Sachdev, AK. Metall. Mater. Trans., 2007, 38A, 1358-1366. [29] Japan Industrial Standard Z2201, ―Test pieces for tensile test for metallic materials‖, 2003, Japanese Standards Association. [30] Bohlen, J; Nünberg, MR; Senn, JW; Letzig, D; Agnew, SR. Acta. Mater, 2007, 55, 2101-2112. [31] for example; Binary Alloy Phase Diagram second edition, TB. Massalski, Ed; ASM Int., Materials Park, OH, 1990. [32] Grobner, J; Kevorkov, D; Schmid-Fetzer, R. Z. Metallkd, 2001, 92, 22-27. [33] Cacciamani, G; De Negri, S; Saccone, A; Ferro, R. Intermetallics, 2003, 11, 1135-1151. [34] Metals Handbook 10th ed; Properties and Selection; Nonferrous alloys and specialpurpose materials ; ASM international: OH, 1990; vol.2, 455-479. [35] Polmear, I.J. Mater.Trans. JIM, 1996, 37, 1, 12-31. [36] Luo, AA. Int. Mater. Rev., 2004, 49, 1, 13-30. [37] Hort , N; Huang, YD; Kainer, KU. Adv.Eng. Mater, 2006, 8, 4 235-240.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.317-333 © 2010 Nova Science Publishers, Inc.

Chapter 10

EX-VIVO APPLICATION OF GADOLINIUM: ITS UTILISATION TO CERTIFY THE VIABILITY OF MARGINAL ORGANS DURING THEIR PERFUSION OF REANIMATION. EXPERIMENTAL STUDY Jean-Bernard Buchs 1, François Lazeyras 2, Raphael Ruttimann 1, Antonio Nastasi 1, and Philippe Morel 3 1

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Research and Development Laboratory, Visceral and Transplantation Service, University Hospital of Geneva, Geneva, Switzerland. 2 Service of Radiology (CIBM), University Hospital of Geneva, Geneva, Switzerland 3 Visceral and Transplantation Service, University Hospital of Geneva, Geneva, Switzerland

ABSTRACT Introduction The scarcity of organs for transplantation imposes on us the need to use marginal organs. Our group uses NMR tests to evaluate marginal organs‘ viability. NMR tests including Gd-Perfusion let us obtain information about intra renal redistribution of flow due to ischemic lesions. Moreover, Gd-Perfusion helps in the visualisation of the vascularisation of the organs. Marginal kidneys are tested after 8 hours of perfusion for their reanimation. The aim is the realization of a score allowing us to distinguish viable and not viable kidneys, the Intensive Magnetic Resonance Diagnosis (IMRD). We have developed a perfusion machine (O2 + HPP) compatible with the Magnetic Resonance technology, because perfusion must continue during the NMR examination.

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Method Porcine kidneys presenting various warm ischemia (WIT) have been studied. Gd sequence was realized: saturation recovery turbo-flash, TR = 500 ms, TE = 1, 3 ms, 60 repeated every 2 seconds. 0.5ml Gd at 0. 5 mM in 4ml NaCl was automatically injected in 10 seconds; 4 slices of 5 mm were made. We used Gd (MetglumineGadoterate) (macrocyclic-Gd) during kidneys perfusion. After the acquisition, we realize first a movie to check the presence of all arteries and the distribution of Gd in the whole kidney. Thanks to a previously realized separation of Cortex (C) and Medulla (M) with the help of ROI s obtained in T2 sequence (Osirix®). After the Gd injection, we practice a flushing to remove Gd out of the organs. An additional test, T1 fast map sequence is realized. The first T1 fm (T1fmA) is realized before Gd injection. After the Gd-perfusion, we make a new T1fm (T1fmB) acquisition. The ratio T1fm B / T1fm A is expressed in%. The measures are realized for both C and M.

Results Results here presented are those from one experiment where one kidney with no WIT was immediately perfused versus the other one perfused after half an hour of in situ warm ischemia. That experiment has been chosen because it illustrates all the modifications of the Gd-perfusion acquisitions due to warm ischemia.

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Conclusion Gd-perfusion is an indispensable help at different levels allowing us to demonstrate not only the viability or not of the kidneys but also the importance of ischemic lesions. The redistribution of the flow from the C to the M is evidenced proving alterations of the microcirculation due to ischemic lesions. It helps to quantify these lesions by cortico-medullar shunts measurement, the shunts being activated by medullar ischemia. Gd-chelated diffuses freely in the interstitial space, consequently if perfusion should be not compatible with the viability of the organ, insufficient quantity of Gd could be removed. As T1fm presents the same results, we have to conclude that Gd-perfusion is an important MRI sequence in kidneys evaluation. The more the ratio (T1fmb/T1fmA) is high, the better is the quality of the organ because of no ischemic redistribution of perfusion, proved by little or no leakage of Gd-chelated in the extra vascular space. Despite its so-called ―nephrotoxicity‖, we continue to use Gdperfusion routinely in our research program because of the positive ratio benefits on risks.

INTRODUCTION A. Marginal Organs The necessity to introduce marginal kidneys in the transplantation field, because of the scarcity of organs, imposes on us the need to find a precise definition of what a viable organ is. Many ways have been explored; we propose here a new approach. We consider as marginal: the kidneys from Non Heart Beating Donors (NHBD Maastricht I and II), the kidneys from donors older than 70 years (Maastricht III + expanded-criteria), and some

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kidneys from difficult multi-organs removal. Their marginality arises from long warm ischemia (WIT) due to long cardiac arrest. Moreover, in older donors sensibility to warm ischemia increases as well as the possibility to find small tumours [1]. Marginality also arises from insufficient temperature management of kidneys during difficult multi-organsharvestings[2].

B. Marginal Organs Conditioning: The Perfusion of Reanimation As demonstrated by the Newcastel transplantation group, Figure 1,[3] perfusion is necessary for marginal organs if we want to introduce them safely into the transplantation program.

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Phase I : kidneys transplantation: donors : Maastricht III Phase II : kidneys transplantation: donors : Maastricht II WITHOUT PERFUSION Phase III : kidneys transplantation: donors : Maastricht II WITH PERFUSION (Reprint with the authorization of Lippincott) Perfusion has to be an Oxygenated Hypothermic Pulsatile Perfusion (O2+HPP)[3, 4] . We aimed to study organs presenting various WIT to define during O2+HPP what is the limit of viability thanks to Magnetic Resonance Imaging (MRI) and Nuclear Magnetic Spectroscopy (NMR) technologies. We have developed a machine (Figure 2) compatible with the O2+HPP concept and with Magnetic Resonance [5]: compatibility with the magnetic fields ( 3 Tesla), with the size of the bore ( 100kPa).

Figure 1. The Newcastel NHBD program Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 2. The Perfusion machine

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Organs are placed in the disposable piece of the perfusion module (Figure 3 and Figure 4). At its bottom we find a home-made P-coil for ATP resynthesis analysis during the perfusion. Figure 5 shows the perfusion module in the bore.

Figure 3. The disposable perfusion module.

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Figure 4. The perfusion module in its ―igloo‖

Figure 5. The perfusion machine in the bore (unconnected P-coil)

C. Demonstration of Kidneys’ Viability by Intensive Magnetic Resonance Diagnosis The aim of this presentation is to demonstrate the viability of marginal organs that are tested by multisequences MRI and NMR spectroscopy of 31P. Collected values allow proposing a score, called IMRD (Intensive Magnetic Resonance Diagnosis). It involves Gdperfusion and T1 fast mapit. The criteria of viability are, first the absence of tumour in the organs or of another major pathology (T2 sequence). ATP resynthesis has to be proved by NMR-spectroscopy (NMR 31P sequence). The preservation of the microcirculation in the organ, allowing a rapid return to a

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normal graft function after transplantation is evaluated by T1fm sequence and Gd-perfusion sequence. In some circumstances, Gadolinium may be nephrotoxic; that aspect in our researches is developed in the conclusion especially because we are trying to use marginal organs.

METHODS We have used kidneys (mean weight: 76 g) from 16 young pigs (mean weight: 35 kg). The organs presented various WIT from 0 min to 60 min. The duration of perfusion was 8 h as generally recommended for their reanimation[3, 6].

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a. The Gd-Perfusion Gadolinium Perfusion (Gd-Perfusion) lets evaluate the vascular anatomy and the perfusion of the whole organ. It also lets measure the distribution of the flow between cortex and medulla in the organs. The progressive brightening of the organ during Gd-perfusion is expressed in Optical Density (O.D.). Ischemic organs present a cortico-medullar shunt. The importance of the cortico-medullar shunt is given by the value of the Optical Density (OD). These values are arbitrary. Another value specified by Gd-perfusion is the time of arrival of the Gd in the Cortex (T0C) and in the Medulla (T0M). T0C is normally shorter than T0M in case of physiological circulation. Gd-based perfusion uses dynamic 2D saturation-prepared turbo flash, with a flip angle of 12°, 1.0 mm x 1.3 mm resolution, 4 slices of 5 mm (1 mm gap), TR 460 ms, TE 1,3 ms. One hundred dynamic scans for a total of 3 minutes is acquired. Saturation recovery 108 ms 60 repetitive of 2s, acquisition 3 min 20 s. All the data have been treated with Osirix® software. 0.5 ml of Gd (Metglumine-Gadoterate) 0.5mM diluted in 4 ml isotonic NaCl were automatically injected in 10 s directly in the organs, after the bubble trap.

b. Other MRI Sequences Used T2 for ROIS MR acquisition (MRI/MRS) was performed at 3T (Trio Siemens). H1 imaging and shimming were performed with the body coil and consisted of a T2 sequence (TSE, TR 5000 ms, TE 108 ms, 12 slices of 3 mm thick). The realization of Regions Of Interest (ROIs) is one important step that lets import, propagate and synchronize data for all the other sequences of MRI thanks to the open source Osirix® software (Figure 6). The use of T2 sequence is justified by the high quality of contrast obtained to separate the Cortex and the Medulla.

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Figure 6. ROIs obtained with Osirix (T2)

T1fast Map: Its use in Microcirculation Analysis T1fm is a sequence that is sensitive to the circulation in the organ. Consequently it lets estimate the flow and its distribution between cortex and medulla. In vivo at 37°C cortical T1fm has a value of 960 ms (± 60ms) and 1300 (± 60) ms in the medulla. The cortical flow in the cortex (C) is faster than in the medulla (M) and we find a gradient (M-C) of 300 ms. The ―ms‖ are those of the T1 relaxation time. During hypothermia (4°C) appears a decrease of cortical and medullar values. After our observations we obtain a mean decrease of 200 ms in both cortex and medulla. This is the shortening effect on T1fm due to the decrease of temperature. When we introduce perfusion (HPP) we observe a new fall of these values due to the movement of perfusate at low T°. That new decrease is of 100 ms. Consequently during HPP we should observe a maximum value of 600 (± 60) ms for the cortex and 900 (± 60) ms for the medulla in a normal organ with the preservation of the 300 ms of the gradient. T1fm allows another very important analysis, the ratio T1fmB/T1fmA, where A is the value before Gd-perfusion and B after Gd-perfusion and organ washing (115 ml of KPS-1) since Gd also shortens the T1fm signal. Gd-chelated is a product which may diffuse out the vascular space during HPP. As a consequence the percentage of the initial relaxation time decreases because of trapped Gd-chelated in the interstitial space that cannot be removed and because of bad organ microcirculation. More the ratio of T1fm B / T1 fm A is high, more Gd has been removed as a consequence of adequate intra renal distribution of flow. It is expressed in% of relaxation time.

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RESULTS As result we have opted to illustrate what can be obtained from the Gd-perfusion and from the multi-sequences analysis; we give here the example of 2 kidneys perfused simultaneously: the left kidney with no warm ischemia and the right kidney having suffered from half an hour of warm ischemia before the perfusion.

T1 fm A before Gd-perfusion

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In the kidney with no WIT and immediately perfused the M-C gradient is preserved at nearly 300 ms but in a pre-damaged organ (RK) this gradient decreases (148 ms, in this example).

A:T1 fm A of the left kidney before Gd-perfusion M-C gradient : 243 ms +/- 60ms

B:T1 fm A of the right kidney before Gd-perfusion M-C gradient: 148ms +/- 60 ms Figure 7A. LK. Figure 7 B: RK. T1fm A of both kidneys before Gd injection Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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T1 fm B and T1 fm A The quantification of Gd leakage in the interstitial space, in relation with bad perfusion inside the organ may be measured by T1fm A and B of both compartments (Figure 8 and 9).

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Figure 8. Values of T1fm speed of the signal before and after Gd injection (LK)

Figure 9. Values of T1fm speed of the signal before and after Gd injection (RK)

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Left renal artery: intact

Right renal artery: intact

Figure 10. Anatomy of the renal arteries

The% signal recuperation decreases if ischemic lesions are present due to leakage of Gd in the interstitial space that can‘t be removed by perfusion or due to insufficient perfusion inside the organ.

The Gd-Perfusion[7]

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The first step is always the realization of a movie allowing to observe the normal circulation in the organ. The arteries are first brightening followed by cortical perfusion, then by the medulla and finally by the venous return.

Intra Renal Microcirculation Values obtained for final microcirculation evaluation are demonstrative in these two analyses.

No shunt: Cortical OD > Medullar OD. T0C < T0M Figure 11. Osirix treatment of the intra renal micro circulation (LK)

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Shunt: Cortical OD < Medullar OD. Simultaneous T0C and T0M Figure 12. Osirix treatment of the intra renal micro circulation (RK).

CONCLUSION The cumulative results obtained seem to correlate with the importance of ischemic lesions present in the organs after warm ischemia.

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T1 fm In immediately perfused organs with no WIT or having not suffered from CSS before perfusion, the gradient remains in the range of 300 ms ± 60 ms even after 24 h. of perfusion. The gradient decreases proportionally with the duration of WIT. The% (T1fmB/T1fmA) values are important in the establishment of the scores of viability of the kidneys. So long as irreversible ischemic lesions are not present, it is possible to remove the extra vascular Gd-chelated (Figure 7A). In the organ (RK) having suffered longer WIT (Figure 7B), we note a decrease of the M-C gradient due to ischemic lesions in the medulla having opened the vascular shunts promoting flow in the medulla. The interpretation of T1fm B / T1fm A seems to be in relation with an inadequate perfusion as well as Gd-chelated sequestration in the interstitial space.

Gd-Perfusion and Intra Renal Microcirculation The macroscopic vascular anatomy is important for the surgeons who will practice the transplantation; its integrity is a prerequisite condition (Figure 10). Ischemic insults to the kidney are associated with a marked decrease of flow in the cortex leading to acute tubular necrosis. The ―primum movens‖ is probably an insufficient pO2 in the medulla leading to the opening of cortico-medullar shunt ( Nitric Oxide mediator (NO) [8]) allowing the increase of medullar flow as demonstrated by Gd-perfusion. In this case we observe a C-M shunt where the flow becomes greater in the medulla than in the cortex due to

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opening of the periglomerular arterial shunts [9]. By the way of separation of C and M (ROIs, Osirix procedure), it is possible to follow the emergence of Gd in the two compartments (Figure 11 and 12). When WIT increases, T0C and T0M become identical and even inversed due to redistribution of flow in the kidney, it is the SHUNT effect. The value of the shunts making the cut-off between can or can‘t be grafted has not been established for the moment.

Comparison with Tests Generally Realized for Viability Assessment With all the other existing perfusion‘s machine, perfusionnal and biological tests are performed. Generally a ―good‖ organ is recognized because the perfusional flow reach 0.5 ml /g / min and its Vascular Resistance decreases during perfusion[10-15]. The determination of total flow doesn‘t take into account the complexities of the renal microcirculation and the possible shunting of flow from cortex to medulla as a consequence of ischemic injury[9, 16]. Probably many organs have been discarded because of ―bad‖ perfusional scores. Some transplantation teams have tried successfully to use those ―bad‖ organs[17]. Among biological tests, the most frequently used for kidneys is the level of Glutathione-STransferase (GST) in the perfusate that must not exceed 200 IU/L for 100 g of kidney[18-22]. Thanks to our perfusionnal technology NMR compatible, it is possible to propose a new way for the evaluation of marginal organs viability. What we call IMRD score, will allow to establish a prognostic score of kidneys viability. It may be criticized because it involves Gadolinium and its so-called nephrotoxicity.

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The Use of Gd-Perfusion to Evaluate Marginal Kidneys We have well-considered the ratio risks on benefits of Gd-perfusion. Gd is a lanthanide belonging to the highly toxic atoms of that family. Today we don‘t know exactly how this toxicity acts. The nephrotoxicity arises only in reason of transmetallation that may occur, liberating the Gd in exchange of another metal or metalloid (Ca, P…) [23, 24]. Direct toxicity of free Gd on kidney is presented in only few studies [25, 26]. It has been demonstrated in 7 cases on 195 chronic renal insufficient patients ( 3.5%) a conversion in acute renal failure. In these studies it was a linear chelated Gd that has been used and at the dose of 2.5 mM/kg (body weight) meaning 2.5 times the normal concentration used. In all the cases described only the linear form is involved, because it is thermodynamically less stable [27, 28]. With normal GFR, Gd-chelated is rapidly eliminated in the urine and has no time for transmetallation. That is not the case during our ex-vivo perfusion where Gd is recirculated during almost 2 hours. But the thermodynamic stability of Gd used (macrocyclic: Metglumine-Doterate) is even increased by the low T° of perfusion (2-4°C). It has been shown that Gd-chelated (macrocyclic) at the dose of < 0.1 mM/kg BW (the concentration we use) in patients with impaired renal function presents no nephrotoxicity [29].

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Figure 13. ATP resynthesis.

At the end of the 8 hours of perfusion, the kidneys recognized as ―good‖ are flushed with 500 ml of Viaspan and continue their preservation under CSS until their implantation. As shown in Figure 13, CSS following Perfusion is not deleterious to the organs, contrarily to the situation of CSS followed by Perfusion. This figure shows the ATP levels in the kidneys in both situations. In the immediately perfused kidney, a return to nearly normal ATP level is observed despite 10 hours of CSS. In the case of the RK, the values of ATP after 18 h. of perfusion are insignificant (poor ratio signal/noise). Because Gd-chelated freely diffuses in the interstitial space, we have introduced the ratio T1fmB/T1fmA. This ratio lets estimate the leakage of Gd that should be in relation with the ischemic lesions and with inadequate perfusion. If the leakage or the impaired perfusion are too important (value entering in the IMRD-score) the organs will probably be discarded. Risks versus benefits: 1. We have obtained the warranty of the thermodynamic stability of MetglumineGadoterate.[30] 2. In case of important leakage of Gd-chelated in the interstitial space that cannot be removed during the flushing means that the kidney should not be used. 3. Chin and al.[31] have demonstrated that the injection of Trifluoperazine in the patient prevents Transmetallation. Immune and inflammatory cells are probably necessary in the development of Nephrotoxic Systemic Fibrosis (NSF). 4. Post transplantation, if necessary, dialysis may be realized to remove the Gd. More the use of Desferroxamine or of other chelates may be used in the recipient [32]. 5. New products where Gd cannot be liberated are in study. They will appear on the market in the next future. Thanks to the different analyses we can built a score of viability of the organs before to be grafted. For that we have created a table, called IMRD-score. It is a multi-sequences analysis. In this chapter ATP resynthesis has not been discussed because it has no relation with Gd-perfusion, but naturally, ATP resynthesis participates totally in the establishment of the diagnosis.

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Figure 14. The IMRD-score after 8 hours of perfusion (LK): score 0.

Figure 15. The IMRD-score after 8 hours of perfusion (RK): score 10.

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In Figure 14, the LK score is 0, meaning an excellent organ. In Figure 15 (RK) the score (10) is worse because of the long WIT. All these results have been compared with histological examination and they correlate[33]. The new technology here presented allows going ahead in the viability evaluation of organs. It presents the advantage to be a no touch technique. We can propose a global evaluation of an isolated organ depending largely on the Gd ex-vivo utilisation. Gadolinium can‘t be discarded despite its so-called nephrotoxicity. As a last point, the cost induced by these investigations must be balanced with the costs of dialysis or with the transplantation of a non viable organ and the risks of subsequent immunisation. Since perfusion is necessary for marginal organs and marginal organs are necessary for increasing the rate of transplantations, it is probably not the time to discuss price.

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REFERENCES [1] Challier, E; Bellin, MF; Fadel, Y; Richard, F; Ghebontni, L; Grellet, J. [Imaging of small renal tumors]. Prog Urol, 1997, 7(3), 484-495. [2] Feuillu, B; Cormier, L; Frimat, L; Coissard, A; Mangin, P; Hubert, J. [Kidney cooling during multi-organ harvesting. Descriptive study]. Prog Urol, 2001, 11(4), 631-635. [3] Balupuri, S; Buckley, P; Snowden, C; Mustafa, M; Sen, B; Griffiths, P; Hannon, M; Manas, D; Kirby, J; Talbot, D. The trouble with kidneys derived from the non heartbeating donor: a single center 10-year experience. Transplantation, 2000, 69(5), 842846. [4] Kwiatkowski, A; Danielewicz, R; Kosieradzki, M; Polak, WP; Wszola, M; Fesolowicz, S; Michalak, G; Lisik, W; Malanowski, P; Lao, M; Paczek, L; Walaszewski, JE; Rowinski, WA. Six-year experience in continuous hypothermic pulsatile perfusion kidney preservation. Transplant Proc., 2001, 33(1-2), 913-915. [5] Buchs, JB; Buhler, L; Morel, P. A new disposable perfusion machine, nuclear magnetic resonance compatible, to test the marginal organs and the kidneys from non-heartbeating donors before transplantation. Interact Cardiovasc Thorac Surg., 2007, 6(4), 421-424. [6] Kootstra, G; Kievit, JK; Heineman, E. The non heart-beating donor. Br Med Bull, 1997, 53(4), 844-853. [7] Buchs, J; Lazeyras, F; Bühler, L; Vallée, J; Nastasi, A; Ruttimann, R; Morel, P. The viability of kidneys tested by gadolinium-perfusion MRI during ex vivo perfusion. In Press. Prog Urol (2009), 2009, 19, 307-312. [8] Zhang, W; Pibulsonggram, T; Edwards, A. Determinants of basal nitric oxide concentration in the renal medullary microcirculation. Am J Physiol Renal Physiol, 2004, 287(6), F1189-1203. [9] Pallone, TL; Zhang, Z; Rhinehart, K. Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol, 2003, 284(2), F253-266.

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[10] Brook, NR; Knight, AJ; Nicholson, ML. Intra-renal resistance reflects warm ischaemic damage, and is further increased by static cold storage: a model of non-heart-beating donor kidneys. Med Sci Monit, 2003, 9(7), BR271-275. [11] Kozaki, K; Sakurai, E; Kubota, K; Iwamoto, H; Hama, K; Narumi, Y; Uchiyama, M; Kikuchi, K; Degawa, H; Matsuno, N; Kozaki, M; Nagao, T. Prediction of kidney nonfunction after transplantation with machine perfusion preservation. Transplant Proc., 2000, 32(2), 275-276. [12] Minor, T; Sitzia, M; Dombrowski, F. Kidney transplantation from non-heart-beating donors after oxygenated low-flow machine perfusion preservation with histidinetryptophan-ketoglutarate solution. Transpl Int., 2005, 17(11), 707-712. [13] Mozes, MF; Skolek, RB; Korf, BC. Use of perfusion parameters in predicting outcomes of machine-preserved kidneys. Transplant Proc., 2005, 37(1), 350-351. [14] Matsuno, N; Konno, O; Mejit, A; Jyojima, Y; Akashi, I; Nakamura, Y; Iwamoto, H; Hama, K; Iwahori, T; Ashizawa, T; Nagao, T. Application of machine perfusion preservation as a viability test for marginal kidney graft. Transplantation, 2006, 82(11), 1425-1428. [15] Wight, J; Chilcott, J; Holmes, M; Brewer, N. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors. Health Technol Assess, 2003, 7(25), 1-94. [16] Anaise, D; Sato, K; Atkins, H; Oster, Z; Asari, H; Waltzer, W; Pollack, W; Bachvaroff, R; Rapaport, F. Scintigraphic evaluation of the viability of cold-preserved kidneys before transplantation. J Nucl Med, 1984, 25(12), 1304-1309. [17] Derveaux, K; Monbaliu, D; Crabbe, T; Schein, D; Brassil, J; Kravitz, D; Fevery, J; Jacobbi, L; Roskams, T; Pirenne, J. Does ex vivo vascular resistance reflect viability of non-heart-beating donor livers? Transplant Proc., 2005, 37(1), 338-339. [18] Balupuri, S; Buckley, P; Mohamad, M; Chidambaram, V; Gerstenkorn, C; Sen, B; Kirby, J; Manas, DM; Talbot, D. Early results of a non-heartbeating donor (NHBD) programme with machine perfusion. Transpl Int., 2000, 13, Suppl 1, S255-258. [19] Balupuri, S; Strong, A; Hoernich, N; Snowden, C; Mohamed, M; Manas, D; Kirby, J; Talbot, D. Machine perfusion for kidneys: how to do it at minimal cost. Transpl Int., 2001, 14(2), 103-107. [20] Van Kreel, BK; Janssen, MA; Kootstra, G. Functional relationship of alpha-glutathione S-transferase and glutathione S-transferase activity in machine-preserved non-heartbeating donor kidneys. Transpl Int., 2002, 15(11), 546-549. [21] Daemen, JW; Oomen, AP; Janssen, MA; van de Schoot, L; van Kreel, BK; Heineman, E; Kootstra, G. Glutathione S-transferase as predictor of functional outcome in transplantation of machine-preserved non-heart-beating donor kidneys. Transplantation, 1997, 63(1), 89-93. [22] Polak, W; Danielewicz, R; Kwiatkowski, A; Kosieradzki, M; Michalak, G; WegrowiczRebandel, I; Walaszewski, J; Rowinski, W. Pretransplant evaluation of renal viability by glutathione S-transferase in machine perfusate. Transplant Proc., 2000, 32 (1), 171172. [23] Cacheris, WP; Quay, SC; Rocklage, SM. The relationship between thermodynamics and the toxicity of gadolinium complexes. Magn Reson Imaging, 1990, 8 (4), 467-481.

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[24] Bartolini, ME; Pekar, J; Chettle, DR; McNeill, F; Scott, A; Sykes, J; Prato, FS; Moran, GR. An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis. Magn Reson Imaging, 2003, 21 (5), 541-544. [25] Sam, AD; 2nd; Morasch, MD; Collins, J; Song, G; Chen, R; Pereles, FS. Safety of gadolinium contrast angiography in patients with chronic renal insufficiency. J Vasc Surg., 2003, 38 (2), 313-318. [26] Arsenault, TM; King, BF; Marsh, JW; Jr., Goodman, JA; Weaver, AL; Wood, CP; Ehman, RL. Systemic gadolinium toxicity in patients with renal insufficiency and renal failure: retrospective analysis of an initial experience. Mayo Clin Proc., 1996, 71 (12), 1150-1154. [27] Weinmann, HJ; Brasch, RC; Press, WR; Wesbey, GE. Characteristics of gadoliniumDTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol, 1984, 142(3), 619-624. [28] Senet, P; Frances, C; Lipsker, D. [Nephrogenic systemic fibrosis]. Ann Dermatol Venereol, 2009, 136(4), 379-386. [29] Ergun, I; Keven, K; Uruc, I; Ekmekci, Y; Canbakan, B; Erden, I; Karatan, O. The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrol Dial Transplant, 2006, 21(3), 697-700. [30] Corot, C; Schaefer, M; Beaute, S; Bourrinet, P; Zehaf, S; Benize, V; Sabatou, M; Meyer, D. Physical, chemical and biological evaluations of CMD-A2-Gd-DOTA. A new paramagnetic dextran polymer. Acta Radiol Suppl., 1997, 412, 91-99. [31] Chin, JL; Stiller, CR; Karlik, SJ. Nuclear magnetic resonance assessment of renal perfusion and preservation for transplantation. J Urol, 1986, 136(6), 1351-1355. [32] Perazella, MA. Gadolinium-contrast toxicity in patients with kidney disease: nephrotoxicity and nephrogenic systemic fibrosis. Curr Drug Saf., 2008, 3(1), 67-75. [33] Goujon, JM; Hauet, T; Menet, E; Levillain, P; Babin, P; Carretier, M. Histological evaluation of proximal tubule cell injury in isolated perfused pig kidneys exposed to cold ischemia. J Surg Res., 1999, 82(2), 228-233.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.335-340 © 2010 Nova Science Publishers, Inc.

Chapter 11

GADOLINIUM COMPOUNDS AND MRI IN DAILY PRACTICE: HOW TO REDUCE INAPPROPRIATE ORDERING AND IMPROVE COMMUNICATION BETWEEN RADIOLOGISTS AND REFERRING PHYSICIANS Sergio Lopes Viana Clínica Vila Rica and Diagnostik (Hospital das Clínicas de Brasília), Brasília, Brazil

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ABSTRACT Inappropriate ordering of gadolinium for magnetic resonance imaging has been rarely addressed in the literature. Errors commonly seen in daily practice include indiscriminate solicitation of contrast-enhanced exams or, on the contrary, failure to request the administration of gadolinium when the clinical scenario so demands. The main causes for such errors from referring physicians seem to be deficient medical formation and lack of knowledge due to neglected continued medical education, while radiologists fail to cooperate with their colleagues aiming to clarify inadequately ordered tests. The sole most important factor, however, comes from both sides, consisting of a dangerous and unacceptable failure of communication based upon selfishness and egocentrism. Improved communication between MRI professionals and referring physicians in association with better medical training and continued medical education are the key points to disseminate knowledge and avoid such errors. As long as radiologists turn out to be better communicators and ordering doctors become open to hear and to learn from them, misuse of gadolinium compounds tends to be less frequent, so that better care can be offered to our patients at a lesser cost.

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INTRODUCTION ―We forget that our wonderful technologic advances must be tempered by equally strong advances in the art of communication.‖ Peggy J. Fritzsche, MD[1]

One of the most underestimated issues about the use of gadolinium compounds is the huge number of magnetic resonance procedures performed improperly. These errors occur either because the administration of these compounds is not requested – sometimes strictly prohibited – by the referring physician even if the clinical setting definitely demands their use or, on the contrary, because gadolinium is given to patients that do not need it at all. Even though articles about malpractice, litigation and lawsuits involving radiologists abound[2-5], questions concerning the use of paramagnetic contrast are rarely discussed[6]. Far from being caused only by lack of knowledge from referring physicians, such inappropriate ordering is more probably the consequence of a dangerous and costly communication failure between radiologists and requesting doctors.

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DISCUSSION Radiologists – like me – have their share of responsibility for this state of things, and it is not a small one. Whenever an incorrect MRI solicitation comes to our hands, we usually take a distant, condescending attitude, shaking our heads or whispering an acid comment. Most of times we give gadolinium to patients if the physician asks for it as long as, if we don‘t perform the exam, the imaging center next door would do that anyway. We almost never get in touch with the referring physician to make things clear about the exam, either because of fear of wounding susceptibilities or merely by inertia. Obviously, although comfortable, this is not a salutary approach, as long as it does not contribute for a better care for the patients and, moreover, keep things exactly as they are. Thus, new and/or relevant information is not transmitted to our colleagues on the other side of the line, like the increasing emphasis put on gadolinium-induced nephrogenic systemic fibrosis[6, 7]. Unfortunately, physicians who take their continued medical education on imaging seriously are the exception and not the rule and, even if the opposite was true, this would not exempt radiologists from their obligation to communicate[8,9]. Medico-legal issues arise when we talk about inappropriately ordered exams. Radiologists, as specialists on imaging, have a legal ―duty of communication‖, being obligated to timely inform the referring physician about any imaging findings which indicate the need for prompt medical intervention contained on their reports (the radiologist is compelled to talk to patient and maintain him or her well-informed as well; however, further discussion is beyond the scope of this brief commentary about the use of gadolinium compounds)[1-4, 10]. This duty establishes the authority of the radiologist and affirms his right and his obligation to guide the conduct of his colleagues through these reports. One of the leading causes of lawsuits involving radiologists in the US is the failure to communicate to the referring physician about ―what to do next‖ (not to be confused with self-referral)[2-4]. In my opinion, telling the requesting doctor that a given MRI exam would require gadolinium

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Gadolinium Compounds and MRI in Daily Practice: How to Reduce Inappropriate… 337 for increased sensitivity and/or specificity (e.g., intravenous contrast for the initial phases of inflammatory arthropathies or magnetic resonance arthrography for labral tears of the shoulder) is a precise example of providing continued medical education while accomplishing legal obligations at the same time, explaining ―what to do next‖ without touching susceptibilities. The report is the essential communication between radiologists and referring physicians and the way by which the former will be unavoidably heard (better saying, read) by the latter. The downside is having the exam already performed and the need for a new one to be eventually carried out to achieve this. However, with the increasing isolation between clinicians and radiologists[11], these cannot afford to overlook this unique channel to talk directly to the ordering physician. In my field of expertise, musculoskeletal radiology, we have and additional problem: the gadolinium compounds can be administered either intravenously or intra-articularly, and many times the intended route of administration is not clear from the solicitation (―contrastenhanced MRI‖). Not rarely the referring physician becomes upset when contacted to clarify this – probably because he or she is confronted with his or her ignorance on the subject. Besides being commonplace to see magnetic resonance arthrography ordered for patients who should rather receive intravenous gadolinium (or vice-versa), even worst, sometimes gadolinium is prescribed for patients who would not benefit of its administration at all, like elderly people with advanced osteoarthritis. This is based on a vague notion that contrast enhanced MRI would be better than MRI without gadolinium, with a hypothetically higher sensitivity. Referring physicians many times do not help, either. As mentioned above, when contacted by radiologists about exams solicited by them, some act aggressively, as if they were personally offended[8]. In other occasions, many of them take an attitude of arrogance and superiority, as if a dogma was broken – even if something like ―MRI of the left shoulder in anteroposterior and lateral projections‖ is written on the order. This sounds like selfdefense, maybe based on the academic Hippocratic tradition of an unquestionable authority of the physician and on a supposed infallibility of their acts. In my daily practice, I have observed – and this comes as no surprise – that the more well-prepared and self-assured a colleague is, the more he or she is prone to hear the radiologist and to clarify an equivocal solicitation. Doctors are scientists, not deities (although medical education sometimes induces students to think so), and no supernatural enlightenment is supposed to guide their medical practice, but hardly acquired knowledge instead. However, even with studies suggesting that there is a general lack of awareness about the appropriateness of imaging studies among referring physicians[2, 8, 9, 11], chances are that they would not like to have their orders questioned or even discussed. It is not uncommon to see less experimented doctors soliciting contrast-enhanced MRI indiscriminately based in the former – and erroneous – belief that gadolinium compounds were inoffensive[6] and on a supposed and invariable ―superiority‖ of contrast-enhanced MRI (―gad is God‖). Part of this inappropriate ordering can be surely credited to the insufficient emphasis put on imaging education during residency training programs. On the other hand, a whole generation of doctors was trained to fear the adverse reactions of iodinated contrast media during the era of ionic compounds; even though this is not reasonable in our days, especially after the advent of non-ionic contrast media, much of this fear was transferred to gadolinium, so that many patients do not receive the contrast they need because of this absurd terror. Even though they are experienced and trustful, these

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physicians had their residency years before the advent of cross-sectional imaging and are not thoroughly familiar with all of its features. Apart from the incorrect management of the patients with inadequately solicited exams, such procedures implicate in wasted money and time. The addition of gadolinium to a MRI solicitation may increase the overall costs in up to 25%, an absolutely non-negligible amount. Furthermore, a second procedure, with the added cost of the contrast, will result in more than twice the price it would have if it was correctly solicited from the beginning. Recalls implicate in loss of time and additional expenses with dislocation for the patient, unnecessary discomfort on the position required for some examinations, work absenteeism and, eventually, need for recurring sedation (for example, in pediatric, elderly, non-cooperative or claustrophobic patients), with all the costs and risks implicated. Knowledge, information and communication are the key words here. The radiologists detain the knowledge and are compelled to transmit it to their colleagues of other specialties[10]; that, on their turn, must be open and receptive to learn from them. However, in the same manner that radiologists cannot neglect their obligation to keep the referring physicians as informed as possible about the imaging methods and their peculiarities (including those related to the use of gadolinium compounds), requesting doctors are ethically and legally obliged not to overlook their continued medical education. Symposia, congresses and similar events of specialties other than radiology must contemplate update on imaging on their programs. On a daily basis, radiologists should orient referring doctors on their reports or contacting them directly, indicating what patients would benefit from the use of gadolinium and why, being up to the imaging experts to ―show the way‖ to their mates of other specialties. Last, but not least, it is urgent to improve the training of our residents. Radiology residents should be stimulated to communicate, to get in touch with the ordering doctor, to leave introversion behind and be talkative, explanative and clear, being ready to learn as well, without arrogance. Treatment choices are always changing, and good communication can make a senior resident better informed in this field than a member of the staff. Residents of other medical specialties should have emphasized the role of imaging on their specific areas (efficacy and appropriateness), being trained to ask for help when in doubt about how to solicit an exam. It is important to tell them that their honor, reputation and trustfulness will remain untouched if they call a radiologist for clarification purposes, no matter what their older colleagues – or even their teachers – say; ignorance of house staff should not be passed from one generation to another.

CONCLUSION We live through fantastic days, days in which information is fairly accessible on the Internet anywhere you are, days in which you can carry entire books in your PDA, days in which one can consult a colleague that is oceans away with audio and video in real time. Books and journals are available as portable electronic documents, and the leading edge of knowledge is around the corner. We are ―seeing better‖ than ever with imaging, and this must be paired with ―knowing more‖[12]. There are no excuses – ethically, medically and legally speaking – for not being up to date with your field of expertise. Our patients demand and deserve the best care we can offer, and we can do the best with imaging primarily through

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Gadolinium Compounds and MRI in Daily Practice: How to Reduce Inappropriate… 339 improved communication[11, 13]. Miscommunication, rather than misdiagnosis, can be the primary cause for litigation[5]. If we can improve communication between radiologists and referring doctors and put less egocentrism on both sides, we are getting near to the heart of the matter. By advocating the patient‘s well being above competitiveness and selfishness we take the first step towards a meaningful medical communication, always bearing in mind that communication goes two ways and both sides must be open to speak, to hear and to learn. Citing Dr. Fritzsche once again, ―in the end, both our patients and our profession will benefit‖[1].

ACKNOWLEDGMENTS The author would like to express his gratitude to Dr. Fábio Marinho Barros, MD, for reviewing this manuscript.

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REFERENCES [1] Fritzsche, PJ. Communication: the key to improved patient care. Radiology, 2005, 234, 13-14. [2] Berlin, L. Duty to directly communicate radiologic abnormalities: has the pendulum swung too far? AJR Am J Roentgenol, 2003, 181, 373-381. [3] Raskin, MM. Why radiologists get sued. Appl Radiol, 2001, 30, 9-13. [4] Raskin, MM. Survival Strategies for Radiology: Some Practical Tips on How to Reduce the Risk of Being Sued and Losing. J Am Coll Radiol, 2006, 3, 689-693. [5] Brenner, RJ; Bartholomew, L. Communication Errors in Radiology: A Liability Cost Analysis. J Am Coll Radiol, 2005, 2, 428-431. [6] Steen, H; Schwenger, V. Good MRI images: to Gad or not to Gad? Pediatr Nephrol, 2007, 22, 1239-1242. [7] Padilla-Thornton, A; Zand, KR; Barrett, B; Stein, L; Andrew, G; Forster, BB. Canadian Association of Radiologists national advisory on gadolinium administration and nephrogenic systemic fibrosis. Can Assoc Radiol J, 2008, 59, 237-240. [8] Bautista, AB; Burgos, A; Nickel, BJ; Yoon, JJ; Tilara, AA; Amorosa, JK. American College of Radiology Appropriateness. Do clinicians use the American College of Radiology Appropriateness criteria in the management of their patients? AJR Am J Roentgenol, 2009, 192, 1581-1585. [9] Gower-Thomas, K; Lewis, MH; Shiralkar, S; Snow, M; Galland, RB; Rennie, A. Doctors' knowledge of radiation exposures is deficient. BMJ, 2002, 324(7342), 919. [10] American College of Radiology. ACR practice guideline for communication of diagnostic imaging findings. In: Practice guidelines and technical standards. Reston, Va: American College of Radiology, 2005, 5-9. [11] You, J; Levinson, W; Laupacis, A. Attitudes of family physicians, specialists and radiologists about the use of computed tomography and magnetic resonance imaging in Ontario. Healthc Policy., 2009, 5(1), 54-65.

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[12] Feldman, F. Musculoskeletal Radiology: Then and Now. Radiology, 2000, 216, 309316. [13] Barkley, JM. Failure to Define the True Problem: Poor Communication by Radiologists. Radiology, 2005, 237, 1121-1122.

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In: Gadolinium: Compounds, Production and Applications ISBN: 978-1-61668-991-9 Editor: Caden C. Thompson, pp.341-350 © 2010 Nova Science Publishers, Inc.

Chapter 12

RARE EARTH GADOLINIUM NANOPARTICLES FOR HYDROGEN INDUCED SWITCHING, SENSING AND STORAGE DEVICES B. R. Mehta, I. Aruna and L. K. Malhotra Thin Film Laboratory, Department of Physics, Indian Institute of Technology Delhi, New Delhi – 110016, India

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1. INTRODUCTION Research interest in rare earth metal (RE) hydrides has received a significant thrust due to the discovery of switchable mirror effect in these materials upon hydrogenation by Huiberts et al. [1] Yttrium (Y) films capped with a palladium (Pd) over layer have been observed to exhibit reversible optical and electronic properties on hydrogen loading and subsequent deloading. Y film transforms from its shiny metallic state (Y) to a dark blue reflecting dihydride state (YH2) on hydrogen exposure and finally approaches the transparent semiconducting trihydride state (YH3) on further uptake of the hydrogen. Due to the small heat of formation of YH3 (-44.9 kJ/mole H) as compared to that of YH2 (-114 kJ/mole H), optical and electronic properties can be switched between the dihydride and trihydride states by subsequent loading and deloading of hydrogen and this phenomena has been successfully utilized to fabricate switchable mirrors [1,3]. The palladium (Pd) over layer plays an important role as a protective catalytic layer in RE switchable mirrors. It prevents oxidation of the underlying RE metal and enhances the dissociation/association of hydrogen molecules at the solid/gas interface [1]. The discovery of switchable effect in Y films has led to an extensive study of the structural, optical and electronic properties of polycrystalline thin films of several rare earth metals (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Tm, Yb and Lu) upon hydrogenation [1-7,14]. In these reports, the hydrogenation of the RE metals has been achieved either by gas phase loading (where H2 is injected into the chamber with RE metal film and pumped out periodically) [1-3,6-9] or in liquid or solid electrolytes (when the electrode of the active metal is polarized cathodically and depolarized) [4,5]. It is also worthwhile to mention that RE metal films also offer a wide range of promising applications,

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such as smart windows, optical displays, hydrogen sensors and hydrogen storage devices [1, 8-10]. The important issues emphasized so far in the RE switchable mirrors are the constant transmittance regions in the visible range known as color neutrality, fast kinetics and mechanical stability upon hydrogenation [1-7]. As the optical absorption edge of the rare earth metal trihydrides falls in between yellow and red in the visible region, attainment of color neutrality is one of the nagging problems in the polycrystalline films. Alloying the RE metals (Gd, Y, Sm, Er, La) with Mg has been tried out to improve color neutrality of the trihydride state [11-14]. In case of Gd-Mg alloy films, which results in better color neutrality, increase in Mg content results in larger switching time of 20 minutes and affects the crystallinity of the films [11,12]. Multilayers of rare earth metals and Mg have also been tried out. Gd-Mg and Y-Mg multilayers structure are observed to improve the switching time as compared to alloy films [15,16]. On the other hand, color neutrality and optical contrast between the switchable states have been observed to be affected in the RE-Mg multilayers [16]. In addition, an enormous volume expansion (32%) during Mg to MgH2 conversion has been observed to cause large stresses and a possible deterioration during repeated switching cycles in the Re-Mg alloy films and multilayers [17]. Recently, ‗nanoparticle route‘ has been successfully used to fabricate RE nanoparticle switchable mirrors to improve the color neutrality without adversely affecting the response time, optical contrast, reversibility, and stability of RE based switchable mirrors [18]. It is well known that the optical band gap of the semiconductor nanoparticles shifts towards lower wavelength side as compared to the bulk and polycrystalline films due to the quantum confinement of charge carriers at nanodimensions [19,20]. In addition, nanoparticles are known to be more reactive to the gaseous species due to the enhanced surface area at nanodimensions [19,22]. The important nanoparticle characteristics of size-induced blue shift in the optical band gap and enhanced surface area at nanodimensions have been successfully utilized to achieve better color neutrality, faster response time, good optical contrast, and enhanced stability in gadolinium (Gd) nanoparticle films based switchable mirrors [18]. This review presents the effect of nanoparticles size on the switchable mirror and hydrogen storage applications.

2. EXPERIMENTAL RESULTS AND DISCUSSION A simple technique of inert gas evaporation has been employed to synthesize Gd nanoparticle films. The schematic diagram of the inert gas evaporation set up is shown in Figure 1. In the IGE technique, high purity Gd (99.999%) was thermally evaporated in the argon ambient using a resistively heated tungsten boat. Before reaching the substrate, the kinetic energy of the evaporant atoms is lost through collisions with the inert gas atoms. The low adatom mobility results in the growth of Gd nanocrystallites or nanoparticles on the substrates. The flow of argon into the deposition chamber was monitored using mass flow controllers and gas regulators. Prior to admitting argon into the vacuum chamber, the chamber was evacuated to 1  10-6 Torr with the help of a rotary pump and a diffstak assembly. The chamber having a base pressure of 1  10-6 Torr was filled with argon gas up to 1 Torr followed by evacuation to 1  10-6 Torr.

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This process of purging with argon was repeated several times to minimize residual oxygen in the chamber. Prior to deposition, a small amount of Gd was evaporated on the shutter covering the substrates. The gettering action of pre-deposited Gd further reduces the oxygen species in the deposition chamber. High deposition pressure (10-4 – 10-3 Torr of Ar), low substrate temperature (Ts = 30C) and high flow rate of argon (F.R = 20 sccm) resulted in the formation of Gd nanoparticles. Transmission electron microscopy studies of samples deposited at argon pressure of 1.7  10-3 Torr and 3.9  10-4 Torr revealed an average particle size of 8 nm and 10 nm respectively [18]. Atomic force microscopy and glancing angle x-ray diffraction have also been used to estimate the particle size in these films. Figure 2. shows a typical AFM image of sample deposited at 1.7  10-3 Torr having average particle size of 9 nm. The height mode AFM has been used to determine the particle size. In the present review we will be referring to the particle size estimated using TEM studies. For comparison Gd polycrystalline sample has been deposited at 1  10-6 Torr base pressure. The rate of deposition and the thickness of the films were continuously monitored and controlled using quartz crystal thickness monitor fitted inside the chamber. A 10 nm thick Pd layer was deposited onto the Gd films by evaporating high purity Pd at 1  10-6 Torr pressure without breaking the vacuum. The films were loaded with hydrogen via gas phase loading by introducing H2 into the chamber at 30 sccm till a pressure of 760 Torr was attained. For deloading, the chamber was evacuated using a mechanical rotary pump.

Figure 1. Schematic diagram of inert gas evaporation set up (B: Dual boat arrangement, S: Shutter, G: inert gas inlet, H: Substrate holder, M: Thickness monitor, A: air inlet valve, L: LT connections, V: to vacuum pumps). Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 2. AFM image of Gd nanoparticle film

Hydrogen induced electrical and optical switching of Pd capped Gd nanoparticle films have been studied in detail as a function of nanoparticle size [18]. A typical curve showing the reversible electrical switching behavior of the Gd nanoparticle sample with average particle size of D = 8 nm is shown in Figure 3 (a). Upon hydrogenation, the electrical resistance of the metallic Gd increases sharply to large value corresponding to semiconducting GdH3-. On deloading the resistance decreases to an intermediate value corresponding to metallic GdH2+. The film can be switched reversibly between the metallic GdH2+ and semiconducting GdH3- state on subsequent hydrogen loading and deloading. The corresponding transmittance curves for the Gd nanoparticle film of average particle size 8 nm under different hydrogenation conditions is shown in Figure 3 (b). The as-deposited sample (curve a) shows a peak due to plasmon confinement characteristic of metal nanoparticles. The position, intensity and width of the plasmon peak depend upon the nanoparticle size and their distribution. Upon hydrogenation, the transmittance increases (curve b) and shows an adsorption edge characteristic of semiconducting GdH3- and on deloading the transmittance spectra decreases (curve c).

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Figure 3. Hydrogen induced (a) electrical and (b) optical switching in Pd capped Gd nanoparticle film (D = 8 nm). Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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Figure 4. A comparison of the constant transmittance region in the visible wavelength range for Gd nanoparticles (D= 8 nm and D = 10 nm) with the polycrystalline, alloy [11] and multilayer films [15].

The constant transmittance region in the transparent trihydride (GdH3-) state has been extended to lower wavelengths to attain color neutrality by controlling the nanoparticle size. Figure 4 shows the wavelength range having the constant transmittance in case of hydrogenated Gd nanoparticle (with particle size D = 8 nm and D = 10 nm) and polycrystalline films (D = 25 nm). For comparison, the constant transmittance region for GdMg alloy [11] and multilayer films [15], reported in literature, are also shown. The Gd nanoparticle sample with average size of 8 nm has the most extended constant transmittance region as compared to polycrystalline, alloy and multilayer films. This is a direct consequence of size-induced blue shift in optical absorption edge as observed in many semiconductor nanoparticles [21-24]. Using the transmittance, reflectance and thickness data, the optical absorption edge of the GdH3- nanophase of different particle sizes has been estimated [25]. The estimated optical absorption edges of hydrogenated Gd nanoparticle samples having average particle size of D = 8 nm, D = 10 nm and polycrystalline sample with D = 25 nm are 2.89 eV, 2.64 eV and 2.55 eV, respectively. The increase in optical absorption edge resulting in attaining color neutrality with decrease in nanoparticle size is attributed to quantum size effects at nanodimensions. According to quantum confinement theory, in semiconductor nanoparticles, the electrons in the conduction band and holes in the valence band are spatially confined by the potential barrier at the nanoparticle boundary and this causes an increase in energy of lowest optical transition from the valence band to the conduction band, resulting in an increase in the optical absorption edge [20]. The size dependent blue shift in the band gap can be explained by effective mass and tight binding approximations [21,26]. It is important to note that in addition to the constant transmittance region, the optical contrast (defined as (TL-TDL)/ TL where TL and TDL are the transmittance values of loaded and deloaded samples, respectively) as well as the switching time (time taken for the resistance to reach to 90% of it final value) can be tuned as a function of nanoparticle size. The variation of optical contrast and switching time as a function of particle size is shown in Figure 5 (a) and (b) respectively. The optical contrast increases and switching time decreases with decrease in

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nanoparticle size. The increased optical contrast is due to the increased diffusivity because of the large nanoparticle boundaries in the nanoparticle samples and the improved switching time is due to the enhanced reactivity of the hydrogen with Gd nanoparticles. Similar enhancement in reactivity and diffusivity of gaseous species has been reported for many semiconductor and metal nanoparticles. This has been attributed to the large number of surface atoms at nanodimensions [27]. The possibility to tune the response time in Gd nanoparticle samples as a function of nanoparticle size is advantageous for hydrogen sensor applications. It is worthwhile to note that the Pd over layer thickness has been maintained to be 10 nm in these switchable mirrors. The switching time as well as the optical contrast depends on many factors, which includes the thickness of the Pd over layer and that of the active RE layer [1-17]. Increasing the thickness of the nanoparticle film and optimizing the Pd over layer thickness can further improve the switching characteristics and the optical contrast of nanoparticle samples. Moreover, the constant transmission region can be further extended to lower wavelength region by reducing the nanoparticle size. 50

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Figure 6. X-ray diffractograms of Gd nanoparticles D = 8 nm (a) as-deposited and (b) hydrogen loaded. For comparison the (hkl) planes corresponding to hcp phase of bulk Gd are also shown by solid lines. The XRD peak at 2 = 40.1 corresponds to the (111) plane of f.c.c structure of Pd, from the Pd over layer.

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Figure 7. Variation in B.E position and FWHM of core level Pd 3d5/2 XPS peak in case of Gd (a) polycrystalline D = 25 nm and (b) nanoparticles D = 8 nm samples.

In addition to the size induced blue shift and enhanced surface area which modify the hydrogen induced optical and electrical properties of Gd nanoparticles making them better candidates for switchable mirrors applications, nanoparticle nature has also been observed to modify their structural properties as well as the nature of Pd-Gd interface [18]. The x-ray diffractograms of as-deposited and hydrogenated Pd capped Gd nanoparticle films of D = 8 nm is shown in Figure 6 (curves a and b, respectively). For comparison, (hkl) values corresponding to bulk Gd are shown as solid lines. Gd nanoparticles (D = 8 nm) are observed to have fcc structure with a = 5.37 Å. On the other hand Gd polycrystalline film also exhibits hcp structure (with a = 3.54 Å and c = 5.82 Å ) as reported for bulk Gd [28]. Thus, a sizeinduced structural transition from hcp to higher symmetric fcc phase is observed on going from D = 25 nm for polycrystalline film to D = 8 nm for Gd nanoparticle sample. Sizeinduced structural transformations reported in many nanoparticle systems have been explained due to the modified surface structure, large concentration of defects present in the nanophase or the change in Gibbs free energy due to the surface energy term [21-24]. A minor fraction (~10%) of fcc phase along with the majority hcp phase has been reported in nanocrystalline Gd powder (size = 12.0 nm) formed by inert gas condensation [29]. It may be mentioned that, the crystal structure of GdH3- is also observed to be fcc (Figure 6 curve b) with lattice constant of 5.48 Å, which is higher in comparison to that of as-deposited Gd nanoparticle film (5.37 Å). This is consistent with lattice expansion due to the occupation of interstitial lattice sites by hydrogen. The polycrystalline Gd is known to undergo hcp  fcc  hcp transition on going from Gd  GdH2+  GdH3-.[28] On the other hand Gd nanoparticles (D = 8 nm) are observed to remain fcc during Gd  GdH2+  GdH3- transition. In the RE switchable mirrors, Pd-RE interface is observed to play an important role in determining the switching behavior. Alloy formation at Pd-Y interface is observed to reduce and even hinder hydrogenation due to the oxygen induced surface segregation on air exposures [3]. A detailed x-ray photoelectron spectroscopy study of the Pd-Gd nanoparticle interface revealed the absence of interfacial alloy. The variation in B.E and FWHM of the core level Pd 3d5/2 XPS peak as a function of sputtering depth in case of Gd polycrystalline (D = 25 nm) and nanoparticle sample (D = 8 nm) are shown in Figure 7(a) and (b)

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B. R. Mehta, I. Aruna and L. K. Malhotra

respectively. It is evident that the B.E position increases and FWHM decreases in Gd polycrystalline sample as interface is approached. In contrast to this, in case of nanoparticle sample D = 8 nm, the B.E as well as the FWHM remains at the elemental position on sputter depth profiling. Similar trend in the B.E and FWHM has been observed on sputter depth profiling incase of valence band spectra [18]. Figure 8 shows the valence band spectra of Pd capped Gd polycrystalline and nanoparticle samples. The increase in the B.E and decrease in the FWHM of Pd XPS transitions are attributed to the alloy formation of Pd with the Gd at the interface. Similar changes in the BE and FWHM of the XPS peaks corresponding to Pd have been observed in the Pd-Gd inter metallic compounds [30,31]. XPS and Auger transitions corresponding to Pd shows shift in binding energy on the formation of alloy with the Y in the polycrystalline yttrium films capped with Pd layer [3]. Thus Pd forms interfacial alloy with Gd in the polycrystalline films. On the other hand, the unaltered B.E and FWHM values of Pd XPS transitions in case of nanoparticle Gd switchable mirrors show a sharp interface with out any alloy formation. The absence of interfacial alloy in Gd nanoparticles has been attributed to the presence of thin Gd2O3 shell around the Gd nanoparticle core. Y (and Gd) nanoparticles prepared by laser ablation have been reported to have Y (or Gd) core surrounded by a thin Y2O3 ( or Gd2O3) shell [32,33]. Whereas hydrogenation in RE films has been possible either in the presence of catalytic Pd over layer or at high temperatures [1-17]. Gd in nanoparticle form is observed to have enhanced reactivity towards hydrogen even in the absence of Pd over layer [34]. Figure 7 shows the variation in resistance upon hydrogen exposures in case of Gd nanoparticles (D = 8 nm and D = 10 nm) and polycrystalline sample (D = 25 nm). It is evident that the Gd polycrystalline film does not interact with hydrogen in the absence of Pd over layer. In contrast the resistance of Gd nanoparticles increases sharply on exposure to hydrogen revealing hydrogenation. In addition to this bare Gd nanoparticles are observed to exhibit enhanced stability in air ambient because of the possible Gd2O3 surface layer. This made it possible to perform ex-situ investigations to study size dependent optical, electrical and structural properties of bare Gd nanoparticles. 1200 D = 25 nm

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Alloy and multilayer of rare earth materials with Mg have been used to improve the colour neutrality of rare earth materials based switchable mirrors. In our laboratory, nanoparticle route has been used to improve color neutrality along with optical contrast and switching time. A detailed study has shown that Gd nanoparticles (D = 8 nm) exhibit better color neutrality as compared to alloy, multilayer and polycrystalline films. Moreover, they show larger optical contrast and faster switching as compared to polycrystalline films synthesized under identical conditions. In addition to the enhanced switching properties, a size-induced structural transition from hcp to higher symmetric fcc phase has been observed on going to Gd nanoparticles D = 8 nm. Gd nanoparticle switchable mirrors shows sharp interface without the presence of any interfacial alloy due to the presence of possible Gd2O3 surface layer around Gd core. Even in the absence of Pd over layer Gd nanoparticles shows similar structural, optical and electrical properties because of the improved stability in air. Because of the large number of surface atoms it is possible to hydrogenate the Gd nanoparticles. It is observed that though it is possible to hydrogenated bare Gd nanoparticles at room temperature and atmospheric pressure, deloading needs higher temperatures. This makes bare Gd nanoparticles a possible candidate for hydrogen storage applications. Further work is in progress to understand H-rare earth nanoparticle interaction and to fabricate single nanoparticle switching devices. One of the authors (I. Aruna) is grateful to University Grants Commission, India for providing the Senior Research Fellowship for carrying out this work.

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REFERENCES [1] Huiberts, J. N., Griessen, R., Rector, J. H., Wijngaarden, R. J., Dekker, J. P., de Groot, D. G., Koeman, N. J. (1996). Nature, 380, 231. [2] Griessen, R., Huiberts, J. N., Kremers, M., van Gogh, A. T. M., Koeman, N. J., Dekker, J. P., Notten, P. H. L. (1997). J. Alloys Comp., 253, 44. [3] van der Molen, S. J., Kerssemakers, J. W. J., Rector, J. H., Koeman, N. J., Dam, B., Griessen, R. (1999). J. Appl. Phys., 86, 6107. [4] Notten, P. H. L., Kremers, M. & Griessen, R. (1996). J. Electrochem. Soc., 143, 3348. [5] Kooij, E. S., van Gogh, A. T. M. & Griessen, R. (1999). J. Electrochem. Soc., 146, 2990. [6] Lee, M. W. & Lin, C. H. (2000). J. Appl. Phys., 87, 7798. [7] Azofeifa, D. E. & Clark, N. (2000). J. Alloys Comp., 305, 32. [8] Ball, P. (1998). Nature, 391, 232. [9] Kerssemakers, J. W. J., van der Molen, S. J., Koeman, N. J., Gunther, R. & Griessen, R. (2000). Nature, 406, 489. [10] Armitage, R., Rubin, M., Richardson, T., O‘Brien, N. & Chen, Y. (1999). Appl. Phys. Lett., 75, 1863. [11] van der Sluis, P., Ouwerkerk, M. & Duine, P. A. (1997). Appl. Phys. Lett., 70, 3356. [12] von Rottkay, K., Rubin, M. & Duine, P. A. (1999). J. Appl. Phys., 85, 408. [13] Ouwerkerk, M. (1998). Solid State Ionics, 113, 431. [14] Isidorsson, J., Giebels, I. A. M. E., Kooij, E. S., Koeman, N. J., Rector, J. H., Gogh, A. T. M. & Griessen, R. (2001). Electrochimica Acta, 46, 2179.

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[15] Giebels, I. A. M. E., Isidorsson, J., Kooij, E. S., Remhof, A., Koeman, N. J., Rector, J. H., van Gogh, A. T. M. & Griessen, R. (2002). J. Alloys Comp., 330-332, 875. [16] van der Sluis, P. (1998). Appl. Phys. Lett., 73, 1826. [17] Baraille, C., Pouchan, M. & Causa, C. (1994). Pisani, Chem. Phys., 179, 39. [18] Aruna, B. R., Mehta, L. K. & Malhotra, S. M. (2004). Shivaprasad, Adv. Mater., 16, 169. [19] Alivisatos, A. P. (1996). J. Phys. Chem., 100, 13226. [20] Lippens, P. E. & Lanno Phy. M. (1989). Rev. B, 39, 10935. [21] Balamurugan, B., Mehta, B. R. & Shivaprasad, S. M. (2001). Appl. Phys. Lett., 79, 3176. [22] Balamurugan, B., Mehta, B. R. & Shivaprasad, S. M. (2003). Appl. Phys. Lett., 82, 115. [23] Babudayal, P., Mehta, B. R., Aparna, Y. & Shivaprasad, S. M. (2002). Appl. Phys. Lett., 81, 4254. [24] Singh, V. N. & Mehta, B. R. (2003). Jpn. J. Appl. Phys., 42, 4226. [25] Suguna, P., Mangalaraj, D., Sa. K. & Narayandass, P. (1996). Meena, Phys. Stat. Sol. (a), 155, 405. [26] Niquet, Y. M., Allan, G., Delerue, C. & Lannoo, M. (2000). Appl. Phys. Lett., 71, 1182. [27] Kruis, F. E., Fissan, H. & Peled, A. (1998). J. Aerosol Sci., 29, 511. [28] Muller Book [29] Michels, D., Krill, III, C. E., Birringer, R. (2002). J Magn. Magn. Mater., 250, 203. [30] Talik, E. & Neumann, M. (1995). J Magn. Magn. Mater., 140, 795. [31] Talik, E., Neumann, M. & Mydlarz, T. (1998). J Magn. Magn. Mater., 189, 183. [32] Bour, G., Reinholdt, A., Stepanov, A., Keutgen, C. & Kreibig, U. (2001). Eur. Phys. J. D, 16, 219. [33] Si, P. Z., Skoprvanek, I., Kovac, J., Geng, D. Y., Zhao, X. G. & Zhang, Z. D. (2003). J. Appl. Phys., 94, 6779. [34] Aruna, B. R., Mehta, L. K. & Malhotra, S. M. Shivaprasad, (communicated to Adv. Func. Mater).

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INDEX

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A A, 76 abdomen, 218, 219, 231, 232, 239, 240, 246 abnormalities, 248, 262, 339 absorption, viii, 53, 70, 71, 72, 74, 85, 87, 88, 89, 90, 91, 92, 97, 103, 107, 110, 111, 130, 131, 133, 136, 137, 198, 230, 246, 267, 268, 271, 273, 280, 285, 286, 287, 313, 342, 345 absorption coefficient, 70 academic, 154, 229, 337 acceptors, 12 acetate, 18, 35 acetic acid, 307 acetone, 110, 111, 112, 116, 117, 118, 119 acid, 16, 18, 19, 21, 22, 24, 25, 26, 28, 29, 31, 32, 36, 194, 195, 196, 197, 198, 199, 200, 201, 204, 206, 208, 209, 213, 215, 233, 236, 237, 247, 266, 274, 307, 336 acidic, 198 ACR, 233, 242, 259, 339 ACS, 192 activation, 54, 76, 333 acute, ix, 143, 144, 160, 172, 189, 198, 224, 238, 243, 247, 248, 249, 251, 252, 253, 258, 259, 260, 263, 327, 328 acute kidney injury, ix, 143, 144, 172 acute renal failure, 238, 243, 328 acute tubular necrosis, 327 additives, 109, 118, 119, 138, 270 adenocarcinoma, 240 adenoma, 226, 233, 235 adenomas, 233 adenosine, 250, 251, 260 adenovirus, 261 adipose, 181 adipose tissue, 181

adsorption, 201, 207, 344 AFM, 36, 37, 343, 344 aggregates, 177, 183 aggregation, 203 agriculture, 296 alanine, 266, 267, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294 albumin, 238 allergic reaction, 144 allografts, 153 alloys, xi, 301, 302, 303, 304, 305, 306, 307, 308, 312, 314, 316 alpha, 54, 108, 132, 133, 209, 257, 332 alpha-fetoprotein, 209 alternative, viii, 143, 144, 147, 149, 160, 162, 170, 173, 197, 240 alternatives, 200 alters, 3 aluminum, 123 ambient pressure, 14 American Heart Association, 248 amide, 207 amine, 19, 203, 231, 208, 295 amino, 32, 203, 204, 209 amino groups, 204 ammonia, 44, 45, 46 ammonium, 267, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 294 amplitude, 107, 108, 113, 114, 115, 116, 138, 275, 277, 278, 279, 281, 284, 285, 293 amyloid, 256, 257 amyloid fibrils, 256 amyloidosis, 256, 261 anatomy, 246, 322, 327 angina, 255 angiogram, 148, 151

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352

Index

angiography, 149, 150, 152, 162, 169, 211, 233, 241, 242, 333 angular momentum, 62 animal studies, 156, 159 animals, 147, 155, 156, 159, 168, 210 anode, 80, 108, 111, 112, 113, 114, 115, 118, 119, 120, 121, 124, 126, 127 anodes, 127 antibody, 195, 209, 210 anticancer drug, 210 antiferromagnetic, vii, viii, 1, 2, 4, 14, 16, 17, 19, 21, 22, 26, 32, 36, 38, 39, 40, 42, 45, 48 antigen, 208 antisense, 208 aorta, 222, 224, 232, 238 apoptosis, 184, 185 application, xi, 69, 101, 102, 125, 128, 137, 187, 195, 200, 209, 211, 218, 220, 246, 259, 301, 302, 313, 314 aqueous solution, 13, 198, 200, 202, 203, 204 arginine, 208 argon, 110, 111, 112, 113, 116, 117, 118, 119, 137, 342, 343 arrhythmias, 253, 255, 256, 257 arterial hypertension, 173 arteries, 221, 222, 223, 224, 232, 242, 250, 318, 326 arteriography, 162 artery, x, 162, 163, 173, 222, 224, 246, 247, 248, 250, 252, 254, 259, 260, 326 ascites, 179 ASI, 49 assessment, x, 162, 164, 238, 241, 245, 247, 250, 252, 259, 260, 261, 333 asthma, 188 asymptomatic, 194, 261, 262 atherosclerosis, 211 atmosphere, xi, 127, 209, 301, 306, 307, 311 atmospheric pressure, 103, 106, 107, 349 atomic nucleus, 61, 65 atoms, 2, 4, 12, 13, 14, 18, 21, 24, 26, 28, 29, 32, 35, 41, 45, 65, 66, 67, 109, 134, 136, 140, 173, 177, 195, 209, 210, 266, 267, 328, 342, 346, 349 ATP, 320, 321, 329 atria, 256 Auger electrons, viii, 53, 55, 56, 57, 62, 63, 64, 65, 80, 81, 82, 83, 84, 85, 86, 87, 103, 113, 135, 136 autoimmune, 174, 252 autoimmune disorders, 174 autopsy, 169, 174, 178, 187, 254, 257, 261 autoradiography, 129 Avogadro number, 66

B background radiation, 124 backscattered, 128, 173 backscattering, 124 band gap, xii, 342, 345 barium sulphate, 273 barrier, 55, 106, 127, 192, 345 basal lamina, 175, 177, 178, 183 BCA, x, 217, 247 beams, 123, 125, 265, 267, 268, 271, 275, 281, 282, 283, 287, 290, 291, 292, 294 beating, 331, 332 benefits, 158, 160, 218, 230, 242, 250, 302, 314, 315, 318, 328, 329 benign, viii, ix, 143, 160, 193, 194, 195, 224 benzene, 132 beryllium, 121 bile duct, 168, 233 biliopancreatic, 190 binding, 12, 135, 145, 146, 157, 184, 194, 199, 201, 208, 232, 233, 235, 237, 238, 345, 348 binding energies, 135, 268 binding energy, 268, 348 biocompatible, ix, 179, 193, 195, 199, 200, 201, 203, 207, 209, 214 biodegradable, 199, 205, 214 biological consequences, 191 biological interactions, 213 biomarkers, 197 biomaterials, 302 biomedical applications, 199, 200 biopsies, 172, 180, 181, 182 biopsy, 154, 172, 174, 178, 252, 256, 257, 262 biotin, 209 biotransformation, 145 bladder, 208 blends, 273, 277, 278, 279, 280, 281, 282, 286, 287, 294 blocks, 31, 174, 204, 307 blood, 146, 147, 174, 175, 176, 177, 178, 182, 183, 184, 188, 192, 194, 196, 203, 204, 207, 215, 218, 220, 230, 232, 238, 246, 247, 251, 256, 257, 259 blood flow, 247 blood supply, 230, 251 blood urea nitrogen, 147 blood vessels, 182, 183, 257 BMA, 196, 237 body fluid, 168 body temperature, 197 body weight, 145, 201, 232, 328 Bohr, 4 boiling, 305

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Index Boltzman constant, 4 Boltzmann distribution, 5 bolus, 222, 230, 233, 247, 250, 256 bonding, 12, 26, 184, 231, 312 bonds, 32, 231 bone, 266, 271, 295 bone marrow, 159, 172 borderline, 194 boric acid, 280 Boron, 132, 133 bovine, 209 bowel, 179, 180 bowel obstruction, 179 brain, 153, 246 branching, 61 breakdown, 119, 120 breast cancer, 212, 231, 240 breathing, x, 217, 219, 222 bubble, 313, 322 buffer, 200 burning, 153 butane, 80 by-products, 314

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C Ca2+, 157, 158 CAD, 250 calcium, 144, 156, 157, 159, 172, 176, 178, 182, 190 calculus, 27 calibration, 266, 279, 280, 294, 307 cancer, 194, 200, 209, 213, 215, 243, 294 cancer cells, 209, 294 candidates, 128, 202, 347 capillary, x, 56, 108, 131, 132, 133, 137, 218, 223, 224, 245, 248, 251 caprolactone, 204, 205 carbohydrate, 203 carbon, 42, 176, 177, 192, 195, 206, 212, 213, 272, 306 carbon atoms, 42, 177 carbon dioxide, 213 carbon nanotubes, 195 carboxylic, 12 carboxylic groups, 12 carcinoma, ix, 193, 194, 198, 200, 206, 211, 219, 224, 227, 228, 230, 236, 240 carcinomas, 224, 233 cardiac arrest, 319 cardiac catheterization, 151 cardiac involvement, 256, 257, 258, 262 cardiology, 246 cardiomyopathy, 251, 253, 254, 255, 260, 261

353

cardiovascular disease, x, 245, 259 carotid arteries, 173 carrier, 195, 197, 199, 203 cast, 304, 306, 307, 308, 312 casting, xi, 301, 303, 305, 306, 307, 315 catalysis, 2 catheter, 160, 180 catheterization, 151 cathode, 120, 121, 124, 126, 127 causal relationship, 183 cavities, 202, 256 CDC, 153 cell, ix, 144, 147, 168, 175, 177, 178, 181, 182, 185, 186, 192, 193, 200, 206, 208, 209, 210, 214, 215, 226, 247, 248, 251, 253, 259, 333 cell culture, 206 cell cycle, 192 cell death, 168, 248, 253, 259 cell line, 214 cell membranes, 144, 247 cell surface, 200 cellular phone, ix, 168 cellular phones, ix, 168 cellulose, 271, 295 Centers for Disease Control, 153 central nervous system, 144, 168 cerium, 16 CERN, 141 cervical carcinoma, 206 channels, 115, 135, 144, 168 charged particle, viii, 53, 54, 55, 56, 57, 65, 66, 67, 106, 107, 111, 112, 114, 123, 130, 139, 140 chelates, ix, 22, 145, 155, 156, 157, 159, 160, 169, 171, 172, 182, 184, 185, 193, 194, 198, 200, 210, 213, 231, 233, 258, 329 chelating agents, 204 chemical etching, 307 chemical interaction, 305 chemical structures, 204 chemokine synthesis, 159 chemotherapy, 210, 215 chirality, 12 chitosan nanoparticles, 200, 213 chloride, 22, 186 cholangiocarcinoma, 229 cholangitis, 229 chromatin, 181 chromium, 306 chronic kidney disease, 150, 164, 191, 238 chronic renal failure, 161, 162, 164 CIN, 147, 148, 152, 239 circulation, 157, 168, 196, 199, 203, 204, 207, 222, 232, 322, 323, 326, 327

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Index

CKD, 146, 149, 150, 151, 152, 153, 154, 155, 157, 159, 160, 164 classical mechanics, 5 claustrophobic, 338 clinical diagnosis, 154 clinical presentation, 252 clinical symptoms, 164, 257 clinically significant, 150 clusters, 195 CO2, 44, 148, 149, 162, 209, 314 coagulopathy, 258 cohesion, 202 cohort, 149, 163, 243 coil, 230, 320, 321, 322 collagen, 155, 159, 169, 172, 174, 175, 177, 178, 181, 183, 184, 188, 200, 251, 257 collisions, 56, 65, 66, 67, 68, 136, 140, 342 colloidal particles, 197, 215 combustion, xi, 301, 306, 307, 310, 311, 313, 315 common bile duct, 234 communication, xii, 163, 335, 336, 338, 339 community, 259 co-morbidities, 144, 146 compatibility, 319 compensation, 45 competitiveness, 339 complement, 207 complement system, 207 compliance, 42, 219 complications, 14, 144 components, xi, 11, 41, 65, 67, 69, 71, 110, 123, 136, 184, 199, 238, 251, 252, 301, 302 composites, 200 composition, xi, 57, 71, 107, 129, 141, 173, 196, 200, 206, 246, 267, 273, 274, 293, 301, 303, 304, 305, 307, 308, 314 compounds, vii, xii, 1, 2, 7, 12, 14, 16, 18, 19, 21, 22, 28, 30, 31, 38, 39, 40, 43, 44, 88, 169, 170, 184, 185, 189, 258, 267, 269, 271, 273, 294, 314, 335, 336, 337, 338, 348 comprehension, vii, 1, 48 Compton electrons, 85 computed tomography, 144, 232, 243, 250, 260, 339 concentration, 116, 117, 118, 119, 131, 138, 148, 149, 150, 151, 152, 154, 159, 197, 198, 199, 206, 207, 210, 231, 237, 303, 328, 331, 347 condensation, 347 conduction, 168, 257, 345 conductive, 129 conductivity, 304, 305, 306, 313 conductor, 91, 137 configuration, 56, 129, 131, 168 confinement, xii, 342, 344, 345

congestive heart failure, 239, 257 conjugation, 199, 203, 207 connective tissue, 159, 175, 178, 182, 183 connectivity, 312 consensus, 257 consent, 56, 160, 314 constant rate, 311 constraints, 12, 230, 302 construction, 61, 108, 133, 134, 135, 306 consumption, 314 contamination, 129, 183 control, 14, 115, 118, 124, 129, 149, 150, 151, 152, 153, 155, 156, 163, 180, 181, 191, 231, 303, 313 control group, 149, 150, 151, 152 controlled trials, 243 convergence, 164 conversion, viii, 45, 53, 55, 57, 59, 61, 62, 63, 64, 72, 82, 85, 91, 92, 98, 103, 106, 107, 109, 110, 112, 113, 114, 115, 116, 119, 125, 129, 130, 131, 133, 134, 135, 136, 137, 138, 328, 342 cooling, 304, 306, 308, 311, 331 copolymer, 200, 201, 202, 203, 205 copolymers, 199, 201, 203, 204 copper, 41, 44, 45, 127, 145, 157, 173, 305 core-shell, 212 coronary arteries, 253 coronary artery disease, x, 173, 246, 247, 252, 254, 259, 260 correlation, viii, 2, 40, 41, 43, 46, 49, 194, 198, 201, 204, 255 correlation function, 41 correlations, 43, 262 corrosion, 303, 305, 314 cortex, 221, 222, 223, 224, 322, 323, 327, 328 cost-effective, 210, 332 Coulomb, 65, 136 coupling, vii, viii, 1, 2, 3, 4, 11, 19, 22, 24, 27, 35, 41, 42, 43, 44, 45, 46, 48, 49, 254 coupling constants, 35, 41, 42 covalent, 12 covering, 343 COX-2, 211 C-reactive protein, 159, 164 creatinine, 145, 147, 148, 149, 150, 151, 152, 159, 239 cross-sectional, 338 crystal growth, 14 crystal lattice, 312 crystal structure, 13, 16, 32, 347 crystal structures, 13 crystalline, 203 crystallinity, 342 crystallization, 306

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Index crystals, 14, 95, 274, 312 CSS, 327, 329 CT scan, 144, 147, 160 culture, 206 cycles, 342 cyclodextrin, 202, 213 cysts, 220, 225, 230 cytokines, 154, 158, 159, 165 cytoplasm, 175, 183 cytoskeleton, 174 cytotoxicity, 184, 190

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D damping, 314 database, 62, 72, 167, 211 death, 194, 251, 255, 257, 262 deaths, 254, 257 decay, 28, 33, 61, 76, 135 decision-making process, 255 defects, 257, 347 defense, 337 deficiency, 257 deficit, 250 definition, 3, 112, 318 deformation, 127, 312 dehydration, 239 delivery, 194, 196, 200, 201, 203, 208, 209, 210, 211, 212, 213, 218 delocalization, 44 demographics, 155 dendrimers, 195, 204, 205, 214 density, 3, 41, 43, 57, 58, 66, 69, 70, 71, 76, 87, 106, 114, 123, 139, 208, 302, 307 density functional theory, 41 deposition, 125, 127, 154, 155, 156, 163, 164, 178, 184, 186, 187, 191, 257, 268, 342, 343 deposits, 154, 163, 168, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 187, 188, 191 derivatives, 202, 208, 214 dermatology, 155, 167 dermis, 175, 177, 178 deviation, 121 DFT, 27, 41 diabetes, 146, 150, 151, 152, 173, 239 diabetes mellitus, 146, 150, 151, 152, 173 dialysis, 146, 152, 153, 157, 159, 160, 162, 164, 169, 170, 179, 183, 186, 187, 188, 190, 191, 203, 236, 239, 329, 331 diamagnetism, 3, 4 diamond, 183, 307 diaphragm, 153 differentiation, 175, 184, 189, 206, 233

355

diffraction, 16, 203, 307, 308, 343 diffusion, 14, 124, 127, 198, 274 diffusivity, 346 digital images, 307 dilated cardiomyopathy, 259, 260, 261 dilation, 254 dimensionality, 14 dimer, 7 dimethylformamide, 19, 32 diodes, 133 dipole moment, 3 direct observation, xi, 301, 315 discipline, 194 discomfort, 338 discrimination, 249 disease progression, 240 diseases, 186, 218, 229, 233 dislocation, 338 dislocations, 312 disorder, 153, 170, 172, 179, 183, 184, 186, 253 dispersion, 184, 196, 198, 199 displacement, 118 disposition, 55 disseminate, xii, 335 dissociation, x, 145, 156, 201, 218, 231, 238, 341 distilled water, 203 distribution, x, 5, 41, 43, 108, 118, 121, 134, 135, 145, 146, 173, 176, 178, 183, 200, 207, 232, 245, 248, 253, 254, 255, 259, 306, 314, 318, 322, 323, 344 diversity, 12 division, 189 DMF, 19, 32 DNA, 215 Dobutamine, 260 doctors, xii, 335, 336, 337, 338, 339 donor, 12, 45, 331, 332 donors, 318, 319, 331, 332 doped, 132, 133 doping, 133 dosage, 169 dosing, 155, 250 DOT, 208 drainage, 218 drug delivery, 195, 198, 200, 210, 214, 215 drug discovery, 194 drug therapy, 209, 210 drugs, 170, 195, 198, 210, 214 ductility, 303, 306 dura mater, 258 duration, 180, 219, 259, 322, 327 dyspnea, 170, 255 dysprosium, 186

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E earth, ix, 2, 3, 41, 44, 167, 186, 246, 302, 341, 342, 349 ecological, ix, 168 economic performance, 306 edema, 172, 249, 254 egocentrism, xii, 335, 339 EKG, 257 electric field, 65, 102, 103, 106, 109, 110, 112, 127, 136, 137 electrical properties, 347, 349 electrical resistance, 344 electrodes, 107, 108, 109, 110, 119, 129, 140 electrolytes, 341 electromagnetic, 61, 135, 314 electron diffraction, 203 electron microscopy, 129, 154, 172, 173, 174, 175, 178, 185, 190, 191, 200, 206, 307, 343 electron paramagnetic resonance, 205, 295 electronic circuits, 135 electronic structure, 41 electrophoresis, 174 electrostatic force, 198 elongation, xi, 301, 303, 304, 307, 312, 315 emboli, 168 embryo, 192 emission, 57, 61, 62, 64, 65, 72, 75, 82, 83, 86, 95, 97, 99, 100, 107, 114, 123, 124, 125, 129, 136, 189, 246, 250, 260, 269, 314 emitters, 95 emulsifier, 198 encapsulated, 196, 197, 199, 204, 205, 207 encapsulation, 201, 204 encoding, 240 endocrine, 240 endocytosis, 208 endometritis, 190 endothelial cell, 180, 181, 200 end-stage renal disease, 163, 172, 187 energy consumption, 314 energy transfer, 66, 67, 68, 267, 268, 273 environmental issues, xi, 301, 302, 314, 315 enzymes, 144, 147, 208 epicardium, 248, 257 epidermis, 174 epithelial cell, 147 epithelial cells, 147 epitopes, 194 EPR, 203, 204, 205, 214 equilibrium, 250, 302, 304, 314 equilibrium state, 250 equipment, 266

erythropoietin, 158, 159, 172 ESI, 173, 176, 177, 178, 180, 182, 183 esophagus, 153 ESR, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 299 ESR spectra, 275, 276, 284 ester, 206, 207 esters, 198 ethanol, 19, 132, 307 ethanolamine, 196 ethylene glycol, 201 ethylene oxide, 215 ethylenediamine, 206 etiology, 153, 257 etiopathogenesis, 179 evaporation, 123, 198, 313, 342, 343 examinations, 174, 180, 184, 230, 243, 338 exchange rate, 194, 204 excitation, 61, 64, 65, 66, 67, 68, 86, 130, 131, 136, 219, 220, 221, 240 exclusion, 145, 252 excretion, 168, 234, 235 extracellular matrix, 200 extraction, 125, 126, 127, 174, 314 extrapolation, 81 extrusion, 303, 304, 312

F fabricate, xii, 341, 342, 349 fabrication, 127, 135, 203, 214 Fabry disease, 257, 262 family physician, 339 fat, 197, 219, 220, 221, 224, 225, 226, 227, 228, 229, 230, 234, 235, 236 ferrite, 211 ferromagnetic, vii, 1, 4, 18, 19, 22, 24, 25, 27, 28, 31, 38, 39, 40, 42, 43, 45, 48 fetal, 209 fiber, 132, 175, 178, 184 fibrils, 177, 200, 256 fibroblast, 159, 192, 200 fibrocytes, 158, 159, 169, 172, 174, 175, 180, 181, 182, 183, 184, 188, 191 field-emission, 189 films, xii, 92, 94, 95, 97, 130, 137, 341, 342, 343, 344, 345, 347, 348, 349 filters, 196 filtration, 144, 145, 147, 148, 152, 170, 172, 238, 258 fission, 54, 76, 128, 271

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FITC, 209 flexibility, 12, 170, 200 flow, xi, 78, 246, 247, 251, 307, 317, 318, 319, 322, 323, 327, 328, 332, 342, 343 flow rate, 307, 343 fluctuations, 122 fluid, 151, 169, 198, 213, 247 fluid extract, 213 fluorescence, 65, 208, 209 fluoride, 44, 46 fluorine, 44 flushing, 318, 329 FMC, 245 foils, viii, 54, 55, 56, 71, 72, 73, 74, 76, 84, 95, 102, 103, 106, 108, 125, 127, 133, 136, 137, 139 folate, 208, 215 folic acid, 195, 208 Food and Drug Administration (FDA), 145, 147, 155, 159, 161, 170, 218, 238, 258, 263 formula, 273 fracture, 307 free energy, 347 free radicals, 190, 266, 267, 271, 273, 274, 275, 285, 289 fuel, 314 fullerenes, 195, 206 fumarate, 24, 35 FWHM, 107, 108, 114, 116, 117, 119, 123, 125, 135, 138, 347

G G4, 206 Gamma, 86 gamma radiation, 85 gamma rays, 54, 61, 132 gas, viii, 54, 55, 56, 91, 102, 103, 107, 108, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 129, 137, 141, 307, 313, 314, 341, 342, 343, 347 gas phase, 341, 343 gases, 66, 94, 109, 110 gastrointestinal, 169 Gaussian, 41 gel, 13, 14 gelation, 199 gene, 200, 213 generation, 205, 206, 208, 246, 337, 338 Geneva, 317 geometrical parameters, 39, 46 Germany, 167, 169, 173, 231, 232, 233, 237 GH, 188 Gibbs, 347

Gibbs free energy, 347 GL, 49, 185, 186, 192 gland, 185 glass, 125, 131, 132 glutamic acid, 199 glutaraldehyde, 209 glutathione, 332 Glutathione-S-Transferase, 328 glycans, 200 glycine, 208 glycol, 201 glycosylated, 211 God, 337 gold, x, 121, 245, 251 gold standard, x, 245, 251 google, 167 Gore, 259 government, iv grading, 242 grain, 303, 304, 305, 308, 313, 315 grain boundaries, 305, 308, 315 grain refinement, 306, 308 grains, 304, 305, 308, 312, 313 granules, 129, 181 graphite, 307 gravity, 127, 307 grids, 119, 120, 125, 126, 173 groups, viii, 2, 12, 32, 36, 40, 43, 44, 46, 72, 94, 143, 147, 148, 150, 151, 152, 156, 160, 172, 194, 200, 203, 204, 207, 208, 239 growth, 14, 95, 97, 106, 107, 123, 159, 200, 201, 209, 210, 213, 342 growth factor, 159 GST, 328 guidelines, 242, 339

H H1, 322 H2, 341, 343 half-life, 58, 145, 158, 172, 183, 194, 204, 258 hamartomas, 227 Hamiltonian, 6, 24 handling, x, 185, 217, 229 hardness, 303, 304, 306, 313 harm, ix, 168, 246 harvesting, 331 health, 160, 167, 170, 210 health care, 160, 210 heart, 153, 179, 239, 246, 250, 251, 253, 254, 257, 259, 260, 331, 332, 339 heart disease, 260 heart failure, 251, 254, 257, 259

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Index

heat, 304, 314, 341 heat capacity, 314 heating, xi, 301, 306, 307, 310, 312, 313 heating rate, 306, 307 heavy metal, 173, 175, 179, 185 heavy metals, 185 height, 107, 115, 123, 124, 307, 343 hemangioma, 225 hemisphere, 71, 75, 78, 85, 95, 96, 97, 108 hemodialysis, 146, 155, 157, 159, 160, 162, 164 hemoglobin, 183 hepatitis, 224 hepatobiliary system, 232 hepatocellular, ix, 193, 194, 198, 211, 219, 224, 226, 230, 233, 240 hepatocellular carcinoma, ix, 193, 194, 198, 211, 219, 224, 230, 233, 240 hepatocyte, 233, 234, 235 hepatocytes, 195, 196, 233 heterogeneous, 227, 235, 306 high pressure, 54, 198, 212, 304 high resolution, 135, 183 high risk, 147, 172, 238 high temperature, 14, 348 high-energy physics, 133 higher quality, 229 high-risk, ix, 143, 148, 157, 160, 241, 263 HIS, 49 histidine, 332 histogram, 59, 62 histological, 156, 174, 262, 331 histology, 156, 191, 260 histopathology, 155, 174 HIV, 208 HIV-1, 208 HK, 50, 213, 240 homogeneity, 228 hospital, 147, 259 hospitalizations, 254 human, 132, 147, 155, 167, 173, 184, 191, 201, 209, 212, 231, 253, 260 humans, ix, 168, 172, 217, 218, 231, 314 hybrid, 41, 56, 107, 137, 140, 195, 212 hydration, 15, 196 hydrides, 341 hydro, 195, 199, 203, 204, 215 hydrogen, xii, 12, 42, 69, 270, 272, 274, 341, 342, 343, 344, 346, 347, 348, 349 hydrogen abstraction, 272 hydrogen atoms, 42, 274 hydrogen bonds, 12 hydrogenation, 341, 342, 344, 347, 348 hydrolysis, 204, 205

hydrophilic, 195, 199, 203, 204, 215 hydrophobic, 195, 196, 197, 202, 203, 204 hydrothermal, 14, 15 Hydrothermal, 50 hydrothermal synthesis, 15 hyperemia, 251 hyperplasia, 225, 226, 233, 234 hypertension, 150, 151, 152 hypertrophic cardiomyopathy, 261 hypertrophy, 255, 256, 257 hypothermia, 323 hypothesis, 159, 165, 180, 184

I IAEA, 139 ICD, 251, 255 idiopathic, 188 imagery, 210 imagination, 198 imaging modalities, 160, 194, 210, 258, 259 imaging systems, 229 imaging techniques, 147, 229, 241, 260, 262 immersion, 307 immunodeficient, 209 immunohistochemistry, 180 immunosuppressive, 170 immunosuppressive agent, 170 implants, 246 in situ, 133, 144, 184, 189, 191, 318 in vitro, 145, 184, 196, 198, 200, 206, 207, 208, 212, 213 in vivo, ix, 144, 164, 188, 192, 194, 200, 201, 206, 207, 208, 209, 210, 213, 214, 217, 218, 231 incidence, viii, 55, 62, 66, 67, 68, 69, 78, 79, 114, 115, 116, 143, 149, 153, 154, 163, 179, 180, 191, 194, 238, 239, 241, 252, 257, 263 inclusion, 31, 39, 40, 41, 198, 202, 204 incubation, 201 independence, 266, 291 indication, 88, 247 induction, 185, 190 industrial, xi, 107, 129, 199, 301, 302, 313, 314 industrial application, 302, 313 industry, ix, xi, 167, 168, 185, 301, 307 inelastic, 72, 173, 176, 177 inert, 129, 144, 164, 205, 342, 343, 347 inertia, 336 infarction, 248 infection, 159, 252 infections, 179 infectious, 170

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Index inflammation, x, 158, 159, 172, 245, 247, 251, 252, 254, 260, 262 inflammatory, x, 159, 165, 172, 174, 175, 181, 229, 245, 246, 247, 251, 252, 253, 257, 258, 260, 329, 337 inflammatory bowel disease, 229 inflammatory cells, 175, 329 inflammatory disease, 257 informed consent, 160 infusions, 168, 183 inhibition, 186 initiation, 173, 222, 228 injection, x, 145, 150, 151, 152, 156, 160, 161, 162, 169, 179, 183, 200, 204, 209, 212, 218, 220, 222, 225, 228, 231, 232, 233, 235, 236, 245, 247, 250, 256, 318, 324, 325, 329 injections, 180 inorganic, 195 insertion, 255 insight, 156, 184, 185, 268, 283 institutions, 238 insults, 327 integration, xi, 199, 301 integrity, 327 intensity, 344 interface, 14, 197, 312, 341, 347, 349 intermetallics, 303, 305 interstitial, x, 145, 159, 181, 217, 218, 219, 220, 221, 225, 226, 228, 229, 232, 233, 234, 235, 236, 254, 255, 256, 318, 323, 325, 326, 327, 329, 347 intervention, 163, 170, 336 intraperitoneal, 179 intrauterine contraceptive device, 190 intravascular, 233, 238 intravenous, 144, 145, 146, 148, 149, 150, 151, 159, 162, 169, 200, 204, 214, 231, 232, 235, 258, 337 intravenous fluids, 150 intravenously, 215, 337 intrinsic, 114, 116, 130, 219 introversion, 338 invasive, x, 245, 252, 261 inversion, 19, 29, 31, 37, 38, 39, 249 inversion recovery, 249 iodinated contrast, 151, 162, 169, 173, 232, 239, 258, 337 iodinated contrast material, 162 iodine, 163, 232 Iodine, 246 ion channels, 144, 168 ionic, 2, 144, 145, 146, 151, 155, 156, 157, 159, 168, 169, 197, 231, 232, 237, 258, 337 ionicity, 232

ionization, 65, 66, 69, 70, 106, 107, 109, 110, 111, 112, 113, 119, 123, 126, 135, 136, 139, 177, 272 ionizing radiation, 129, 259, 265, 266, 267, 268, 271, 287 iron, 154, 157, 159, 172, 177, 178, 182, 183, 184, 191, 194, 195, 247, 305 irradiation, 64, 76, 77, 80, 132, 201, 265, 266, 271, 273, 274, 278, 280, 283, 287, 288, 290, 292, 293, 294 irradiations, 56 ischemia, x, 245, 248, 251, 318, 319, 324, 327, 333 ischemic, xi, 149, 151, 224, 248, 251, 253, 254, 255, 257, 259, 260, 261, 317, 318, 326, 327, 328, 329 isobutane, 123, 126 isolation, 337 isotope, viii, 53, 55, 56, 57, 58, 59, 60, 74, 75, 79, 81, 82, 83, 84, 85, 92, 94, 95, 97, 116, 136, 271, 275 isotopes, viii, 53, 54, 58, 60, 73, 74, 76, 81, 95, 128, 129, 135, 136, 139 isotropic, 7, 58, 71, 72, 103, 114 IVC, 223

K kidney, viii, ix, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 155, 156, 157, 158, 159, 160, 161, 164, 169, 172, 189, 190, 191, 238, 318, 324, 327, 328, 329, 331, 332, 333 kidney transplantation, 191 kidneys, xi, 144, 145, 153, 156, 232, 233, 258, 317, 318, 319, 322, 324, 327, 328, 329, 331, 332, 333 kinetic energy, 62, 65, 68, 136, 342 kinetics, 207, 251, 256, 342 knees, 170, 171

L L1, 64, 86 L2, 64 labeling, 200, 206 lack of control, 152 lactating, 185 lactic acid, 199, 201, 215 lamella, 207 lamellar, 196 lamina, 175, 177, 178, 183 lanthanide, vii, 1, 2, 3, 7, 12, 13, 14, 16, 22, 29, 31, 36, 41, 144, 328 large-scale, 135 laser, 130, 348 laser ablation, 348

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Index

late-stage, 195 latex, 213 lattice, 203, 218, 312, 347 lattices, 203 leakage, 134, 158, 184, 196, 204, 318, 325, 326, 329 lecithin, 198 lectin, 199, 213 left ventricle, 250, 254, 255, 256 left ventricular, 248, 255, 262 legal issues, 336 lesions, ix, xi, 153, 155, 156, 164, 169, 181, 183, 184, 193, 194, 195, 223, 224, 225, 226, 227, 229, 230, 231, 233, 242, 262, 317, 318, 326, 327, 329 LGE, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257 liberation, 145 life-threatening, 170, 179, 231, 256 lifetime, 134, 194, 207, 258 ligands, viii, ix, 1, 2, 12, 13, 14, 16, 17, 19, 21, 24, 25, 27, 28, 29, 31, 32, 35, 36, 43, 44, 45, 46, 48, 168, 208, 217, 218, 231 limitations, 153, 200 linear, 5, 6, 66, 144, 146, 155, 156, 157, 158, 159, 160, 168, 169, 170, 182, 199, 229, 231, 238, 303, 328 linear dependence, 303 linear function, 278, 280, 292 lines of force, 3 links, 13, 21, 27, 28, 31 lipid, ix, 193, 195, 196, 197, 198, 207, 212, 213, 214 lipophilic, 214 liposomal membrane, 197 liposome, 196, 197, 207, 211 liposomes, 186, 195, 196, 197, 207, 212, 214, 215 lithium, 267, 282 litigation, 336, 339 liver, ix, 153, 159, 169, 179, 185, 186, 187, 188, 193, 194, 195, 201, 207, 208, 209, 210, 211, 212, 214, 218, 219, 221, 222, 223, 224, 225, 227, 228, 230, 231, 232, 233, 234, 235, 239, 240, 241, 242, 258 liver cells, 195 liver damage, 240 liver disease, 159, 188, 223, 241 liver metastases, 231, 240 liver transplant, 187, 227, 258 liver transplantation, 187, 258 lobby, 55, 83, 97, 103 localised, 180 localization, 107, 123, 124, 126, 173, 177, 182, 184, 192, 199, 200, 262 location, 123, 124, 196, 248, 259 locus, 125 long period, 124

long-term retention, 156, 164 losses, 56, 65, 66, 70, 71, 111, 112, 136 low molecular weight, 194 low power, 127 low risk, viii, 143, 158 low temperatures, 3 low-density, 123 lubricants, 307 lumen, 160, 175, 204 luminescence, 129 lungs, 153, 170, 190, 194, 212, 258 lupus, 253 lupus erythematosus, 253, 261 lymph node, 212 lysine, 203, 214 lysosomes, 184

M M1, 64 macromolecules, 199 macrophages, 154, 158, 168, 172, 180, 181, 182, 184, 185, 186, 195, 206, 214 magnesium, xi, 172, 176, 178, 190, 301, 302, 306, 314 magnesium alloys, 306 magnet, 168 magnetic field, x, 3, 5, 9, 10, 168, 203, 217, 218, 246, 319 magnetic materials, 313 magnetic moment, 3, 4 magnetic properties, 4, 7, 13, 16, 19, 21, 31, 41, 43, 247, 303 Magnetic Resonance Imaging (MRI), viii, ix, xi, 2, 143, 144, 161, 162, 168, 188, 191, 193, 200, 201, 203, 207, 211, 212, 213, 217, 241, 242, 245, 246, 259, 260, 261, 262, 263, 319, 335, 339 magnetism, 3, 4, 12, 41 magnetization, 3, 5, 6, 219, 220, 221 magnetizations, 5 maintenance, 118, 160 malignancy, 194 malignant, ix, 192, 193, 194, 195, 246 malnutrition, 179 malpractice, 336 management, 241, 259, 260, 263, 319, 338, 339 manganese, 44, 211, 305 manifold, 54 man-made, 184 manufacturing, 92 mapping, 177, 178, 182, 273 market, 154, 155, 157, 329 market share, 154, 155, 157

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Index marrow, 159 mass, 342, 345 mast cell, 181 materials science, 2 matrix, 14, 62, 185, 197, 200, 251, 312, 315 measurement, 3, 4, 17, 208, 307, 318 measures, 152, 196, 238, 258, 318 mechanical properties, 303, 304, 305, 315 media, ix, 146, 161, 162, 168, 194, 214, 239, 243, 260, 337 mediators, 158 medical diagnostics, 130 medication, 210 medicine, 2, 168, 184, 246, 259 MEDLINE, 154 medulla, 322, 323, 326, 327, 328 melanoma, 200, 201, 213 melt, 304, 305, 306, 307, 313 melting, 197, 303, 307 membranes, 181, 190, 195, 247 mesenchymal stem cell, 206 mesenchymal stem cell (MSC), 206 mesons, 66 mesothelium, 181 meta-analysis, 154, 163, 243 metabolic, ix, 153, 168, 172, 193 metabolic acidosis, 153, 172 metabolism, 185 metabolites, 169 metal ions, vii, 1, 2, 11, 12, 32, 41, 43, 44, 45, 48 metal nanoparticles, 344, 346 metallurgy, 304 metals, 2, 41, 42, 206, 302, 341, 342 metastases, 212, 224, 225, 226, 229, 230, 231, 233, 240 methane, 119 micelles, 195, 201, 203 microcirculation, 212, 318, 321, 323, 326, 328, 331 microcosm, 185 microcrystalline, 272 micrometer, 107, 199 microscope, 173, 189 microscopy, 154, 173, 174, 175, 178, 181, 185, 206, 208, 209, 343 microspheres, 215 microstructure, xi, 301, 303, 304, 305, 306, 307, 308, 309, 312, 314 microtome, 183 migration, 294 mines, 128 mining, ix, 107, 168 mitochondrial, 190 mixing, 198, 202, 203, 307

mobility, 153, 170, 173, 208, 342 modalities, 160, 194, 210, 258, 259 modality, 160, 199, 246 mode, 343 modeling, 55, 56, 62, 79, 138 models, 27, 41, 43, 44, 45, 46, 56, 156, 184 modulus, 304 moieties, 197, 203, 208 molar volume, 3 mole, 341 molecular orbitals, 44 molecular pathology, 260 molecular weight, 146, 194, 204, 208, 256 molecules, 4, 19, 22, 31, 36, 44, 116, 140, 144, 168, 197, 198, 206, 208, 266, 270, 285, 341 monoclonal, 195, 208, 209, 210 monoclonal antibodies, 208, 209, 210 monoclonal antibody, 195 monoenergetic, 87 monomers, 199 morbidity, 147 morphological, 261 morphology, 246, 305 mortality, 147, 153, 188, 191, 239, 243, 255 mortality risk, 239 motion, x, 56, 217, 218, 219, 220, 248, 312 MRA, 152, 242 mRNA, 208 MRS, 322 MSC, 206 mucin, 172 multidimensional, 12 multilayer films, 345 multimedia, ix, 167, 168 multiplication, 107, 124, 125, 126, 127 muscle, 144, 153, 187, 204, 252, 258 muscles, 170, 179 musculoskeletal, 337 myalgia, 187 myocardial infarction, 247, 248, 249, 252, 259 myocardial necrosis, 248 myocardial tissue, 250, 251, 261 myocarditis, x, 246, 247, 252, 253, 254, 259, 260, 261 myocardium, x, 170, 245, 246, 247, 248, 250, 251, 252, 253, 256, 257, 258 myocyte, 250, 251, 252, 254 myofibroblasts, 183, 188

N N-acety, 151, 200 NaCl, 318, 322

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Index

nanocomposites, 211, 212 nanocrystalline, 347 nanodimensions, xii, 342, 345, 346 nanohorns, 185, 192 nanomedicine, 195, 208, 211 nanometer, 199 nanometers, 268, 270 nanoparticles, ix, xii, 190, 193, 195, 197, 198, 199, 200, 201, 206, 207, 208, 209, 210, 212, 213, 214, 215, 342, 343, 344, 345, 346, 347, 348, 349 nanoparticulate, 200, 202, 203 nanostructures, 195 nanotechnology, ix, 167, 185, 193, 198, 200, 201 nanotubes, 185, 195, 212 NATO, 49 natural environment, ix, 168, 314 natural polymers, 199 NCS, 208 Nd, 304, 341 necrosis, 147, 224, 247, 248, 252, 327 neoangiogenesis, 181 neon, 119, 138 neoplasm, 226, 229, 240 neoplastic tissue, 188 nephrectomy, 156 nephritis, 187 nephrologist, 170 nephropathy, viii, 143, 144, 147, 148, 149, 151, 152, 224, 236, 239, 242, 243 nephrotoxic, 147, 151, 152, 239, 322 nephrotoxicity, viii, 143, 147, 149, 150, 151, 152, 163, 169, 242, 318, 328, 331, 333 neutron source, 58 Ni, 42, 261 nickel, 267, 305 nitrate, 32 nitric oxide, 186, 191, 331 nitric oxide synthase, 191 nitrogen, 32, 42, 147 nitroxide, 206 nitroxide radicals, 206 NMR, xi, 2, 212, 213, 317, 319, 321, 328, 333 nodules, 194, 257 noise, x, 76, 107, 124, 127, 130, 134, 194, 219, 229, 230, 241, 245, 329 non-invasive, x, 245, 246, 250, 251, 257, 259 nonionic, 149, 155, 156, 159, 231, 232, 238, 243 nontoxic, 200 non-uniform, 152 nuclear, 2, 44, 54, 58, 61, 62, 66, 67, 68, 69, 108, 130, 135, 136, 139, 246, 313, 331 nuclear charge, 44, 69 nuclear magnetic resonance, 2, 331, 333

nuclear reactor, 313 Nuclear Regulatory Commission, 138 nucleation, 14, 306, 312 nuclei, 3, 54, 57, 82, 93, 184, 267, 268, 269, 270, 271, 283, 290, 294 nucleic acid, 208 nucleus, viii, 2, 53, 55, 57, 61, 65, 81, 88, 92, 136, 168, 175, 265, 267, 268, 271, 280 nuclides, 269

O observations, 184, 307, 315, 323 occlusion, 259 oceans, 338 odds ratio, 153, 155 oil, viii, 54, 95, 107, 110, 119, 129, 199, 307 oligomers, 208 oncological, 239 optical, xii, 102, 104, 105, 110, 119, 131, 132, 137, 173, 182, 341, 342, 344, 345, 346, 347, 348, 349 optimism, 79 optimization, 208 opto-electronic, 2 orbit, 4, 41 organ, 144, 223, 226, 240, 242, 253, 318, 321, 322, 323, 324, 325, 326, 327, 328, 331 organic, ix, 2, 12, 118, 119, 144, 195, 198, 206, 217, 218, 231, 302 organic compounds, 119, 265, 268, 284, 290 organic solvent, 198 organic solvents, 198 orientation, 312 orthogonality, 45 oscillator, 66 osmolality, 144, 149, 150 osteoarthritis, 337 oxalate, 35, 44 oxidation, 272, 313, 341 oxide, 32, 129, 186, 191, 194, 195, 202, 204, 214, 215, 313, 331 oxide nanoparticles, 195, 214 oxide thickness, 129 oxides, 186, 247, 311 oxygen, 12, 13, 14, 24, 26, 28, 29, 32, 39, 42, 43, 44, 45, 343, 347 oxygenation, 319

P palladium, 341 pancreas, 221, 222, 223, 224, 226, 240

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Index pancreatic, 218, 223, 224, 240 pancreatic fibrosis, 224 pancreatitis, 190, 224 paraffin-embedded, 174 parallel, 271, 288 parallelism, 120, 121 paramagnetic, vii, 1, 3, 4, 44, 144, 168, 194, 196, 197, 198, 202, 205, 206, 207, 209, 210, 212, 214, 247, 333, 336 parameter, 11, 69, 135, 266 parenchyma, 221, 225, 233 parenchymal, 222, 224, 227, 228 parenteral, 198 Parietal, 181 passive, 207 pathogenesis, 172, 183 pathogenic, 183 pathology, x, 155, 210, 245, 260, 321 Pathophysiological, 172 pathways, 16 patient care, 339 PCR, 49 PDC, 32 pendulum, 339 peptide, 208, 210, 215 peptides, 208 perfusion, x, xi, 220, 245, 246, 247, 250, 251, 260, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333 periglomerular, 327 periodic, ix, 167 Periodic Table, 269 peripheral blood, 188 peripheral vascular disease, 149 peritoneal, 146, 157, 159, 160, 162, 170, 179, 180, 181, 182, 183, 190, 191, 229 peritoneal carcinomatosis, 229 peritoneum, 181, 191 permeability, x, 203, 204, 214, 245, 251 permit, 120, 230 perturbation theory, 61 PET, 130, 250 PGA, 199 pH, 14, 172, 196, 198, 212, 231, 258 pH values, 198 phagocytic, 207, 215 phagocytosis, 154, 186, 196 pharmaceutical, 196, 198, 212 pharmacokinetic, 146, 155, 161 pharmacokinetics, 146, 149, 160, 186, 204, 212, 232 pharmacological, 186, 231 phase diagram, 302, 303, 304, 305, 314 phosphate, 157, 158, 159, 176, 273

363

phosphatidylethanolamine, 197 phospholipids, 195, 197, 207 phosphor, 107, 130, 131 phosphorus, 145 photoelectron spectroscopy, 347 photoluminescence, 211 photons, 87, 88, 108, 112, 119, 125, 127, 130, 250, 260, 265, 267, 268, 269, 273, 275, 278, 279, 283, 292, 294 physical features, 266 physical properties, 2, 41, 305 physical therapy, 170 physicians, viii, xi, 143, 147, 335, 336, 337, 338, 339 physicochemical, 203, 214 physicochemical properties, 203, 214 physics, 133, 139, 140, 266, 297 physiological, 196, 198, 231, 322 plaques, 153, 169, 175, 183 plasma, 145, 172, 198, 199, 201 plastic, 127, 312 plastic deformation, 312 plasticity, 308, 312 plastics, 302 platforms, 195, 203 PLGA, 199 PNA, 208 polarity, 61 polarization, 66 polybutadiene, 204 polycrystalline, xii, 16, 341, 342, 343, 345, 347, 348, 349 polydispersity, 201 polyethylene, 130, 204 polymer, 13, 14, 199, 202, 203, 204, 208, 209, 215, 333 polymerase, 261 polymerase chain reaction, 261 polymerization, 199 polymers, 2, 3, 12, 14, 198, 199, 202, 204, 214 polynuclear complexes, vii, 1 polysaccharides, 199, 208 polystyrene, 199, 207 pores, 14, 22, 24, 204, 192, 196, 305 porosity, 12 porous, 123, 204, 205 portal vein, 222, 223, 228, 232 positron, 61, 85, 88, 250, 267 positron emission tomography, 250 positrons, 65, 66 powder, 15, 16, 129, 130, 203, 213, 307, 347 power, 65, 71, 127, 136, 140, 167, 302, 314 precipitation, 13, 14, 15, 199, 303, 304 prediction, 241, 242

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

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364

Index

predisposing factors, 242 pressure, 14, 54, 56, 80, 94, 103, 106, 107, 108, 113, 119, 123, 124, 125, 126, 127, 137, 140, 196, 198, 212, 304, 319, 342, 343, 349 prevention, 152, 160, 170, 172 probability, viii, 53, 56, 57, 61, 62, 65, 70, 71, 72, 78, 82, 107, 119, 125, 129, 135, 136, 137, 267, 268, 280, 294 probe, 206 production, ix, 61, 88, 154, 158, 159, 168, 183, 194, 198, 212, 314 pro-fibrotic, 158, 159 prognosis, 194, 254, 256, 260 program, 41, 129, 318, 319 pro-inflammatory, 159, 165 project, 295 proliferation, 191, 229 propagation, 312 properties, 266, 267, 268, 274, 280, 282, 293 property, iv, 3, 4, 22, 41, 196, 201, 305, 306, 307 prophylaxis, 149, 150, 151, 152 proportionality, 289 protection, 130, 198, 307 protein, 145, 146, 174, 208, 232, 233, 235, 238, 256 protein binding, 145, 146, 232, 235, 238 proteins, 207 proteoglycans, 184 protocols, 149, 151, 218, 241, 246, 249, 250, 252, 256, 262 protons, 54, 66, 68, 144, 201, 218, 232, 246, 265, 268, 271, 273, 292, 293, 294 prototype, 108, 127, 133, 202 pulmonary circulation, 250 pulse, 107, 123, 124 pulses, 246, 251 pumps, 343 pure water, 307

Q quality assurance, 295 quanta, viii, 54, 59, 60, 61, 74, 76, 85, 87, 88, 89, 90, 91, 92, 111, 112, 113, 114, 130, 137 quantum, xii, 5, 7, 59, 61, 62, 63, 64, 82, 85, 86, 90, 91, 107, 109, 110, 111, 114, 130, 137, 195, 211, 212, 342, 345 quantum confinement, xii, 342, 345 quantum dot, 195, 211, 212 quantum dots, 195, 211, 212 quantum mechanics, 5 quantum theory, 5 quartz, 343

R radiation therapy, 267 radical formation, 190 radicals, 273, 294, 295 radiography, 107, 123, 129, 130 radiological, 231 radiologists, xi, 151, 161, 335, 336, 337, 338, 339 Radiologists, vi, 335, 336, 339, 340 radionuclides, 246 radioresistance, 201 radiotherapy, 271, 296 radius, 2, 67, 71, 114 Raman, 139 rare earth, ix, 2, 3, 41, 44, 167, 185, 302, 341, 342, 349 rare earths, 185 Rayleigh, 88 reactants, 14 reactions, 267, 269, 270, 282, 283 reactivity, 14, 304, 346, 348 reagents, 2, 207, 307 real time, 133, 338 reception, 107, 137 receptors, 197, 208 recognition, 144, 153, 174 recombination, 274, 289 recombination processes, 274 reconstruction, 266 recovery, 251, 318, 322 recrystallization, 305 red blood cells, 190, 215 redistribution, xi, 317, 318, 328 redness, 153 reflection, 246 regenerative medicine, 200 regional, 255, 259 regression, 278, 279, 282, 293 regulators, 342 relationship, vii, 2, 64, 154, 163, 183, 199, 314, 332 relaxation, 144, 198, 201, 207, 218, 230, 247, 267, 273, 323 relaxation rate, 198, 267, 273 relaxation time, 144, 201, 218, 230, 247, 323 renal artery stenosis, 162, 163 renal disease, 163, 172, 187, 238 renal dysfunction, 169, 238, 258 renal failure, 156, 162, 163, 169, 173, 186, 187, 190, 333 renal function, 145, 157, 161, 162, 170, 173, 232, 236, 238, 239, 258, 328 renal medulla, 331 renal profile, viii, 143, 149

Gadolinium: Compounds, Production and Applications : Compounds, Production and Applications, edited by Caden C. Thompson, Nova Science

Index renal replacement therapy, 151, 163 renal scan, 147 research and development, 314 reservation, 175, 184, 331, 332 residues, 203, 312 resin, 173, 174, 177, 307 resistance, 302, 303, 305, 307, 314, 332, 344, 345, 348 resistive, 56, 137 resistivity, 134, 303 resources, 209 respect, 282 respiration, 218, 220 response time, xii, 342, 346 retention, 156, 164, 189, 200, 203 rhodium, 267 rifting, 110, 116 right ventricle, 255, 256 risk benefit, 239 risk factors, 150, 152, 158, 159, 172, 191, 239, 241 risks, x, 158, 160, 218, 231, 242, 318, 328, 331, 338 rods, 303, 307 ROI, 318

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S SAC, 107, 138 safety, 147, 148, 149, 150, 152, 162, 169, 238, 239, 241, 262, 333 saline, 149, 150, 151, 155, 156 salts, 13, 176, 178, 185, 267 samarium, 186 sarcoidosis, 257, 258, 262 Sarin, 192 satisfaction, ix, 193, 194 saturation, 124, 191, 277, 289, 318, 322 scalar, 41 scanning electron microscopy, 128, 154, 172, 189, 191, 307, 309 scar tissue, 225, 251 scarcity, xi, 317, 318 scattering, 88, 123, 127, 139, 173, 267 scintillation detectors, 54, 62, 64, 125 scintillators, 56, 137 scleroderma, 174 sclerosis, 190, 191 SCP, 126 secretion, 145 sedation, 338 segregation, 307, 347 self-assembling, 195 self-assembly, 198, 201, 203 SEM, 307, 308

365

SEM micrographs, 308 semiconductor, xii, 54, 342, 345, 346 sensitivity, ix, 54, 80, 106, 107, 125, 126, 173, 184, 193, 194, 197, 240, 252, 265, 267, 268, 269, 273, 274, 279, 280, 282, 283, 285, 287, 290, 291, 292, 293, 294, 337 sensors, 133, 342 separation, 14, 15, 318, 327 sepsis, 258 septum, 253, 254, 255 series, ii, 2, 35, 103, 107, 119, 130, 153, 178, 207, 242, 250 serum, 146, 147, 148, 149, 150, 151, 152, 159, 191, 209, 233, 238, 239 serum albumin, 233, 238 serum ferritin, 191 SH, 10, 186, 212, 316 shape, 2, 178, 305, 307, 311 shoulder, 337 shunts, 318, 327, 328 side effects, 210 Siemens, 322 sign, 253 signaling, 311 signals, 111, 112, 115, 124, 130, 138, 177, 182, 183, 184, 200, 266 signal-to-noise ratio, 127, 229 signs, 153, 180, 182, 183, 184 silica, 195, 212 silicon, 56, 108, 133, 134, 137 silver, 32, 189 simulation, 287, 288, 289, 290, 292, 293, 294 simulations, 35 single crystals, 13, 14 singular, 177, 178, 182 SIR, 259 siRNA, 211, 212 SIS, 173 sites, 197, 201, 210, 347 skeletal muscle, 153, 187, 252, 258 skin, 153, 155, 156, 164, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 183, 184, 191, 258, 304 SLE, 253, 254 Sm, 341, 342 SNR, 229, 230 sodium, 14, 156 soil, 128 solid state, 2, 12, 140, 266, 267 solid tumors, 192, 204 solidification, 303, 304, 305, 308, 314 solid-state, viii, 53, 54, 55, 56, 79, 92, 102, 106, 116, 137

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Index

solubility, 303 spatial, viii, 45, 48, 53, 54, 55, 56, 72, 94, 103, 107, 108, 113, 114, 115, 116, 120, 125, 130, 138, 173, 184, 189, 200, 229, 246, 259 spatial frequency, 130 species, xii, 76, 164, 194, 206, 272, 273, 274, 342, 343, 346 specificity, ix, 193, 194, 197, 199, 208, 252, 337 SPECT, 250 spectral analysis, 182 spectroscopy, 154, 172, 189, 190, 208, 212, 307, 321, 347 spectrum, 61, 76, 115, 124, 129, 167, 173, 177, 178, 179, 182, 188 speed, 65, 67, 69, 325 speed of light, 67 spermatids, 190 spin, vii, 1, 4, 6, 7, 11, 17, 31, 41, 43, 44, 68, 194, 206, 218, 219, 266, 274 spindle, 158, 172, 174, 175 spine, 246 spleen, 186, 207, 212, 215, 221, 222, 223, 224 splenomegaly, 224 sputtering, 127, 347 squamous cell, 200 squamous cell carcinoma, 200 SRD, 172 SSB, 245 stability, x, xii, 107, 119, 123, 124, 138, 156, 169, 186, 197, 198, 199, 201, 203, 207, 218, 231, 232, 238, 328, 329, 342, 348, 349 stabilization, 107, 118, 138, 198 stabilize, 118 stages, 126, 158, 159, 238 stainless steel, 14, 15, 124, 127 standard deviation, 292 steel, 14, 15, 124, 127, 307 stem cells, 206 stenosis, 173, 250 stiffness, 254, 261 stomach, 194 storage, x, xii, 246, 257, 272, 332, 342, 349 strain, 307, 308, 310, 315 strategies, 188, 207 stratification, 260 strength, x, xi, 3, 4, 110, 112, 126, 203, 217, 218, 301, 302, 303, 304, 305, 306, 307, 312, 315 stress, 250, 260, 304, 307, 310 strong interaction, 44 strontium, 306 structural characteristics, 2 structural transformations, 347 subcutaneous tissue, 174

subgroups, 148 substances, 3, 65, 66, 92, 159, 198, 210 substrates, 94, 204, 342, 343 subtraction, 148, 149, 150, 152, 162, 203, 242, 276, 277 sulfate, 206 sulfur, 273 sulphate, 31 supercritical, 198, 213 supercritical carbon dioxide, 213 superimposition, 178 superior vena cava, 148 supernatural, 337 superposition, 115 suppression, 200, 213, 219, 229, 251 supramolecular, 202, 213, 214 surface area, xii, 342, 347 surface chemistry, 214 surface energy, 347 surface layer, 129, 348, 349 surface structure, 347 surfactant, 197 surgeons, 327 surgery, 159, 172, 173, 258 surrogates, 224 survey, 294 survival, 170, 212, 257 survival rate, 170 susceptibility, 3, 4, 5, 6, 11, 19, 30, 203 sustainability, 314 swelling, 153, 258 switching, 342, 344, 345, 346, 347, 349 symbols, 61 symmetry, 12, 41 symptoms, 153, 164, 170, 255, 257 synthesis, vii, 1, 2, 13, 14, 15, 159, 204, 208, 213 systemic lupus erythematosus, 261 systems, vii, x, 1, 4, 41, 42, 45, 144, 198, 203, 206, 210, 213, 217, 219, 230, 231, 250, 257, 314, 347 systolic pressure, 319

T tachycardia, 254, 255, 261 target organs, 194 targets, 71, 208 tau, 249 technology, xi, 132, 134, 144, 160, 184, 198, 199, 201, 317, 328, 331 teflon, 14, 15 temperature, xi, 3, 4, 14, 17, 20, 33, 113, 118, 119, 127, 197, 301, 303, 304, 305, 306, 307, 311, 313, 314, 319, 323, 343, 349

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Index temporal, 229, 246 tensile, xi, 301, 304, 306, 307, 308, 312, 314, 316 tensile strength, xi, 301, 304, 307, 315 Tesla, 240, 241, 246, 319 testes, 170, 258 thawing, 118 therapeutic agents, 210 therapeutic interventions, 170 therapeutics, 198, 210 therapy, 159, 160, 170, 199, 200, 211, 213, 215, 253, 258, 266, 282, 294 thermal analysis, 313 thermal deformation, 127 thermal evaporation, 127 thermal treatment, 14 thermalization, 94 thermodynamic, x, 218, 231, 238, 328, 329 thermodynamic stability, x, 218, 231, 238, 328, 329 thermodynamics, 332 thermoluminescence, 266, 272 thin film, 123, 341 Thomson, 163 three-dimensional, 15, 16, 17, 19, 20, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 threshold, 66, 126, 157 threshold level, 157 thrombosis, 228, 258 thrombotic, 172 time resolution, 56, 108, 112, 117, 118, 119, 123, 125, 134, 135, 137, 138 TIP, 33 tissue characteristics, 246 tissue engineering, 200 tissue perfusion, 220 titanium, 306 topological, 177 topology, 204 total energy, 271, 293, 294 toxic, ix, 144, 156, 160, 168, 170, 172, 189, 206, 212, 218, 314, 328 toxic effect, 144, 160, 168, 170, 172 toxicity, 144, 145, 148, 152, 160, 162, 168, 169, 173, 182, 185, 190, 194, 198, 199, 211, 214, 247, 328, 332, 333 toxins, 170 tracking, 206, 222 training, xii, 335, 337, 338 training programs, 337 trajectory, 111, 127 transfection, 215 transferrin, 191 transformations, 347 transgenic, 208

transition, vii, 1, 2, 41, 42, 44, 61, 62, 65, 81, 109, 119, 345, 347, 349 transition metal, vii, 1, 2, 41, 42, 44 transition metal ions, vii, 1 transitions, 41, 61, 116, 136, 348 transmission, 44, 124, 129, 144, 185, 189, 190, 200, 346 Transmission Electron Microscopy (TEM), 129, 173, 185, 189, 200, 343 transmittance spectra, 344 transparency, 102, 104, 105, 110, 119, 137 transparent, 341, 345 transplant, 153, 180, 187, 227 transplant recipients, 153 transplantation, xi, 170, 179, 180, 187, 191, 258, 317, 318, 319, 322, 327, 328, 329, 331, 332, 333 transthoracic echocardiography, 246 treatment methods, 224 trends, 268, 269, 277, 278, 285, 287, 292, 348 trichloroacetic acid, 22 triggers, ix, 143, 183, 268 tritium, 130 tryptophan, 332 tubular, 145, 147, 327 tumor cells, 208 tumor growth, 200, 201, 210 tumors, 192, 194, 203, 204, 207, 209, 224, 242, 294, 319, 321, 331 tungsten, 121, 342 two-dimensional, 28, 32, 34, 35, 108, 125

U ultrasonography, 147, 160 ultrasound, 196, 246 ultrastructure, 175, 184, 188 ultraviolet light (UV), 112, 124, 129 umbilical cord, 319 urinary, 147 urine, 148, 149, 328 uveitis, 187

V variation, 118, 121, 345, 346, 347, 348 variations, 280, 294 vascular disease, 149 vascular membranes, 247 vascular surgery, 173 vascular system, 218, 221 vascularization, 207 vasculature, 144, 147, 159, 160, 203, 242

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Index

vasculitis, x, 246, 253 vein, 204, 222, 223, 228, 232, 247, 250 velocity, 3, 14, 109, 128, 198 ventricles, 254, 256 ventricular arrhythmia, 255, 257 ventricular arrhythmias, 255, 257 ventricular fibrillation, 168 ventricular tachycardia, 254, 255, 261 vesicle, 204, 205 vessels, 168, 224, 225 Vickers hardness, 306, 313 viral infection, 252 viral myocarditis, 254, 260, 261 viruses, 253, 261 viscosity, 144, 147, 148, 149, 150, 152, 232 visible, 81, 84, 85, 88, 94, 112, 116, 118, 177, 178, 219, 248, 342, 345 visualization, 44, 173, 199, 210, 233, 250, 251, 252, 256 vitamin C, 273

W

wavelengths, 58, 82, 84, 93, 94, 95, 108, 125, 135, 136, 345 weak interaction, 39, 44 weight reduction, 314 wound healing, 183, 200

X xenograft, 209, 212 XPS, 347 X-ray diffraction (XRD), 129, 308, 343, 346 X-rays, 85, 87, 126, 131, 135 xylene, 132

Y yttrium, 348

Z zeta potential, 201 Zinc (Zn), 145, 157, 302, 303, 305, 307, 314

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water-soluble, 196, 210, 212, 214

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