Nanomedicine for Ischemic Cardiomyopathy: Progress, Opportunities, and Challenges [1 ed.] 012817434X, 9780128174340

Table of contents :
Cover
NANOMEDICINE
FOR ISCHEMIC
CARDIOMYOPATHY
Progress, Opportunities,
and Challenges
Copyright
Contributors
1
Ischemic cardiomyopathy
Pathophysiology of heart failure
Pathophysiology of stunned or hibernating myocardium
Reperfusion injury
Clinical implications
Stages in the development of heart failure
References
2
Nanotechnology and nanomedicine
Brief history of nanotechnology
Brief history of nanomedicine
Synopsis of recent advances in nanomedicine
Future of nanomedicine
Overview of nanotechnology in cardiology
References
3
Atherosclerosis and thrombosis heart failure
Prevention of heart failure in atherosclerotic conditions
Nanoparticulate systems for the prognosis and treatment of coronary atherosclerosis
Nanotechnologies for diagnosis and treatment of thrombosis
Conclusion
References
4
Device-based treatment of heart failure
Implantable cardioverter-defibrillators
Cardiac resynchronization therapy
Treatment for refractory heart failure
Mechanical circulatory support systems
Cardiac transplantation
Surgical ventricular reconstruction
Cardiac contractility modulation
References
5
Stem cells and heart tissue regeneration
Introduction
Fibrosis after MI
Conventional therapies in HF
Cardiac regeneration
Cardiac cell therapy and tissue engineering
Struggles in cardiac cell therapy
Cell maturity and heart regeneration
Stem cells in heart regeneration
Bone marrow stem cells
Cardiac and cardiosphere-derived stem cells
Induced pluripotent stem cells
Embryonic stem cells
Umbilical cord stem cells
Adipose-derived stem cells
Conclusion
References
6
Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases
Introduction
Biogenesis and composition of the exosomes
The therapeutic potential of endogenous exosomes in an ischemia-injury heart
Cardiomyocyte-derived exosomes
Cardiac endothelial cell-derived exosomes
Cardiac fibroblast-derived exosomes
Cardiac progenitor cell-derived exosomes
Stem cell-derived exosomes
Mesenchymal stem cell-derived exosomes
Exosomes from induced pluripotent stem cells (iPSCs) and iPSCs derivatives
Exosomes with artificially modified cargo
Biodistribution of exosomes in vivo
Exosomes as biomarkers of cardiovascular disease
Conclusion and future perspective
References
7
Use of nanoparticulate systems to salvage the myocardium
Overview of micro- and nanoparticulate-based medicines for cardiovascular diseases
Nanoparticles
Nanoparticles for MI
Nontargeted
Targeted
Size
Shape
Surface charge
Surface composition
Elasticity and degradation
Administration routes
Targeting approaches
Passive targeting
Active targeting
References
8
Nanoparticulate systems for monitoring of therapeutic cells
Stem cell therapy for cardiac repair
Potential mechanisms of adult SCs in cardiovascular regeneration
Different kinds of stem cells for heart treatment:
Stem cell and NP integration
NPs for genetic engineering in stem cells
Stem cell targeting
MRI tracking
Optical tracking
Multimodal tracking
Stem cell retention
Stem cell therapy potential
References
9
Cell-nanoparticle interactions
In vitro studies
References
10
Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium
Polymer-based nanodelivery systems
Lipid-based nanodelivery systems
Nucleic acid-based nanodelivery systems
Cell-based nanodelivery systems
Imaging nanodelivery systems
Nanoparticles as sensors for detection of cardiac biomarkers
References
Further reading
11
Nanoparticulate systems for sustained delivery of paracrine factors
Different types of nanoparticulate systems for encapsulation and delivery of paracrine factors
Lipid-based delivery systems
Polymer-based delivery systems
Synthetic polymers
Natural polymers
Inorganic nanoparticulate systems for growth factor delivery
Nanofibers for growth factor delivery
Nanoparticle-embedded scaffolds as a growth factor delivery strategy
References
Further reading
12
Nano-bioink solutions for cardiac tissue bioprinting
Nanomaterials in cardiac bioinks
Electrical conductivity of bioinks
Imaging properties of bioinks
Mechanical and biochemical properties of nano-bioinks
DNA-NP bioinks
Antibacterial nano-bioinks
Conclusions and future perspectives
References
13
Clinical cardiovascular medicine and lessons learned from cancer nanotechnology
Tissue/bioengineering approaches in clinical cardiovascular medicine
Lessons learned in cancer nanotechnology facilitates successful clinical translation of cardiac nanotechnology
Conclusions
References
Index
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D
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Back Cover

Citation preview

NANOMEDICINE FOR ISCHEMIC CARDIOMYOPATHY

NANOMEDICINE FOR ISCHEMIC CARDIOMYOPATHY Progress, Opportunities, and Challenges Edited by

MORTEZA MAHMOUDI

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-817434-0 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Masucci, Stacy Acquisitions Editor: Chan, Katie Editorial Project Manager: Young, Samuel Production Project Manager: Raviraj, Selvaraj Cover Designer: Hitchen, Miles Typeset by SPi Global, India

Contributors

Seyed Hesameddin Abbasi Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Morteza Aieneravaie Department of Medicine, University of Basel, Basel, Switzerland Ahmad Amin Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Science, Tehran, Iran Leila Arabi Department of Medicine, University of Basel, Basel, Switzerland Malini Basu Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Alexander C. Cetnar Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States Ivette Chen Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Petrina Georgala Sloan Kettering Institute for Cancer Research, New York, NY, United States Doina Ghegeliu Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Carmen J. Gil Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States Yassira Gonzalez Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Mohammad Javad Hajipour Precision Health Program, Michigan State University, East Lansing, MI, United States

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Contributors

Kirsten Herrera Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Jim Q. Ho Albert Einstein College of Medicine, Bronx, NY, United States Mohammad Imani Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Najmeh Javdani Montreal Clinical Research Institute, Montreal, QC, Canada Serena Jones Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Seyed Ebrahim Kassaian Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Farjana Khaled Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Angie Kim Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Michelle Lam Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Asia Le Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States James Lee Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Sarah Liang Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Morteza Mahmoudi Precision Health Program, Michigan State University, East Lansing, MI, United States

Contributors

Mehdi Mehrani Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Syeda Mehreen Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Katherine Pham Do Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States Shahram Rabbani Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Marjan Rafat Department of Chemical and Biomolecular Engineering; Department of Biomedical Engineering, Vanderbilt University; Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, United States Mohammad Reza Sepand Department of Medicine, University of Basel, Basel, Switzerland Vahid Serpooshan Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology; Department of Pediatrics, Emory University School of Medicine; Children’s Healthcare of Atlanta, Atlanta, GA, United States Mohammed Sharaf Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States Andrea S. Theus Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States Martin L. Tomov Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States Merlyn Vargas Volgenau School of Engineering, Department of Bioengineering, George Mason University, Fairfax, VA, United States Evgeniya A. Vaskova Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

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Contributors

Remi Veneziano Volgenau School of Engineering, Department of Bioengineering, George Mason University, Fairfax, VA, United States Phillip C. Yang Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States Steven Zanganeh Department of Chemical and Biomolecular Engineering, New York University; Sloan Kettering Institute for Cancer Research, New York, NY, United States

CHAPTER 1

Ischemic cardiomyopathy Mehdi Mehrania, Seyed Hesameddin Abbasia, Ahmad Aminb, Seyed Ebrahim Kassaiana, Morteza Mahmoudic a Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Science, Tehran, Iran c Precision Health Program, Michigan State University, East Lansing, MI, United States b

Pathophysiology of heart failure Ischemic cardiomyopathy is the result of pathophysiological conditions disturbing the balance between perfusion and contraction [1]. The main reason for this mismatch between perfusion and contraction is the irreversible loss of the myocardium after myocardial infarction, which leads to myocardial fibrosis and eventually a “remodeling” process [2]. As the initial phase after MI, remodeling results from fibrotic repair of the necrotic area with scar formation, and consequences include thinning and myocyte elongation of the infarcted area. At first, these changes are beneficial and associated with maintaining or even improving cardiac output. However, the remodeling process is driven predominantly by hypertrophic myocyte elongation in the noninfarcted zone. This cellular rearrangement of the ventricular wall is associated with a significant rise in the LV volume, rendering it less elliptical and more spherical [3], with the magnitude of the remodeling being roughly related to the infarct size [4]. The myocardium consists of myocytes tethered together and supported by a connective tissue network composed largely of fibrillar collagen. The interstitium contains mainly of type I and type III collagen fibers, which are resistant to degradation by most proteases. Some enzymes, including metalloproteinases, have collagenolytic activity. In the wake of myocardial infarction, fibroblast stimulation augments collagen synthesis and begets fibrosis of both the infarcted and noninfarcted regions of the myocardium. In the healthy heart, metalloproteinases are present in their inactive form in the ventricle; however, myocardial injury triggers the activation of these proteases [5] and thus contributes to an increase in the chamber dimension and subsequent processes including myocyte slippage, which is thought to contribute to chamber remodeling [6]. For example, the marked overexpression of MMP-9 after myocardial infarction may be a mediator of collagen accumulation and remodeling [7, 8]. There is an association between progressive heart failure and neurohumoral activation, which may initially be regarded as compensatory but may further the

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progression of structural abnormalities. For example, the concentration of plasma brain natriuretic peptide (BNP), which has some capacity to protect the failing heart against pathologic remodeling [9], is increased in progressive HF and is positively correlated with prognosis [10]. Another example is angiotensin-converting enzyme (ACE). In several clinical trials, its elevated inhibitors demonstrated improved survival after HF and can slow, and in some cases, even reverse certain parameters of cardiac remodeling [10, 11]. Research has shown that impaired LV function in patients with coronary heart disease is not always irreversible. It is noteworthy that transient postischemic dysfunction is termed “stunned” myocardium, while chronic but potentially reversible ischemic dysfunction due to a stenosed coronary artery is called “hibernating” myocardium.

Pathophysiology of stunned or hibernating myocardium LV dysfunction is a significant consequence of CAD and can arise from either myocardial ischemia or myocardial infarction [12]. The term “stunned myocardium” was initially used to describe a condition demonstrated in the laboratory in which a total coronary artery occlusion lasting only between 5 and 15 min (a period not associated to cell death) created an abnormality in the regional LV wall motion that lingered for hours or days after reperfusion [13–15]. Consequently, the chief characteristics of the stunned myocardium scenario are short-term, total, or near-total decrease in coronary blood flow; reestablishment of the coronary blood flow; and resultant LV dysfunction of limited duration. In the clinical setting, there is a likelihood of the superimposition of stunned myocardium on ischemia or infarction following the reestablishment of blood flow [16]. The term “hibernating myocardium” denotes a condition in which myocardial and LV functions are persistently impaired at rest, secondary to a chronically diminished coronary blood flow that can be partially or fully restored to the normal state either through augmenting blood flow or by decreasing oxygen demand [17, 18]. Failure to provide timely treatment for hibernating myocardium may lead to progressive cellular damage, recurrent myocardial ischemia, myocardial infarction, heart failure, and ultimately death [19]. In patients undergoing revascularization, the presence of hibernating myocardium foretells an improvement in the chances of survival [20]. A meta-analysis of 24 viability studies on 3088 patients suffering from CAD and LV dysfunction with a mean left ventricular ejection fraction (LVEF) of 32% reported a rate of 42% for the prevalence of hibernating myocardium viability [21].

Reperfusion injury Myocardial injury in the context of acute myocardial infarction is a consequence of ischemic and reperfusion injury. Reperfusion therapies such as fibrinolysis therapy and

Ischemic cardiomyopathy

primary percutaneous coronary intervention swiftly restore blood flow to the ischemic myocardium and curb infarct size. Unexpectedly, nonetheless, the reestablishment of blood flow can beget additional cardiac damage and complications, referred to as reperfusion injury [22–24]. Reperfusion injury is typified by vascular, myocardial, or electrophysiological dysfunction brought about by the return of blood flow to ischemic tissue. When the blood flow to cardiac myocytes is disrupted by the occlusion of a coronary artery, a series of events results in cellular injury and death. In the context of acute myocardial infarction, it has been posited that reperfusion injury is responsible for up to 50% of the final myocardial damage [25]. One of the main side effects of reperfusion injury is generation of reactive oxygen species (ROS), which are produced by several processes/pathways involving the myocardium and/or infiltrating inflammatory cells [26–28]. ROS deteriorate vital functions of cardiac cells including their growth, metabolism, and proliferation through several pathways (e.g., damage to cell membranes and activation of apoptotic pathways) [29, 30]. Therefore, strategies that minimize ROS after reperfusion injury are clinically important and can diminish the deteriorative effects of reperfusion injury on the myocardium.

Clinical implications According to epidemiological studies, about 40% of myocardial infarctions are associated with heart failure, suggesting that heart failure is a common occurrence after myocardial infarction [31]. One frequently used method to assess the severity of HF following myocardial infarction is the Killip classification: – Class 1: no evidence of HF – Class 2: rales in lung fields or a third heart sound and systolic blood pressures 90 mm Hg – Class 3: frank pulmonary edema and systolic blood pressures 90 mm Hg – Class 4: cardiogenic shock with rales and systolic blood pressure 150 ms) [1, 2].

Treatment for refractory heart failure Mechanical circulatory support systems Mechanical circulatory support devices were initially designed to support hemodynamically unstable patients, but they are now used in several clinical conditions, including refractory chronic heart failure with reduced ejection fraction (HFrEF). There are two major types of such devices: short-term mechanical circulatory support devices [including intra-aortic balloon pump (IABP), percutaneous circulatory assist devices (e.g., Tandem Heart, Impella), and extracorporeal membrane oxygenation (ECMO)], and long-term mechanical circulatory support devices [including left ventricular assist devices (LVAD) and biventricular support (e.g., total artificial heart)]. Long-term Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00004-0

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mechanical circulatory support devices can be used either as a bridge to transplantation in patients awaiting cardiac transplantation or as a destination therapy (permanent mechanical support) in selected patients who are ineligible for cardiac transplantation.

Cardiac transplantation Cardiac transplantation is recommended for selected patients with refractory end-stage HF. Observational evidence shows that cardiac transplantation improves survival and quality of life in patients with severe refractory HF [1, 3–8].

Surgical ventricular reconstruction The fundamental role of LV chamber dilation, myocardial fibrosis, and hypertrophy in the pathophysiology of ischemic cardiomyopathy is the basis of recent interest in developing surgical ventricular reconstruction (SVR) techniques to restore LV volume and geometry toward normal size, shape, and physiology. Several observational studies showed that SVR reduces LV volume and improves LV systolic function relatively safely in association with improved symptoms and high survival rates at 5 years [9–11]. SVR also improves LV mechanical synchrony, resulting in more efficient pump function [12]. A few other observational studies investigated SVR procedures concomitantly with myocardial revascularization (CABG) or mitral valve surgery (for ischemic mitral regurgitation) [13–16]. However, there is still considerable controversy regarding the survival advantages from surgical reversal of LV remodeling in different subgroups of patients with ischemic cardiomyopathies. More recently, promising safety and feasibility of percutaneous ventricular restoration (PVR) therapy have been shown using the Parachute device in patients with ischemic cardiomyopathy [17–20].

Cardiac contractility modulation As described above, CRT is currently used in a subset of symptomatic HF patients with low EF and wide QRS complex to improve symptoms and survival via coordinating the timing of contractility within the LV as well as between ventricles. However, this benefit is limited to patients with QRS duration of >120 ms; patients with normal or modestly prolonged QRS duration CRT have been shown to have opposite effects or worse outcomes [21, 22]. Thus, a relatively new therapeutic technique, cardiac contractility modulation (CCM), was designed to improve symptoms and function in patients with moderate-to-severe systolic dysfunction and normal or mildly prolonged QRS duration who are not candidates for CRT. CCM delivers nonexcitatory biphasic high-voltage electrical signals to the right ventricular septum during the absolute refractory period of the action potential, eliciting a positive inotropic effect without increasing myocardial oxygen consumption. The first observational study of CCM was FIX-HF-3, which

Device-based treatment of heart failure

enrolled 22 patients across Europe and showed an improvement in quality of life, left ventricular ejection fraction, NYHA function class, and 6-min walk test after 8-week follow-up [23]. CCM is currently approved for use in Europe. Several ongoing studies in Europe and the United States are investigating long-term efficacy and safety of CCM in patients with HFrEF receiving optimal medical therapy.

References [1] Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. [2] Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. [3] Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013; https://doi.org/10.1161/CIR.0b013e31829e8807. [4] Saha K, et al. Regulation of macrophage recognition through the interplay of nanoparticle surface functionality and protein corona. ACS Nano 2016;10:4421–30. [5] Arnold JMO, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol 2006;22:23–45. [6] Heart Failure Society of America. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 2010;16:e1–e194. [7] Lund LH, et al. The registry of the International Society for Heart and Lung Transplantation: thirtysecond official adult heart transplantation report—2015; focus theme: early graft failure. J Heart Lung Transplant 2015;34:1244. [8] Srivastava R, Keck BM, Bennett LE, Hosenpud JD. The results of cardiac retransplantation: an analysis of the joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. Transplantation 2000;70:606–12. [9] Athanasuleas CL, et al. Surgical ventricular restoration in the treatment of congestive heart failure due to post-infarction ventricular dilation. J Am Coll Cardiol 2004;44:1439–45. [10] Di Donato M, et al. Outcome of left ventricular aneurysmectomy with patch repair in patients with severely depressed pump function. Am J Cardiol 1995;76:557–61. [11] Menicanti L, et al. Surgical therapy for ischemic heart failure: single-center experience with surgical anterior ventricular restoration. J Thorac Cardiovasc Surg 2007;134:433–41. e432. [12] Di Donato M, et al. Surgical ventricular restoration improves mechanical intraventricular dyssynchrony in ischemic cardiomyopathy. Circulation 2004;109:2536–43. [13] Jones RH, et al. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med 2009;360:1705–17. [14] Wu AH, et al. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol 2005;45:381–7. [15] Deja MA, et al. Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation 2012; https://doi.org/10.1161/CIRCULATIONAHA.111.072256. [16] Samad Z, et al. Management and outcomes in patients with moderate or severe functional mitral regurgitation and severe left ventricular dysfunction. Eur Heart J 2015;36:2733–41. [17] Costa MA, Mazzaferri EL, Sievert H, Abraham WT. Percutaneous ventricular restoration using the Parachute® device in patients with ischemic heart failure: three-year outcomes of the PARACHUTE First-inHuman study. Circ Heart Fail 2014; https://doi.org/10.1161/CIRCHEARTFAILURE.114.001127. [18] Mazzaferri EL, et al. Percutaneous left ventricular partitioning in patients with chronic heart failure and a prior anterior myocardial infarction: results of the PercutAneous Ventricular RestorAtion in Chronic Heart failUre PaTiEnts Trial. Am Heart J 2012;163:812–20. e811.

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[19] Yang Y-J, et al. Percutaneous ventricular restoration therapy using the Parachute device in Chinese patients with ischemic heart failure: three-month primary end-point results of PARACHUTE China study. Chin Med J 2016;129:2058. [20] Thomas M, et al. Percutaneous ventricular restoration (PVR) therapy using the Parachute device in 100 subjects with ischaemic dilated heart failure: one-year primary endpoint results of PARACHUTE III, a European trial. EuroIntervention 2015;11:710–7. [21] Ruschitzka F, et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395–405. [22] Shah RM, Patel D, Molnar J, Ellenbogen KA, Koneru JN. Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval 130 ms: insights from a meta-analysis. Europace 2014;17:267–73. [23] Stix G, et al. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J 2004;25:650–5.

CHAPTER 5

Stem cells and heart tissue regeneration Shahram Rabbani, Mohammad Imani

Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

Introduction Heart failure (HF) is a major public health problem that takes the lives of 17.9 million people every year, about 31% of all global deaths [1], with an increasing prevalence due to the growing aged population. Myocardial infarction (MI) is one of the main causes of HF. After MI, up to 1 billion cardiac cells die, ending in scar tissue formation as a response to the injury that, in turn reduces heart function significantly [2]. The adult mammalian heart has a very limited capacity to regenerate after injury, and the injured cells are replaced by a fibrotic tissue [3]. This replacement causes the remodeling of the peripheral myocardium and finally leads to impaired cardiac output and reducing myocardial function. The remodeling process leads to hypertrophy and fibrosis of the MI region [4]. The fibrotic response process after MI, that is, a type of scar formation, tries to prevent ventricular rupture [5], but it increases the mechanical stresses after MI via hormonal and paracrine mediators. This process induces the proliferation and expansion of connective tissue in the peripheral zone of the infarcted site [6]. This fibrotic tissue formed in the border zone of the injured myocardium leads to increased ventricular stiffness and decreasing cardiac output and myocardial function. In addition to the said effects of fibrous scar tissue formation on myocardial contractility, the normal electrical conduction system of the heart can also be damaged, ending in arrhythmia [7]. Myocardial fibrosis is well identified as a risk factor for sudden cardiac death and leads to higher mortality and morbidity rates in patients affected by HF [8]. Three main cardiac cell types, that is, cardiomyocytes, endothelial cells, and fibroblasts, are present in the heart in different populations. The populations depend on the species, age, and gender of the species. Also in common, the percentage of cardiomyocytes varies between infants, young people, and adults [9]. Endothelial cells and cardiomyocytes are the most abundant cell types in number in the adult murine and human heart, whereas fibroblasts take third place. Fibroblasts play an important role in the postinfarction repair and remodeling process when they are expanded and replace the majority of cells in the infarcted area in response to the injury [10]. In addition to the local cardiac fibroblasts, other cell types such as hematopoietic bone-marrow-derived progenitor cells and endothelial cells can transdifferentiate into myofibroblasts and may form fibrosis [11–13]. Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00005-2

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Adhesion proteins present in the cardiac extracellular matrix (ECM) bring about a structural scaffold for cardiomyocytes and participate in biochemical signaling [14]. Synthesized and secreted by fibroblasts, collagen chains provide the needed mechanical support throughout the ECM for cardiomyocytes, who build the myocardial wall and help in the contraction of the heart [15].

Fibrosis after MI The necrosis of cardiomyocytes after MI occurs to prevent further damage and rupture of the heart wall by replacing the dead cells. Zebra fish as well as embryonic and neonatal rodents are able to fully regenerate an injured myocardium [16, 17]. In these animals, the injured area is initially replaced by a fibrin clot, followed by replacement with a temporary collagen-based scar and normal myocardial tissue [18]. This process is not fully distinguished but may be a part of controlled inflammatory response or proliferation of cells such as myofibroblasts and cardiomyocytes [19]. The regenerative capacity of neonatal rodents disappears during the first weeks of postnatal life [16] as a result of the inability of postnatal cardiomyocytes to proliferate. Therefore, in adult mammals, the dead cardiac cells are replaced with a permanent fibrous tissue instead of new cardiomyocytes [20] (Fig. 1).

Fig. 1 Fibrosis and regeneration after myocardial infarction. Cell death leads to the activation of myofibroblasts and a generation of fibrosis in the infarcted area. (From Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 2016;365(3):563–81. https://doi.org/10.1007/s00441-016-2431-9.)

Stem cells and heart tissue regeneration

Reversing fibrosis at the infarcted area is the main goal in cardiac tissue regeneration. The flexibility of cardiac fibroblasts and myofibroblasts and their high population in the injured area make them a suitable starting cell population for the generation of de novo cardiomyocytes to repair the injury [21]. The success of reprogramming fibroblasts directly into cardiomyocyte-like cells both in vitro and in vivo requires stem cell therapy or methods such as iPSC-derived cardiomyocytes [22]. Additionally, direct reprogramming suffers from the risk of potential teratogenicity, which will be discussed in detail later [23]. In this way, an ideal therapy for MI-induced cardiac injury would combine the inhibition of reactive fibrosis (and other remodeling processes) in noninfarcted areas with the induction of the regeneration of the infarcted myocardium.

Conventional therapies in HF As mentioned earlier, HF is a major public health issue that is associated with more than 26 million hospitalizations per year globally [24]. The 1-year mortality rate after HF hospitalization has remained high, at the level of 20%–30%, in contrast to all the advancements achieved during the past decades [25]. Normally, the costs imposed by HF are expected to rise as the prevalence of HF increases. Many therapies have been tested in HF patients, but its consequences have remained nearly unchanged over the past 40 years. The current management of patients with acute myocardial infarction focuses on invasive medical procedures such as coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and finally heart transplantation [26]. Despite many advancements in developing new drugs to manage cases affected by acute myocardial infarction, ischemic heart disease remains a major global cause of death and disability [27]. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. The treatment of HF depends on its etiology. If HF remains untreated, it rapidly progresses and deteriorates the quality of life [28]. Stem cell therapy is one of the newest technologies introduced for the treatment of HF patients [29]. This chapter reviews how these cells contributed in ischemic cardiomyopathy.

Cardiac regeneration Except for some animals, mammals (including humans) cannot amend heart muscle loss and therefore show little cardiac regeneration, as discussed earlier. Fibrotic tissue formation prevents ventricular wall rupture in the infarcted human heart. The substitution of damaged tissue by other tissue is called “repair,” but the substitution of damaged tissue by the same is known as “regeneration” by definition. Regeneration is mostly regulated by complex molecular mechanisms. The terms “repair” and “regeneration” are often used interchangeably, mostly by mistake, and although they can occur in the same organ, these two processes should be considered different biological characteristics [30].

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Repair occurs by massive deposition of a fibrotic ECM and is a normal response after damage. In humans, these responses may be clinically relevant when heart cannot regenerate. The adult mammalian heart is the best example for the inability of an organ to regenerate spontaneously [16]. We do not know exactly whether the ability to regenerate is present in the human postnatal heart. Some researchers have reported the presence of adult cardiac resident stem cells (CSCs) and their differentiation toward cardiovascular cell types [31, 32] (Fig. 2). Paying attention to these findings, it seems that the mammalian heart possesses a level of regeneration potential, but it does not effectively work after a severe injury. Continuing research in this field may be an excellent strategy to discover new therapies for cardiac regeneration. In the 20th century, it was considered that the mammalian heart was a terminally differentiated organ, that its composing cells (cardiomyocytes, CMC) could not differentiate and regenerate. The heart response to injury was identified as hypertrophy of CMC. Then, in the 1990s, mitotic characteristics in CMC were observed, and calculations of significant CMC replicative activity were reported thanks to advanced, well-known methodologies to study cell biology [33]. In addition, evidence was provided for the presence of specific populations of stem or precursor cells in the mammalian heart, which was organized into a microenvironment called a stem cell niche [34, 35]. These myocardial stem cells have the ability to possess the properties of self-renewal, potency, and immunomodulation [36, 37], and they were contributing to CMC replacement in pathological situations. Nowadays, a new paradigm has arisen, stating that the mammalian heart is not a terminally differentiated organ but an organ with a cell population that is capable of generating new CMC [36]. At the same time as this new paradigm was advanced, reports were published demonstrating the very low mitotic activity of CMC in mature mammalian hearts [38, 39]. Novel studies confirmed a very low level of regeneration in the mammalian heart [40]. There is a consensus that the level of CMC renewal in the mammalian heart is approximately 0.5%–2% per year [41]. For a long time, scientists interpreted that the replication of cardiac stem cells was an important mechanism for CMC renewal [42, 43]. With growing science, it has been confirmed that reprogramming of the mature CMC is the major mechanism for the lowlevel turnover of CMC in the myocardium [41]. Myocardial infarction following coronary artery disease is well characterized by the regional necrosis of CMC and the replacement of fibrous tissue [44, 45]. Experimental findings support an increment in CMC turnover at the borders of infarcts during the process [46]. But this endogenous replicative activity does not lead to a significant level of myocardium regeneration. The progression of both ischemic and nonischemic cardiomyopathies resulted in myocardial remodeling [42, 43, 45]. This process increases CMC loss by several mechanisms and increases CMC replication as a compensatory phase. When the pathological stress persists, myocardial remodeling leads to terminal HF with a poor prognosis, and finally the only therapeutic intervention is limited to ventricular assist devices and cardiac transplantation [47]. Thus, the mature mammalian heart can be considered a terminally differentiated organ with a limited capacity for CMC

Stem cells and heart tissue regeneration

Fig. 2 Myocardial regeneration by stimulation of resident stem cells. PW1 known as paternally expressed gene Peg3 is expressed in all adult stem cells. (From Yaniz-Galende E, Roux M, Nadaud S, Mougenot N, Bouvet M, Claude O, Lebreton G, Blanc C, Pinet F, Atassi F, Perret C, Dierick F, Dussaud S, Leprince P, Tr
egouët DA, Marazzi G, Sassoon D, Hulot JS. Fibrogenic potential of PW1/Peg3 expressing cardiac stem cells. J Am Coll Cardiol 2017;70(6):728–41.)

regeneration response. The molecular basis for this limited replicative capacity of CMC is unknown [48–50]. The regenerative activity of the heart is mediated by parenchymal cells with significant replicative potential and precursor cells that participate in the

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regenerative process [51], but the response to the infarction region is scar formation rather than cardiac tissue regeneration. Heart is a terminally differentiated organ, and the healing of infarctions through scar formation is a pathological phenomenon, that is, myocardial remodeling. This process leads to biologically relevant realities that can be effectively modulated by stem cell therapy.

Cardiac cell therapy and tissue engineering Cellular cardiomyoplasty offers an ideal therapy in combination with tissue engineering to repair the damaged myocardium. In the cell therapy approach, stem cells are injected into the myocardium to repair the damaged tissue [52]. Singh and Sharma reported the efficacy of a variety of stem cells such as mesenchymal stem cells (MSCs), cardiosphere-derived cells (CDC), and cardiac stem cells for repairing the myocardium [53]. These transplanted cells can be differentiated into a wide variety of cells, including cardiomyocytes, endothelial, and smooth muscle cells in the damaged heart. Transplanted cells were successfully delivered into the infarcted region, but the main mechanism of action to repair the myocardial damage was due to the paracrine factors released by the transplanted cells, rather than the cell transplantation itself [54]. To improve the efficacy of stem cells in cardiac regeneration, additional support should be employed to improve the cell adhesion, viability, and tissue regeneration, all commonly referred to as the scaffold/matrix [55]. In contrast to cell therapy alone, cardiovascular tissue engineering offers a novel, promising approach to build new tissue that can be integrated into the host myocardium using a combination of stem cells and biomaterial scaffolds (Fig. 3) [56]. Recent advances in nanotechnology and biomaterials have brought about some different approaches to produce scaffolds for tissue engineering using nanofibers [55], metallic nanoparticles [57], hydrogels [58], injectable gels [59], polymeric microparticles [60], nanogels [61], liposomes [62], and dendrimers [63]. It is worth noting that the main focus of this chapter is to report on the application of cells in cardiac regeneration and subjects related to scaffolds will be discussed in other chapters.

Struggles in cardiac cell therapy The current struggles in cardiac cell therapy are the alignment and adhesion of cells, the conduction of electrical impulses between the cells, the contractility of the regenerated tissue, the development of tissue junctions, and the nutrient/oxygen supply to the tissue as a function of thickness [64–66]. To this end, scaffolds have been designed to encourage cell adhesion and promote alignment of cardiomyocytes. Furthermore, obtaining a uniform contractility from the injected cells is a very challenging task because transplanted cells are in an isolated form and exhibit a mismatch with each other due to differences in their adhesion and cell-cell junctions [67]. Likewise, synchronized contractions of cardiomyocytes are critical for their response to electrical impulses to avoid any unwanted arrhythmia [68]. During cardiac contraction, cardiomyocytes contract in the direction of

Stem cells and heart tissue regeneration

Fig. 3 Various strategies for cardiac tissue engineering. (From Zheng CX, Sui BD, Hu CH, Qiu XY, Zhao P, Jin Y. Reconstruction of structure and function in tissue engineering of solid organs: toward simulation of natural development based on decellularization. J Tissue Eng Regener Med 2018; 12(6):1432–4.)

their alignment, resulting in a similar contraction in their host tissue. Therefore, it is very important for the implanted cells to match and align with the host tissue to improve the functionality of the native heart. [69]. In addition to the above difficulties, the thickness of the regenerated myocardium is very important [70]. Problems associated with the oxygen supply to the thick tissue layer may be resolved by vascularization of the synthetic myocardium [71]. Vascularization in turn requires perfusion with multiple blood arteries and veins as well as maintenance of a coculture environment [72]. Providing all these factors and optimizing them with native host tissue have remained very challenging tasks after several decades of angiogenesis research, and need a huge amount of further research to develop fully functional heart tissue. Another important challenge is the right selection of cell sources and their maturity.

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Cell maturity and heart regeneration The common choices of donor cell sources for damaged heart tissue and regeneration consist of somatic muscle cells (including fetal/neonatal cardiomyocytes and skeletal myoblasts), cardiomyocyte-generating cells (including embryonic stem cells, pluripotent stem cells, adipose-derived stem cells, bone-marrow derived stem cells, and cardiac progenitor cells), and angiogenesis-inducing cells such as fibroblasts and endothelial progenitor cells [73, 74]. There is much evidence supporting the fact that the maturation stage of the stem cells is crucial in their survival and integration with the host tissue [75–81]. The ideal maturation stage required for stem cell transplantation and cardiac tissue regeneration is highly disputable. In the case of cardiomyocytes, early stage cardiomyocytes (fetal/neonatal CM) were considered a better candidate than fully matured ones because of the better survival in vivo [82]. According to Fernandes et al. [82] the human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and mesodermal cardiovascular progenitor cells (CPCs) performed better than the human bone marrow mononuclear cells (hBMMNCs), which were among the most widely studied cells throughout the clinical trials. Interestingly, no difference was observed in cardiac repair efficacy between hESCCMs (more matured) and CPC (less matured) according to their study. There are many in vitro strategies to enhance the maturation of cardiomyocytes by biochemical stimulation (using cytokines, hormones, and other small molecules), biophysical stimulation (electric current and mechanical), and also by providing necessary three-dimensional (3D) microenvironments [83–85]. Information about the maturation stage in the successful engraftment of stem cells into the ischemic heart is rare and further studies are required to compare the transplantation of mature versus immature cells (human IPS-derived cardiomyocytes/CPCs) to determine the efficacy of therapeutic stem cell therapy for cardiac regeneration.

Stem cells in heart regeneration Stem cell therapy has emerged as an alternative to conventional concepts in heart repair and regeneration because the self-healing capacity of cardiomyocytes in adults is limited [86, 87]. SCs are specified as undifferentiated cells that possess the ability to generate and replace terminally differentiated cells via unlimited replication. They demonstrate two basic features: continual self-renewal and the capability to differentiate into a specialized cell type under appropriate conditions [88]. SCs are generally categorized into two main groups: embryonic SCs (ESCs) and adult or somatic SCs. A third category of “embryonic-like” cells has been added in recent years called induced pluripotent cells (iPSCs), which are genetically reprogrammed by pluripotent transcription factors [89]. The therapeutic application of pluripotent SCs (ESCs,

Stem cells and heart tissue regeneration

iPSCs), including the capacity to differentiate into all cell types of an organ, is limited in cardiac regenerative medicine due to the risks of immune rejection, genetic instability, and tumorigenic potential (iPSCs) as well as ethical issues (ESCs) [89–91]. The safety and efficacy of multipotent adult SCs (differentiation into limited cell types, for example, mesenchymal SCs, cardiac SCs) or unipotent adult SCs (differentiation into one cell type) have been investigated for cardiac regeneration in clinical trials over the last 20 years. Different types of adult SCs have been examined such as multipotent bone marrowderived SCs (BM-SCs, including hematopoietic (HSCs), mesenchymal (BM-MSCs), endothelial stem cells), mesenchymal SCs (MSCs), skeletal myoblasts, and cardiac SCs (CSCs) [92]. In cardiac regeneration, skeletal myoblasts were the first cell type evaluated both in preclinical and clinical studies. Lately, it is not under consideration because of inconsistent effect and occurring arrhythmias [93, 94]. Multipotent CSCs are able to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells, but their numbers are limited and their clinical use is restricted due to the invasive nature of obtaining them via myocardial biopsies. BM-derived cell types, especially BM-MSCs, are attractive for therapeutic use in cardiac regenerative medicine due to their easy accessibility and further isolation from autologous bone marrow or blood in addition to their differentiation capacity, angiogenic potential, and favorable tolerance by the immune system. It is worth noting that the exact mechanisms of cardiac repair by the cell transplantation approach are still unknown. Two main hypotheses are: (a) direct cardiomyogenic/vasculogenic differentiation and (b) indirect stimulation of the regenerative processes through paracrine and immunomodulatory effects by the secretion of cytokines and growth factors [95, 96]. Different types of stem cells used to treat damaged hearts are shown in Fig. 4 and tabulated to provide more details in Table 1.

Bone marrow stem cells Undifferentiated cells in bone marrow are mesenchymal and hematopoietic stem cells. These mononuclear cells consist of at most 4% of a hematopoietic type and only 0.01% in the form of the mesenchymal type [97]. These cells have various antigens on their surface that make them easily identifiable, such as CD4 [98], CD45, CD34, CD90 [99], stem cell factor (SCF), prominin 1, endoglin [100], and aldehyde dehydrogenase [101]. They do not express a lin marker, which makes them distinguishable from other stem cell types [102]. These stem cells affect heart tissue by inducing angiogenesis [103] as well as antiapoptotic [104] and antifibrotic activities [105]. Hematopoietic stem cells, which produce blood cells, also can be differentiated into cardiomyocytes. CD34+ cells, express C-kit, CD31, GATA4, and myocyte enhancer factor [106]. Long-term results in a study performed by Ahmadi et al. indicated that transplantation

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Fig. 4 Different types of stem cells reported for cardiac tissue engineering including pluripotent stem cells (ESCs: embryonic SCs; iPS: induced pluripotent cells), which are generally differentiated to cardiac progenitor/cardiomyocytes, and multipotent/unipotent stem cells (myoblast; BMSCs: bone marrowderived SCs; MSCs: mesenchymal stem cells; CSCs: cardiac resident stem cells) are generally used to restore heart function directly. (From Sheng CC, Zhou L, Hao J. Current stem cell delivery methods for myocardial repair. Biomed Res Int 2013;2013:547902.) Table 1 Various types of cells used for cardiac tissue regeneration Stem cell source

Potency

Advantages

Disadvantages

Bone marrow

Multipotent

Antiapoptotic, vasculogenic, fewer side effects, no immunogenicity, easily available

Cardiac

Multipotent

Embryonic

Pluripotent

High regeneration ability, antiapoptotic, angiogenic, no immunogenicity Most efficient myogenic

Umbilical cord

Multipotent

Vasculogenic, myogenic, minimal side effects

Induced pluripotent

Pluripotent

Differentiate into a variety of cell types, high cell count, disease modeling

Adipose tissue

Multipotent

Immunogenicity, antiinflammatory

Low cell count, weak electrical and myogenic properties, fewer regenerative abilities, and negative effect on cardiac function Weak myogenic properties, low cell count, age-dependent response, limited growth Teratoma, ethical concerns, incontrollable differentiation, immunogenicity, arrhythmias Immunogenicity, ethical concerns, GVHD, low cell count, contamination with other cells Arrhythmia, genetic instability, tumorigenicity, immunogenicity, requirement of vector system, time and cost Tumorigenic capabilities

Stem cells and heart tissue regeneration

of CD133+ is a safe and feasible procedure; however, they could not show any major benefit in patients [107]. In another clinical trial, the use of hematopoietic stem cells to treat left ventricular dysfunction following myocardial infarction was evaluated [108]. In phase III of the (PERFECT) trial, intramyocardial administration of CD133 + bone marrow cells significantly improved cardiac function after CABG surgery [109]. Cardiac function in patients with MI was repaired by Strauer et al. [110]. Mononuclear BMSCs were obtained autologous to avoid immune rejection. In most of the trials, after injection, the left ventricular ejection fraction (LVEF) and cardiac function were improved with a decrease in the infarct size. This effect was attributed to the ability of BMSC to differentiate into cardiomyocytes [111, 112]. However, a recent study has concluded less significant outcomes [113]. Assmus et al. (2006) reported a significant rise in global and regional LVEF after ischemic heart disease using bone marrow cells, which was attributed to the ability of BMSCs to contract [114]. Improved myocardial function using BMSCs has been shown in many animal studies [115–119]. Cell transplantation routes are either surgical or percutaneous, such as using a catheter led by the chemokines and integrins to provide a suitable environment for stem cell placement. Nonetheless, the number of cells that are retained in the infarcted area is very low, which seems not to be viable [120]. Yang et al. explained a novel approach for the placement of stem cells in a noninfarcted vessel to induce angiogenesis and the regeneration process and reduce fibrillation and arrhythmias [121]. However, the long-term efficacy of these cells is still controversial. The effect of these cells is quite dependent on the dosage, the time duration postinfarction, and the baseline levels of the LVEF [122]. In the STAR-heart study, a significant improvement was observed in patients with LVEF< 35% after stem cell therapy [110]. The cells are effective in fibrous tissue repair and can reduce the infarct size [123]. Allogenic MSCs were demonstrated to leave minimal serious adverse effects compared to the autologous ones. Allogenic cells, like the autologous ones, lead to an improvement in cardiac function [124]. The downregulation of histone deacetylase 1 [125] and the overexpression of protein kinase B support the mesenchymal BMSC cardiogenic potency and protect them from cell death [126]. Guti
errez-Ferna´ndez et al. showed that IV administration of bone marrow MSCs to treat a stroke in the brain was combined with the production of tissue repair factors such as VEGF, apoptosis reduction, and the promotion of cell proliferation [127]. Surprisingly, there was a greater incidence of adverse effects in patients who received autologous transplants than the allogenic ones. Moreover, the left ventricular function increased more in the allogenic group [128]. In addition, MSCs from bone marrow can also play a role as pacemaker cells by the expression of the hyperpolarization-activated cyclic nucleotide-gated 2 gene (HCN-2) [129]. In general, MSCs have a limited capacity to induce a myogenic response, minimal electrical properties, and fewer effects on cardiac function [66].

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Cardiac and cardiosphere-derived stem cells The existence of nonterminally differentiated cardiac myocytes possessing the properties of stem cells has been proved in various studies. These cells play a significant role in the development of cardiac tissue [130, 131]. Successful differentiation of these cells leads to cardiac cells [132]. Nonterminally differentiated cardiac myocytes come from bone marrow and have properties similar to BMSCs [130]. These cells are found in the myocardium, presenting C-kit and other antigens with multipotent stem cell properties. However, due to the absence of CD45 antigen, the origin of these cells is nonhematopoietic [133]. Cardiac stem cells exhibit rebuilding capabilities to regenerate the myocardium and improve heart functionality in response to heart injury, perhaps due to the overexpression of proto-oncogene kinase [134]. This concept is also due to the presence of undifferentiated myogenic cells that can self-renew [135]. Animal studies showed that nonterminally differentiated cardiac myocytes have a higher ability to repair cardiac defects than BMSC [136]. Nonetheless, in large animals, poor results have been obtained [137]. Apoptotic responses decreased after administration of these cells, but the proliferation of new cells was improved via angiogenesis [138]. In a TICAP (phase I) trial, autologous cardiac progenitor cells were administered in the coronary artery. Improvement in the right ventricular ejection fraction as well as a decline in HF incidence and the size of the right ventricular and associated valvular components was seen in the treated patients [139]. Cardiospheres are spherical clusters of cardiac cells with mesenchymal properties [140] that are undifferentiated stem cells and can be extracted through an atrial or ventricular biopsy of the neonatal heart [121]. The neonatal cardiosphere-derived stem (CDS) cells have greater potencies of cardiac tissue repair that the adult ones. C-kit, nuclear transcription factors, nkx2-5, GATA4, flk-1, and ISL-1 are some of the significant antigens appearing on their surface [141]. A comparison of cardiospheres with the bone marrow and adipose stem cells revealed much higher angiogenic, myogenic, and antiapoptotic activity for cardiospheres than the other stem cells [140]. An animal study in a porcine model showed that these cells lead to tissue repair by the promotion of new tissue formation and the stabilization of the hemodynamics [142]. However, because of their large size, they cannot be used intracoronary [143]. In a CADUCEUS trial, cardiosphere-derived autologous stem cells were utilized to reverse ventricular dysfunction using autologous CDS cells to treat ventricular dysfunction. Without any adverse effects, 1-year patient followups showed a massive reduction in the infarction scar, with an increase in the ejection fraction [144]. Similar results were observed in a phase I trial of cardiac stem cell therapy in patients with ischemic cardiomyopathy (SCIPIO) [145]. A combination of mesenchymal and cardiac stem cells as a new therapy for cardiac regeneration (CONCERT-HF) is in phase II of a clinical trial to determine and compare the efficacy of BMSCs, CDS cells, and combinational therapy in ischemic patients [146]. Allogenic transplantation of cardiospheres does not promote an immune response and

Stem cells and heart tissue regeneration

is therapeutically effective compared with autologous cells [147] because of the expression of major histocompatibility complex II (MHC II) [148]. Some of the significant limitations of these cells are low cell population in the heart, the absence of a specific marker, age-dependent deterioration, and limited differentiation [149].

Induced pluripotent stem cells Induced pluripotent stem cells are pluripotent in nature. Four embryonic genes are incorporated in the somatic cells using a viral vector system to achieve pluripotency [150]. Due to the tumorigenic properties of the c-Myc gene, the estrogen-related receptor beta (Essrb) receptor along with the Oct4 and Sox2 genes have embryonic cell-like properties [151]. These cells can be derived from smooth muscles and dermal fibroblast as well as the stomach, blood, adipose tissue, liver, and even the brain [152, 153]. Several gene delivery methods are under study and practice, including viral vectors, transposons, recombinant proteins, and episomal plasmids [154]. Cardiomyocytes for therapeutic applications can be produced using iPSCs, demonstrating characteristics of the original cells by the expression of the Oct4, Sox2, and nanog genes [155, 156]. iPSCs have several advantageous effects when used to treat myocardial defects and injuries, such as the reduction of scarring, degradation of the tissue, and stimulation of angiogenesis. Due to the genetic manipulation of these cells, they are highly prone to abnormal genetic modifications. This process is time consuming and requires vector-based systems for gene expression, thereby adding extra cost and complications to the process. Also, tumorigenicity and teratoma formation are some of the problems in this area [66, 149].

Embryonic stem cells Cells extracted from the inner layer of the blastocysts have the ability to differentiate into many different types of cells. The expression of GATA-2, Gef 2, NK2-5, troponin, and connexin in the ESCs gives them the cardiogenic properties [157]. Because of ethical concerns associated with these cells, human studies have been restricted in this area. Murine allogenic blastocyst cells were genetically manipulated to express cardiac α-myosin heavy chain or elongation factor under lacZ promoter-control conditions. Upon induction of infarction conditions in animals, thereby creating abnormalities in cardiac function, stem cell treatment was provided to the animals. Several cardiac outcomes were improved, such as blood flow and ejection fraction. However, tumorigenesis was seen in the hearts transplanted with either type of cells [158]. Qiao et al. [159] showed that ESCs express cardiac cell-specific genes, are safe to be transplanted to the infarcted area and lead to repair of the injured tissue, increasing global ejection fraction, and improving contractility. These cells are the only cell line with effective myogenic capabilities, but teratoma formation and immunogenicity are

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the major concerns in ESC studies, along with ethical issues [66]. Studies have also reported the induction of arrhythmias during cell treatment for MI [160].

Umbilical cord stem cells Umbilical cord-derived stem cells are widely used in therapeutic applications such as thalassemia, blood cancer, and cardiovascular diseases [161]. These stem cells are obtained from the umbilical cord using enzymes such as collagenase and trypsin. Upon cell processing, they are tested for stem cell-like markers. These cells can have osteogenic, neuronal, skeletal, and adipogenic characteristics. Animal studies have shown that cells with these properties can also differentiate into cardiac, endothelial, and smooth muscle cells, and hence, have therapeutic benefits [162]. The markers of these cells are CD34+, CD133 +, CXC chemokine receptor, and stromal cell-derived receptors [161]. Mesenchymal cells derived from the umbilical cord express hepatocyte growth factor, which is responsible for myogenesis as well as organ and wound repair [118, 119]. Intravenous administration of these cells in patients with HF can result in repair and restoration of normal cardiac function with no critical side effects [163]. Wharton’s jelly cells (WJCs) have a fibroblast-like morphology and are pluripotent MSCs obtained from the jelly-like substance between blood vessels and the umbilical cord, which can easily be isolated and then proliferate. They express various MSC-like surface antigens such as thy-1, SCF, and CD105. Chemoattractant properties are also seen in these cells due to the expression of VEGF, stromal cell-derived factor, and angiopoietin [164]. Some of the attractive characteristics of these cells are their property to inhibit the immune response by repressing T-cell proliferation as well as their noncarcinogenic abilities and angiogenesis [165]. Animal studies revealed that these cells are adherent to cardiac tissue (ischemic and normal) and they can integrate into ventricular tissue. The transplant of human umbilical cord stem cells in infarcted rabbits showed vasculogenesis and proliferation of the cells [118, 119]. In a clinical trial with 18 months of follow up, restoration of the blood flow in occluded vessels and rise in LVEF were seen in patients treated with WJCs. In another study, allogenic WJCs were transcoronary infused in the infarcted vessels and successful results were obtained with no serious adverse effects [166]. An ischemic porcine model study has also given similar results [167]. A randomized clinical trial of intravenous infusion of umbilical cord MSCs in a cardiopathy (RIMECARD) clinical trial showed a significant increase in ejection fraction and ventricular function [163]. Moreover, these cells were taken from the child’s umbilical cord, and therefore disease and ethical issues are under argument. The major problems associated with the application of these cells are contamination with the mother’s cells, graft versus host reaction, genetic instability, and a low cell count for adult recipients.

Stem cells and heart tissue regeneration

Adipose-derived stem cells These are multipotent cells derived from adipose tissues through which they are capable of differentiating into various cell types, including adipocytes, fibroblasts, myocytes, and cardiac cells [168]. They express STRO-1, myeloid antigen, and some cell adhesion antigens on their surface [169]. Upon differentiation into cardiac cells, they express GATA-2, NK2–5, myosin light chain, α-actinin, and connexins, along with contractility activity. The absence of MHC II expression in these cells makes them a suitable candidate for allogenic transplants [170]. Bai et al. showed that human-derived adipose tissue stem cells have the ability to treat infarction in an animal experiment [171] and helped to restore cardiac function. In contrast to BMSCs, they provide fast recovery from the infarction [172]. The applied proteogenomics organizational learning and outcomes (APOLLO) clinical trial supported the treatment of acute MI using autologous adipose stem cells upon intracoronary administration of cells and ejection fraction in treated patients was improved with the reduction in infarct size [173]. In a prospective randomized trial of the optimal evaluation of cardiac symptoms and a revascularization (PRECISE) trial with infusion of adipose stem cells intracoronary in ischemic patients, ventricular repairs with no side effects were seen [174]. In a recent trial based on adipose tissue stem cells for cardiac repair in a patient with coronary artery disease, no ventricular improvement was observed [175].

Conclusion In the past decades, stem cell transplantation has proved a safe and successful method in treating a damaged myocardium. But some studies reported adverse effects related to cell transplantation [176]. Also, a hematoma of bone marrow cells at the injection site was observed [177]. In a trial, restenosis of the coronary artery after intracoronary infusion of peripheral blood stem cells was observed [178]. In some studies performed on animals, a few poor outcomes were obtained [179]. Clinical application of MSCs is limited because of the poor survival of these cells [180]. However, the overall safety profile of stem cell therapy is excellent based on evidence achieved in many studies. Stem cell therapy faces many challenges. The growth, preservation, and transport of stem cells are difficult tasks. Hematopoietic stem cells possess the greatest capacity of transdifferentiation into multiple cell lineages. However, their potential efficacy to regenerate the myocardium is poor and some failures raise questions about stem cell therapy that require further investigation to establish an evidential consensus about its therapeutic efficacy [181]. Ethics in stem cell therapy is another complication of this field. For example, using fetal stem cells might be unethical because the fetus cannot provide informed consent, which is required to obtain stem cells [182]. According to the US Food and Drug Administration guidelines for stem cell therapy, each patient should sign the informed

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consent that explains the risk of any infection or genetic material transmission from donor tissue and also the rejection of implanted cells, safety and efficacy of stem cell therapy [183]. For the last word, with a view to the literature, the induction of angiogenesis, prolonged cell survival, and paracrine factors are essential for successful stem cell transplantation. The most frequent adverse effect is the restenosis of coronary vessels, but the overall safety is significant. Clinical trials and animal studies that have been performed in the past few years showed significant improvement in cardiac function and angiogenesis. The long-term success rate of stem cell therapy is debatable, as some failures of this therapy were also reported in the literature. Ethically, embryonic stem cell transplantation is a most important topic that requires further assessment.

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egh AMD, SJJo L, GPJv H, Currie GL, Sena ES, et al. Cardiac stem cell treatment in myocardial infarction. Circ Res 2016;118(8):1223–32. Bao L, Meng Q, Li Y, Deng S, Yu Z, Liu Z, et al. C-Kit positive cardiac stem cells and bone marrowderived mesenchymal stem cells synergistically enhance angiogenesis and improve cardiac function after myocardial infarction in a paracrine manner. J Card Fail 2017;23(5):403–15. Ishigami S, Ohtsuki S, Tarui S, Ousaka D, Eitoku T, Kondo M, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome. Circ Res 2015;116 (4):653–64. Li T-S, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 2012;59(10):942–53. Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, et al. Intracoronary bone marrow cell transfer after myocardial infarction. Circulation 2006;113(10):1287–94. Johnston PV, Sasano T, Mills K, Evers R, Lee S-T, Smith RR, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009;120(12):1075–83. Ashur C, Frishman WH. Cardiosphere-derived cells and ischemic heart failure. Cardiol Rev 2018;26 (1):8–21. Malliaras K, Makkar RR, Smith RR, Cheng K, Wu E, Bonow RO, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol 2014;63(2):110–22. Bolli R, Chugh AR, D’Amario D, Loughran JH, Stoddard MF, Ikram S, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 2011;378(9806):1847–57. Tendera M, Wojakowski W, Ruz˙yłło W, Chojnowska L, Kępka C, Tracz W, et al. Intracoronary infusion of bone marrow-derived selected CD34 +CXCR4 + cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of

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enard V, Menard C, Andr
e M, Puceat M, Perez A, Garcia-Verdugo J-M, et al. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res 2004;94(2):223–9. Joo HJ, Kim J-H, Hong SJ. Adipose tissue-derived stem cells for myocardial regeneration. Korean Circ J 2017;47(2):151–9. Guti
errez-Ferna´ndez M, Rodrı´guez-Frutos B, Ramos-Cejudo J, Otero-Ortega L, Fuentes B, Vallejo-Cremades MT, et al. Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: proof of concept in rats. J Transl Med 2015; 13(1):46. Bai X, Yan Y, Song Y-H, Seidensticker M, Rabinovich B, Metzele R, et al. Both cultured and freshly isolated adipose tissue-derived stem cells enhance cardiac function after acute myocardial infarction. Eur Heart J 2009;31(4):489–501. Paul A, Srivastava S, Chen G, Shum-Tim D, Prakash S. Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells. Cell Biochem Biophys 2013;67(2):263–73. Houtgraaf JH, den Dekker WK, van Dalen BM, Springeling T, de Jong R, van Geuns RJ, et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2012;59(5):539–40. Perin EC, Sanz-Ruiz R, Sa´nchez PL, Lasso J, P
erez-Cano R, Alonso-Farto JC, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 2014;168(1). 88-95.e2. Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, et al. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv 2017;89(2):169–77. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet (London, England) 2003;361 (9351):45–6. Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel Jr HC, Kormos R, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005;130(6):1631–8. Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet (Lond, Engl) 2004;363(9411):751–6. Vulliet PR, Greeley M, Halloran SM, MacDonald KA, Kittleson MD. Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet (Lond, Engl) 2004;363 (9411):783–4. Mao J, Lv Z, Zhuang Y. MicroRNA-23a is involved in tumor necrosis factor-alpha induced apoptosis in mesenchymal stem cells and myocardial infarction. Exp Mol Pathol 2014;97(1):23–30. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004;428 (6983):664–8. McLaren A. Ethical and social considerations of stem cell research. Nature 2001;414(6859):129–31. Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies. N Engl J Med 2006;355 (16):1730–5.

CHAPTER 6

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases Evgeniya A. Vaskova, Phillip C. Yang

Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Introduction Ischemic cardiomyopathy (IC) is currently defined as significantly impaired left ventricular dysfunction (left ventricular ejection fraction
40%), which results from coronary artery disease (CAD) and is considered to be the most common cause of heart failure [1]. At the cellular level, IC is characterized by cardiomyocyte (CM) death. This results in cardiac remodeling, primarily due to myocardial fibrosis, and results in decreased cardiac function, arrhythmia, and cardiac conduction system impairment [2]. Current treatment of IC is mainly aimed at reducing heart failure symptoms and fails to address the underlying problem of irreversible loss of the myocardium [3]. A number of preclinical and clinical studies have shown that stem cell-based therapy may be a promising therapeutic approach for the treatment of IC. The initial theory hypothesized that the transplanted stem cells would differentiate into CMs, engraft into the host myocardium, and augment the cardiac function. However, despite significant restoration of cardiac function and viability following delivery, de novo cardiac differentiation of the transplanted stem cells was rare. In addition to poor engraftment and suboptimal survival of the stem cells in an ischemic heart, the risks of immune reaction and teratoma formation act as a deterrence for stem cell-based therapies to work in a clinical setting. At the same time, mounting evidence suggests that the primary mechanism of action for cell therapy is mediated via paracrine effects in which the exosomes play a major role [3–13]. Exosomes are nano-sized vesicles, with the diameter ranging from 30 to 150 nm [14, 15], released from all cell types. Exosomes contain biologically active cargo such as mRNAs, DNAs, small molecules, and proteins and are able to transfer their cargo to recipient cells to modulate target gene expression and cell function [3, 16–19]. Cell type of origin, physiological condition, and pathological stimuli dictate the compositions of exosomal cargo. In cardiovascular system, exosomes from different cell types have been

Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00006-4

© 2020 Elsevier Inc. All rights reserved.

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shown to be involved in promotion of physiological processes, such as cardiac growth, development, and angiogenesis, as well as pathological states, including inflammation, ischemic-reperfusion (I/R) injury, apoptosis, and cardiac remodeling/fibrosis, contributing to restoration and impairment of heart function. Thus, exosomes may represent a new cell-free tool for regenerative or reparative medicine. Exosomes impact specific target genes and pathways to attenuate myocardial injury and stimulate endogenous cardiac repair. The relative stability of exosomes, originating from any native cells, enables effective transfer of their cargo to practically any recipient cells while retaining structural stability anywhere throughout the body. Finally, the contents and quantities of exosomes are sensitive to different pathological stimuli, making them a valuable source of diagnostic biomarkers. In this review article, we have summarized the findings about the role of exosomes and their cargo from different cell types involved in various cardiovascular diseases. Specific focus is placed on their therapeutic and diagnostic potential in IC.

Biogenesis and composition of the exosomes During the past decade, extracellular vesicles have emerged as important players in cellto-cell communication in normal physiological and pathological conditions. According to their size and biogenesis pathways, extracellular vesicles can be divided into three main types: exosomes, microvesicles (also called microparticles), and apoptotic bodies. Exosomes are commonly considered to represent a homogeneous population with a size between 30 and 150 nm in diameter, and they typically display a cup-like shape [20]. However, recently, it was demonstrated that there are different subpopulations of exosomes with distinct molecular compositions and biological properties [21]. Exosomes are derived from the endolysosomal pathway and are generated by the intraluminal budding of endosomal compartments, forming the intraluminal vesicles in intracellular multivesicular bodies. Then, they are released by the cells upon fusion of multivesicular bodies with the plasma membrane [22, 23]. The cellular origin, composition, and internal cargo of the exosomes determine the outcome of their intercellular communication [22, 24, 25]. Their lipid composition includes ceramide, sphingomyelin, phosphatidylcholine, and phosphatidylserine within the membrane bilayer and the cholesterol content inside the exosomes [26, 27]. Exosome-specific proteins include the ubiquitously expressed tetraspanins CD81, CD9, CD63, CD82, heat shock protein-70 (HSP70), HSP60, and Alix (apoptosis-linked gene 2-interacting protein X); annexins and cytoskeletal proteins; and unique cargo proteins [20, 25, 28]. Moreover, exosomes contain a distinctive repertoire of microRNAs (miRNA), other small noncoding RNAs (piRNA, snRNA, snoRNA, scaRNA,

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

Y RNA), natural antisense RNAs, tRNAs and their fragments, mRNAs and their fragments, rRNAs, and long noncoding RNAs [24, 29]. Once secreted, the exosomes can enter target cells or travel into the body fluids. The exosomes can be internalized into target cells via different ways such as endocytosis, ligand-receptor binding, or membrane fusion [3, 18, 30]. Taken together, these features of the exosomes have made them a promising tool in response to different physiological and pathological settings as signal mediators, potential therapeutic targets, and biomarkers.

The therapeutic potential of endogenous exosomes in an ischemiainjury heart The adult mammalian heart is composed of many cell types, including CMs, fibroblasts, endothelial cells (ECs), smooth muscle cells, neuronal cells, immune cells, and resident cardiac stem cells. To provide normal heart function, metabolism, and homeostasis, all of these cells act in a highly regulated and coordinated manner, which is mediated mainly via exosomes [31–33]. We will review the effects of the exosomes from different cell types on cardiac cells and processes in both healthy and ischemic hearts. The specific components of exosomal cargo and potential mechanism of action are summarized in Table 1. Table 1 The effect of the exosomes and their cargo Biological effect

Antiapoptotic + antioxidative effect

Source of the exosomes

Stimuli/ condition

Rat CMs

Hypoxia/ reoxygenation Hypoxia

Rat CMs (cell line:H9c2) Rat CMs (cell line:H9c2) Mice CPCs Mice CPCs Murine cardiac fibroblastsderived iPSCs iPSCs-derived CMs iPSCs-derived CMs

Hypoxia/ reoxygenation H2O2treatment H2O2treatment H2O2treatment Myocardial IR – Hypoxic

Cargo

HSP60 [28] miR-21-5p, miR-378-3p, miR-152-3p, let-7i-5p [34] miR423-3p [35] miR-451 [36] miR-21 [37] miR-21, miR-210 [38]

miR-92a-3p, miR-122-5p, miR-320 [5, 39] miR-106a-363 [40, 41] Continued

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Table 1 The effect of the exosomes and their cargo—cont’d Biological effect

Pro-apoptotic Pro-angiogenic

Pro-hypertrophic

Pro-fibrotic

Antiinflammatory

Source of the exosomes

Stimuli/ condition

Cargo

CMs from neonatal rats Rat neonatal CMs and H9c2 cell line CMs from piglets Plasma

Hypoxia

TNF-α [42]

Human dermal microvascular ECs (cell line: HMEC-1) MSCs from human adipose tissues Mouse CMs (cell line: HL-1)

Rat CMs (cell lines: H9c2 and 3T3 cells) Neonatal rat fibroblasts Rat CMs

Rat CMs (cell lines: H9c2 and 3T3 cells) Human dermal microvascular ECs (cell line: HMEC-1)

miR-222, miR-143 [43]

Hypoxia

Hsp20 [44]

Myocardial ischemia patients –

miR-939 [45]

–

miR-125 [46]

TGF-β2treatment PDGF-BB treatment –

NFAT5; HDAC5

–

miR-21*

Hypoxia or Angiotensin II-treatment –

miR-208a [48]

TNF-αtreatment

Upregulation: TNIP1 (TNFAIP3 interacting protein 1); TNFAIP3 (tumor necrosis factor, alphainduced protein 3); ICAM1 (intracellular adhesion molecule 1) Downregulation: CO5 (complement component 5); APOM (apolipoprotein M); COIA1 (collagen, type XVIII, alpha 1) [49]

miR-214

HDAC5 miR-217 [47]

miR-217 [47]

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

Cardiomyocyte-derived exosomes Gupta and Knowlton [28] first demonstrated that the adult rat CMs secreted exosomes both in physiological and hypoxic conditions. Noteworthy from this study was the finding that the release of exosomes was enhanced by hypoxia and their cargo was enriched with HSP-60. Extracellular HSP-60 was known to be toxic to cardiac cells [50], but HSP-60 contained in exosomes were bound to the membrane and were not released, preventing the pro-apoptotic effects [51]. In another study, it was also shown that the hypoxic condition enriched exosomes with cardioprotective miRNAs which play an important role in the HIF-1 signaling pathway and in apoptotic pathways such as the TNF, MAPK, and mTOR signaling [34]. In an ischemic heart, CMs were characterized by activation of autophagy, an intracellular degradative process. The process was shown to be regulated by CMs-derived exosomes by the transfer of miR-30a [52], indicating its protective role during postmyocardial infarction cardiac remodeling. However, along with the cardioprotective cargo, CMs-derived exosomes also contain pro-apoptotic molecules. Thus, Yu et al. [42] demonstrated that the CMs exposed to hypoxic released exosomes which promoted apoptosis in the nearby CMs due to the presence of tumor necrosis factor-α (TNF-α) in their cargo. In addition to regulation of apoptosis, CMs-derived exosomes are involved in crosstalk between the CMs and ECs. Ribeiro-Rodrigues et al. demonstrated that the intramyocardial delivery of ischemic CM-derived exosomes improved neovascularization following myocardial infarction. The effect was mainly attributed to the enrichment of miR-222 and miR-143 in their cargo [43]. Additionally, the exosomes displayed higher levels of metalloproteinases (MMP)-2 and -9, capable of degrading the extracellular matrix (ECM) and promoting the production and release of MMPs by the ECs. In CMs from newborn piglets subjected to hypoxia, hypoxia inducible factor 1 α (HIF-1α) upregulation resulted in the induction of Hsp20 [44]. Hsp20 triggered angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF) receptor-2 in ECs, which stimulated angiogenesis in the myocardium. Clinically, exosomes derived from the plasma of IC patients had greater activities in the proliferation and migration of ECs and tube formation via the activation of iNOS-NO pathway by miR-939. The authors found out that biogenesis-related marker proteins were activated in ischemic myocardium and hypoxic CMs, but not in ECs or fibroblasts which indirectly supported the primary role of CMs as the source of bioactive exosomes. However, the study noted that the exosomes were isolated from plasma, which contains exosomes circulating throughout the whole body; thus, the source of the exosomes could not be confirmed and may be different from the CMs [45]. As stated previously, external stimuli on the parental cells influence the payload of the exosomes. Genneb€ack et al. [17] analyzed the mRNA content of the exosomes from CMs treated with transforming growth factor β2 (TGF-β2) and platelet-derived growth

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factor BB (PDGF-BB). Both growth factors are known to be involved in chronic and acute hypertrophy [53]. As a result, stimulation with two different factors resulted in unequivocal response in terms of transcriptional contents of secreted exosomes. Interestingly, in the exosomes released by TGF-β2-treated-CMs, overexpression of nuclear factor of activated T-cells 5 was found [17] which stimulates the expression of hypertrophic genes and is involved in cellular proliferation [54]. Furthermore, in the group of transcripts that were common for both growth factors, histone deacetylase 5 (HDAC5) was found [17]. HDAC5 is known to regulate the differentiation of mesodermal cells into cardiac muscle cells [55] and repress the expression of hypertrophic genes [56]. These data indicated that the growth factor stimulation in vitro altered the mRNA-cargo of CMs-derived exosomes, mediating signals for proliferation, development, and hypertrophy. Rat CMs exposed to hypoxic condition or treated with Angiotensin II in vitro produced exosomes with elevated level of miR-208a, which transfer their cargoes to cardiac fibroblasts, resulting in their proliferation and differentiation [48]. Nie et al. [47] demonstrated that the rat CMs-derived exosomes, containing miR-217, enhanced the proliferation of fibroblasts in vitro. It was also correlated clinically where miR-217 expression was upregulated in the plasma of chronic heart failure patients and cardiac tissue samples, which modulated cardiac hypertrophy via the PTEN-AKT pathway [57]. Thus, the interaction between CMs and fibroblasts is important in the progression of chronic heart failure, promoting the development of cardiac hypertrophy and dysfunction. To sum up, CMs release exosomes under normal and pathological conditions. When exposed to different stimuli, the content and quantity of the exosomes are significantly changed. In the heart, the exosomes have been shown to modulate such processes as apoptosis, angiogenesis, and hypertrophy, which might have either beneficial or detrimental effect.

Cardiac endothelial cell-derived exosomes In the heart, ECs are one of the most abundant cell types—not in total volume but in total number [58]. They play a crucial role in establishment and maintenance of vascular integrity, cardiovascular homeostasis, modulation cardiac contractility [59, 60], and cardiac remodeling [61, 62]. Here, we discuss the functional role of the exosomes released by the ECs in these processes. First, EC-derived exosomes have been shown to be involved in endothelial cell-tocell communication, particularly, to manage angiogenesis. In vitro human dermal microvascular ECs release miR-214-containing exosomes, which stimulate migration and angiogenesis in recipient cells. Additionally, treatment of mice with miR-214-enriched exosomes results in increased number of blood vessels [63].

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

Second, the exosomes released by ECs can modulate the function and characteristics of other cardiac cell lines. Cardiac ECs exposed to hypoxic condition release HIF-1-enriched exosomes, which contribute to cardiac progenitor cells’ (CPCs) increased tolerance of ischemic stress [64]. This response may be mediated by regulation of the ERK1/2 MAPK signaling pathway [65]. In addition, miR-126- and miR-210-enriched exosomes from hypoxia-exposed ECs were shown to increase the resistance of CPCs to hypoxic stress through stimulation of PI3K/Akt and other pro-survival pathways [66]. Third, the cell-to-cell communication between ECs and smooth muscle cells has been also described. ECs-derived exosomes enriched with miR-143/145 were shown to transfer their cargo to smooth muscle cells, in which they reduce the level of expression of miR-143/145 targets to prevent smooth muscle cell de-differentiation [67]. Finally, exposure to TNF-α to mimic inflammation resulted in abundance of exosomal cargo factors related to superoxide protection, immune response, and nuclear factor κB pathway [49, 68]. The components of the ECs may serve as specific antigens to initiate a specific immune response to induce antigen-specific immune reactions, such as to induce allograft rejection or other immune responses. Recently, it has been shown that cardiac ECs-derived exosomes carry integrin αvβ6. After exposure to the exosomes, B cells differentiate into TGF-β+ B cells which result in release of TGF-β, one of the major immune regulatory molecules, into the culture supernatant and suppress effector T cell proliferation [69].

Cardiac fibroblast-derived exosomes Unlike other cardiac cell types, cardiac fibroblast-derived exosomes have been associated primarily with pathological conditions such as induction of cardiac hypertrophy. Bang et al. [70] demonstrated that miR-21* was enriched in cardiac fibroblast-derived exosomes, which were shuttled to CMs, leading to cellular hypertrophy by affecting target genes (SH3 domain-containing protein 2 and PDZ and LIM domain 5). Later, Tian et al. [71] showed that secreted exosomes can inhibit Nrf2 translation and subsequent transcription of downstream targeting genes, contributing to cardiac hypertrophy. Furthermore, Abrial et al. demonstrated that in an in vivo mouse model of myocardial infarction and in an in vitro model of isolated neonatal rat cardiac fibroblasts, presence of cardiac fibroblasts increased CM viability against hypoxia-reoxygenation injury. However, in their work, they did not characterize the specific cardioprotective components of cardiac fibroblasts secretome [72]. Later, Luo et al. reported that this effect might be associated with the upregulation of miR-423-3p in the exosomal cargo during the acute phase of I/R injury and during chronic heart failure phase. miR423-3p regulates the expression of Ras-related protein Rap-2c. Knockdown of the protein increased cell viability and reduced apoptosis in CMs after hypoxia-reoxygenation injury [35].

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Cardiac progenitor cell-derived exosomes Chen et al. [36] demonstrated that the delivery of CPCs-derived exosomes in an acute mouse myocardial I/R model inhibited CM apoptosis by 53%, and protected CMs from oxidative stress by inhibiting caspase 3/7 activation in vitro. Xiao et al. [37] revealed that CPCs exosomes exposed to oxidative stress enriched with miRNA-21 inhibited the apoptosis pathway through downregulation of programmed cell death 4 (PDCD4). Furthermore, CPCs from atrial appendage explants from patients who underwent heart valve surgery were injected into the infarct border zone. This study demonstrated that the CPCs mitigated CM apoptosis, augmented blood vessel density, and reduced scar formation, while increasing viability of the infarct zone, and cardiac function [73]. Finally, it was previously shown that cardiomyocyte progenitor cells-derived exosomes contained several MMPs, suggesting that the exosomes themselves were able to break down the extracellular matrix or to activate proactive MMPs [74]. Interestingly, hypoxic preconditioning of CPCs, which reflect the state of postinfarct tissue, even enhanced the therapeutic efficacy in an animal MI model. Thus, the delivery of exosomes derived from CPCs subjected to hypoxic condition improved both acute and chronic function, while inhibiting fibrosis in vivo and inducing tube formation, which indicates angiogenic effect in vitro [75, 76]. Interestingly, exosomes from the CPCs isolated from the right atrial appendages of children undergoing cardiac surgery were not protective when administered intramyocardially to athymic rats after I/R when compared to those from neonatal heart; however, hypoxic culture condition of CPCs did restore some of the protective ability of their exosomes [77]. Cardiomyocyte-progenitor cell-derived exosomes were able to enhance migration of endothelial cells via an EMMPRIN-mediated mechanism, suggesting that upon transplantation they might be involved in the activation of endogenous cells and thereby result in increased capillary density [63].

Stem cell-derived exosomes Mesenchymal stem cell-derived exosomes The multilineage differentiation potential, immunosuppressive properties, and robust culture and isolation method in vitro presented mesenchymal stem cells (MSCs) as one of the most promising cell sources for ischemic heart disease therapy [78, 79]. IC patients benefited mostly from MSCs antifibrotic properties and subsequent reverse remodeling as indicated by a reduction in sphericity index and end-systolic volume [35]. Recent reports suggested that some of the reparative mechanisms were mediated by paracrine factors of exosomes secreted by MSCs. Lai et al. were the first to show that exosomes from MSCs reduced infarct size in a mouse model of myocardial I/R injury [35]. Furthermore, MSCs-derived exosomes reduced systemic inflammation, restored

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

bioenergetics, reduced oxidative stress, and activated pro-survival signaling, thereby enhancing cardiac function and geometry after myocardial I/R injury [80]. Human umbilical cord MSC exosomes have also been shown to be protective in a rat model of permanent coronary artery ligation. In addition to improved cardiac systolic function and reduced cardiac fibrosis, protection of myocardial cells from apoptosis and promotion of tube formation in angiogenesis and migration in vitro were detected [81]. There is evidence that MSC-derived exosomes also mediate cardiac function via direct effects on cardiac contractility. Exposure of human-engineered cardiac tissue to exosomes from human MSCs increased expression of calcium-handling genes such as SERCA2a and the L-type calcium channel and, consequently, improved contractility while protecting from the potential pro-arrhythmic effects of heterocellular coupling in the engineered tissue [18].

Exosomes from induced pluripotent stem cells (iPSCs) and iPSCs derivatives Since iPSCs’ discovery by Shinya Yamanaka in 2006 [82], there has been a rapid progression in the field of cardiac regenerative medicine. iPSCs is a type of pluripotent stem cells which can be generated from adult cells by transfection of a cocktail of four specific genes encoding transcription factors including Oct3/4, Sox2, Kfl4, and c-Myc [82, 83]. The advantages of using iPSCs are their human origin, easy accessibility, robust expandability, pluripotency, elimination of any ethical concerns associated with human embryonic stem cells, and the potential of using patient-specific iPSCs [84]. iPSCs have been shown to restore cardiac function, following delivery into injured myocardium in both clinical and preclinical studies, and the exosomes are considered as one of the main mechanisms of its action [13]. In a recent study, Adamiak et al. compared the safety and efficacy of iPSCderived exosomes and iPSCs’ administration for cardiac repair in vivo. Interestingly, even though both treatments exhibited improved left ventricular function, iPSC-derived exosomes demonstrated superior cardiac repair with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy than iPSCs transplantation. These beneficial effects of the exosomes may be related to their molecular cargo, which includes numerous miRNAs (e.g., miRNAs from miR-17-92 cluster) and proteins (e.g., bone morphogenetic protein 4, PDGF alpha, teratocarcinoma-derived growth factor 1, thrombospondin 1, and VEGF C) which have been implicated in cytoprotection and angiogenesis [85, 86]. Wang et al. identified exosomes harvested from murine cardiac fibroblast-derived iPSCs, which contained cardioprotective miRNAs such as the Nanog-regulated miR-21 and HIF-1α-regulated miR-210. These secreted exosomes protected CMs against H2O2-induced oxidative stress in vitro and MI/R injury in vivo [38]. The capability of iPSCs to differentiate into different cardiac cell types in vitro has opened a new avenue of investigation [6, 87–89]. Interestingly, the exosomes from

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iPSC-derived CMs had greater effects on reducing infarct size, hypertrophy, and apoptosis when compared to the iPSCs-derived exosomes. One of underlying mechanism is that the exosomes from iPSCs-derived CMs were able to affect the injured heart through more CM-specific pathways, including pathological hypertrophy [90]. It has been shown that the exosomes and their cargo underlie the mechanism of action of iPSC-derived CMs in salvaging the injured CMs in the peri-infarct region against apoptosis, necrosis, inflammation, remodeling, and fibrosis [4, 39–41, 91]. iPSC-derived CMs under normoxic condition released exosomes which improved postmyocardial function by regulating autophagy/apoptosis in ischemic condition. The cargo of the exosomes was enriched with the miRNAs which target apoptotic pathways (miR-92a-3p, 122-5p, -320). Transcriptomic analysis of the CMs from the peri-infarct region showed overexpression of Bcl-2 and Bcl-xL, pro-autophagic/antiapoptotic targets of mTOR pathway, a central modulator of the autophagy-apoptosis axis [92]. Furthermore, iPSCs-derived CMs exposed to hypoxic condition produced exosomes with overexpression of miR106a-363 cluster. This cluster had been shown to stimulate endogenous repair by restoring the ischemic damage to the autologous iPSCs-derived CMs and murine myocardium by attenuating apoptosis and oxidative stress [40, 41].

Exosomes with artificially modified cargo As the exosomal cargo is strongly associated with the cell type and its gene expression profile, an increasing number of researchers have engineered the exosome-producing cell lines in vitro in order to generate exosomes with specific features and/or to enhance their therapeutic effect. Gnecchi et al. [93] published a pivotal study demonstrating that Akt-overexpressing MSCs produced a cardioactive secretome, which exerted remarkable beneficial cardioprotective effect when administered to a preclinical rodent model of acute myocardial infarction. Ma et al. engineered human umbilical cord MSCs to overexpress Akt and found that the exosomes produced by these cells had a greater ability to stimulate angiogenesis. Interestingly, Akt itself was detected in these exosomes, although the proangiogenic stimulation was attributed to PDGF-D that was also present within them [94]. Yu et al. [95] demonstrated that the exosomes derived from MSCs overexpressing GATA-4 demonstrated greater cardioprotective effect which was associated with enrichment of miR-19a in their cargo.

Biodistribution of exosomes in vivo For future therapeutic applications, clear delineation of the in vivo fate of the exosomes is of utmost importance as its biodistribution to organs and subsequent cellular uptake influences not only their efficacy, but also their offsite toxicity.

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

It is widely reported that, after intravenous injection, most exosomes show rapid clearance from the circulation, accumulating predominantly in the liver, spleen, gastrointestinal tract, lungs, and kidneys and eliminated through biliary excretion, renal filtration, or the reticuloendothelial system [96–99]. Another alternative is that the exosomes act on the endothelium, as these scavenging cells can certainly take up all types of exosomes including MSC exosomes [46, 100]. By altering the route of exosome administration, it is possible to improve nonmodified exosome biodistribution to the heart. For example, when compared to systemic delivery, intramyocardial delivery of nontargeted cardiosphere-derived exosomes resulted in increased cardiac retention at 2 h [99]. Prior studies demonstrated a reduction in scar size and preservation in left ventricular ejection size only when cardiosphere-derived exosomes were delivered via an intramyocardial but not intracoronary injection [99]. Since exosomes are varying forms of cellular microvesicles, they express certain lipid and cellular adhesion molecules which have specificity for certain types of cellular receptors. To improve exosome targeting and delivery of cardioprotective cargo to CMs, Mentkowski et al. engineered human cardiosphere-derived cells to generate exosomes, expressing CM binding peptide on their surface. This surface modification improved exosomal uptake by CMs in vitro, reduced CM apoptosis, and increased exosome cardiac retention in vivo [99]. In another study, infarct-targeting exosomes were developed via binding directly with cardiac homing peptide [101, 102]. These exosomes resulted in increased in vitro uptake by CMs, as well as increased functional recovery in an animal model by reducing fibrosis, inducing CM proliferation, and increasing angiogenesis [103].

Exosomes as biomarkers of cardiovascular disease Exosomes are distributed in many body fluids such as blood, saliva, and urine and can be relatively easily and quickly isolated. Also, they have relatively stable structure, which can protect their cargos from destruction. These characteristics have made the exosomes a promising source of biomarkers for the diagnosis and prognosis of a number of diseased conditions. It is also supported by a growing number of companies such as Exosome Diagnostics (http://www.exosomedx.com/), Exosome Sciences (http://www. exosomesciences.com/), Caris (http://www.carislifesciences.com/), and Hansa Bio Med (http://www.hansabiomed.eu/) which have been developing exosome-based diagnostics based on the analysis of their RNA and protein constituents [24]. With respect to cardiovascular diseases, it has been shown that patients with coronary artery disease exhibit increased levels of circulating exosomes enriched with miR-199a and miR-126, thus showing a great potential to serve as biomarkers [104]. Elevated levels of miR-1 and miR-133 have been identified in the exosomes from serum of patients with acute coronary syndromes and have been shown to correlate well with troponin values

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[105]. Interestingly, compared with established biomarkers for cardiac ischemia such as cardiac troponins (troponin I and troponin T), expression levels of exosomal miRNAs change much faster and earlier in the circulation [27]. miRNA-1 and miRNA-133a showed the highest plasma levels 2.5 h after the onset of symptoms in myocardial infarction patients [26, 27]. Moreover, detection of circulating cardiac-specific miRNAs had higher sensitivity and specificity than troponin T [28]. In patients with acute myocardial infarction, various miRNAs inside exosomes have been associated with the occurrence of heart failure during the postinfarction period. Matsumoto et al. [106] showed that exosomal-derived miRNA-192, miRNA-194, and miRNA-34a were significantly increased in patients with acute myocardial infarction and miR-194 and miR-34a expression levels were significantly correlated with left ventricular end-diastolic dimension 1 year later. In addition to noncoding RNAs, exosomal proteins also may serve as potential biomarkers for different cardiovascular conditions. de Jong et al. [49] demonstrated that, under hypoxic condition, ECs exosomes had an increased level of lysyl oxidase like-2 (LOXL2); when treated with TNF-α intercellular adhesion molecule 1 (ICAM-1) and tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) were significantly abundant in exosomal cargo. Using label-free quantitative proteomics approach, Cheow et al. compared the protein cargo of the extracellular vesicles, including exosomes from plasma between patients with myocardial infarction and from patients with stable angina. As a result, six upregulated biomarkers reflected key factors in myocardial infarction progression: complement C1q subcomponent subunit A (C1QA), complement C5 (C5), apolipoprotein D (APOD), apolipoprotein C-III (APOCC3), platelet glycoprotein Ib alpha chain (GP1BA), and platelet basic protein (PPBP). This novel biomarker panel was validated in 43 patients using antibody-based assays [107]. Taken together, these data demonstrated that the exosomes, circulating in human body, may represent a novel source of diagnostic biomarkers and/or therapeutic targets which can be further developed for early clinical diagnostic use to benefit patients with cardiovascular diseases.

Conclusion and future perspective As efficiency and safety of stem cell-based therapy have been widely discussed, the exosomes as natural nanocarriers with cardioprotective features, low immunogenicity, and ability to permeate through biological barriers represent a promising therapeutic and diagnostic tool for cardiovascular diseases. In the heart, exosomes from different cell types have been shown to regulate a broad spectrum of processes under normal and ischemic conditions. They play important roles in regulating processes such as apoptosis, contractile function, hypertrophy, fibrosis/remodeling, and angiogenesis as well as immune response. Cell types and environmental stimuli are reflected in exosomal cargo. Even

Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

though the majority of the studies demonstrated that exposure of the cells to stress conditions resulted in the production of the exosomes loaded with cardioprotective cargo, many issues still need to be resolved. Some considerations include the mechanism of cargo selection, delivery, untoward side effects for the heart or other tissue/organs, and off-target effects in different tissue/organs in vivo. In this review, we also summarized the current data of using the exosomes for diagnostic purposes. This idea came from their capacity to load its cargo depending on pathological condition. The exosomes are able to maintain their biological stability and protect their cargo in almost all biological fluids. Current research has demonstrated that the exosomes may create an effective diagnostic platform, although this development is still in its infancy. An important question seems to be to evaluate the additional diagnostic benefit of the exosomes relative to the current well-established biomarkers. Taken together, the exosomes represent promising opportunities for the development of new cell-free therapies for myocardial repair and a new diagnostic platform for cardiovascular diseases. However, further study of exosomes and their composition are required to prove the potential therapeutic and diagnostic use of the exosomes in cardiovascular medicine.

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Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases

[75] Tang YL, Zhu W, Cheng M, Chen L, Zhang J, Sun T, et al. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ Res 2009 May 22;104(10):1209–16. [76] Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, Platt MO, et al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 2015 Jan 16;116(2):255–63. [77] Agarwal U, George A, Bhutani S, Ghosh-Choudhary S, Maxwell JT, Brown ME, et al. Experimental, systems, and computational approaches to understanding the MicroRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients. Circ Res 2017 Feb 17;120(4): 701–12. [78] Zomer HD, Vidane AS, Gonc¸alves NN, Ambro´sio CE. Mesenchymal and induced pluripotent stem cells: general insights and clinical perspectives. Stem Cells Cloning 2015;8:125–34. Dove Medical Press Ltd. [79] Madonna R, Van Laake LW, Davidson SM, Engel FB, Hausenloy DJ, Lecour S, et al. Position paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J 2016;37:1789–98. Oxford University Press. [80] Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor ENE, et al. Mesenchymal stem cellderived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res 2013 May;10(3):301–12. [81] Zhao Y, Sun X, Cao W, Ma J, Sun L, Qian H, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int 2015;2015:761643. [82] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006 Aug 25;126(4):663–76. [83] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007 Nov 30;131(5):861–72. [84] Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 2017;16:115–30. Nature Publishing Group. [85] Adamiak M, Cheng G, Bobis-Wozowicz S, Zhao L, Kedracka-Krok S, Samanta A, et al. Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs. Circ Res 2018 Jan 1;122(2):296–309. [86] Adamiak M, Sahoo S. Exosomes in myocardial repair: advances and challenges in the development of next-generation therapeutics. Mol Ther 2018;26:1635–43. Cell Press. [87] Park M, Yoon YS. Cardiac regeneration with human pluripotent stem cell-derived cardiomyocytes. Korean Circ J 2018;48:974–88. Korean Society of Circulation. [88] Lalit PA, Hei DJ, Raval AN, Kamp TJ. Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. Circ Res 2014;114:1328–45. Lippincott Williams and Wilkins. [89] M€ uller P, Lemcke H, David R. Stem cell therapy in heart diseases-cell types, mechanisms and improvement strategies. Cell Physiol Biochem 2018;48:2607–55. S. Karger AG. [90] Liu B, Lee BW, Nakanishi K, Villasante A, Williamson R, Metz J, et al. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng 2018 May 1;2(5):293–303. [91] Dougherty JA, Kumar N, Noor M, Angelos MG, Khan M, Chen C-A, et al. Extracellular vesicles released by human induced-pluripotent stem cell-derived cardiomyocytes promote angiogenesis. Front Physiol 2018;9:1794. [92] Santoso M, Sano H, Tada Y, Sierra R, Goldstone A, von Bornstaedt D, et al. Exosomes from induced pluripotent stem cell-derived cardiomyocytes salvage the injured myocardium by modulation of autophagy. J Am Coll Cardiol 2018 Mar;71(11):A13. [93] Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 2006 Apr;20(6):661–9.

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[94] Ma J, Zhao Y, Sun L, Sun X, Zhao X, Sun X, et al. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med 2017 Jan;6(1):51–9. [95] Yu B, Kim HW, Gong M, Wang J, Millard RW, Wang Y, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 2015;182(C):349–60. [96] Faruqu FN, Wang JTW, Xu L, McNickle L, Chong EMY, Walters A, et al. Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice—a novel and universal approach. Theranostics 2019;9(6):1666–82. [97] Wiklander OPB, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, M€ager I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 2015;4(2015):1–13. [98] Chen G-H, Xu J, Yang Y-J. Exosomes: promising sacks for treating ischemic heart disease? Am J Physiol Heart Circ Physiol 2017 Jun 24;313(3):H508–23. [99] Mentkowski KI, Lang JK. Exosomes engineered to express a cardiomyocyte binding peptide demonstrate improved cardiac retention in vivo. Sci Rep 2019;9(1):10041. Available from: http://www. nature.com/articles/s41598-019-46407-1. [100] Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017;8(28):45200–12. [101] Won YW, McGinn AN, Lee M, Bull DA, Kim SW. Targeted gene delivery to ischemic myocardium by homing peptide-guided polymeric carrier. Mol Pharm 2013 Jan 7;10(1):378–85. [102] Kanki S, Jaalouk DE, Lee S, Yu AYC, Gannon J, Lee RT. Identification of targeting peptides for ischemic myocardium by in vivo phage display. J Mol Cell Cardiol 2011 May;50(5):841–8. [103] Vandergriff A, Huang K, Shen D, Hu S, Hensley MT, Caranasos TG, et al. Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide. Theranostics 2018;8(7):1869–78. [104] Boulanger CM, Loyer X, Rautou PE, Amabile N. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol 2017;14:259–72. Nature Publishing Group. [105] Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, et al. Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet 2011 Aug;4(4):446–54. [106] Matsumoto S, Sakata Y, Suna S, Nakatani D, Usami M, Hara M, et al. Circulating p53-responsive MicroRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ Res 2013 Jul 19;113(3):322–6. [107] Cheow ESH, Cheng WC, Lee CN, De Kleijn D, Sorokin V, Sze SK. Plasma-derived extracellular vesicles contain predictive biomarkers and potential therapeutic targets for Myocardial Ischemic (MI) injury. Mol Cell Proteomics 2016 Aug 1;15(8):2628–40.

CHAPTER 7

Use of nanoparticulate systems to salvage the myocardium Morteza Aieneravaiea, Jim Q. Hob, Leila Arabia, James Leec, Kirsten Herrerac, Syeda Mehreenc, Najmeh Javdanid, Petrina Georgalae, Mohammad Reza Sepanda, Marjan Rafatf,g,h, Steven Zanganehc,e a Department of Medicine, University of Basel, Basel, Switzerland Albert Einstein College of Medicine, Bronx, NY, United States c Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States d Montreal Clinical Research Institute, Montreal, QC, Canada e Sloan Kettering Institute for Cancer Research, New York, NY, United States f Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States g Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States h Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, United States b

When the heart can no longer meet the body’s demands by providing sufficient blood pressure and/or flow, heart failure arises. The body responds to this failure, such as releasing neurohormones that stimulate the organs, retaining salt and water by the kidneys, and changing cellular and organ structure and function by activating intracellular signaling pathways in the vasculature and heart. At first, lower cardiac performance can be counteracted by these “compensatory” responses. However, these responses eventually contribute to disease progression by raising the probability of organ failure and exacerbating clinical prognosis. Heart failure may present with many variations in clinical presentation, but some symptoms are common, such as fatigue, fluid retention, and shortness of breath. Systolic heart failure (dilated heart and contractile failure) occurs in approximately 50% of all people. Diastolic heart failure (heart failure with a preserved ejection fraction (HFpEF)) comprises the other 50% and usually presents with a hypertrophied, nondilated heart which contracts normally. There is a rise in the worldwide prevalence of HFpEF, but the condition has not been well-investigated. Over 23 million people around the world suffer from heart failure (HF), which is a significant public health problem. As the population ages, HF prevalence is on the rise. HF is most frequently a result of myocardial infarction (MI). Due to ischemia, as many as one billion cardiac cells die after an MI [1, 2]. Irreversible destruction of cardiomyocytes that are terminally differentiated leads to HF, irrespective of the pathological basis. For MI, a technique with great therapeutic potential is cell replacement therapy, which aids in repairing the heart and restoring contractile function. According to some studies, the heart muscle can be repaired to a certain extent when various types of cells are administered into the damaged heart. In addition, the size of infarction can be contained and Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00007-6

© 2020 Elsevier Inc. All rights reserved.

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Fig. 1 The heart wall.

cardiac function can be improved with the therapy. Most of the heart is composed of myocardium or cardiac muscle tissue. Positioned between the outer epicardium (visceral pericardium) and inner endocardium, the heart wall (Fig. 1) has a thick myocardium layer and a structure consisting of three layers. Lining the cardiac valves and cardiac chambers is the inner endocardium, which connects to the endothelium lining the blood vessels leading to the heart. The epicardium, which is on the external side of the myocardium, makes up a portion of the pericardial sac which encloses, lubricates, and protects the heart [3]. The postinjury regenerative capacity of adult mammalian hearts is especially limited, and fibrotic scars replace the cell loss. Subsequently, the surrounding myocardium is remodeled, which ultimately gives rise to reduced cardiac function. The left ventricular wall becomes stiffer (fibrosis) and thicker (hypertrophy) as part of the remodeling process [4]. Replacement fibrosis and reactive fibrosis are the two kinds of fibrosis that may develop in response to an MI. Fibroblasts and myofibroblasts mediate both types of fibrosis. Following ischemic injury, an important process that prevents the ventricular wall from rupturing is replacement fibrosis (scar formation). Furthermore, expansion of connective tissue in regions distant from the infarction may be caused by paracrine and hormonal mediators, along with higher mechanical stress after an MI. Cardiac output is impaired by modified chamber compliance and greater ventricular stiffness due to this

Use of nanoparticulate systems to salvage the myocardium

reactive fibrosis of the infarct border zone and distant undamaged myocardium. The relatively small amount of cellular engraftment in the heart continues to be a substantial shortcoming of cell replacement techniques. In spite of syngeneic transplantation conditions, stable engraftment in the heart occurs in only about 1%–5% of injected cells according to previous studies. Physical and biological mechanisms may be the main causes of cell loss, but the exact reasons are unknown so far [5, 6]. The highest death rates around the world are due to cardiovascular diseases (CVD), and ischemic heart disease (IHD) accounts for more than a third of the casualties related to CVD [7, 8]. Myocardial injury results from IHD, and the heart’s capacity to recover from the ischemia is very limited. Scarring, thinning, hypertrophy, and dilated ventricular walls arise from MI, which proceeds from the ischemic insult [9, 10]. Without any cures available currently, heart failure is an irreversible, pathological condition. Therapeutics now improve the care of HF patients by only addressing the symptoms or prolong disease progression without curing the condition [4, 11, 12]. A lasting solution for HF is thus necessary. Uncovering the fine intricacies of the cellular and molecular mechanisms that mediate the pathological etiology of HF allows for greater insight into the fundamental pathways that contribute to HF. As time passes, this enigma has gradually been untangled. Novel therapeutic targets can be discovered through elucidating the unique pathological development of HF. Research into therapeutic strategies aside from the clinically available implantable devices and medications for HF patients is ongoing. Examples of investigations that address shortcomings of currently available therapies and seek to protect and restore cardiac function include cardiac tissue engineering, cell therapy, and particulate systems [13–16]. The routes of administration of novel therapeutic approaches, including cardiac tissue engineering and cell therapy, are invariably very invasive [17, 18]. Preferable for patient adherence are oral or intravenous (i.v.) routes of administration. This is a major consideration for translating therapies into the clinic. Minimally invasive routes of administration, e.g., i.v., are appropriate for nanoparticulate systems, giving them an advantage. In addition, nanocarriers are flexible platforms for designing functional nanosystems because of properties that are tunable. Some examples of tunable properties include the kind of material, porosity, size, surface area, or surface chemistry [19, 20]. As a result, multiple payloads with varying or alike physicochemical characteristics can potentially be delivered. Imaging, response to stimuli, targeting specificity, or other qualities can be merged into a single nanocarrier, enabling flexible applications for various diseases [21–24]. A multidisciplinary field, nanotechnology encompasses describing, designing, and creating materials in the nanometer (10 9 m) range with defined shapes. Nanobiotechnology and nanomedicine are some of the most active domains of inquiry in nanotechnology. Nanomedicine, which applies nanostructures in health care and medicine to prevent, diagnose, and treat pathologies, is an innovative field [25, 26].

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Nanotechnology usually involves examining and manipulating nanoparticles and nanostructures with sizes of 1–100 nm [27]. The biomedical community considers somewhat larger structures as nanoparticles as well. Distinctive biological and physicochemical properties such as crossing tissue barriers and cell membranes are present among nanoparticles with these size characteristics. This enables nanoparticles to interact with similar sized cell components including intracellular proteins and other macromolecules. At the molecular level, this leads to very specific and reactive interactions [28–31]. Through regulated processes of stimulating, responding to, and interacting with tissues or cells that are targeted, nanoparticles can generate the intended physiological effects and minimize unwanted responses [32–35]. For instance, precise locations of injury in the heart can potentially be targeted by nanoparticles. The release of adsorbed, conjugated, or encapsulated therapeutic molecules can also be managed by nanoparticles [36]. Alterations in structure and morphology by stimuli that are applied externally, magnetism, surface plasmon resonance, and very specific surface area along with reactive area are additional examples of favorable characteristics of certain nanoparticles [37]. Novel alternatives to conventional diagnostic and treatment approaches using nanoparticles are made possible by these unique properties. Their multifunctional capabilities reveal the immense promise of hybrid nanocomposites and nanoparticles for various clinical uses, including theragnostics [38–40].

Overview of micro- and nanoparticulate-based medicines for cardiovascular diseases Drug delivery systems (DDSs) of various sizes have been synthesized to satisfy the physiological needs of different drug targets. DDSs with at least one dimension >1 mm are usually called macroscale DDSs [41, 42]. Different types of macroscale devices have been created, including mucoadhesives, long-term drug-releasing implants, and wearable devices. Polymers are the preferred material for forming DDSs that are suitable physiologically [25, 43–46]. Synthetic polymers like poly(-amino ester) or poly(lactic-coglycolic acid) (PLGA) or natural polymers such as alginate, chitosan, dextran, and gelatin are typical polymers for these devices [47]. After being loaded into a “reservoir,” the drugs are surrounded by a polymeric membrane. Drugs can also be loaded into a “matrix,” in which they are placed in polymeric networks [48]. Drugs can be released via diffusion (driven by the polymer scaffold’s steric hindrance), competitive dissociation (specific affinity of the drug for the polymeric carrier), or degradation (dissolving, enzymatically digesting, or hydrolyzing the polymer scaffold). For smart delivery of drugs, another method may involve integrating environmental signal sensitivity into polymeric systems. Microscale DDSs usually take the form of microparticles, which can be locally administered into the tissue. Inappropriate for administering systemically

Use of nanoparticulate systems to salvage the myocardium

are large diameter (1 mm) microparticles which would be detected by hepatic Kupffer cells or become trapped in capillaries. The movement of microparticles that are injected locally is restricted by steric hindrance from the extracellular matrix, thereby keeping them in the injection site. For this reason, microparticles have been extensively used as drug depots [39, 49–52]. Passage through blood vessel fenestrations in the liver and tumor tissue entry via the enhanced permeability and retention (EPR) effect are possible due to the nanoscale size (usually 200 nm) of nanocarriers, which differ from microparticles [37, 53–57]. As a side point, solid tumors are not the only ones affected by the EPR effect. Various diseases including fungal infections, heart failure, hepatitis A, renal-associated diseases, and sclerosis involve the EPR effect [58–61]. Finely controlling the size of nanocarriers is important because the kidneys quickly remove smaller nanocarriers (8 nm) and macrophages phagocytose larger nanocarriers (500 nm). Nanocarriers, which are highly researched DDSs, have been used most to examine cancer [62–64]. Polymer-based nanogels, micelles, polymersomes, and dendrimers are some examples of materials for creating nanocarriers. Other examples include inorganic materials (gold nanoparticles, carbon nanotubes, graphene, nanodiamonds, magnetic particles, and liquid metal nanoparticles), lipid-based materials (solid lipid nanocarriers, liposomes, or lipid-like lipidoids), and macromolecular assembly-based materials (DNA and protein nanocarriers). While numerous therapeutic strategies are available for MI, no cure exists for this condition. As noted earlier, there is a high prevalence of morbidity and mortality, and patient quality of life is strongly impacted by therapeutics and invasive procedures which have deleterious adverse effects and limited efficacy. Among the new therapeutic approaches that are actively being explored, there is currently a rise in making and utilizing micro- and nanomedicines for CVD [13, 65]. Just a tiny proportion of nanocarriers reach their target location, because many barriers from the injection site to the destination prevent their passage. Manipulating the properties of nanocarriers has become feasible due to breakthroughs in material science (Fig. 2) [66–68]. Large payloads can be enclosed in liposomes [69], and the functionalization of polymeric and metal oxides with different ligands can be customized for various purposes [27, 37, 70]. Biodistribution may also be enhanced with functionalization [71–73]. Nanoparticles may have intrinsic therapeutic capabilities or can carry drugs which are not very water-soluble. The large surface-to-volume ratio of nanoparticles can increase their rate of dissolution [19, 74–76].

Nanoparticles Some research teams have investigated the application of nanoparticles for drug delivery to the ischemic heart, because cells have a greater chance of taking them up as opposed to

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Fig. 2 Modifying the shape (A), size (B), rigidity (C), surface functionality (D), and surface charge (E) can change the properties of carriers so that various physiological barriers to targeted drug delivery can be surmounted. (Adapted from Agrahari V, Burnouf PA, Burnouf T, Agrahari V. Nanoformulation properties, characterization, and behavior in complex biological matrices: challenges and opportunities for brain-targeted drug delivery applications and enhanced translational potential. Adv Drug Deliv Rev 2019;148:146–80.)

microparticles. In addition, the likelihood of embolization for nanoparticles is lower if they enter the circulation. The invasiveness of systemically administering particles laden with small molecules or growth factors is lower than directly injecting them into the heart or limb. Since the vasculature is more permeable under hypoxic conditions due to angiogenic factors being released and endothelial cells migrating, nanoparticles concentrate in infarcted muscle. Nevertheless, the enhanced permeability after an MI is shorter in duration than

Use of nanoparticulate systems to salvage the myocardium

Fig. 3 Numerous factors influence the uptake of nanomaterials. (Adapted from Katsuki S, Matoba T, Koga JI, Nakano K, Egashira K. Anti-inflammatory nanomedicine for cardiovascular disease. Front Cardiovasc Med 2017;4:87.)

in cancer (EPR effect) (Fig. 3), so the postinjury timing for delivering the nanoparticles is key. Although animal models of acute hindlimb ischemia demonstrated significance in the timing of delivery, humans with peripheral artery disease (PAD) have longer periods of hypoxia, which allows for more time to deliver the nanoparticles. We will briefly review some vehicles that have been created for treating MI via systemic drug delivery in this section [77–80].

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Nanoparticles for MI Nontargeted The relative permeability of injured and healthy heart muscle to micelles (10 nm) and liposomes (100 nm) has been analyzed by several studies in order to design nanocarriers which can be systemically delivered and can accumulate enough therapeutic within the infarcted tissue before renal elimination. After i.v. administration, the preferential accumulation of micelles and liposomes in damaged heart muscle was observed [77, 81–84]. The administration of liposomes loaded with PGE1 in dogs was performed by Feld and colleagues to increase vasodilation at the start or termination of a 2-h long coronary artery occlusion, followed by reperfusion. When delivered at the start of the occlusion, the effectiveness of free PGE1 and PGE1-laden liposomes at decreasing the size of the infarct was similar, but when delivered right before reperfusion, free PGE1 was less effective. However, these data came from two different studies and the investigators noted discrepancies in the infarct size after free PGE1 therapy due to large collateral blood flow and little at-risk area in those animals [85]. Liposomes (150–200 nm) encapsulating adenosine triphosphate (ATP) or coenzyme Q10 (CoQ10) were administered by Torchilin’s research team to the heart following MI to examine the treatment on infarct size with the goal of restoring normal cell metabolism and decreasing post-MI injury from free radicals. In rabbits, the delivery of ATP-laden liposomes right before MI was performed first [86]. An enhancement in function was anticipated due to the restoration of ATP-dependent ion channel function by the delivered ATP. This is because ischemic situations may see a decrease of up to 80% in ATP levels [87]. Cell swelling and apoptosis resulted from lower ion channel activity. Another compound that falls immediately after MI is CoQ10, an endogenous antioxidant. Immediately prior to MI, liposomes enclosing CoQ10 were administered in rabbits [88]. Relative to those treated with empty liposomes, infarct size decreased for both liposomes with therapeutics. The result of preventive use was explored by these investigations based on levels of ATP and CoQ10 immediately post-MI. Whether administration of these therapeutics directly after injury can impact infarct size should be investigated, since, clinically, it is difficult to foresee ischemic incidents. The cardioprotective properties of purine nucleoside adenosine have only been demonstrated to be effective at large concentrations [89]. Takahama and colleagues administered adenosine-loaded liposomes (130 nm) in rats immediately before reperfusion to augment the fraction that accumulates in the infarct. There was a preferential accumulation of the liposomes in the infarct compared with uninjured myocardium and a reduction in the size of the infarct versus the empty liposome or free adenosine treatment. Compared with free adenosine, fewer harmful effects on blood pressure and heart rate were observed for the encapsulated adenosine as well [90].

Use of nanoparticulate systems to salvage the myocardium

Targeted Delivery to the infarct improved when moieties targeting cell surface receptors that are upregulated after ischemic injury, including angiotensin-1 (AT1) and P-selectin, were included [77, 83, 84]. In spite of the specific targeting of cells, the greatest accumulation occurs within several hours to days after MI and substantially diminishes if administered 1–2 weeks after MI [77, 82–84]. Endogenous closing of the leaky vasculature could be a reason for this decrease [91]. Therefore, acute treatment may be most appropriate for this systemic delivery approach. In rats immediately post-MI, Scott and colleagues delivered liposomes (180  13 nm) conjugated with P-selectin and enclosing VEGF in an effort to reduce off-target effects of free VEGF administered systemically [83]. Following therapy with the targeted VEGF liposomes, there was a decrease in hypokinesis of the heart wall. At 2, 3, and 4 weeks, the fractional shortening (FS) increased relative to the empty liposome, IgG-conjugated VEGF liposome, or systemic VEGF treatment. Hearts administered with the targeted VEGF liposome had more perfused vessels, which may explain these therapeutic enhancements. However, only a comparison was made with the number of perfused vessels in hearts that were not treated, so it is still unknown if the greater vessel perfusion was due to targeting or the delivery of liposome alone. We will briefly describe the favorable characteristics of nanocarrier parameters in the following sections to give a clear and concise idea of designing efficient nanocarriers.

Size A prime concern in nanoparticle design is size, which should be maintained within a specific range that is optimal therapeutic delivery. The discussion in this section about size will focus on spherical nanocarriers for treating cancer, instead of delving into other complex shapes [92]. Glomerular filtration rapidly removes nanocarriers that are too minuscule (10 nm) from the circulation. Due to the small diameter of capillaries (5 μm), nanocarriers that are too big (2 μm) may obstruct them. The EPR effect, which is optimal for particles in the size range 200–500 nm, should be considered while planning the size of tumor-targeted nanocarriers [93–97]. Clearance by other organs, including the liver, spleen, or lung, is more likely for nanocarriers >200 nm, which decreases their halflife in circulation. Sub-100 nm nanocarriers can infiltrate dense solid tumors, making them more efficient carriers aside from just tumor accumulation. Nanocarriers with a diameter of 50 nm exhibited the greatest accumulation in tumors and were most effective in penetrating tumors compared with smaller (20 nm) or larger (200 nm) nanocarriers, according to a comprehensive report on monodispersed silica-based nanocarriers [98, 99]. Appropriate for tumor-targeted drug delivery are nanocarriers generally with size 10–200 nm (100 nm [83]. There is a substantial advantage of spheres over rods in investigations using sub-100 nm NPs [84, 85]. Overall cellular uptake was reduced when the aspect ratio of nanorods was elevated in this size range. A nanomaterial’s ligand density and engineered geometry influence how ligands bound to NPs interact with cellular receptors [86]. How many ligands interact with the receptor of interest is determined by the design of the NP scaffold. The interaction of various NP ligands with various cellular receptors leads to a multivalent effect [87]. With greater binding strength than the individual affinities added together, the ligand complex may be measured by their avidity. Antibodies with at least two sites that bind antigens reveal this phenomenon. Total avidity of the NP ligands for accessible receptors on cells depends on the density of ligands on NP surfaces over a particular curvature.

Fig. 1 Interactions between nanoparticles (NPs) and cells. (A) NP-cell interactions are affected by multiple factors at the nano-bio interface. (B) NPs coated in ligands interact with cells. Membrane receptors are bound by ligand-coated NPs that do not enter the cell. This leads to a signaling cascade. Cells may endocytose and exocytose ligand-coated NPs as well. The NPs do not leave the vesicle. After binding to the membrane receptor and entering the cell, they leave the cell. NPs taken up by the cell can escape the vesicle and interact with different organelles. After binding to membrane receptors and entering the cell, NPs target subcellular structures. There may be nonspecific interactions between the NPs and cell-surface membrane. The NPs are then taken up by the cell. (C) The uptake of various transferrin-coated 15-nm gold NPs by HeLa cells into vesicles inside the cells [82].

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For example, Herceptin has a binding affinity to the ErbB2 receptor of 1.5  10 13 M on a 70 nm NP, 5.5  10 12 M on a 10 nm NP, and 10 10 M in solution [88]. Due to a greater density of proteins on the surface of the NP, as the NP size increases, the binding affinity of the ligand proportionally increases as well. Characteristics aside from binding affinity, such as the ErbB2 receptor’s downstream signaling, should be taken into account as well, because gold NPs in the 40–50 nm size range gave rise to the largest effect. In relation to free ligands in solution, cell signaling may be influenced by the design of NPs according to a few studies. For instance, a change in cellular apoptosis due to effects on caspase enzyme activation was seen in the previously noted 40–50 nm gold NPs which were coated in Herceptin [88]. The capacity to induce angiogenesis was likewise enhanced by the conjugation of receptor-specific peptides to the surface of NPs [89]. Based on receptor-mediated signaling, angiogenesis was augmented by peptide presentation on a structured scaffold. These discoveries underscore the benefits of ligand binding to NPs compared with free ligands in solution. The avidity may increase and cell signaling may change due to a dense area of ligands on the NP surface. However, there are also disadvantages. Unanticipated cell signaling changes may result from nanomaterials. Intercellular adhesion molecule I (ICAM-I) protein-coated NPs may be taken up by cells, for instance. Since endocytosis is not known to be induced by ICAM-I, this is an atypical phenomenon. However, unforeseen internalization occurs when numerous ICAM-I proteins are added onto the surface of a nanomaterial [90]. A different investigation reported the interaction of 14 nm carbon NPs with β1-integrins and epidermal growth receptors on alveolar II epithelial cells of rats. The Akt signaling pathway became activated due to this trigger, leading to cell proliferation [91]. Proteins may become denatured when they bind to the engineered surface of NP-ligand complexes, causing another problem. Greater nonspecific interactions, issues with receptor binding, or inflammation may arise from protein denaturation. For example, the denaturation of lysozymes and their interaction with other lysozyme molecules to form protein-NP aggregates may occur when they bind to gold NPs [92]. Once it binds to the surface of gold NPs coated with polyacrylic acid, fibrinogen unfolds as well. After the fibrinogen denatures, it may bind to the Mac-1 integrin receptor and cause inflammation [93]. In vitro systems in which interactions take place between NPs and constituents of the cell culture medium before contacting any cells can regularly determine cellular interactions due to the impact of NP physico-chemical properties [94, 95]. Fig. 2 shows that, upon suspension in a cell culture medium (CCM) containing electrolytes and proteins, NPs enter a complex environment. Illustrated in the figure is a 40 nm gold sphere NP in CCM. Various biomolecules such as ionic salts (red dots) and amino acids (blue spheres), along with serum albumin

Cell-nanoparticle interactions

Fig. 2 Model displaying the suspension of a gold nanoparticle (NP) in a cell culture medium supplemented with 10% serum. The medium volume at various size scales is depicted by the boxes. At 100 nm3, the gold NP is visible and surrounded by serum proteins (violet spheres) [96].

or globulins (violet spheres), are examples of the main proteins in CCM, which is a buffered solution. A NP’s hydrodynamic behavior is affected by these components. Instability in the stabilized NPs may arise due to loss of surface functionality or molecule/protein adsorption, and aggregates may form in effect. NP mobility and in vitro behavior may be additionally affected by these processes. Although research has demonstrated that cellular interactions and effects are influenced by alterations in the NP dispersion state, there has been infrequent and inadequate consideration of the CCM’s influence on NP colloidal behavior [65, 71, 73, 97]. In the biological environment, it is difficult to experimentally evaluate colloidal stability. Another factor adding to the complexity is the variety of CCM which has various components. Aside from proteins, the large amount of ions may affect the chemical and colloidal properties of NPs once they enter the CCM (Fig. 2). While examining how colloidal stability was impacted by electrolyte ionic strength, investigators observed that electrostatic interaction screening may undermine stability. Aggregation may develop from the screening. The electric double layer’s (EDL) effect on stabilization was inhibited at higher efficiency by multivalent electrolytes than by monovalent ions. In addition, the morphology and rate in which the aggregate formed were determined by the nature of electrolytes and ionic strength [98]. Important for colloidal stability was a change in conformation driven by pH with regard to the adsorption of polyelectrolytes onto NPs [99]. The chemical equilibrium between deprotonated functional groups (NH2 or COO ) and protonated functional groups (NH3 + or COOH) makes the surface charge of NPs ending in amine and carboxyl groups pH-dependent. Ions may be released by

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NPs (e.g., quantum dots, Ag, or ZnO). Particle functionalization and size, along with the local environment, may affect the rate that ions are released. Furthermore, a correlation has been found between their breakdown and cytotoxic effects (e.g., producing reactive oxygen species) [100–105]. The influence of the intracellular environment needs to be considered as well. As NPs are internalized by cells via endocytosis, the environment around them changes. The pH is 7.4 in the extracellular medium, then decreases to 5.5 in late endosomes, and further drops to 4.5 in lysosomes [106, 107]. Multiple ramifications may arise under the new conditions, such as the fast degradation of adsorbed or bound proteins. Among the most extensively investigated engineered NPs are silver NPs, and their dissolution in endosomes and lysosomes has been reported. The NP coating or whole NPs may degrade due to large amounts of hydrolytic enzymes, which are also in the acidic lysosomes. Changing conditions inside cells should be taken into consideration, including the impact of electrolytes, enzymes, and other proteins on the stability and degradation of NPs [108–110]. The complexity of interactions between nonspherical NPs and cells appears to be much greater, even though only a small number of investigations have examined them. Two distinct orientations of interactions between rod-shaped NPs coated with ligands and cells are possible. Cell-surface receptors have many more interactions with the long axis than the short axis [111]. The presentation of the ligand to target cell receptors for spiky nanostructures (e.g., gold nanourchins) is influenced by its position on or between the spikes [112]. Greater control over presenting ligands to target receptors may be possible with asymmetrical NPs in terms of engineering. For a certain geometric shape, overall cellular internalization is dependent on the dimensions of the nanomaterial. To achieve the highest cellular uptake rate and concentration inside cells, the ideal diameter is 50 nm for quantum dots, silica NPs, single-walled carbon nanotubes, and spherical gold NPs in some mammalian cells [111, 113, 114]. Aside from size and shape, internalization is influenced by nanomaterial composition. For nanomaterials with diameter of 50 nm, the rate of endocytosis for gold NPs is 10 6 min 1 and for single-walled carbon nanotubes is 10 3 min 1. The dissimilar intrinsic properties between gold and carbon may account for this difference of three orders of magnitude. Biological downstream effects are impacted by the composition of ligands coating the nanomaterial as well. When two different proteins that target an identical receptor were used to coat the NPs, they exhibited different cytotoxic and internalization effects [115]. NPs usually gain entry into the cell after binding to their receptor through receptormediated endocytosis [85, 88, 116]. The Gibbs free energy decreases locally when the NP-ligand conjugate binds to the receptor. In effect, the NP is surrounded by the membrane, leading to a closed-vesicle structure [116]. An endosome forms with the budding off of the vesicle from the membrane and fusion with other vesicles. The endosome then fuses with lysosomes which degrade materials. The process involved in the membrane

Cell-nanoparticle interactions

wrapping around the NP is probably associated with the dependence on size for NP uptake. The interaction of ligands with receptors is lower for smaller NPs. Just one or two receptors of the cell may interact with a 50-kDa protein-coated 5 nm NP. On the other hand, the interactions between ligands and receptors for each NP are much higher for a 100 nm NP. For sufficient free energy to be generated to induce membrane wrapping, receptors need to be bound by some small NPs (coated in ligands) which are in close proximity. Uptake can be stimulated by larger NPs which cross-link and cause receptors to cluster. In terms of thermodynamics, membrane wrapping may be driven by a 40–50 nm NP, which can recruit and bind sufficient receptors. NPs larger than 50 nm bind too many receptors, which actually restricts uptake. To offset the reduction locally, receptors are redistributed by diffusion on the cell membrane. NPs above 50 nm have high affinity for many receptors and may restrict more NPs from binding. No shortage of NP ligands and localized cell-surface receptors lead to optimal endocytosis, according to a mathematical model of this process [117, 118]. NPs with diameters of 30–50 nm have optimal ligand density, allowing the ideal conditions to be met. However, investigations showing that uptake is influenced by the diameter of NPs mainly used immortalized cell lines. The examined cells (e.g., immortalized HeLa cells as opposed to primary macrophages) may affect the optimal size of NPs for internalization, since every kind of cell has a distinct phenotype. Different mechanisms of uptake may be used and varying target receptor levels may be expressed by different kinds of cells. Primary and immortalized cells in a variety of cell culture configurations (monolayer and 3D) should, therefore, be used to further assess the phenomenon. The optimization of cellular internalization and intracellular accumulation through wide-ranging improvements in engineered parameters can then be achieved. An ongoing enigma is NP behavior inside endolysosomal vesicles. The protease Cathepsin L may cleave NP ligands in these vesicles, according to some reports [119]. Enzymes gradually degrade the core component of quantum dots in intracellular vesicles of macrophages [120]. The type of cell and nanomaterial size may affect the localization of CdTe quantum dots in various organelles. The nucleus favors entry of sub-2.1 nm quantum dots, while the cytoplasm contains 4.4 nm quantum dots [121]. Peptides (e.g., mitochondrial localization sequence) may control the location of NP compartmentalization inside the cell. NPs can go into the cytosol if they are designed to evade the endolysosomal system. Many organelles may interact with the NPs in the cytosol and cell behavior may be influenced by the NPs. Generating reactive oxygen species, interfering with mitochondrial function, and initiating the oxidative stress-mediated signaling cascade are examples of biological effects induced by NPs. Oxidative damage to DNA, harmful effects on the mitochondrial genome, and formation of micronuclei are all consequences of generating reactive oxygen species [122–124]. In addition, detrimental effects on nuclear DNA, which may result in gene mutations, development of cancer, arrest of the cell cycle, or cell death may be driven by some NPs. Numerous experimental designs

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have demonstrated the oncogenic effect of hydrophilic titanium oxide NPs [125]. The return of NPs to the endolysosomal system enables their exocytosis. Otherwise, they will stay in the cytoplasm. Daughter cells arising from mitosis will continue to retain NPs in the cytosol [126]. The effect of NPs on successive generations of cells is not yet known. Regarding NP toxicity and NP properties within the cytoplasm, no general agreement currently exists. There was greater production of reactive oxygen species by 30 nm amorphous TiO2 and 15 nm silver NPs than by NPs of other sizes [127, 128]. Some studies, however, have not shown the size of NPs to have a major effect. For example, the NP size did not influence the expression of inflammatory cytokines (e.g., IL-1β, MIP-2, and TNF-α) which were generated when macrophages internalized quantum dots and silver NPs [120, 127]. To better comprehend the safety and outcomes of NPs that are taken up by cells, more research is needed. For determining the fate of cells, the importance of surface charge should not be overlooked, in addition to the ligand density, shape, and size of nanomaterials mentioned earlier. More rapid uptake rate is observed in NPs with a positive charge relative to those having a negative or neutral charge [129, 130]. The small negative charge of the cell membrane and the induction of cellular internalization due to electrostatic attractions may explain this phenomenon [114, 115]. In one study, internalization resulted from adhesion of NPs onto the surface of the cell, which was promoted by the electrostatic attraction between positively charged NPs and the cell membrane. Ca2+ may enter cells and cellular proliferation may be impeded due to disturbance of the cell membrane potential by positive charges for tiny NPs (2 nm) [53]. Lipid bilayers may be reconstructed in response to the surface charge for larger NPs (4–20 nm) [131]. Fluidity results from the binding of NPs with positive charges to a lipid bilayer, while local gelation results from the binding of NPs with negative charges. The importance of surface charge in biological effects downstream to NPs has been shown by some studies. A corona composed of various proteins swiftly surrounds the nanomaterial’s surface charge in serum or other biological conditions. The impact of corona composition may have been reported by investigations examining NPs with positive and negative charges since composition of the corona is influenced by the surface charge. The incubation of citrate-capped gold NPs having negative charges with cell cultures led to this observation [85, 111]. The interaction of DNA-coated NPs having negative charges with serum proteins led to cellular uptake in a different study [132]. It is important to evaluate colloidal stability in physiological fluids. The accurate assessment of the NP dispersion state in biological settings is challenging due to the complicated analytical techniques, along with the involvement of many chemical and physical forces. The variety of complicated physiological fluids that interact with NPs increases the difficulty. The dispersion state of NPs and their physico-chemical properties are often analyzed using several different methods, including novel innovative techniques.

Cell-nanoparticle interactions

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CHAPTER 10

Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium Leila Arabia, Jim Q. Hob, Najmeh Javdanic, Mohammed Sharafd, Michelle Lamd, Morteza Aieneravaiea, Petrina Georgalae, Mohammad Reza Sepanda, Marjan Rafatf,g,h, Steven Zanganehd,e a Department of Medicine, University of Basel, Basel, Switzerland Albert Einstein College of Medicine, Bronx, NY, United States c Montreal Clinical Research Institute, Montreal, QC, Canada d Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States e Sloan Kettering Institute for Cancer Research, New York, NY, United States f Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States g Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States h Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, United States b

Cardiovascular diseases (CVDs) are considered one of the main causes of death across the globe. Among them, myocardial infarction (MI) is the major contributor to heart failure and the most severe ischemic heart disease [1, 2]. Reduced blood supply to the heart following MI causes cardiac cell death and damage and heart failure. Therefore, discovering methods to regenerate cardiac tissues and recover blood vessels is the main research avenue for treating MI [3]. The available treatment for CVDs is limited to oral pharmaceutical therapy or invasive surgery for device implants and organ transplantation. In this regard, nanotechnology and multifunctional nanoparticles may provide a novel approach for diagnosis and treatment of CVDs by overcoming physiological barriers and improving therapeutic outcomes in patients [4–7] (Fig. 1). However, compared with the field of tumor/cancer therapeutic delivery, targeted delivery to the cardiovascular system is still in its infancy. Previously, Mahmoudi et al. reviewed the current nanoparticulate system (Fig. 2A) for treatment and inhibition of ischemic heart injuries [8]. This chapter provides a brief overview of recent advances in the use of different nanoparticles and nanostructures (Fig. 2B) for early detection and treatment of injured myocardium.

Polymer-based nanodelivery systems Various injectable hydrogels, including natural (collagen, gelatin, hyaluronic acid, alginate, agarose, chitosan, and decellularized extracellular matrix materials) and synthetic Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00010-6

© 2020 Elsevier Inc. All rights reserved.

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Single cell imaging

Early detection

Biocompatibility and better dispersibility Tissue regeneration

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Coating Treatment possibilities with nanomedicine

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In situ diagnostics monitoring

Cardiovascular diseases and its challenges

Precise surgery

Labeling

Nanoparticle

Drugs/siRNA/ DNA/peptides

Targeting Antibody or ligand

Surface modified nanoparticles with different geometry, size, and functional property

Specific therapeutics

Fig. 1 Summary of cardiovascular diseases challenges and treatment possibilities with nanoparticles. (Adapted from Gupta P, Garcia E, Sarkar A, Kapoor S, Rafiq K, Chand HS, et al. Nanoparticle based treatment for cardiovascular diseases. Cardiovasc Hematol Disord Drug Targets 2019;19:33–44.)

(polyacrylic acid, polyethylene oxide, polyvinyl alcohol, and polypeptide chains) hydrogels, could be used for cardiac tissue engineering [9, 10] and cardiac tissue repair post-MI [11]. It is worth mentioning that a first-in-human study was conducted with intracoronary injection of an acellular alginate-based bioabsorbable scaffold in 27 patients with MI [12]. Among different types of polymers, poly(lactic-co-glycolic acid) (PLGA) is a biodegradable FDA-approved polymer and has been widely investigated [13, 14]. It has been shown that PLGA nanoparticles loaded with pitavastatin protect the heart from ischemiareperfusion injury in a rat model [15]. Moreover, PLGA nanoparticles with sustained release of atorvastatin increased availability of drug in systemic circulation and showed effective treatment of postinfarct myocardium by supporting mesenchymal stem cell survival [16]. Segura-Ibarra et al. investigated the kinetics of PLGA nanoparticles regarding myocardial penetration and retention. Nanoparticles loaded with fluorophores were capable of penetrating into the myocardium with a long retention (half-life of around 7 days) in heart tissue [17]. PLGA nanoparticles were also developed for carrying vascular endothelial growth factor (VEGF) to promote neovascularization in the heart. This formulation showed sustained release of VEGF and improved cardiac function in a murine MI model [18]. Some herbal medicines with cardiovascular protective effects have been encapsulated in polymeric nanoparticles. Hydrophobic icariin, an active ingredient used in Chinese medicine, was modified with polyethylene glycol polymer [19]. In another study, oral administration of polymer-based curcumin nanoparticles improved myocardial function and limited cardiac injury post-MI in an animal model [20]. In addition, several researchers used polymeric micelles for CVDs [21–23].

Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium

Fig. 2 (A) Applications of different nanoparticulate systems in the prevention and treatment of cardiovascular disease. (B) Different types of nanoparticles for delivery and imaging mentioned in this review. ((A) Adapted from Mahmoudi M, Yu M, Serpooshan V, Wu JC, Langer R, Lee RT, et al. Multiscale technologies for treatment of ischemic cardiomyopathy. Nat Nanotechnol 2017;12:845–55. (B) Adapted from Kiessling F, Mertens ME, Grimm J, Lammers T. Nanoparticles for imaging: top or flop?. Radiology 2014;273:10–28.)

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Dendrimers are nano-sized polymeric macromolecules with highly branched star shapes. With several functional groups on the surface, dendrimers are attractive candidates for targeting CVD-associated markers. In one study, dendrigraft poly-L-lysine (DGL) decorated with angiotensin II receptor type 1 (AT1) peptide and loaded with anti-miR-1 antisense oligonucleotide (AMO-1) was designed to target and accumulate in the infarcted heart. Intravenous administration of this nanovector decreased apoptotic cell death in the infarct area [24]. Likewise, other groups applied anticardiac troponin I (cTnI) antibody-decorated liposomes encapsulating AMO-1 for delivery of oligonucleotides to ischemic myocardial tissues [25]. In another study, polyamidoamine dendrimer conjugated to cyanine-5 fluorescent dye was selectively localized in ischemic myocardium compared with healthy myocardium in a rabbit model [26].

Lipid-based nanodelivery systems Liposomes are sphere-shaped vesicles composed of an aqueous core and one or more bi-layered phospholipid membranes. They are used for delivery of variety of cargoes, including small molecules, imaging agents, peptides, proteins, and nucleic acids, with the ability to slowly release an encapsulated agent [27, 28]. Several groups have successfully developed liposomes which can specifically target cardiac cells. Previously, Dvir et al. developed nanoliposomes targeting AT1, which is overexpressed in the early stages of the infarcted heart. They showed specific targeting and delivery to the injured myocardium using functionalized liposomes [29]. Lipinski et al. used different imaging modalities to show that liposomes with size of 100 nm preferentially target and can be used to image ischemic myocardium in a murine MI model [10]. However, in a different study, 70 nm liposomes showed significantly greater accumulation in the myocardium and mitochondria compared with 100 nm liposomes. Yamada et al. showed that liposomes loaded with erythropoietin and granulocyte-colony stimulating factor have a synergistic effect in an animal MI model and cause neovascularization and activation of prosurvival signals. Interestingly, even the empty liposomes demonstrated cardioprotective properties via vasodilatory and membrane-stabilizing effects. These studies demonstrate that the size of liposomes is critical for myocardial accumulation during ischemia and influences their effect on ischemia-reperfusion injury [30]. In another study, berberin, which is a small fluorescent alkaloid with antiinflammatory, antioxidative, and cardioprotective properties, was encapsulated in liposomes. Compared with control liposomes and free berberin, the liposomal formulation significantly improved the bioavailability of berberin and preserved the cardiac ejection fraction in C57BL/6J mice around 1 month after MI [31]. Recently, thermosensitive α-tocopherol liposomes with an appropriate sol-to-gel transition temperature were designed. They distributed uniformly in the porous structure of chitosan hydrogel. This complex supports the adhesion of cardiomyocytes and their survival [32]. In addition, in clinical trials, intravenous administration of liposomal prostaglandin E1 showed promising results in

Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium

decreasing the incidence of periprocedural myocardial injury (PMI) in 110 patients with unstable angina [33]. In addition to liposomes, other lipid-based nanoparticles have been used to target the injured myocardium. Polyethylene glycol (PEG)-modified solid lipid nanoparticles (SLNs) [34, 35], lipid core nanoparticles (LDE) [36], and micelles [36–38] have been applied for treatment of MI in different animal models.

Nucleic acid-based nanodelivery systems Nanobiomaterials have also been used in the delivery of gene/nucleic acids for the treatment of CVDs [39]. Targeting cardiac macrophages with microRNA-based therapy is one approach for treatment of MI. Anionic nanoparticles are used for delivery of miRNA-21 mimic cardiac macrophages post-MI to switch the proinflammatory cardiac macrophages phenotype to reparative ones which promote angiogenesis and improve cardiac healing [40]. Additionally, the composite of injectable hydrogel and polymeric nanoparticles for localized delivery of miRNA demonstrated repair of infarcted myocardium and improved cardiac function in MI rats [41]. Recently, lipidoid nanoparticles were applied for delivery of modified mRNA (modRNA) to the myocardium in rodent models via intramyocardial and intracoronary injection [42]. siRNA delivery has also been used for MI therapy. For example, polyethylenimine nanoparticles modified with deoxycholic acid have been used for delivery of siRNA against receptor for advanced glycation end products (RAGE) in acute MI. Suppression of RAGE signaling showed promising results for protecting from MI after ischemic injury in rat [43].

Cell-based nanodelivery systems Cell transplantation and stem cell delivery have been successfully used as novel therapies for treatment of ischemic heart disease. Cell-based cardiac repair has been the main approach for myocardial regeneration [44]. Different cell types have been employed for remodeling of the damaged myocardium. However, improving therapeutic efficacy of the delivered cells for the treatment of MI requires locational accuracy while preserving their survival, integrity, and functional properties after implantation. The combination of nanobiomaterials with stem cells is a rational approach in cardiac repair and overcomes the limitations of conventional stem cell therapy. Different types of nanomaterials have been used with stem cells to control the therapeutic behavior of stem cells for cardiac repair. Superparamagnetic iron oxide nanoparticles (SPIONs) are the main nanoplatform for improving the engraftment of cells in heart tissue [45, 46]. In one study, to enhance the short- and long-term engraftment of cells, magnetic nanoparticles loaded with labeled embryonic cardiomyocytes and embryonic

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stem cell-derived cardiomyocytes were used. Applying a magnetic field increased heart function by long-term engraftment of intramyocardial-injected magnetic nanoparticles (MNP)-loaded cells post-MI [47]. It has been shown that transplantation of endothelial progenitor cells (EPCs) and adipose-derived stem cells (ASCs) promoted myocardial neovascularization and regeneration after MI [44, 48]. Statins with pleiotropic effects enhance the potential of autologous ASCs for treatment of ischemic heart diseases. ASCs loaded with simvastatin-PLGA nanoparticles with local and sustained release of statins induced intrinsic cardiac regeneration in the infarcted myocardium in vivo [49]. However, one of the reasons for the poor clinical efficacy of EPC and ASC application for MI treatment is their low retention in the infarcted area. In one study, magnetized EPCs (labeled with silica-coated magnetic iron oxide nanoparticles) showed higher aggregation in an ischemic area and improved long-term cardiac functions in rats. These magnetic labeled cells were able to reach the region of interest by using external magnetic force [50]. In another study, ASCs were magnetized with SPIONs. Application of a magnetic field increased the cardiac retention and cardiac function of injected magnetized cells in the infarcted hearts of rats [48]. Preclinical studies showed that cardiac stem cell-derived exosomes are able to promote cardiac regeneration following MI. In a recent study, cardiac homing peptide (CHP)-conjugated exosomes were used to target the infarcted heart. This modification augmented exosome retention within heart sections [51]. Implantation of mesenchymal stem cells (MSC) is a potential therapy for MI. However, reactive oxygen species (ROS) generated in the ischemic myocardium could diminish the survival of MSCs. In one study, graphene oxide nanoparticles were used to inhibit ROS-mediated MSC death by adsorbing extracellular matrix proteins [52]. Recently, cationic gold nanoparticles (AuNPs) loaded with reprogramming factors (Gata4, Mef2c, and Tbx5) were used for heart regeneration and cardiac reprogramming of cardiomyocytes (iCMs) in vivo, and cardiac function was improved with low cytotoxicity after MI [53]. Besides nanoparticles, in very recent studies, scaffolds [54–58] and patches [59–66] have been developed to support and stimulate the growth of cells and cardiac regeneration after MI (Fig. 3). Moreover, tissue-engineering approaches including decellularized matrices [67] and three-dimensional (3D) bio-printing have shown promising results [68, 69] for cardiovascular regeneration.

Imaging nanodelivery systems Imaging has an important role in the diagnostic and identification of the early stages of cardiovascular disorders. One of the main problems in the treatment of injured myocardium is the lack of diagnostic tools to determine the affected regions of the tissue and

Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium

Injectable material applications

Patch-based material applications

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Disadvantages Potential shear stress to the injected cells. Limited to certain biomaterials. No control over cell growth and differentiation. Potential for cell loss -

Advantages - Tight control over cell proliferation and differentiation. - No cell loss during administration procedure - Precise positioning on injured area

(F)

Disadvantages Limited nutrient diffusion. Invasive therapy application. Potential integration issues for remuscularization based therapies

Fig. 3 The two major engineering approaches currently being used in stem cell delivery to the myocardium. Injectable materials (cross-linking materials (A) or microcarrier (B)) and patches (fabricated by combination of cells and material (C), seeding cells on prefabricated scaffolds (D), 3D-printing of bioink containing cells (E), or material-free cell sheets (F)). (Adapted from Feyen DAM, Gaetani R, Doevendans PA, Sluijter JPG. Stem cell-based therapy: improving myocardial cell delivery. Adv Drug Deliv Rev 2016;106;104–15.)

delivery of therapeutics to the injured areas. Different nanoplatforms with intrinsic imaging modalities including magnetic and gold nanoparticles have been applied for cardiovascular imaging and drug delivery. Contrast agents based on these nanoparticles are able to track different phases of MI and healing heart tissue [70–74]. Cardiovascular MRI (CMR) is considered a noninvasive gold standard technique for the visualization of structural changes in myocardial tissue. Iron oxide nanoparticles are the most explored type of nanoparticles for detection of MI [75, 76]. SPIONs are applied for diagnosis and visualization of MI using CMR. SPIONs showed advantages over

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gadolinium-based compounds for cardiac imaging in patients with acute MI [77–80]. In addition, Ferumoxytol (an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)) has been used in clinical trials for targeting, molecular imaging, and detailed characterization of the myocardium in patients with acute MI [81, 82]. An early clinical study in 2012 showed the uptake of USPIO into the myocardium of patients with MI [83]. On the other hand, AuNPs are inert and stable materials which have also shown great promise in cardiovascular imaging [84, 85]. AuNPs with different shapes including rods, clusters, stars, cubes, etc. [86] are able to accumulate in the injured heart tissue with cardioprotective effects [87] and anti-MI properties [88]. In one study, a contrast agent based on AuNPs was developed for computed tomographic (CT)-based molecular imaging. Particles were functionalized with proteins for specific targeting of collagen in injured myocardium in a rat model [89]. It is worth mentioning that nanoplatforms such as AuNPs with optical and plasmonic properties could be employed for diagnostic imaging and drug delivery in one delivery system known as “theranostics,” to overcome some imaging limitations and approach personalized medicine [10, 90, 91].

Nanoparticles as sensors for detection of cardiac biomarkers During the myocardial injury process, some cardiac biomarkers such as cardiac troponin I (cTnI) release into the blood circulation. Therefore, the early detection of these markers is crucial for immediate treatment of patients. Fig. 4 shows different approaches for detecting cTnI since 2015.

2.5%

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Optical (n = 9) Au nanorod-based SPR sensing Colourimetric (n = 2)

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A fluorogenic heterogeneous immunoassay A HRP-based chemiluminescence immunoassay

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Detection limit of cTnl (ng mL-1) 100 10 10 6.79 5.6 5 1.1938

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Fig. 4 (A) Different approaches for detection of cardiac troponin I (cTnI). (B) Comparison of reported methods for the detection of cTnI. ((A) Adapted from Regan B, O’Kennedy R, Collins D. Point-of-care compatibility of ultra-sensitive detection techniques for the cardiac biomarker troponin I—challenges and potential value. Biosensors (Basel) 2018;8. (B) Adapted from Chen F, Wu Q, Song D, Wang X, Ma P, Sun Y. Fe3O4@PDA immune probe-based signal amplification in surface plasmon resonance (SPR) biosensing of human cardiac troponin I. Colloids Surf B: Biointerfaces 2019;177:105–11 with revision.)

Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium

In this regard, different nanoparticles have been used as nanosensors for the detection of markers involved in CVD. One study reported immunogold nanorods as highly sensitive biosensors for detecting acute myocardial damage [92]. In a different investigation, an aptamer-based biosensor array was developed for detection of multiple cardiac biomarkers such as cardiac troponin T (cTnT) and cTnI [93–95]. In another study, a quantitative and sensitive immunochromatography test strip (ICTS) was developed for simultaneous detection of the two biomarkers of acute MI: CK-MB and cTnI. Furthermore, MNPs [96], carbon dots [97], gold nanorods [98], hollow gold nanoparticles (HGNPs) [99], and 3D gold nanovesicles [100] were designed for simultaneous detection of acute MI biomarkers. In summary, the studies reviewed here demonstrate that nanoparticulate systems are alternatives to the current pharmacological and surgical treatments for CVDs. Nanotechnology holds great promise for application in the treatment of CVDs and selective delivery to injured myocardium. There are a few ongoing trials regarding the use of nanotechnology in CVDs, including the NanoAthero project funded by the European Commission [101]. In addition, randomized clinical trials by the US National Library of Medicine on the uses of nanotechnology in drug-eluting stents demonstrated promising results (https://clinicaltrials.gov/ct2/show/NCT02594501). However, further in vivo studies and clinical trials are needed to understand the exact role of nanoparticulates in increasing patients’ quality of life.

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Further reading Chen F, Wu Q, Song D, Wang X, Ma P, Sun Y. Fe3O4@PDA immune probe-based signal amplification in surface plasmon resonance (SPR) biosensing of human cardiac troponin I. Colloids Surf B: Biointerfaces 2019;177:105–11. Feyen DAM, Gaetani R, Doevendans PA, Sluijter JPG. Stem cell-based therapy: Improving myocardial cell delivery. Adv Drug Deliv Rev 2016;106:104–15. Kiessling F, Mertens ME, Grimm J, Lammers T. Nanoparticles for imaging: top or flop? Radiology 2014;273:10–28. Regan B, O’Kennedy R, Collins D. Point-of-care compatibility of ultra-sensitive detection techniques for the cardiac biomarker troponin I—challenges and potential value. Biosensors (Basel) 2018;8.

CHAPTER 11

Nanoparticulate systems for sustained delivery of paracrine factors Leila Arabia, Jim Q. Hob, Najmeh Javdanic, Serena Jonesd, Ivette Chend, Mohammed Sharaf d, Morteza Aieneravaiea, Petrina Georgalae, Mohammad Reza Sepanda, Marjan Rafatf,g,h, Steven Zanganehd,e a Department of Medicine, University of Basel, Basel, Switzerland Albert Einstein College of Medicine, Bronx, NY, United States c Montreal Clinical Research Institute, Montreal, QC, Canada d Department of Chemical and Biomolecular Engineering, New York University, New York, NY, United States e Sloan Kettering Institute for Cancer Research, New York, NY, United States f Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States g Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States h Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, United States b

There is an increasing body of evidence demonstrating the importance of several paracrine factors in multiple diseases [1, 2]. Paracrine factors such as growth factors (GFs) and cytokines are soluble signaling proteins synthesized and secreted by cells and can diffuse over short distances to induce changes in neighboring cells. They act locally and show short and slow diffusion in the extracellular matrix [3] to interact with their receptors to activate signaling pathways which control a variety of cellular processes such as proliferation, survival, migration, and differentiation [4]. This phenomenon is called a paracrine interaction, and the secreted soluble polypeptides are called paracrine factors or growth and differentiation factors (GDFs). A variety of these paracrine factors can be categorized into four major groups based on their structures including: fibroblast growth factor (FGF), Hedgehog, Wingless (Wnt), and the TGF-β superfamily [5]. Several GFs including vascular endothelial growth factors (VEGFs), bone morphogenetic proteins (BMPs), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1/IGF-2), basic fibroblast growth factors (bFGFs), transforming growth factor-beta (TGF-β), nerve growth factors (NGF), glial cell-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) are used in tissue engineering. Table 1 shows the most well-known paracrine factors including different growth factors in tissue regeneration. It is worth mentioning that different biological barriers can decrease the delivery of these factors to several organs. One example is the blood-brain barrier (BBB) in delivery to the brain. GFs such as BMPs have short half-lives (6–7 min) as a result of massive clearance in nonhuman primates [6, 7]. Moreover, they are sensitive to denaturation and protease degradation in the systemic circulation. Delivery systems are needed to extend the Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00011-8

© 2020 Elsevier Inc. All rights reserved.

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Table 1 The most well-known growth factors in tissue regeneration Abbreviation

Tissues treated

Representative function

Ang-1 Ang-2

Blood vessel, heart, muscle Blood vessel

FGF-2

Blood vessel, bone, skin, nerve, spine, muscle

BMP-2 BMP-7

Bone, cartilage Bone, cartilage, kidney

EGF

Skin, nerve

EPO

Nerve, spine, wound healing

HGF

Bone, liver, muscle

IGF-1

NGF PDGF-AB (or -BB) TGF-α TGF-β

Muscle, bone, cartilage, bone liver, lung, kidney, nerve, skin Nerve, spine, brain Blood vessel, muscle, bone, cartilage, skin Brain, skin Bone, cartilage

Blood vessel maturation and stability Destabilize, regress, and disassociate endothelial cells from surrounding tissues Migration, proliferation and survival of endothelial cells, inhibition of differentiation of embryonic stem cells Differentiation and migration of osteoblasts Differentiation and migration of osteoblasts, renal development Regulation of epithelial cell growth, proliferation, and differentiation Promoting the survival of red blood cells and development of precursors to red blood cells Proliferation, migration, and differentiation of mesenchymal stem cells Cell proliferation and inhibition of cell apoptosis

VEGF

Blood vessel

Survival and proliferation of neural cells Embryonic development, proliferation, migration, growth of endothelial cells Proliferation of basal cells or neural cells Proliferation and differentiation of boneforming cells, antiproliferative factor for epithelial cells Migration, proliferation, and survival of endothelial cells

Ang, angiopoietin; bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TFG, transforming growth factor; VEGF, vascular endothelial growth factor. (Adapted from Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J R Soc Interface 2011;8:153.)

half-life and guarantee stability, bioactivity, and sustainability. These bio-inspired systems are able to control the amount, time, and location of release of paracrine factors. To preserve the native form of paracrine factors, several strategies have been developed for their delivery. Nanoparticles (NPs) with unique properties such as small size, large surface area-to-volume ratio, high loading efficiency, and sustained release of encapsulated agents are considered great candidates in the field of biomedical engineering [8–12]. Altogether, there are essential parameters in designing the sustained delivery system of GFs, including biological considerations, material selection, and delivery strategies (Fig. 1). This chapter provides the latest advances in the development of different

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Biological considerations

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O C

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Fig. 1 Pivotal components for growth factor delivery. (Adapted from Caballero Aguilar LM, Silva SM, Moulton SE. Growth factor delivery: defining the next generation platforms for tissue engineering. J Control Release 2019;306:40–58.)

nanoparticulate systems for the delivery of paracrine factors by emphasizing on GFs to increase availability, preserve bioactivity, functionality, and stability, and control release of paracrine factors to the region of interest.

Different types of nanoparticulate systems for encapsulation and delivery of paracrine factors The latest nanoparticulate systems used for GF loading and release include synthetic and natural polymers, lipid-based NPs, inorganic NPs, nanofibers, and scaffolds [13–15]. Fig. 2 shows different types of nanoparticulate systems in the delivery of paracrine factors.

Lipid-based delivery systems Lipid-based NPs are biocompatible and nontoxic delivery systems with amphiphilic properties [16, 17]. Liposomes, which are bilayers of phospholipids with an aqueous core, have been used for oral delivery of recombinant human epidermal growth factor (rhEGF)

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Fig. 2 Different nanoparticulate systems for the delivery of growth factors (GFs) (A–F). GF-encapsulated nanocarriers embedded into functionalized scaffolds (G). (Adapted from Wang Z, Wang Z, Lu WW, Zhen W, Yang D, Peng S. Novel biomaterial strategies for controlled growth factor delivery for biomedical applications. NPG Asia Mater 2017;9:e435.)

[18]. Liposomes can be coated with polymers in order to improve stability and control the release profile of encapsulated growth factors. In one study, a three-dimensional (3D) layer-by-layer structure composed of polysaccharide was used to coat liposomes containing EGF. This biopolymer-coating resulted in sustained delivery of EGF [17, 19]. Besides liposomes, solid lipid particles (SLN) with solid lipid cores and nanostructured lipid carriers (NLCs) with liquid lipid cores [20] have been developed as paracrine factor carriers. For instance, gelatin NLCs with solid matrix were used for the delivery of bFGF to the brain [21], and later, for the delivery and sustained release of nerve growth factor (NGF) [22].

Polymer-based delivery systems A variety of natural and synthetic polymers have been investigated to engineer nanoparticulate systems for the encapsulation and delivery of paracrine factors (Fig. 3).

Nanoparticulate systems for sustained delivery

Fig. 3 Structures of common synthetic and natural polymers used to develop nanoparticulate systems for the encapsulation and delivery of paracrine factors.

Synthetic polymers Polylactide (PLA), polyglycolide (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(N-isopropylacrylamide) (PNIPAAm) are the most used synthetic polymers for NP fabrication with controlled release of cargo [23–26]. PLGA as a biodegradable FDA-approved polymer with high encapsulation efficiency has been widely investigated to encapsulate and deliver paracrine factors [27, 28]. PLGA NPs modified with lectin encapsulating bFGF was developed for brain delivery via nasal administration [29]. Moreover, linear-dendritic NPs containing PLA and poly(L-lysine) dendrons were loaded with nerve growth factor (NGF). This thermoresponsive nanocarrier showed sustained and thermal targeted release of NGF in neuron-like PC12 cells [30]. Nanocarriers can be applied as dual-drug delivery systems [31–33]. Especially in bone regeneration, a repair process that requires multiple factors, dual-drug delivery strategies are highly desired to achieve effective formation of new bone. Recently, a PLGA NP decorated with an antimicrobial peptide was developed for wound healing application. This multicargo delivery system contained vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) with very high entrapment efficiency [34].

Natural polymers The most commonly used natural polymeric materials include: collagen, hyaluronic acid, gelatin, chitosan, alginate, and chondroitin sulfate. They are biocompatible polymers with low toxicity, high stability, and derivatizable functional groups, which make them great candidates for the preparation of drug-encapsulated NPs [35, 36].

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Among them, chitosan is the most used cationic polymer with mucoadhesive properties used to deliver therapeutics specifically to the brain [37] and bone [38] and for tissue engineering [39]. GFs like BMP-2 [40] and bFGF [41] were efficiently encapsulated into chitosan-based nanocapsules with sustained, slow release. Nerve growth factor (NGF) and gold NPs encapsulated in chitosan NPs with controlled release over 7 days were developed for the differentiation of human adiposederived stem cells (h-ADSCs). This complex has potential for being applied to nerve tissue regeneration [42]. In another study, co-delivery of doxorubicin and interleukin-2 in chitosan NPs enhanced antitumor activity [43]. Besides NPs, patches and scaffolds have been used for the delivery of paracrine factors. For instance, chitosan patch scaffolds were used for delivering a stem cell cytokine named insulin-like growth factor-binding protein 2 (IGFBP2) [44]. In addition, hybrid materials based on chitosan, such as membranes, films, sponges, nanocomposites, and hydrogel sheets, were recently developed for wound healing [45].

Inorganic nanoparticulate systems for growth factor delivery Several inorganic nanoparticulate systems such as magnetic NPs, calcium phosphatebased nanomaterials, and mesoporous silica NPs (MSNs) or nanoporous silica NPs have received considerable attention for the delivery of paracrine factors due to their stable properties and appropriate surface chemistry [46–48]. Very recently, a nanocomposite consisting of hydroxyapatite with recombinant human BMP-2 was developed as artificial bone for repairing bone defects [49]. Dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) with size of 50 nm and conjugated with recombinant human EGF were used as contrast agents in imaging EGFR-overexpressing brain tumors [50]. Magnetic NPs conjugated to brainderived neurotrophic factor (BDNF) were developed to cross the blood-brain barrier in an in vitro model [51]. Calcium phosphate-based biomaterials are applied for bone regeneration because of their similarity to the mineral phase of bone [52]. In one study, a biphasic calcium phosphate collagen composite was used as a carrier of rhBMP-2 for the formation of new bone [53]. Mesoporous silica NPs (MSNs) with their porosity and high surface area are attractive candidates for carrying GFs. In one study, dexamethasone-loaded mesoporous silica NPs decorated with BMP-2-derived peptide showed osteoblast differentiation and bone regeneration after intramuscular implantation in rats [54]. Nanocarriers can be applied as dual-drug delivery systems [55]. For instance, a mesoporous silica NP composite with PLGA was developed for the encapsulation of IGF-I and TGF-β1 [56]. A metallic implant coated with BMP-2 and silver NPs containing

Nanoparticulate systems for sustained delivery

hydroxyapatite was developed in another study. This coating showed significant antibacterial properties against Staphylococcus epidermidis and Escherichia coli and increased bone formation in rabbit [57].

Nanofibers for growth factor delivery Nanofibers prepared from polymers have several biomedical applications and are used to deliver growth factors [58]. Recently, application of these composite materials introduced a new possibility for delivery systems [39]. A composite consisting of polycaprolactone (PCL), chitosan, and collagen was employed as a biomimetic nanofiber in wound healing. This composite of natural and synthetic materials was loaded with antibiotic, EGF, and bFGF with an ability to have controlled release [59]. In another study, a PCL-collagen nanofiber carrying BMP-2 was used as bone tissue scaffold with osteoprogenitor cells [60]. Interestingly, a hybrid system composed of alginate and a nanofiber mesh for delivery of rhBMP-2 was designed and showed longer-term release and improved bone regeneration [61]. In an additional study, a three-component composite consisting of PEG-PCL-PEG copolymer-collagen-nano-hydroxyapatite was developed for the delivery and sustained release of BMP-2 in cranial defects in rabbits [62].

Nanoparticle-embedded scaffolds as a growth factor delivery strategy NPs encapsulating GFs incorporated into functionalized scaffolds are able to mimic extracellular matrix and deliver bioactive molecules locally. These multiphase systems are composed of NPs, paracrine factors, and scaffolds. In this context, NPs can be used for sequential delivery of several GFs. In one study, NPs made of a PLGA core and poly(sebacic acid) coating dispersed in a hyaluronan hydrogel were designed for delivering epidermal growth factor (EGF) and erythropoietin (EPO) to simulate regeneration of the brain after stroke [63]. PLGA NPs incorporated into 3D collagen scaffolds mimic the aortic smooth muscle microenvironment. This complex resulted in controlled and sustained release of TGF-β1 and doxycycline as a matrix metalloprotease inhibitor [64]. Chitosan NPs incorporated in chitosan-gelatin porous scaffolds, which stimulate the 3D structure of the extracellular matrix, were developed for bFGF delivery. This nanocomposite scaffold demonstrated enhanced proliferation of fibroblast cells for tissue engineering [65]. PLGA NPs carrying fibroblast growth factor-2 (FGF2) were embedded in a hyaluronan and methylcellulose scaffold. This NP-hydrogel composite showed sustained and localized delivery of FGF2 for spinal cord injury therapy [66].

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Fig. 4 Encapsulation of carrier systems loaded with growth factor in hydrogels. (i) Schematic representation of rhBMP-2 release from nanoparticles into hydrogels. (ii) Histological and micro-CT evaluation of bone formation of rhBMP-2-containing hydrogels at 12 weeks. (Adapted from Guan X, Avci-Adali M, Alarcin E, Cheng H, Kashaf SS, Li Y, et al. Development of hydrogels for regenerative engineering. Biotechnol J 2017;12.)

To have sustained release of growth factors, NPs loaded with GFs can be incorporated into hydrogel scaffolds. This could be considered noncovalent immobilization of GFs in hydrogels [67] (Fig. 4). Recently, biodegradable NPs encapsulating a PDGF-BB phospholipid complex were developed for the sustained release of PDGF-BB in collagen hydrogel scaffolds [44]. Moreover, bovine serum albumin NPs embedded in a nanofiber scaffold demonstrated sustained release of BMP-2 and dexamethasone for repair of bone defects in bone tissue engineering [68]. Mesoporous silica NPs containing VEGF and cephalexin (an antibiotic) were embedded in 3D porous scaffolds based on agarose and nanocrystalline apatite for bone reconstruction [69]. In another study, mesoporous silicate NPs were incorporated into a 3D nanofibrous gelatin scaffold served as a biomimetic osteogenic microenvironment. The composite was fabricated for sustained release of BMP2 and short-term release of deferoxamine as an FDA-approved hypoxia-mimetic drug which can trigger angiogenesis by activating hypoxia-inducible factor-1 alpha [70] (Fig. 5). In a very recent study, bone scaffold complexes were engineered by 3D printing. The complex composed of rhBMP-2 loaded chitosan nanocarriers with a PLGA/HA scaffold

Nanoparticulate systems for sustained delivery

Fig. 5 Synthesis procedure of 3D growth factor scaffolds. (Adapted from Yao Q, Liu Y, Selvaratnam B, Koodali RT, Sun H. Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release 2018;279:69–78.)

effectively controlled the early burst of rhBMP-2 for repairing large jaw defects in rabbit [71]. In summary, several approaches have been employed for delivery and sustained release of paracrine factors as an important strategy in tissue engineering. Most of the nanoparticulate delivery systems presented in this chapter demonstrated the enhanced stability and therapeutic potential of the GFs. As reviewed here, different particulate systems seem to be promising potential GF carriers. However, further studies are necessary to determine the stability of paracrine factors during delivery, their accumulation pattern in the body, and their long-term toxicology. Moreover, more researchers and multidisciplinary approaches that employ engineering, biomaterials, medicine, and pharmaceutical sciences should be conducted.

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Further reading Caballero Aguilar LM, Silva SM, Moulton SE. Growth factor delivery: defining the next generation platforms for tissue engineering. J Control Release 2019;306:40–58. Wang Z, Wang Z, Lu WW, Zhen W, Yang D, Peng S. Novel biomaterial strategies for controlled growth factor delivery for biomedical applications. NPG Asia Mater 2017;9:e435.

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Nano-bioink solutions for cardiac tissue bioprinting Martin L. Tomova, Merlyn Vargasb, Carmen J. Gila, Andrea S. Theusa, Alexander C. Cetnara, Katherine Pham Doa, Remi Venezianob, Vahid Serpooshana,c,d a Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States b Volgenau School of Engineering, Department of Bioengineering, George Mason University, Fairfax, VA, United States c Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States d Children’s Healthcare of Atlanta, Atlanta, GA, United States

Nanomaterials in cardiac bioinks Design and fabrication of tissue-specific bioinks are rapidly growing along with the continuous development of advanced formulation methodologies and bio-manufacturing processes [1–5]. Addition of nano-biomaterials can further help widening the range of bioink functionalization, especially in the field of cardiovascular tissue engineering (Fig. 1). The cardiac niche is highly specific and is controlled via a wide variety of enzymatic and nonenzymatic modifications based on external and internal cues, which are the basis of cardiovascular extracellular matrix (ECM) remodeling during and after injury. Biomaterials that closely mimic the natural ECM can be used in basic science studies of cell-cell and cell-biomaterial interactions, as well as in more translational applications focused on development of functional bioinks with enhanced clinical potentials [1,5–7]. Although still in its early stages, the field of cardiovascular nanomedicine has advanced rapidly, largely owing to the recent breakthroughs in the nano-biomaterial sciences. Application of various nano-biomaterial systems, such as nanocarriers/nanoparticles (NPs) and nanostructured scaffolds, has shown great promise in developing novel therapies with enhanced regeneration and/or neovascularization of the injured tissue [8]. Nanostructured constructs have been used as cardiac patches for functional tissue replacement [9–12]. However, a major challenge to develop clinically relevant tissue-engineered implants is recapitulating the unique morphological, physiological, and functional properties of the myocardial tissue [1,13,14]. Functionalized NPs have also shown promise to tune properties of currently available biomaterials, transforming them into more appropriate tissue-mimetic bioinks which would be translationally applicable, both as a regenerative medicine tool and as in vitro drug screening and disease modeling platforms [8,9,15]. In particular, we will highlight nanomaterial-functionalized bioinks with modified/enhanced electrical conductivity, imaging properties,

Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00012-X

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Fig. 1 Design and various applications of cardiovascular nano-bioinks. (Adapted from Memic A, Alhadrami HA, Hussain MA, Aldhahri M, Al Nowaiser F, Al-Hazmi F, Oklu R, Khademhosseini A. Hydrogels 2.0: improved properties with nanomaterial composites for biomedical applications. Biomed Mater 2015;11(1):014104).

physiomechanical properties, and antibacterial effects. Such biomaterials can be designed and bioprinted to support viability and function of contractile cardiovascular tissue [16–18].

Electrical conductivity of bioinks To create viable and functional cardiovascular tissue analogues, the employed hydrogels will have to closely resemble the cardiac cell niche, its 3D microarchitecture, and be able to sustain conductivity at physiological levels. Poorly conductive nature of commonly used hydrogel biomaterials often results in cardiac constructs with suboptimal performance [2,4,19]. Incorporation of conductive nanomaterials could provide an efficient method to significantly and controllably improve the electrical properties and function of next-generation cardiovascular bioinks [20–22]. The resulting nanocomposite hydrogels could enhance cardiomyocyte alignment, maturation, and electrophysiological functions [22,23]. Further, such biomimetic nanocomposite-enhanced bioinks can facilitate

Nano-bioink solutions for cardiac tissue bioprinting

Fig. 2 Conductive cardiovascular nano-bioinks applications. (Reprinted from Lu H, Zhang N, Ma M. Electroconductive hydrogels for biomedical applications. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2019:e1568.)

proper electro-conductive network and establish controlled beating behavior within the cardiac cells, priming them for transplantation into injured heart tissue or as functional drug screening platform (Fig. 2) [21]. To enhance scaffold conductivity for cardiovascular tissue engineering, conducting polymers (such as polyaniline, polythiophene, and their derivatives [24,25]) and NPs such as carbon nanotubes (CNTs) [26], silver [27], and gold nanorods (GNRs) [15], or conductive biomolecules such as the pigment melanin [28] can be incorporated into the tissue matrix. Melanin is an interesting case, as at low concentrations, it improved cardiac-specific protein expression after electrical stimulation, also aligning the cardiomyocytes along the direction of the induced field [28]. It can also improve bioprinting resolution and fidelity [28,29]. Developing these biomimetic nanocomposite hydrogels can facilitate proper electro-conductive network and establish spontaneous beating behavior within the cardiac cells. It has been demonstrated that addition of gold nanowires and NPs to hydrogels can significantly enhance electrical communication between neighboring cardiac cells within the 3D microenvironment [1,23,30]. Cardiac cells incorporated into a CNT-functionalized gelatin methacrylate (gelMA) bioink exhibited a synchronous response to electrical pacing and generated proper excitation-contraction coupling with each beat [31]. Further, these patches have shown improved cell adhesion and cell-cell interactions when the bioink contained CNTs. These include large (centimeters)-scale constructs which have shown controllable cyclic contractions, pumping, and macroscale movements [31].

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Another effective way to increase conductivity in nanomaterial-functionalized bioinks is to encapsulate GNRs into the bioink [32]. The GNR concentration can be modulated to promote effective cardiac microenvironment where cardiomyocytes are able to expand, self-organize, and mature into contractile cardiac tissue, without compromising the mechanical and chemical properties of the bioink. In such NP-modified hydrogels, the conductivity of the GNRs lowers the overall bioink electrical resistance, which promotes cell-cell coupling and synchronized contractility of large cardiovascular tissue constructs. For instance, the gelMA-coated GNRs (G-GNR) were shown to increase cardiomyocytes adhesion and retention [32]. Encapsulated cardiomyocytes and cardiac fibroblasts displayed greater metabolic activities in printed construct in comparison to when using native gelMA [32]. Further, higher expression levels of troponin I and connexin-43 were found with cardiomyocytes cultured in the G-GNR. Overall, the usage of G-GNR showed improved cell adhesion and organization, cell-to-cell coupling, and promoted synchronized contractions. In sum, incorporation of CNTs, GNRs, and other conductive nanomaterials into cardiac-specific bioinks could be of great importance when designing multifunctional scaffolds for basic science and therapeutic purposes. There are, however, several prospective challenges which could arise and need to be addressed. One possible disadvantage of using NP-modified inks could be longer or less-effective crosslinking processes. Further, precautions should be taken for future applications of particles such as GNRs since there have been reports of apoptosis and necrosis associated with some of these NPs [33].

Imaging properties of bioinks Bioinks loaded with various contrast agents offer an attractive method to study different properties and functionalities of 3D scaffold structures using a variety of imaging modalities [34]. A common contrast agent used for magnetic resonance imaging (MRI) is gadolinium (Gd). Due to its unique magnetic properties, Gd enhances the MRI contrast in the areas where it is most concentrated. Over the past decades, there has been a significant growth in the number of NP systems used as computed tomography (CT) and/or MRI contrast agents. This is mainly due to multiple advantages that NPs offer over small molecule agents, including longer circulation half-lives, enhanced retention within 3D scaffolds, the potential for tracking cells and other molecules, and targeted imaging applications [35]. In clinical applications, Gd-based contrast agents are composed of small gadolinium ions, typically in the form of gadolinium oxides (Gd2O3), bonded with conjugated macromolecules [36]. Gd2O3 NPs are superior compared to other forms of Gd-chelates since they exhibit higher enhancement efficiency for T1-weighted MR image [37]. However, since Gd3+ is toxic, retention of these ions in the human body over longer periods has been linked to nephrogenic systemic fibrosis [38]. Thus, in order to create biocompatible

Nano-bioink solutions for cardiac tissue bioprinting

Gd-based contrast agents, the size of the NP must be optimized for renal excretion. For instance, ultra-small Gd2O3 NPs coated with polyacrylic acid with diameter of 2 nm have been reported to be efficient contrast materials with low cytoxicity [39]. Alternatively, the coating agents of Gd-NPs can be selected to improve biodegradability when used to generate MRI data in patients with renal dysfunctions [40]. Gd-chelates have also been used in conjunction with other biocompatible materials like liposomes to decrease toxicity while increasing their stability. When Gd-chelates are used with liposomes, they can be either encapsulated in the interior core of liposomes [41] or used as a conjugate on the liposome surface [42]. The liposome-Gd NP complexes have several distinct advantages, such as longer in vivo half-life and lower leakage of Gd ions which reduces their toxicity [43]. As a result, these contrast agent particles have been used in a wide range of vascular imaging systems ranging from the central nervous system [44] to general cardiovascular imaging [45] and atherosclerotic plaque characterization [46]. In addition, by combining the two different methods of attaching the Gd-chelates to the liposomes, the T1-weighted MRI imaging can be enhanced significantly, thus allowing for reducing dosage of the Gd-chelates while enhancing imaging sensitivity [47]. Additionally, liposome NPs can be used as a platform for Gd and other contrast agents to improve imaging resolution in ultrasounds, photoacoustic imaging, and also in fluorescence spectroscopy and photoacoustic imaging [48]. Within the field of bioprinting, Gd-based contrast agents have been used for in vivo tracking of endothelial cells and stem cells seeded in a polysaccharide-based scaffold material (Fig. 3) [49]. Bermejo-Velasco et al. applied Gd-hyaluronic acid as a labeling material to investigate the degradation of hydrogel materials [6]. Catanzaro et al. used Gd-based

Fig. 3 MRI imaging of stem cells in polysaccharide-based scaffold using Gd2O3 contrast agent NPs. (Reprinted with permission from Catanzaro V, Digilio G, Capuana F, Padovan S, Cutrin JC, Carniato F, Porta S, Grange C, Filipovic N, Stevanovic M. Gadolinium-labelled cell scaffolds to follow-up cell transplantation by magnetic resonance imaging. J Funct Biomater 2019;10(3).)

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NPs as labeling agent incorporated into the poly(lactide-co-glycolide) and chitosan scaffolds for MRI imaging [50]. Gadolinium-loaded liposomes have also been used to quantify the enzyme activity in matrix metalloproteinase-2 [51]. Besides Gd-chelates, other contrast agents for MRI, like L-arginine [52], have also been used to study the cell viability by sensing pH levels in vivo. Other NP systems that could be used as potential contrast agents in the bioinks for tissue bioprinting include polymeric NPs, solid metal NPs, silica, metal oxides or other salts, CNTs, and graphene sheets [35,53,54]. A potential future application of liposome and other imaging NPs is in characterization and noninvasive in vivo monitoring of cellor drug-laden bioinks which are used for 3D bioprinting of cardiovascular tissue constructs, where clinical imaging modalities such as MRI, CT, and ultrasound could be used to track construct integration and function postimplantation.

Mechanical and biochemical properties of nano-bioinks Mechanical properties of bioinks and printed scaffolds have to be precisely tailored to the specific in vitro or in vivo application. To rebuild injured heart tissue, autologous or allogenic cardiac cells are either encapsulated within the bioink hydrogel and directly 3D printed, or seeded into the construct following printing. Cellular bioprinted constructs will be subsequently cultured and matured using conventional (static) tissue culture platforms, or via perfusion bioreactors which provide the necessary microenvironmental cues [55]. Improving the physiomechanical properties of nanomaterial-functionalized bioinks would allow for more accurate and biomimetic cell-drug interactions and importantly could be used in translational applications such as cardiac patches for cardiovascular tissue regenerative therapies [16,18,56]. To successfully accomplish cardiac tissue repair using a bioprinted cardiac patch, the scaffold structure must closely recapitulate biophysical and chemical properties of native cardiac ECM. As it comprises of secreted fibrous proteins, water, glycoproteins, proteoglycans, and other soluble molecules, their quantity, structure, and composition have to be closely matched if effective regenerative therapies are to be developed. Bioink synthesis methods that can accommodate multimaterial fabrication will improve hydrogel printability, stability, and cell support [1,3,5]. Importantly, these methods can add a range of new nanomaterials to the bioink synthesis processes to further refine the mechanical and physical properties needed to faithfully mimic the cardiovascular niche [2,19,30,57,58]. One example that can be leveraged for cardiovascular treatments is tailoring properties of injectable hydrogels, such as gelMA or polyethylene (glycol) diacrylate (PEGDA)-based hydrogels. Bioink properties such as printability, crosslinking, viscosity, and stiffness can be tuned by encapsulating a variety of functional NPs within the bioink [59]. These bioinks could be delivered as single or multiple injection runs or sites, greatly improving their ability to cover large areas of the heart in a controlled and

Nano-bioink solutions for cardiac tissue bioprinting

precise manner. This could be particularly important in cardiac tissue engineering considering the complex microenvironment of heart tissue with varied stiffness, vascularization deficiencies, and/or cell loss across an infarcted heart. Several reports have demonstrated successful use of micro- and nano-particles for tuning mechanical and chemical properties of bioprinted constructs. For example, poly(lactide-co-glycolide)-PEG (PLGA-PEG) microparticles significantly enhanced bioink viscosity and stiffness of cell-laden carboxymethyl cellulose constructs, matching those of cancellous bone [60]. To improve structural and mechanical properties of cardiac nano-bioinks, recent reports have looked at incorporating CNTs [31] and structural DNA strands [61] within bioinks. CNTs were able to improve the structural stability of the bioink, while also enhancing its conductivity and cell alignment [31]. DNAmodified bioinks were able to induce defined responses from the encapsulated cells in addition to serving as a mechanically tunable scaffold, adding a significant mechanical boost to the functionality of the developed inks [61]. While promising results have been reported for enhancing biomechanical and structural properties of bioinks with addition of various NPs, there are certain issues that must be addressed. Higher contents of particles are shown to adversely affect cell viability and/or function, due to inherent cytotoxicity of some particles or exerting elevated levels of stress to the cells during the printing process [62–65]. Incorporation of excessive amounts of NPs in the bioink could also deteriorate the printability and printing fidelity of hydrogels [64,66]. Therefore, further work is needed to achieve a fine balance between NP-modified bioink functionality, cytocompatibility, and printing quality and resolution.

DNA-NP bioinks DNA is the storage medium of the genetic information for all living organisms, but from a tissue engineer’s point of view, it is also a polymeric biomaterial with unique mechanical and structural properties that can help overcome the unmet challenges of cardiac tissue bioprinting. Single-stranded DNA (ssDNA) molecules can specifically self-assemble in solution by hybridization with user-defined complementary strands. This assembly process follows the Watson and Crick Base-pairing rules to form stable double-stranded DNA (dsDNA) helices with a periodicity of 10.5 base pairs (or 3.4 nm) and a diameter of 2 nm. The molecular specificity of DNA combined with its structural predictability makes it an ideal biomaterial for programmable and high-fidelity assembly of nanoarchitectures. Hence, over the past decades, DNA has been used to design and assemble 1-, 2-, and 3D discrete NPs and lattices using DNA tiles or more complex motifs such as DX-tiles [67–69]. More recently, Paul Rothemund developed the DNA origami technique enabling high yield assembly of discrete, monodisperse, and pure DNA-NPs into any arbitrary shape and size in 1-, 2-, and 3D in a one-pot reaction [70]. This technique relies on the annealing of a long ssDNA strand (typically M13mp18 circular ssDNA),

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which play the role of scaffold, with several complementary synthetic oligonucleotides called “staples strands.” DNA-NPs are now widely used for biomedical applications including drug delivery and nanosensing [71]. Moreover, their ease of conjugation makes them highly attractive as template for nanoscale organization of various biomolecules (e.g., peptides, proteins, and lipids). To this end, staple strands can be modified at their 50 - or 30 - ends or internally with functional or chemical groups including ssDNA overhangs, free amine groups, or click chemistry groups among others to allow for a wide range of NPs and bioink functionalization. DNA-NPs are biocompatible and biodegradable which allow for direct use with cells and tissues. Their ability to control the nanoscale organization and stoichiometry of various biomolecules, as well as the unparalleled orthogonality that can be achieved for bioconjugation, would increase significantly the degree of functionalization obtained with classical NPs-loaded bioink [72]. DNA-NPs could also play a role in the mechanical properties of the bioink if associated with the other structural components. Indeed, the mechanical properties of the DNA-NPs can be modulated by changing the type of structural motifs used to assemble DNA-NPs in order to create highly rigid brick-like structure or more flexible wireframe structure [73–75]. Given the importance of the scaffold mechanical properties to control behavior and differentiation of cells, this feature will be of high interest for tissue engineering. Finally, DNA-NPs can be designed to react and actuate in response to certain factors in its environment such as temperature, pH, ions, and enzymes enabling higher responsiveness of the bioink [76]. However, to this date, only few DNA-based bioinks and hydrogels have been developed [57,77]. For example, Li et al. have recently used ssDNA and dsDNA as scaffold materials with polypeptide to produce a two-components bio-ink for 3D printing of tissue-like structures [77]. Using DNA technology, they designed two bioinks which rapidly formed a hydrogel when mixed at physiological conditions. The structures were tested for 3D encapsulation of cells, showing great biocompatibility, permeability, and biodegradability by nucleases. Hence, the presence of DNA in these structures has shown to incorporate its fabulous attributes, making them extremely promising for tissue engineering applications. The limited use of DNA-NPs for bioprinting or tissue engineering scaffold assembly can be in part explained by the current roadblocks faced by DNA nanotechnology field. Even if nucleic acids-based NPs have demonstrated their immense potential for various biomedical applications [5] and appear to be well-suited as bioink complement, there are some major limitations that need to be addressed first. Notably, due to the size limitation of the currently available scaffolds, creating large-scale structure or lattices requires the assembly of multiple small DNA motifs or DNA-NPs, which can potentially lead to the formation of defects in the final assembly and reduce downstream bioconjugation precision. It is also important to consider the limitations in the structural stability and rigidity of DNA-based scaffold. The persistence length of dsDNA is about 50 nm (150 base pairs) and creating large structure would reduce the rigidity of the assembled

Nano-bioink solutions for cardiac tissue bioprinting

NPs. Moreover, DNA is prone to rapid degradation in the presence of nucleases; therefore, modification of DNA-NPs with PEG group or by introducing phosphorothioate group in the backbone might be necessary to increase the stability of the DNA-NPs and ensure that their engineered properties will be maintained during the lifetime of the bioink. There is also an acute need to develop strategies to ensure large-scale production of NPs toward industrial-scale production, if they would be clinically relevant. The mechanical properties of DNA scaffolds that can be leveraged for tissue engineering in combination with the cell-material interactions at the nanoscale level would be fundamental in determining individual cell fate and to ensure the formation of highly functional biological tissues. Therefore, nanomaterial-modified bioinks characterized by highly tunable mechanical properties and precision of assembly down to the nanoscale control over presentation of biomolecules would represent an important step toward creating highly functional bioinks. Moreover, the orthogonality of functionalization on the surface and interior of DNA-NPs will allow for combination of multiple therapeutic (cardioprotective) biological factors, such as follistatin like-1 (FSTL1), VEGF, and other peptides or drugs, which would be useful for efficient cardiac tissue printing in basic science and in clinical translational applications.

Antibacterial nano-bioinks Biomaterials used in cardiovascular tissue engineering have certain limitations such as low resistance to infections and contaminations. Bacterial infections that may originate from an implanted graft are serious clinical concerns postimplantation and often lead to graft failure and infection-related morbidity and mortality in patients [78,79]. In cardiac tissue engineering, a major concern is the formation of biofilms which usually occurs after protein adsorption and allows for microbial adhesion [80]. Common biofilms prevalent in the clinic are Staphylococcus aureus (S. aureus), Staphylococcus epidermidis, and Pseudomonas [81]. Modified bioinks can serve as suitable carriers to incorporate NPs with antibacterial properties. There are several low-toxic antimicrobial agents which can be used in cardiac tissue engineering such as CNTs, graphene oxide (GO), silver (Ag), and super paramagnetic iron oxide NPs (SPIONs). These particles are easily miscible with polymer-based bioinks such as gelMA, sodium alginate, and collagen, which are commonly used in cardiac tissue bioprinting applications [10,16,82,83]. For an ideal antibacterial bioink, nanoscale particles are of high interest in cardiac tissue engineering. They can interact with and manipulate the extracellular environment and play a key role in cell-cell and cell-matrix signaling. CNTs, for instance, have been shown to promote growth and aid in electrophysiological properties of cardiac cells such as cardiomyocytes [19]. The size and shape of NPs can play a critical role in their antibacterial potential. In a previous study, it was shown that single-walled CNTs (SWCNTs) are more toxic to Escherichia coli than multiwalled CNTs (MWCNTs) [84,85].

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Silver NPs (AgNPs) are one of the more studied NPs in the medical field for their strong antimicrobial activity and antiinflammatory properties [86,87]. They have been extensively applied in multiple environmental, clinical, and biomedical applications. Specifically, for biomedical applications, AgNPs have been used for therapeutic purposes such as various cancer treatments. But their use in cardiac tissue engineering as an antibacterial agent has not been extensively explored so far, mostly due to their high toxicity in biological systems [88]. By altering the size or surface modification of AgNPs, researchers have been able to mitigate the nonspecific biological toxicity of AgNPs, while eliciting the desired response in tissue regeneration, opening the possibility for their wider application in the field. Hosoyama et al. developed a peptide-modified AgNP collagen patch with a concentration of 0.025 μM (Ag) which demonstrated to be nontoxic toward cardiac fibroblasts, while promoting an increase of connexin-43 levels in cardiomyocytes in comparison to empty collagen gels [89]. Iron oxide NPs, specifically SPIONs, have been previously shown to have an inhibitory effect on S. aureus in a concentration-dependent manner [90]. Taylor et al. found that bacteria density decreased as SPION concentration increased from 100 μg/mL and greater [81]. Their results indicated the inhibition of bacteria colony formation observed for 12 h and continuing for up to 48 h in agreement with other researchers [91,92]. SPIONs can easily be incorporated into a bioink used for cardiac tissue bioprinting. They also have a dual role with their potential to be used as MRI contrast agents in vivo [93,94]. Mahmoudi et al. developed SPION-laden cardiac patches to repair damaged myocardium and tested their patch against the empty collagen control in vitro and in vivo in T2*-weighted images, which showed MRI visibility while displaying antibacterial properties [10]. The optimal antibacterial effects of nano-bioinks should be able to interact with the extracellular environment in a desirable manner without disrupting the electrophysiological properties of native cardiac cells postimplantation. It is unlikely that one ideal NP will be identified for the development of antibacterial bioinks used in cardiac tissue engineering, since every NP have their own significant intrinsic and extrinsic properties. To that end, further development of biomaterial approaches is needed to create diverse and tunable antimicrobial nanomaterial-modified bioinks. This includes surface modification and polymer conjugation of NPs, efficient encapsulation, and the accurate release of them.

Conclusions and future perspectives Hydrogels that are supportive of cell viability and function, modifiable for material and chemical properties, readily imaged and traceable, and printable would make excellent bioink options. Development of nanomaterial-modified bioinks is predicted to be a major advance in the field of tissue bioprinting. In addition to their set properties of

Nano-bioink solutions for cardiac tissue bioprinting

matrix mechanics, biochemical composition, and favorable rheology, nanomaterialenhanced bioinks will be able to provide a more dynamic adaptation of these properties as the bioprinted constructs interact and integrate with their targets. A biochemically defined, NP-tagged, and mechanically tuned cardiac patch, for example, could be traced in the body, while it instructs the host heart to repair itself, rather than forming scar tissue. As nanocomposite biomaterials are being developed, it would be important to target these materials to specific biomedical applications. Using bioink backbones from “generally recognized as safe” materials will provide great possibilities for clinical translation. There remain some major challenges to their translation which must be addressed. In shorter terms, bioinks for cardiovascular tissue engineering must be able to vascularize in a reproducible and predictable way, to maintain cell viability and function. Such constructs must also be amenable to high-throughput production with consistency, to offer an alternative for next-generation drug screening platforms. Long-term biosafety and efficacy of the novel materials, specifically as it relates to the nanomaterials used, is the chief concern. Vascularization of the bioprinted cardiac constructs, optimizing fabrication, and improving consistency between production batches are especially important in nano-functionalized bioinks and will be critical milestones toward clinical/industrial-scale fabrication of functional tissues and organs.

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Clinical cardiovascular medicine and lessons learned from cancer nanotechnology Morteza Mahmoudia, Vahid Serpooshanb,c,d a

Precision Health Program, Michigan State University, East Lansing, MI, United States Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States c Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States d Children’s Healthcare of Atlanta, Atlanta, GA, United States b

Tissue/bioengineering approaches in clinical cardiovascular medicine Cardiovascular tissue engineering (CVTE) enables biologically based restoration, maintenance, or improvement of the function and/or structure of damaged cardiac tissue, coronary blood vessels, and valves [1–3]. CVTE uses a combination of biodegradable three-dimensional (3D) biomaterials (i.e., scaffolds) that resemble the extracellular matrix (ECM) of the target tissue [4–7], cells with regenerative capacity [8–10], and biologically active macromolecules (e.g., growth, differentiation, or angiogenic factors) [11, 12]. Recently a variety of scaffold-based [13–16], cell-based [9, 17], and macromolecule-based [18, 19] tissue engineering modalities (or a combination thereof [20]) have been developed and actively investigated as the new-generation cardiovascular regenerative therapies. While in vitro tissue engineering has traditionally been aimed at creating tissue substitutes in a dish, followed by transplantation, complications in maintaining viable and functional cells, lack of biomimicry, and poor survival postgrafting have slowed progress toward clinical applications [21, 22]. Thus, to bypass ex vivo processes and improve grafting efficiency, in situ tissue engineering has been recently developed by harnessing the endogenous regenerative capacity of the human body [23, 24]. This approach uses a target tissue-specific scaffold system to effectively regulate cardiac repair processes through recruitment of native stem/progenitor cells in the tissue microenvironment. While conventional tissue engineering methods (i.e., using scaffold cells to grow substitute tissue) have been increasingly investigated, a number of alternative bioengineering approaches have been developed to address some of the unresolved challenges in the field of cardiovascular regenerative medicine. For instance, cardiovascular 3D bioprinting (additive manufacturing) has recently attracted growing attention as a unique platform

Nanomedicine for Ischemic Cardiomyopathy https://doi.org/10.1016/B978-0-12-817434-0.00013-1

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that enables manufacturing complex 3D tissue constructs through layer-by-layer deposition of various biological materials including biomaterials, cells, and support molecules (i.e., bioink) [25–29]. Vascular-cardiovascular tissues can be constructed through spatially controlled deposition of heterogeneous bioinks. Cardiovascular bioinks may include cardiac stem/progenitor cells [28, 30, 31], cardiac fibroblast [28], endothelial [28, 32] and smooth muscle cells [28, 33, 34], adult cardiomyocytes [28, 29], and cardiac valve cells [34, 35]. A suspension of cardiac/vascular cells in a variety of printable hydrogels (e.g., gelatin and gelatin methacrylate [34, 36], alginate [34], hyaluronic acid [35], and decellularized ECM [30]), with or without support molecules, is loaded into the printing heads, allowing for manufacturing of 3D functional living tissues with customized architecture. Parallel to conventional tissue engineering and 3D bioprinting efforts, a number of diverse, multiscale bioengineering approaches have been recently developed, aimed at the creation of biomimetic cardiac tissue constructs for both disease modeling in vitro and regenerative therapies in vivo [37–39]. For instance, decellularized heart/heart tissue has been repopulated with various cardiac cells (e.g., cardiomyocytes and endothelial cells) and tested both in vitro and in vivo, as perfusable organ/tissue substitutes [40–42]. In another new scalable technique, Faraday waves were utilized for rapid patterning of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) into programmed 3D cardiac tissues, resembling the cellular density and architecture of native heart tissue [43, 44]. A variety of microfabrication techniques have also been used to create micropatterned hydrogel systems that resemble the native cardiac tissue and promote cardiac cells’ attachment, alignment, communication, and function [45, 46]. A number of clinical trials have now begun to further evaluate the translational potential of tissue/bioengineering approaches in clinical interventions (e.g., the SCIPIO [47], MAGIC [48], STAR-heart [49, 50], and SYNERGRAFT [51] trials) [52]. SCIPIO was the first randomized, open-label human trial that examined transplantation of autologous c-kit+ cardiac stem cells in ischemic HF patients. Cardiac MRI demonstrated the significant regenerative effect of stem cell infusions, with enhanced global and regional LV function, diminishing apoptosis and infarct size for up to 1-year posttreatment [47]. In another unblinded trial, additional intracoronary injections of autologous bone marrow-derived stem cells resulted in a prolonged (> 60 months) improvement in LV performance, quality of life, and survival in 191 chronic HF patients (LVEF