Sustainable Agriculture Reviews 36: Chitin and Chitosan: Applications in Food, Agriculture, Pharmacy, Medicine and Wastewater Treatment [1st ed.] 978-3-030-16580-2;978-3-030-16581-9

Table of contents :
Front Matter ....Pages i-ix
Nutritional and Additive Uses of Chitin and Chitosan in the Food Industry (Carla Harkin, Norbert Mehlmer, Dirk V. Woortman, Thomas B. Brück, Wolfram M. Brück)....Pages 1-43
Chitosan for Seafood Processing and Preservation (Piotr Kulawik, Ewelina Jamróz, Fatih Özogul)....Pages 45-79
Applications of Chitosan as Food Packaging Materials (Patricia Cazón, Manuel Vázquez)....Pages 81-123
Applications of Chitin in Agriculture (Julia L. Shamshina, Tetyana Oldham (Konak), Robin D. Rogers)....Pages 125-146
Chitosan-Based Hydrogels (Janaina Oliveira Gonçalves, Vanessa Mendonça Esquerdo, Tito Roberto Sant’Anna Cadaval Jr, Luiz Antonio de Almeida Pinto)....Pages 147-173
Chitin and Chitosan in Drug Delivery (Rabinarayan Parhi)....Pages 175-239
Application of Chitosan-Based Formulations in Controlled Drug Delivery (Jacques Desbrieres, Catalina Peptu, Lacramiora Ochiuz, Corina Savin, Marcel Popa, Silvia Vasiliu)....Pages 241-314
Design of Nano-Chitosans for Tissue Engineering and Molecular Release (Sheriff Adewuyi, Iriczalli Cruz-Maya, Onome Ejeromedoghene, Vincenzo Guarino)....Pages 315-334
Chitosan for Direct Bioflocculation Processes (Eric Lichtfouse, Nadia Morin-Crini, Marc Fourmentin, Hassiba Zemmouri, Inara Oliveira Carmo do Nascimento, Luciano Matos Queiroz et al.)....Pages 335-380
Cross-Linked Chitosan-Based Hydrogels for Dye Removal (Grégorio Crini, Giangiacomo Torri, Eric Lichtfouse, George Z. Kyzas, Lee D. Wilson, Nadia Morin-Crini)....Pages 381-425
Back Matter ....Pages 427-428

Citation preview

Sustainable Agriculture Reviews 36

Grégorio Crini Eric Lichtfouse Editors

Sustainable Agriculture Reviews 36

Chitin and Chitosan: Applications in Food, Agriculture, Pharmacy, Medicine and Wastewater Treatment

Sustainable Agriculture Reviews Volume 36

Series Editor Eric Lichtfouse Aix-Marseille Universite´, CNRS, IRD, INRA Coll France, CEREGE Aix-en-Provence, France

Other Publications by Dr. Eric Lichtfouse

Books Scientific Writing for Impact Factor Journals https://www.novapublishers.com/catalog/product_info.php?products_id¼42242 Environmental Chemistry http://www.springer.com/978-3-540-22860-8 Sustainable Agriculture Volume 1: http://www.springer.com/978-90-481-2665-1 Volume 2: http://www.springer.com/978-94-007-0393-3 Book series Environmental Chemistry for a Sustainable World http://www.springer.com/series/11480 Sustainable Agriculture Reviews http://www.springer.com/series/8380 Journal Environmental Chemistry Letters http://www.springer.com/10311 Sustainable agriculture is a rapidly growing field aiming at producing food and energy in a sustainable way for humans and their children. Sustainable agriculture is a discipline that addresses current issues such as climate change, increasing food and fuel prices, poor-nation starvation, rich-nation obesity, water pollution, soil erosion, fertility loss, pest control, and biodiversity depletion. Novel, environmentally-friendly solutions are proposed based on integrated knowledge from sciences as diverse as agronomy, soil science, molecular biology, chemistry, toxicology, ecology, economy, and social sciences. Indeed, sustainable agriculture decipher mechanisms of processes that occur from the molecular level to the farming system to the global level at time scales ranging from seconds to centuries. For that, scientists use the system approach that involves studying components and interactions of a whole system to address scientific, economic and social issues. In that respect, sustainable agriculture is not a classical, narrow science. Instead of solving problems using the classical painkiller approach that treats only negative impacts, sustainable agriculture treats problem sources. Because most actual society issues are now intertwined, global, and fast-developing, sustainable agriculture will bring solutions to build a safer world. This book series gathers review articles that analyze current agricultural issues and knowledge, then propose alternative solutions. It will therefore help all scientists, decision-makers, professors, farmers and politicians who wish to build a safe agriculture, energy and food system for future generations.

More information about this series at http://www.springer.com/series/8380

Grégorio Crini • Eric Lichtfouse Editors

Sustainable Agriculture Reviews 36 Chitin and Chitosan: Applications in Food, Agriculture, Pharmacy, Medicine and Wastewater Treatment

Editors Grégorio Crini Chrono-Environnement, UMR 6249 Université Bourgogne Franche-Comté Besançon, France

Eric Lichtfouse Aix-Marseille Université CNRS, IRD, INRA Coll France, CEREGE Aix-en-Provence, France

ISSN 2210-4410 ISSN 2210-4429 (electronic) Sustainable Agriculture Reviews ISBN 978-3-030-16580-2 ISBN 978-3-030-16581-9 (eBook) https://doi.org/10.1007/978-3-030-16581-9 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

La chitine des arthropodes, traitée par la potasse à 180 C, puis lavée à l’eau, devient soluble dans l’acide acétique étendu, et la solution donne avec la potasse un volumineux précipité. Ce corps, nommé chitosane, présente des propriétés basiques et fournit des sels cristallisables, solubles dans l’eau.* 1894, The Discovery of Chitosan Professor Felix Hoppe-Seyler Professor of Physiological Chemistry and Hygiene, Strasbourg *Arthropod chitin treated with potassium hydroxide, then water-washed, becomes soluble in diluted acetic acid. This solution yields a bulky precipitate, named chitosan, upon addition of potassium hydroxide. Chitosan has basic properties and provides crystallizable salts that are soluble in water.

Professor Felix Hoppe-Seyler (1825–1895). (Source: Baumann E and Kossel A. Zur erinnerung an Felix Hoppe-Seyler. Zeitschrift für Physiologische Chemie, volume 21 (1895) pp. I–LXI)

Most commercial polymers are actually derived from petroleum-based raw products using chemical processes, which are not always safe and environmental friendly. Over the past three decades, there has been a growing interest in developing natural alternatives to synthetic polymers, namely, biopolymers. Biopolymers are

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polymers derived directly from living organisms or extracted from renewable resources. Biopolymer production has been growing steadily due to their biodegradability and absence of toxicity. Biopolymers include polysaccharides such as chitin and chitosan. Chitosan is produced by deacetylation of chitin, which is the structural element in the exoskeleton of crustaceans, such as crabs and shrimp, and cell walls of fungi. Due to their remarkable macromolecular structure, physical and chemical properties, and bioactivities, chitin and chitosan have received much attention in fundamental science, applied research, and industrial biotechnology. This book is the second volume of two volumes on Chitin and Chitosan published in the series Sustainable Agriculture Reviews. Written by 57 international contributors coming from 21 different countries who are leading experts in the chitin and chitosan field, these two volumes focus on the developments, research trends, methods, and issues related to the use of chitin and chitosan for both fundamental research and applied technology. The first volume focuses on the history, fundamentals, and innovations of chitin and chitosan. This second volume presents the applications of chitin and chitosan in food, agriculture, pharmacy, medicine, and wastewater treatment. The first chapter by Carla Harkin et al. discusses the nutritional and additive uses of chitin and chitosan in the food industry. The second chapter by Piotr Kulawik et al. describes the functional properties of chitosan in the context of recent discoveries in seafood processing and preservation. The applications of chitosan as food packaging materials are detailed by Patricia Cazón and Manuel Vázquez in Chap. 3. Then, Julia Shamshina et al. present the use of chitin in agriculture in the fourth chapter. The synthesis and applications of chitosan-based hydrogels are presented by Janaína Oliveira Gonçalves et al. in Chap. 5. Applications of chitin and chitosan in pharmacy and medicine are detailed in three chapters: for drug delivery in Chap. 6 by Rabinarayan Parhi and in Chap. 7 by Jacques Desbrieres et al. and for tissue engineering and molecular delivery in Chap. 8 by Sheriff Adewuyi et al. The last chapters summarize recent applications of chitosan in wastewater treatment. The use of chitosan for direct bioflocculation processes is given by Eric Lichtfouse et al. in Chap. 9; then, Grégorio Crini et al. describe the use of cross-linked chitosan hydrogels for dye removal in Chap. 10. The editors extend their thanks to all the authors who contributed to this book for their efforts in producing timely and high-quality chapters. The creation of this book would not have been possible without the assistance of several colleagues and friends deserving acknowledgment. They have helped by choosing contributors and reviewing chapters and in many other ways. Finally, the editors would like to thank the staff of Springer Nature for their highly professional editing of the publication. Besançon, France Aix-en-Provence, France

Grégorio Crini Eric Lichtfouse

Contents

1

Nutritional and Additive Uses of Chitin and Chitosan in the Food Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carla Harkin, Norbert Mehlmer, Dirk V. Woortman, Thomas B. Brück, and Wolfram M. Brück

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Chitosan for Seafood Processing and Preservation . . . . . . . . . . . . . Piotr Kulawik, Ewelina Jamróz, and Fatih Özogul

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3

Applications of Chitosan as Food Packaging Materials . . . . . . . . . . Patricia Cazón and Manuel Vázquez

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Applications of Chitin in Agriculture . . . . . . . . . . . . . . . . . . . . . . . 125 Julia L. Shamshina, Tetyana Oldham (Konak), and Robin D. Rogers

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Chitosan-Based Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Janaina Oliveira Gonçalves, Vanessa Mendonça Esquerdo, Tito Roberto Sant’Anna Cadaval Jr, and Luiz Antonio de Almeida Pinto

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Chitin and Chitosan in Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . 175 Rabinarayan Parhi

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Application of Chitosan-Based Formulations in Controlled Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Jacques Desbrieres, Catalina Peptu, Lacramiora Ochiuz, Corina Savin, Marcel Popa, and Silvia Vasiliu

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Design of Nano-Chitosans for Tissue Engineering and Molecular Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Sheriff Adewuyi, Iriczalli Cruz-Maya, Onome Ejeromedoghene, and Vincenzo Guarino

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Chitosan for Direct Bioflocculation Processes . . . . . . . . . . . . . . . . . 335 Eric Lichtfouse, Nadia Morin-Crini, Marc Fourmentin, Hassiba Zemmouri, Inara Oliveira Carmo do Nascimento, Luciano Matos Queiroz, Mohd Yuhyi Mohd Tadza, Lorenzo A. Picos-Corrales, Haiyan Pei, Lee D. Wilson, and Grégorio Crini

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Cross-Linked Chitosan-Based Hydrogels for Dye Removal . . . . . . . 381 Grégorio Crini, Giangiacomo Torri, Eric Lichtfouse, George Z. Kyzas, Lee D. Wilson, and Nadia Morin-Crini

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

About the Editors

Dr. Grégorio Crini 52, is researcher at University Bourgogne Franche-Comté, Besançon. His current interests focus on the design of novel polymer networks and the environmental aspects of polysaccharide chemistry. He published over 190 papers in international journals and books and is a highly cited researcher. The total citation of his publications is over 9000, h-index of 33. https://www.researchgate.net/profile/ Crini_Gregorio

Dr. Eric Lichtfouse 59, is a biogeochemist at Aix Marseille University who has invented carbon-13 dating, a molecular-level method allowing to study the dynamics of organic compounds in temporal pools of complex environmental media. He is chief editor of the journal Environmental Chemistry Letters and the book series Sustainable Agriculture Reviews and Environmental Chemistry for a Sustainable World. He is the author of the book Scientific Writing for Impact Factor Journals, which includes an innovative writing tool: the micro-article. https://cv.archives-ouvertes.fr/ eric-lichtfouse

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Chapter 1

Nutritional and Additive Uses of Chitin and Chitosan in the Food Industry Carla Harkin, Norbert Mehlmer, Dirk V. Woortman, Thomas B. Brück, and Wolfram M. Brück

Abstract Chitin is the first polysaccharide identified by man. Chitin and its numerous oligomeric and monomeric, acetylated or deacetylated derivates have many physiological functions and applications. Chitin is found in the cuticles of arthropods and is a major constituent of cell walls from fungal, yeast and algae, from where chitin can be extracted chemically, enzymatically or by fermentation. The principal sources of chitin and chitosan are actually crustacean shells. Worldwide, more than 13.000.000 tons of crustaceans are caught from marine habitats each year, thus generating huge amounts of food waste. The unique biodegradability, biorenewability, biocompatibility, physiological inertness and hydrophilicity of chitin and chitosan make them of high interest for research and industry. In this chapter, we review the use of chitin, chitosan and their oligomers and monomers as food additives. In particular, their use in the regulation of lipid digestion and hypocholesterolemia, their functioning as an antigastritic agent and prebiotic is highlighted. Literature shows that oligomerization and the degree of deacetylation influences the development of chitin/chitosan-based nutraceuticals. The absence of chitinases and chitosanases in the human gut renders those biopolymers resistant to even partial degradation. For food applications, they are used as emulsifying, fining, thickening and stabilizing agents, antioxidants, and low calories food mimetics. Keywords Chitin · Chitosan · Food additive · Prebiotic · Dietary fibers · Lipid binding · Antioxidant · Fining agents · Stabilizers · Gastritis C. Harkin School of Biomedical Sciences, Ulster University, Coleraine, UK N. Mehlmer · D. V. Woortman · T. B. Brück Department of Chemistry, Werner Siemens-Chair for Synthetic Biotechnology, Garching bei München, Germany e-mail: [email protected]; [email protected]; [email protected] W. M. Brück (*) Institute of Life Technologies, University of Applied Sciences Western Switzerland, Sion, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_1

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1.1

C. Harkin et al.

Introduction

Chitin was the first carbohydrate polymer identified by mankind and was apparently isolated from mushrooms in 1811 by Henry Braconnot (1780–1855). Thus its isolation preceded cellulose by about 30 years (Labrude and Becq 2003). Chitin may be found in the cuticles of arthropods and is a main constituent fungal, yeast and algae cell walls (Sato et al. 1998; Einbu and Vårum 2008; Kikkawa et al. 2008). As such, it is considered the second most abundant biopolymer after cellulose, with 1010–1011 tons available (Gooday et al. 1991; Gopalan Nair and Dufresne 2003). As cellulose in plants, chitin contributes to the structural integrity in crustaceans. As such, it is closely associated with proteins, calcium carbonate, lipids and pigments (Percot et al. 2003). Chitin occurs in three distinct crystalline polymorphic forms: alpha-, beta- and gamma-chitin. The difference of these forms are based on the arrangement of the molecular chains. Alpha-chitin, by far the most abundant form has an antiparallel chain arrangement. Beta-chitin has chains that are arranged in parallel. Gamma-chitin is a mixture of the alpha and beta form (Noishiki et al. 2003; Zhang et al. 2005; Dahiya et al. 2006). Alpha-Chitin is predominately found in shellfish exoskeletons and fungal cell walls while beta-Chitin is mainly found in squid pens and diatoms. Beta-chitin is also irreversibly transformed into alpha-chitin by steam (Kurita 2001). Gamma-chitin is found in squid and cuttlefish stomach linings (Hayes et al. 2008). The chitin polysaccharide itself is a linear macromolecule composed of two subunits: D-glucosamine and N-acetyl-D-glucosamine at a ratio of 90:10 (N-acetyl-D-glucosamine: D-glucosamine). However, this ratio varies depending on the chitin source (Dong et al. 2002; Einbu et al. 2004; Campana-Filho et al. 2007). Due to the high degree of acetylation, chitin is hydrophobic making it insoluble in water and most organic solvents (Kurita 1998; Rinaudo 2006). Deacetylating the polysaccharide to a level below 50% increases its water solubility and influences its flexibility, polymer conformation, chemical reactivity, bioactivity and viscosity (Peter et al. 2009; Bajaj et al. 2011; Dash et al. 2011). The length of the polymer units additionally influences the viscosity. The term “chitosan” was given to chitin deacetylated to below a level of 50% by Hoppe-Seiler in 1894 (McKay 1995). Due to its properties, chitosan has been described as “nature’s most versatile biomaterial (Sandford 1989). The principal source of chitin and chitosan at this time are crustacean shells. Worldwide more than 13.000.000 tons of crustaceans are caught from marine habitats each year. Up to 50% of this catch is shell waste (Global Production Statistics 1950–2014) that consists of 30–40% protein, 30–50% calcium carbonate and 20–30% chitin (Cho et al. 1998). The isolation of chitin from shellfish waste consists of three steps: deproteination (DP), demineralization (DM) and decolorization (DC). The principal method to extract chitin from crustacean waste is by chemical deproteination using a strong alkali such as sodium hydroxide, and demineralization with the use of a strong acid such as hydrochloric acid (Lynch et al. 2016). Within the frame of an European Union funded project, the “ChiBio” a biorefinery concept combines a sustainable chitin demineralization process by microorganisms and an enzymatic degradation of the biopolymer into chitosan,

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chitin/chitosan oligomers and its basic building blocks, n-acetylglucosamine and glucosamine (Sieber et al. 2018) (Fig. 1.1). While chitin, chitosan and its monomers and chito-oligosaccharides (COS) remained an unused natural resource for a long time, its unique biodegradability, biorenewability, biocompatibility, physiological inertness and hydrophilicity has a attracted vast interest for a number of applications in medicine, agriculture and food (Ravi Kumar 2000; Kurita 2006). As such, the chitosan market had a value of 63 billion USD in 2015 and is expected to increase to 4.2 billion USD in 2020 (Analysts 2014).

1.2 1.2.1

Nutritional Uses Dietary Fibers

Dietary fibers are non-digestible carbohydrate polymers that have a beneficial physiological effect in humans (Elleuch et al. 2011). More specifically, these compounds should evade hydrolysis, digestion and absorption in the human small intestine having while a physiological effect by either increasing faecal bulk, stimulating colonic fermentation, reducing postprandial blood glucose or reducing pre-prandial cholesterol levels (Fuentes-Zaragoza et al. 2010). Dietary fibers possess mechanisms of preventing lipid digestion. They bind to other substances that have a critical role such as digestive enzymes, thereby inactivating them. They can form a protective capsule around lipid droplets preventing digestive enzyme access, increase viscosity or promote lipid aggregation, therefore, limiting lipid surface exposure to digestive enzymes (Espinal-Ruiz et al. 2014). Dietary fibers may be of plant or animal origin or synthetically made or modified (Borderías et al. 2005). Aminopolysaccharides of animal origin that are part of the traditional diets of indigenous peoples inhabiting the northern circumpolar regions such as chitin and chitosan, for example, are also considered dietary fibers. Chitin and chitosan may also be found naturally as part of the fibrous content of tempeh. Chitin and chitosan, depending on the degree of deacetylation, are suitable for the use in foods as stabilizers and thickeners in mayonnaise and peanut butter (Furda 1983). Furthermore, chitosan has been associated with strong hypocholesterolemic activity in and a reduction in lipid adsorption (Miyazawa et al. 2018; Jin et al. 2017). The amount of total dietary fiber in chitin and chitosan was observed to be 90.6% (Maezaki et al. 1993).

1.2.2

Chitosan and Chito-Oligosaccharides as Prebiotics

Chitosan and chito-oligosaccharides (COS) are known for their antibacterial and antifungal properties and evidence suggests that partial depolymerization may enhance this effect (Choi et al. 2001; Jeon and Kim 2001; Roller and Covill 1999). However, not many studies have examined their effects on medically

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Fig. 1.1 Preparation of chitin rich wastes for the production of chitin, chitosan, COS, glucosamine and N-acteylglucosamine for food applications. Chitin-rich wastes may be deprotonated and deacetylated using acids and bases, commercial enzymes or by fermentation. Downstream steps then either yield chitosan, chitin/chitosan oligomers or monomers

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important bacteria. In particular, there is indication that low-molecular weight chitosan may have a growth stimulating effect on probiotics such as lactobacilli and Bifidobacterium (Lee et al. 2002). COS have been used as a natural preservative and probiotic for the production of symbiotic tofu to provide economic and social value-added benefits (Harti et al. 2015). In tofu, the addition of COS significantly augmented the growth of probiotic Lactobacillus strains while increasing its shelflife to 7 days without organoleptic changes or increased in enteroathogens of fecal indicator organisms (Harti et al. 2015). In a study by Lee et al. (2002), enzymatically prepared chitosan polymer did show a significant antibiotic effect against lactic acid bacteria, bifidobacteria and others at concentrations between 0.16 and 0.31%. Basal medium with 0.1% COS, however, showed a growth stimulatory effect on Bifidobacterium bifidum KCTC 3440 and most of the lactic acid bacteria tested in the study. This effect was larger than that observed with fructooligosaccharides, which have a well-known prebiotic effect (Lee et al. 2002). Similar was observed in a more recent study examining the effects of low molecular weight COS on the human fecal microbiota and short-chain fatty acid production (Mateos-Aparicio et al. 2016). However, it was concluded that while COS did not negatively affect the fecal microbiota, acetylated chitosans and their COS are not potential prebiotics.

1.2.3

Lipid Binding

Obesity is a risk factor for the development of many serious conditions such as diabetes, hypertension, metabolic syndrome and cardiovascular diseases (World Health Organisation 2013). Cardiovascular diseases account for 17.5 million deaths in 2012 which is projected to rise to 22.2 million in 2030 (World Health Organisation 2016). Dietary changes and increased energetic activity can help to alleviate the build-up of lipids; however, supplementation with fat-binding agents may increase the effects and increase the rapidity of lipid loss. There are many natural substances, which have been employed in this application such as: red yeast rice, curcumins, anthocyanins, green teas extracts and garlic among others (Sahebkar et al. 2016). Chitosan, as it is cationic, forms electrostatic interactions with fatty acids and triglycerides and could either remove free fatty acids from a larger lipid and allow access of lipase and promote digestion, or prevent access if it forms a protective layer (Espinal-Ruiz et al. 2014). In theory, the cationic nature of chitosan and its solubility in acidic pH, it may be expected that it can bind to anionic lipid molecules in the gastric environment and prevent absorption as the chitosan precipitates out in the intestinal environment (Panith et al. 2016). Chitosan has demonstrated lipidbinding and cholesterol-binding properties in various studies (Panith et al. 2016; Jin et al. 2017). In fact, chitosan is a component of a lipid-lowering nutraceutical

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(Spigoni et al. 2017). This demonstrated a significant reduction in non-HDL cholesterol and LDL cholesterol in patients receiving treatment over 4 and 12 weeks compared to those receiving a placebo. However, there are other active ingredients in the formulation with lipid-binding properties also, so the effectiveness of chitosan alone in this instance could not be determined independently. The impact of chitosan (MW 1930–310 kDa, 75–85% DD, viscosity 1%) on emulsified corn oil in a simulated gastrointestinal tract was investigated compared to an anionic pectin and charge-neutral methyl cellulose (Espinal-Ruiz et al. 2014). Mixtures of corn oil emulsion and standard solutions of the dietary fibers were applied to oral, gastric and intestinal fluid simulations. The physiochemical properties of the emulsions were investigated. Overall, the addition of chitosan demonstrated only a slight decrease in lipid digestion compared to methyl cellulose and pectin. Flocculation of lipid droplets was promoted by chitosan under acidic conditions by bridging effect. The molecular weight (MW) of the chitosan used can have an effect on its lipidbinding properties and there are conflicting reports on whether a large MW or a smaller MW is more effective. Further physiochemical characteristics such as tapped density, melting temperature and viscosity with relation to lipid-binding efficacy were investigated in simulated gastric conditions (Panith et al. 2016). A higher molecular weight chitosan (2100 kDa) was found to be more effective than lower molecular weight samples. In addition, a higher tap density chitosan showed the superior fat-binding capacity at 27.50
2.29 g oil/g chitosan compared to a lower density chitosan of the same molecular weight with 11.87
1.61 g oil/g chitosan at the same chitosan: oil ratio. A higher density may mean larger surface area for reactions with lipid molecules. Chitosan showed greater binding in a higher chitosan: oil ratio and for the most effective chitosan, the majority of binding had occurred within the first 30 min when reaction times were compared. In contrast, when water-soluble chitosan of varying molecular weights were added to simulated gastric fluids, a 3000 kDa chitosan was more effective than a 7000 kDa, 9000 kDa and 1000 kDa chitosan at absorbing peanut oil (7.08 g oil/g chitosan which is comparable to the 2100 kDa (low density) above) (Jin et al. 2017). A suggested reason for this is that larger MW chitosans have decreased motility due to their size and cannot move as quickly towards the lipid molecules. The intention of using water-soluble chitosan was to reduce the adverse side effects such as constipation and nausea in patients undergoing treatment. Similarly, chitosan microspheres and capsaicin-chitosan cross-linked microspheres were shown to inhibit triglycerides significantly after 48 h in cultured hepatocytes compared with chitosan alone (Wu et al. 2017). In addition, the effect of a 1000 Da COS was found to have a greater effect on intracellular lipid accumulation after only 24 h compared to a 3000 Da COS in an hepatocellular carcinoma cell line HepG2 (Cao et al. 2016). In vivo studies on mice and rats show the anti-obesity and lipid-binding effects of chitosan in different forms and in combination with other treatments. The use of ultrasound has been proposed as a treatment method for obesity. This, in combination with a chitosan treatment (MW 300 kDa, DD 97%) was investigated in mice over a 5 week period (Liao et al. 2013). Triglyceride levels in plasma were decreased

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further in the combined treatment than with chitosan alone, 47.9% and 39.6% decreases, respectively. Ultrasound alone did not significantly reduce plasma triglycerides. There was also a significant decrease in weight in groups that received chitosan treatment in combination with ultrasound compared with ultrasound and chitosan used alone, 11.12%, 5.8%, 9.3%, respectively. Chitooligosaccharides of varying molecular weights (1000 Da and 3000 Da) were supplemented to the diets of obese rats. After 5 weeks, the lower molecular weight chitooligosaccharides was more effective at preventing weight gain than the higher, however, the larger MW chitooligosaccharides was more effective at reduction of body fat and body fat ratio (Huang et al. 2015). Both chitooligosaccharides were effective at reducing fatty deposits in the liver and were significantly more effective than Orlistat, an obesity-treatment drug. The lower molecular weight hitooligosaccharides was more effective at altering plasma lipids favorably, in the same way that a 1000 Da chitosan was found to be more effective than a 3000 Da chitosan in hepatocytes (Cao et al. 2016). Chitosan microspheres (Wu et al. 2017) and media-milled chitosan (Zhang and Xia 2015) were applied in lipid-binding studies in comparison with chitosan alone. It was found that the microspheres and media-milled chitosans had increased lipidreduction properties than the larger chitosan molecules. Chitosan microspheres were found to be well distributed in the bodies of rats, particularly in the liver and kidney and were not found in the body after 24 h, suggesting easy clearance. An 8 week study which compared media-milled chitosan (380 kDa, 740 nm particles) and chitosan alone (450 kDa, 336 μm particles) demonstrated the superior performance of the media-milled chitosan at reducing body weight and blood and liver lipids (Zhang and Xia 2015). Body weight gain was 407.0
19.6 g in the milled chitosan compared to 434.3
18.7 g and 468.1
19.1 g for chitosan and high fat control, respectively. The reducing effects of chitosan on serum triglycerides, total cholesterol and low density lipoprotein cholesterol were improved by milling, resulting in reduction of 10.1%, 7.5% and 10.2%, respectively. This was also shown in liver and triglycerides and total cholesterol with reduction of 16.2 and 14.6%, respectively (Zhang and Xia 2015). The lipid content of feces was also determined. Again, the media-milled chitosan performed better, with an increased lipid concentration in the feces while still having a relatively large MW compared to other studies (Huang et al. 2015; Cao et al. 2016; Li et al. 2016a, b). This shows the ability to bind and remove lipids before absorption (Zhang and Xia 2015). It is suggested that the smaller particle size increased dissolution, and resulted in a larger number of molecular chains of smaller size that increased absorption through tissues and increased lipid binding. In contrast, a study carried out on broiler chickens, found that feed supplementation with a higher MW chitosan performed better at decreasing fatty deposits in the liver, muscle and serum (Li et al. 2016a, b). However, the MW range used in this study was 2, 5 and 50 kDa, which is small compared to other studies (Liao et al. 2013; Zhang and Xia 2015). Therefore, this supports the theory that smaller MW chitosans are effective, but suggest there may be a threshold limit to the efficacy. This may be due to the molecular chains being eventually too small to effectively bind to lipids.

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Animal and cell studies are contradictory in determining if a low or high molecular weight chitosan is more effective. In other applications such as antioxidant activity, a microsphere or nanoparticle was found to be increasingly effective in comparison to a larger chitosan molecule, but the mechanisms involved and the target molecules are very different in this case. Contradictory suggested mechanisms make a case for larger and smaller MW chitosan molecules, suggesting that a larger molecule would bind more easily and completely to a lipid molecule (Panith et al. 2016) and also that smaller molecules move more easily and can permeate tissues thereby validating its usefulness (Jin et al. 2017). Chitosan in combination with organic acids (ascorbic acid, tartaric acid) has been applied in studies involving human participants (Pohkis et al. 2015; Cornelli et al. 2017). A 24 week study with 115 participants showed significant reductions in both body weight and body mass index (BMI) using a 125–145 kDa chitosan in combination with organic acids. A 12 month study by the same research group with 97 participants (Cornelli et al. 2017) was more heavily involved with implementing strict dietary measures and increased exercise. In this way, it demonstrated the effect of chitosan in combination with a healthy lifestyle, not with a high-fat diet, as most animal studies show. The body weight decrease in the chitosan group was 12.1 kg (212.7%) compared with 8.0 kg (28.4%) in the placebo group. BMI and triglyceride reduction in the chitosan group was greater compared to the placebo group. After 12 months, the difference in triglycerides from the baseline was 17.3% compared to 12.2% in the placebo. The dietary and lifestyle changes made by participants would also contribute to reduction in triglycerides alone, which accounts for the reduction in the placebo group. Serum total cholesterol, and low density lipoprotein cholesterol also improved but there was no significant improvement in high density lipoprotein cholesterol cholesterol. Treatment with a chitosan capsule (500 mg dose, 5 per day) resulted in significant body weight reduction after 45 and 90 days, 77.75
11.56 kg and 76.89
11.88 kg respectively, compared to the placebo group, 80.89
12.15 kg and 80.76
12.31 kg (Trivedi et al. 2016). Decreased BMI of 29.71
3.07 kg/m2 compared to baseline 30.93
2.69 kg/m2 was also observed. This was similar to the BMI reduction in a similar study carried out over 4 months on participants with hypertriglyceridemia and with a 125 mg/d dose (Rizzo et al. 2013). Prior to treatment BMI was 30
5 kg/m2 which was reduced to 29
4 kg/m2 after chitosan treatment. The two studies show a further similarity in that serum LDL showed no significant changes but there were increased observed in HDL (Rizzo et al. 2013; Trivedi et al. 2016). Serum triglycerides were significantly decreased in this study 228 + 72 to 176 + 54 mg/dl after treatment, in contrast to the study by Trivedi et al. (2016), in which there were no significant changes. This was unexpected as the dosage of chitosan per day was much higher in this case. A chitosan-glycan complex has been demonstrated to significantly lower oxidised low density lipoprotein cholesterol over a 6-week study (Bays et al. 2013). There was a significant reduction in serum low density lipoprotein, but no other serum lipids were affected. In an attempt to determine the mechanism of chitosan on serum LDL, the effects on serum markers were investigated (Lütjohann et al. 2018). No

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association was found after 12 weeks. There was a reduction in low density lipoprotein cholesterol but not in any other parameters compared to the placebo. Interestingly, the body weight reduction in these participants was greater if the initial weight was lower, suggesting chitosan may be more effective as a preventative measure. Chitosan is also effective at inhibiting pancreatic lipase which is active in lipid digestion (Li et al. 2016a, b; Jin et al. 2017). Fatty acid synthase, lipoprotein lipase and hormone sensitive lipase levels were tested in broiler chickens after treatment with chitosan (Li et al. 2016a, b). Reduction in fatty acid synthase and increase in lipoprotein lipase and hepatic lipase were observed in 2 kDa and 5 kDa chitosans. The higher MW chitosan did not have a marked effect, but reduced fatty acid synthase. Water-soluble chitosan was also shown to inhibit pancreatic lipase dosedependently in vitro (Jin et al. 2017). In contrast, activities of larger MW (5000, 7000 and 9000 kDa) chitosans were more effective than lower MW (1000 and 3000 kDa). The genetic expression of genes involved in adipocyte differentiation and several pathways such as lysosome bile excretion and biosynthesis of unsaturated fatty acids are also affected by chitosan (Huang et al. 2015). In conclusion, there are many studies which demonstrate lipid-binding effects in animals and human participants. There are conflicting reports on the effectiveness of molecular weight in lipid binding and the effectiveness of incorporation into microspheres or other forms. Further characterisation is needed to determine the most effective chitosan type and effectiveness for the application. And further investigation into the mechanism of action is required to support this.

1.2.4

Hypocholesterolemic Effect

Hypercholesterolemia is characterised by elevated levels of the low-density lipoprotein cholesterol in the blood. Cholesterol is part of a larger group of molecules called lipoproteins which contain; low-density lipoproteins, high-density lipoproteins, very low density lipoproteins, intermediate-density lipoproteins, and chylomicrons (Al-Fartosy et al. 2017). A build-up of cholesterol and other fatty deposits in the lumen of blood vessels lead to the formation of plaques and development of atherosclerotic disease which can lead to myocardial infarction or stroke (World Health Organisation 2011). Risk factors for these diseases include obesity, diabetes, hypertension and behavioural risks such as tobacco use, unhealthy diet, lack of physical activity and alcohol abuse (World Health Organisation 2013). Cardiovascular diseases account for 17.5 million deaths in 2012 which is projected to rise to 22.2 million in 2030 (World Health Organisation 2016). Low density lipoprotein is believed to contribute to the initiation of atherosclerosis which leads to cardiovascular disease and so is the main therapeutic target when treating cholesterol-related conditions along with the emerging target non high-density lipoproteins cholesterol (Bays et al. 2013; Spigoni et al. 2017).

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The in vitro cholesterol-binding capabilities of chitosan were investigated using the addition of chitosan to cholesterol micellar solutions (Panith et al. 2016; Jin et al. 2017). Following incubation, un-bound cholesterol micellar solution was removed by centrifugation. Molecular weight was shown to alter the binding effects of chitosan. In a study involving the use of water-soluble chitosan of MW from 1000–9000 kDa, it was found that the most effective cholesterol-binding was observed in chitosans of 3000 and 5000 kDa with absorption rates of 63.48 and 62.91 mg cholesterol/g chitosan, respectively. Chitosan of MW 7000 and 9000 kDa were not as effective. However, nor was the 1000 kDa chitosan. Similarly a 2100 kDa chitosan with a high tap density was shown to bind cholesterol at a much higher rate of 820.9
21.43 mg cholesterol/g chitosan (Panith et al. 2016). This demonstrates chemical and physical properties of chitosan have an effect on cholesterol-binding capabilities. In vivo animal studies using chitosan as a dietary supplement demonstrate conflicting results with respect to the effects on low-density lipoproteins and highdensity lipoproteins cholesterol. The anticholesterolemic properties of chitosan were demonstrated several studies by reduction in serum total cholesterol, and low-density lipoproteins (Al-Fartosy et al. 2017; Ibrahim 2016; Bahijri et al. 2017; Miyazawa et al. 2018). A 26% decrease in low-density lipoproteins cholesterol was observed in rats treated with a combination of chitosan and ultrasound over 5 weeks (Liao et al. 2013). Media-milling treatment of chitosan improved the anticholesterolemic qualities of chitosan in rats (Zhang and Xia 2015). Compared to chitosan, the reducing effects of media-milled chitosan were improved for total cholesterol and LDL by 7.5% and 10.2%, respectively. An increase in high-density lipoproteins was observed in mice fed high fat diets supplemented with varied amounts of chitosan over a period of 6 weeks (Miyazawa et al. 2018). Similarly, chitosan supplementation increased serum HDL in chickens (Li et al. 2016a, b). However high-density lipoproteins were reduced in rats also on supplemented high fat diets over 12 weeks (Bahijri et al. 2017) and 10 weeks (Chiu et al. 2017). A further study demonstrated no significant effect on low-density lipoproteins cholesterol or high-density lipoproteins cholesterol when a hypercholesterolemic mouse model was treated with chitosan nanofibres, however, total cholesterol was significantly decreased comparison to the control group and very low-density lipoproteins were significantly lowered in comparison to cellulose nanofibres (Azuma et al. 2015). Similarly, no effect on total cholesterol and high-density lipoproteins weres observed when pigs were treated with chromium-loaded chitosan nanoparticles (Wang et al. 2014a, b). The use of capsulated chitosan compared to placebos in human participants also resulted in conflicting conclusions. A randomised, double-blind, placebo-controlled study was carried out in which a group of randomly-selected participants underwent treatment with a chitosan tablet for 12 weeks and another group treated with a placebo (Lütjohann et al. 2018). In this study, the only confirmed independent effect of the chitosan group was the decrease in low-density lipoproteins cholesterol in comparison to the placebo. In contrast, a similar, randomised, single-blind study found no significant changes in low-density lipoproteins, nor triglycerides or very

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low-density lipoproteins. However, there was a slight increase observed in highdensity lipoproteins, but it was not significant (Trivedi et al. 2016). Similarly, treatment with a fungal chitosan for a period of 4 months resulted in no significant change in low-density lipoproteins, however, total cholesterol was reduced by 8% and high-density lipoproteins increased by 14% (Rizzo et al. 2013). In a 12 month study, low-molecular weight chitosan with organic acids significantly improved all variables apart from high-density lipoproteins (Cornelli et al. 2017). Chitosan has also been applied in investigations into the side effects of hypercholesterolemia. Arginase is required in the production of nitrous oxide, which has a role in oxidative homeostasis, the negative effects of which cause oxidative stress in blood cells and affect their function. Hypercholesterolemia increases the level of reactive oxygen species in cells and leads to lipidemic stress. This causes nitrous oxide levels to be decreased and the oxidative balance disturbed. (Harisa et al. 2017). Erythrocytes have been shown to be a source of nitrous oxide production, however, if their function is disturbed, they are a source of reactive oxygen species and detrimental to the oxidative balance. Methods of lowering lipids in an effort to reduce this problem can have major side effects. Dietary fibres such as chitosan are preferred. Studies into the effect of chitosan on nitrous oxide generation found that chitosan promoted nitrous oxide generation and those with a higher degree of deacetylation were more effective (Zhang et al. 2014). The above studies demonstrate the potential of chitosan in the treatment of hypercholesterolemia. Interestingly, a nutraceutical called TegraDOC contains chitosan amongst other components and was shown to lower non-HDL cholesterol in comparison with a placebo over 12 weeks in 39 subjects (Spigoni et al. 2017). TegraDOC contains berberine monacolin K, chitosan and coenzyme Q. Berberine is a compound isolated from plants, monacolin is isolated from red yeast rice and both have cholesterol properties (Wang et al. 2014a, b; Gerards et al. 2015). As such, the protective effect may be due as much to the other ingredients as to the chitosan. There is evidence, which shows the potential chitosan has as an anticholesterolemic agent and, indeed, it is already being used in such an application. However, many of the chitosan samples applied in animal and human participant studies were not characterised. Structural and chemical properties such as molecular weight and degree of deacetylation determine the binding capacities of chitosan. These parameters would have a deciding effect on the effectiveness of chitosan binding to cholesterol, allow findings to be comparable and allow for potential optimisation of the reaction. In addition, experimental durations and dietary and exercise variables also have an effect on cholesterol. A high fat diet supplemented with chitosan would not be as effective as a fat-reduced diet with the same supplement. In conclusion, the anticholesterolemic properties of chitosan are evident, but further characterisation and use of more advanced chitosans such as nanoparticles or microspheres will allow for optimisation and increased efficacy in their use in this application.

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Antigastritis Agent

The stomach lining consists of specialised epithelial cells that produce two mucosal layers for protection from gastric secretions. One layer is firmly attached to the epithelial cells and one is loose (Engstrand and Lindberg. 2013). Inflammation in these linings is referred to as gastritis. It can be caused by bacterial infection, excessive consumption of alcohol and overuse of non-steroidal anti-inflammatory drugs (NSAIDS) (Budkevich et al. 2015). Helicobacter pylori is a serious gastric pathogen associated with many illnesses such as chronic gastritis, peptic and duodenal ulcers and gastro-oesophageal reflux, among others (Choi et al. 2014; Madureira et al. 2015). It has also been listed as a carcinogen and associated with the development of gastric cancer (IRAC 2014). Up to 50% of humans may be infected with H. pylori but not all develop gastric complications (De Falco et al. 2015). Treatment includes the use of antibiotics such as amoxicillin (Altinisik and Yurdakoc 2013; Jing et al. 2018), tetracycline (Gür et al. 2017) and Metronidazole (Majekodunmi and Akpan 2017) in combination with a proton pump inhibitor (PPI). The inhibition of the hydrogen potassium ATPase pump in gastric parietal cells reduces gastric secretions, increasing the pH to prevent degradation and thereby increase the efficacy of antibiotics. These treatments fail in 20% of cases due to reoccurrence of infection, failure of patient compliance and antibiotic resistance (Fernandes et al. 2013). In addition, the retention time of the antibiotic in the stomach is lowered by the gastric environment and the use of broad spectrum antibiotics affects the natural microbiota of the stomach (Arif et al. 2018). A meta-analysis study in Korea investigating the effectiveness of the PPI treatment in combination with amoxicillin and clarithromycin (Gong et al. 2015(a)) determined that effectiveness of treatment decreased rapidly from 1998 to 2013 and a suggested causes were increased antibiotic resistance and inadequate exposure time of the antibiotic to the infected site. Recent research looks at the use of microspheres and nanoparticles for antibiotic delivery to the stomach as an alternative to the triple treatment of PPI and two antibiotics (Fernandes et al. 2013; Gonçalves et al. 2013; Arif et al. 2018). A more targeted application of only one antibiotic reduces antibiotic exposure by half and may reduce the development of antibiotic resistance. Without the use of the PPI, problems may arise in the damage of the drug by the acidic gastric environment and the short retention time of the drugs in the GI tract. Encapsulation can overcome this by providing a protective barrier around the drug and can allow for optimal release and increase the retention time at the target site (Fernandes et al. 2013). The biocompatibility, biodegradability, low toxicity and muco-adhesive properties of chitosan make it suitable for application in active foods and drug delivery and incorporation into nanoparticles, microspheres and hydrogels for many applications. The treatment of H. pylori in the prevention of gastritis and other gastric complications is one such area. Due to the solubility of chitosan in acidic conditions brought about by the free protonatable amino groups present in the D-glucosamine units (Goncalves et al.

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2013), cross-linking of chitosan with additional compounds is necessary for stability. Incorporation of additional materials to improve nanoparticle stability can aid controlled release at targeted sites (Arif et al. 2018; Jing et al. 2018). Genipin (Lin et al. 2013) and sodium triphosphate pentabasic (Gonçalves et al. 2013; Majekodunmi and Akpan 2017; Jing et al. 2018) are two of the more common cross-linking agents for chitosan microspheres and nanoparticles. Other specific linkages add to the selectivity of chitosan-based particles for H. pylori, for example, A fucose linkage (Lin et al. 2013) can bind to specific receptors on the cell surface of H. pylori and in the mucosal layer. The addition of an ureido modification exploits the ability of H. pylori to transport urea into the cytoplasm to produce ammonia and provides a pH targeted response (Jing et al. 2018). Thiolated chitosan/PLMA (poly malic acid) nanoparticles offer a pH sensitive delivery of antibiotic to the target area (Arif et al. 2018). Ionotropic gelation, which involves the interaction of an ionic polymer with an oppositely charged ion, is a method used to prepare microspheres and nanoparticles with a cross-linking agent. Generally, microspheres and nanoparticles are characterised by FTIR and physical properties such as size, zeta potential, encapsulation efficiency and release profiles of encapsulated compounds (Fernandes et al. 2013; Gonçalves et al. 2013; Lin et al. 2013; Majekodunmi and Akpan 2017; Jing et al. 2018). Encapsulation efficiency can be determined by centrifugation of the nanoparticles or microspheres after a loading step with the desired compound. The levels remaining in the supernatant can be analysed by HPLC (Lin et al. 2013) or spectrophotometry (Jing et al. 2016). The loading efficacy of a chitosan particle (Genipincross-linked fucose chitosan/heparin) of 249.6
4.2 nm in size, with a zeta potential of 27.2
1.6 mV was found to be 48.7
2.8% (Lin et al. 2013). A slightly smaller particle (UCCs-2/TPP) of size 228.6
2.3 nm and a zeta potential of 18.4
0.3 mV was found to be 26.2
3.4% (Jing et al. 2016). The particles are similar in size, however, with different cross-linkages, genipin and TPP, respectively. Zeta potential is an indication of stability, and the higher zeta potential of the genipin cross-linked particle, and therefore higher stability, may affect its loading efficiency. The importance of the cross-linking agent genipin was demonstrated in genipincross-linked fucose chitosan/heparin nanoparticles containing amoxicillin (Lin et al. 2013). Drug release was determined at varying pH levels with and without the genipin cross-linkage. At a gastric pH (1.2), release from the genipin-linked nanoparticles showed a 17.1
1.9% release after 120 min as opposed to a 43.9
3.6% release with a non-genipin linked nanoparticle. This demonstrates the action of genipin at preventing a “burst” effect when reaching the stomach and protecting the active compound within (Lin et al. 2013). Similarly, the release profiles of an ureido-conjugated chitosan nanoparticle cross-linked with TPP was examined at 37  C and at varying pH levels (Jing et al. 2016). Release at gastric pH (1.2) was low compared to pH 6.0 and 7.0. This was due to the electrostatic interaction between the ureido-conjugated chitosan and TPP which became

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weakened at a higher pH. It demonstrates the delayed release of amoxicillin at gastric pH which signifies an increased retention time at the target site. Another desirable quality for the application of H. pylori eradication is the mucoadhesive abilities of the microspheres or nanoparticles as they require attachment to the gastric mucosal layer. Muco-adhesion occurs through the primary amine groups which are also active in cross-linking; therefore, an ideal cross-linking balance must be established (Fernandes et al. 2013). Regarding stability at gastric pH, a chitosan TPP and genipin microsphere (~170 μm) was incubated in solutions of varying pH (7.4, 6.0, 4.0, 2.6, and 1.2). The size of the microspheres doubled at pH 1.2 compared with pH 6 and 7 but did not dissolve (Goncalves et al. 2013). The same microspheres were tested at pH 1.2 for a longer duration and the effect of genipin cross-linking on swelling was investigated (Fernandes et al. 2013). An increase in cross-linking duration time lessened the swelling in simulated gastric fluid. A crosslinking duration of 0.5 h resulted in a particle size of 326
77 μm after 1 min and 382
101 μm after 7 days. When compared to a 2 h cross-linking duration with a 1 min and 7 day size of 207
48 μm and 241
49 μm, respectively, it can be seen that an increase in cross-linking time results in a reduced swell of the microspheres in simulated gastric fluid (Fernandes et al. 2013). Chitosan has been shown to exhibit antimicrobial properties against H. pylori. In a study to determine the microbial inhibitory properties of chitosan (60% deacetylated) ascorbate against 17 strains of H. pylori, it was found that the lowest concentration of chitosan ascorbate (MIC in ranges 0.06–0.25 mg/mL) was active against 6 (35%) of the strains. While there was some variation in susceptibility of strains to varied concentrations of chitosan ascorbate, all were susceptible to concentrations >2.0 mg/mL strains (Kedzia et al. 2016). The incorporation of chitosan into nanoparticles containing antibiotics increases the microbial inhibitory effect of the antibiotic. Chitosan nanoparticles containing heparin and fucose, cross-linked with genipin and containing amoxicillin had a higher inhibitory effect on H. pylori than amoxicillin alone 53.5
6.3% and 23.9
0.9%, respectively (Lin et al. 2013). In an alternative treatment of microspheres for H. pylori infection, rather than utilising the particles as a drug carrier, the microspheres were proposed for use as binding agents to bind H. pylori and remove it from the GI tract (Fernandes et al. 2013; Goncalves et al. 2013). In order to facilitate this, themuco-adhesive properties were investigated. Absorption of mucins decreased as cross-linking time increased to 2 h. This is because the amine groups of the chitosan polymer utilised in crosslinking are also responsible for muco-adhesive properties. To test the retention time of chitosan microspheres in the GI tract of mice, a 2 mg/ mL suspension was administered by gavage and mice were euthanised after several time points. After 0.5 h 78% of microspheres were found in the stomach, (remainder in intestine), 68% after 2 h, 2% having reached large intestine. After 4 h only 4% remained in the stomach, 50% in the small intestine and 46% in the large intestine (Fernandes et al. 2013). The effect of chitosan-based nanoparticles on the eradication of H. pylori in the GI tract of mice was investigated (Lin et al. 2013). In this case, mice were administered cultures of H. pylori over a period of 10 days. After which, some mice were treated with genipin-linked fucose chitosan/heparin nanoparticles. Mice were euthanized after specific time periods and the inhibition of H. pylori was

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investigated by serial dilution. The mean count of an amoxicillin-loaded genipin fucose chitosan/heparin nanoparticle was 75.8
18.5 CFU/stomach compared to 278.3
31.5 CFU/stomach from an amoxicillin solution alone and 521.5
83.3 CFU/stomach from nanoparticles not loaded with antibiotic. This shows the incorporation of an antibiotic into a chitosan-based nanoparticle is more effective than an antibiotic alone at eradication of H. pylori in vivo. Gastric lesions can develop from the use of non-steroidal anti-inflammatory drugs (NSAIDs). Chitosan has been demonstrated to have a healing and protective effect on such lesions when taken in combination with dairy products (Budkevich et al. 2015). In rats administered with aspirin, the protective effect of a colloidal chitosan/ sodium alginate solution in pasteurised milk was investigated. The protective effect of dairy was enhanced by the presence of chitosan, indicated by the lower level of lesions produced after administration of aspirin and milk with sodium alginate and chitosan. Chitosan is in many ways suitable for the effective eradication of H. pylori and treatment of other gastric complications. Muco-adhesive, biodegradable, biocompatible properties, in addition to incorporation into a microsphere or nanoparticle which due to the presence of reactive groups, can bind cross-linking agents and antibiotics make it an effective candidate for use in H. pylori treatment. Chitosanbased particles incorporating antibiotics have been shown to eradicate H. pylori more efficiently than an antibiotic alone (Lin et al. 2013). The potential use of chitosan nanoparticles to bind and remove H. pylori from the GI tract without antibiotic use is a promising treatment which will avoid increased development of antibiotic resistance (Fernandes et al. 2013; Goncalves et al. 2013). Further research is needed to investigate the potential applications in humans in vivo, and perhaps the incorporation of a specific, targeted molecule to increase the selectivity of nanoparticle binding. Chitosan-based particles have the potential to be incorporated into targeted drug delivery systems and functional foods for the treatment of gastritis by H. pylori infection and gastric lesions.

1.3 1.3.1

Additive Uses Chitosan and Chitin-Based Fining

Finings agents are substances that are used to remove unwanted organic compounds to improve the quality of the liquid product. The average consumer prefers clear beverages and is accustomed to find no suspended solids in wine, beer or juices. Therefore, clarification is an important step in the industrial production of beverages. Successful chitosan-based clearance of beverages has been shown for apple, bayberry, green tea, grape, lemon, orange and passion fruit juices (Sota-Peralta et al. 1989; Chatterjee et al. 2004; Fang et al. 2007; Oszmiański and Wojdyło 2007; Rao et al. 2011; Domingues et al. 2012; Taştan and Baysal 2017). Moreover, the pretreatment of passion fruit juice with chitosan enhanced liquid properties that enabled the highest, permeate flux in the microfiltration process of pretreated passion

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fruit juice (Domingues et al. 2014). In contrast to fruit juices, the majority of consumers does not accept cloudy wines and in particular white wines. Typical compounds may be proteins, sulfides, polyphenols, benzenoids or copper ions that can be bound and removed by fining agents. Polyphenols are essential flavor compounds in wine which are subject to oxidation affecting the quality of the wine (Margheri et al. 1980). Thus, modulating the polyphenol content is an important task. In a comparative study on the fining of red wine, the binding capacity of caseinate, PVPP chitin and chitosan to polyphenolic compounds were analysed. Chitosan could show good binding capacities on polyphenols while the adsorbance capacity of chitin is very low (Spagna et al. 1996). However, chitin could be used to significantly lower the chitinases in wine (Vincenzi et al. 2005). Conversely, in opposite to chitosan, the use of chitin in winemaking is not allowed in the EU (Commission Regulation, No 53/2011 of 21 January 2011). In addition to the fining, the use of chitosan has positive aspects. Ochratoxin a (OTA) is a mycotoxin produced as metabolite by certain Penicillium and Aspergillus fungal species and it is one of the most abundant food-contaminating mycotoxins (Al-Anati and Petzinger 2006). In red wine, treatment with chitin and chitosan could reduce the OTA content significantly. Chitin could be used to remove OTA up to 18% without noticeably affecting wine quality. Chitosan-based OTA removal could reach up to 67% but the wine-quality parameters were strongly affected (Quintela et al. 2012). The clearing of beer was analyzed in a comparative study evaluating turbidity, viscosity, total polyphenols, zeta potential, suspended solids and total solids using the fining agents chitin, chitosan, stabifix and bentonite. Chitosan and chitin (5 mg/L) performed better than conventional flocculants for beer clarification at laboratory and industrial scales. Chitin and chitosan gave the highest total solids and total suspended solids reduction at both laboratory and industrial scales (Gassara et al. 2015).

1.3.2

Texture Controlling Agent

Chitin and chitosan derived from shrimp, insects and crab processing residues are currently not “generally regarded as safe” (GRAS) by the FDA (Federal Drug Administration, USA). This means all food additives for human consumption based on chitin need an approval in the US. (For further information: https://www. fda.gov/food/ingredientspackaginglabeling/gras/). It remains a difficult task to quantify risks associated with novel food products based on waste product streams. Texture is generally defined as “structural, mechanical, and surface properties of foods detected through the senses of vision, hearing, touch, and kinesthetics” (Szczesniak 2002). Chitin derived texture controlling agents could possibly include chitosan derived hydrogels. Recently, it has been shown that chitin gels matrix can be used to reinforce protein gels (Yuan et al. 2014; Nie et al. 2016).

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1.3.3

17

Chitosan-Based Emulsifiers

An emulsion is a mixture of two or more normally immiscible liquids without visible segregation. In an emulsion two liquids, such as oil and water, form a uniformly dispersed mixture based on small droplets of one phase surrounded by the other phase. An important component of emulsions is the emulsifier, which facilitates the formation of droplets and counteracts the phase segregation. Chitosan has been demonstrated to be a promising natural emulsifier and stabilizer of emulsions. Schulz et al. (1998) showed that chitosan becomes a positively charged amphiphilic substance in acidic condition that could stabilize multiple emulsions. Moreover, the degree of deacetylation of chitosan influences the emulsification properties. Del Blanco et al. (1999) could show that chitosan emulsions with different degree of deacetylation were highly stable under temperature changes and ageing conditions. Chitosan with a degree of deacetylation of 81% and 88% showed the best emulsifying properties (Del Blanco et al. 1999). In a later study using sunflower oil and hydrochloric acid together with different concentrations of chitosan, degree of deacetylation between 75% and 95% were analyzed. The droplet size distribution was unimodal at low degree of deacetylation and at high degree of deacetylation, for all used concentrations; at intermediate degree of deacetylation, distribution was unimodal only when the most concentrated solutions were used. Emulsion viscosity, emulsion stability and ageing were proportional to chitosan concentration (Rodrı́guez et al. 2002). Moreover, Li and Xia (2011) analyzed the effects of concentration, degree of deacetylation and molecular weight on emulsifying properties of chitosan. In this study, chitosan with degree of deacetylation 60.5% and 86.1% showed superior emulsifying activity and stability. Chitosan with low MW exhibited better emulsifying activity than those with high MW. Chitosan with MW 410 kDa and 600 kDa exhibited best emulsifying activity in the test range and with rising Mw, emulsifying stability of chitosan increased (Li and Xia 2011).

1.3.4

Food Mimetic

The biocompatible and biodegradable properties of chitosan enable it to be consumed and utilised in nutraceutical and pharmaceutical applications. Its physical characteristics can have a positive impact on food quality and enable the replacement of undesirable food stuffs with this useful polymer. Chitosan has been used as a meal replacement in oil emulsions fortified with nutrients (Qinna et al. 2013). The purpose was to produce a low-calorie replacement which gave a similar feeling of satiety to the consumer without any negative effects. A combination of chitosan (1%) and pectin (6%) was found to be optimal, having less phase separation in this ratio and more desirable rheological properties. Safety tests on rats resulted in no behavioural changes and no significant changes in blood chemistry. There were slight increases in cholesterol and low density lipoprotein

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cholesterol in serum but these levels were not significant. Application of the meal replacement reduced body weight, food and water intake (Qinna et al. 2013). In baking, chitosan has been used to facilitate and stabilise the replacement of wheat flour with rice flour for use in gluten- free applications (Sansano et al. 2018). While not replacing the flour itself in this instance, it proved valuable as a co-replacement, enhancing the properties of the rice flour and making it fit for purpose. The addition of chitosan increased the viscosity of the mixture as the portion of rice flour increased from 371 mPa s to 1006 mPa s and also improved the rheological behaviour. Similarly, chitosan derivatives have been investigated as a fat replacement in cake (Rios et al. 2018). Succinyl chitosan was applied as this modification was found to improve the stability of chitosan. The effects of chitosan replacement were investigated over various degrees of fat replacement with a 2 g/ 100 g succinyl chitosan. No significant changes in batter pasting properties apart from breakdown which decreased with a decrease in fat content up to 50% reduction but increased again, possibly due to the stabilising action of chitosan on the starch molecule. The crumb structure was also found to be similar to full fat and the hardening rate was reduced. However, the drying rate of the mixture was accelerated with the addition of chitosan. The fat in this mixture could be replaced with chitosan up to 50% without negative effects such as density. The addition of dietary fibres as fat replacements to a meat batter found that chitosan reduced the cooking loss of water, 10.8%, however carboxymethyl cellulose yielded a loss of only 4.2% (Han and Bertram 2017). Chitosan also reduced the expressible water to 4% compared to a control value of approx 5%. Similarly, a higher moisture content was observed when chitosan was incorporated into batter for Kurdish cheese nuggets (Ansarifar et al. 2015). This had the effect of reducing oil uptake, as the moisture retained prevented porosity. This quality is desirable to produce a healthier product. The highest reduction in oil uptake was observed in a 1.5% chitosan concentration. There was no change in springiness or chewiness with the addition of any of the dietary fibres but chitosan increased the hardness of the mixtures. Incorporation into a batter for Kurdish cheese nuggets similarly increased the hardness and crispiness of the batter with increasing chitosan content (Ansarifar et al. 2015). The nature of chitosan makes it suitable to act as a fat replacement. In addition, chitosan possesses many other qualities which enhance its usefulness in food systems. The incorporation of chitosan into a low fat pork sausage had many beneficial effects (do Amaral et al. 2015). The antimicrobial and antioxidant properties were evident and advantageous in preventing microbial and oxidative spoilage when compared to controls containing no chitosan but the same fat concentration. When the sausages were stored at 4  C, the level of lipid oxidation in a sausage containing 20% fat was reduced by 55% at day 0 and 64% after 15 days when chitosan was present compared to the control sample (do Amaral et al. 2015). The antioxidant properties were also evident when the colour changes of the sausages were observed. Values obtained for L* increased initially due to the chitosan but over time decreased, while the L* value of the control increased. Similarly, a lower reduction in the a* values of chitosan samples compared to the control sample also demonstrates an antioxidant quality. The water retention capacity was higher in

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chitosan samples, however, interestingly; the fat content was lower compared to controls which had the same fat content initially. This was believed to be due to the fat-binding capabilities of chitosan. Importantly, while there was a more intense red colour observed in sensory evaluations of the sausages, due to the antioxidant properties, there were no negative sensory reports compared to the control (do Amaral et al. 2015). Chitosan has also been demonstrated to reduce the formation of carcinogens in pork and batter systems (Oz et al. 2016; Sansano et al. 2016). The reduction of heterocyclic aromatic amines was observed in pork chops. The total content of these compounds increased as the cooking temperature increased but were reduced as chitosan concentration was increased. In a similar way, 60
7% inhibition of carcinogenic acrylamide was observed with chitosan. The replacement of gelatin with chitosan has also been tested in ice milk (El-Sisi 2015). In this case the properties of chitosan were affected as the concentration rose above 60%. The freezing point and ash content of the ice cream rose with chitosan concentration, thought to be due to the molecular weight and higher fibre content of the chitosan. Similarly, the overrun and viscosity increased as chitosan concentration increased, however, above a concentration of 60%, they decreased again. In the same way, the weight per gallon and melting resistance decreased to a concentration of 60%, then rose again. These affects seem to suggest a limitation of 60% concentration in this application. The use of antibiotic additives is becoming increasingly worrisome as a risk of generation of antibiotic resistant microbial strains. Supplementation with additives such as ionophores function to enhance the digestibility of protein and other energy sources in cows, but incorporation of chitosan in the diet of lactating cows was found to have beneficial properties as an alternative (Gomes de Paiva et al. 2016; Mingoti et al. 2016; Del Valle et al. 2017). Chitosan treatment increased crude protein digestibility in cows, the latter of which was evidenced by increased serum urea (Gomes de Paiva et al. 2016; Mingoti et al. 2016; Del Valle et al. 2017). It was also shown to increase digestibility of dry matter and organic matter (Mingoti et al. 2016; Del Valle et al. 2017). There are conflicting reports on whether or not it affected milk yield, but generally chitosan improved the quality of digestibility and energy efficiency in lactating cows and is considered a useful replacement for ionophores in the diet. Similarly, when used in the same way as a growth promoter for weaned pigs, there were increased serum levels of growth hormone and body weight gain and intestinal morphologies improved (Xu et al. 2013). In addition, as a supplement to diets of sucking pigs, chitooligosaccharides exhibited a glucose lowering effect (Xie et al. 2015). Fish meal is an expensive food source in the fish farming industry. Chitosan was investigated as a replacement in the diets of pacific white shrimp (Rahimnejad et al. 2018). It was found to enhance antioxidant activity and the immune responses of the shrimp. In contrast, a replacement of antibiotic treatments with chitosan as growth promoters in piglets resulted in negative effects such as diarrhoea, lower weight gain and a shorter long intestine in the piglets (Oliveira et al. 2017). The concentration of

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chitosan was low compared to other studies, if it had been higher, the properties may have been enhanced. Chitosan as a feed additive improved growth performance, feed conversion ratio and dry matter digestibility in broiler chickens while having no effect on the proximate composition or fatty acid contents of breast meat (Swiatkiewicz et al. 2014). Chitosan has been demonstrated to be effective as a fat replacement in various food applications while retaining organoleptic characteristics of the product. Additional properties which increase the nutritional benefits of the food product such as: glucose-lowering effect (Xie et al. 2015), antioxidant activity and immune response enhancement (Rahimnejad et al. 2018), and anti-carcinogenic properties (Oz et al. 2016; Sansano et al. 2016)

1.3.5

Thickening and Stabilizing Agent

Emulsifiers are often added to protect water – and – oil emulsions from degradation events over time such as: creaming, coalescence, flocculation and the effects of oxidation (Dammak and do Amaral Sobral 2018a). This treatment improves the stability of the emulsion by lowering interfacial tension and causing electrostatic repulsion to prevent particle collision. Common emulsifiers include: lecithin (Li et al. 2016a, b), casein, and surfactants such as monoglycerides, polysorbates and sucrose esters (Dammak and do Amaral Sobral 2018a). Emulsification is important in the food industry to increase the shelf life of emulsified products. However, emulsifiers may become unstable under certain conditions such as extreme pH or temperature (refrigeration and freezing) or when treated with UV irradiation which is a common preservative process (Li et al. 2016a, b). Stabilisers can also be added to increase the stability of emulsions. They act as blockades between emulsified droplets, barricading interaction between them and therefore, preventing coalescence. They also add viscosity to the system, thickening the solution which increases the shearing force and keeps droplets small and more uniformly dispersed (Chang et al. 2018a, b; Dammak and do Amaral Sobral 2018a; Dammak and do Amaral Sobral 2018b). Chitosan can act as an emulsion stabiliser by forming interfacial complexes with emulsifiers and increase electrostatic repulsion forces between droplets. One mechanism of action of emulsifiers is the prevention of large droplet formation, thus preventing coalescence. In some cases, the addition of chitosan as a stabiliser was found to create larger droplets as the concentration increased. This was believed to be due to the molecular weight of chitosan used. Stabilization of a rutin emulsion with lecithin and chitosan resulted in a slight increase in droplet size at a 0.2% chitosan concentration and a significant increase as concentrations rose above this level (Dammak and do Amaral Sobral 2018a). Pre-treatment of chitosan nanoparticles with ultrasonication was found to increase droplet size when compared to non-ultrasonicated self-aggregated chitosan nanoparticles (Ho et al. 2016); 82–144 mm compared to 53–73 mm. This was thought to be due to reduced hydrophobicity when depolymerisation occurred through ultrasonication.

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Interestingly, a study found that covalent complexes with chitosan and chlorogenic acid formed smaller droplets than physical complexes and a chitosan only control; 364.3
0.8 nm compared with 809.9
0.7 nm and 551.1
11.3 nm, respectively (Wei and Gao 2016). Similarly, droplet size was decreased in chitosan/stearic acid conjugate used to stabilise an allyl isothiocyanate emulsion compared to that stabilized by Tween 80 and Span 80 controls; 120–124 nm and 130–166 nm, respectively (Yang et al. 2017). In contrast, when a gallic acid was added to the same conjugate to stabilise a limonene emulsion, the droplet size was larger than that of the controls; 170–188 nm and 150–163 nm, respectively (Yang et al. 2017). The emulsion stability index (ESI) is a measure of the tendency of an emulsion to form aggregates over time. A higher ESI value indicates a lesser phase separation (Dammak and do Amaral Sobral 2018a). Chitosan addition to a lecithin emulsification of rutin increased the ESI value of the emulsion from 0.43 to 0.55–0.65 for the chitosan concentration range of 0.25–2% (Dammak and do Amaral Sobral 2018a). This shows that chitosan can increase the resistance to aggregation in these emulsions. An investigation into emulsion optimisation found a chitosan nanoparticle concentration of 1.1%, a lecithin concentration of 4.4% and an oil-to-water ratio of 0.24 achieved the highest ESI, a value of 0.78, using lecithin and chitosan to stabilise hesperidin (flavanoid). It was found that all of these parameters played important roles in emulsion stability, however, chitosan had the most effect, followed by lecithin and oil-to-water ratio, respectively (Dammak and do Amaral Sobral 2018b). Polydispersity index (PDI) is a measure of the distribution of molecular mass within a polymer mixture, therefore, a measure of non-uniformity in an emulsion. A smaller value indicates a more uniform particle suspension. In thiol-modified β-lactoglobulin emulsified complexes, the application of chitosan as a stabiliser resulted in an inverse correlation between PDI and chitosan concentration (Chang et al. 2018a, b). This was believed to be due to the enhancement of electrostatic repulsion by chitosan due to its cationic nature. The lowest concentration of chitosan applied had the highest value for PDI, believed to be due to the inability of the lower concentration to fully envelop the emulsified droplets (Chang et al. 2018a, b). A covalent complex between chitosan and chlorogenic acid to encapsulate β – carotene found that a covalent complex had a lower PDI than a physical chitosan – chlorogenic acid complex (Wei and Gao 2016).Therefore, concentration and complex formulation have effects on the polydispersity index within an emulsion. Chitosan, due to its cationic nature, has a tendency to increase the zeta potential of emulsified droplets. For example, the zeta potential of β-lactoglobulin fibrils alone was negative; however a 40 mV value was obtained when chitosan was incorporated in a concentration of only 0.2% (Chang et al. 2018a, b). Chitosan also increased the zeta potential of soybean oil emulsions using hydroxypropyl methylcellulose as an emulsifier with chitosan and the bacterium Lactobacillus lactis as co-stabilisers (Rattanaburi et al. 2018). Chitosan increased the zeta potential of the bacterial cells from 13.25
0.75 mV to ~0 mV, neutralising the surface. Ultrasonication of self- aggregated chitosan nanoparticles did not affect the zeta potential and a positive zeta potential of 11–14 mV was retained (Ho et al. 2016). Chitosan was found to improve the ionic stability of nano-emulsions when sodium chloride

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(1 mol l-1, 0.5 mol l-1 and 0.2 mol l-1) was added to nano-emulsions encapsulating curcumin (Li et al. 2016a, b). Contrastingly, addition of sodium chloride in 0–500 mM concentrations lead to reduced zeta potential and increased aggregation in pickering emulsions (Mwangi et al. 2016). Viscosity is an important parameter when evaluating emulsion stabilisation. An increased viscosity lowers the motility of droplets, preventing collision and aggregation. Chitosan has demonstrated abilities to increase the viscosity of samples in correlation with its concentration (Chang et al. 2018a, b; Dammak and do Amaral Sobral 2018a). The viscosity of a rutin (flavanoid) emulsion increased as chitosan was added to the lecithin emulsified mixture. As the concentration reached a critical level, 0.25% in this case, the viscosity significantly increased (Dammak and do Amaral Sobral 2018a). This suggests full adsorption of cationic chitosan to the droplets coated with negatively charged lecithin. The consistency index (K), measure of viscous nature, also increased from 0.01–1.6 Pa sn in correlation with the concentration of chitosan (Dammak and do Amaral Sobral 2018a). The addition of chitosan increased the viscosity of wheat flour and rice flour mixture from 371 m Pas to 1006 mPa-s and also improved the rheological behaviour, thereby stabilising the replacement of wheat flour with rice flour (Sansano et al. 2018). In addition, viscosity of a covalent chitosan/chlorogenic acid complex to emulsify β- carotene was greater in comparison to a physical complex of the same agents, showing that a covalent preparation of emulsifying agents has a more efficient effect on the emulsification process (Wei and Gao. 2016). In contrast, ultrasonication decreased the viscosity of chitosan particles; up to 50% decrease at 50% amplitude was observed (Ho et al. 2016). This was expected as depolymerisation occurred in this reaction reducing the viscous nature of the chitosan. The equilibrium interfacial tension of a droplet in water (6.9 mN/m) was lowered with the addition of chitosan (5 mN/m) resulting in a more miscible emulsion (Ho et al. 2016). In addition, the interfacial tension was further lowered with the formation of self-aggregated chitosan nanoparticles, whether ultrasonicated (4.9 mN/m) or non-ultrasonicated (4.5 mN/m). A reduction in hydrophobicity in the ultrasonicated samples was believed to be the reason for the slightly higher interfacial tension when compared to non-ultrasonicated samples (Ho et al. 2016). In contrast, a study with similar chitosan nanoparticles resulted in a slight increase in interfacial tension (Mwangi et al. 2016). The incorporation of chitosan solution into the emulsion resulted in an interfacial tension slightly higher than pure water, 17.87
0.09 mN/m and 17.47
0.36 mN/m, respectively. Chitosan particulate emulsion increased the interfacial tension further to 18.24
0.50 mN/m. Stability in various storage conditions is important to determine usefulness in a food setting. Stabilizers are applied to increase the shelf-life of a food product and duration of emulsion under stressed conditions is an important property to measure. In thermal studies, generally the emulsified droplet size increased as the temperature increased, possibly due to chitosan rearrangement. This was true for chitosanstabilized thiol-modified β-lactoglobulin emulsions when stability was tested at 63  C and 100  C. For example at a 0.2% chitosan concentration, droplet size increased from an initial 0.45
0.01 nm to 1.30
0.06 nm and 1.27
0.00 nm

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for 63  C and 100  C, respectively. (Chang et al. 2018a, b). Self-aggregated chitosan emulsions were stable up to 50  C after which the droplet size increased (Mwangi et al. 2016). Similarly, in chitosan stabilized emulsions with Lactobacillus lactis and hydroxypropyl methylcellulose phase separation occurred above 60  C in all concentrations tested (Rattanaburi et al. 2018). Droplet size increase was believed to be due to an increase in kinetic energy due to a higher temperature, therefore, an increase in Brownian motion and also, surface charge which increased the hydrophilicity of the complex (Mwangi et al. 2016). A nano-emulsion (MCT tween 80 lecithin encapsulating curcumin) stabilised by chitosan for 1 month storage at room temperature remained stable apart from a slight increase in size and decrease in zeta potential for the 3 kDa and 30 kDa chitosan coating, which can be attributed to rearrangement of molecules to a more thermostable arrangement (Li et al. 2016a, b). Degradation of the emulsified compounds gave further indication of its stability at various storage temperatures. The stability of an allyl isothiocyanate solution encapsulated with a chitosan/stearic acid conjugate was investigated at 35  C over various time periods (Yang et al. 2017). The degradation rate was reduced in comparison to a Tween 80/Span 80 control with 66.6% allyl isothiocyanate remaining compared with 36.7% after 14 days and 62.5% compared with 18.7% after 21 days (Yang et al. 2017). In the same way, thermal studies on addition of chitosan to lecithin- emulsified rutin demonstrated protective effects against of the multilayer emulsion against rutin degradation at 4  C, 25  C and 40  C (Dammak and do Amaral Sobral 2018a). This is also consistent with curcumin-loaded emulsions loaded with chitosan (3 kDa, 30 kDa and a 190–310 kDa), which reported an increased level of remaining curcumin after thermal treatment at 63  C and 100  C compared to a control (Li et al. 2016a, b). It was demonstrated that pH has an important role in emulsion stability with chitosan as when emulsions were treated with the same 0.5% chitosan concentration at alternate pH levels, there were differences in the droplet size and PDI (Chang et al. 2018a, b). Similarly, emulsions stabilized with self-aggregated chitosan nanoparticles were stable at pH 7–8. From pH 6–3 the droplet size began to increase, eventually leading to demulsification at pH 2 (Mwangi et al. 2016). Creaming of an emulsion is an undesirable occurrence that reduces the shelf life of a product. It is caused by gravitational separation or Brownian motion acting on droplets and causing them to separate to the top or bottom of an emulsion. Creaming was found to be increased in self-aggregated chitosan nanoparticles which had been pre-treated with ultrasonication (Ho et al. 2016), attributed to the initial larger droplet. However, the creaming rate was observed to decrease with increased chitosan concentration in self-aggregated chitosan nanoparticles which were not treated with ultrasonication (Mwangi et al. 2016). Interestingly, while higher concentrations of chitosan were found to improve the creaming stability of a thiolmodified β-lactoglobulin fibrils-chitosan complex at both pH 8 and 9, a lower concentration (0.1%) of chitosan was found to be less effective than the β- lactoglobulin fibrils alone (Chang et al. 2018a, b). This was thought to correlate with the PDI value of this emulsion, which was the highest tested. This implied a non-uniform dispersion of droplets which may have an effect on creaming. Also bridging flocculation was believed to have occurred due to insufficient CS to cover whole droplet (Chang et al. 2018a, b).

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It was found that the oxidative stability of fish oil emulsions increased as the chitosan concentration increased, with the lowest peroxide value (PV) achieved at 0.5% chitosan, indicating increased oxidative stability (Chang et al. 2018a, b). The cationic nature of chitosan may have repelled protons and metal ions. Similarly, oxidative protection was investigated with a chitosan/stearic acid/gallic acid emulsion. Gallic acid has antioxidant properties and so was included in the emulsion to provide protection to the emulsified limonene which is sensitive to oxidation (Yang et al. 2017). The chitosan- containing emulsion was found to have a higher concentration of limonene present compared to the control after heating at 35  C for 3 days (85.4% compared to 44.2%) and 14 days (57.7% compared to 11.4%). The same was true when illumination was applied to the emulsified systems, the chitosancontaining emulsifier provided increased oxidative protection compared to the control (68% remaining after 14 days treatment compares to 11.5% in the control) (Yang et al. 2017). This may be due to the presence of the antioxidant gallic acid in the mixture, however, not the chitosan. In conclusion, there are many properties that make chitosan an effective stabilizer. It can reduce the droplet size of emulsified oils, improve the zeta potential and interfacial tension and increase viscosity allowing a more miscible solution. It shows thermal and oxidative protection qualities which is important in a food setting. Combination with other emulsifiers seems to be beneficial, particularly with an antioxidant. The two complexes compliment the strength of the other and together serve to increase the overall strength of emulsions tested.

1.3.6

Color Stabilization

Attractive color in food products suggests freshness and quality to a consumer and influences purchasing decisions. For this reason, the colouring of food is an important parameter to consider in the food industry. Storage conditions such as light and air exposure, temperature and pH all contribute to colour change. Many foods possess colour naturally, but in a great many cases, it is improved or enhanced by various means. Some methods preserve the natural colour of the product itself and protect the colour-producing pigments from decay. Colour producing pigments, or colorants, either synthetic or natural, can also be added to the product to create or enhance colour in alternative methods. The use of synthetic colorants in food has been progressively changing towards natural sources. Synthetics have been shown to cause toxic effects and allergic reactions (Martins et al. 2016) and the European Food and Safety Authority (EFSA) and Food and Drug Administration (FDA) are the regulatory bodies governing their use. A change in the consumer preference towards natural foods and, consequently additives has lead to increased interest in utilising natural pigments such as: anthocyanins (Ge et al. 2018a), carotenoids (Di Martino et al. 2018), and curcumins (Tan et al. 2016).

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Natural pigments, however, are also sensitive to the changes in the surrounding atmosphere and studies have investigated methods to prolong and protect these pigments, such as protective coatings and films (Kulig et al. 2017) and encapsulation in small particles (Ge et al. 2018a). Due to biocompatibility and nontoxicity, ability to form clear gels (Xiao et al. 2015) and complex-forming abilities, chitosan has been used in many of these applications. Colorants may have more effects on food than just colour. Some can act as a preservative and also have properties in the body such as: antioxidant activity (Ge et al. 2018a, b), vitamin activity (Rutz et al. 2016) and anti-tumour activity (Jardim et al. 2015). Functional foods are in increasing demand due to consumer concern for consumption of healthy foods. Many additives are incorporated for multiple reasons as they have multiple properties. Colour change in food samples is measured using hand-held colorimeters. There are two colour spaces that give indications of colour changes. Defined by the Commission Internationale de l’Eclairage (CIE), the L*a*b* colour space uses 3 parameters namely: lightness (L*) (+ lighter,  darker), red to green (a*) (+ red,  green) and yellow to blue (b*) (+ yellow,  blue). A second set of parameters describe a different colour space using L* as before, but also chroma (C*) (+ brighter,  duller) and difference in hue (h*) (Cardoso et al. 2016; Kulig et al. 2017). The effect of different chitosan applications were tested on the stability of quality of catfish fillets during storage (Bonilla et al. 2018). The colour changing effects of dipping, spraying and vacuum tumbling the fillets with a chitosan-acetic acid solution were determined using a hand-held colorimetric device. The vacuum tumbling method of chitosan application increased the initial lightness (L*) of the catfish fillets compared to other methods and the control. The colour remained stable over time as did the L* values for the spraying method. There were also no significant changes in a* values over time for vacuum tumbling and spraying methods. The dipped method, however, showed a significant increase in lightness between 0 and 8 days compared to the control. Values for a* in the dipped fillets showed an increase in redness over the storage time, similar to the control, while the other methods lessened this change. There were no significant changes in the b* values for treatment samples or control over time. However, there was a slight yellowing in the chitosan treatment samples. The application of chitosan coatings has also been demonstrated to improve the quality of the red colour of beef (Cardoso et al. 2016; Kulig et al. 2017). In meat, oxidation of oxymyoglobin can lead to the formation of metmyoglobin which indicates a browning of the meat surface. Vacuum packing, due to the anaerobic environment can lead to deoxymyoglobin formation which indicates a purple colour (Cardoso et al. 2016). Thus, a coating which slows oxidation would help retain oxymyoglobin and the red colouring. Chitosan complexes were applied by immersion or dipping to bovine semitendinosus muscle, wrapped and stored at 4  C under fluorescent light to imitate retail display conditions (Cardoso et al. 2016; Kulig et al. 2017). Colour observation was carried out using hand-held colorimeters over various time periods to investigate changes in storage.

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Application of chitosan complexes were found to prevent the lightening and loss of red colour during storage when compared to controls. After 5 days in simulated retail conditions (4  C under timed fluorescent lights), the L* values of chitosan/ alginate coated 20 mm beef cuts were darker than the control sample, L* ¼ 46.69 and 51.98, respectively (Cardoso et al. 2016). This is similar to the concentration dependent effect of chitosan/gelatin coated cuts after 14 days in which a higher ratio of chitosan lessened the L* of the samples compared to lower ratios (Kulig et al. 2017). The same effect was observed in chicken noodles where chitosan application reduced the L* value compared to the control (Khare et al. 2014). This was attributed to antioxidant effect and prevention of metmyoglobin formation. After 5 days in simulation retail conditions, a* values were higher when glycerol concentration was lower, therefore, chitosan and gelatin had a positive effect on redness (Cardoso et al. 2016). While not affected by the composition of the mix applied, coated samples demonstrated a more intense red colour and hue than control samples: C* ¼ 25.13 and h* ¼ 47.91 compared to C* ¼ 20.65 and h* ¼ 61.65, respectively (Cardoso et al. 2016). Initial a* values were lowered with the addition of a chitosan/sodium alginate mix but after 24 h, they rose and stabilised, suggesting that the milky colour of the coating was affecting the initial readings (Kulig et al. 2017). The effect of redness stabilisation was increased when an antioxidant sodium erythorbate, was incorporated into the chitosan/sodium alginate mix, preventing the oxidation of oxymyoglobin (Kulig et al. 2017). Similar redness stabilisation with chitosan was observed in chicken noodles (Khare et al. 2014), also attributed to its antioxidant capabilities. Chitosan complexes were also applied in cheese processing to limit the transference of the colorant ammatto to the whey and promote it being retained in the curds (Celli et al. 2018). A capsulation method using casein-chitosan complexes containing ammatto was applied to a simulated coagulation system with milk. The complexes resulted in deceased L* values in curds and increased L* values in the whey in comparison to controls, suggesting that ammatto was retained to a higher degree when the chitosan complex was applied. In curds, increased a* values in comparison with the use of ammatto powder alone were higher, indicating a redder curd colour (with the exception of the fat-free sample). Values were decreased in the whey using chitosan complex. The ammatto powder alone resulted in higher b* values than the chitosan complex in the curd, but they were lower in the whey sample, suggesting a better control of retention of ammatto in curds (Celli et al. 2018). A chitosan coating was shown to lessen colour change in plum peel while in storage over a 35 day period (Kumar et al. 2017). The 2% chitosan coating was believed to delay the ripening of the fruit, thereby delaying peel darkening. Hue angle and chroma were measured and the reduction in both was lessened in the chitosan-coated samples. A 1% chitosan coating on blueberries demonstrated the decrease of hue values alongside the control for 6 days storage, but then they began to rise and were not significantly different from the control after 14 days (Mannozzi et al. 2018). Perhaps a higher concentration of chitosan would have had a more preventative effect. A 1% chitosan coating showed L* values significantly lower

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than an uncoated control and a chitosan combined with procyanidins (flavanoids with antioxidant properties), demonstrating prevention of darkening in blueberries (Mannozzi et al. 2018). Both coatings increased a* values initially but began to balance out and by day 14 had lower values than the control. The use of chitosan in wine fining has been proposed and the effect on wine browning has been investigated among other properties (Colangelo et al. 2018). Browning is a consequence of oxidation of polyphenols and is detrimental to wine quality. Chitosan derived from Aspergillus basiliensis with an average DD of 77.5% was applied in a 1 g/L concentration to white wine for 12 h at 20  C, under stirring. There was no significant difference in L* between the sample and control. However, there a change in redness was observed between chitosan sample and control, 0.70
0.09 and  0.91
0.04, respectively (Colangelo et al. 2018). The redness was slightly increased by the chitosan which is surprising as it would be expected that the chitosan would prevent “pinking” also caused by oxidation. In contrast, an expected decrease in the b* values, occurred in the chitosan sample compared to the control: 5.81
0.38 and 6.65
0.14, respectively (Colangelo et al. 2018). This demonstrates the ability of chitosan to reduce browning in white wine. Anthocyanins are naturally occurring, red, blue and purple colour-producing pigments found in fruits such as blueberries (Mannozzi et al. 2018), black carrots (Atay et al. 2018), and others. Anthocyanins possess many more properties such as antioxidant and anti-inflammatory action (Ge et al. 2018a). Their colour is sensitive to pH change and interestingly they have been incorporated with chitosan into intelligent pH-sensitive films for more efficient visual detection of food spoilage (Yoshida et al. 2014; Halász and Csóka 2018). Anthocyanins are susceptible to degradation by outside factors such as light, oxidation, temperature and pH. Encapsulation has been applied to anthocyanins to investigate the degree of protection that can be achieved and employed. Chitosan complexes have been investigated for such a purpose, including carboxymethyl chitosan and chitosan hydrochloride (He et al. 2017; Ge et al. 2018a, b), chitosan cellulose nanocrystals and chitosan tripolyphosphate (TPP) (Wang et al. 2017) and chitosan/gelatin electrosprayed microparticles (Atay et al. 2018). Release of anthocyanins in simulated gastric conditions resulted in a lower release from a chitosan nanoparticle complex compared to a free anthocyanin solution, 30.61% and 50.49%, respectively (He et al. 2017). In the same way, chitosan hydrochloride/ carboxymethyl chitosan nanocomplexes were shown to protect anthocyanin release at varying pH after 6 days (Ge et al. 2018a). At pH 2 and 3, the remaining anthocyanin in the complexes was 96.6% and 92.8%, respectively, compared to 90.2% and 42.5% in anthocyanin aqueous solutions. The degradation rate increased with pH in both the nanocomplexes and aqueous solution. At pH 6, remaining anthocyanin was 77.4% and 2.1% in nanocomplex and aqueous solution, respectively (Ge et al. 2018a). Incorporation of β-lactoglobulin to these complexes further increased their protective properties (Ge et al. 2018b). After incubation in simulated gastric conditions without enzymes for 6 h, the residual anthocyanin concentration was 28.0 μg/mL using chitosan hydrochloride/carboxymethyl chitosan complexes

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and 42.5 μg/mL using nanocomplexes with β-lactoglobulin incorporated. The same was true in simulations without enzymes; 1.23 μg/mL in chitosan/carboxymethyl cellulose alone and 5.19 μg/mL in β-lactoglobulin incorporated complexes (Ge et al. 2018b).This demonstrates that chitosan nanocomplexes can also protect anthocyanins in the body as they carry out their other functions as part of functional foods. Carotenoids are pigments which generate yellow, orange or red colours in foods and can be obtained naturally from a variety of sources including algae, fungi and plants (Rutz et al. 2016). A synthetic form of the carotenoid β-carotene, which also had antioxidant properties was microencapsulated in chitosan/carboxymethyl cellulose or chitosan/sodium tripolyphosphate and the effects tested in simulated gastric conditions. A higher yield was obtained using the chitosan/carboxymethyl cellulose microcapsules. Release profiles in aqueous, gastric an intestinal simulated fluids showed that chitosan/sodium tripolyphosphate microparticles did not show ideal behaviour, showing a burst release in gastric conditions and insufficient release in intestinal fluid. However, the chitosan/carboxymethyl cellulose particles showed a low release in all conditions, which while shows protection in gastric conditions, does not show a high intestinal release. Chitosan/carboxymethyl cellulose released less carotenoid during storage (Rutz et al. 2016). Amphiphilic chitosan (conjugated with polylactic acid) microcapsules have been formed with low molecular weight DNA to encapsulate β-carotene (Di Martino et al. 2018). They were found to be stable in storage. A higher β-carotene loss was observed at 25  C in comparison to 4  C but there was still >90% remaining. Curcumin encapsulation using chitosan complexes has also been investigated using xanthan gum, kafirin and chondroitin sulphate to form complexes with chitosan (Jardim et al. 2015; Xiao et al. 2015; Tan et al. 2016). Xanthan gum used in tandem with chitosan was tested in both the form of an emulsion and nanoparticles (Tan et al. 2016). Encapsulation efficiency was >90% when chitosan was incorporated with xanthan gum (Tan et al. 2016) which is similar to the 86.1
2.1% value obtained when kafirin was used in contrast to kafirin alone (55.0
1.1%) (Xiao et al. 2015). The release rate in simulated gastric fluid (SGF) was found to be higher in the emulsion (70% after 3 h) compared to the nanoparticles (16% after 3 h). Similarly, but to a lesser extent, nanoparticles incorporating kafirin incorporated with carboxymethyl chitosan released less curcumin in SGF than those formulated from kafirin alone, 42.4% and 50.3% after 2 h, respectively (Xiao et al. 2015). The pH of chitosan solution at time of nanoparticle preparation has an effect on the release profile of nanoparticles. As is evident in the curcumin release of chitosan/chondroitin sulphate, there was a much slower release at pH 1.2 by nanoparticles prepared at pH 6.0, compared to pH 4.0 and 5.0 (Jardim et al. 2015). In intestinal fluids, nanoparticles had a higher release rate than emulsions (Tan et al. 2016) and a more significant burst compared to SGF (Jardim et al. 2015; Xiao et al. 2015). Protonation of amine groups at pH 1.2 should result in chitosan expansion and dissolution but when in a complex electrostatic forces may form which reduce this effect as seen in chondroitin sulphate (Jardim et al. 2015). Chitosan has a protective effect on colorants, both in storage and under simulated gastric environments. Applied as films, coatings or used as encapsulation agents, the colour of various meats, fruits, beverages have been improved and sustained. Many

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natural colorants serve multiple functions in food serving as antioxidants, antiinflammatory and anti-tumor agents and vitamins. Chitosan can protect these molecules in gastric environments in order for them to carry out functions in the body as well as protecting them from retail storage conditions and extending the shelf life of products.

1.3.7

Antioxidants

Equilibrium between free radicals and antioxidants is required for the correct metabolic functioning of the human body. Overproduction of reactive oxygen species in the early pathogenesis of several diseases or by external factors, such as smoking, UV light or chemical reagents, can lead to oxidative stress. This causes damage to cells and tissues and promotes the development of several conditions such as diabetes, Alzheimer’s disease, hypertension and atherosclerosis (Carocho et al. 2018). Reactive species are named for the molecules they contain: reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulphur species (RSS). The superoxide radical (O2) is an example of a ROS and is one of the most reactive. It works by scavenging electrons from the electron transport chain in mitochondria. Other examples include the nitrous oxide radical (NO) and the thiyl radical (RS). All reactive oxygen species can react with proteins, lipids and DNA molecules, affecting structure and function and causing irreversible damage to cells and tissues (Vo et al. 2017). The presence of sufficient levels of antioxidants in the body is important to maintain the equilibrium with free radicals involved in metabolic functions. Endogenous antioxidants are not plentiful enough to deal with situations of stress in the redox balance, and so, extra antioxidants can be taken in to the body exogenously through food (Carocho et al. 2018). The use of antioxidants in food does only to provide a supply to the consumer, but can also protect the food itself from oxidation and autoxidation, which can affect food quality: taste, texture, color and nutritional value. Examples of antioxidant additives in food include gallates, tocopherols, ascorbates, lactates, citrates and phosphates (Carocho et al. 2018). Natural examples include anthocyanins (Mannozzi et al. 2018), curcumin (Tan et al. 2016) and carotenoids (Di Martino et al. 2018). Free radical scavenging and metal chelating abilities of antioxidant compounds can be quantified by various assays: DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) scavenging, hydroxyl radical scavenging, superoxide radical scavenging, Ferrous ion chelating (Li et al. 2013; Vo et al. 2017; Chang et al. 2018a, b). Reducing power and lipid oxidation has also been used to demonstrate antioxidant properties of molecules (Zhao et al. 2013; Zhang et al. 2018). Chitosan and its derivatives exhibit antioxidant activity. The hydroxyl and amine groups are responsible for the radical scavenging and metal chelating activity (Chang et al. 2018a, b). The antioxidant activity of a chitosan molecule increases as the molecular weight (MW) decreases (Mengíbar et al. 2013; Chang et al. 2018a, b).

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The depolymerisation of chitosan into smaller molecules by degradation enzymes form chitooligosaccharides. These, smaller molecules exhibit increased activity in comparison to larger chitosan molecules, thought to be due to the complex structure restricting the reactive scavenging hydroxyl and amine groups (Chang et al. 2018a, b). It has been demonstrated that the molecular weight of the chitosan or chitooligosaccharide has an effect on oxidative properties. In one study, chitooligosaccharide samples in the range 156–2.2 kDa were generated by cellulose degradation and radical and metal ion scavenging abilities were investigated (Chang et al. 2018a, b). The lowest MW chitooligosaccharide, 2.2 kDa showed the highest scavenging activity on hydrogen peroxide (H2O2), DPPH and ferrous iron chelating. The scavenging effect at 20 mg/L of the 2.2 kDa and 3.3 kDa on H2O2 was 100.0%. A similar trend followed for the effect on DPPH and ferrous iron scavenging, with lower MW chitooligosaccharides exhibiting higher activities. For all chitooligosaccharides tested, the effects were higher on radical scavenging than metal chelating (Chang et al. 2018a, b). A similar study demonstrated that DPPH scavenging activity increased as MW decreased for a chitooligosaccharide fraction degraded by the enzyme chitosanase (Mengíbar et al. 2013). The opposite was true for a chitooligosaccharide fraction degraded by lysozyme, perhaps due to the particular enzyme method of cleavage. In the same way, a study by Qu and Han (2016) showed the higher antioxidant activity of a lower MW chitooligosaccharide mix. At a chitooligosaccharide concentration of 5 mg/mL the DPPH scavenging ability of a 1.5 kDa chitooligosaccharide was 89.1%. When compared to the result obtained for the same assay for a 2.2 kDa chitooligosaccharide, a scavenging ability of approximately 60%, it was clear that at a lower MW, the antioxidant capabilities were increased (Chang et al. 2018a, b). Another determining factor for antioxidant activity of chitooligosaccharides is the degree of acetylation (DA). That is, the number of units with acetyl groups (CH3CO) attached to carbon 5 of the monomer. In a study carried out on chitooligosaccharides separated by size, DA seemed to have no effect on the antioxidant activity. However, when expressed as a ratio of acetylated vs. deacetylated (A/D) units in the molecule sequence, a chitooligosaccharide with a lower A/D ratio showed the best antioxidant activity (Mengíbar et al. 2013). This suggests that the balance between acetylated and deacetylated units effects antioxidant activity. In contrast, a study involving the activity of partially acetylated and fully deacetylated chitotrioses (3 monomers) demonstrated that the fully deactylated chitotriose had the least amount of antioxidant activity. While chitotrioses with the same A/D ratio, i.e. 2, the chitotriose in favour of acetylated units (2 acetylated units, 1 deacetylated) had a greater antioxidant activity that that in favour of deacetylated units (2 deacetylated, 1 acetylated) (Li et al. 2013).While having the same ratio, the presence of the acetyl group played a role in performance of the chitooligosaccharides. Chelation or grafting of chitosan to another, more powerful, antioxidant has been explored to increase their stability and reactivity (Vo et al. 2017; Kadam et al. 2018; Zhang et al. 2018). Phenolic acids, for example, are themselves powerful antioxidants but they degrade quickly in the body. Attaching a slow digestible compound such as chitosan prevents premature degradation by decreasing their hydrophilicity

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(Carocho et al. 2018). Encapsulation of curcumin into chitosan/gum arabic nanoparticles increased the antioxidant activity when compared to an emulsion and curcumin powder alone (Tan et al. 2016). With DPPH scavenging activities of 74.3
1.9% for the nanoparticles compared to 69.3
1.4% and 63.2
1.2% for the emulsion and powder, respectively, it is clear that encapsulation of curcumin enhanced the antioxidant activity. In the same way, a chitosan/nucleic acid polyplex used to encapsulate β-carotene was shown to increase the DPPH radical scavenging activity and ferrous ion chelation (Di Martino et al. 2018). After 20 min, over 90% DPPH scavenging activity was observed in encapsulated samples compared to 50% in the free samples. The ferrous ion chelating activity was also improved in encapsulated samples (Tan et al. 2016; Di Martino et al. 2018) The biocompatibility, biodegradability and non-toxic nature of chitosan make it an appealing substance for use in the pharmaceutical and food industries. There have been many studies investigating the antioxidant activity of chitosan and its derivatives when bonded to a phenolic compound (Vo et al. 2017; Kadam et al. 2018; Zhang et al. 2018).This allows stability of the phenolic compounds while retaining the natural, biological properties of chitosan. In general, the antioxidant activity is much higher when compared to a chitosan or chitooligosaccharide control and the antioxidant activity of the phenolic molecules are much higher than that of chitosan. In a study investigating the effect of a gallic acid/chitooligosaccharide graft on protection of lung epithelial cells, it was found that its DPPH scavenging activity was much higher than that of chitooligosaccharides alone, 70% to 36%, respectively (Vo et al. 2017). Although, chitooligosaccharides did show some activity in a dose dependent manner. In a similar way, the protective effects of gallatechitooligosaccharides on DNA treated with H2O2 were much higher than that of chitooligosaccharides alone which showed weak activity (Vo et al. 2017). The addition of a N-acyl group to chitosan and chitooligosaccharides in the form of N-furoyl chitosan and N-furoyl chitooligosaccharides demonstrated that a chitooligosaccharide derivative was more effective than its chitosan counterpart with half inhibition concentrations (IC50) on DPPH of 0.76 and 1.3 mg mL1, respectively. However, in this case, the N-furoyl chitooligosaccharides did not perform better than chitooligosaccharides alone, with an IC50 of 0.62 mg mL1. The same was true also for hydroxyl radical scavenging and reducing power assays (Zhao et al. 2013). The addition of N-furoyl to a chitooligosaccharide removes a reactive amine group, possibly reducing the capabilities of the chitooligosaccharides alone. In comparison to other phenolic compounds, gallic acid, for example, it does not possess many reactive sites, which may explain its lower activity. Applications of chitosan in food include its use in the formation of films for preservation and storage, owing to its many suitable properties such as, biocompatibility, biodegradability, antimicrobial activity, and antioxidant capabilities. However, this can have limitations, as the films can be brittle and have low mechanical strength. Incorporation of phenolic compounds into chitosan films to combat this (Kadam et al. 2018). Tannic acid grafted on to chitooligosaccharides improved the tensile strength of the film. In a similar way, the grafting of Nigella sativa seedcake phenolic extract to chitooligosaccharides improved the elongation at break of the

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film. Both additions also increased film thickness and lowered the moisture content. DPPH radical scavenging activity and ferric ion reducing activities increased by Nigella sativa seedcake extract-chitooligosaccharide concentration and was higher in water than ethanol suggesting effectiveness in a natural environment (Kadam et al. 2018). In a similar way, a food coating prepared with chitooligosaccharides and bamboo vinegar showed reduction in lipid oxidation on pork chops when the coating was applied. The combined coating was more effective than the chitooligosaccharide coating alone (Zhang et al. 2018). In vivo testing demonstrates the significance of chitooligosaccharides in the diets of mice. The introduction of chitooligosaccharides of ~1.5 kDa into the high fat diets of mice showed no significant change in body weight when compared to normal diet controls and high fat diet (no chitooligosaccharides) mice. Activities of antioxidant enzymes such as catalase, glutathione peroxidase and superoxide dismutase decreased in mice fed the high fat diet in comparison with the control group. However, in mice fed chitooligosaccharides with a high fat diet, the levels of enzymes were increased. Chitooligosaccharides can act as antioxidant in vivo maintaining the activity of antioxidant enzymes (Qu and Han. 2016). The impact of chitooligosaccharides as antioxidants is well documented. Activity increases with lower molecular weight and is dependent on degree of acetylation. The biocompatibility, biodegradability and anti-microbial properties of chitosan and derivatives make them suited to use in food applications. The application in food can be seen in the grafting of phenolic compounds to chitosan to increase their antioxidant effect and in the application of the same principle to incorporating antioxidants into chitosan films to increase antioxidant activity.

1.3.8

Livestock and Fish Feed Additive

Utilizing shrimp and crab processing residues has a long tradition in agriculture (Winkler et al. 2017). Historically, it has been mainly used as fertilizer and stimulant for plant growth. The conversion of this waste product to a value added edible form has been studied extensively. Not only as feed additive, for example in poultry farming, but also as a general substitution to traditional feed (Hirano et al. 1990; Khempaka et al. 2011). Depending on fish and livestock species these applications are limited by the digestibility of chitin and current restrictions by European law. Digestibility of chitin or chitosan by animals: Fish: Chitin degradation by fish has been shown, especially in cod fish high conversion rates were observed (Ringø et al. 2012). Highly active chitinolytic enzymes are expressed endogenous by many fish digestive systems, but also by their gut microbiota (Banerjee et al. 2015; Fines and Holt 2010). The high apparent digestive conversion (ADC) of chitin by fish make crustacean processing wastes in aquaculture an attractive feed (Fines and Holt 2010).

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Poultry: Birds naturally consume insects, containing significant amounts of chitin and related oligosaccharides. Research showed that chitosan addition to poultry feed is biosafe and that appetite loss was only reported when exceeding 3,6–4,2 gram Chitosan per kilogram body weight. Multiple studies showed that Chitosan had positive effects on growth performance and the overall condition of broilers at low dosages (Swiatkiewicz et al. 2015). Also, chitin did not show adverse effects on poultry growth performance at even higher percentages (Razdan and Pettersson 1994). Ruminants and monogastric mammals: There is a limited number of studies on the digestibility of chitin by ruminants. The described antibiotic effect of chitosan has been verified by reduction of Enterohemorrhagic Escherichia coli in cattle sheddings (Jeong et al. 2011). Publications on the digestibility of chitin or chitosan by sheep showed only very slow conversion rates. Although it can serve as nitrogen source for the microbial flora, it remains unsuitable for feeding of ruminats (Fadel El-Seed et al. 2003). Chitinolytic enzymes remain as fossil genes in most genomes of higher mammals, also humans express these evidently (Tabata et al. 2018). In general, the number of functional copies of chitinolytic enzymes expressed correlates to the predominant diet (Emerling et al. 2018).

1.4

Conclusions

The versatility of chitin and its derivatives, their physiological activities and their many applications in the food industry should be studied more extensively to further examine the role of molecular weight and chain length on the their application. In particular, oligomerization and degree of deactelyation may have an important impact on the development of chitin/chitosan-based nutraceuticals as the limited efficacy of chitinases and chitosanases in the human gut may render them resistant to even partial degradation. This, on the other hand may provide benefits outside the gut such as in antimicrobial packaging and edible film formation based of chitin/ chitosan biopolymers as these would provide protection from food spoilage while remaining inert in the body after ingestion and passage through the gut.

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WHO (2016) Hearts: technical package for cardiovascular disease management in primary health care [online]. Available: http://www.who.int/cardiovascular_diseases/hearts/en/. Accessed 22 Aug 2018 Winkler AJ, Dominguez-Nuñez JA, Aranaz I, Poza-Carrión C, Ramonell K, Somerville S, Berrocal-Lobo M (2017) Short-chain chitin oligomers: promoters of plant growth. Mar Drugs 15:1–21 Wu S, Pan H, Tan S, Ding C, Huang G, Liu G, Guo J, Su Z (2017) In vitro inhibition of lipid accumulation induced by oleic acid and in vivo pharmacokinetics of chitosan microspheres (CTMS) and chitosan-capsaicin microspheres (CCMS). Food Nutr Res 61(1). https://doi.org/10. 1080/16546628.2017.1331658 Xiao J, Nian S, Huang Q (2015) Assembly of kafirin/carboxymethyl chitosan nanoparticles to enhance the cellular uptake of curcumin. Food Hydrocholl 51:166–175. https://doi.org/10.1016/ j.foodhyd.2015.05.012 Xie C, Guo X, Long C, Fan Z, Xiao D, Ruan Z, Deng ZY, Wu X, Yin Y (2015) Supplementation of the sow diet with chitosan oligosaccharide during late gestation and lactation affects hepatic gluconeogenesis of suckling piglets. Anim Reprod Sci 159:109–117. https://doi.org/10.1016/j. anireprosci.2015.06.004 Xu Y, Shi B, Yan S, Li T, Guo Y, Li J (2013) Effects of chitosan on Body Weight Gain, Growth Hormone and Intestinal Morphology in Weaned Pigs. Asian Australas J Anim Sci 26:1484–1489. https://doi.org/10.5713/ajas.2013.13085 Yang TS, Liu TT, Lin IH (2017) Functionalities of chitosan conjugated with stearic acid and gallic acid and application of the modified chitosan in stabilizing labile aroma compounds in an oil-inwater emulsion. Food Chem 228:541–549. https://doi.org/10.1016/j.foodchem.2017.02.035 Yoshida CMP, Maciel VBV, Mendonça MED, Franco TT (2014) Chitosan biobased and intelligent films: monitoring pH variations. Food Sci Technol 55:83–89. https://doi.org/10.1016/j.lwt. 2013.09.015 Yuan Y, Sun YE, Wan ZL, Yang XQ, Wu JF, Yin SW, Wang JM, Guo J (2014) Chitin microfibers reinforce soy protein gels cross-linked by transglutaminase. J Agric Food Chem 62:4434–4442. https://doi.org/10.1021/jf500922n Zhang W, Xia W (2015) Effect of media milling on lipid-lowering and antioxidant activities of chitosan. Int J Biol Macromol 72:1402–1405. https://doi.org/10.1016/j.ijbiomac.2014.10.049 Zhang Y, Xue C, Xue Y, Gao R, Zhang X (2005) Determination of the degree of deacetylation of chitin and chitosan by X-ray powder diffraction. Carbohydr Res 340:1914–1917. https://doi. org/10.1016/j.carres.2005.05.005 Zhang CM, Yu SH, Zhang LS, Zhao ZY, Dong LL (2014) Effects of several acetylated chitooligosaccharides on antioxidation, antiglycation and NO generation in erythrocyte. Bioorg Med Chem Lett 24:4053–4057. https://doi.org/10.1016/j.bmcl.2014.03.083 Zhang H, He P, Kang H, Li X (2018) Antioxidant and antimicrobial effects of edible coating based on chitosan and bamboo vinegar in ready to cook pork chops. LWT Food Sci Technol 93:470–476. https://doi.org/10.1016/j.lwt.2018.04.005 Zhao D, Wang J, Tan L, Sun C, Dong J (2013) Synthesis of N-furoyl chitosan and chitooligosaccharides and evaluation of their antioxidant activity in vitro. Int J Biol Macromol 59:391–395. https://doi.org/10.1016/j.ijbiomac.2013.04.072

Chapter 2

Chitosan for Seafood Processing and Preservation Piotr Kulawik, Ewelina Jamróz, and Fatih Özogul

Abstract Recently, a greater attention has been directed to a more effective exploitation of chitin, the second most available polysaccharide in crustacean’s products. The shellfish processing industry produces unusable waste, thus posing a practical challenge. Approximately 75% of the total weight of crustaceans ends up as waste and there are actually no acceptable waste management solutions. Thus, the extraction of chitin from the shells of crustaceans, such as shrimps, crabs, prawns, lobster or krill, and its further use in the unprocessed or processed condition minimizes waste and produces valuable compounds. Chitosan, a deacetylated derivative of chitin, has many functional properties which can be used for various applications such as processing, preservation and food additives. Recently, sustainable and cost-effective methods for chitosan preparation and use have been developed. Methods of chitosan application, such as edible coatings, direct addition to the batter or tumbling in chitosan solution, allows chitin use for almost every type of seafood. Chitosan exhibits properties including antioxidant, antimicrobial and film-forming properties, and thus yields promising results as food additive. Moreover, the use of chitosan for seafood products is solving two major spoilage issues: increased oxidation and microbiological spoilage. Indeed, we observe decreased deterioration of sensory scores during storage, and prolonged shelf-life seafood products treated with chitosan.

P. Kulawik Department of Animal Products Technology, Faculty of Food Technology, University of Agriculture in Cracow, Krakow, Poland e-mail: [email protected] E. Jamróz Institute of Chemistry, Faculty of Food Technology, University of Agriculture in Cracow, Krakow, Poland e-mail: [email protected] F. Özogul (*) Department of Seafood Processing Technology, Faculty of Fisheries, Cukurova University, Adana, Turkey e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_2

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Keywords Chitosan · Chitin · Seafood processing · Food preservation · Functional compounds

2.1

Introduction

Recent findings on consumer trends show that more and more consumers are looking for food products without the artificial food additives which are often regarded as “unhealthy” (Asioli et al. 2017). As this “Clean label” trend is gaining popularity it has led to the increased interest in natural and “green” ingredients which would be accepted by the consumers, while exhibiting a number of bioactive properties. Chitosan, a polysaccharide biopolymer, normally obtained from seafood wastes, can be used as such green and natural food ingredient (Kyzas and Bikiaris 2015; Patel 2015). In recent years chitosan has been a subject of hundreds of research studies and has been proven effective in preserving the quality of various food products (Zargar et al. 2015; Hamed et al. 2016; Zou et al. 2016; Muxika et al. 2017). This chapter focuses on the recent findings related to the application of chitosan on seafood products, covering factors influencing specific bioactive properties of chitosan, application methods depending on the type of seafood to be treated with, as well as the effect such a treatment has on the product.

2.2

Sources of Chitin in Seafood

Chitin is one of the most commonly occurring polysaccharides in the world, second only to cellulose, with total annual production by marine species estimated at millions metric tonnes (Souza et al. 2011). Chitin processing is the main source for obtaining chitosan, which on an industrial scale is performed through its deacetylation from seafood and its wastes, mostly from crustacean shells. In general chitin content in shellfish wastes is within the range of 20–30% (Kaur and Dhillon 2015), however the shells of some crustacean species have much higher content of chitin. For example shells from Crangon crangon contain 46% of chitin, the shells of Nephro and Homarus lobsters contain up to 60–75% of chitin and the shells of Cancer and Carcinus crabs contain 72 and 64% of chitin respectively (Xu et al. 2008; Hamed et al. 2016). From mollusks species wastes, the krill and squid pen are also a good source of chitin (approx. 40%). Other seafood sources of chitin include beard worms (Siboglinidae), Cnidaria or Brachipods, with chitin content reaching up to approx. 30%. Not all shellfish wastes are good sources of chitin. The blue crab (Callinectes) contains 14% of chitin, while clam and oyster shells have chitin content in the range of 4–6% (Kaur and Dhillon 2015; Hamed et al. 2016). Chitosan can also be obtained directly from certain fungi, such as Absidia coerulea, Mucor rouxii, Gongronella butleri, Phycomyces blakesleeanus, Absidia blakesleeana, Rhizopus oryzae or yeasts such as Zygosaccharomyces rouxii or Candida albicans. The direct extraction of chitosan from fungi and yeast has

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many advantages over acquiring chitosan from chitin, including obtaining product with higher quality (Rane and Hoover 1993; Pochanavanich and Suntornsuk 2002).

2.3

Chitosan Production from Seafood Waste

The annual production of shell wastes from the crab, shrimp and lobster is estimated at the level of 6–8 million tonnes, and the costs of the disposal of these wastes can be high (Yan and Chen 2015). Meanwhile, these wastes can be used to obtain highvalue products such as chitin which is further processed to chitosan. Shellfish chitin usually occurs in a complex matrix together with proteins, pigments and calcium carbonate (Shamshina et al. 2016), requiring a specific extraction process which includes demineralization, deproteination and pigment removal steps. The chemical demineralization is usually performed through acid treatment, with HCl being most commonly used, due to its efficiency in inorganic salts removal. The deproteination step is usually carried out through alkali treatment, usually with NaOH, at high temperatures of 60  C and above. The pigment removal is performed using various organic or inorganic solvents such as NaOCl or KMnO4 with H2O2. The last step involves deacetylation of chitin chain, which is usually carried out by thermal treatment, with the temperatures of 100  C with concentrated alkali, such as NaOH or KOH (Kaur and Dhillon 2015; Shushizadeh et al. 2015). The chemical extraction requires the use of many solvents and other chemicals, high energy input and processing with high temperatures. This negatively affects the environment, reduces the economic viability of the process and often results in lower quality of the obtained product (Pachapur et al. 2016). To overcome these problems, different methods such as microbiological fermentation or enzymatic treatment, have been proposed for deproteination, both methods exhibiting promising potential (Xu et al. 2008; Sedaghat et al. 2016; Lopes et al. 2018). For example high deproteination rates were reported by Hamdi et al. (2017) who obtained chitin from blue crab and shrimp shells, using proteases from Portunus segnis viscera, and by Hammami et al. (2017) who obtained chitin from shrimp waste using proteases from Bacillus invictae. On the other hand Younes et al. (2014) has used different microbial and fish viscera proteases for the deproteination of shrimp shell wastes and compared the acquired chitosan with the one obtained through chemical method. As in previous studies, the enzymatic method showed high deproteination rate. Nevertheless, the biological activity, including antitumor, antioxidant and antimicrobial properties of acquired chitosan, were lower than of chitosan acquired by means of chemical method. It probably resulted from lower molecular weight of chitosan obtained by the chemical deproteination. The use of microbial fermentation allows to replace both deproteination and demineralization steps, which can be achieved by using protease and lactic acid-producing bacteria (Chen et al. 2017). Hajji et al. (2015) used different Bacillus strains to treat crab shells and observed the deproteination and demineralization rates ranging from 76–94% and 58.5–83% respectively. Moreover the authors reported that the process

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can be further enhanced by the addition of glucose into the fermentation medium, which resulted in the increase of both process rates to the levels of 80–95% and 73–89%. The positive influence of the glucose addition is due to low levels of the fermentable compounds in crab shell wastes, which limits the cell growth of fermentation microorganisms. The chitosan obtained through the fermentation method had a high antioxidant and antimicrobiological activity. Zhang et al. (2017) expanded further the microbiological fermentation method, proposing a large-scale three-stage fermentation method which consists of the deproteination performed by Serratia marcescens, demineralization by Lactobacillus plantarum and deacetylation of chitin to chitosan by Rhizopus japonicus. The deacetylation of chitin can also be achieved through an enzymatic method, by the addition of various chitin deacetylates of bacterial (f.e. Rhizobium sp. Vibrio cholera, Bacillus sp.), fungal f.e. Crytococcus neoformans, Puccinia graminis) or even viral (Chlorovirus) origin (Hembach et al. 2017). Apart from the chitosan production methods, another parameter influencing the properties of chitin derived chitosan is the chitin source. The quality and properties of the chitosan can be of substantial difference depending on the waste material used. For example Kumari et al. (2017) obtained chitosan from fish scales and shrimp and crab shells. They concluded that the best material for the preparation of chitosan was from shrimp shells, due to its high average molecular weight, high degree of deacetylation value and solubility. The summary of various chitosan acquisition methods is shown in Fig. 2.1. The enzymatic and fermentation methods are two novel chitosan production methods which allow to obtain chitosan in more environmentally friendly and cost effective manner than the traditionally used chemical method. The enzymatic method can be substituted during deproteination and deacetylation steps, while the fermentation method can be used during deproteination, demineralization and deacetylation steps. According to the economic analysis performed by Ravi Kumar (2000), chitosan production from seafood wastes is economically feasible, especially since during the chitosan recovery, many other biologically active compounds can be obtained. For example, Cahú et al. (2012) proposed the processing method of Pacific white shrimp head wastes, which allowed to simultaneously obtain protein hydrolysate, chitin and chitosan, carotenoids including astaxanthin and glycosaminoglycans including sulphated glycosaminoglycans. Such methods allow improving the economic viability of the whole process and produce high value products from worthless wastes. The current prices of food grade chitosan powder differ depending on the products purity and quality and on the quantity of product ordered and ranges from 5–150 USD/kg. Recently there has been a number of improvements of the traditional chemical chitosan acquisition method, which allow to obtain high-value chitosan in a more environmentally friendly, and cost-efficient way.

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Fig. 2.1 Comparison of three chitosan production processes from seafood wastes

2.4

Functional Properties of Chitosan for Food

Chitosan and its derivatives are known to have a wide range of biological actions such as antioxidant activity, antimicrobial function, antifungal properties, filmforming properties and food additives properties, which could be used in the food industry to enhance food safety, quality, and shelf-life.

2.4.1

Antioxidant Activity

Chitosan is reported as a polymer with excellent antioxidant property (Anraku et al. 2018). This activity of chitosan is correlated with the source of the material, molecular weight and degree of deacetylation. Chitosan from the crab shell and shiitake stripes exhibited excellent antioxidant activity (Yen et al. 2007; Yen et al. 2008). Several reports have shown that chitosan molecular weight is a crucial factor that determines its antioxidant activity. In the study by Chang et al. (2018), chitosan,

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with molecular weight of 300.0 kDa, was enzymatically degraded to obtain six chitosan types with different molecular weights of 156.0, 72.1, 29.2, 7.1, 3.3 and 2.2 kDa. The antioxidant scavenging activities of chitosan measured through DPPH radical-, H2O2 -scavenging assay and ferrous-ion chelating assay, were significantly increased with chitosan’s decreasing molecular weight. The similar results were observed in other works (Chien et al. 2007; Feng et al. 2008). The antioxidant activity of chitosan was examined both in vivo and in vitro. The addition 0.02% chitosan into lard and crude rapeseed oil caused the increase in antioxidant property of those products (Xia et al. 2011). Moreover coatings containing 1, 2 and 3% of chitosan prolonged the quality of the guava (Psidium guajava L.) fruit during the storage, through the increase in the radical scavenging ability (Silva et al. 2018). In addition, the presence of chitosan coatings contributes to an increase in the activity of antioxidant enzymes that control the reactive oxygen species metabolism (Pasquariello et al. 2015). In the last decades, chitosan nanostructures have been intensely examined for their unique properties. These nanoparticles are an excellent antioxidant, with their mechanism related to the presence of nitrogen in the C-2 position of chitosan (Si Trung and Bao 2015; Divya et al. 2018).

2.4.2

Antimicrobial Function

Recently, several mechanisms of antimicrobial activity of chitosan have been proposed (Fig. 2.2). One of the hypothesis claims that chitosan could inhibit the growth of bacteria by complexing with essential elements or nutrients (Roller and Covill 1999; Li et al. 2010; Yuan et al. 2016). Another potential mechanism of antimicrobial activity of chitosan can be related to binding of the positively charged chitosan to the negatively charged bacterial surface, that leads to intracellular leakage and, consequently, cell death (Severino et al. 2015). The presence of amine groups (NH3+) of glucosamine in chitosan causes the ability to interact directly with the cell membrane (Raafat et al. 2008; Li et al. 2015; Ma et al. 2017). The teichoic acid in Gram-positive bacteria and lipopolysaccharides in Gram-negative bacteria are responsible for creating bonds with chitosan (Raafat et al. 2008). In this way, an impermeable coat is created around the cell, which prevents the transport of essential substances into the cell (Choi et al. 2001). The last proposed mechanism of antimicrobial activity of chitosan includes the interaction between chitosan and hydrolysis products from microbial DNA, which leads to the inhibition of the mRNA and protein synthesis (Hosseinnejad and Jafari 2016; Yuan et al. 2016). Various intrinsic and extrinsic factors (Fig. 2.3) are known to influence antimicrobial activity of chitosan (Hosseinnejad and Jafari 2016; Ma et al. 2017). The antimicrobial activity of chitosan depends on the type of the tested microorganisms. Generally, chitosan shows more potent bactericidal effects on Gram-positive bacteria than Gram-negative bacteria (No et al. 2002; Fernandez-Saiz et al. 2009). However, not all of the literature is consistent on this issue (Devlieghere et al. 2004).

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Fig. 2.2 Proposed mechanism of the antimicrobial effect of chitosan on Gram-positive and Gramnegative bacteria. The interaction of chitosan with Gram-positive bacteria leads to cell death, whereas in the case of Gram-negative bacteria, the penetration happens with difficulty due to the presence of lipoteichoic acid

Fig. 2.3 Factors influencing the antimicrobial activity of chitosan

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Fernandez-Saiz et al. (2009) concluded that the negative charge of teichoic acids in the cell membrane of Gram-positive bacteria may help the interaction with cationic chitosan, while the lipopolysaccharide layer of Gram-negative bacteria limits the penetration. In addition, it is important to pay attention to the different growth stages of bacteria or the initial microorganism population, as these factors may also affect antimicrobial efficiency of chitosan (Fernandez-Saiz et al. 2009; Ma et al. 2017). An antimicrobial activity of chitosan and its derivatives depends on intrinsic factors such as molecular weight, the degree of deacetylation, positive charge density and the interaction with certain materials. In many works, chitosan with lower molecular weight had a higher antimicrobial activity (Liu et al. 2006; Kong et al. 2008). Chitosan with higher deacetylation degree shows more effective antimicrobial activity, which is related to the presence of higher number of free amino groups on the polymer structure (Kong et al. 2008; Mellegård et al. 2011; Perinelli et al. 2018). Chitosan solubility and charge density increased significantly with the increase in the degree of deacetylation. There is a correlation between the degree of deacetylation levels and the density of positive charge. The positively charged NH3+ groups of chitosan can interact with negatively charged bacterial surface. It was demonstrated that chitosan with higher positive charge density had stronger antimicrobial activity (Kong et al. 2010; Ma et al. 2017). A metal chelating ability is another intrinsic factor that influences the antimicrobial activity of chitosan. To improve the antimicrobial properties of chitosan, the modification of loading metal ions has been used in many works, including the addition of Zn2+, Ag+, Pb2+, Cu2+, Fe2+ and Cr4+ or Ni2+ (Yi et al. 2003; Guibal 2004; Varma et al. 2004; Wang et al. 2004; Vijaya et al. 2008; Sharma et al. 2017). Two environmental factors are important for chitosan adhesion to the bacterial cell, such as pH and temperature. The pH values under 5.5 caused an increase in an antimicrobial activity of chitosan, due to its protonation and higher solubility in acidic environment. The temperature effects of an antimicrobial activity of chitosan have been examined, and it was demonstrated that the best antimicrobial activity of chitosan was obtained at 37  C (No et al. 2006; Kong et al. 2010). The summary of antimicrobial properties of chitosan and its derivatives against different bacterial strains is shown in Table 2.1. Chitosan can be easily modified by the presence of hydroxyl and amine groups. The modifications are aimed at improving the antimicrobial properties of chitosan, and thus increasing the spectrum of applications. Chitosan nanoparticles are currently attracting more attention because they show higher antimicrobial properties than chitosan in regular form. The polycationic chitosan nanoparticles with higher surface charge density could better interact with bacterial cells, compared to chitosan itself (Qi et al. 2004). Chitosan nanoparticles have been found effective against Escherichia coli, without raising bacterial resistant (Garrido-Maestu et al. 2018). Qi et al. (2004) demonstrated that chitosan nanoparticles exhibited an antimicrobial activity against E. coli, Salmonella choleraesuis, Salmonella typhimurium, and Staphylococcus aureus. Another study proved that nanoparticles with low molecular weight chitosan showed higher

Table 2.1 In vitro studies of antimicrobial activity of chitosan or/and its derivatives Type of chitosan Chitosan and its derivative chitosan oligosaccharide lactate

Microorganisms A. hydrophila, E. ictaluri and F. columnare in warmwater finfish

Chitosan

Gram-negative bacteria: P. aeruginosa, S. typhimurium, E. coli Gram-positive bacteria: S. aureus, S. faecalis

Chitosan and its derivative chitosan oligomers

Gram-negative bacteria: E. coli, P. fluorescens, S. typhimurium and V. parahaemolyticus Gram-positive bacteria: L. monocytogenes, B. megaterium, B. cereus, S. aureus, L. plantarum, L. brevis and L. bulgaricus

Chitosan

E. coli

Chitosans from shiitake stripes and from crab shells

Gram-positive bacteria: B. cereus, L. monocytogenes, S. aureus Gram-negative bacteria: E. coli, Flavobacterium sp., V. aeruginosa, S. typhimurium, V. parahaemolyticus

Effect Chitosan oligosaccharide lactate showed better antimicrobial activity than chitosan More molecules of chitosan were absorbed by Gramnegative than Grampositive bacteria Chitosan with higher deacetylation degree showed the best adsorption At pH 4.0, chitosan was better adsorbed by bacterial cells than at pH 5.0 Chitosan had higher antimicrobial activity than chitosan oligomers Chitosan showed higher antimicrobial activity for Gram-positive than Gramnegative bacteria The best activity of chitosan oligomers: chitosan oligomers with molecular weight of 1 kDa against Gram-negative bacteria, chitosan oligomers with molecular weight of 2 and 4 kDa against Gram-positive bacteria Chitosan with molecular weight from 5.5  104 to 15.5  104 Da showed antimicrobial activity against E. coli Chitosan with low molecular weight had better antibacterial effect on the growth of E. coli Shiitake stripes and crab shell chitosan exhibited antimicrobial activity against all pathogens Shiitake stripes chitosan was more effective than crab shells chitosan

References YildirimAksoy and Beck (2017) Chung et al. (2004)

No et al. (2002)

Liu et al. (2006)

Chien et al. (2016)

(continued)

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Table 2.1 (continued) Type of chitosan Chitosan, N-methyl chitosan, trimethyl chitosan, diethyl methyl chitosan and carboxymethyl chitosan

Microorganisms S. aureus and E. coli

Chitosan and sulfonated chitosan

S. aureus and E. coli

Chitosan and its derivatives anhydride-grafted chitosans (modified chitosans)

S. aureus and E. coli

Chitosan based films with nisin, sodium lactate, sodium diacetate, potassium sorbate or sodium benzoate

L. monocytogenes on cold-smoked salomon

Effect Trimethyl chitosan had shown the best cytocompatibility and antimicrobial activity Antimicrobial activity appeared in order: diethyl methyl chitosan < carboxymethyl chitosan < chitosan < Nmethyl chitosan < trimethyl chitosan Sulfonated chitosan exhibited higher antimicrobial activity than chitosan The minimum inhibitory concentration values of sulfonated chitosan and chitosan was 0.13 and 0.50 mg/mL (E.coli); 2.0 and 4.0 mg/mL (S. aureus) Modified chitosans showed better antimicrobial activity than chitosan The inhibitory effect of modified chitosans was 96.04–100% (S. aureus) and 82.62–99.24% (E. coli) Chitosan –sodium lactate films were the most effective against L. monocytogenes

References Bakshi et al. (2018)

Sun et al. (2017)

Braz et al. (2018)

Ye et al. (2008)

antimicrobial impact against Streptococcus mutans biofilms than nanoparticles prepared from high molecular weight chitosan (de Paz et al. 2011). Schiff bases of chitosan are another type of modification of chitosan, which have an excellent antimicrobial activity. Schiff bases are formed by reaction of amino groups of chitosan and aldehydes (Anush et al. 2018). This modified chitosan has a better antimicrobial activity against Gram-positive and Gram-negative bacteria, compared to unmodified chitosan (Anush et al. 2018; Sabaa et al. 2018). However, the contradictory results were obtained by Tamer et al. (2016), who prepared two chitosan Schiff bases with higher activity against E. coli, Pseudomonas aeruginosa and Salmonella sp. than S. aureus and Bacillus cereus.

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Fig. 2.4 Proposed mechanism of antifungal activity of chitosan on fungi

2.4.3

Antifungal Properties

According to the literature, chitosan has a great antifungal activity against chitosan sensitive fungi (Verlee et al. 2017). The hypothesis (Fig. 2.4) predicts that positive charged chitosan can interact with the negatively charged phospholipids of fungal cell membrane, causing destruction of membrane and entrance to the cell (PalmaGuerrero et al. 2009; Verlee et al. 2017). The cell membrane of chitosan-resistant fungi forms a barrier for chitosan, and this polysaccharide remains at the outer surface. Palma-Guerrero et al. (2010) found the reason for the difference in permeation into chitosan-resistant fungi and chitosan-sensitive fungi. They concluded that the plasma membranes of chitosan-sensitive fungi had more polyunsaturated fatty acids than chitosan-resistant fungi, suggesting that their permeabilization by chitosan may be dependent on membrane fluidity. This was proven by examining antifungal activity of chitosan against a mutant of Neurospora crassa with reduced plasma membrane fluidity compared with wild type of N. crassa. The mutant strain of N. crassa with a reduced amount of unsaturated fatty acids showed increased resistance to chitosan. Chitosan easily passes through the cell membrane, leading to its destruction and subsequent death of the fungal cell. Tayel et al. (2010) concluded that fungal chitosan with low molecular weight and a high deacetylation degree had the highest antifungal activity against Candida albicans. A recent study by Garcia et al. (2018) showed that the influence of chitosan molecular weight on Candidia spp. was correlated with the type of strain. When molecular weight of chitosan increased, the growth of Candida tropicalis and Candida parapsilosis decreased. However, changes in molecular weight did not affect the growth of C. albicans.

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As in the case of antibacterial properties, chitosan nanoparticles are recently attracting much interest due to their antifungal properties. Divya et al. (2018) tested the antifungal activity of different chitosan nanoparticles against four different plant pathogenic fungi: Rhizoctonia solani, Fusarium oxysporum, Colletotrichum accutatum and Phytophthora infestans. In every case high inhibition zones against tested fungi could be observed. The authors concluded that the potential mechanism of antifungal activity of chitosan nanoparticles is based on disturbance of cell membrane permeability by chitosan nanoparticles. The smaller size of chitosan nanoparticles allows penetration into the fungus cell, causing the destruction of the integrity of the cell membrane. Moreover, chitosan nanoparticles had inhibitory effect on the growth of Candida albicans and caused morphological and ultrastructural changes in Fusarium oxysporium (Dananjaya et al. 2017; Mousavi et al. 2018). This type of nanosystems can be used as a plant growth promoter and green biocide with broad spectrum of activities (Sathiyabama and Parthasarathy 2016).

2.4.4

Film-Forming Properties

Consumer preferences regarding food quality and safety lead to the design of an active packaging, whose task is to extend the shelf life of food products (Kaewprachu et al. 2015). Chitosan is the most widely investigated polysaccharide-based film. Chitosan-based films have good film forming abilities and excellent oxygen barrier properties. However, chitosan-based films showed poor mechanical properties (Fathima et al. 2018). Various methods have been attempted to improve the properties of chitosan-based films including blending with other materials. In combination with chitosan, there are several materials that provide beneficial effects in the films formation. Some of these materials are biopolymers, for example, alginates, gelatine or starch (Li et al. 2013; Dang and Yoksan 2016; Dumont et al. 2018; Gomaa et al. 2018; Merino et al. 2018; Mohammadi et al. 2018; Patel et al. 2018; Rezaee et al. 2018; Suriyatem et al. 2018; Uranga et al. 2018; Zhuang et al. 2018). Active films have been obtained with the use of various bioactive agents, for example, plant extracts, essential oils or nanoparticles that have been incorporated into the chitosan matrix (Souza et al. 2017; Azadbakht et al. 2018; Kalishwaralal et al. 2018; Kaya et al. 2018; Kurek et al. 2018; Priyadarshi et al. 2018; Salari et al. 2018; Serrano-León et al. 2018; Shankar and Rhim 2018; Sogut and Seydim 2018; Wu et al. 2018; Zhang et al. 2018). Recently published works revealed the application of chitosan-based films on real matrix food systems, such as seafood, fruits, meat, vegetables and cheese (Leceta et al. 2015; Kumar et al. 2018a; Lin et al. 2018; Lotfi et al. 2018; Yu et al. 2018). Chitosan is the most abundant biopolymer that can be used in food industry as a coating, packaging material and thickening agent due to its biodegradability, biocompatibility, non-toxicity and biofunctionality with an excellent antimicrobial and antioxidant activity. The solubility of chitosan is a disadvantage, because it

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can be dissolved only in an acidic environment. To solve this problem, the nanomaterial form of chitosan can be obtained and applied. Chitosan nanoparticles have both general properties of chitosan and general characteristics of nanomaterials. Nano sized chitosan has better interaction with the surrounding environment due to its increased charge density, surface area and quantum size effects (Vinodhini et al. 2017). Chitosan can also be used as a matrix for intelligent packaging pH indicators, in which an indicator is incorporated into the film matrix of the packaging material. A pH indicator generally contains a dye that is sensitive to pH changes and shares the information about the packed products quality. For food packaging application, polyvinyl alcohol-nanochitosan intelligent films with mulberry extract were successfully developed. The obtained results indicated that this type of films can detect the quality changes of fish (Abdul Khalil et al. 2017). Similar results were observed in chitosan-corn starch films with a red cabbage (Brassica oleracea) extract (SilvaPereira et al. 2015). Gas permeability is a very important physical property of edible films and coating. The appropriate oxygen and carbon dioxide barrier of the packaging contributes to the improvement of food quality and extension in shelf life of a food product. In addition, packaging materials should reduce the transfer of water between the food product and the environment. Chitosan-based films have moderate values of oxygen permeability and poor mechanical properties compared to other biopolymer-based films. The mechanical properties of chitosan-based films increased with increasing chitosan molecular weight. This behaviour can be assigned to organization of polymer structure and the chain entanglement, which increase with chitosan molecular weight (Rong Huei and Hwa 1996; Bierhalz et al. 2016). The incorporation of active agents to the neat chitosan contributes to improvement of physical properties of the films. The barrier and mechanical properties of chitosan-based films can be improved by the addition of active agents, for example plant extracts (Siripatrawan and Harte 2010; Ashrafi et al. 2018). The interaction between a chitosan network and polyphenolic compounds from extracts leads to the decrease in the affinity of chitosan films towards water and improvement in tensile strength and elongation at break. Another method to improve barrier and mechanical properties of chitosan-based films is polymer blending. The addition of TEMPO-oxidized cellulose nanofibres into chitosan matrix resulted in the reduction of oxygen and water vapor transmission rates due to strong interactions between carboxylate group of TEMPO-oxidized cellulose nanofibres and ammonium groups of chitosan (Soni et al. 2016). The optical properties of films and coating influence the quality of packaged food, because they contribute to products final appearance. The color and transparency of the packaging are main factors which determine the consumer’s choices. Chitosan films are transparent and have light-yellow surface (Rivero et al. 2009; EscárcegaGalaz et al. 2018). The transparency of chitosan films increased with increasing concentration of biopolymer (Escárcega-Galaz et al. 2018).

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Food Additive Properties

Apart from the various biological functions, chitosan can also be used as a food additive. Chitosan with high molecular weight was more effective as a food additive compared to low molecular weight chitosan (Shimojoh et al. 1998). The study published by Ravi Kumar et al. (2018b) demonstrated that chitosan can be added to extruded snack, causing the improvement in physical, textural, chemical, structural and colour properties of tested snacks. Improved chitosan derivatives such as chitin, chitosan and oligochitosan whiskers, reduced to nanosize, can prevent the loss of soluble protein (Chantarasataporn et al. 2013). Khan et al. (2018) concluded that chitosan could be one of the components of nano-carrier system for nisin, e.g. chitosan nanoparticles modified with monomethyl fumaric acid. The obtained results indicated that chitosan nanoparticles modified with monomethyl fumaric acid could also be used as a food preservative, due to its excellent antimicrobial activity. Qinna et al. (2013) proposed new functional food based on 1% chitosan and 5% pectin, which could be used as a meal replacement diet. Chitosan can also be used as a dietary supplement acting as a dietary fibre. However, it does not show such consistency in production and preparation compared to oats, soy and bran fibres (Hayes et al. 2008). Anandan et al. (2012) concluded that the dietary supplementation of chitosan had an protective effect on a lipid oxidation and cardiac antioxidant defence system in the induced myocardial infarction in rats (an animal model of myocardial infarction in man), which is probably due to a counteraction against free radicals or/and normalization of the free radical enzymes activities. Moreover, this effect probably is related to the presence of glutathione (GSH) in a normal level, which protects the myocardial membrane against oxidative damage. Due to its antioxidant, antimicrobial and film-forming properties, chitosan has received notice in various fields of food industry. It should be noted however, that some of chitosan applications are still in laboratory scale, and further investigations are required to confirm its possible use during commercial production. Further research should also focus on better understanding of the mechanism of the antimicrobial action of chitosan.

2.5

Application of Chitosan for Seafood Preservation

Although chitosan shows a number of biological properties in vitro, it firstly has to be effectively administered in order to actually work on food matrix. The effectiveness of the biological activity of chitosan depends on viscosity, a particle size and the degree of deacetylation chitosan (Jeon et al. 2002; Chouljenko et al. 2017). There is a number of different possible applications, all of which have their advantages and disadvantages, depending on the type of seafood product. Table 2.2 shows different possible application methods of chitosan on seafood.

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Table 2.2 Possible application methods of chitosan, depending on the type of seafood Type of seafood Whole unprocessed seafood Whole processed seafood

Application method Edible coatings Edible coatings Curing Marinating

Comminuted seafood products

Edible coatings Direct addition into the batter

Seafood processing step for application Prior to packing Prior to packing Injection Tumbling Tumbling Mixing Prior to packing Mincing Bowl cutting Mixing

Chitosan can be applied to both processed and unprocessed seafood. The most effective and easiest applications is the direct addition of chitosan into the batter of comminuted seafood products, while the fresh and unprocessed seafood has to be covered in chitosan containing edible coatings. The easiest application method has been used in the case of comminuted products, such as fish balls, fish fingers or fish sausages, where chitosan can be added directly into the seafood batter (Shahidi et al. 2002; Tayel 2016; Martin Xavier et al. 2017). This allows for a uniform distribution of the chitosan within the sample and the use of this method usually provides a significant shelf-life extension and increases the quality of the final product. The obvious disadvantage of this method is the limited number of products to which it can be applied for. In the case of noncomminuted seafood products, the use of edible coatings is often employed. As mentioned in Sect. 2.4, chitosan as a polysaccharide has not only film forming properties, allowing the incorporation of other bioactive compounds but also shows various biological properties by itself. The edible coating can be administered using different methods such as wrapping, rolling, brushing, casting, dipping or spraying (Galus and Kadzińska 2015). The employed method depends on the type of product to which the film is to be applied, and all of these application methods have their disadvantages. Wrapping involves the use of previously dried film, the coating is visible for the consumer and is not so effective in the case of products with irregular surface. Dipping allows to coat the whole product, even with irregular surface, however it might result in thick and non-uniform layer of the coating, which might affect the appearance and quality of the coated product (Costa et al. 2018). Spraying allows to receive thinner layers of the coating however when using this technique the problem with uneven application and surface runoff results in low efficiency of the method. To further improve this method an electrostatic spraying (electrospraying) technique can be used. The method involves the application of an electric filed to the coating solution during spraying. The charged solution particles are attracted to the ground food sample, and disperse throughout the whole surface of the product. Electrostatic spraying results in better coating

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uniformity and allows using thinner layers of the coating while the biological efficiency of the coating is improved over the regular spraying technique (Ganesh et al. 2010; Peretto et al. 2017). In recent years, nanocoating through layer-by-layer technique has been proposed the food industry. The layer-by-layer procedure is based on applying oppositely charged polyelectrolytes, therefore, due to cationic nature of chitosan, it could be used to obtained nanolayers (Fabra et al. 2016). In the case of cured or marinated seafood products, the vacuum tumbling technique can be used also to effectively administer chitosan not only on the surface but also into the interior parts of the product, with retaining the integrity of the seafood flesh (Chouljenko et al. 2017; Bonilla et al. 2018). The recent development of the whole spectrum of the possible methods of the application of chitosan allows its use on almost every type of seafood, both fresh and processed. Though, in the case of processed and comminuted seafood various more effective methods can be applied during such processes as mixing, curing or marinating. This enables a broader use and implementation of the technology directly into the industry.

2.6

The Effect of Chitosan on Shelf-Life and Quality of Seafood

Seafood is highly susceptible to spoilage with limited shelf-life that is few days to 2 weeks. The main causes for such rapid spoilage are microbiological growth and, in the case of fatty fish species, lipid oxidation. Apart from potential toxicity, both of these spoilage mechanisms result in the reduction of sensory attributes (Gram and Huss 1996; Sivertsvik et al. 2002). As mentioned in Sect. 2.4, chitosan has various bioactive properties, including potent antioxidant and antimicrobial properties and its administration into food products can affect the products shelf-life and quality. The effectiveness of these properties depends on the application method, type of seafood, chitosan properties and chitosan concentration used. Table 2.3 summarizes the effect of chitosan application on various seafood products, depending on the type of application. The most popular method is the use of chitosan containing coatings. The use of chitosan coatings often results in lower oxidation rates and inhibition of bacterial growth (Fernández-Saiz et al. 2013; Qiu et al. 2016). Moreover chitosan coatings can also reduce formation of total volatile basic nitrogen, which in the case of fish consists mostly trimethyloamine and ammonia, responsible for specific odour of spoiled fish, as well as reduces the formation of various other compounds, such as hypoxanthine or propanal, responsible for off-flavors and off-odours of stored fish products (Jeon et al. 2002). Thus the use of chitosan results in a better quality of the stored seafood and slower deterioration of its sensory scores (Mohan et al. 2012; Yu et al. 2018). The observed shelf-life extension for chitosan coated seafood stored at refrigerated conditions is usually within the range of 4–9 days (Table 2.3).

Sensory

Dipping for 5 min in 2% chitosan solution and 0, 0.1, 0.5 and 1% of clove bud essential oil

Deacetylation degree: 85% Molecular weight: 400 kDa

Deacetylation degree: 91.3, 89.3 and 86.4%

Deacetylation degree: 80–95% No additional data provided

Chitosan properties

Grass carp fillets Stored: 15 days at 4 C

Dipping for 0.5 min in 1% chitosan, 1% acetic acid solution

Dipping for 10 min in 1.5% chitosan, 0.6% acetic acid and 1% licorice extract/ 0.5% citric acid solution

Application method details

Molecular weight: 660, 960 and 1800 kDa Viscosity: 14, 57 and 360 cps

Antioxidant

Antioxidant

Properties studied

Stored: 12 days at 4 C

Cod and herring fillets

Product Coatings Ovate pompano fillets Stored: 6 months at 18  C

Table 2.3 Effects of chitosan on the shelf life and quality of seafood products

Inhibition of oxidation rate (thiobarbituric acid reactive substances, peroxide value). Reduction of free fatty acids formation Reduction in drip loss Slightly more pronounced effect of chitosan and licroice extract than of chitosan alone. Significant inhibition of peroxide value, conjugated dienes and thiobarbituric acid reactive substances increase during storage with higher efficiency observed for chitosan with lower viscosity Significant inhibition of trimethyloamine, hypoxanthine, total volatile basic nitrogen, total volatile aldehydes and propanal increase, with higher efficiency observed for chitosan with higher viscosity. Inhibition of sensory scores reduction during storage Reduction in formation of trimethyloamine, volatile oxidation products, off-taste nucleotides and histidine Improved shelf-life by at 4–8 days

Effect

(continued)

Yu et al. (2018)

Jeon et al. (2002)

Qiu et al. (2016)

Reference

2 Chitosan for Seafood Processing and Preservation 61

Stored: 12 days at 4 C

Stored: 18 days at 2 C Fresh silver carp fillets

Product Indian white prawn

Sensory

Antioxidant

Antimicrobial

Properties studied Antimicrobial

Table 2.3 (continued)

Dipping for 20 min in 1% acetic acid solution with 2% chitosan and chitosan nanoparticles

Application method details Polyactic acid films with 0.5, 1 and 2% of chitosan nanoparticles

Molecular weight: 850 kDa

Deacetylation degree: 83%

Deacetylation degree: 80.9% Moisture: 3% Viscosity: 74 cps

Chitosan properties Particle size: 10–100 nm

Significant reduction in total volatile basic nitrogen, mesophilic and psychrotrophic counts throughout storage, with chitosan nanoparticles exhibiting higher efficiency. Significant reduction of pH increase during storage Slight reduction in thiobarbituric acid reactive substances at the last days of storage No significant difference in sensory scores between groups for the first 6 days of storage, but significant improvement of sensory scores for both chitosan and chitosan nanoparticles groups after day 6 compared to control. Shelf-life extension by up to 6 days

Effect Reduction of total volatile basic nitrogen and free fatty acids content during 18 days of storage by films with 1% chitosan nanoparticles. Slight (3 log cfu/g reduction). Significant inhibition of pH increase by chitosan nanoparticles Slight reduction in thiobarbituric acid reactive substances at the last days of storage by chitosan nanoparticles Significant inhibition of hardness and springiness reduction during storage, with chitosan nanoparticles exhibiting higher efficiency. Inhibition of total viable counts, total volatile basic nitrogen, thiobarbituric acid reactive substances and peroxide value increase throughout the storage period Higher sensory scores and water holding capacity throughout the storage period The efficiency improves with higher young apple polyphenols addition Reduced deterioration of sensory scores

(continued)

Mohan et al. (2012)

Sun et al. (2018)

Wang et al. (2015)

2 Chitosan for Seafood Processing and Preservation 63

Stored: 16 days at 4 C

Tumbling Catfish fillet

Stored: 15 days at 4 C

Fresh sole and hake fillets

Product

Antimicrobial

Antioxidant

Antimicrobial

Properties studied

Table 2.3 (continued)

Comaprison of three methods: spraying (15 mL), dipping (10 min) and vacuum tumbling (10 min in 0.5% chitosan, 1% acetic acid solution

Molecular weight: low

Wrapping in 3% chitosan film packed in air and vacuum

No additional data provided

Molecular weight: medium

Deacetylation degree: 83.3%

Chitosan properties

Application method details

Slight or no reduction in aerobic plate counts for spraying and dipping methods. More pronounced effect for vacuum tumbling method. Reduction of total volatile basic nitrogen increase with vacuum tumbling exhibiting the highest efficiency

Effect Improved shelf-life by 3–5 days (from 5 to 8–10 days) The effect was more pronounced with 2% chitosan treatment Significant reduction in the total viable counts, Pseudomonas and H2S producing bacteria, with more pronounced effect observed for combination of chitosan and vacuum packing Slight reduction in lactic acid bacteria Significant reduction of L. monocytogenes (previously inoculated) counts The reduction of Enterobacteriaceae counts more related to vacuum packaging then to chitosan content Shelf-life extension by at least 7–9 days (from 6–8 days to 15 days and above)

Bonilla et al. (2018)

FernándezSaiz et al. (2013)

Reference

64 P. Kulawik et al.

Antimicrobial

Stored: for 4 months at 20  C

Antimicrobial

Stored: for 4 months at 20  C

Sensory

Antioxidant

White shrimp meat

Sensory

Antioxidant

White shrimp meat

Sensory

Vacuum tumbling in 0.5% water-soluble and regular chitosan solution for 10 min at 2270 g

Vacuum tumbling in 0.5% solutions of chitosan and chitosan nanoparticles for 10 min at 2270 g

Molecular weight: 115.6 and 375.2 kDa

Water solubility: 89.5 and 1%

No additional data provided

Molecular weight: medium

Significant reduction in thiobarbituric acid reactive substances at the last days of storage for all application methods Small increase in yellowness of the chitosan treated fillets. No changes in redness and lightness and no changes in cutting strength observed during storage. Shelf-life extension by 4 days for spraying and dipping techniques and by 8 days for vacuum tumbling technique Significant reduction of aerobic plate counts throughout the storage period but no difference in yeasts and molds counts. Inhibition of oxidation rate, reduced moisture loss and reduced color deterioration by both chitosan treated samples, but no changes in cutting force. No significant differences between chitosan and chitosan nanoparticles observed Significantly lower aerobic plate counts and thiobarbituric acid reactive substances increase throughout the storage, with more pronounced effect observed for water soluble chitosan None or slight reductions in yeasts and molds counts Moisture loss, color parameters and cutting force was not significantly different then from tumbled control sample (continued)

Chouljenko et al. (2016)

Chouljenko et al. (2017)

2 Chitosan for Seafood Processing and Preservation 65

Sensory

Antimicrobial

Properties studied Antioxidant

Application method details Dipped in 2% chitosan solution and 1% acetic acid (control) for 120 min

Direct addition into batter formulation Fish sticks Sensory Addition of 0.5, 1, 1.5 and 2% of chitosan from rohu gel during batter mixing Antioxidant

Product Gutted fresh silver carp carcass Stored: for 30 days at 3 C

Table 2.3 (continued)

Deacetylation degree: 86% Molecular weight: 76.5 kDa Viscosity: 100 cps

Molecular weight: 160 kDa

Chitosan properties Deacetylation degree: 85%

Significantly reduced oxidation rate, measured by peroxide value and thiobarbituric acid reactive substances. Reduced total volatile basic nitrogen content Reduction of all texture profile analysis parameters, except cohesiveness Increased redness and yellowness All effects were more pronounced with higher chitosan content

Improved coating pickup and cooking yield. Reduced frying loss. Reduced fat uptake during frying

Effect Inhibition of total viable counts from day 10 till the end of storage, reaching approx 1.5 log cfu/g reduction Significantly reduced thiobarbituric acid reactive substances and total volatile basic nitrogen formation throughout the storage Reduced pH increase during storage Reduced sensory scores deterioration during storage Shelf life extension by 5 days (from 25 to 30 days) measured by microbiological and sensory analysis

Martin Xavier et al. (2017)

Reference Fan et al. (2009)

66 P. Kulawik et al.

Stored: 12 days at 4 C

Antioxidant

Addition of 0.005, 0.01, 0.015 and 0.02% of chitosan to the batter during homogenization

Deacetylation degree: 91.3, 89.3 and 86.4% Molecular weight: 660, 960 and 1800 kDa Viscosity: 14, 57 and 360 cps

Addition of 1.5% of chitosan powder or 1.5% chitosan gel during bowl cutting for the total time of 10 min and additionally treated with high pressure (350 MPa)

Comminuted herring meat

Antimicrobial

Cod sausage

Deacetylation degree: 91% Viscosity: 77 cps Deacetylation degree: 97%

Molecular weight: 29 kDa

No additional data provided

Sensory

Stored: 28 days at 4 C

Addition of 1.5% of chitosan solution during batter mixing

Stored: 25 days at 2 C

Antimicrobial

Fish sausages from Nile tilapia

Slightly lower total viable counts in sausages with chitosan gel. Significantly higher total viable counts and lactic acid bacteria counts for sausages with powdered chitosan. Significantly lower total volatile basic nitrogen in sausages with chitosan gel. No differences between control and sausages with chitosan powder. The main antimicrobial effect was mainly due to high-pressure treatment. Effect of chitosan addition was very low. Peroxide value, thiobarbituric acid reactive substances, propanal and total volatiles content significantly reduced throughout the storage compared to control, but antioxidant power of chitosan was lower than of butylated hydroxytoluene and tertbutylhydroquinone. The higher antioxidant power was observed for samples with lower viscosity chitosan.

Significant reduction in total viable counts, yeasts and molds, coliforms, Entrobacteriaceae, E. coli and S. aureus counts through the storage period Improved odor and taste scores of treated sausages, slightly improved color and texture scores.

Janak et al. (2002)

LópezCaballero et al. (2005)

Tayel (2016)

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There is a number of studies which show the effectiveness of chitosan application on the various seafood products. The application of chitosan based preservation methods allows improving the sensory quality as well as inhibits the progress of oxidation and microbial growth. It should be underlined that these effects are confirmed by various authors using different analytical methods to measure an oxidation rate, and microbial activity. Chitosan nanoparticles seem to be a promising agent for further improvement of the chitosan coatings efficiency. Coatings containing chitosan nanoparticles are more effective in inhibiting microbial growth then coatings with normal chitosan, and allow retaining high sensory scores of the stored fish fillets and shrimp flesh (Ramezani et al. 2015; Wang et al. 2015). Oppositelly, not all studies with chitosan nanoparticles show such promising results. Fathima et al. (2018) used polyactic acid films with nanochitosan in the range of 0.5–2%, as coatings for Indian white prawn meat stored for 18 days at 2  C. The study showed that polyactic acid films with 1% nanochitosan reduced the total volatile basic nitrogen and free fatty acids formation in shrimps. They also slightly reduced the aerobic plate counts, resulting in 3 days extension of stored shrimps (from 15 to 18 days). Moreover the films with 2% nanochitosan addition did not affect total volatile basic nitrogen and free fatty acids formation at all. Although coating is currently the most common application technique used, vacuum tumbling have proven to be even more effective in shelf-life extension of stored seafood. Bonilla et al. (2018) compared the spraying dipping and vacuum tumbling technique of 0.5% chitosan solution application onto catfish fillets and observed that vacuum tumbled fillets had longer shelf-life extension (by 8 days compared to control, while the other techniques only by 4 days). This was due to high microbial growth inhibition, as measured by aerobic plate counts analysis and by lower total volatile basic nitrogen content. The resulting difference was attributed to higher chitosan solution uptake, since the solution penetrated deeper into the product during tumbling. Similarly significant antimicrobial and antioxidant impacts have been observed for frozen white shrimp muscle, vacuum tumbled in chitosan and chitosan nanoparticles solutions (Chouljenko et al. 2017). It is important to use chitosan with high water solubility properties, when vacuum tumbling technique is to be used, since it allows for a better and easier penetration of chitosan into the muscle (Chouljenko et al. 2016). All the above-mentioned studies show that vacuum tumbling does not negatively affect the texture and colour parameters of treated fish and shrimp muscle. The addition of chitosan solution or gel into the comminuted fish batters significantly improves the microbiological quality of the final product. Tayel (2016) added 1.5% of chitosan solution into Nile tilapia sausage batter and observed a reduction of over 4 log cfu/g in total viable counts throughout the 28 days of storage. Similarly, high reductions were observed for coliform bacteria (above 3 log reduction), yeasts and molds (above 2 log reduction), Enterobacteriaceae (above 3 log reduction), E. coli (2 log reduction) and S. aureus (complete inhibition). The authors also

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reported the increase in sensory scores of the stored sausages. Moreover, chitosan addition into comminuted fish batter significantly improved the oxidation status of batter, significantly inhibiting the peroxide value as well as thiobarbituric acid reactive substances, propanal and total volatiles formation. It should be noted though, that the antioxidant potential of the chitosan is still significantly lower than of commercial artificial antioxidants such as butylated hydroxytoluene or tertbutylhydroquinone (Janak et al. 2002). The addition of chitosan into fish batter formulations can not only improve its microbiological quality and oxidation status, but also affects its many physicochemical and sensory properties. According to Martin Xavier et al. (2017), the addition of 0.5–2% of chitosan into the fish sticks results in significantly lower cooking and frying losses, which improves not only the texture and sensory parameters of the product but also increases the economic viability of the whole production process. Moreover the chitosan addition leads to lower fat uptake during frying, which is beneficial in terms of nutritional value of the product. The impacts were more pronounced with increasing chitosan content. The addition of chitosan to seafood products allows to handle two main spoilage factors: increased oxidation and microbiological spoilage. This results in decreased deterioration of sensory scores during storage and prolonged shelf-life of chitosan treated seafood products.

2.7

Future Challenges and Trends in Wide-Ranging Use of Chitosan

The biggest challenge faced by chitosan researchers is to elaborate nano-systems, which result in the preservation of smaller amount of bioactive agents, connected with controlled delivery. Chitosan, with high biocompatibility and good stability, could be one of the components of the nanosystems, such as nanoparticles, nanocapsules, nanofibers, nanoliposomes, nanoemulsions etc. Further studies are necessary to clarify the aspects such as compatibility of biopolymer and encapsulated active agents and their influence on food matrix and potential toxicity. To extend the shelf life of the packaged food, scientists increasingly propose innovative active packages, which is based on addition of active agents with carbon dioxide emitting/generating, antimicrobial or antioxidant activity. The chitosanbased films generally have intrinsic antioxidant and antimicrobial activity, selective permeability to gases (Elsabee and Abdou 2013), therefore they are good alternatives for active packaging matrix. Future trends in food technology will rely on non-toxic, biodegradable, biocompatible and active packaging materials. The biggest challenge in this area is to create natural, active packaging materials with physical and mechanical properties similar to features of synthetic materials.

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Conclusion

Chitosan is undoubtedly one of the most important biomaterials of the twenty-first century. Newly developed methods for acquiring chitosan from seafood derived chitin, allow to obtain high quality chitosan with predetermined properties, and with much lower negative impact on the environment then standard chemical methods. Chitosan can be a part of a functional food or used as part of an active packaging, exhibiting antioxidant and antimicrobial properties with its effectiveness recently confirmed on real seafood products. Moreover the growing interest in the use of chitosan as part of nanosystems can further enhance its bioactive properties. With a number of novel application methods, chitosan can be added to all types of seafood, from comminuted fish products to whole unprocessed seafood and therefore its importance for the seafood industry is expected to increase.

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Uranga J, Puertas AI, Etxabide A, Dueñas MT, Guerrero P, de la Caba K (2018) Citric acidincorporated fish gelatin/chitosan composite films. Food Hydrocoll. https://doi.org/10.1016/j. foodhyd.2018.02.018 Varma AJ, Deshpande SV, Kennedy JF (2004) Metal complexation by chitosan and its derivatives: a review. Carbohydr Polym 55:77–93. https://doi.org/10.1016/j.carbpol.2003.08.005 Verlee A, Mincke S, Stevens CV (2017) Recent developments in antibacterial and antifungal chitosan and its derivatives. Carbohydr Polym 164:268–283. https://doi.org/10.1016/j.carbpol. 2017.02.001 Vijaya Y, Popuri SR, Boddu VM, Krishnaiah A (2008) Modified chitosan and calcium alginate biopolymer sorbents for removal of nickel (II) through adsorption. Carbohydr Polym 72:261–271. https://doi.org/10.1016/j.carbpol.2007.08.010 Vinodhini PA, Sangeetha K, Thandapani G, Sudha PN, Jayachandran V, Sukumaran A (2017) FTIR, XRD and DSC studies of nanochitosan, cellulose acetate and polyethylene glycol blend ultrafiltration membranes. Int J Biol Macromol 104:1721–1729. https://doi.org/10.1016/j. ijbiomac.2017.03.122 Wang X, Du Y, Liu H (2004) Preparation, characterization and antimicrobial activity of chitosan– Zn complex. Carbohydr Polym 56:21–26. https://doi.org/10.1016/j.carbpol.2003.11.007 Wang Y, Liu L, Zhou J, Ruan X, Lin J, Fu L (2015) Effect of chitosan nanoparticle coatings on the quality changes of postharvest Whiteleg shrimp, Litopenaeus vannamei, during storage at 4 C. Food Bioprocess Technol 8:907–915. https://doi.org/10.1007/s11947-014-1458-8 Wu Z, Huang X, Li YC, Xiao H, Wang X (2018) Novel chitosan films with laponite immobilized Ag nanoparticles for active food packaging. Carbohydr Polym 199:210–218. https://doi.org/10. 1016/j.carbpol.2018.07.030 Xia W, Liu P, Zhang J, Chen J (2011) Biological activities of chitosan and chitooligosaccharides. Food Hydrocoll 25:170–179 Xu Y, Gallert C, Winter J (2008) Chitin purification from shrimp wastes by microbial deproteination and decalcification. Appl Microbiol Biotechnol 79:687–697. https://doi.org/10. 1007/s00253-008-1471-9 Yan N, Chen X (2015) Don’t waste seafood waste: turning cast-off shells into nitrogen-rich chemicals would benefit economies and the environment. Nature 524:155–158 Ye M, Neetoo H, Chen H (2008) Effectiveness of chitosan-coated plastic films incorporating antimicrobials in inhibition of Listeria monocytogenes on cold-smoked salmon. Int J Food Microbiol 127:235–240. https://doi.org/10.1016/j.ijfoodmicro.2008.07.012 Yen MT, Tseng YH, Li RC, Mau JL (2007) Antioxidant properties of fungal chitosan from shiitake stipes. LWT Food Sci Technol 40:255–261. https://doi.org/10.1016/j.lwt.2005.08.006 Yen MT, Yang JH, Mau JL (2008) Antioxidant properties of chitosan from crab shells. Carbohydr Polym 74:840–844. https://doi.org/10.1016/j.carbpol.2008.05.003 Yi Y, Wang Y, Liu H (2003) Preparation of new crosslinked chitosan with crown ether and their adsorption for silver ion for antibacterial activities. Carbohydr Polym 53:425–430. https://doi. org/10.1016/S0144-8617(03)00104-8 Yildirim-Aksoy M, Beck BH (2017) Antimicrobial activity of chitosan and a chitosan oligomer against bacterial pathogens of warmwater fish. J Appl Microbiol 122:1570–1578. https://doi. org/10.1111/jam.13460 Younes I, Hajji S, Frachet V, Rinaudo M, Jellouli K, Nasri M (2014) Chitin extraction from shrimp shell using enzymatic treatment. Antitumor, antioxidant and antimicrobial activities of chitosan. Int J Biol Macromol 69:489–498. https://doi.org/10.1016/j.ijbiomac.2014.06.013 Yu D, Xu Y, Regenstein JM, Xia W, Yang F, Jiang Q, Wang B (2018) The effects of edible chitosan-based coatings on flavor quality of raw grass carp (Ctenopharyngodon idellus) fillets during refrigerated storage. Food Chem 242:412–420. https://doi.org/10.1016/j.foodchem. 2017.09.037 Yuan G, Lv H, Tang W, Zhang X, Sun H (2016) Effect of chitosan coating combined with pomegranate peel extract on the quality of Pacific white shrimp during iced storage. Food Control 59:818–823. https://doi.org/10.1016/j.foodcont.2015.07.011

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Zargar V, Asghari M, Dashti A (2015) A review on chitin and chitosan polymers: structure, chemistry, solubility, derivatives and applications. Chem Biol Eng Rev 2:204–226. https:// doi.org/10.1002/cben.201400025 Zhang H, Yun S, Song L, Zhang Y, Zhao Y (2017) The preparation and characterization of chitin and chitosan under large-scale submerged fermentation level using shrimp by-products as substrate. Int J Biol Macromol 96:334–339. https://doi.org/10.1016/j.ijbiomac.2016.12.017 Zhang Z-J, Li N, Li H-Z, Li X-J, Cao J-M, Zhang G-P, He D-L (2018) Preparation and characterization of biocomposite chitosan film containing Perilla frutescens (L.) Britt. essential oil. Ind Crop Prod 112:660–667. https://doi.org/10.1016/j.indcrop.2017.12.073 Zhuang C, Jiang Y, Zhong Y, Zhao Y, Deng Y, Yue J, Wang D, Jiao S, Gao H, Chen H, Mu H (2018) Development and characterization of nano-bilayer films composed of polyvinyl alcohol, chitosan and alginate. Food Control 86:191–199. https://doi.org/10.1016/j.foodcont.2017.11. 024 Zou P, Yang X, Wang J, Li Y, Yu H, Zhang Y, Liu G (2016) Advances in characterisation and biological activities of chitosan and chitosan oligosaccharides. Food Chem 190:1174–1181. https://doi.org/10.1016/j.foodchem.2015.06.076

Chapter 3

Applications of Chitosan as Food Packaging Materials Patricia Cazón and Manuel Vázquez

Abstract The interest in biopolymers has increased due to the depletion of the fossil fuel reserve and the environmental impact caused by the accumulation of non-biodegradable plastic-based packaging materials. Many biopolymers have been developed from food waste products to reduce this waste and, at the same time, to obtain new food packaging materials. Chitosan is thus an alternative to synthetic polymers, and a raw material for new materials. To assess the suitability of a material as a food packaging material, it is necessary to study their mechanical and permeability properties. Mechanical properties allow to predict the behaviour of films during transportation, handling and storage of packaged foods. Barrier properties play a key role in maintaining the food product quality. Properties values depend on the type of chitosan used. Mechanical and barrier properties of pure chitosan films are suitable for food packaging and active packaging. These properties can be modified by combining chitosan with other components such as plasticizers, other polysaccharides, proteins and lipids. These combinations adapt the properties of the final polymer to the needs of the food to extend its useful life, while maintaining quality properties of the food and the biodegradability of the polymer. Chitosan displays antimicrobial activity against a wide range of foodborne filamentous fungi, yeast, and gram-negative and gram-positive bacteria. This antimicrobial property and film-forming capacity has made chitosan the reference polymer to develop active packaging with the ability to inhibit the growth of microorganisms and improve food safety. Regarding the optical properties, pure chitosan films in the visible range show high transmittance values, being optically transparent films. This is an important parameter related to the acceptability of the films by the consumer. In addition, chitosan-based films exhibit remarkable UV absorbance, which allows to protect food from lipid oxidations induced by UV radiation. Keywords Film · Mechanical properties · Barrier properties · Antimicrobial · UV protect · Active food packaging P. Cazón · M. Vázquez (*) Department of Analytical Chemistry, Faculty of Veterinary, University of Santiago de Compostela, Lugo, Spain e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_3

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Introduction

Over the last decades, there has been a growing interest to find alternatives to petroleum-based plastics due to environmental concerns. Plastic waste becomes a serious problem. One approach for solving this problem is to use biodegradable materials instead of non-renewable polymers in packaging. These materials have the potential effect of reducing environmental pollution by lowering solid disposal waste. From few years ago, the applications of synthetic films in food packaging have grown quickly. Synthetic polymers of petrochemical origin such as polyethylene terephthalate, polyvinylchloride, polyethylene, polypropylene, polystyrene and polyamide are used as packaging materials because they have optimal properties, such as good mechanical properties, heat sealability and good barrier to several compounds such as oxygen, carbon dioxide, water vapour and aroma compounds. Moreover, synthetic polymers of petrochemical origin can be obtained at low cost. However, this type of polymers presents a great disadvantage: they are non-biodegradable. Today, incineration is a common method to get rid of polyolefines, but this unfortunately leads to high emission of carbon dioxide. Besides, their accumulation led to a serious environmental problem. The development of biodegradable polymers to eco-friendly food packaging is among the strategies to minimize the problem of the accumulation of plastics in the environment. Nowadays, the complete replacement of petrochemical-based polymers with biodegradable polymers is impossible to achieve. But the new biopolymers developed can be a solution to a partial replacement of non-biodegradable polymers depending on their application due to their capabilities to prevent moisture loss, aromas loss, solute transport, water absorption in the food matrix or oxygen penetration (Kerch and Korkhov 2011; Cazón et al. 2017). In addition, these materials are gaining particular attention in food preservation. They offer the possibility to extend the shelf life by direct contact with fresh or processed foods, due to its own properties or because it acts as a transport for other food additives (Elsabee and Abdou 2013). The raw materials studied to develop new biopolymers are from renewable natural sources such as proteins, lipids, polysaccharides and all combinations among them. Sometimes, the incorporation of additives is used to improve the properties of the films (Cazón et al. 2017). Chitosan is one of the most studied polysaccharides. More than 9000 articles on chitosan films have been published since 2016 until the beginning of 2019 (ScienceDirect®). Chitosan has received attention for its commercial applications in the biomedical, food, and chemical industries because is nonantigenic, non-toxic, biodegradable, biocompatible, bio-functional, with forming-films capacity and antimicrobial properties (Aider 2010; Cazón et al. 2017). It has been approved as a food additive in Korea and Japan since 1995 and 1983, respectively. Shrimp-derived chitosan was submitted to the US Food and Drug Administration (FDA) to be considered as generally recognized as safe (GRAS) based on the scientific procedures for use in foods in general since 2001 (No et al. 2007). Furthermore, it is the second most abundant polysaccharide in the world and it can be obtained from plentiful renewable sources, primarily waste from the shellfish

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Fig. 3.1 Sample of pure chitosan film prepared from an aqueous solution of 1% (w/w) of chitosan with molecular weight in the range 100–300 kDa and with 1% (v/v) of acetic acid. The film was obtained by the cast method in a Petri dish and dried at room temperature for 2 days. Note the brightness and transparency of pure chitosan films

industry. Therefore, it is inexpensive and commercially available. This is very important because a low cost material is needed as the contribution of the packaging material to the total product cost is highly significant (Kim et al. 2006; Aider 2010; Cazón et al. 2017). The film-forming properties of chitosan allow the production of films and coating materials with good mechanical properties, a selective permeability to CO2 and O2 and antimicrobial properties to apply directly on food in order to improve food safety and shelf life. Figure 3.1 shows a chitosan film obtained in our laboratory. Several strategies have been proposed to improve the functional properties of chitosan films and expand its potential applications, like modifications of the deacetylation degree, pH, solvent type and mixing with plasticizers or other components such as proteins or polysaccharides (Elsabee and Abdou 2013).

3.2

Chitosan Film and Coating Properties

Chitosan is a high-molecular-weight cationic natural polymer composed of randomly distributed chains of β-(1–4) D-glucosamine (deacetylated units) and N-acetyl-D-glucosamine (acetylated unit). Chitosan is a derivate of chitin, one of the most abundant biological materials in the world. After cellulose, it is the second most abundant biopolymer. Chitin is mainly isolated from crustacean wastes (shrimp and crabs). Alternative chitin or chitosan sources are fungi, yeast, protozoa, green microalgae, and insects, although their industrial application is limited (Chenite et al. 2001; Rinaudo 2006; Kerch and Korkhov 2011; Van Den Broek et al. 2015). Chitin is found complexed with other substances such as proteins and minerals. To obtain chitin, it is necessary to treat the wastes with an acid treatment (decalcification) followed by an alkaline treatment (deproteination), and finally a

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decolorization step. In order to prepare chitosan, an additional alkaline treatment is performed to deacetylate chitin. Chitin is highly acetylated and is insoluble in water. To obtain chitosan, it is needed a degree of N-acetylation lower than 50%, depending on the origin of the polymer. Hence, chitosan is a derivate of chitin by alkaline deacetylation. Chitosan does not identify a single unique substance, it is used to describe a series of polymers with different average molecular weights (50–2000 kDa) and degrees of deacetylation (40–98%). In solid state, it is semi-crystalline and with property of solubility in dilute organic acids such as acetic acid. These different ranges of molecular weights and degrees of deacetylation depend on the conditions of the deacetylated reaction. The alkali concentration, incubation time, ratio chitin to alkali, temperature, atmosphere, type of chitin source (including polymorph type), particle size and heterogeneous/homogeneous N-deacetylation affect the film properties of chitosan. Regarding the solubility of chitosan to get film solutions, it depends on the degree of deacetylation, the distribution of acetyl groups along the main chain, the molecular weight and the nature of the acid used. Due to the nature of the polymer, the simplest dissolution method is through slightly acidic solutions. In this case, the solubilization occurs by protonation of the amino groups on the C2 position of the D-glucosamine repeat unit. These amino groups have a pKa value around 6.5, which leads to a protonation in dilute acid. The concentration of protons needed is at least equal to the concentration of –NH2 units involved (i.e. acetic, lactic, adipic, formic, malic, malonic, propionic, pyruvic, succinic acids). At concentrations above >2% (w/w) of chitosan, solutions become very viscous, making it difficult to manipulate the solution (Van Den Broek et al. 2015; Leceta et al. 2013; Morgado et al. 2011; Rinaudo 2006). The main drawback for the application of chitosan solutions is the acid pH at which the solution must be maintained. By increasing the pH of the solution above 6.2, the formation of a precipitated hydrated gel occurs, due to the neutralization of the amino groups. To maintain chitosan solution up to a neutral pH, and expand the applications of chitosan solutions, it was studied the stability of chitosan solutions at pH 7.0–7.4 by adding glycerophosphate salt (Chenite et al. 2001). The results suggested that the addition of this salt provide the correct buffering and other physicochemical conditions, like the control of hydrophobic interactions and hydrogen bonding, which are necessary to retain chitosan in solution at neutral pH. However, this method has not been widely extended in subsequent studies of chitosan-based films. It has been developed a new solvent system, as alternative to acidic aqueous solution to dissolve chitosan, using alkaline system (alkali/urea) to dissolve chitosan via the freezing-thawing method, a solvent that has previously been developed to dissolve cellulose (Zhang et al. 2005). The complete dissolution of mediummolecular-weight chitosan (157.5 kDa) and low-molecular-weight chitosan (53.4 kDa) in NaOH/urea solution after six or five cycles of freeze–thaw treatments have been reported successfully (Zhang and Xia 2014). Other alternatives to the NaOH/urea system are to use LiOH or thiourea. Chitosan was successfully dissolved

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Fig. 3.2 Process of elaborating chitosan films through the casting method. (a) First step, to get the dissolution, in this case a solution of 1% (w/w) of chitosan in an aqueous solution of 1% (v/v) acetic acid. (b) Second step, the solution is poured over a Petri dish. (c) Third step, the solution is spread homogeneously on the plate. This step is important to obtain a homogeneous thickness throughout the entire film. (d) Finally, the solution is allowed to dry, evaporating the solvent, and the chitosan film is peeled off

in LiOH/urea aqueous solution (Fan and Hu 2009) and NaOH/thiourea aqueous solution (Almeida et al. 2010). Anyway, to develop films or coating for food packaging, the solution of chitosan with a slightly acidic medium like acetic acid remains as the most used method. Among all methods to obtain chitosan-based films, the casting method is the most extended (Fig. 3.2). For the casting method, it is necessary to obtain a homogenous solution of chitosan in suitable solvents (Fig. 3.2a). The solution is poured on a flat surface, usually a Petri dish (Fig. 3.2b, c). Then, if the solvent method used is by acid solution, film forming solutions are evaporated at room temperature or at a specific temperature to allow the solvent evaporation. Finally, films are peeled of the dish, as it is shown in Fig. 3.2d. Using alkali/urea method, it is necessary a step of film regeneration by immersion of the mould with the film forming solutions into a coagulating bath (Almeida et al. 2010). Then, the regenerated films are dried to peel off the mould. The film formation occurs due to the preservation of chain entanglements and intermolecular interactions formed during the drying process, such as electrostatic and hydrogen bonding (Muxika et al. 2017). Chitosan is not thermoplastic, therefore, it cannot be extruded or molded and the films cannot be heat-sealed. It degrades before the melting point. This behavior limits the production of chitosan films at a commercial level and narrows the applications. The blending of chitosan with thermoplastic

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polymers like poly(butylene succinate), poly(butyleneterephthalate adipate), poly (butylene succinate adipate), represents an alternative to improve thermal properties of this material (Van Den Broek et al. 2015; Muxika et al. 2017).

3.2.1

Mechanical Properties

The study of mechanical properties such as tensile strength and percentage of elongation of biopolymers developed as film for food packaging helps to predict the behaviour and integrity during handling, storage and transport. In addition, it is important to take into account the packed product with protuberances. Although it is not usual, it is also important to analyse the axial mechanical properties, such as puncture force and puncture deformation (Campos et al. 2011; Leceta et al. 2013). Comparing these values with the mechanical properties of commercial synthetic polymers used helps to predict the suitability and future application of the new biopolymer (Rouhi et al. 2017). Mechanical properties like tensile strength, percentage of elongation at break, puncture force and puncture deformation depend on the film composition, the nature of components, measuring equipment and measuring conditions (relative humidity and temperature). A texturometer is usually used to measure the mechanical and puncture properties of biodegradable films. Tensile strength (MPa) is the maximum stress supported by the film before breaking. It represents the resistance to elongation. Percentage of elongation at break (%) is the maximum elongation of the film before rupture (Miller and Krochta 1997; Spotti et al. 2016; Rouhi et al. 2017). There is usually an inverse relationship between tensile strength and percentage of elongation at break of biopolymer films. The extensibility of films is reduced (lower percentage of elongation at break) when strength of films increased (greater tensile strength) (Park et al. 2002). Tensile strength and percentage of elongation at break are usually calculated through the curve stress-strain, given by the software of texturometer. The test is carried out according the standard method ASTM D-882. Figure 3.3 shows an example of a mechanical test of a chitosan film. The film is placed between the grips of the texturometer fixture. Once the test is started, the upper arm of the texturometer separates in a vertical direction at a constant speed until the rupture of the film. The texturometer measures the force that needs to apply to maintain constant the speed and the distance. The arm moves to break the film. With these values, the stress-strain graph is obtained (Fig. 3.4), from which the tensile strength and percentage of elongation can be calculated. For pure chitosan films, there is a broad range of reported mechanical properties data in literature, as shown Table 3.1. According to the studies carried out, these variations are due to the different characteristics of the chitosan used (deacetylation degree, molecular weight), the solvent method used to obtain the film, the chitosan content of the film, the storage time and the measurement conditions before and during the performance of the test. Chitosan forms hydrogen bonds between hydroxyl groups and amino groups into the film. During the film formation, hydrogen bonding in the

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Fig. 3.3 Sample of 1% chitosan film fixed in grips of the texturometer ready to run the mechanical test according to standard method ASTM D-882. With this test and depending on the initial parameters as speed of test run, initial separation of the grips and film thickness, the texturometer software provides a graph that represents the stress-strain of the film: It is used to calculate the mechanical properties

Stress vs Strain 70.000 60.000

Stress (MPa)

50.000 40.000 30.000 20.000 10.000 0.000 0.000 -10.000

0.010

0.020

0.030

0.040

0.050

0.060

Strain (%)

Fig. 3.4 Example of a typical stress-strain graph obtained in the measurement of chitosan films. From this graph and knowing the initial parameters of the test run (speed, area of the film, thickness), the values of tensile strength and elongation percentage at break, among other parameters, can be calculated

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Table 3.1 Mechanical properties of pure chitosan films at different conditions Percent of elongation (%) 7.6–5.5 41.9–117.8 19.6–31.1 17.8–29.9 –

49.6–59.4

5.40–8.35

Srinivasa et al. (2004)

–

55.6

8.0

Srinivasa et al. (2003)

–

39.1

10.84

Srinivasa et al. (2007)

25  C 50% RH

61.8

4.59

Leceta et al. (2013) Leceta et al. (2013) Bof et al. (2015)

Chitosan 1% Chitosan 2%

Acetic

Chitosan 2%

Acetic

Chitosan 1%

Acetic

Chitosan 1%

Acetic

DD 80% Mw 100 kDa DD 78% Mw 100 kDa DD 78% Mw 200 kDa High Mw

Chitosan 1%

Acetic

Low Mw

25  C 50% RH

55.8

4.58

Chitosan 2.5%

Acetic

~58.0

Acetic

25  C 60% RH 25  C 60% RH

~10.0

Chitosan 2.5%

~18.0

~85.0

Bof et al. (2015)

Chitosan 2.5%

Acetic

DD 85% Low Mw DD 85% Medium Mw DD 85% High Mw

25  C 60% RH

~60.0

~5.0

Bof et al. (2015)

Composition Chitosan 2%

Chitosan properties DD 95% Mw 37–920 kDa

Tensile strength (MPa) 68.8–50.2 6.7–17.4 17.1–62.6 27.4–62.4 87.68

Acid used Acetic Citric Lactic Malic Acetic

Mw 150 kDa

Conditions 25  C 50% RH

25  C 20% RH 25  C 50% RH

References Park et al. (2002)

Li et al. (2010)

The values allow to analyze how the properties of the film vary according to the deacetylation degree, molecular weight, the solvent method used to obtain the film, the chitosan content of the film and the measurement conditions DD degree of deacetylation, RH relative humidity, Mw molecular weight

chitosan films increased with the increasing amount of amino and hydroxyl groups. For this reason, the chitosan molecular weight affects on the type and number of polymer-polymer and polymer-solvent interactions. High molecular weight chitosan has high polymerization degree chains, which favours polymer-polymer interactions, leading to strong matrices and decreasing to decrease the molecular weight. At higher interactions to increase the molecular weight produce an increase of the tensile strength and a decrease of percentage of elongation values, as can be seen in Table 3.1 (Park et al. 2002; Kerch and Korkhov 2011; Bof et al. 2015). The storage time has effect on mechanical properties of the films. It was observed an increase of tensile strength, regardless of the molecular weight. The authors explained it by conformational changes of chitosan macromolecules and decrease

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Fig. 3.5 Example of the texturometer accessory to carry out puncture tests. The texturometer measures the force on the cylindrical probe needed to penetrate the film at constant speed and the distance at the breaking point. The film is held between the two rings of the texturometer accessory. This test allows to predict the resistance of the developed film to protuberances of the food products

of free volume during storage. These conformational changes can be responsible for the increase of tensile strength (Kerch and Korkhov 2011). Regarding the percentage of elongation, the behaviour as function of the molecular weight, depends on the solvent used (Park et al. 2002). Analysing the mechanical properties in function of the solvent employed, higher tensile strength values were obtained with acetic acid as solvent. However, higher percentage of elongation at break values were obtained with citric acid (Park et al. 2002; Kerch and Korkhov 2011). The authors explained that in acetic acid solution, chitosan forms dimers, indicating that the intermolecular interaction is relatively strong. It suggests that chitosan films prepared with acetic acid had tighter structure than those prepared with other acid solutions (Park et al. 2002; Kim et al. 2006). To obtain the films, it is necessary a drying step. According to the studies carried out analysing three different methods of drying (ambient temperature drying, oven drying and infrared drying), the results showed that the drying method used does not significantly affect the mechanical properties of films (Srinivasa et al. 2004). For other hand, puncture test determines the film strength to penetration of a cylindrical probe at constant speed (puncture force, N/mm) and the distance at the breaking point (puncture deformation, mm) (Spotti et al. 2016). Figure 3.5 shows an example of a texturometer accessory to perform puncture tests. There are not many puncture data reported in the literature. However, it is important to know these values to predict the resistance to protuberances of the food products. It was reported puncture force values of 520.69 N/mm and puncture deformation of 1.20 mm to films obtained from chitosan solution of 1% w/w low molecular weight chitosan (~150 kDa) in 1% v/v acetic acid, previously conditioned at 25  C and 20% RH (Li et al. 2010). Pure chitosan films elaborated from a 2.5% (w/w) chitosan dissolved in 1.25% (w/w) acetic acid reported values of puncture force ranged (8.87–10.23 N) and to deformation ranged (1.82–3.66 mm). The values depend on the chitosan

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molecular weight, being higher puncture force values to higher chitosan molecular weight, but lower puncture deformation (Bof et al. 2015).

3.2.2

Barrier Properties

The barrier properties of a polymeric film are crucial for estimating or predicting the product shelf-life when used as food packaging. One of the main functions of food packaging films is to retard the molecules transfer between food and the environment, for the preservation of the food quality. Measuring these properties allows to know the permeability and transfer through the film of certain molecules like gases such as O2 or CO2, water vapour, organic vapour or liquids. Plastics are relatively permeable to small molecules. They may transfer from the internal or external environment through the polymer package wall, resulting in a continuous change in product quality and decreasing shelf-life (Siracusa et al. 2008; Aider 2010; Leceta et al. 2013). The water vapour permeability is the most extensively studied property of biodegradable films. Mainly because the importance of the role of water in deteriorating reactions, keep the food freshened, crispy or prevent the dehydration, depending on the food and partly because of the ease of measurement. On the other hand, oxygen permeability, a value less studied because a special measurement equipment is needed, but important parameter. Oxygen is involved in many degradation reactions in foods, such as oxidation reactions, responsible for changes in color, odor, and taste of food, microorganism growth, enzymatic browning and vitamin loss. In addition, the permeability to oxygen is essential for respiration of fresh fruits and vegetables. Generally, hydrophilic biopolymer films show good oxygen barrier property and higher water vapour permeability (Ayranci and Tunc 2003; Siracusa et al. 2008; Aider 2010; Rao et al. 2010; Leceta et al. 2013). According to these parameters of permeability, it can be known for which food or applications the developed biofilm will be more suitable (Aider 2010; Leceta et al. 2013). Water vapour permeability quantifies the amount of water that permeates per unit of area and time (g/s m Pa) considering the pressure differential and thickness of the material. The standard method ASTM E96 is usually the most widely used to study the water vapour permeability by gravimetry. Chitosan films, like many other polysaccharide edible films, exhibit relatively low water barrier characteristics due to their high hydrophilic nature (Park et al. 2004; Aider 2010) as shown in Table 3.2. The values reported in the literature must be compared with caution. The water vapour permeability values depend on properties of films such as the molecular weight, degree of deacetylation and content of chitosan. Besides, these values are affected by various external factors such as the measuring method, measuring conditions (relative humidity and temperature), correction of air gap effect, and the storage time and conditions. Generally, the molecular weight and degree of deacetylation of chitosan and the type of solvent used to prepare the dissolution does not significantly affect the water vapour permeability values reported (Wiles et al. 2000; Park et al. 2002; Leceta et al.

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Table 3.2 Water vapour permeability data for pure chitosan films at different conditions

Chitosan 2%

Acid used Acetic Citric Lactic Malic Acetic

Chitosan 1%

Acetic

Chitosan1%

Acetic

Chitosan 1%

Acetic

DD 78% Mw 200 kDa High Mw

Chitosan 1%

Acetic

Low Mw

Chitosan 2.5%

Acetic

Chitosan 2.5%

Acetic

Chitosan 2.5%

Acetic

DD 85% Low Mw DD 85% Medium Mw DD 85% High Mw

Composition Chitosan 2%

Chitosan properties DD 95%

Conditions 25  C

Mw 370–920 kDa

50% RH

DD ~80% Mw 100 kDa Mw ~150 kDa

38  C 90% RH 25  C 50% RH 90% RH

38  C 90% RH 38  C 90% RH 5 C 2000 Pa 5 C 2000 Pa 5 C 2000 Pa

Water vapour permeability (g/m s Pa) (3.1–3.2)
10 10 (4.0-5.1)
10 10 (4.7–6.9)
10 10 (2.6–4.1)
10 10 (4016–4500) g/m2 day

References Park et al. (2002)

Srinivasa et al. (2004)

3.53 g mm/m2 h kPa

Li et al. (2010)

0.01322 g m/m2 day kPa

Srinivasa et al. (2007)

8.07
10

13

Leceta et al. (2013)

8.07
10

13

Leceta et al. (2013)

4.14
10

10

Bof et al. (2015)

3.38
10

10

Bof et al. (2015)

4.55
10

10

Bof et al. (2015)

The values allow to analyse how the properties of the film vary according to the deacetylation degree, molecular weight, the solvent method used to obtain the film, the chitosan content of the film and the measurement conditions DD degree of deacetylation, RH relative humidity, Mw molecular weight

2013; Bof et al. 2015). On the contrary, the water vapour permeability depends on the molecular weight, increasing to increase the molecular weight of chitosan used (Kerch and Korkhov 2011). However, in this study the authors analysed chitosan with different molecular weight and degree of deacetylation, being difficult to conclude if the molecular weight, the degree of deacetylation or both are the responsible of the variation on the water vapour permeability. The film permeability changes during the storage time. Experimental data showed an increasing of water vapour permeability over storage time at room temperature for both high and low molecular weight chitosan films. The authors explained that during the storage, it happens conformational changes of chitosan macromolecules and decrease of free volume. Though free volume of polymer decreases, the conformations of chitosan macromolecules change from random to more extended, responsible of increase of water vapour permeability (Kerch and Korkhov 2011). Regarding oxygen permeability, it is usually determined according to the standard method ASTM D-3935 (Park et al. 1993; Butler et al. 1996; Park et al. 2002; Vartiainen et al. 2004; Souza et al. 2015). Less commonly, it can also been

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Table 3.3 Oxygen permeability data for pure chitosan films at different conditions Acid Composition used Chitosan 2% Acetic Citric Lactic Malic Chitosan 2% Acetic

Chitosan properties DD 95%

Conditions Oxygen permeability 25  C (1.4–5.8)
10 8 cc/m day atm (3.3–3.0)
10 8 cc/m day atm Mw 0% RH (2.7–2.7)
10 8 cc/m day atm 370–920 kDa (0.8–1.9)
10 8 cc/m day atm  DD ~80% 27 C (38.0–56.0) ml/m2/day atm Mw 100 kDa 65% RH Chitosan 1% Acetic High Mw 23  C 6.65 cm3 μm/m2 day kPa 50% RH Chitosan 1% Acetic Low Mw 23  C 7.70 cm3 μm/m2 day kPa 50% RH

References Park et al. (2002)

Srinivasa et al. (2004) Leceta et al. (2013) Leceta et al. (2013)

The values allow to analyze how the oxygen permeability of the film depends on the deacetylation degree, molecular weight, the solvent used, the chitosan content and the measurement conditions DD degree of deacetylation, RH relative humidity, Mw molecular weight

determined according to the standard method ASTM D-1434 (Srinivasa et al. 2004). The oxygen permeability of edible films is attributable to capillary mechanisms. Low oxygen permeability of films makes them ideal for use in food packaging and the chitosan films exhibit excellent oxygen-barrier properties. These are similar values to those of commercial polyvinylidene chloride (PVDC) or ethylene vinyl alcohol copolymer films (Park et al. 2002; Valenzuela et al. 2013). In the literature can be found different values of oxygen permeability as it can be seen in Table 3.3. Factors such as the molecular weight of chitosan, the solvent used to prepare the filmforming solution affect the oxygen permeability of pure chitosan films (Park et al. 2002; Leceta et al. 2013; Valenzuela et al. 2013).

3.2.3

Antimicrobial Properties

Consumers demand less use of chemicals to increase the self-life food products. For that reason, there has been a growing interest in recent times to develop materials with film-forming capacity and having antimicrobial properties, which help improve food safety and shelf life. The use of antimicrobial agents of natural origin is gaining attention in the development of new food packaging materials as a natural alternative to chemically synthesized antimicrobial polymers. In addition, antimicrobial agents of natural origin is a strategy to increase shelf life and quality of foodstuff, by inhibiting the growth of microorganisms on the surface of the food, due the direct contact with the film or coating (Moreira et al. 2011; Van Den Broek et al. 2015). Chitosan is among the most studied antimicrobial agents for food packaging due to

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its property to form films and coating. Chitosan has antimicrobial activity against a wide range of foodborne filamentous fungi, yeast, and bacteria, being more active against yeasts (Helander et al. 2001; No et al. 2007). The mechanism of the antimicrobial activity of chitosan has not yet been fully elucidated. However, three main hypotheses about the mechanisms of antimicrobial action of chitosan have been proposed. The most accepted hypothesis is a change in cell permeability by electrostatic stacking of the cell surface. Chitosan, due to the positive charge of the amino group at C2 below its pKa (pH 6.3), creates a polycationic structure, that interacts with the microbial cell membranes (negative charge). This interaction leads to the leakage of proteinaceous and other intra cellular constituents. Other mechanism proposed is the penetration capacity of chitosan in the nucleus of the cell due to its low molecular weight, blocking the transcription of the DNA to RNA due to the adsorption to the DNA molecules. The last proposed mechanism is based on that chitosan can also act as a chelating agent for essential nutrients, inhibiting the production of toxins and microbial growth (Helander et al. 2001; Vartiainen et al. 2004; No et al. 2007; Van Den Broek et al. 2015). For other hand, there are intrinsic factors such as the deacetylation and polymerization degree that affect the antimicrobial activity of chitosan. In this sense, the antimicrobial activity depends on the number of protonated amino groups (–NH2) present in chitosan, which increases to higher degrees of deacetylation, because of their greater solubility and charge density (Moreira et al. 2011; Elsabee and Abdou 2013). For that, chitosan with a high degree of deacetylation (>85%) and a molecular weight of 28 kDa to 1671 kDa has shown the strongest antibacterial effects in aqueous solutions regardless of the type of acid used for solubilization (No et al. 2002). The proposed mechanisms are based on results where the action was studied by addition of microorganism to a liquid or solid culture media with chitosan. In the case of films, the inhibition mechanism has not been explained. There are also other external factors such as anaerobic conditions or asphyxia which should be considered (MartínezCamacho et al. 2010). In addition, it has been observed that the antimicrobial effect depends on the food composition (starch, proteins, NaCl, oil) (Devlieghere et al. 2004) and the interaction force between the polymer matrix and the antimicrobial compound, such the interaction yam starch-chitosan (Durango et al. 2006a, b). Table 3.4 summarizes some groups of gram-negative and gram-positive bacteria, fungi and yeasts, which have been used to study the antimicrobial effect of chitosan films. Many studies document the antimicrobial activity and mode of action of chitosan, inhibiting the growth of a wide variety of bacteria and fungi, avoiding food spoilage. Both effects are influenced by a variety of factors, such as molecular weight, deacetylation degree, pH, temperature, salinity, among others. These properties that play a significant role in the antimicrobial activity. These variations makes almost impossible to compare them and establish a minimum inhibitory concentration for each microorganism (Helander et al. 2001). For example, chitosan tested at low pH values shows an increased activity against several microorganisms (Tayel et al. 2010). The temperature is an important factor for the growth of bacteria or fungi, but it is also influenced by the antimicrobial

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Table 3.4 Some groups of Gram-negative, Gram-positive bacteria, fungi and yeasts, which have been used to study the antimicrobial effect of chitosan films Gram negative

Gram positive

Yeast Fungi

Microorganism Salmonella enteritidis Pseudomonas fluorescens Enterobacter aeromonas Photobacterium phosphoreum Escherichia coli Pseudomonas aeruginosa Salmonella typhimurium Brochothrix thermosphacta Lactobacillus plantarum Lactobacillus curvatus Pediococcus acidilactici Bacillus cereus Listeria monocytogenes Lactobacillus sakei Staphylococcus aureus Candida lambica Cryptococcus humiculus Sclerotinia sclerotium Botrytis cinerea Monilinia fructicola Rhizopus stolonifera Aspergillus niger

References Durango et al. (2006b) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Helander et al. (2001) Helander et al. (2001) Helander et al. (2001) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Devlieghere et al. (2004) Martínez-Camacho et al. (2010) Devlieghere et al. (2004) Devlieghere et al. (2004) Martínez-Camacho et al. (2010) Romanazzi et al. (2002) Martínez-Camacho et al. (2010) Martínez-Camacho et al. (2010) Martínez-Camacho et al. (2010)

activity of chitosan. It was observed a difference between the minimum inhibitory concentration value for different temperatures (Tayel et al. 2010). The effect of temperature and pH was investigated for different molecular weight samples of chitosan. The results showed that the antibacterial activity increases when the temperature increases and the pH decreases. The pH had also an influence on the effect of the molecular weight. These results showed that it was important to report the pH, the temperature, the molecular weight and the degree of deacetylation, to can compare between similar procedures.

3.2.4

Optical Properties

One of the desired characteristics of packaging material is the protection of foods from the effects of light, especially the UV radiation. UV radiation is responsible for the oxidation of lipids, since the UV light in the range of 200–280 nm is one of common oxidation initiators in food system. These oxidations are responsible for the appearance of undesirable flavours and odours in food. Hence, developing active films with good barrier properties against the UV-light help to slow the oxidation

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process of the lipids, increasing the shelf life of the food product keeping the food quality and adequate organoleptic properties (Cazón et al. 2018b). Furthermore, an important parameter of optical properties is the transparency that has a direct impact on the consumer acceptability. Consumers prefer transparent packaging to can see the product content and to observe the visual quality (Vilela et al. 2017). Therefore, it is important to formulate films with good protective barriers against UV radiation while maintaining adequate transparency. The UV-visible spectra of pure chitosan films shows a transmittance of 88–93% in the visible range (400–700 nm), being optically transparent films (Vilela et al. 2017). Furthermore, chitosan-based films exhibit remarkable UV-absorbing. The absorption capacity of the radiation observed in the band about 270–280 nm comes from unsaturated bonds, mainly C–O bonds present in the chitosan (Hajji et al. 2016; Souza et al. 2017; Cazón et al. 2018b). It is necessary to consider these properties in the possible combinations that are made of chitosan with other components to develop new polymers with adequate optical properties.

3.3

Combination of Chitosan with Other Components

Polymer blending is one of the most effective methods to obtain new material with desired properties. By mixing chitosan with other components with different mechanical, permeability and optical properties permit to obtain films with adapted properties to the desire application. Blending chitosan with a compound to have better elongation properties, it is possible to modify the water vapour permeability of the final film. It usually produces modifications in the water vapour permeability of the blend composite by adding in the chitosan matrix a hydrophobic component such as lipids. Sometimes, the aim is to develop active films, that may operate as carriers of many functional ingredients, which can include preservation agents, such as antimicrobial or antioxidant agents from natural extracts. It improves the functionality of the chitosan films. The main components used to improve chitosan-based films are usually natural components. This maintains the biodegradable and edible properties. Other studied option with satisficed results is by adding synthetic biodegradable plasticizers to modify the mechanical properties of the chitosan films.

3.3.1

Combination with Plasticizers

Compared with synthetic plastic films, an important limitation of chitosan-based films is their mechanical properties, especially their capacity to elongation. One of the most common means to improve the mechanical properties of the biopolymer films is to add a plasticizer into the film formulation (Thakhiew et al. 2015). Plasticizers are additives used to make films with higher percentage of elongation at break and more flexible, necessary to facilitate the polymer processing and

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applications (Park et al. 2002). Several theories have been proposed to explain the mechanisms of plasticization action. One of them is based on the plasticizers can act as internal lubricants, reducing frictional forces between polymer chains. Other theory establishes that the rigidity of polymer comes from three-dimensional structures where plasticizers take effect by breaking polymer-polymer interactions (e.g., hydrogen bonds and van der Waals or ionic forces) (Leceta et al. 2013). By combining chitosan with plasticizers, it seeks to reduce the stiffness of the films, reducing frictional forces between polymer chains, mainly hydrogen bonds. This way, it is possible to improve mechanical properties, increasing the percentage of elongation at break. However, it reduces the tensile strength values as shown Table 3.5 (Leceta et al. 2013). The combination of biopolymer with plasticizers can be by mixing with the film-forming solution, or by immersing the biodegradable film into a bath of plasticizer solution (Cazón et al. 2018a, b, c). For that, ideal plasticizers should be miscible and compatible with chitosan. Types of plasticizers widely used in chitosan films are polyols such as glycerol, sorbitol, and polyethylene glycol, sugars such as glucose and sucrose and lipids (Suyatma et al. 2005; Cazón et al. 2017). Glycerol is the most used plasticizer in biodegradable polymers, especially in chitosan films. The glycerol is found in the formulation of many chitosan films reported, since the presence of glycerol facilitates the handling of the film. In chitosan films, the glycerol has an effect on mechanical properties, reducing the tensile strength values and increasing the percentage of elongation at break. It was reported a variation of tensile strength from 63.1 to 22.0 MPa, and percentage of elongation from 7.2 to 84.2% to add glycerol to chitosan films (Suyatma et al. 2005). Nevertheless, the same way that affects the data to pure chitosan films, the effect of glycerol in chitosan matrix depends on the solvent used, pH of the solution, degree of deacetylation, molecular weight of the chitosan and storage time among others. Analysing the mechanical properties of chitosan-glycerol films, the tensile strength and percentage of elongation at break values of the final film depend on the solvent used, the properties of the chitosan employed and the glycerol content, as shown in Table 3.1 (Kim et al. 2006; Ziani et al. 2008). Besides, it was observed that the presence of glycerol increases the moisture content of films, emphasizing the plasticizing effect of glycerol (Ziani et al. 2008). Several homogenization and drying methods were studied with the aim of improving the values of mechanical properties previously obtained for chitosanglycerol films (Thakhiew et al. 2010; Thakhiew et al. 2015). About homogenization techniques, rotor-stator homogenization and high-pressure homogenization combined with heat- or non-heat-treated solution were studied. The objective of homogenization is to reduce the size and disperse the glycerol droplets into the film matrix, since the principal mechanism of glycerol plasticization is based on interfering with the polymer chains. In addition, by heating the film-forming solution seeks to induce thermal cross-linkage of chitosan polymer chains. Because by heating the film solutions, the hydrogen bonding among polymer chains disrupt, producing more open structures, which allow more chain-to-chain interactions, promoting the formation of intra- and intermolecular cross-linkage interactions. Results showed that combining head treatment and homogenization produce a synergistic effect on the

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Table 3.5 Mechanical properties, tensile strength and percentage of elongation of different combinations of chitosan-based films with plasticizers

Chitosan combined with Polyvinyl alcohol Poly(ethylene oxide) Polyvinyl alcohol

Glycerol Ethylene glycol Poly (ethylene glycol) Propylene glycol Glycerol

Chitosan properties Mw 150 kDa DD 78% Mw 100 kDa DD 98%

Conditions 25  C 20% RH –

23  C 50% RH

Tensile strength (MPa) 64.8–60.8 62–3.0 32.0–47.0

Percent of elongation (%) – – 26.8–70.6

31.8–59.5 33.2–53.7 36.6–65.1 36.3–74.2 20.0

19.1–84.2 16.8–67.0 12.1–19.7 6.4–44.3 35.0

High Mw

25  C 50% RH

Glycerol Glycerol

High Mw Low Mw

25  C 50% RH

31.9–43.4 23.9–36.9

30.5–11.1 27.2–37.7

Glycerol

DD 90.2% Mw 900 kDa DD 90.2% Mw 900 kDa

25  C

49.4–38.5

32.2–29.1

46.2–46.4

37.2–35.9

Rotor-stator homogenization with/without heating Glycerol High pressure homogenization with/without heating

75% RH 25  C 75% RH

References Li et al. (2010) Srinivasa et al. (2003) Suyatma et al. (2005) Souza et al. (2017) Leceta et al. (2013) Thakhiew et al. (2015) Thakhiew et al. (2015)

The values depend on the plasticizer used, the properties of the chitosan and the conditions of relative humidity DD degree of deacetylation, RH relative humidity, Mw molecular weight

mechanical properties of the films. Chitosan film exhibited an increase of about 22% in the tensile strength and 30% in the percent elongation with respect to control film (Thakhiew et al. 2015). The effect of several drying methods on mechanical properties such as hot air drying, vacuum drying and low-pressure superheated steam drying were investigated. Results showed that the drying methods significantly affect the drying time, but also affect the values of tensile strength and percent elongation at high glycerol concentration (Thakhiew et al. 2010). Glycerol was compared with other hydrophilic compounds as ethylene glycol, poly(ethylene glycol), and propylene glycol as plasticizer to chitosan (Kolhe and Kannan 2003; Suyatma et al. 2005). It was observed that the behaviour and suitability of the plasticizer depends on the concentration. Propylene glycol manifested an anti- plasticizing behaviour at low concentrations, disappearing to increase the propylene glycol content. Comparing the results obtained for the different chitosanplasticizers, at the same concentration, glycerol and poly(ethylene glycol) show

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higher plasticization efficiency, better stability during storage, higher strain, and lower tensile stress than films plasticized by propylene glycol. Films made with ethylene glycol have high strain and low stress comparable to films made with glycerol and poly(ethylene glycol). However, they are not stable during storage (Suyatma et al. 2005). Besides, the moisture affinity of the compounds due to their hydrophilicity affects the plasticizer effect and the stability during storage. The elongation of plasticized films decreased during the storage time due to the recrystallization of chitosan and the loss of moisture and plasticizer from the film matrix (Suyatma et al. 2005). Other usual polyol is sorbitol. It produces an increase of the percentage of elongation at break values of chitosan films (from 10.8 to 42.5%). The results showed films more flexible than chitosan films plasticized with glycerol and polyethylene glycol, but the concentration of chitosan was lower to the formulation with sorbitol (Srinivasa et al. 2007; Martínez-Camacho et al. 2010). Poly(N-vinyl-2-pyrrolidone) and poly(ethylene oxide) were also analysed, manifesting the same modification on mechanical properties (Alexeev et al. 2000; Li et al. 2010). In addition, the behaviour of the mechanical puncture properties of the films with these plasticizers was analysed. The puncture force of the films decreased significantly as the poly(N-vinyl-2-pyrrolidone) and poly(ethylene oxide) fraction increased, being poly(ethylene oxide) more efficient in reducing the puncture force of the films (Li et al. 2010). For the other hand, another plasticizer widely used in biodegradable polymers is the polyvinyl alcohol. The main difference of polyvinyl alcohol with most plasticizers is that it is a polymer and it has the ability to form films. For this reason, the combination of a polymer with polyvinyl alcohol is a blend of two polymers. Polyvinyl alcohol manifested the typical plasticizer effect on the chitosan films, decreasing the tensile strength values and puncture strength and an increase of the percentage of elongation at break values with the increase of polyvinyl alcohol (Srinivasa et al. 2003; Bonilla et al. 2014a, b). It was reported chitosan-polyvinyl alcohol films with a variation of tensile strength from 55.56 to 32.0 MPa, and percentage of elongation at break from 8 to 70.55% (Srinivasa et al. 2003). Other option to improve the mechanical properties of chitosan films is to combine them with several plasticizers simultaneously, for example; polyvinyl alcohol with sorbitol and sucrose, decreasing the tensile strength and increase the percentage of elongation (Arvanitoyannis et al. 1997). On the other hand, the water vapour permeability of chitosan films blended with this kind of plasticizers suffer variations. The hydrophilic nature of these components usually eases the water vapour diffusion through the film, increasing the water vapour permeability respect to pure chitosan films (Table 3.6). These variations depend on the concentration of the plasticizers and the storage time. For example, the water vapour permeability rises when glycerol or polyvinyl alcohol concentration is increased (Butler et al. 1996; Li et al. 2010). However, decreasing when the storage time is increased a higher glycerol concentrations (Butler et al. 1996). On the contrary, although the hydrophilic nature of the polymer employed, it can produce a tendency to decrease the water vapour permeability of the blend films. The final film structure is probably more compact as result of the strong intermolecular

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Table 3.6 Water vapour permeability values of several combinations of chitosan-based films with plasticizers Chitosan combined with Polyvinyl alcohol Polyethylene oxide Glycerol Glycerol

Chitosan properties Mw ~150 kDa

Conditions 25  C 50% RH

Water vapour permeability (g/m s Pa) (1.2–1.8)
10 9 (7.4–10.6)
10 10

References Li et al. (2010)

High Mw Low Mw

38  C 90% RH

(8.4–8.8)
10 10 (10.1–10.2)
10 10

Leceta et al. (2013)

The values depend on the chitosan properties, the plasticizer and the temperature and relative humidity DD degree of deacetylation, RH relative humidity, Mw molecular weight

interactions between chitosan and the other component, producing shorter intermolecular bonds. Besides, if the plasticizer has higher crystallinity by the percolation of water molecules around the insoluble crystals, it could hinder the water molecules diffusion through the film matrix. This effect was observed in chitosan-poly (ethylene oxide) films (Li et al. 2010). Plasticizer concentration and storage time affect the oxygen permeability property of the chitosan films (Table 3.7). Oxygen permeability values increased when glycerol content was increased (Leceta et al. 2013). The storage time of films with glycerol produces an increase of the oxygen permeability. This increase in permeation rates as function of storage time is justified as a film deterioration (Butler et al. 1996). Other study which analyses the oxygen permeability of chitosan-glycerol films reports a permeability value of 8.47
10 10 cm3/m day Pa (Kurek et al. 2018). Sometimes, the aim of the researches is to develop active chitosan-plasticizer films adding functional components with antimicrobial and antioxidant properties, such as natural extracts. For example, it is chitosan-polyvinyl alcohol with mint extract and pomegranate peel extract (Kanatt et al. 2012).

3.3.2

Combination with Other Polysaccharides

It has been studied how affect the combination and interaction of chitosan with other polysaccharides such as cellulose, kefiran, starch, xanthan gum, guar gum, among others. The modifications on the film properties due to the interaction between polysaccharide-polysaccharide depends on the structure and intrinsic properties of the polysaccharide selected (Table 3.8). Cellulose is the most abundant biopolymers on earth, and its origin can be vegetable (isolated from wood and plant-based) or microbial (synthesized by tunicates and microorganisms). Its abundant availability makes it an important polysaccharide to focus efforts on developing biopolymers from chitosan-cellulose. The vast majority of the blending films are from the dissolution of both components. However, cellulose is not soluble in common solvents. For this reason, most of the films

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Table 3.7 Oxygen permeability values of different combinations of chitosan-based films with components Chitosan combined with Glycerol Glycerol Quinoa protein

Solvent used Acetic acid Citric acid

Chitosan properties High Mw Low Mw DD 75–80%

Thyme extract/ glycerol

Acetic acid

High Mw

Tannic acid/ glycerol

Acetic acid

High Mw

Pea starch/glycerol

Acetic acid

High Mw

Measurement conditions 23  C 50% RH 23  C 0% RH 25  C 75% RH 25  C 75% RH 25  C 75% RH 25  C 75% RH

Oxygen permeability (cm3 μm/m2 day kPa) 20.0–37.4 21.9–38.2 24.1

References Leceta et al. (2013) Valenzuela et al. (2013)

336.0

Talón et al. (2017)

206.0

Talón et al. (2017)

158.4

Talón et al. (2017)

Tannic acid/pea Acetic High Mw 93.6 Talón et al. starch/thyme acid (2017) extract/glycerol The values depend on the chitosan properties, the plasticizer and the conditions of measurement DD degree of deacetylation, RH relative humidity, Mw molecular weight

developed chitosan-vegetable cellulose are based on the addition of nanofibrillated, nanowhiskers or nanocrystalline cellulose as reinforcing agent to the chitosan solution, to avoid the use of complex or incompatible solvents to develop films for food application. The addition of cellulose to the chitosan matrix usually produces an increase of the stiffness, increasing the tensile strength, with the consequent decrease of percentage of elongation. This effect is due to the incorporation of cellulose filler into the chitosan matrix which results in a strong interaction between the compounds, mainly hydrogen bonding. A reinforcing effect takes place that occurs through the effective transfer of tensions at the interface of nanofibrillated/ nanowhiskers/nanocrystalline cellulose and chitosan (Fernandes et al. 2010; Khan et al. 2012; Rong et al. 2017). The combination of vegetable cellulose-chitosan by dissolving both components according to the alkali/urea method (Almeida et al. 2010; Morgado et al. 2011), or by immersing vegetable regenerated cellulose films in a bath of chitosan solutions, forming a chitosan coating on the cellulose film (Cazón et al. 2018b, c) has been scarcely studied. By the alkali/urea method, the developed films are brittle, with low mechanical properties. It is improved by increasing the chitosan fraction (Morgado et al. 2011). Combined regenerated cellulose films with chitosan by coating bath showed that the mechanical properties values are predominated by the properties of cellulose. These values improve with the presence of chitosan, indicating an interaction cellulose-chitosan chains, probably due to the appearance of new hydrogen bond (Cazón et al. 2018b, c). By the other hand, there are cellulose derivatives that

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Table 3.8 Mechanical properties, tensile strength and percentage of elongation, of different combination polysaccharide-polysaccharide Chitosan combined with Cellulose Xanthan gum/glycerol

Corn starch Corn starch

Corn starch Cassava/potato starch with/without glycerol/ glucose Banana flour/glycerol

Corn starch/glycerol

Chitosan properties DD 97% High Mw DD 86.3% DD 85% Low Mw DD 85% Medium Mw DD 85% High Mw DD 95% Mw 149 kDa DD 85% Mw 65 kDa DD 90%

Waxy corn starch/ glycerol

DD 90%

Kudzu starch

DD 88.1% Mw 420 kDa DD 88.1% Mw 420 kDa DD 88.1% Mw 420 kDa High Mw

Kudzu starch Lactic acid Kudzu starch Malic acid Pea starch/glycerol

Tensile strength (MPa) 55.0–75.0

Percent of elongation (%) 6.0–17.0

9.7–17.0

30.1–23.5

25  C 60% RH 25  C 60% RH

17.0–18.0

25.0

5.0–6.0

90.0

Bof et al. (2015)

25  C 60% RH 30  C 60% RH

17.0–18.0

18.0

Bof et al. (2015)

8.21–11.68

–

Santacruz et al. (2015)

Ambient temperature and RH

5.2–14.2

1.7–2.6

Pitak and Rakshit (2011)

25  C 50% RH 25  C 50% RH 25  C

26.0–40.0

47.0–62.0

Xu et al. (2005)

20.0–25.0

32.0–48.00

Xu et al. (2005)

13.7

56.6

Zhong et al. (2011)

5.5

82.3

Zhong et al. (2011)

10.1

52.5

Zhong et al. (2011)

9.8

29.0

Talón et al. (2017)

Conditions 25  C 50% RH

References Fernandes et al. (2010) de Morais Lima et al. (2017) Bof et al. (2015)

53% RH 25  C 53% RH 25  C 53% RH 25  C 75% RH

The type of polysaccharide used and the properties of chitosan affect the final values obtained DD degree of deacetylation, RH relative humidity, Mw molecular weight

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are soluble in water, facilitating their combination with chitosan. For example methylcellulose (Pinotti et al. 2007), hydroxypropyl methylcellulose (de Moura et al. 2009; Sánchez-González et al. 2011), among others. Kefiran is a water-soluble polysaccharide from kefir grains. Chitosan-kefiran films showed a decrease on the mechanical properties when kefiran fraction is increased. It indicates that by decreasing the content of chitosan, the ability to form hydrogen bonds between chitosan and kefiran decreases, which weakens the mechanical properties of the film (Sabaghi et al. 2015). In the case of starch, the interactions chitosan-starch are more complex, and the modifications on the mechanical and barrier properties depend on the origin and structure (amylose-amylopectin ratio) of the starch, the chitosan properties and the solvent used. Evaluating the mechanical properties reported of the starch-chitosan blends, the presence of corn starch in chitosan films produced a decrease of tensile strength, without variation of percentage of elongation at break. This is because the stress resistance values of the starch are lower than those of pure chitosan films. By combining both polysaccharides, a decrease in this tension occurs. Regarding the percentage of elongation, both polysaccharides in pure films have reported similar values of elasticity. It was not observed any modification of the flexibility when combining them (Bof et al. 2015; Garcia et al. 2006). The solvent used modified the mechanical properties of chitosanstarch films, as well as it happens on pure chitosan films. Kudzu starch-chitosan films have different values of the mechanical properties as function of the solvent used (acetic, lactic and malic acid) (Zhong et al. 2011). As it was observed for pure chitosan films properties as function of the solvent used (Park et al. 2002), it was obtained lower tensile strength values and higher percentage of elongation using lactic acid as chitosan solvent than using acetic or malic acid (Zhong et al. 2011). Two types of corn starch in chitosan–starch composite film was studied to evaluate the effect of the structure of the starch on the mechanical properties of chitosan films: regular starch with 25% amylose and waxy starch with 100% amylopectin. Composite film with higher amylose content showed higher tensile strength (Xu et al. 2005). Xanthan gum is also a potential polysaccharide to blend with chitosan to develop biodegradable films. Both polymers are polyelectrolyte with opposite charges. Xanthan gum is considered an anionic polyelectrolyte due to carboxylate groups. The mixture of oppositely charged polyelectrolytes results in a polyelectrolyte complex, which exhibits electrostatic interactions that are considered stronger than secondary binding interactions. The results obtained of mechanical properties showed that the addition of xanthan gum enhanced the tensile strength. However, it significantly reduced the percentage of elongation. These modifications of the mechanical properties is probably due to the stronger electrostatic interactions between the polymer-polymer, which reduce the molecular mobility and increase the brittleness (de Morais Lima et al. 2017). Guar gum produce an increase of the tensile strength and puncture values, due to the formation of intermolecular hydrogen bonding between NH3+ of the CH backbone and OH of the guar gum (Rao et al. 2010). It is possible to improve the percentage of elongation by adding glycerol or other plasticizer to polysaccharide-polysaccharide films (Garcia et al. 2006; Santacruz et al. 2015; Cazón et al. 2018a; Valencia-Sullca et al. 2018). Analyzing the effect of each polysaccharides on the water vapour permeability of chitosan-based films, it

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was observed a different behavior as function of the polysaccharide structure (Table 3.9). As a rule, the presence of cellulose has a great impact on the reduction of water vapour permeability of chitosan-based films. The presence of cellulose nanocrystals hinders the diffusion of water vapour through the film. The degree of crystallinity of cellulose influences the final permeability values, because water vapour diffuses more easily through the amorphous zones (Khan et al. 2012). Water vapour permeability of chitosan-starch composites depend on the properties of chitosan (mainly, deacetylation degree and molecular weight) and the starch (nature and structure) as shown Table 3.9. Blending chitosan-starch increase water vapour permeability of composite films to increase starch content (Garcia et al. 2006). Blending chitosan-kefiran increase water vapour permeability of composite films to increase kefiran fraction (Garcia et al. 2006; Vásconez et al. 2009; Sabaghi et al. 2015). Authors attributed this effect of chitosan to the development of a more compact and dense structure, indicating hydrocolloids compatibility as well, based on the similar chemical and geometrical linear structure of both polymers and due to residual hydrophobic acetyl group of chitosan that act as a barrier to transportation of water vapour (Garcia et al. 2006; Sabaghi et al. 2015). The water vapour permeability of chitosan films containing xanthan gum and guar gum showed no significant difference (Rao et al. 2010; de Morais Lima et al. 2017). For the other hand, the solvent used to obtain starch-chitosan solutions does not significantly affect the final values of water vapour permeability (Zhong et al. 2011). The combination of polysaccharides with plasticizers usually produces an increase of the water vapour permeability due to the hydrophilic nature of plasticizers (Cazón et al. 2018c).

3.3.3

Combination with Proteins

The combination of chitosan with proteins has been the focus of a wide number of studies due to their potential as edible film. They can be made from a variety of materials to control water and gas diffusion. Protein blending include gelatin, quinoa protein, whey protein, soy protein, among others. Films obtained adding proteins to chitosan showed a modification of the mechanical properties, decreasing the tensile strength values and increasing the percentage of elongation at break values. Table 3.10 shows some examples. Analyzing some combinations reported, cuttlefish skin gelatin in chitosan films produced a decrease of the tensile strength from 59.4 to 45.90 MPa and an increase of percentage of elongation at break from 1.26% to 3.96% (Jridi et al. 2014), although variations in the mechanical properties were very slight. Bovine hide gelatin manifested the same effect of skin gelatin on mechanical properties of chitosan films with more significant variations, going from tensile strength values of 17.34 MPa for pure chitosan films to 6.27 MPa for chitosangelatin films. The percentage value of elongation were double from 44.2% to 85.4% (Pereda et al. 2011). The origin of gelatin affects the percentage of elongation at break of gelatin-chitosan films. It was attributed to different amino acid contents,

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Table 3.9 Water vapour permeability of different combination polysaccharide-polysaccharide

Corn starch/glycerol

Chitosan properties DD 85% Low Mw DD 85% Medium Mw DD 85% High Mw DD 95% Mw 149 kDa DD 85% Mw 65 kDa DD 90%

Waxy corn starch/glycerol

DD 90%

Kudzu starch

Xanthan gum/glycerol

DD 88.1% Mw 420 kDa DD 88.1% Mw 420 kDa DD 88.1% Mw 420 kDa DD 86.3%

Pea starch/glycerol

High Mw

Chitosan combined with Corn starch Corn starch

Corn starch Cassava/potato starch with/ without glycerol/glucose Banana flour/glycerol

Kudzu starch/lactic acid

Kudzu starch/malic acid

Conditions 5 C 2000 Pa 5 C 2000 Pa

Water vapour permeability (g/m s Pa) (2.0–2.5)
10 10

References Bof et al. (2015) Bof et al. (2015)

5 C 2000 Pa 25  C 3160 Pa

5.0
10

24  C 65% RH

4.3–4.8
10

25  C 50% RH 25  C 50% RH 25  C 75% RH

(44.0–54.0) g/m2 h

Xu et al. (2005)

(47.0–59.0) g/m2 h

Xu et al. (2005)

4.4
10

10

Zhong et al. (2011)

25  C 75% RH

4.8
10

10

Zhong et al. (2011)

25  C 75% RH

3.8
10

10

Zhong et al. (2011)

9

Bof et al. (2015)

(1.1–1.6)
10

10

(1.3–1.4)
10 25  C 75% RH

1.1
10

10

10

10

Santacruz et al. (2015) Pitak and Rakshit (2011)

de Morais Lima et al. (2017) Talón et al. (2017)

The type of polysaccharide used and the properties of chitosan affect the final values obtained DD degree of deacetylation, RH relative humidity, Mw molecular weight

giving bovine-hide gelatin a higher degree of molecular rigidity likely favouring collagen-like polypeptide self-assembling (Gómez-Estaca et al. 2009, 2011). In chitosan-based films using lactic acid as solvent, the addition of quinoa protein manifested a plasticizing effect, decreasing the values of tensile strength from 22.2 to 2.3 MPa and increasing the percentage of elongation at break from 73.6 to 237%. Authors indicated that hydrogen bonding takes place during chitosan film formation when it was blended with quinoa protein. Different molecular interactions between these macromolecules are established, such as ionic and hydrophobic interactions.

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Table 3.10 Mechanical properties, tensile strength and percentage of elongation at break, of different combination chitosan-protein films Proteins combined with chitosan Quinoa protein Citric acid Cuttlefish skin gelatin/ glycerol Brewer’s spent grain/ glycerol Konjac glucomannan/soy protein isolate Gelatin/cinnamon/guarana/ rosemary/boldo-do-chile ethanolic extracts/glycerol Gelatin/glycerol Bovine hide gelatin

Tuna skin gelatin

Chitosan properties DD 75–80%

Conditions 23  C 60% RH

DD 88% DD 75% High Mw DD 85% DD 75–85% Medium Mw DD 90% DD 85% Mw 141 kDa DD 85% Mw 141 kDa

25  C 50% RH 23  C 60% RH 25  C

Tensile strength (MPa) 2.7

Percent of elongation (%) 177.8

59.4–45.9

1.3–4.0

11.0–26.21

54.6–28.5

16.8–50.4

1.3–7.2

Jia et al. (2009)

3.0–4.0

24.0

Bonilla and Sobral (2016)

17.3–6.3

44.2–85.4

18.4–18.6 (N)

11.0–19.9

Pereda et al. (2011) GómezEstaca et al. (2011)

13.2–20.0 (N)

68.2–40.0

53% RH

References Valenzuela et al. (2013) Jridi et al. (2014) Lee et al. (2015)

GómezEstaca et al. (2011)

The origin of the protein affects the properties of the final film. DD: degree of deacetylation RH relative humidity, Mw molecular weight

Proteins can also interact through disulfide bonds when they are denatured (Abugoch et al. 2011). Using citric acid as chitosan solvent, tensile strength manifested similar values (13.4 to 2.7 MPa) with the addition of quinoa protein, but with lower increase of percentage of elongation at break (20.7 to 177.8%) (Valenzuela et al. 2013). The addition of whey proteins to chitosan matrix, also produced a decreased of the tensile strength values. But unlike the effect observed in films with quinoa protein, when adding whey proteins there was a decrease in the flexibility of the film depending on the increase in the amount of protein (Di Pierro et al. 2006). The elasticity of the films is improved by adding plasticizers to chitosan-protein films (Lee et al. 2015). For other hand, observing the effect of the proteins in chitosan matrix on permeability properties, the presence of proteins usually produces an increase in water vapour permeability values (Table 3.11). Results showed that the chitosan-protein films obtained were more hydrophilic than pure chitosan films (Di Pierro et al. 2006; Abugoch et al. 2011; Fakhreddin Hosseini et al. 2013). Oppositely, it was observed that bovine gelatin-chitosan films showed lower water vapour barrier properties than pure chitosan film. Therefore increasing the content of bovine gelatin in chitosan films decrease the water vapour permeability values (Gómez-Estaca et al. 2011; Pereda et al. 2011).

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Table 3.11 Water vapour permeability of different combination chitosan-protein films

Chitosan combined with Quinoa protein/citric acid Brewer’s spent grain/glycerol Konjac glucomannan/soy protein isolate Gelatin/cinnamon/guarana/rosemary/boldo-do-chile ethanolic extracts/glycerol Gelatin/glycerol Bovine hide gelatin

Tuna skin gelatin

Chitosan properties DD 75–80% DD 75% High Mw DD 85% DD 75–85% Medium Mw DD 90% DD 85% Mw 141 kDa DD 85% Mw 141 kDa

Conditions 23  C 60% RH 25  C 50% RH 25  C 83% RH 25  C

Water vapour permeability (g/m s Pa) 4.6
10 12 (2.7–2.8)
10

9

(4.0–9.6)
10

11

(1.17–1.99)
10 10

(4–5.3)
10

10

11

(4.9–5.5)
10

Jia et al. (2009) Bonilla and Sobral (2016)

53% RH (1.9–1.2)
10

References Valenzuela et al. (2013) Lee et al. (2015)

11

Pereda et al. (2011) GómezEstaca et al. (2011) GómezEstaca et al. (2011)

DD degree of deacetylation, RH relative humidity, Mw molecular weight

Regardless the oxygen permeability values, the variations depend on the protein origin. It was observed an slightly decreased film permeability to oxygen in whey proteins-chitosan films (Di Pierro et al. 2006). However, quinoa-chitosan films manifested an increase of oxygen permeability. Authors explained this increase of oxygen permeability is due to new protein-chitosan interactions, which can disorder the structure (Valenzuela et al. 2013).

3.3.4

Combination with Lipids

A feasible way to enhance chitosan films functional properties enlarging their potential applications is to blend with essential oil. The essential oils are lipid substances from plants, formed by terpens, terpenoids, phenolic compounds and other aromatic and aliphatic components. Most of these essential oils have antioxidant and antimicrobial properties of interest to develop active food packaging. Furthermore, due to be hydrophobic components, help to reduce the water vapour permeability of the films (Jianglian 2013; Shen and Kamdem 2015; Hafsa et al. 2016). The incorporation of higher proportion of lipids usually leads to changes in mechanical properties of the films, namely lower resistance and stiffness (Table 3.12). It is observed a general decrease of tensile strength values, but the

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Table 3.12 Mechanical properties, tensile strength and percentage of elongation, of chitosan-based films combined with lipids or natural extracts Chitosan combined with Citronella Eo Cedarwood oil Zataria multiflora Boiss Eo/glycerol Grape seed extract/ glycerol Glycerol/tween 80/cinnamon Eo Glycerol/clove Eo Bergamot Eo

Tween 80/oleic acid Caraway Eo/tween 20/beeswax Thyme extract/ glycerol Tannic acid/ glycerol

DD 75–85%

Conditions 22  C 30% RH 25  C

Tensile strength (MPa) 33.0–17.1 36.5–22.3 6.0

Percent of elongation (%) 14.5–8.3 25.8–5.1 19.0

Mw~450 kDa

52% RH

16.0

21.0

DD 75–85% Mw 190–310 kDa DD 75% Mw190–310 kDa DD 82.7% High Mw

25  C 51% RH

29.2

3.6

Ojagh et al. (2010 )

25  C 50% RH

~12.0

~22.0

Lee et al. (2018)

65.0–22.0

7.0–1.7

15.0–11.0

18.0–7.0

SánchezGonzález et al. (2010) Vargas et al. (2009a, b)

44.5–2.0

31.5–5.6

13.0

39.0

15.0

64.0

Chitosan properties DD 75%

DD 82.7% High Mw DD 80% High Mw High Mw

25  C 75% RH 25  C 75% RH 25  C 75% RH

References

Moradi et al. (2012)

Hromiš et al. (2015) Talón et al. (2017) Talón et al. (2017)

Tannic acid/pea High Mw 11.0 36.0 Talón et al. starch/thyme (2017) extract/glycerol DD degree of deacetylation, RH relative humidity, Mw molecular weight, Eo essential oil

behaviour of percentage of elongation at break depends on the added lipid and the characteristics of the chitosan film. There are examples in which percentage of elongation at break increases and others in which it decreases with the addition of lipids to the chitosan matrix. This effect on mechanical properties is attributed to the heterogeneity introduced in the film structure and the negative effect on the cohesion forces of matrix by oil incorporation. Moreover, essential oils posses differences in reactivity in binding or interacting with the polymer network, which also depends on the source of chitosan, the acid medium used to disperse the polymer and the experimental conditions (Valenzuela et al. 2013; Shen and Kamdem 2015). Moreover, the water vapour permeability values decreased with the presence of lipids. It is explained by the formation of an interconnecting lipid network within the film matrix, which provides hydrophobicity and thus reduces the adsorption of water molecules as shown in Table 3.13

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Table 3.13 Water vapour permeability of chitosan-based films combinated with lipids or natural extracts Chitosan combined with lipids or natural extracts Citronella Eo

Measurement Conditions 23  C

Water vapour permeability (g/m s Pa) (3.5–3)
10 10

97% RH

(3.3–1.5)
10

DD 75–85%

25  C

WVTR ~(23–24) g/m2 day

Mw~450 kDa

52% RH

DD 75–85% Mw190–310 kDa DD 75% Mw190–310 kDa DD 82.7% High Mw

25  C 75% RH 25  C 50% RH

Chitosan properties DD 75%

Cedarwood oil

Zataria multiflora Boiss Eo/glycerol Grape seed extract/ glycerol Glycerol/tween 80/cinnamon Eo Glycerol/clove Eo Bergamot Eo

Tween 80/oleic acid Thyme extract/ glycerol Tannic acid/glycerol

DD 82.7% High Mw High Mw High Mw

25  C 75% RH 25  C 75% RH 25  C 75% RH

10

References Shen and Kamdem (2015) Shen and Kamdem (2015) Moradi et al. (2012)

1.0
10

10

Ojagh et al. (2010)

2.9
10

10

Lee et al. (2018)

13.0–6.5
10

10

(1.5–0.8)
10

10

SánchezGonzález et al. (2010) Vargas et al. (2009a, b)

1.3
10

10

Talón et al. (2017)

1.4
10

10

Talón et al. (2017)

Tannic acid/pea High Mw 8.5
10 11 Talón et al. starch/thyme extract/ (2017) glycerol DD degree of deacetylation, RH relative humidity, Mw molecular weight, Eo essential oil

(Valenzuela et al. 2013). Reviewing the literature, there are multiple combinations with essential oils and different lipids. Analysing some examples, grape pomace seeds extract composed (70% of linoleic acid, 18% of oleic acid, 7% of palmitic acid, and 5% of stearic acid) was added to chitosan films, producing a decrease of tensile strength values, but no significant differences were observed in the flexibility (Ferreira et al. 2014). Active biodegradable films from chitosan containing citronella essential oil and cedarwood oil (10% to 30% w/w) were developed (Shen and Kamdem 2015). Films showed the expected changes in tensile strength values, decreasing to increase the oil content. But the percentage of elongation at break suffered variation depending on the essential oil used and the final concentration added. However, both essential oils manifested the same behaviour, a decrease in the plasticizer effect was observed increasing the oil content. The addition of either citronella essential oil or cedarwood

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oil significantly reduced the water vapour permeability of the films, having attained a maximum permeability reduction of 63% in the film prepared with 30% (w/w) cedarwood oil. In some cases, the effect of the addition of essential oils is to improve the antimicrobial and antioxidant properties of the chitosan. For example, combined chitosan films with eucalyptus globulus essential oil, the essential oil added enhanced the antioxidant and antimicrobial properties against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Candida parapsilosis among others (Hafsa et al. 2016). Combined ginger, Rosemary, sage, tea tree and thyme essential oil, with chitosan-glycerol solution, the results of mechanical properties showed non-significant differences respect to chitosan sample control. But in this case, probably due to the incorporation of Tween 80 as emulsified to the films with the essential oils. Other examples of essential oils which the general behaviour added to chitosan films are clove essential oil, Zataria multiflora Boiss essential oil, grape seed extract (Moradi et al. 2012; Souza et al. 2017; Lee et al. 2018). Complex system blending more than two components such as protein-chitosan films with lipids is a strategic to combine the different properties of each component to obtain better results. An example studied is chitosan-quinoa protein-sunflower oil blends films. The increase of sunflower oil decreased the tensile strength values and percentage of elongation at break. The water vapour permeability values were reduced by 30% relative to the values of the chitosan films. The oxygen permeability values increased drastically with the addition of sunflower oils. This increase was probably due to a significant decrease in the crystalline spacing by matrix restructuring after the addition of lipids molecules, which generate channel sand pores in the network; this facilitates O2 diffusion (Valenzuela et al. 2013).

3.4

Applications of Chitosan as Film or Coating in Food Packaging

During the last years, the interest of the study of the potential applications of chitosan as films or coating in food packaging has increased. This is due to their film-forming, antioxidant and antimicrobial properties, but also due to their mechanical and barrier properties studied as films. The objectives of these studies were to develop an active packaging based on chitosan pure or combined with other components and evaluating their potential to improve the storability of perishable foods and extend their shelf life. In addition, by combining chitosan with other natural antimicrobial agents, it is possible to obtain food products that guarantee food safety against a wide spectrum of altering and pathogenic microorganisms (Tharanathan 2003; No et al. 2007; Yen et al. 2008; Aider 2010; Falguera et al. 2011). As an active food packaging, chitosan can be applied to the food as a thin edible film or edible coating. The edible coating is a thin layer formed as a coating on a food product, which is applied in liquid form, by dipping the product in a chitosan solution, or by spray, pulverizing the film forming solution using an aerosol spray

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coating. While, the chitosan film is a preformed thin layer, which once formed can be placed on or between food components (Falguera et al. 2011; Muxika et al. 2017). Application of semipermeable chitosan film or coating is promising to improve the shelf life of perishable fruits and vegetables as post-harvest treatment. It is possible to find in the literature many studies with suitable results increasing the shelf life of the food. Overall, chitosan regulate gas exchange, inhibit the respiration rate of post-harvest fruits (Ghouth et al. 1991) and lower rate of ethylene production than the control fruit during the period of storage (Li and Yu 2001). Moreover, it is fungistatic. It is able to induce host defence responses, including the accumulation of antifungal hydrolysates and phytoalexin (Li and Yu 2001). Besides, the studies show that by applying chitosan there are a beneficial effect on retaining the firmness, titratable acidity, water content, total solid content and the upkeep of the colour throughout storage in vegetables and fruits applied (Li and Yu 2001; Chien and Chou 2006; Leceta et al. 2015). Table 3.14 shows studies made with chitosan films and Table 3.15 show studies with chitosan coatings in food products. Peaches were preserved by a chitosan coating and compared with peaches pretreated with prochloraz. Results showed that chitosan reduced significantly the incidence of brown rot caused by Monilina fructicola and Rhizopus stolonifera. Chitosan-treated peaches were firmer and higher titratable acidity and vitamin C than prochloraz-treated peaches. In addition, the coating reduced the malondialdehyde formation, stimulating superoxide dismutase activity and maintaining membrane integrity (Li and Yu 2001). Peeled litchi fruit has a short shelf-life. It was possible to increase its shelf life by coating of chitosan. Chitosan coatings retarded weight loss and the decline in sensory quality, keeping higher contents of total soluble solids, titratable acid, and ascorbic acid, and suppressed the activity of polyphenol oxidase and peroxidase (Dong et al. 2004). Chitosan coating effectively prolongs the quality attributes and extends the shelf life of sliced mango fruit, retarding water loss and the drop in sensory quality, increasing the soluble solid content, titratable acidity, vitamin C and inhibiting the growth of microorganisms (Chien et al. 2007a, b). The effect of chitosan on respiration, ethylene production, and quality attributes of tomato was studied. Coating the fruit with chitosan solutions reduced the respiration rate and ethylene production. Chitosan-coated tomatoes were firmer, higher in titratable acidity, less decayed, and exhibited less red pigmentation than the control fruit at the end of storage (Ghaouth et al. 1992). Applying chitosan coating on freshcut mushrooms, it was delayed discoloration associated with reduced enzyme activities of polyphenoloxidase, peroxidase, catalase, phenylalanine ammonia lyase and laccase, and lower total phenolic content. Besides, enzyme activities of cellulase, total amylase and α-amylase and the number of colonies of bacteria, yeast and mould were reduced with the presence of chitosan (Eissa 2007). It was studied the antimicrobial effects of chitosan-glycerol on the native microflora (mesophilic, psychrotrophic, yeast and molds, lactic acid bacteria and coliforms) and on the survival of E. coli O157:H7 inoculated in broccoli. It was demonstrated that the use of blending chitosan/glycerol coating is a viable alternative to control the microorganisms present in minimally processed broccoli, improving its sensory quality, and inhibited the yellowing and opening florets (Moreira et al. 2011).

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Table 3.14 Applications of chitosan-based films in different food products Chitosan based film combined with Glycerol/Zataria multiflora Boiss essential oil/grape seed extract Gelatin/grape seed extract/Ziziphora clinopodioides essential oil

Food Ready-to-eat mortadella-type sausages Minced trout fillets

Gelatin with essential oil clove/fennel/cypress/lavender/thyme/herb- of-the-cross/pine/rosemary Cassava starch/glycerol/polyethylene glycol

Cod fillets

Thymus moroderi/Thymus piperella essential oil

Cooked cured ham

Zataria multiflora essential oil/Cinnamomum zeylanicum Sunflower oil edible

Green chilli

Banana flour/glycerol

Oregano essential oil

Asparagus, baby corn, oyster mushroom, Chinese cabbage Bologna slices

Lysozyme/glycerol

Mozzarella cheese

Glycerol/peanut skin/pink pepper

Restructured chicken product

Pork meat slices

Pork meat hamburgers

References Moradi et al. (2011) Kakaei and Shahbazi (2016) Gómez-Estaca et al. (2010) ValenciaSullca et al. (2018) Ruiz-Navajas et al. (2015) Mohammadi et al. (2016) Vargas et al. (2011) Pitak and Rakshit (2011) Chi et al. (2006) Duan et al. (2007) Serrano-León et al. (2018)

Baby carrots were coating using spraying and dipping techniques, observing that the weight loss was slightly higher for dipped samples when compared with sprayed samples. It was probably due to the thickness of the coating that was higher when applied by dipping. Chitosan-based coatings delayed microbial spoilage without causing adverse impacts on the quality attributes of baby carrots with positive effects on product colour and texture. Besides, sensory analysis was carried out to determine the degree of acceptability of the carrots. Sensory analysis showed that overall acceptability of coated baby carrots were similar to uncoated samples (Leceta et al. 2015). Regarding meat products, microbial growth is generally responsible for the spoilage in meats and meat products, especially in minced meat (Devlieghere et al. 2004). Furthermore, oxygen has a negative effect on the quality of many food products, mainly those with high fat content. The presence of oxygen produces oxidative deterioration of fats and oils, which are the responsible of rancid odours and flavours. It decreases the quality and shelf life of the meat products. Chitosan films had good oxygen-barrier properties. It has effectively protected meat fat from oxidation in comparison to unprotected meat products. In addition, the films are effective in controlling microbial growth in meat. Furthermore, the uses of chitosan coating or films with meat products is an interesting strategy to extend the shelf life

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Table 3.15 Applications of chitosan-based coating in different food products Pure chitosan or chitosan based coating combined with others Chitosan Chitosan Beeswax/glycerol Semperfresh™/glycerol/stearic acid Zataria multiflora essential oil Cinnamomum zeylanicum Glycerol Methylcellulose/oleic acid Yam starch/glycerol Gelatin/essential oil of clove/fennel/ cypress/lavender/thyme/herbof-the-cross/pine/rosemary Thyme/rosemary Agar/Artemisia annua oil Thymus moroderi/Thymus piperella Chitosan Cassava starch/glycerol/polyethylene glycol Chitosan Citric acid/glycerol Sunflower oil edible Banana flour/glycerol

Food Citrus fruit Logan fruit Strawberries Kiwifruit Cucumber

References Chien et al. (2007a, b) Jiang and Li (2001) Velickova et al. (2013) Fisk et al. (2008) Mohammadi et al. (2016)

Baby carrots Fresh cut carrots Carrots Cod fillets

Leceta et al. (2015) Vargas et al. (2009a, b) Durango et al. (2006a, b) Gómez-Estaca et al. (2010)

Hot smoked rainbow trout Cherry tomato Cooked cured ham Green coffee beans Pork meat slices

Doğan and İzci (2017)

Acetic acid/lauric acid/ cinnamaldehyde/propionic acid Lysozyme/glycerol Chitosan Chitosan

Frozen salmon Green Chilli Pork meat hamburgers Asparagus, baby corn, oyster mushroom, Chinese cabbage Vacuum-packed cured meat products Mozzarella cheese Tankan citrus fruit Apples

Chitosan Glycerol Chitosan

Mushroom Eggs Mangoes

Ascorbic acid Chitosan

Litchi fruit Litchi fruit

Chitosan Chitosan Chitosan

Salmon fillets Tomatoes Strawberries

Cui et al. (2017) Ruiz-Navajas et al. (2015) Ferreira et al. (2018) Valencia-Sullca et al. (2018) Soares et al. (2013) Priyadarshi et al. (2018) Vargas et al. (2011) Pitak and Rakshit (2011)

Ouattara et al. (2000) Duan et al. (2007) Chien and Chou (2006) Choi et al. (2002) and Shao et al. (2012) Eissa (2007) Kim et al. (2007) Srinivasa et al. (2002), Chien et al. (2007a, b) and Djioua et al. (2010) Sun et al. (2010) Jiang et al. (2005), Dong et al. (2004) Souza et al. (2010) Ghaouth et al. (1992) Ghouth et al. (1991) (continued)

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Table 3.15 (continued) Pure chitosan or chitosan based coating combined with others Glycerol Hydroxy propylmethylcellulose/bergamot essential oil Glycerol Chitosan Clove oil Tween 80 Chitosan

Food Blueberries Grapes

Calcium gluconate

Cut broccoli Peach fruit Cooked pork sausages Papaya fruit Fresh-cut Chinese water chestnut L.T. Strawberries

Ascorbic acid/calcium chloride Chitosan

Fresh-cut ‘Fuji’ apples Silver carp

References Duan et al. (2011) Sánchez-González et al. (2011) Moreira et al. (2011) Li and Yu (2001) Lekjing (2016) Ali et al. (2011) Pen and Jiang (2003) Hernández-Muñoz et al. (2006) Qi et al. (2011) Fan et al. (2009)

of fresh meat. Chitosan can be an alternative to the use of antimicrobial and antioxidant additives of synthetic origin, giving an added value to the final product (Bonilla et al. 2014a, b). The application of chitosan films enriched with essential oils in pork fat and minced pork meat was studied (Bonilla et al. 2014a, b). It was observed that to high moisture content, the presence of essential oils worsens the permeability properties. However, the barrier properties are still good, avoiding oxidation of pork fat. In the case of minced meat, the changes produced in the colour can diminish the acceptability of the consumer. The available oxygen reduction in the minced meat coated leads to the conversion of myoglobin to metmyoglobin, which produces a dark colour of the meat. Moreover, safety aspects are improved by chitosan films, increasing the product shelf life. Cooked pork sausages were preserved with a coating based on chitosan, glycerol and clove oil blending. The result showed that it is possible to get pork sausages with sensory parameters acceptable until 20 days in refrigeration (Chi et al. 2006). It was analysed the effect of chitosan dipping with oregano oil combined on modified atmosphere packaged chicken breast meat (Chi et al. 2006). The inhibition effect on the growth of microorganisms extended the shelf life of chicken products that were sensorial acceptable during the entire refrigerated storage period of 21 days. In this case, being a cooked product, the change in colour due to the coating with chitosan was not significant. Other kind of product that products are highly susceptible to quality deterioration due to lipid oxidation are seafood products. Furthermore, seafood quality is highly influenced by autolysis, contamination by and growth of microorganisms, and loss of protein functionality (No et al. 2007). Apart of the antimicrobial effect, chitosan

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showed good antioxidant capacity in fresh fish muscle, slowing lipid oxidations (Souza et al. 2010). Chitosan may retard lipid oxidation by chelating ferrous ions present in the fish model system, thus eliminating prooxidant activity of ferrous ions or preventing their conversion to ferric ion (No et al. 2007). It was evaluating the effect of chitosan coating on shelf life extension of salmon fillets during storage at 0  C. Fish samples coated presented a significant reduction for pH and ATP breakdown products value after 6 days, and for total volatile base nitrogen, trimethylamine and thiobarbituric acid values after 9 days of storage. In terms of microbial growth, a slower increase in total aerobic microorganism was observed, indicating that chitosan-based coatings are effective in extending for an additional 3 days the shelf life of the salmon fillets (Souza et al. 2010). Other type of food products evaluating was Mozzarella cheese by coating with chitosan-lysozyme. Due to the increase of the production of Mozzarella cheese, there is a great need to improve microbial safety of cheese by controlling or eliminating post-processing microbial contaminants. Chitosan films and coating were analysed as inhibitors of Listeria monocytogenes, Escherichia coli, Pseudomonas fluorescens, Candida inconspicua and molds. Involved in cheese-associated outbreaks, that may cause defects in flavour, texture, and appearance of cheese. It results in economic losses or even in severe illness. Chitosan-lysozyme films showed the greatest antimicrobial effect due to the higher concentration of chitosan and lysozyme than in laminated films and coatings (Duan et al. 2007). Finally, in addition to the applications of chitosan-based films or coating to extend the shelf life of food, other applications of great interest have been developed within the food packaging, for example intelligent films. Based on chitosan films it has been possible to develop pH indicators, which can monitor and inform consumers about food conditions in real-time. Sese smart films are chitosan-based films enriched with blueberry and blackberry pomace extracts. These films show different colours between pH 2–12 (Kurek et al. 2018). Other example is chitosan-corn starch enriches with red cabbage extract apply as fish deterioration indicator and chitosanpolyvinyl alcohol films with red cabbage tested in milk (Pereira et al. 2015; SilvaPereira et al. 2015).

3.5

Conclusions

There is a growing need for the development of new biodegradable polymers, which also allow the development of active food packaging that increase the shelf life of food. It is needed to ensure food safety, minimizing waste of both food and packaging from the food industry. The raw materials study to develop new biopolymers should be from renewable natural sources, to avoid the environmental concerns with petroleum-based polymers. Chitosan is a potential raw material to develop new biopolymers. The film-forming properties of chitosan allow the

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production of films and coating materials with good mechanical properties and a selective permeability to oxygen. In addition, chitosan has antimicrobial properties against a wide range of foodborne filamentous fungi, yeast, and bacteria, being more active against yeasts. Therefore, chitosan films or coating apply directly on food allow to increase the shelf life. Chitosan is also an alternative to antimicrobial and antioxidant synthetic agents. Chitosan is a polymer that allows its easy combination with other components, such as other polysaccharides, plasticizers, proteins or lipids. This property allows to develop mixing components and modify the different properties of the films according to the needs of the food on which it is wanted to apply. Due to the favourable results in foods obtained using films or coating from chitosan or combinations with chitosan, it is important to continue studying this polymer and its modifications to extend its application in the food industry.

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Chapter 4

Applications of Chitin in Agriculture Julia L. Shamshina, Tetyana Oldham (Konak), and Robin D. Rogers

Abstract As sustainable agriculture becomes more urgent, biocontrol using natural compounds such as chitin, a carbohydrate chain polymer, and its derivatives, is a promising strategy. Chitin and its derivatives induce or enhance natural defensive mechanisms in plants. They are recognized as plant growth regulators, growth stimulants, and elicitors for the production of secondary metabolites. They have beneficial effects as fertilizers, soil conditioning agents, plant disease control agents, antitranspirants, ripening retardants, and seed and fruit coatings. Keywords Agriculture · Sustainable Development · Chitin Fertilizer · Biocide · Elicitor · Plant Growth Regulator

Abbreviations NH4+ C:N CAT CMV CERK1 CEBiP DA DHA DNA F. oxysporum HMWC

Ammonium Carbon to Nitrogen Ratio Catalase Cauliflower Mosaic Virus Chitin Elicitor Receptor Kinase 1 Enzyme Chitin Elicitor-Binding Protein Degree of Acetylation Dehydrogenase Activity Deoxyribonucleic Acid Fusarium oxysporum High Molecular Weight Chitin

J. L. Shamshina (*) · T. Oldham (Konak) Mari Signum Mid-Atlantic, LLC, Rockville, MD, USA e-mail: [email protected] R. D. Rogers 525 Solutions, Inc., Tuscaloosa, AL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_4

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mRNA MAMP MHA MAP MW GlcNAc N-P-K NYDB PGPR PPO POD ROS S. marcescens SOD sp. EPA TMV U.S. Pat. w/w

4.1

Messenger Ribonucleic Acid Microbe-Associated Molecular Pattern Microbial Dehydrogenase Activity Modified Atmosphere Packaging Molecular Weight N-Acetylglucosamine Nitrogen to Phosphorus to Potassium Ratio Nutrient Yeast Dextrose Broth Plant Growth Promoting Rhizobacteria Polyphenol Oxidase Polyphenol Peroxidase Reactive Oxygen Species Serratia marcescens Superoxide Dismutase species The US Environmental Protection Agency Tobacco Mosaic Virus United States Patent Weight to Weight

Introduction

Due to strict federal, governmental and state regulations in the pesticide, fertilizer, and plant growth regulator markets (US EPA 2017), there is an increased demand for viable organic alternatives. Due to the constant unselective use of large amounts of synthetic agrochemicals to control the microorganisms that cause infection and plant diseases such as fungi and oomycetes, and to improve plant growth, this problem has become a widespread societal issue, of worldwide scale (Aktar et al. 2009). ‘Sustainable agriculture’ through the use of naturally friendly methods and products while replacing current plant protection products with lower environmental impact substances becomes more urgent every day. Among these, biocontrol using natural compounds is one of the most promising strategies. In this regard chitin, the second most abundant biopolymer after cellulose, is one of the promising natural alternatives (Klemm 2004; Barikani et al. 2014). Chitin is a carbohydrate polymer composed of repeated 2-(acetylamino)-2-deoxy-D-glucose units (Fig. 4.1, left), with a chemical name poly-(1 ! 4)-β-N-acetyl-D-glucosamine and molecular formula (C8H13NO5)n. Chitin is obtained from the exoskeleton of shellfish, insects, or the cell wall of fungi, by treatment of the respective biomass with hydrochloric acid and sodium hydroxide (No et al. 1989; Cho et al. 1998; Barber et al. 2013; Younes and Rinaudo 2015). While chitin is used in agriculture, a significant drawback is that the polymer is insoluble in water and common solvents, and the ‘special’ solvent systems that are

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Fig. 4.1 Structure of chitin (left), chitosan (center), N,N-diacetylchitobiose dimer (right: top) and N-acetylglucosamine (GlcNAc) monomer (right: bottom)

employed for chitin dissolution (Austin 1977; Yusof et al. 2001; Pillai et al. 2009; Xie et al. 2017) are not utilized in this industry. Because of insolubility of chitin, a water-soluble chitin derivative, chitosan, or oligosaccharides of chitin are often used instead in agricultural applications. Chitosan is the fully or partially deacetylated derivative of chitin (Fig. 4.1, center), which differs from chitin polymer by the presence of free amine groups on C-2 atom of D-glucose unit, in place of acetamide groups present in chitin. Due to presence of these free amines, chitosan is soluble in slightly acidic aqueous solutions, which are often employed in agricultural applications. Chitin can also be partially depolymerized into oligosaccharide derivatives of varied chain length (Fig. 4.1, right, top: dimer), or even fully depolymerized to Nacetylglucosamine GlcNAc (Fig. 4.1, right, bottom: monomer), which is also widely applied for the purpose (Ramírez et al. 2010). Experimental trials on crop plants demonstrated the beneficial use of chitin and its derivatives as fertilizers, soil conditioning agents, plant disease control agents such as fungicides, oomyceticides, bactericides, nematicides, antitranspirants, fruit retardants, and seed coatings. Chitin and its derivatives enhance or induce natural defensive mechanisms in the plant (Hassan and Chang 2017), and are recognized as plant growth regulators, growth stimulants, anti-stress agents, and elicitors for the production of secondary metabolites (Orzali et al. 2017). Because the whole family of compounds, chitin, chitosan, and oligosaccharide derivatives, is safe for humans, farm animals and the environment, the overall production of these compounds for agriculture is enormous. The production constituted 17,600 metric tons in 2015, with expectations to double by 2021 and reach 37,800 metric tons (Chitin Market 2017). Revenues are also expected to increase from $75 million to $170 million during the same period (Chitin Market 2017). While there are multiple reviews available on chitosan in agriculture (El Hadrami et al. 2010; Sharp 2013; Malerba and Cerana 2018), we would like to narrow down this mini-review to the agricultural use of chitin polymer, and not the chitosan of much lower degree of acetylation (DA) and much higher solubility. The emphasis of this review is thus given from an industrial/applications perspective rather than a molecular biology viewpoint. Table 4.1 summarizes the main points that are covered in this review.

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Table 4.1 Chitin use in agriculture and its mode of action Action Fertilizer

Biocides: Fungicides, Oomyceticides, bactericides, antivirals, nematicides

Elicitor for the production of secondary metabolites

Direct growth regulator/bio-stimulant/ anti-stress agent

Mode of action 1. Utilization of nitrogen from chitin’s acetamide groups: chitin is enzymatically degraded to its oligomers under the influence of endochitinases and exochitinases, and then to monomers under the influence of β-N-acetylhexosaminidases bacteria. Monomers, in turn, decompose to ammonia and nitrates for direct nitrogen uptake by plants (Chernin and Chet 2002; Andronopoulou and Vorgias 2004; Manucharova et al. 2006); 2. Eliciting activity of chitin monomers and/or oligomers and resultant stimulation of innate plant defense mechanisms (Velásquez and Pirela 2016). 1. Chitin has no ‘direct’ antibacterial effect. Its biocidal action is brought about by induction of plant defense mechanisms where chitin and its oligomers act as elicitors to induce plant immunity (Shibuya and Minami 2001; Okada et al. 2002; Velásquez and Pirela 2016); 2. Degrading cell walls of pathogens using chitinases (Velásquez and Pirela 2016); Note: Activity depends on MW of chitin polymer chain (Egusa et al. 2015). 1. Plants are able to recognize chitin via specific receptors such as chitin elicitor-binding protein (CEBiP, Kaku et al. 2006) or the chitin elicitor receptor kinase 1 enzyme (CERK1, Miya et al. 2007). Such ‘recognition’ of elicitor by the plant serves as a signal for the plant to initiate a systemic acquired resistance in healthy uninfected plant tissues, which allows the entire plant to prepare to repel an attack (Shibuya and Minami 2001); 2. Enzymes which are responsible for the formation of phytoalexins normally exist in an inactive state in a healthy plant cell and are bound by certain inhibitors. Such inhibition gets removed under the action of an elicitor (Velásquez and Pirela 2016). 1. Induction by PGPR: through: (1) nitrogen fixation, making nitrogen available nutrient to the plant, (2) degrading cell walls of pathogens using chitinases, and (3) growth regulation through activation of various signaling molecules (Maximov et al. 2011); 2. Eliciting activity discussed above. Note: Bio-stimulants are specifically formulated multicomponent products; thus, classification should be based on efficacy testing, without elucidation of a specific mode of action (Yakhin et al. 2017). (continued)

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Table 4.1 (continued) Action Antitranspirant, wood and leaf sealant

Postharvest biocontrol Seed treatment

4.2

Mode of action 1. Formation of a barrier minimizing evaporation from tissues and preventing the pathogen from invading plant healthy tissues (Hirano et al. 1996); Note: Activity depends on the length of chitin oligomers and longer oligomers demonstrate higher activity. Chitosan oligomers did not display any noticeable activity (Barber et al. 1989). 1. Unknown 1. Some seed treatments express antifungal, antiviral, antibacterial properties, others promote seed’s germination rate and plant growth (Yu et al. 2008).

Chitin as a Fertilizer

Fertilizer is any material that is applied to soil or a plant in order to supply the plant with needed nutrients (US EPA 2018a). There are several classifications of fertilizers, such as those based on the type of specific nutrient that fertilizer supplies: nitrogen, potassium, phosphorus and ‘compound’ fertilizers (Cole et al. 2016). Nitrogen fertilizers are typically used to promote leaf growth (Liu et al. 2014), while phosphorus fertilizers promote growth of the roots, flowers, seeds, and fruits (Razaq et al. 2017). Potassium fertilizers promote strength of the stem, movement of water in the plant, and also improve flowering and fruiting (Barber et al. 1963). According to their origin, fertilizers can be divided into organic and inorganic. Inorganic fertilizers are man-made chemicals widely available on the market, while organic fertilizers are mostly plant or animal derivatives. Even though the growth effect on crops from organic and inorganic fertilizers (Anwar et al. 2005; Amujoyegbe et al. 2007) are reported to be comparable, the use of inorganic fertilizers has damaging effects on the soil (Šimek et al. 1999). Many inorganic fertilizers are harmful for humans and the environment, posing concerns about their safety (Viets and Lunin 1975; Damalas and Eleftherohorinos 2011). With growing public concern of possible harm from man-made fertilizers and growing interest in organic food, interest in chitin as a natural fertilizer has also increased (Harper and Makatouni 2002). In agriculture, chitin is used as a component for the preparation of fertilizers and is considered to be an ‘organic’ fertilizer of ‘nitrogen type’. An important quality of nitrogen fertilizer is the carbon to nitrogen (C:N) ratio, the ratio of mass of carbon to mass of nitrogen in fertilizer (USDA 2011). This C:N ratio (w/w), among other factors, determines how fast the fertilizer decomposes and hence becomes available for the plant (USDA NRCS 2011). Efficient fertilizers maintain a C:N ratio of some 25–30. Too high carbon to nitrogen ratio, more than 25:1 with excess of carbon usually means that fertilizer will decompose slowly. If the C:N ratio is, contrarily, too low with excess of nitrogen, it may lead to immobilization of plant nutrients in the soil (Jat et al. 2012). Chitin and chitosan have C:N ratio

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of ca. 6 for fully deacetylated chitosan, to 7 for fully acetylated chitin. Another important ratio is the percentage of nitrogen (N), phosphorus (P), and potassium (K) that the product contains; this is usually indicated as ‘N-P-K ratio’ on the fertilizer label; chitin has no phosphorus or potassium (Kaplan et al. 2016). In respect to the mechanism of action, the fertilizer effect of chitin or chitosan is caused by either biodegradation of the polymer in the soil into ammonia-derived compounds which have fertilizer effect on their own due to presence of aminogroups, promoting of growth of selected microorganisms (Dahiya et al. 2006). Said decomposition of chitin in the soil is achieved by bacterial chitinases, enzymes that degrade chitin. There are many different chitinases with optimal temperature of action from 30 to 60  C and optimal pH of 4.0–9.0. Chitinolytic enzymes are divided in three types: endochitinases, exochitinases, and N-acetyl-β-1,4-Dglucosaminidases, also called β-N-acetylhexosaminidases (Andronopoulou and Vorgias 2004). Endochitinases catalyze the hydrolysis of random bonds over the whole length of the chitin polymer chain, producing soluble oligomers that are further degraded. Exochitinase catalyzes the process of releasing diacetylchitobiose units at the polymer ends. Finally, β-N-acetylhexosaminidases produce GlcNAc monomers from oligomers (Velásquez and Pirela 2016). At the end of the cycle, chitin decomposes to ammonia and nitrates and can be consumed by plants. Such decomposition of chitin under the influence of various bacteria such as Flavobacterium sp. and actinomycetes 5A and 8A, and F. oxysporum fungus has been studied, and while there was no difference in CO2 production between the chitin-amended and -unamended microcosms, production of NH4+ was significantly higher in all of the chitin-amended microcosms (Gould et al. 1981). Even before a purified chitin polymer became available as a fertilizer, people started to use shrimp and crab meal in the form of a ground biomass as a good source of nitrogen for soil. It was demonstrated that crab and shrimp meal is high in nitrogen, phosphorus, several micronutrients, and that using crab and shrimp meal as a fertilizer improves crop and plant growth (Costa 1977). Shrimp meal fertilizer, for example, contains 8.5% of nitrogen, 2.6% of phosphorus, and 1% of potassium with N-P-K ratio of 8.5–2.6-1 (Gravel et al. 2012). In these crab and shrimp meal fertilizers, chitin is the main component containing nitrogen. There are many commercial versions of shrimp/crab shell fertilizers on the market: Down to Earth Crab Meal Fertilizer, Neptune’s Harvest CS604 Crab Shell Multi-Purpose Plant Food, OptiVeg Chitin Based Soil Amendment, Tidal Vision All-Natural Plant Size & Immune Booster, Plant Magic Plant Food 100% Organic Fertilizer, etc. Shrimp and crab meals have also been compared to man-made fertilizers. Aklog et al. (2016) demonstrated an increase in the growth of tomato plants fertilized hydroponically with a mixture of proteins, chitin, and calcium carbonate prepared by mechanical milling of the crab shells to the level of nanofibers (no chemical treatment was applied). Tomato plants were treated with this mixture once per week. Results were compared with plants treated with distilled water (control) and with plants treated with commercial fertilizer HYPONeX, with N-P-K ratio of 10–10-10. It was demonstrated that protein/chitin/calcium carbonate mixture while was

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effective as a fertilizer, was not as efficient as commercially available HYPONeX fertilizer. It was hypothesized that the presence of calcium carbonate in shrimp meal results in lowering the fertilizer’s decomposition rate and, thus, results in a slow release of fertilizer (Helyar and Anderson 1974; Fenn and Kissel 1975). To offset this undesired outcome, the use of purified chitin polymer as a plant fertilizer was first shown by Peniston and Johnson (1980) who reported that “chitin can be used as a fertilizer to release nitrogen, slowly, into the soil and thereby over a relatively long period of time increase the nitrogen content of the soil.” Hence, in order to demonstrate fertilizing ability, chitin must degrade and release nitrogen; this process of chitin degradation is caused by chitinoclastic bacteria (Zobell and Rittenberg 1938; Manucharova et al. 2006). This process defines how chitin degrades and therefore, releases nitrogen in the form consumable for plants; the type and the time of chitin degradation defines the chitin’s fertilizing ability. Xu et al. (2005) reported use of chitin and chitosan as slow release fertilizers, and compared them with a commercially available slow release fertilizer Osmocote 18–11–10, and control with no actives, in oil-contaminated beach sediments soil type. In addition to use of chitin, chitosan and Osmocote, two mixtures, namely chitin/Osmocote and chitosan/Osmocote were also studied (Xu et al. 2005). As a measure of the activity, microbial dehydrogenase activity (DHA) and respiration rates were determined on the days 0, 3, 7, 14, 21, 28, 36, 42, 49, and 56. It was found that chitosan had a high fertilizing activity, although not as high as Osmocote. Chitin was found to be effective albeit less than Osmocote, as a nutrient source, and released considerably higher amounts of nitrogen than chitosan (Xu et al. 2005). Chitin also resulted in much higher dehydrogenase activity of microbes relative to the control, acting as both a carbon and nitrogen source (Xu et al. 2005). In contrast, the presence of the chitosan had no noticeable beneficial effect on dehydrogenase activity. However, due to the presence of free amino- groups on chitosan, it was able to chelate polycyclic aromatic hydrocarbons in oily sediments, improving the oil conditions (Xu et al. 2005). Xue et al. (2018) reported effect of nanochitin in the form of nanowhiskers on the enhancement of the growth yield in wheat. The measurement of chitin activity was conducted through determination of photosynthetic rate, and yield/quality of the grains. It was found that the crop yield was proportionally dependent on amount of chitin, although chitin’s effect on quality of grains was not that straightforward and certain amounts chitin seemed to be excessive.

4.3

Chitin as a Biocide Such as Fungicide, Oomyceticide, Bactericide, Antiviral, Nematicide, and Insecticide

The US EPA defines biocides as ‘any poison that kills a living organism’ (US EPA 2018b). Since such definition is a relatively broad one, biocides have been divided in smaller groups according to the type of living organism that they poison. Biocides,

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hence, include fungicides which are active toward fungus, oomyceticides which are active toward oomycetes, bactericides which are active toward bacteria, antivirals which are active toward viruses, nematicides which are active toward nematodes, and insecticides which are active toward insects (Milholland 1973). Fungicides are a very important type of biocide. Fungi are dangerous for plants causing numerous plant diseases such as gummy stem blight and Alternaria leaf spot on berries, leaf blight and powdery mildew on carrots (Vulsteke et al. 1996), white mold on beans (Steadman 1983), etc. Due to oomycetes being fungi-like organisms, oomyceticides’ mechanism of action is the same as that for fungi; often oomyceticides are referred to as to fungicides (Beakes et al. 2012). While chitosan derivatives demonstrated pronounced ‘direct’ fungicide activity (Parra and Ramírez 2002) arising from chitosan being an antibacterial agent on its own, chitin does not exhibit significant ‘direct’ antibacterial properties due to the absence of free amino groups in the structure. It was reported that ‘direct’ antimicrobial activity of chitosan is linearly proportional to DA, i.e., to the number of free amino groups (Goy et al. 2009). Higher number of protonated amino groups in chitosan correlated with an increase in its antibacterial properties, while a low DA correlated with lack of such properties. The suggested antibacterial action of chitosan is explained by the interaction of positively charged chitosan molecules with the negatively charged pathogen surface, leading to damage of the pathogen cell due to an increase in the cell membrane permeability, i.e., the ionic surface interaction resulting in cell wall leakage (Rabea et al. 2003). Also important is the formation of an impermeable layer of chitosan on the cell resulting in the inability of a cell to receive needed nutrients, i.e., the formation of an external metal-chelating barrier that results in the suppression of essential nutrients to microbial growth (Xing et al. 2015). One more mechanistic hypothesis suggests the binding of chitosan with microbial DNA inhibiting mRNA and protein synthesis (Goy et al. 2009), although the exact mechanism is not fully understood. Even though chitin lacks ‘direct’ antimicrobial activity, it is included in multiple fungicidal formulations such as a patented immune-prophylactic fungicidal mixture (IN 2009CH01198 A 20111202), made of acetylsalicylic acid, monosodium of 1-hydroxy ethylidene-1,1-diphosphonic, CM-cellulose, potassium sulphate, and chitin (Sundaresan 2011). The reason for including chitin in these herbicidal formulations is indirect inhibition of the pathogens caused by chitin decomposition by-products. Chitin also supports growth of microorganisms, and exhibits eliciting activity; this phenomenon is covered in the next section of this review. When chitin acts as an elicitor, the protective action is brought about not by ‘direct’ antibacterial action of the compound but by activating the plant’s immune defense mechanisms instead (Velásquez and Pirela 2016). Such eliciting activity takes place through the activation of chitin-degrading enzymes, chitinases, that decompose chitin to oligomeric fragments. When plants undergo fungal attacks, chitinolytic enzymes are released by plants. These fragments act as elicitors to induce plant-innate immunity against the invading pathogen (Pusztahelyi 2018). Once chitinolytic enzymes degrade chitin to respective

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oligomers, they are recognized as one of the microbe-associated molecular patterns (MAMPs) which in turn triggers various defense responses in plants (Okada et al. 2002; Shibuya and Minami 2001). The antifungal effect of chitin has been validated in a field study on beans and radishes, in which root-rot and vascular wilt diseases, respectively, were caused by Fusarium sp. fungi (Leuba and Stossel 1986). A significant reduction of plant disease severity was observed after soil application of chitin which acted as ‘indirect’ fungicide through acceleration of action of antibiotic-producing actinomycetes bacteria (Leuba and Stossel 1986). The aforementioned indirect fungicidal activity of chitin also depends on the molecular weight of the polymer. It has been shown that high molecular weight chitin in nanofibrillated form when used as pre-treatment of Arabidopsis leaves effectively reduced pathogen infection by both the fungus Alternaria brassicicola and the bacterium Pseudomonas syringae pv. tomato DC3000 (Egusa et al. 2015). Nematicide is a substance that can kill plant-parasitic nematode worms (Chitwood 2003). There are many species of nematodes and more than half of them are parasitic. Nematodes live in both salt and fresh water, in the soil from arctic to tropical regions, and from low to high elevation. Depending on the species, nematodes can be useful or harmful to the plants. The most popular way to apply plant nematicide is through soil fumigation/ irrigation (Taylor 1963). Chitin, as a mixture with urea, has been shown to be effective in decreasing the number of plantparasite nematodes. Thus, experiments were conducted on several plants (Westerdahl et al. 1992): tomato (root-knot nematode species: Meloidogyne incognita), potato (root-knot nematode species: Meloidogyne chitwoodi), walnut (rootlesion nematode species: Pratylenchus vulnus), and brussels sprouts (beet cyst eelworm species: Heterodera schachtii) through irrigation using a subsurface drip irrigation system. These experiments demonstrated a significant nematode control. Addition of chitin-containing mixtures to the soil rather than irrigation has also demonstrated a similar effect (Radwan et al. 2011). It was reported that chitosan was more effective as a nematicide than chitin (Radwan et al. 2011). It is not expected for chitin to demonstrate insecticide properties because chitin naturally functions as scaffold material in insects. However, chitin derivatives act as antivirals, i.e., substances able to kill a virus. Plant viruses are intercellular parasites without any molecular structure that replicate themselves without a host (Lodish et al. 2000). Tobacco mosaic virus (TMV) and cauliflower mosaic virus (CMV) are typical examples of plant viruses, although it is important to note that plant viruses are studied significantly less than animal and human viruses. Commercially available Cytovirin and Trichotherin are typical antiviral substances used on plants (Shanks and Chapman 1965). It was reported that chitosan is able to inhibit development of viruses and increase the immune response in plants (Pospieszny et al. 1991). There is no proposed explanation for viruses being inactivated by chitosan; neither have studies of use underivatized chitin on viruses been conducted. There is a hypothesis that the effectiveness of chitosan against plant viruses is brought about by modifying the plants response to infection and disrupting the viral particle transfer (Sharp 2013). It was also shown that chitosan derivatives, such as

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chitosan sulphate, act through interaction with a positive charge on the cell surface glycoprotein. As a result, this part of the cell becomes shielded and the virus cannot bind to the cell (Okazaki et al. 1991; Neyts et al. 1992; Kari and Gehrz 1992).

4.4

Chitin as Elicitor of Plant Response

Partially covered in the sections above, chitin acts as a substance that enhances plant resistance through the activation of defense genes and altering the metabolism of plant tissues, eliciting plant response. Elicitors are artificial ‘parasite’ compounds recognized by the plants (Mishra et al. 2012). Recognition of the elicitor by the plants serves as a signal for these plants to initiate a plant-innate immune response, usually when the elicitor compound comes into contact with the surface of the plant. Both chitin and chitosan are considered to be powerful elicitors, which is typical for carbohydrates (Shibuya and Minami 2001). Not much is known about the mechanism of action of elicitors. Typically, plant tissues produce special substances in response to contact with an elicitor called phytoalexins (Keen and Bruegger 1977), and each plant family produces phytoalexins of different types and chemical structures, synthesized by different enzyme systems (Hammerschmidt 1999). Due to such variability, it is very difficult to study elicitors’ mechanism of action. It has been proposed that a group of genes responsible for the formation of enzymes that synthesize phytoalexins is suppressed in a healthy plant (Shimizu et al. 2008). Induction of plant response is associated with the expression of these parts of the cell’s genome, resulting in the synthesis of enzymes. Thus, it has been shown that two phytoalexins in rice (Oryza sativa), namely phytocassanes and momilactones, were induced by chitin elicitor (Shimizu et al. 2008). The same authors showed that plants are able to recognize high-molecular-weight chitin (HMWC) via specific receptors (Shimizu et al. 2010). Kaku et al. (2006) identified this plasma membrane glycoprotein receptor, chitin elicitor-binding protein (CEBiP). Another hypothesis suggests that enzymes which are responsible for the formation of phytoalexins normally exist in an inactive state in a healthy plant cell and are bound by certain inhibitors. Such inhibition gets removed under the action of an elicitor. Thus, in the Brassicaceae family (Arabidopsis genus) and the Fabaceae family (Medicago genus), the chitin elicitor receptor kinase 1 enzyme (CERK1) functions as a component for the perception of the chitin oligosaccharide (Miya et al. 2007). Even though it is known that chitin elicits plant defense responses, polymeric chitin is insoluble in common solvent systems, thus many studies on chitin-induced immune responses have been conducted using chitin oligomers of low molecular weight. To determine whether high molecular weight chitin can result in the same plant reaction and provoke plant resistance, chitin nanofibers of submicron thickness have been prepared from high molecular weight polymer and then evaluated (Mayumi et al. 2015). Chitin nanofibers have been dispersed in water and Brassicaceae

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family sprouts (Arabidopsis seedlings), 10-days old, were treated with aqueous dispersion of chitin nanofibers. Chitin triggered production of reactive oxygen species (ROS, important for signaling role in growth, development) and induced defense-related gene expression in Arabidopsis seedlings. Furthermore, pre-treatment of Arabidopsis leaves with chitin nanofibers effectively reduced pathogen infection by both the fungus Alternaria brassicicola and the bacterium Pseudomonas syringae pv. tomato DC3000. These results demonstrated that chitin nanofibers exhibited elicitor activity. Similarly, the chitin nanofibers of various nanofibrillation degree were evaluated for elicitor activity in cabbage and strawberry plants. Here, cabbage and strawberry plants challenged with fungal pathogens, Alternaria brassicicola and Colletotrichum fructicola, were grown in a soil/chitin nanofibers mixture. Plants demonstrated a reduction in the number of spots caused by pathogens. Gene expression analysis revealed that the defense-related genes in cabbage plant grown in chitin nanofibers-containing soil were significantly upregulated, indicating that chitin nanofibers are suitable for systemic stimulation of disease resistance, in both cabbage and strawberry plants (Parada et al. 2018).

4.5

Chitin as a Bio-stimulant

Agricultural bio-stimulants are formulations of compounds applied to plant foliar or soils, to promote ‘productivity’ either as plant growth and yield or quality and stress tolerance, through stimulation of natural processes and enhancing nutrient uptake and efficiency. Given that the particular composition typically includes various compounds and differs from crop protection products in that there are no direct actions against pests or disease, there is an evident difficulty in determining their modes of action. Yakhin et al. (2017) in their review on bio-stimulants in plant science, proposed the definition of a bio-stimulant as ‘a formulated product of biological origin that improves plant productivity as a consequence of the novel, or emergent properties of the complex of constituents, and not as a sole consequence of the presence of known essential plant nutrients, plant growth regulators, or plant protective compounds, and suggested that bio-stimulant testing should be conducted based solely on efficacy testing, without a requirement for the elucidation of a specific mode of action (Yakhin et al. 2017). Yet one well-established mode of action has been through bio-stimulation induced by rhizobacteria. PGPRs are the soil bacteria living on plant roots and beneficially involved in promoting plant growth (Kevin 2003). PGPRs are classified into two classes by the types of relationships they form with the plant, namely rhizospheric, those that colonize the surface of the root and endophytic, those growing within the host plant in the apoplastic space). The main processes PGPRs are involved into are: (1) nitrogen fixation, the process of conversion of gaseous nitrogen (N2) into ammonia (NH4+) making nitrogen available as a nutrient to the plant, (2) degrading cell walls of pathogens

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using chitinases, and (3) growth regulation through activation of various signaling molecules (Maximov et al. 2011). Thus, PGPR Bacillus bacteria is able to emit chitinases into culture medium and PGPR S. marcescens GPS 5 is able to hydrolyze high molecular weight chitin into chitin oligomers. In the case of pathogen containing chitin as an essential part of the carbohydrate skeleton of the fungal cell wall, Bacillus bacteria is able to emit chitinases resulting in fungicidal action. Contrarily, when chitin is used as a fertilizer, PGPR S. marcescens GPS 5 results in direct enhancement of nitrogen uptake by plant and eliciting activity of resultant chitin oligomers that promote plant immune response.

4.6

Chitin as Antitranspirant, Wood Sealant and Leaf Sealant

Antitranspirants are compounds applied to the leaves of plants to reduce transpiration through the formation of a physical barrier around pathogen penetration sites. Chitin has been shown to form a physical barrier preventing the pathogen from invading plant healthy tissues. Hirano et al. (1996) reported that application of various chitin films onto the tree bark tissues (Dendropanax, Camellia, Maple, Cherry, and Spear-flower) resulted in enhanced tissue healing. The composition of films included rubber for easier adherence, and the films of the following compositions have been applied to the wounded tree bark: 1/1/1.2 chitin/chitosan/rubber, 1/1.1/1.1 chitin/starch/rubber, 1/1.1/1.1 chitin/cellulose/rubber, and 1/2.3 chitin/rubber. In addition, a composition with no rubber has also been attempted, such as a nonwoven chitin-cellulose 1/1.2 sheet. Data indicated that only chitin was active for stimulation of chitinase in the wounded tree bark tissues, while no activity was found for cellulose, rubber, and starch. The chitin film’s activity was attributed to the degradation of chitin into oligosaccharides and their eliciting action, however no in-depth study of this mechanism with elucidation of specific proteins or enzymes participating in this mechanism has been conducted. Depending on the composition, biodegradation, and thus healing, took 4–24 weeks after implantation. Barber et al. (1989) tested chitin and chitosan oligomers for lignification of wounded wheat leaves and a significant portion of this study was directed to comparison of chitin and chitosan activity as leaf sealants. The monomer of chitin, N-acetylglucosamine, and dimer did not show any measurable activity in lignification while higher molecular weight chitin oligomers (trimer, tetramer, pentamer and hexamer) exhibited significant dose-dependent activity, proportional to molecular weight of oligomers with highest activity being found for hexamer (highest MW oligomer tested in this study). It was also shown that chitosan oligomers, in contrast, did not demonstrate any noticeable activity, confirming the difference between chitin and chitosan and a need for acetamide group.

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Chitin as an Agent for Seed Treatment

Seed treatment is a process of coating seeds with chemical or biological substance that has properties beneficial for the plant. There are many reasons to use seed treatment. Some seed treatments have antifungal, antiviral, antibacterial, or insecticide properties while others promote seed’s germination rate and plant growth. Among the advantages of seed treatment is the lowering of the amount of chemicals needed for plant growth, ease in controlling herbicidal spills, uniform distribution of chemicals, perfect timing and targeting. The main disadvantages of the method are the same as those associated with the use of pesticides such as risk for workers, and potential harm for the environment (ODA 2001). Typical seed treatment agents can be contact or systematic. Systematic agents penetrate the seed shell and affect seed movement inside of the plant. Contact agents remain on the surface of the seed. In general, chemicals that are chosen for seed treatment are the same as those chosen for an adult plant. For example, streptomycin is often used as a bactericidal seed treatment (Taylor and Dye 1975) and difenoconazole (Brancato et al. 2018) is applied as a fungicidal seed treatment, etc. Both chitin and chitosan can be used as standalone seed treatments, or be supplemented to existing formulations. It has been shown that chitin has a positive effect on seed germination, increasing grass seed germination rates. Chitin also increases the production of carbohydrates in plants, and improves their frost tolerance. For example, the addition of chitin to chitinolytic PGPR B. subtilis AF 1 has been tested (Manjula and Podile 2005). Here, chitin was supplemented to AF 1 formulation, and this formulation evaluated as a seed treatment. Addition of chitin increased the emergence and dry weight of pigeon pea seedlings by 29 and 33%.

4.8

Chitin as an Agent for the Biological Control of Postharvest Diseases

The United Nation Environment Program has estimated that about one third of all food produced in the world in 2009 was lost or wasted (Lipinski et al. 2013). About 24% of all food lost was due to storage and handling. There are several approaches to this problem and the postharvest treatment of fresh fruits and vegetables is one of them. When fruits are collected from the plants, the concentration of the biologically active molecular gases, such as O2 and CO2, changes. As a result, the cell renovation process stops, metabolic loss increases, fruits ripen, and then degrade. The gases’ concentration and respective exchange rate depends on several factors that can be taken into account in order to increase postharvest life span of fruits and vegetables (Dhall 2013). There are many different types of postharvest treatments, such as heat treatment, irradiation, coatings, etc. (Mahajan et al. 2014). Different treatments have different benefits, for example, heat treatment can postpone ripening, edible coating

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helps to minimize loss of moisture, antimicrobial agents provide protection against microbial growth, etc. Depending on the produce, the relevant procedure has to be chosen. For instance, it is common for bananas and mango to be treated with nitrogen oxide, while carrot and strawberry in general are getting coated with edible coatings (Mahajan et al. 2014). Several parameters are usually evaluated: browning index, leakage rate, assay of enzymes such as (1) superoxide dismutase or SOD, an enzyme that protects plants from decomposition, (2) Catalase or CAT, enzymes that participate in the breathing process, (3) polyphenol oxidase and peroxidase or PPO and POD, respectively, enzymes that participate in browning mechanism. While chitosan is an effective edible coating material for postharvest fruits, and coatings prepared from it have been shown to be effective on cherry tomatoes (Won et al. 2018) and mushroom (Liu et al. 2016), etc., there is not much literature available related to coatings made of chitin, probably due to the insolubility of chitin polymer. Ghosh et al., reported an increase in the shelf life of litchi after it was coated with chitin-containing wax (Ghosh et al. 1998). Here, modified atmosphere packaging (MAP) was used together with coating and consisted of wax emulsion, chitin in tartaric acid and shellac. Samples without coatings were considered as a control. Weight loss after 15 days of storage was 1.16% in samples coated with chitin, 3.19% for samples coated with shellac, and 3.23% for samples coated with pure wax. The control group demonstrated a 3.47% weight loss. Titrable acidity and amount of ascorbic acid were measured. Both of them decreased with time, but samples coated with chitin demonstrated more acidity and more ascorbic acid after 15 days of storage. Total amount of sugar increased with storage time, but it was lower in samples covered with chitin compared with all other tested coating and control. Sun et al. (2018) demonstrated the effect of chitin coating on tomatoes. Chitin suspension was used for coating. Tomatoes were immersed in chitin suspensions with 0.1%, 0.5% and 1% of chitin. The control group was immersed in water. After that tomatoes were wounded and Botrytis cinereal were injected in tomatoes on the wound side. Effectiveness of chitin in reducing bacterial activity was measured. It was demonstrated that chitin increases the ability of tomato to resist to Botrytis cinereal. One typical problem is the attack of harvest by mold. Chitin has been used for enhancing the antagonistic activity of yeasts employed in postharvest biocontrol. Thus, the recent study conducted to evaluate the effect of chitin on the antagonistic activity of yeast species Cryptococcus laurentii used against the postharvest blue mold rot caused by Penicillium expansum in pear fruit showed an increase in the activity of the yeast with addition of 0.5–1.0 wt% chitin (Yu et al. 2008). While the addition of chitin did not influence the growth of C. laurentii yeast in nutrient yeast dextrose broth (NYDB) media, its population was found to increase rapidly in pear fruit wounds. Moreover, the biological activity of C. laurentii against blue mold rot on pear fruit was greatly enhanced. It was suggested that enhanced population of yeast was likely a major reason for increased biocontrol, although the mechanism for the enhancement of the yeast growth in fruit after chitin treatment remained unclear.

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Outlook

Synthetic plant protection products are mostly toxic, bio-accumulative, persistent in the environment and harmful for both humans and animals. Use of chitin polymer as a promising environmentally-friendly natural alternative to synthetic herbicides, in order to control plant diseases and to regulate plant growth, has recently attracted significant attention. According to EPA’s final registration review decision, chitin ‘satisfies the statutory standard and can perform its intended function without unreasonable adverse effects on human health or the environment’ (US EPA 2018a, b, case #6063). The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) FIFRA Section 3(g) and 40 CFR 155.58(c) provides authority for this action (UA EPA 2008). In agriculture, the most common use of chitin is a fertilizer, due to the polymer’s ability to slowly degrade, releasing needed nutrients to plants; chitin provides no risk of overfertilizing. Likewise, chitin is utilized as a soil conditioning agent which improves the soil structure and increases its ability to hold water. It also has been shown that chitin acts as a PGPR stimulator, and participates in direct enhancement of nitrogen uptake by plants. In addition, chitin has been shown to enhance or induce natural defensive mechanisms in plants being recognized as a plant growth regulator. Both chitin and its derivatives are considered to be powerful elicitors, inducing plants’ phytoalexins activity and promoting plant immune response. Even though chitin lacks ‘direct’ antimicrobial activity, it is often utilized as a fungicide due to indirect inhibition of the pathogens caused by chitin decomposition by-products, and the polymer’s eliciting activity. The fungicidal activity of chitin depends on its molecular weight. Furthermore, chitin is also applied as a plant nematicide through soil fumigation/irrigation or addition of chitin-containing mixtures to the soil. Chitin has been shown to form a physical barrier preventing the pathogen from invading a plants healthy tissues and improves lignification of wounded leaves. It can be used as standalone seed treatment. In food postharvest applications, chitin increases the ability of fruits to resist diseases and is used as a postharvest biocontrol treatment. Chitin also increases carbohydrate production in the plant, and improves plant’s frost tolerance. Table 4.2 below summarizes the products currently used in agriculture where chitin can make a difference. We would also like to note here that while chitosan is extensively used in agricultural applications, chitin is not used extensively – partially due to its low solubility but also because of no commercial production in North America. Mari Signum Mid-Atlantic, LLC founded in 2016 is integrating its unique chitin extraction process (Shamshina and Rogers 2018) into an industrial-scale facility in Richmond, VA with estimated initial annual production of 210,000 pounds of chitin biopolymer, extracted from an approximate volume of 1 million pounds of raw shell biomass. One of the markets Mari Signum Mid-Atlantic, LLC is planning to tackle is the use of chitin in agriculture.

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Table 4.2 Current agricultural products used Type Biocide

Fertilizer Growth regulator (yield improvement)

Action Fungicide, Oomyceticide, Bactericide, Viricide (antiviral), Nematicide, Oomyceticide Fertilizer Direct growth regulator/bio-stimulant/ Stress alleviator

Elicitor for the production of secondary metabolites

Antitranspirant

PGPR stimulator (plant growth promoting rhizobacteria).

Ripening retardant Soil conditioning

Mycorrhizal stimulators (work by attaching themselves to the root of the plant extending the root system in order to get more water and nutrients Ripening retardant Soil conditioning

Representative examples of current products Various synthetic and organic pesticides, fungicides, viricides (depends on type of disease) Various granulated fertilizer products (soil-dependent) Various synthetic growth regulators and hormone inhibitors, humic and fulvic acid, seaweed extracts. Commercial names, e.g., NPK Industries Raw Humic Acid Fertilizer, Pac Low Plant Growth Regulator, Botanicare Seaplex. Jasmonates, salicylates, benzoic acid. Commercial products, e.g., Jasmonic Acid 95% – Plant Growth Regulator Kits Synthetic polymers: e.g., di-1-pMenthene. Commercial names, e.g., Wilt Pruf 07011 Antitranspirant Concentrate, Haven® antitranspirant Commercial names, e.g., Asthra (liquid PGPR), Polyglycerol Polyricinoleate by A.B. Enterprises, PGPR 4150 by Palsgaard Commercial names, e.g., Humboldt Nutrients Myco-Madness, Microbe Life Hydroponics Plus-C, Plant Success – PRPSGW25 by Neobits Controlled-environment storage, 1-methylcyclopropene Polyacrylamide and cellulose-based products. Commercial products, e.g., Soil binder granular polyacrylamides, liquid polyacrylamides; soil polyacrylamides power blocks

Notes Dr. Robin D. Rogers is a named inventor on related patents and applications and has partial ownership of 525 Solutions, Inc., and Mari Signum Mid-Atlantic, LLC. J. L. Shamshina is an inventor on related patents and applications, former employee of 525 Solutions, Inc., and CTO of Mari Signum Mid-Atlantic, LLC.

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Chapter 5

Chitosan-Based Hydrogels Janaina Oliveira Gonçalves, Vanessa Mendonça Esquerdo, Tito Roberto Sant’Anna Cadaval Jr, and Luiz Antonio de Almeida Pinto

Abstract Chitosan is a deacetylated derivative of chitin. This polysaccharide has received a great attention due to its biocompatibility, low toxicity, biodegradable, furthermore can be used into different shapes, such as beads, hydrogels, powders, films and membranes. Chitosan hydrogels may be formed by different mechanisms, as physical association or chemically cross-linked, thus can vary its geometries, formulations and shapes. Usually, hydrogels are prepared using a conventional sol-gel process, where polymer is dissolved in dilute acid to form an aqueous solution, after complete dissolution the cross-linking agents are subsequently incorporated, and the solution/gel transition depends on the number cross-links between the polymer chains and the cross-linking agents, and these should be enough until reaching the formation of a network. The chitosan hydrogels are formed from crosslinking of hydrogen bonds, hydrophilic interactions and crystalline groups of chitosan present in the sol-gel. Chitosan hydrogels have been largely used in drug delivery systems, wastewater and dye remediation, and tissue engineering supporting cell attachment and growth. In the food industry, chitosan hydrogels are used to maintain and/or improve the perception of flavor, release of fragrance compounds and increase shelf life. In the biomedical and biotechnological fields, these are used for controlled release formulations, for example, of compounds chemicals, volatiles, or proteins. Chitosan hydrogels can be used in dressing to adsorb the secretion of the injured area and release water on the wound surface, thus keeping it hydrated. Thus, the researches for employment of this material have been increasingly developed due to its favorable properties, such as durability, permeability, flexibility and its wide applicability. Keywords Chitosan · Polysaccharide · Hydrogel · Scaffold · Modification · Crosslinked · Biomaterial · 3D networks · Flexible · Porosity

J. O. Gonçalves · V. M. Esquerdo T. R. Sant’Anna Cadaval, Jr · L. A. de Almeida Pinto (*) Industrial Technology Laboratory, School of Chemistry and Food, Federal University of Rio Grande–FURG, Rio Grande, RS, Brazil e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_5

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Introduction

Chitosan biopolymer is obtained from the alkaline deacetylation of chitin, which is present in abundance in nature and its main natural sources are crustacean shells, such as crab, shrimp and lobster, and the insect exoskeletons, mollusks and fungal cell wall. In addition, chitosan is versatile, allowing chemical and physical modifications, as the introduction of functional groups in its structure and changes in their configuration, that enhance the chitosan performance as a biomaterial (Rinaudo 2006; Vakili et al. 2014; Zhou et al. 2014; Xing et al. 2018). Due to the wide possibility of application, there is a continuous research of materials with different physical, chemical and morphological characteristics that allow their implementation in the most diverse fields of science. Chitosan as the only cationic polysaccharide in nature, exhibits favorable properties, such as low toxicity, good biocompatibility, biodegradability and mucoadhesive. Chitosan and its derivatives are recognized as versatile biomaterials because they can be easily molded into different shapes and sizes. The most used chitosan derivatives are beads, powders, films, scaffolds, sponges, membranes and hydrogels (Nettles et al. 2002; Yang et al. 2010; Cheung et al. 2015; Guo and Li 2016; Vakili et al. 2016). Hydrogels are hydrophilic materials, featuring a 3D network, in which is able to retain a large amount of water. These materials can be obtained by different processes, as through of either physically associated or chemically cross-linked networks, by covalent bonds or electrostatic, hydrophobic, and hydrogen bonding forces. These conditions define the type of hydrogel, which can be reversible or irreversible. The hydrogels can be prepared at room temperature in an aqueous solvent, however, can be sensitive to variations in pH. In relation to solubility, the materials may be soluble when formed from weak bonds, or insoluble when obtained from cross-links between the polymer-indicated chains (Berger et al. 2004; Lin and Metters 2006; Croisier and Jérôme 2013; Poon et al. 2014; Gonçalves et al. 2017). The modification of chitosan hydrogels has increased its use in different areas, such as pharmaceutical, medical, engineering and food, splicing different applications, like tissue engineering, water treatment, wound healing, wound dressing and drug delivery. Desirable characteristics in the hydrogel will depend on the purpose of its application, biodegradation, antifungal, antibacterial and non-toxic, are factors to be considered when applied in the biomedical area. In the area of effluent treatment, a stable hydrogel with high mechanical properties and reusability are fundamental for its applicability (Pakdel and Peighambardoust 2018; Pellá et al. 2018) In addition, the hidrogels are of the biomaterials most studied for controlled drug delivery. However, its wide use implies increasing research on the factors that influence its obtained and also on the search for new promising materials. Thus, the purpose of this chapter is to provide relevant information on the application of chitosan-based hydrogels and to present how the different types of chitosan hydrogels are elaborated and what the properties are relevant to their formation.

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5.2

149

Chitosan

In 1811, the first chitin was extracted from mushrooms and was named initially as fungine by French professor Henri Braconnot. Until the beginning of the twentieth century, the similarity of chitin, chitosan and cellulose polymers caused difficulties for researches in the distinguishing between them. Although chitin was discovered 30 years before cellulose, most of the research was focused only on cellulose. In this epoch, there was a high investment of the textile industries, thus, chitin and chitosan remained restricted only to basic research. Around 1970, the investigations began and later the applications directed to the chitosan (Rinaudo 2006). Currently, the highest production of chitin and chitosan is found in Japan and the United States, after, to a lesser scale, in India, Norway, Canada, Italy, Poland, Chile and Brazil. It is estimated that in 2007 the production of chitin-rich waste generated by the fishery industry was around 1,440,000 t. In 2015, Argentine red shrimp (Pleoticus muelleri) presented a record number due to its capture according to the FAO (2018) approaching around 144,000 tonnes. In addition, in 2016 the catch of shrimp, along with other crustaceans of valuable species such as lobster and crab, established a new record of significant catch (Campana-Filho et al. 2007; BessaJunior and Gonçalves 2013; FAO 2018). Chitosan is a natural biopolymer composed of β-(1-4)-D-glucosamine, obtained by alkaline N-deacetylation of chitin, which is composed of β-(1-4)-linked N-acetyl glucosamine. These polymers present chemical characteristics similar to cellulose, and relevant physical-chemical properties too, such as bioactivity and non-toxicity due to the presence of hydrolytic enzymes (lysoenzyme, chitinase and chitosanase) (Muzzarelli 1997). Chitin is the second most abundant natural amino polysaccharide, losing only for cellulose, because the chemical structures of these polymers are similar. The characteristic that differentiates the structure of chitin and chitosan is the substitution of the acetamide group at position 2. This particularity directly influences in the solubility properties of these compounds, with chitin being insoluble and inert, and chitosan soluble in weak and reactive acids (cationic polyelectrolyte). In acid medium, the protonation of the (̶ NH3+) groups of the chitosan occurs and, depending on concentration, it can form viscous solutions to obtain gelification with polyanions (Muzzarelli and Rocchetti 1986; Rinaudo 2006; Crini and Badot 2008; Zargar et al. 2015). The degree of deacetylation defines the amount of D-glucosamine units formed from the partial disruption of N-acetyl linkages, indicating the percentage of deacetylated monomers present in their chains. When the degree of deacetylation value is above 60%, the polymer already is considered chitosan, since it becomes soluble in acidic medium. Many analytical tools can be used to determine this parameter, among them, IR-spectroscopy, enzymatic reaction, UV spectrophotometry, titration methods and among others. The choice of technique depends on several factors such as the purification process, sample solubility and availability of equipment (Rinaudo 2006; Gupta 2009).

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The average molecular weight of chitosan is another important characteristic for the development of materials. Normally, commercial chitosan shows molecular weight values between 100,000 and 1,200,000 Dalton, which will depend on the reaction conditions. The most widely used method for determining molecular weight is viscosimetry because of its simplicity and rapidity when compared to other methods (matrix-assisted laser desorption/ionization; gel permeation chromatography, GPC; laser light scattering) (Muzzarelli and Rocchetti 1986; Rinaudo 2006). In the potentiometric titration method, the linear titration curve is obtained plotting a graph of f(x) as a function of the corresponding volume of sodium hydroxide solution. This alkaline solution volume at the end of titration is calculated by extrapolating linear titration curve as a function of the volume of the added NaOH solution. Jiang et al. (2003) developed a new linear potentiometric titration method for the determination of deacetylation degree of chitosan. The viscosity of a solution is directly related to its intrinsic viscosity and its concentration. The reduced viscosity is determined using the Huggins equation, afterward, it can be converted into molar mass by means of the Mark-HouwinkSakurada equation (Zhang and Neau 2001). Already, Wu (1988) realized study to the determination of chitosan molecular weight distribution by high-performance liquid chromatography.

5.2.1

Source and Production

Chitosan is derived from chitin, usually obtained from natural sources such as residues of shrimp, crab and lobster, green algae and fungal mycelia. This biopolymer can also be found in exoskeletons of insects and fungal cell walls as shown in the sketch of Fig. 5.1. Chitin content relative to the exoskeleton can reach up to 68%, already in fungi this content varies between 42% and 44%. Therefore, the crustaceans are the largest producers of chitin available for the industrial process. Chitin content can range with the amount of protein, minerals and carotenoids diversify depending on the species, age, nutritional status, reproductive cycle phase and also the peeling conditions during the processing (Rinaudo 2006; Campana-Filho et al. 2007; Berger et al. 2018). Chitin can be isolated from shrimp waste and, commonly performed by the chemical sequences: demineralization, deproteinization, and decolorization. (Weska et al. 2007; El Knidri et al. 2019). The deacetylation can be performed from enzymatic hydrolysis, microwave radiation or acid hydrolysis, the latter being more used (Weska et al. 2007; Al Sagheer et al. 2009). However, most often, the reaction is carried out using concentrated sodium hydroxide solution, with varying the temperatures and times. Moura et al. (2015) studied the effects of these factors on the deacetylation reaction and verified that these parameters directly affected the degree of deacetylation and molecular weight of the polymer. Biological treatments are an alternative to avoid the environmental impact, and usually, are carried out using enzymatic methods by chitin deacetylase (El Knidri et al. 2019).

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Fig. 5.1 Main sources of chitin

The drying operation of chitosan assures product quality for stored, thus maintaining its characteristics. In this operation, one of the fundamental parameters is the temperature, because chitosan is composed mainly of carbohydrate monomer units that, at high temperatures, are capable of undergoing caramelization this polymer. Dotto et al. (2011) carried out the study of the effect temperature inlet air in the drying of the polymer, used a spouted bed (slot-rectangular and conicalcylindrical geometries). The authors observed that as occurred temperature increase (90, 100 and 110
C) caused an increase in powder darkening, molecular weight (147–225 kDa) and increased particle size (100–200 μm). The best powder quality was obtained at 90
C, resulting in a final moisture content was in the commercial range (10%).

5.2.2

Properties and Applications

Chitosan and its derivatives are applied in several areas, such as agriculture, medicine, biotechnology, engineering, pharmaceuticals, drinks and food. The tendency of the use of this polymer is for products of high added technological value such as cosmetics, semipermeable membranes and polymer films. These implementations are directly related to the biopolymers properties such as degree of deacetylation, molecular weight, viscosity, biodegradability and bioactivity (Crini and Badot 2008; Gonçalves et al. 2015; Mozalewska et al. 2017).

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One of the characteristics that make chitosan a versatile polymer is hydrophobicity since it allows the use of this biomaterial in the form of micro and nanoparticles, injectable gels and membrane as a vehicle for drug release. Other intrinsic properties make chitosan an efficient adsorbent material, for example, biocompatibility, bioadhesiveness, polyfunctionality, and especially its polycationic character in acid medium and capability to form hydrogen bonds, Van der Walls interactions, and electrostatic interactions. In addition, allows a series of chemical modifications (cross-linking, grafting and complexed) where functional groups different can be introduced in their structure, to intensify their potentiality as material and to extend their applications (Guibal 2004; Prashanth and Tharanathan 2007; Sousa et al. 2009; Croisier and Jérôme 2013; Vakili et al. 2014; Zheng et al. 2015). In order to obtain chitosan-based material such as hydrogels, membranes, sponges, films, blends, composites and cross-linked, the modifications in chitosan can be physical or chemical. In polymer blends, there is no chemical reaction, they consist only of the mixture of polymers or copolymers. This modification type is intended to improve the mechanical and biological properties of the polymer network and is called of blend. The chemical modifications in chitosan improved its chemical stability, its selectivity and adsorption capacity, mechanical resistance, reduced costs, increase its limited surface area and acid solubility (Ngah et al. 2011; Vakili et al. 2014). Santos et al. (2018) developed chitosan-edible oil blends based-materials as upgraded adsorbents for textile dyes, remazol red and methylene blue. The adsorbent was obtained from blends on chitosan and either a saturated (babassu) or an unsaturated oil (soybean). The authors verified that the chitosan blends were able to extend the working pH range and increased the adsorption capacity of the adsorbent. Chitosan molecule has three reactive groups attractive for chemical modifications: two hydroxyl groups (primary or secondary) and a primary amine. The site of modification is chosen according to the intended application of the final chitosan derivative. Composite materials based on biodegradable polymers combinations, such as chitosan are discussed as suitable materials for scaffolds manufacturing. These composites provide differentiated physical, biological and mechanical properties, and predictable degradation behavior. The appropriate selection of a compound to an application particular requires a detailed understanding of competent cells and/or expected response (Venkatesan and Kim 2010; Riva et al. 2011). Zheng et al. (2015) developed a novel diatomite/chitosan Fe (III) composite to use as an adsorbent for anionic azo dye removal. Firstly, was prepared the mixture of chitosan and Fe (III), that after was placed in an ethanol solution in contact with glutaraldehyde for the Schiff’s reaction. The adsorbent was further characterized by SEM, FTIR, XPS and the composite also showed favorable adsorption properties for other four anionic azo dyes. Lan et al. (2015) allied the characteristics of two polymers to produce a gelatin-chitosan sponge and test the hemostatic properties of this scaffold. The material was cross-linked with tannins and then freeze-dried. They found a better hemostatic effect when the two polymers have been associated, probably due to its ability to readily absorb blood platelets, being considered an effective absorbable hemostatic material.

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Biopolymer films are formed from natural polymers of animal or vegetable origin, where their main characteristic is biodegradability. The formation of such biomaterials requires at least one solvent such as water, ethanol, water/ethanol, acetic acid, among others, and in some cases a plasticizer, glycerol or sorbitol, for example. Membranes and chitosan films must have good mechanical properties, larger surface area, and low crystallinity (Chandra and Rustgi 1998; Denavi et al. 2009). Dotto et al. (2013) carried out a study using chitosan films for the adsorption of acid red 18 and FD & C blue no. 2 dyes in aqueous systems. Currently, chitosan for being non-toxicity, and low price have gained a special place has and been used as a raw material for synthesis of hydrogels in a wide range of potential applications such as drug delivery, wastewater treatment and tissue engineering. Where such topics will be addressed in order to contribute to the use of chitosan hydrogels by the scientific community in their research.

5.3 5.3.1

Chitosan Hydrogels Definition

Currently, the search for biomaterials that present biocompatibility, stability, biodegradability, and adequate mechanical properties has been increasingly investigated. Among the most researched biomaterials are the hydrogels that are comprised of cross-linked polymer networks present high water retention capacity, however are insoluble due to the presence of inter and intra molecular bonds in the matrix polymer. Gels are composed of two main phases: solid and liquid. The solid phase is responsible for the firmness, consistency, resistance of the gel and also water retention capacity. The liquid phase is usually composed of water and sometimes the active agents (Hamidi et al. 2008; Croisier and Jérôme 2013; Kakkar and Madhan 2016; Pellá et al. 2018). The functional groups of the hydrogel present in the polymer network, making it sensitive to pH, temperature, ionic concentration, electric field, and light. Normally, it can be formed only by natural polymers combination, such as gelatin and fibrin, polysaccharides, due to their ability to form gels under well-defined conditions. The polymers are present in abundance and variety in nature, so the choice of this becomes important in the characteristics of the desired hydrogel. Therefore, it is necessary to analyze the properties of which directly influence the achievement of the hydrogel, such as the degree of swelling and the mechanical characteristics. In the pharmacological area, these characteristics are of great relevance because of the improved drug penetration through the expansion of pathways between the epithelial cells. In the chemical and environmental area, the hydrogels must have good mechanical resistance so that they remain intact and can be reused (Peppas et al. 2000; Drury and Mooney 2003). The polymers studied in hydrogel formation are cellulose, xanthan and chitosan. The chitosan has received a great deal of attention due to its biocompatibility, low

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toxicity, biodegradable, and it is readily processed into different shapes (beads, hydrogels, powders, films and membranes), due to the presence of amine and hydroxyl reactive groups. Furthermore, acts as an adhesive agent due to its positive charges at physiological pH, increasing the research using this polymer. Various factors influence in the gelation, such as mechanical stirred, amount of polymer and cross-linker in the hydrogel and pH, in the case chitosan, can be accelerated by pH increase. The chitosan solution viscosity is directly in relation with cross-linker agent. The greater the amount and the contact time of the cross-linker with the polymer, the faster the formation of the gel point (Kumar et al. 2004; Kildeeva et al. 2009). Hydrogels are friable and porous materials, and also called scaffolds. Chitosan scaffolds are solid three-dimensional structures, soft, flexible and with high porosity. Polymers have been widely used as biomaterials for the production of these structures in different areas. Polymeric scaffolds are attracting a great attention due to their unique properties, such as high surface area, high porosity, high capacity for fluid absorption, biodegradability, biocompatibility and versatility. The main features to be observed in the scaffolds are their strength, degradation rate, porosity and microstructure. Their shapes and sizes are easily reproduced using polymeric supports. These structures can be obtained by freeze-drying, where a chitosan solution is frozen and dried by solvent sublimation under vacuum. This process is considered simple and efficient (Jayakumar et al. 2011; Croisier and Jérôme 2013).

5.3.2

Preparation of Chitosan Hydrogel

Chitosan hydrogels can be formed by different mechanisms, by physically associated or chemically cross-linked varying its geometries and formulations. Normally, they are prepared using a conventional sol-gel process, where chitosan polymer is dissolved in dilute acid in order to form an aqueous solution, after complete dissolution, the cross-linkers are subsequently incorporated, using covalent bonding between polymer chains obtaining the hydrogel permanent networks. The transition solution/gel depends upon the cross-links between the polymer chains and the crosslinking agent until achieving the formation of a network, in very dilute solutions does not occur sufficient crosses number among links between them (Ginani et al. 1999; Poon et al. 2014).

5.3.2.1

Physical Cross-linking

The hydrogels formation by physical associated can be reversible due to the interactions are weak, that is, non-covalent. Normally, the reversible interactions are by hydrogen bonding, hydrophobic interactions or electrostatic interactions. Those interactions are not very stable, dependent on several factors such as temperature, pH, nature component and concentration, thus the gelation can be reversible (Berger

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et al. 2004; Croisier and Jérôme 2013). Thus, the hydrogels are not chemically stable and may disintegrate and/or dissolve, depending on the conditions under which they are subjected. The hydrogel may be formed using only chitosan neutralized without the addition of any complexing agent or the presence of another polymer. The amine groups neutralization of the chitosan leads to the inhibition of the polymer chains repulsion. The hydrogel is formed from cross-linking of hydrogen bonds, hydrophilic interactions and crystalline groups of chitosan present in the sol-gel. The self-cross-linking hydrogel exhibits biocompatibility, a characteristic property of chitosan, being pointed as a suitable and safe material for biomedical purposes due is not necessary the presence of a solvent or a cross-linking agent in the formation it. However, this possibility of modifying the charge density gives the biomaterial inferior mechanical characteristics to the cross-linked hydrogels (Peppas et al. 2000). Xu et al. (2017a, b) showed the development of self-cross-linking chitosan hydrogels by utilizing the pH- and ionic strength-dependent. The chitosan hydrogel was analyzed according to cell viability and stimulus-responsive properties, where the study demonstrated that biomaterial was high cytocompatibility and sensitive to extremes changes of pH. Moreover, without the addition of cross-linking agents, chitosan hydrogels can be formed from ionic bonds between anionic polymers, such as pectin, alginate, cellulose, xanthan combined with chitosan (Tsuchida and Abe 1982; Fujiwara et al. 2000; Dash et al. 2011). The association of chitosan with other polymers could to influence in the density, hardness, and dissolution of the hydrogel, thus improving its properties and diversifying its applicability. The physical modification chitosan-based hydrogels is largely used in the clinical area, since they are reversible interactions and can make feasible characteristics such as the rearrangement itself. Aqueous solutions of chitosan and pectin can form polyelectrolytes networks under suitable conditions, from electrostatic attractions between the NH3 and COO groups of the polymers. Usually, the polyelectrolytes networks are nanoparticles, thin films, millibeads and microbeads (Maciel et al. 2015). Tentor et al. (2017) developed hydrogels based in the combination chitosan and pectin, containing the addition of gold nanoparticles applied in osteoblast cells. The results showed that gelation temperature decreased when the number of gold nanoparticles increased and pectin concentrations decreased. In addition, the composites were entirely biocompatible with several cell types, confirming their performances acting as biomaterials. The authors concluded that hydrogel had a high potential for applications in the medical field, especially bone cell. Chitosan hydrogels formed by polyelectrolytes through electrostatic interactions are stronger than other secondary binding interactions, such as van der Waals or hydrogen bonding. This complex does not require the presence of cross-linking agents, catalysts, or organic precursors, so their use in tissue engineering and drug delivery is safe. In addition, the interaction between polyelectrolyte and chitosan is simple and hydrogel can be reversible. The stability of the polyelectrolytes hydrogel is directly related to type anionic molecule, charge density, pH, interaction time, polymeric solution concentration, temperature and ionic strength (Tsuchida and Abe 1982; Bhattarai et al. 2010).

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Other alternative method in relation the physical association is a so-called freezethaw. The freezing procedure induces the formation of ice crystals which act as cross-linking agents in the obtaining of the hydrogel. During the thawing step occur the formation of crystalline regions and porous structures. Baghaie et al. (2017) developed hydrogels from the combination of polymers which were subjected to freezing-thawing cycles, the authors observed the mechanical properties and performed pathological tests, where they obtained satisfactory and effective results in wound healing. Other techniques may be used in combination with freezethawing, for example, irradiation or systematic X-ray powder diffraction. Afshari et al. (2015) evaluated the formation of hydrogels of polyvinyl alcohol with chitosan from the combined technique of irradiation followed by freeze-thawing, where verified that improvement of swelling degree, thermal stability and mechanical strengths.

5.3.2.2

Chemical Cross-linking

The cross-linked chitosan, chemical modification, is formed by covalent bonds that connect the polymeric chains of chitosan and provide the material with a porous network, improving its properties. Cross-linking agents are substances having low molecular weight and functional groups reactive to allow cross-linking between the chains. The most used agents in the chitosan cross-linking process are glutaraldehyde, cyanoguanidine, epichlorohydrin, ethylene glycol diglycidyl ether, some aldehydes and carboxylic acids, among others (Berger et al. 2004; Crini and Badot 2008). Gonçalves et al. (2015) obtained cyanoguanidine cross-linked chitosan to adsorption of food dyes in the aqueous binary system, and the authors showed that cyanoguanidine was successfully inserted on the chitosan polymeric chains, and it was an efficient adsorbent. The chitosan hydrogels obtained from chemical cross-links are irreversible and have high stability, due to involving the covalent bonding between of reactive functional groups, including amino and hydroxyl groups chitosan chains. Usually, for the formation of chitosan hydrogels, the most commonly used cross-linking agent is the glutaraldehyde, from the covalent bond a copolymeric material is formed, which presents a porous three-dimensional network (Crini and Badot 2008; Poon et al. 2014). In addition, other di-aldehydes are also used as crosslinking agents, formaldehyde, genuine, epichlorohydrin, among others. Glutaraldehyde is a cross-linking agent widely used for the formation of hydrogels because it presents ease in the cross-linking process and also due to its low cost. The reaction of chitosan with glutaraldehyde occurs through the formation of a Schiff base between the aldehyde groups of the glutaraldehyde and the amino groups of the polymer, forming an imine bond (C¼N) (Chen and Chen 2009; Gonçalves et al. 2017). Figure 5.2 shows an illustrative schematic of the cross-linking of chitosan with glutaraldehyde and its possible formations: hydrogel and scaffold hydrogel. Genipin is a natural cross-linking agent and acts as an effective cross-linked for polymers containing amino groups, and it is widely used with chitosan even though

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Fig. 5.2 Representative scheme of the glutaraldehyde cross-linking in the formation of hydrogels

it is not as effective as glutaraldehyde. Chitosan and genipin hydrogel are biocompatible, biodegradable and have no cytotoxicity, thus being indicated for biological use. Injectable hydrogels produced from cross-linked chitosan with genipin were studied by Gilarska et al. (2018) for bone regeneration. The authors showed that the biomaterial had an anti-inflammatory effect, viability on the hydrogel surfaces, had no cytopathologic effect and improved the cell adhesion. Chitosan hydrogels can also be formed using the presence of metal ions, such as Pt (II), Pd (II), and Mo (VI), through covalent bonds. This material is obtained from a coordination complex cross-linking and is highly resistant, but their use is not very indicated of the biomedical area (Brack et al. 1997). Inorganic particles can confer magnetic properties and sensitivity to changes in pH. An injectable chitosan magnetic hydrogel cross-linked with ethylene glycol was reported by Xie et al. (2017). The hydrogel was applied in codelivery system, which was magnetic field-triggered, and this biomaterial presented a more efficient antitumor effect of cancer chemotherapy. Zhu et al. (2016) developmented macroporous magnetic chitosan-hydrogels with modified Fe3O4 for removal of Cd2+ and Pb2+. The structure can be tuned with the amount of stabilized particles, volume fraction of dispersed phase and the amount of the cosurfactant. The authors related in adsorption experiments that the adsorption equilibrium was rapidly and with high adsorption capacities. In addition, they showed that magnetization with Fe3O4 nanoparticles assisted the hydrogel integrity and could be reused several times.

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Another type of chemical cross-linking is photocross-linking in which the solution containing the polymer is subjected to ultraviolet irradiation and a chemical photoinitiator. Qiao et al. (2017) studied the preparation of a hydroxyethyl hydrogel of chitosan from photocross-linking. The hydrogel loaded with heparin was applied in surgeries for glaucoma, being used as a drug delivery system. The authors performed live tests, where they verified that the hydrogel presented excellent biocompatibility and biodegradability. In the modification through grafted the free radicals are produced in the chitosan chain, where they will react with the monomers be they of the type nonionic, cationic and anionic, thus forming the grafted hydrogel. The type of initiator and its concentration are directly related to the properties required for the hydrogel, affecting its mechanical strength and absorption capacity. Other factors, such as grafting time and temperature, also influence the obtaining of the hydrogel (Zhang et al. 2016). For example, studies showed that acrylamide grafted to chitosan and used montmorillonite with cross-linking agent produced a porous hydrogel with a high swelling degree. (Mahdavinia et al. 2004). Ferfera-Harrar et al. (2015) development in your research a multi-functional superadsorbent composite for wastewater purification. Hydrogels were prepared by via graft polymerization of acrylamide onto chitosan backbone in presence of gelatin, using different initiator. The hydrogels were also partially hydrolyzed to improved adsorption capacity and increase swelling degree. The grafted network had a porous structure and a more stable thermal degradation than its compounds. The hydrogels were excellent adsorvent materials and exhibited the highest pH and saline sensitivity. In addition, the material presented a reuse possibility, can be extended to the application systems in wastewater treatment. Among other applications of chitosan grafts, the biomaterial has been highly targeted in the biomedical area in the conventional treatment of injured bone tissue (Pellá et al. 2018). In Table 5.1 are shown the main advantages and disadvantages of chemical and physical cross-linking for obtainment chitosan hydrogels, by different types of preparation.

5.3.3

Properties of Chitosan Hydrogels

The polymer hydrophilic character is the major structural component of a hydrogel, which depends on various factors, the main are the type binding the polymer chains within the gel network and the amount of water the hydrogel can to adsorb. Among the widely used hydrophilic polymers are polyacrylamide, polymethacrylic acid and polyvinyl alcohol. This property is very important in the pharmaceutical field, for controlling the drug release from the polymer degradation rate further increases stability, protect from oxidation and other reactions. The hydrophilic character in encapsulation is considered relevant in the solubilization of active agents, thus improving the performance of the cosmetic product and appearance (Ratner et al. 1996; Drury and Mooney 2003; Baysal et al. 2013).

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Table 5.1 Chemical and physical cross-linking methods, by different types of preparation, for obtainment of chitosan hydrogels Cross-linking Physical cross-linking

Process Hydrophobic interaction

Advantages Nontoxic, biocompatibility and high swelling degree

Freezethaw

Nontoxic, noncarcinogenic, biocompatibility, high adsorption capacities and absence of crosslinking agents Mild conditions to obtain; excellent compatibility and degradabity, exhibiting interesting swelling characteristics and nontoxicty High thermal stability and pH change; reuse capacity and improves the cell adhesion Flexible hydrogel and optimal release of controlled drugs

Polyelectrolyte complexation

Chemical cross-linking

Cross-linkers

Photo crosslinking Chemical grafting

Lack of need for chemical initiators or catalysts; ease of preparation, and ease of grafting degree control

Disadvantages Sensible to pH change and temperature; low gel strength High operating cost, low stability in acid medium and low thermal stability Sensible to pH change

Generally, they are toxics; lower adsorption capacities Cytotoxicity, fragile and decreased thermal stability Sensible to pH change, instability and low mechanical resistance

Furuike et al. (2017) in preparation of chitosan hydrogel verified its solubility in organic acids. The hydrogel was prepared from the dissolution of chitosan into acetic acid and addition of a sodium hydroxide, remaining stable in the wet state for a long period of time even at room temperature. In addition, the authors concluded that the hydrogel could be readily dissolved due to ionic bonding by addition of acids, such as acetic and other organic acids. The use only of polymer for scaffolds production can result in materials with low mechanical strength. Despite its general acceptance as a biocompatible material, chitosan is mechanically weak and unstable, and unable to retain a preset shape depending on the application. In the quest to find a material that meets these characteristics, is common to mix two or more polymers or add nanocomposite and/or metals for the scaffolds preparation (Yuvarani et al. 2015; Guo and Li 2016). Other factors those are important in the formation of hydrogels, as the crosslinking degree, gel strength and swelling degree. The cross-linking degree can be determined using assays containing 1 mL of ninhydrin solution heated at 80
C for 25 min. The samples are diluted with water and after, the absorbance can be obtained using Biospectro with reading at 570 nm, against a blank, gel-free assay. Thus, the cross-linking degree CD can be calculated from Eq. 5.1 (Dash et al. 2011; Gonçalves et al. 2017).

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 ACH CD ¼ 1   100% ABNCH

ð5:1Þ

where ACH (nm) is absorbance of cross-linked hydrogel, and ABNCH (nm) is absorbance of non-cross-linked hydrogel. The gel strength (presented in g) is usually measured by a texture analyzer, using a Teflon probe with a defined diameter, which presses the gel at a certain speed (Gonçalves et al. 2017). In measured of swelling degree, usually, hydrogels are weighed and immersed in distilled water, afterward stirred at 298 K for 24 h. The excess surface water is removed and swollen samples are weighed and the swelling degree SD can be determined by Eq. 5.2.  SD ¼

minitial  mhydrated minitial

  100%

ð5:2Þ

where minitial (g) is initial hydrogel, and mf (g) is the final mass, after swelling. Gonçalves et al. (2017) and Poon et al. (2014) showed in their studies the formation of chitosan hydrogels using different concentrations of glutaraldehyde. The authors found that the addition of this cross-linking agent is a qualitative indicator; when concentration increases, the solution passes from a weak yellow to a more orange color, indicating the intermolecular and intramolecular bonds of glutaraldehyde and the amine groups of chitosan. In addition, Gonçalves et al. (2017) also observed that the increase of the concentration of this agent is directly associated with the swelling degree, gel strength and cross-linked degree of the hydrogel. Figure 5.3 shows the chitosan hydrogel formed from glutaraldehyde cross-linking and imagens of scanning electron microscopy. In Fig. 5.3a the hydrogel with 4% of chitosan and 1.5% of glutaraldehyde, under the conditions described by Gonçalves et al. (2017), where the hydrogel presented an orange color, characteristic of the presence of the cross-linker. Figure 5.3b shows the hydrogel after the freeze-drying process (scaffolds or 3D supports) a highly porous material. Figure 5.3c and d presents the SEM images of the hydrogel of chitosan, before and after the freezedrying process. It can be seen that the hydrogel presented a smooth, homogeneous surface. However, the scaffold hydrogel of chitosan presented an irregular and porous surface. Lyophilization forms the ice crystals and draws water from the material through sublimation. Thus, keeping the material in its original but dry shape and creating pores in the place where there was water. Chen et al. (2017) developed chitosan-based cryo-hydrogels, where the authors verified the same behavior in SEM images when the hydrogel goes through the lyophilization process. Miranda et al. (2016), developed different types of hydrogels scaffolds, from the combination of chitosan and hyaluronic acid and of the isolated compounds, where the authors verified that the hydrogel scaffold of chitosan presented a more homogeneous porous surface than with other compounds.

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Fig. 5.3 Chitosan hydrogels: (a) hydrogel with glutaraldehyde (b) chitosan scaffold with glutaraldehyde (c) SEM image before freeze-drying (d) SEM image after freeze-drying

5.3.4

Applications of Chitosan Hydrogels

Besides the properties that highlight the biopolymer, chitosan has aroused interest in different areas, mainly in medicine and pharmacology. The hydrogels have been largely used in drug delivery systems, wastewater and dye remediation and tissue engineering (supporting cell attachment and growth). Yang et al. (2010) prepared a series of chitosan porous scaffolds by freeze-drying of chitosan hydrogels. According to the authors, the chitosan concentration variation caused changes in the scaffolds characteristics. Using lower concentrations, there was an increase in water adsorption and porosity and, reduced the resistance to compression. Verified that higher chitosan concentration led to a decrease in the porosity and increased the tensile strength of the scaffolds. Li et al. (2009) prepared biocompatible hydrogels based on water-soluble chitosan-ethylene glycol methacrylate and polyethylene glycol diamethacrylate, synthesized by photopolymerization. The hydrogel was characterized by different analyzes. The results indicated that the hydrogels were sensitive to pH of the medium, justified by the covalently cross-linked bonds and molecular weight of chitosan. The photopolymerization chitosan hydrogels showed high swelling degree

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at low pH ( intranasal drug solution (Shah et al. 2016). In situ nasal spray formulations of amantadine hydrochloride were developed with Pluronic® 127 as thermosensitive polymer and carboxymethyl cellulose or chitosan mucoadhesive polymer. The optimized formulations exhibited gel transition at nasal cavity temperature (34  1
C), which was also confirmed by a 3-stage gelation phenomenon in rheological study. In vitro human nasal airway model with optimized chitosan formulations exhibited slower drug release 43–44% compared amantadine hydrochloride alone (79  4.58%). These results indicated that mucoadhesive property of chitosan prolonged the residence time (Lungare et al. 2018). Major hurdle for the antiepileptic drugs in crossing the blood-brain barrier (BBB) after oral administration is due to the presence of p-glycoprotein and multidrug transporters, which prevent such drug entry into brain resulting in drug resistance in epilepsy. Therefore, nasal route was selected to deliver antiepileptic drug carbamazepine by incorporating it in caboxymethyl chitosan nanoparticles. The nanoparticles have small particle size of (218.76  2.41 nm) with higer DL (36%) and EE (80%). The intranasal application of these nanoparticles resulted in brain/ plasma carbamazepine exposure in AUC was 150% (Liu et al. 2018).

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6.5.7

R. Parhi

Pulmonary Drug Delivery

Drug molecules are commonly administered through the respiratory tract for the prophylaxis or treatment of local diseases such as asthama, lung infection and pulmonary hypertension. But pulmonary route can be used to deliver drug molecules for systemic activity owning to its enormous surface area, highly vascularized due to presence of abundant capillaries with good blood supply and thinness in blood-air barrier (alveolar membrane) leading to rapid onset of action. Furthermore, lung has very poor metabolic activity that avoids pre-systemic melabolism (Groneberg et al. 2003; Salomon et al. 2017). Therefore, pulmonary route can be considered as a better alternative to oral route as poorly absorbed drug such as sodium chromoglycate and drugs undergoes pre-systemic metabolism, e.g. propranolol, isoprenalin. In addition, administration of large molecules, including proteins and peptides viz. growth hormone, insulin and hormones such as oxytocin can be administered for systemic activity (Patil and Sarasija 2012). The airways can be divided into three functional regions such as (i) nasopharyngeal region including nasal cavity, sinuses, larynx and pharynx, (ii) tracheabrocnhial region starting from trachea to terminal bronchiols and (iii) pulmonary region consists of bronchiols to alveoli. The former two regions are not suitable for the drug administration particularly for systemic absorption as mere 10% or less than that of the administered dose will be available for absorption because of poor blood flow, small surface area, ciliated mucous layer which propels the drug out of the region (Evans and Koo 2009). Though these obstacles are not there for the latter region, but other factors such as size of pores, tight junctions in alveoli and proteolytic degradation coupled with phagocytosis mechanism leading to accumulative toxicity where particles of nanorange can be cleared by alveolar macrophages can limits the administration of drug through pulmonary route (Palecanda and Kobzik 2001; Lytting et al. 2008). Particulate systems such as microparticles and nanoparticles are considered as effective delivery systems for paulmonary route. This is not only due to higher exposed surface area and thereby increasing drug bioavailability, but also due to the requirements of very small particles below 3 μm together with high tapped density. Based on the size requirements, microparticulate systems were used to target upper part of lungs whreas nanoparticulates systems are used to deliver drugs in the lower part of the lungs (Jyothi et al. 2010). With an intention to treat upper part of lungs in asthama pateint, chitosan based microspheres loaded with levosalbutamol sulphate was developed employing spray drying method and compared their properties with that of flax seed mucilage based microspheres. At lower chitosan ratio with drug (2:1) the obtained microspheres produced higher mucoadhesive ability (89.50%), and drug loading (29.00  0.11%) compared to flax seed mucilage with 85.11% mucoadhesion and 21.60  0.23% of drug loading. Microspheres of both the batches were found to be spherical, with smooth surface and released the drug for up to 8 h. Aerosolization behavior of both the optimized batches was found to be comparable

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to market formulation and did not show any change in characteristics during the stability studies (Patel et al. 2013). Chitosan aerogel microparticles of salbutamol were developed by both novel supercritical fluid (SCF) and freeze drying techniques. Compared to freeze drying, SCF technique produced lower average particle size of 10 μm and tapped density  0.12 g/mL without surface deformities such as cracks and took significantly less time of only 2 h and highly stable (Obaidat et al. 2015). Dapson is used to treat opportunistic pneumonia coused by Pneumocystis carinii which, when administered in oral route, suffers from high hepatic metabolism leading to decreased therapeutic index and also generate metabolite causing unwanted side effects (Chougule et al. 2008). Therefore, to treat pneumonia effectively, spray dried chitosan coated microcapsules of dapson were developed. These microcapsules were found to have approximately 7 μm of geometric particle size, and the aerodynamic and mass median aerodynamic diameter were observed as 4.5 and 4.7 μm, respectively. The fine particle fractions indicated 50% of the particles were within the size range which can exert pharmacological action. The low toxicity with adequate deposition in the lung tissue demonstrated the above formulation can be a promising drug delivery tool to treat pneumonia (Ortiz et al. 2015). To develop low density and suitable aerodynamic particles, chitosan and HPMC based ethionamide microparticles in dry powder form was developed to treat multi drug resistance tuberculosis. Compared to previous study the microparticles produced were having comparatavely larger size of upto 8.5 μm with rough surface. However the mass median aerodynamic diameter and fine particle fraction were found to be in the range of 2.28–3.33 μm and more than 50% (54.58–75.74), respectively. In addition there were > 97% of in vitro deposition of emmited dose and when blended with inhalac 230 resulted in the increase in fine particle fraction and increase in dispersibility of powder on inspiration. This formulation has well in vitro-invivo correlation established by pharmacokinetic study (Bhavya et al. 2016). Jafarinejad et al. (2012) developed chitosan nanoparticles of itraconazole to treat pulmonary infections and found to be advantageous with respect to aerosolization of particles leading to better deposition in the respiratory tract. The above property further enhanced when the final powder formulation was prepared by mixing itraconazole nanoparticles with lactose, mannitol and leucin (Jafarinejad et al. 2012). Rawal et al. (2017) successfully formulated dry powder inhalation of rifampcin nanoparticles with chitosan to treat tuberculosis. An increased Cmax, AUC and improved mean residence time (MRT) were observed for the above nanoparticles in in vivo study. Further the formulation not produced toxicity at both cell and organ and exhibited sustained drug release upto 24 h (Rawal et al. 2017). Baclofan, a GABAB receptor agonist, functionalized with trimethyl chitosan by TPP crosslinker as polymeric nanocarriers for siRNA (siSurvivin) was develoved followed by addition of mannitol to form final powder formulation for metered dose inhalaer. This formulation has fine particle fractions of 45.39  2.99% and can be used to deliver siRNA to deep lung for the control of proliferation and apoptosis of ling tumour (Ni et al. 2017). Oral administration of prothionamide, a second line

212

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antitubecular drug, demonstrated unpredictable absorption leading to frequent administration. In order to avoid above problem Debnath et al. (2018) developed chitosan coated prothionamide nanoparticles by ionic gelation technique followed by freeze drying to treat and manage tuberoculosis. The obtained nanoparticles were spherical in shape with particle size 3114.37  3.68 nm and aerodynamic particle size of 1.76 μm. In vitro release study exhibited sustained release of up to 24 h with 96.91% PTM release with an initial burst release. The prothionamide concentration was found to be above minimum inhibitory concentration (MIC) for more than 12 h after single drug administration in vivo (Debnath et al. 2018). With an intention to develop a delivery system which can produce a long-term release of drug after single inhalation, Lee et al. (2013) developed nanoparticles of palmitic acid-modified exendin-4 (Pal-Ex4) using two step process to treat type 2 diabetes. In the first step, PLGA based nanoparticles of Pal-Ex4 were prepared and in the second step these nanoparticles were coated with chitosan. Prepared nanoparticles exhibited good aerosolization characteristics and when applied in mice, the nanoparticles remained in the lungs for ~72 h and displayed protracted hypoglycemic effects. The results was believed to be due to; (i) mucoadhesive effect of surface chitosan, (ii) sustained release properties of palmitic acid and PLGA, (iii) longer circulation time of nanoparticles due to albumin binding (Lee et al. 2013). In another investigation, in order to enhance inhalation characteristics of chitosan nanoparticles loaded with salmon calcitonin were co-spray dried with mannitol. There were improvement in in vitro properties such as mass median aerodynamic diameter, fine particles fraction, emitted dose and dispersiblity for co-spray dried particles compared to powder without carrier. The in vivo study on rats showed that co-spray dried particles had reached Cmax of 56  4.56 pg/mL in 45 min (Tmax) and relative bioavalability was found to be highest (1.71) for co-spray dried particles compared to subcutaneous administration (Sinsuebpol et al. 2013). Huang et al. (2016) observed a biphasic release feature of gentamicin nanoparticles with chitosan and fucoidin i.e. gentamicin released for first 10 h in zero order manner and up to 72 h the release was sustained. These nanoparticles displayed multiple antimicrobial capabilities and can be used to treat pneumonia (Huang et al. 2016). In order to avoid high drug resistance, low local drug concentrations short half-life and poor solubility of chemotherapeutic agents such as pacilitaxel and quercetin and at the same time to prolong the retention time a nanoparticles composed of oleic acid-conjugated chitosan was developed followed by their conversion into microspheres by spray drying with carrier such as lactose, mannitol and hydroxypropyl-β-cyclodextrin. The obtained nanoparticles and microspheres were in the size range of 250–350 nm and 1–5 μm, respectively. The microspheres exhibited slow release characteristics at pH 4.5 and 7.4, however the retention of pacilitaxel increased due to the presence of quercetin and there was a significantly higher concentration of pacilitaxel in lungs up to 6 h (Liu et al. 2017). There are many other application of chitosan in pulmonary delivery of isoniazid (Kundawala et al. 2013), ofloxacin (Park et al. 2013), levofloxacin (Merchant et al. 2014), and ethambutol dihydrochloride (Ahmad et al. 2015).

6 Chitin and Chitosan in Drug Delivery

6.5.8

213

Vaginal Drug Delivery

The vaginal route can be considered as logical alternatives to the oral or parenteral drug routes due to avoidance of pre-systemic metabolism, rich vascularization, poor enzymatic activity, obvious large surface area and absence of GI irritation and side effects. In addition, it provides scope for self administration. However, low bioavailability especially for large molecule, personal hygiene, local irritation, poor patient compliance, gender specificity, limited market size along with poor acceptance (Hussain and Ahsan 2005; Muraleedhara et al. 2013). Due to mucoadhesive preopery of chitosan, it has been used to develop various vaginal dosage forms such as hydrogels, tablets, films, pessaries, cream, and more recently, liposomes to treat diseases coused by bacteria and fungus (El-Kamel et al. 2002; Perioli et al. 2008; Casettari et al. 2013; Bigucci et al. 2015a, b; Palmeira-de-Oliveira et al. 2015; Andersen et al. 2017;). Peroral progesterone is widely used in treatment of endometrial hyperplasia and primary endometrial carcinoma. However, hepatic first-pass metabolism lowers its bioavailability and synthetic P4 produces undesirable side effects such as acne, depression. Therefore, Almomen et al. (2015) developed glycol chitin based progesterone gel to treat endometrial hyperplasia. Hydrogel composed of 5% (w/v) and 0.1% (w/v) of glycol chitin and progesterone, respectively in pH 4.2 was able to maintain a stable gel with desired sol-gel temperature at body temperature. The above composition released 50% of loaded progesterone in 4 h after exposure to simulated vaginal fluid (SVF) in vitro. In vitro toxicity study on vaginal epithelial cell line (VK2/E6E7) showed no significant decrease in % viability and able to arrest the progression of endometrial hyperplasia in in vivo mouse model (Almomen et al. 2015). The vaginal candiasis is generally being treated with azole-based anti-fungals, but organisms such as Candida genus developed resistance to these drugs. Therefore, natural antifungals such as curcumin was used to prepare curcumin loaded liquid crystal precursor mucoadhesive system containing 40% (w/w) of modified cetyl alcohol, 50% (w/w) of oleic acid and 10% (w/w) of chitosan dispersion (0.5%) with the addition of 16% of poloxamer 407. In vitro antifungal study reveals that the above formulation was 16-fold and two-fold more potent against standard Candida strain and clinical stain, respectively compared to free curcumin (Salmazi et al. 2015). To treat genital herpes and to prevent the transmission of herpes simplex virus (HSV), compacts and compacted granules of acyclovir with chitosan and HPMC combination was developed. These formulations have good mucoadhesion property (upto 72 h to vaginal mucosa) and delivered a complete and sustained release of drug for a period of 8–9 days. Further these solid dosage forms did not show toxic effect when studied using two human cell lines namely, MT-2 (lymphoblastic cell line) and HEC-1-A (a uterous/endometrium epithelial cell line (Sánchez-Sánchez et al. 2015).

214

R. Parhi

Clotrimazole microparticles with chitosan using cross-linking agent glycerol 2-phosphate (βGP) were developed and characterized. Results showed that with increase in βGP concentration the size of microparticles and release of drug decreases but produces smooth and intact microparticles. However the addition of βGP decreases the mucoadhesive property compared to unmodified chitosan microparticles because of rough surface and presence of more water in the later. The cytotoxicity study in VK2/E6E7 human vaginal epithelial cellline exhibited the occurance of cytotoxicity which was evident from the presence of apoptotic cell (Szymánska et al. 2016). Vaginal mucoadhesive tablets of antiviral drugs tenofovir with chitosan, HPMC, gaur gum and Eudragit RS and the chitosan based tablets were found to have mucoadhesive potential for 48 h and released total amount of incorporated drug till it adhere to bovine vaginal mucous layer. It was also found to have low toxicity and expected to have ability to prevent HIV transmission (NotarioPérez et al. 2017). Chitosan incorporated liposomes and chitosomes of metronidazole inhibited the growth of Candida albicans to a large extent compared with, carbopol containing liposomes and plain liposomes as well as metronidazole control solution. This was attributed to the mucoadhesive propert of chitosan in the liposomes. This property not only increasesd the mucoadhesive property of the chitosomes but also ensure the sustained drug release of drug for the synaergistic treatment of vaginal infections caused by various microbes (Andersen et al. 2017). Peptide loaded chitosan nanoparticles in fast dissolving hydrophilic sponge-like cylinder was able to deliver the peptide in two steps: (i) the hydrophilic system quickly dissolves upon contact with vaginal fluid, and (ii) chitosan nanoparticles adhere to mucous layer in the vagina and release the drug (Marciello et al. 2017). Park et al. (2017) demonstrated that pre-treatment vagina with chitosan enhanced the association of nanoparticles with immunogenic antigen presenting cells in the submucosa of vagina, thereby significantly improved the translocation of nanoparticles across the multiple layer of vaginal epithelium to target draining lymph nodes (Park et al. 2017). Imiquimod, an immune response modifier used to treat genital warts and superficial basal cell carcinoma cuased by human papillomavirus infecton, is developed into both chitosan coated poly(E-caprolactone) nanocapsule embedded in hydroxyethylcellulose and chitosan gel. The former formulation showed higher mucoadhesive property whereas later demonstrated drug permeation and overall chitosan gel containing chitosan coated poly(E-caprolactone) nanocapsules was selected as best delivery system for imiquimode (Frank et al. 2017). Other drugs such as metronidazole (Andersen et al. 2013) were incorporated in pectosomes and chitosomes; chlorohexidine was encapsulated in vaginal inserts composed of chitosan and carboxymethylcellulose (Bigucci et al. 2015a, b); clotrimazole in chitosan tablets. All of them were developed and evaluated for their pharmacological action (Szymańska et al. 2014).

6 Chitin and Chitosan in Drug Delivery

6.5.9

215

Rectal Drug Delivery

Antomically, rectum is the part of colon which is about 15–20 cm in length and is perfused with abundans of blood and lymphatic vessels. It is commonly used as alternative route to oral route when patient is not in a postion to use oral route because old age inability to swallow or GI tract side effects such as nousea, vomiting and irritation. Furthermore, rectal route can avoid first pass metabolism. However the absorption of drug from formulations are limited by small surface area dueto absence of villi or microvilli, rectum contains only 2–3 ml of mucous shich generally helps in formulation adherence and finally lack of motility especially in resting stage reduces the absorption (Baviskara et al. 2013). Chitosan and derivatives were also studied for rectal delivery of various drugs to improve not only the patient compliance but also increase drug bioavailability by avaoiding pre-systemic metabolism. El-Leithy et al. (2010) fabricated mucoadhesive hydrogels incorporated with diclofenac sodium chitosan microspheres and observed that the above hydrogel formulations demonstrated a controlled release of drug with eaching 34.6–39.7% at the end of 6 h. In addition the formulations showed a decereased irritation to the mucosal tissue (El-Leithy et al. 2010). In another study quaternized N-trimethyl chitosan of different degrees (TMC-L with 12.3% quaternized and TMC-H with 61.2% quaternized) and chitosan hydrochloride were used to deliver insulin rectally as well as nasally from solution formulations. Out of three types of solution, formulation containing TMC-H showed higher absorption of insulin at pH of 7.4 whereas at pH 4.4 all formulations demonstrated higher rate of drug relase. This result was attributed to low charge density of TMC-L and inability of chitosan hydrochloride to soluble at neutral pH (du Plessis et al. 2010). Pendekal and Tegginamat (2012) developed matrix tablet of 5-fluorouracil with chitosan and polycarbophil interpolyelectrolytic complex (IPEC) in order to enhance efficacy and minimize toxic effect. The developed tablets were used for rectal, vaginal and buccal delivery of 5-fluorouracil. Formulation containing IPEC 100 mg, microcrystalline cellulose 25, talc 5 mg and 5-fluorouracil of 20 mg showed pH independednt controlled release of 5-fluorouracil without burst effect in all above routes. However formulation composed of 80 mg of IPEC and 20 mg of chitosan exhibited highest mucoadhesive property leading to desired residence time. Addition of 3% sodium deoxycholate to the above formulaion improved the drug permeation without impacting mucoadhesion property (Pendekal and Tegginamat 2012). Ulcerative colitis is being treated with sulfasalazine that can be administered either through oral or rectal route. The administration of sulfasalazine through oral route cause the drug absorption into small intestine and the efficacy of rectal sulfasalazine formulations are limited by their lower residence time in colon. Therefore, to

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circumvent above issues a mucoadhesive hydrogel formulation of sulfasalazine with catechol modified chitosan followed by its crosslinking by genipin was developed. The rectal administration above hydrogel formulation demonstrated higher therapeutic effect, produces lower plasma concentration and equivalent histological scores compared to oral sulfasalazine administration (Xu et al. 2017).

6.5.10 Parenteral Drug Delivery Unlike other routes, parenteral route is considered as invasive way of administering the drugs in the form of injectables implant infusion into blood vessel, tissue space or body compartments. The common sites of parenteral routs includes intravenous (IV), Intramuscular (IM), subcutaneous (SC), and intra-arterial, intratheal (Ahmed and Aljaeid 2016). Generally, implants administered by IM and SC route and colloidal systems containing nanoparticles are injected into IV route. But the biggest challenge for the injected nanoparticles is to bypass phagocytosis by macrophages in the systemic circulation. This can be avoided by PEGylation (nanoparticles surface modified with PEG) (Guo and Huang 2011). In this context chitosan can be used to prepare both nanoparticles and implants for parenteral drug delivery. The water solubility and size of nanoparticles greatly influences its biodistribution after administration through IV route. The hydrophilic PEGylated nanoparticles with smaller size less than 100 nm can bypass phagocytosis carried out by macrophages. Howerver these nanoparticles are unable to penetrate into tissues easily. But the hydrophobic nanoparticles have the advantage in this regard (Guo and Huang 2011). The particle size more than 10 μm can avoid clogging of microvessels in our body and particle less than 100 nm can bypass reticuloendothelial systems (RES) in the spleen, lung, liver and bone marrow (Tiyaboonchai 2003). Doxorubicin incorporated chitosan nanoparticles were found to enhance drug distribution to the RES followed by reduction in systemic toxicity as well as cardiotoxicity after IV injection (Huo et al. 2010). In one research paclitaxel was successfully loaded into nanomicelles carrier made up of N-octyl-O-glycol chitosan (OGC). These micelles were having low critical micellar concentration (5.3–32.5 mg/L) in aqueous environment and the cutotoxicity studies revealed that paclitaxel loaded OGC micelles were having lower toxicity and better tolerated compared marketd injectable form of paclitaxel (Taxol ((R)) (Huo et al. 2010). In another study, paclitaxel was conjugated with trimethyl chitosan (TMC-paclitaxel) for both IV and oral administration. These amphillic conjugates into spherical nanoparticles with size ranges 170 nm wheres as folic acid modified TMC conjugates (folic acid-TMC-paclitaxel) demonstrated slightly higher size (187 nm) but it showed better in vivo antitumor efficacy compared to TMC-paclitaxel. In addition both types of conjugates demonstrated better in vivo tumor ratadation and survival rate compared to free paclitaxel after IV administration (He and Yin 2017). Different types of dosage forms with their compositions (drug and polymer) used in various drug delivery routes are presented in Table 6.1.

Routes of drug delivery Oral Ofloxacin

Tolbutamide Insulin Paclitaxel Egg yolk immunoglobulin (IgY) Tinidazole

Chitosan-g-poly(acrylamide)/Zn Chitosan and xanthan gum N-succinyl chitosan (NSC) and poly (acrylamidecoacrylic acid) (P-AAm-co-AA) Chitosan Chitosan and alginate Polyacrylic acid (PAA) and S-chitosan Chitosan-modified PLGA Chitosan and phospholipid (lecithin) Chitosan grafted polycaprolactone Chitosan and pectinate Chitosan and sodium alginate Chitosan and eudragit S100/L100 Chitosan and Mg2Al Hydroxyethylacrylic chitosan and sodium alginate

Films

Hydrogels

Nanoparticles

Beads Hydrogel

Nanoparticles Self-assembled nanoparticles Self-assembled amphiphilic micelles Microbeads

Microbeads

Enteric coated capsule Bio-nanocomposite beads Hydrogels

Budesonide 5-aminosalicylic acid (5-ASA) Paracetamol

Insulin Insulin

L-asparagin(ase

5-fluorouracil

Amoxicillin

Drug (s) Aceclofenac

Polymers Chitosan and Boswellia gum resin

Dosage form Composite and the particulate composite Nanocomposite

Table 6.1 Different types of dosage forms with their compositions (drug and polymer) used in various drug delivery routes

(continued)

Lanjhiyana et al. (2013) Wakure et al. (2013) Ribeiro et al. (2014)

Bahreini et al. (2014) Tahtat et al. (2013) Mukhopadhyay et al. (2014) Shi et al. (2018) Liu et al. (2016) Almeida et al. (2018) Xing et al. (2017)

Pathania et al. (2016) Monga and Wanchoo (2014) Bashir et al. (2017)

References Jana et al. (2015)

6 Chitin and Chitosan in Drug Delivery 217

Buccal

Routes of drug delivery

Chitosan and eudragit S-100® Chitosan and 2-HP-β-CD Chitosan and eudragit S-100® Chitosan Chitosan Chitosan Chitosan and alginate Chitosan and eudragit® RS and RL Chitosan, pectin, HPMC, chitosan-pectin and chitosan-HPMC Chitosan Chitosan, dimethyl ethyl chitosan (DMEC) and thiolated dimethyl ethyl chitosan (T-DMEC). Chitosan and poly (ethylene oxide) (PEO) Chitosan lactate Chitosan and HPMC K4M Catechol-functionalized chitosan (cat-chitosan) and genipin Chitosan

Enteric coated nanoparticles Microspheres Enteric coated nanoparticles

Capsule Capsule Microcapsule Microspheres and hydrogel Nanoparticles

Films

Electrospun scaffolds

Wafers

Tablets Hydrogel

Sponges

Gels Nanoparticles

Polymers

Dosage form

Table 6.1 (continued)

Buspirone hydrochloride

Levosalbutamol sulphate Lidocaine

Tizanidine HCL

Insulin

Celecoxib Insulin

Miconazole nitrate

5-fluorouracil and Leucoverin Curcumin Insulin and trans-activating transcriptional peptide (tat) 5-ASA Rebamipide Albendazole Nystatin Fluconazole

Drug (s)

Kassem et al. (2015)

Cid et al. (2012) Mortazavian et al. (2014) Lancina III et al. (2017) El-Mahrouk et al. (2014) Thonte et al. (2014) Xu et al. (2015)

Tozaki et al. (2002) Huang et al. (2008) Simi et al. (2010) Martín et al. (2015) Rençber et al. (2016) Tejada et al. (2017)

References Treenate and Monvisade (2017) Li et al. (2015) Jyoti et al. (2016) Chen et al. (2017)

218 R. Parhi

Topical and transdermal

Periodontal

Chitosan Chitosan Chitosan and HPMC Chitosan Chitosan and EC Chitosan and human periodontal ligament stem cells (PLSCs) Chitosan Chitosan/PVA/hydroxyapatite (HA) Chitosan/PVA/HA Chitosan/alginate/PLGA

Intrapocket films

Subgingival films

Intrapocket bioerodible chips

Dental film Intrapocket dental films Bioactive glass scaffold

Mats and films Electro-spun fibers and films Microparticles Chitosan, egg albumin and Carbopol 940 Chitin Chitin Chitosan

Nanogels Nanoagels Nanogels

Microspheres

Biodegradable films

Chitosan and HPMC Chitosan and PVA Chitosan and β-glycerophosphate Chitosan, β-glycerophosphate and poloxamer

Tablets Films Thermoresponsive gel In situ gels

Polyphenol from olive leaf extract

Metronidazole and levofloxacin Piroxicam Meloxicam Insulin like growth factor, IGF-1) and progression factor Aceclofenac 5-fluorouracil Clobetasol

Clotrimazole Lincomycin HCl Ciprofloxacin

Satranidazole

Satranidazole

Moxifloxacin

Piroxicam Zolmitriptan Minocycline Moxifloxacin

(continued)

Jana et al. (2014) Sabitha et al. (2013) Panonnummal et al. (2017) Acosta et al. (2015)

Farooq et al. (2015) Yar et al. (2016) Duruel et al. (2017)

Kepsutlu et al. (2016) Kumria et al. (2018) Ruan et al. (2014) Sheshala et al. (2018) Deepthi and Velrajan (2013) Nair and Anoop (2014) Nair and Anoop (2013) Nayak et al. (2015) Ganjoo et al. (2016) Abdelfattah et al. (2016) Khan et al. (2016)

6 Chitin and Chitosan in Drug Delivery 219

Ocular

Routes of drug delivery

Chitosan and lecithin Chitosan Chitosan and PVA Chitosan and transcutol® Chitosan Chitosan and Allyl 2-cyanoacrylate Chitosan and hyaluronan Chitosan and PVA Chitosan Chitosan, poly(N-isopropylamide-co-acrylic acid and cellulose laurate Poloxamer 407 and chitosan

Nanogel Film

Matrix transdermal patchs Transdermal film Transdermal adhesive film

3D porous patch Transdermal film

Transdermal patch Microparticles

Nanoparticles

Chitosan and pluronic Chitosan Thiolated chitosan Chitosan and HPMC

Surface modified micelles

Biological membrane

Disc-shaped hydrogel Polymer matrix

Thermosensitive mucoadhesive hydrogel

Polymers Chitosan

Dosage form Microemulsion

Table 6.1 (continued)

Mitomycin C and 5-fluorouracil Ranibizumab and Aflibercept Timolol maleate

Tretinoin and clindamycin phosphate Neomycin sulphate and Betamethason sodium phosphate Metipranolol

Metoprolol tartarate Rivastigmine

Bovine serum albumin (BSA) Thiocolchicoside

Alprazolam Ondansetron Ketoprofen

Diflucortolone valerate Zidovudine

Drug (s) Clotrimazole

Moreno et al. (2017) Gupta et al. (2010)

Lin and Chang (2013) Wu et al. (2013)

Deepthi and Jose (2018)

References Kumari and Kesavan (2017) Özcan et al. (2013) Singh and Upasani (2013) Maji et al. (2013) Can et al. (2013) Ramchandani and Balakrishnan (2012) Lim and Lee (2014) Bigucci et al. (2015a, b) Gandhi et al. (2014) Sadeghia et al. (2016) Shamsi et al. 2017

220 R. Parhi

Nasal

Shitosan and sodium tripolyphosphate Chitosan Chitosan PLGA, chitosan, PVA and pluronic F-108 Chitosan, hyaluronic acid and HPMC

Nanoparticles Nanoparticles

Nanoparticles

Nanoparticles Nanopaticle loaded in isotonic solution Nanoparticles Nanodispersion in polymeric films Ocular insert Chitosan, PVP and carbopol Chitosan, PVP and Carbopol Chitosan and thiolated chitosan Chitosan Chitosan and poly(L-aspartic acid)

Mucoadhesive hydrogels Nasal gel Nanoparticles

Nanoparticles Submicron biodegradable capsules

Chitosan Chitosan, HPMC E15 and eudragit RL100/HPMC K4M Chitosan, PVP/PVA, eudragit S100 and zein

Cyclosporine A Carteolol

Chitosan Chitosan

Sumatriptan succinate Insulin

(continued)

Mirzaeei et al. (2018) Alsarra et al. (2009) Das et al. (2012) Shahnaz et al. (2012) Gulati et al. 2013 Zheng et al. (2013)

Triamcinalone acetomide Acyclovir Penciclovir Leuprolide

Fathalla et al. (2016) Morsi et al. (2017)

Yang et al. (2016) Silva et al. (2017)

Ketorolac tromethamine Ketorolac tromethamine

Dexamethasone-sodium phosphate Hydrocortisone butyrate Ceftazidime

Rosmarinic acid Norfloxacin

Başaran et al. (2014) Ameeduzzafar et al. (2014) da Silva et al. (2016) Upadhayay et al. (2016) Kalam (2016)

Ibrahim et al. 2013

Celecoxib

Chitosan, carboxymethyl chitosan and glycerophosphate Chitosan and alginate

Microspheres in thermosensitive gel Nanoparticles in eye drops, in-situ gel and preformed gel Nanoparticles Nanoparticles

Leveofloxacin

Aggarwal and Kaur (2005) Kong et al. (2018)

Timolol maleate

Chitosan

Niosomal

6 Chitin and Chitosan in Drug Delivery 221

Pulmonary

Routes of drug delivery

Chitosan Trimethyl chitosan Chitosan PLGA and chitosan Chitosan and mannitol Chitosan and fucoidin Oleic acid-conjugated chitosan (OA-CS), lactose, mannitol and hydroxypropyl-β-cyclodextrin

Nanoparticles Polymeric nanocarriers Nanoparticles

Nanoparticles

Nanoparticles

Nanoparticles Nanoparticles

Gentamicin Pacilitaxel and Quercetin

Palmitic acid-modified exendin-4 (Pal-Ex4) Salmon calcitonin

Rifampcin Baclofan, siRNA (siSurvivin) Prothionamide

Carbamazepine Levosalbutamol sulphate Salbutamol Dapson Ethionamide Itraconazole

Ebastine Zidovudine (ZV) prodrug UDCA-ZV Quetiapine fumarate Amantadine hydrochloride

Chitosan Chitosan chloride

Nanoparticles Microspheres Aerogel microparticles Microcapsules Microparticles Nanoparticles

Drug (s) Olanzapine

Polymers Chitosan

Chitosan Pluronic® 127, carboxymethyl cellulose or chitosan Caboxymethyl chitosan Chitosan and flax seed mucilage Chitosan Chitosan Chitosan and HPMC Chitosan

Nanoparticles Nasal spray

Dosage form Nanoparticles and Nanosolution Nanoparticles Microparticles

Table 6.1 (continued)

Sinsuebpol et al. (2013) Huang et al. (2016) Liu et al. (2017)

Shah et al. (2016) Lungare et al. (2018) Liu et al. (2018) Patel et al. (2013) Obaidat et al. (2015) Ortiz et al. (2015) Bhavya et al. (2016) Jafarinejad et al. (2012) Rawal et al. (2017) Ni et al. (2017) Debnath et al. (2018) Lee et al. (2013)

Khom et al. (2014) Dalpiaz et al. (2015)

References Baltzley et al. (2014)

222 R. Parhi

Rectal

Vaginal

Chitosan Chitosan Quaternized N-trimethyl chitosan, chitosan hydrochloride

Microspheres in hydrogels

Solutions

Pectosomes and Chitosomes

Tablets

Chitosan

Chitosan and carboxymethylcellulose

Chitosan

Nanoparticles in FD spongelike cylinder Nanoparticles

Inserts

Chitosan

Liposomes and Chitosomes

Chitosan, poly(E-caprolactone), and hydroxyethylcellulose Chitosan

Immunogenic antigen presenting cells Imiquimode

Chitosan, HPMC, gaur gum and eudragit RS

Tablets

Nanocapsule embedded in gel

Peptide

Chitosan

Microparticles

Insulin

Diclofenac sodium

Clotrimazole

Chlorohexidine

Metronidazole

Metronidazole

Tenofovir

Clotrimazole

(continued)

Andersen et al. (2013) Bigucci et al. (2015a, b) Szymańska et al. (2014) El-Leithy et al. (2010) du Plessis et al. (2010)

Frank et al. 2017

Sánchez-Sánchez et al. (2015) Szymánska et al. (2016) Notario-Pérez et al. (2017) Andersen et al. (2017) Marciello et al. (2017) Park et al. (2017)

Acyclovir

Curcumin

Cetyl alcohol, oleic acid, chitosan, and ploxamer 407 Chitosan and HPMC

Liquid crystal precursor mucoadhesive system (LCPM) Compacted granules

Almomen et al. (2015) Salmazi et al. (2015)

Progesterone

Glycol chitin (GC)

Hydrogel

6 Chitin and Chitosan in Drug Delivery 223

Parenteral

Routes of drug delivery Polymers Chitosan and Polycarbophil Catechol modified chitosan Chitosan N-octyl-O-glycol chitosan (OGC) Trimethyl chitosan

Dosage form Tablets

Hydrogels Nanoparticles Nanomicelles Nanoparticles

Table 6.1 (continued)

Sulfasalazine Doxorubicin Paclitaxel Paclitaxel

Drug (s) 5-fluorouracil

References Pendekal and Tegginamat (2012) Xu et al. (2017) Huo et al. (2010) Huo et al. (2010) He and Yin (2017)

224 R. Parhi

6 Chitin and Chitosan in Drug Delivery

6.6

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Conclusion

This chapter is a collection of literature pertaining to properties of chitosan and its derivatives which enabling them to be developed into different types of dosage forms that can be administered through different routes. Properties such as mucoadhesive, biodegradability, biocompatibility, swelling and mechanical strength of chitosan resulted in their wide applications in conventional as well as novel DDS. Thus, therapeutic systems based on chitosan used to deliver all most all clases of drugs including anti-inflammatory, antibiotics, anticancer, protein and peptide derived drugs etc. Mucoadhesive property of chitosan improves the residence time of dosage form to mucos surface resulting in enhancement of encapsulated drugs and thereby not only increasing bioavailability of the drug but also the target specific drug release. Modified form of chitosan such as trimethyl chitosan, chitosan-cysteine and chitosan-N-acetylcysteine further enhances this mucoadhesive property. Development of DDS such as inserts and implants based on chitosan are possible due to their biodegradability and biocompatibility qualities. Despite of having all above advantages chitin and chitosan suffer from limitations such as low solubility, high swelling, poor mechanical strength and unable to incorporate hydrophobic drugs. The low solubility of chitosan in physiological fluids (pH 7.4) is due to its weakly basic nature (pka ¼ 6.2–7). The high swelling property of chitosan in aqueous environment leading to fast or burst release of drug from chitosan based DDS. High mechanical strength is essential for chitosan if it has to be used in tissue engineering. Many investigations have been performed in last two decade or so to improve upon these drawbacks of chitosan. The most popular way to neutralize these limitations is modification or derivatization of chitosan. This derivatization is possible due to the presence of –NH2 or –OH groups on chitosan. As a result of this, (i) hydrophobic moiety including steroids fatty acids can be conjucated to chitosan in order to encapsulate hydrophobic drugs, (ii) 3D scaffold with polymer such as collagen and hydroxyapatite to improve mechanical strength, and (iii) chemical modifications to improve solubility in physiological medium, mucoadhesion to increase residence time of various doasage forms. However, chemical modification of chitosan has drawbacks including poor reproducibility, particularly for chitosan modified hydrophobically, poor solubility in organic solvents required for synthesis. Another major limitation of chitosan and its derivatives is that their immunological and toxicological profiles are not studied thoroughly and thus far complete safety profile is not available. More recently, study on laboratory mice demonstrated chitosan has LD50 value of 16 g/kg of body weight which is similar to that of sugars and salts (Izumrudov et al. 2010). But, there is no toxicological report on derivatives of chitosan. Threfore, not only pre-clinical studies but also clinical studies on chitosan and its derivatives is the need of the hour. In addition, development of chitosan derivatives with precise physicochemical properties and scalling up of the chemical synthesis are also essential for the success of chitosan as polymer in drug delivery.

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Chapter 7

Application of Chitosan-Based Formulations in Controlled Drug Delivery Jacques Desbrieres, Catalina Peptu, Lacramiora Ochiuz, Corina Savin, Marcel Popa, and Silvia Vasiliu

Abstract Chitosan has very specific and interesting properties, either structural or physico-chemical, which make chitosan a raw material for drug delivery formulations. Chitosan is a natural, biodegradable, biocompatible, cationic, non-toxic, and mucoadhesive polysaccharide that can be modified with chemical and biological molecules. Chitosan can be formulated in various solid pharmaceutical forms, liquids and gels. For instance, mucoadhesive formulations, liposomes and microand nanoparticulate systems provide the premises for achieving the intended therapeutic goals. This chapter presents the preparation methods for obtaining capsules, spheres and hydrogels. Then we discuss applications of chitosan-based formulations in controlled delivery sytems. These systems include digestive, respiratory, cardiovascular, renal, vaginal, bone or immune sytems, thus demonstrating the diversity of the domains and the interest in using chitosan based formulations. Among the most

J. Desbrieres (*) Université de Pau et des Pays de l’Adour, Pau, France e-mail: [email protected] C. Peptu · C. Savin Faculty of Chemical Engineering and Protection of the Environment, Department of Natural and Synthetic Polymers, Technical University Gheorghe Asachi, Iasi, Romania e-mail: [email protected]; [email protected] L. Ochiuz Faculty of Pharmacy, University of Medicine and Pharmacy “Gr.T. Popa”, Iasi, Romania e-mail: [email protected] M. Popa Faculty of Chemical Engineering and Protection of the Environment, Department of Natural and Synthetic Polymers, Technical University Gheorghe Asachi, Iasi, Romania The Academy of Romanian Scientists, Bd. Independentei, Iasi, Romania Apollonia University of Iasi, Iasi, Romania e-mail: [email protected] S. Vasiliu “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_7

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interesting properties allowing the development of chitosan in this domain are its cationic nature, mucoadhesiveness, biocompatibility and antibacterial activity. Keywords Chitosan · Drug delivery · Capsules · Particles · Hydrogels · Biomedical applications · Digestive system · Respiratory system · Cardiovascular system · Renal system · Vaginal system · Bone system · Immune system

Abbreviations CS Da DA FT-IR GIT IOP Mw NP PEG

7.1

Chitosan Dalton Degree of Acetylation Fourier Transform Infra-Red Gastrointestinal Tract Intraocular Pressure Average Weight Molar Mass Nanoparticle Poly(ethylene glycol)

Introduction

Over the past 60 years due to the difficulties to develop new drug entities and the recognition of therapeutic advantages of novel drug delivery, the development of controlled release drug delivery systems was speeded up. The controlled delivery systems are ones which deliver the drug at a predetermined raet, locally or systemically, for a specific period of time. They help in maintaining the drug level within the therapeutic range, in reducing the number of adinistrations, and in increasing the efficacy of the drug and the patient compliance. Moreover they achieve extended therapeutic effect and they imply predictability in drug release kinetics. Sucessive generations drug delivery systems were developed (Yun et al. 2015) to overcome major problems such as the physico-chemical and biological barriers. In any case, they frequently use polymers and among them polysaccharides which present a lot of necessary properties such as biocompatibility, biodegradability. Chitosan is one of the promising polysaccharides and it is available from different sources. It is obtained by a deacetylation reaction of chitin, one of the most present polymers at the earth surface as a component of crustaceous shells, insects or fungi sources. It dates back to 1811 when Professor Henry Braconnot isolated chitin from mushrooms (Sun et al. 2018). It consists of 2-acetamido-2-deoxy-β-D- and 2-amino2-deoxy-β-D-glucopyranose units connected across β1 ! 4 glucoside bonds. The degree of acetylation (DA), defined as the molar fraction of acetylglucosamine units,

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is responsible for solubility, degradation, electrostatic properties, and structural conformation of chitosan chains, which condition the pathways in which chitosan can be carried and taken up by cells, as well as the interaction with nucleic acids and mucosal surfaces (Arca et al. 2009; Lai and Lin 2009). The degree and type of deacetylated chitosan influences cellular interactions and its charge. Chitosan is soluble in acid media and remains in solution at pH 6–6.5; under this pH, a large part becomes insoluble and precipitates, which is a disadvantage. Solubility can be increased by reducing the molecular weight, but is not sufficient. In recent years, research has been focused on chitosan preparations with a 70–95% deacetylation degree, which is soluble in acid, but precipitates below pH 6.5. It presents very interesting properties for biomedical applications such as its possible cationic character and its ability to interact with polyanionic macromolecules (under polyelectrolyte complexes) including DNA, or its mucoadhesivity. Moreover, thanks to the presence of functional groups such as hydroxyl or amino groups, it may be chemically modified. In addition to chitosan with varying degrees of acetylation, a series of chitosan derivatives can be prepared by the inserting hydrophilic groups such as hydroxyalkyl, carboxyalkyl, succinyl thiol and sulfate, or by grafting solubility-enhancing polymers such as polyethylene glycol and poloxamer (Singh et al. 2018). Moreover, chitosan as well as its derivatives can be prepared under different forms according to the aimed applications, hydrogels, films, capsules, particles, etc. This allows extending the biomedical applications of this polysaccharide in various domains. This chapter will describe some of these specific applications within the controlled delivery domain.

7.2

Chitosan and Derivatives Based Drug Delivery Systems – Preparation Methods

The main challenge for researchers in the last decades is to deliver the active principle at the right place and in the right dose and for this they developed “controlled drug delivery systems” which are representing a physical or chemical combination between the active principle and a vehicle/carrier. The most important advantages of these modern drug delivery systems are the following: • Reduction of the number and frequency of doses required to maintain the desired therapeutic response, reducing this way the total amount of drug administered over the period of drug treatment. • Reduction in the incidence and severity of side effects associated with high plasmatic concentration of drug/toxicity of the drug. • Protection of drug against the first metabolic pass and digestive degradation increasing the efficiency of the drug • Increased patient compliance.

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Scheme 7.1 The main types of chitosan-based drug delivery systems

More recently, another important challenge for the most severe diseases is represented by release the active principle to the specific site of action which leads to more complicated structures named “targeted drug delivery systems” involving the presence of either magnetic or ligands components (Saikia et al. 2015). Chitosan represents one of the most versatile natural derived polymer intensively used in pharmaceutcs and food industry. In the current chapter only the pharmaceutical formulations will be described from the point of view of their preparation methods related to their specific properties. In the Scheme 7.1 the most important formulations are presented. The main methods for obtaining micro/nanocapsules, micro/nanospheres and hydrogels will be further detailed.

7.2.1

Chitosan Micro and Nanocapsules

Chitosan is a cationic polyelectrolyte which is frequently used for preparation of capsules for active principle protection against phisiological environment. There are two main methods for chitosan capsules preparation: • Coacervation method – generally, the chitosan solution is blown into a nonsolvent and stirred, chitosan will precipitate on the nonsolvent droplets and forming the capsules. Using the active principle dissolved in the nonsolvent will lead to loaded chitosan capsules. • Coating method – is very similar to coacervation method, the oil phase containing the active principle is blown into chitosan solution, the polysaccharide precipitating at oil droplet surface (Landfester 2006).

7 Application of Chitosan-Based Formulations in Controlled Drug Delivery Fig. 7.1 Principle of extrusion-dripping method

Motor stirrer

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Chitosan - CaCl2 solution

dripping needle

alginate solution

Interfacial condensation technique has been used by our research group to obtain submicron capsules based on chitosan and the synthetic polymer (poly(maleic anhydride-alt-vinyl acetate); poly(MAVA)) (Iurea (Rata) et al. 2013). The interface between the aqueous and organic phases was obtained by the reaction of a –NH2 group of the chitosan chain from the aqueous phase with the cyclic anhydride monomer of the copolymer in the organic phase. Extrusion-dripping method was developed mainly for obtaining alginate – chitosan capsules using a very simple principle (Fig. 7.1): a chitosan – calcium chloride solution is extruded into the sodium alginate solution through hypodermic needles (Lim et al. 2013). This method is currently used for chitosan beads preparation (Choo et al. 2016).

7.2.2

Chitosan Micro and Nanospheres

In order to obtain micro and nanospheres the literature reports the following methods: A. Ionotropic gelation or ionic crosslinking method – can be applied to form spheres via a rapid crosslinking reaction between cationic chitosan and multivalent anionic counter-ions as a crosslinking agent. The main disadvantage is that this method does not support the use of organic solvents or high temperatures. The ionic crosslinker can be either a small molecule such as sodium sulphate, sodium tripolyphosphate or anionic macromolecules like sodium alginate, hyaluronic acid etc. (Hassani et al. 2018). Ionotropic gelation is sometime preferred, despite the lack of mechanical stability of the final particles, to

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Fig. 7.2 Preparation of micro/nanoparticle by crosslinking in reverse emulsion method

covalent crosslinking due to the low toxicity of ionic crosslinkers in comparison with covalent crosslinkers. This process is taken place either using a direct precipitation or an emulsion technique (Dash et al. 2011) B. Covalent crosslinking method – chitosan can be covalently crosslinked using glutaraldehyde, glyoxal, ethylene glycol diglycidyl ether, diisocyanate, and diacrylate as crosslinkers which bring a certain toxicity to the final chitosan spheres (Jayasuriya 2017). In order to obtain micro and nanospheres, crosslinking in reverse emulsion method is generally used (Fig. 7.2). There are two types of factors which are influencing the morphology and properties of the micro/ nanoparticles: crosslinking reaction parameters like concentration of chitosan solution, the amount of the crosslinker, the crosslinking time and also emulsion parameters such as stirring speed, amount of surfactants, the phases ratio. C. Emulsification and solvent evaporation method – also known as suspension crosslinking method and involves the preparation of w/o emulsion as it was mentioned above. In order to homogenize the emulsion, different equipments like sonifiers, and high-pressure homogenization can be used (Asua 2002). In this case, the solvent is allowed to evaporate during stirring. Also, for hardening, the chitosan particles are crosslinked using specific crosslinkers. D. Double crosslinking in reverse emulsion – is a method developed by our research group in order to increase the mechanical stability of chitosan particles ionically crosslinked and to decrease the toxicity given by covalently crosslinkers. In this case, the ionic crosslinker is added to the aqueous phase in

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a certain amount to ensure the gelation of chitosan droplets and the covalent crosslinker is added afterwads in a minimum amount (under 20% from chitosan amonium groups will covalently crosslink) to harden the soft gel particles. By this way it is possible to obtain solid micro and nanoparticles with an increased stability in time (Peptu et al. 2010). Moreover, it was possible to obtain nanoparticles using different ionic crosslinkers (sodium sulphate or sodium tripolyphosphate).

7.2.3

Chitosan Hydrogels – Membranes and Films

Hydrogels are crosslinked networks made from the same or different types of polymers which are presenting high capacity for water absorption but are prevented from dissolving due to the chemical or physical bonds formed between the polymer chains. As it is already well known, chitosan is soluble in acid medium due to the presence of amine groups from D-glucosamine units; in this acid pH medium, ammonium units are positively charged and the interchain interactions are limited (Pellá et al. 2018). It seems that chitosan based hydrogels crosslinked by itself present weak mechanical properties and uncontrolled dissolution (Kiene et al. 2018). This inconvenience is generally avoided by combining chitosan with either natural or synthetic polymers or by chitosan chemical modification moduling by this way hydrogels final properties. Mostly, chitosan hydrogel membranes or films are used for transdermal delivery of included active principle. Being a polysaccharide, chitosan will ensure the bioadhesiveness of the film/membrane to the skin, all other physical and mechanical properties can be adjusted by varying the parameters of preparation protocol (Zhao 2012). Chitosan based membranes/films can be prepared using one of the following methods: a) solvent cast – evaporation method – chitosan as it is or together with another polymer is dissolved in a certain concentration, pourred in a Petri dish and allowed to dry in the air or in the oven. In order to ensure the stability of the film it is necessary to add an ionic or/and covalent crosslinker. The crosslinking step can be performed either before the solvent evaporation or after by immersing the film in a crosslinker bath for a certain period of time b) electrospinning – by using this method, nanofibers films based on chitosan fibers can be obtained. Recently, the researchers demonstrated that the films obtained by this method present superior mechanical properties in comparison with those obtained by solvent cast-evaporation method (Ghosal et al. 2018). Generally, an electrospinning system consists of an anode (the needle), a cathode (the substrate which will collect the fibers), a high voltage power supply and an injection system for the polymer solution.

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Applications of Chitosan-Based Formulations in Controlled Delivery Systems Skin

The skin, the largest organ of the body, has been used since ancient times as a way of administering medications for local or general action after diffusion of the drug through the cellular layers of the cutaneous barrier. Although the skin, by its structure, acts as a selective barrier for large (i.e., Mw > 500 Da) water-soluble molecules, with an n-octanol partitioning smaller than 1 or greater than 3, however this way in of drugs was studied extensively as it has numerous biopharmaceutical advantages, including: avoidance of the first-pass hepatic, minimal fluctuations in the plasmatic drug concentration, ability to function as a reservoir by accumulation of drug substances in the skin layers and their prolonged release, obtaining a local or systemic therapeutic effect after controlled drug delivery, and last but not least, increased compliance in patients (Popovici et al. 2017). Over time, various strategies for modulation and optimization of transdermal drug delivery have been investigated. In particular, these methods are based on the following three principles: 1. incorporation of the drug substance in a pharmaceutical form favoring absorption (e.g., hydrogels, vesicular therapeutic systems, microencapsulated nanoemulsions, films, and transdermal pathways, etc.); 2. development of some systems that allow for permeation of the drug by physical phenomena without disrupting the epidermis (e.g. iontophoresis); and 3. use of some systems that facilitate transepidermal permeation based on physical or mechanical processes (e.g. sonophoresis, electroporation, and microneedles) (Kamaly et al. 2016; Philibert et al. 2017). Biocompatibility, physical-chemical properties and cationic nature of chitosan that allow for ionic interactions with many compounds have created the premises of extensive research and use of chitosan in pharmaceutical forms with topical application. Within this context, the efficacy of chitosan as a modulating agent of therapeutic systems that allows for absorption through various mechanisms is emphasized. In addition, chitosan has antibacterial, haemostatic and wound healing action, which makes chitosan and its derivatives the most used biomedical materials in obtaining products with cutaneous application or for epithelial regeneration. Chitosan and its derivatives, such as N-trimethyl chitosan and carboxmethyl chitosan, act as transdermal penetration enhancers. Chitosan interacts with the negative charges present in the junctions between corneocytes of the stratum corneum, allowing for the diffusion of the drug into deeper skin layers (Vaddi et al. 2002; Taveira et al. 2009). The mechanism of transdermal enhancement of chitosan, trimetyl chitosan and carboxmethyl chitosan consists in changing the secondary structure of keratin in stratum corneum, increasing the water contain of this skin layer and enhancing the cell membrane fluidity to various degrees (He et al. 2009). Chitosan is an excellent film forming agent intended for skin application both for local effect and transdermal penetration of drug molecule for systemic action. This polymeric system finds many applications in drug delivery systems as a carrier for a

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large variety of drug substances ranging from small molecules like antibiotics to macromolecules such as protein and nucleic acids (Akbar and Shakeel 2018). It was reported that crosslinking process improves both physical and mechanical properties of films based on chitosan. Aranaz et al. (2016) investigated ciprofloxacin hydrochloride loaded chitosan films intended to achieve a local controlled release of antibiotic. The release was easily controlled by the degree of crosslinking and film thickness. Moreover, the drug release profile exhibited an initial burst effect followed by sustained release. This pattern was favorable for ciprofloxacin hydrochloride since its concentration was above minimum inhibitory concentration of tested microorganisms. Hassani et al. (2018) reported that by graft-copolymerization of chitosan with poly[2-(acryloyloxy) ethyltrimethylammonium chloride] results a quaternized chitosan that forms films with enhanced antibacterial activity against Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonasaeruginosa compared to the unmodified chitosan film (Mohammad Mahbubul Hassan 2018). Chitosan films obtained by polyelectrolyte complexing, in combination with alginate, showed great stability to pH changes and were effective for the controlled release of various active pharmacological agents in the skin (Yan et al. 2001). In cosmetology it was proved that chitosan-based films neutralized with buffer citrate exhibit an exfoliating effect on the stratum corneum cells as a result of bioadhesive power of chitosan which results in decreasing the cohesion of corneocytes thereby facilitating desquamation (Libio et al. 2016). Exfoliation is a basic process within anti-aging techniques applied in dermocosmetology because it induces cell proliferation, allows for the renewal of the stratum corneum of the skin, increases the thickness of epidermis and dermis by increasing the concentration of dermal glycosaminoglycans, thereby increasing the density of collagen fibers and reducing the fine lines of the wrinkles in the early stage (Ramos-e-Silva et al. 2013). Hydrogels are topical pharmaceutical forms with a three-dimensional structure and a cross-liked network, capable of absorbing and retaining a large amount of water, which gives a smooth skin application with an increased patient compliance. Chitosanbased hydrogels are pH sensitive and the swelling degree is mainly dependent on the degree of ionization of amino groups from the chitosan backbone (Zhang et al. 2012). Dai et al. (2008a) studied the swelling behavior and delivery characteristics of pH sensitive alginate-chitosan hydrogel loaded with nifedipine, an antihypertension drug usually orally administered. The amount of nifedipine released from the hydrogel increases with increasing pH. Chitosan-based hydrogels showed prolonged release capacity over a 48-h period for glimepride, a sulfonylurea derivative, classified as oral antidiabetic of third generation characterized by low oral bioavailability due to its poor solubility. This research suggested possible effectiveness of chitosan-based hydrogel loaded with glimepride in the clinic (Ammar et al. 2008). Chitosan-based topical formulations have been used in a number of wound healing applications. Chitosan itself has a number of biomedical properties such as: antimicrobial, antiplatelet, haemostatic and wound healing activity (Hamedi et al. 2018). Chitosan has been demonstrated to have hemostatic properties promoting erythroid aggregation. Activating the coagulation cascade is an important factor in

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acute, deeper cutaneous lesions. The main factor in accelerating the wound healing process can be attributed to the presence of N-acetyl-β-D-glucosamine that initiates the proliferation of fibroblasts (Paul and Sharma 2004; Busilacchi et al. 2013; Bano et al. 2017). Healing of the wound depends not only on the quantitative presence of N-acetyl-D-glucosamine, but even more on the molecular structure. The higher the degree of deacetylation, the more healing effects is (Minagawa et al. 2007). Chitosan promotes the migration of inflammatory cells, such as leukocytes, polymorphonuclears and macrophage cells, which are able to produce proinflammatory processes and growth factors in an early stage of healing (Prabaharan and Mano 2006; Pradhan et al. 2011). Chitosan-based dressings are widely applied to stimulate regeneration of the cutaneous extracellular matrix in tissue engineering. Chitosan, like other natural polymers such as collagen and gelatin, are successfully used in producing dressings because chitosan and its derivatives are the main structural components of the extracellular matrix. In addition, chitosan stimulates cell proliferation and tissue histo-architecture (Croisier and Jérôme 2013). Among the dressings used in therapy we mention some examples: Chitipack-C®, and Chitipack-P® (Eisai), Chitoseal® (Abbott), Chitopoly® (Fuji Spinning), etc. (Oryan and Sahvieh 2017). Carboxymethyl chitosan derivatives have been studied as agents for the prevention of adhesion of post-surgical dressings, thus acting in favor of the healing process. The anti-adhesive effect of N,O-carboxymethyl chitosan gel has been demonstrated on various surgical models, such as the uterine horn, small-bowel laceration and cardiac surgery in rat or rabbit models. The results showed a consistent reduction in size, strength and number of adhesions. Moreover, the histopathological analysis exhibited fewer inflammatory cells, fibroblasts and an extensive proliferation of collagen fibers (Costain et al. 1997; Zhou et al. 2010; Chen et al. 2002a, b). Chitosan also exhibits antibacterial action apparently as a result of the interaction between the positively charged amino groups within the chitosan structure and the thiol groups, negatively charged within the bacterial cell structure. This interaction leads to microbial membrane disintegration and subsequently to leakage of proteins and other intracellular constituents (Kong et al. 2010). Antibacterial activity of chitosan can be improved by increasing the number of positively charged groups available in its structure. This can be accomplished by grafting positively charged amino acids such as L-asparagine, L-arginine or L-lysine. In addition, Shi et al. have demonstrated that L-arginine also possesses the ability to improve collagen deposition, a fundamental aspect of the healing process of cutaneous lesions (Shi et al. 2007; Hajji et al. 2017). Antimicrobial activity of chitosan is pH dependent, it has been reported that chitosan displayed antibacterial activity only in an acid environment (Helander et al. 2001). Antibacterial properties of chitosan can be increased by mechanisms synergic when combined with some metal ions such as Cu2+ and Ag2+, thereby increasing antimicrobial properties and healing effects on wounds. Various chitosanbased composites such as silver nanocomposites have been reported as having a good healing and scarring activity of cutaneous lesions (Mohandas et al. 2018). In cosmetics, chitosan, especially in the form of hydrogels, is used in formulating creams and lotions for skin care due to its ability to form elastic, protective and moisturizing films on the skin surface, having the ability to fix other active

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components that act at the cutaneous level (Pourjavadi and Mahdavinia 2006). It has been demonstrated that introducing a carboxymethyl group on the C6 position creates an active site for moisture absorption and retention. In contrast, the higher molecular weight plays an important role in improving the moisture retention ability of chitosan and its derivatives (Chen et al. 2002a, b; Muzzarelli et al. 2002). In hair care products (i.e., shampoo, conditioner, fixative, etc.), chitosan and its derivatives are increasingly used, to the detriment of conventional polymers increasingly used, because chitosan tonifies and protects the scalp, reduces dandruff and improves hair suppleness. Acylated chitosan derivatives with saturated or unsaturated organic anhydrides enter the composition of some face masks with hydrating action (Draelos 2016). In conclusion, chitosan and its derivatives are one of most important family of natural polymers used in topical applied formulation in pharmaceutical products with controlled drug release, dermo-cosmetics and wound-healing dressings.

7.3.2

Ophthalmology

Eye disorders are the most common causes of visual impairment which lead to blindness, and therefore directly affect the quality of human life. The estimated number of people with visual impairments in the world is steadily increasing due to the extension of the world population; impaired vision and blindness are becoming ubiquitous causes of disability (Weng et al. 2016; Huang et al. 2017b). The eye can be rightly named one of the most complex and highly accurate devices created by nature for the human body. The eye structure can be divided into two large segments: the anterior segment and posterior segment. The anterior segment represents about one-third of the eye, the rest part being the posterior segment. Tissues such as cornea, conjunctiva, aqueous humor, iris, ciliary body and lens are part of the anterior segment. The posterior segment includes sclera, choroid, retina, optic nerve and vitreous humor. Pathologies affecting the anterior segment are dry eye syndrome, glaucoma, conjunctivitis, anterior uveitis and cataracts. Infections affecting the posterior segment include age-related degeneration, posterior uveitis, endophthalmitis, diabetic retinopathy, retinal vascular occlusion, diabetic macular edema, proliferative vitreoretinopathy (Peptu et al. 2015; Janagam et al. 2017). The eye is a target organ which provide different opportunities for drug delivery. Drug delivery systems have appeared as an alternative method for disorders treatment, thus allowing the encapsulation of one or two drugs into a carrier or device, which after is providing a controlled and sustained drug release at a specific site and with a specific rate, thereby avoiding an over dose and reducing side effects. The major challenge facing the scientists and pharmacologists on developing a new ophthalmic drug delivery system is the achievement of the effective active substance dose in the affected tissue and, at the same time, minimize systemic and local side effects (Sheardown and Saltzman 2006). The first impediment in the case of delivery of drug alone or in a formulation is given by the unique anatomy of the eye which presents protective barriers such as cornea, sclera and retina resistant

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structures, respectively blood aqueous and blood retinal barrier which complicate all the pharmacokinetic processes. Also, barriers like choroidal and conjunctival blood flow, nasolacrimal drainage effect, and tear dilution are highly significant regarding the permeability of the drug macromolecules mainly to the posterior eye segment. Compared with drug delivery to other parts of the human body, ophthalmic drug delivery represent a challenge set by the ocular barriers previously mentioned, and can be achieved by different routes like: topical; oral/systemic; intravitreal; intracameral; subconjunctival; subtenon; retrobulbar and posterior juxtascleral (Gaudana et al. 2010; Janagam et al. 2017). Conventional ocular dosage forms (tablets, capsules, creams, ointments, eye drops) no longer constitute an optimal therapy. Most of these conventional systems present many drawbacks: they are often inconvenient; provide immediate release of the drug without having control over the release rate, which may lead either to an increase concentration above the toxic level or to a subtherapeutic dose; necessity to use large drug amounts that can be “lost”, thus failing to reach the target site (Filippo et al. 2016; Shen et al. 2004). Controlled ocular drug delivery systems compared to the conventional ones, present advantages like: prolonged and/or sustained release capacity of drugs with one single administration; targeted delivery of the active principle, followed by a controlled and sustained release; biocompatibility; low toxicity, diminished side effects (Uhrich 1999; Shen et al. 2004). In the last years, major progress have been made in developing new controlled/ sustained-release ocular drug delivery systems to better treat vision loss. The currently being available systems to improve ocular drug bioavailability follow two ways, first one by prolonging precorneal residence time and diminishing precorneal loss; and secondly, maximizing ocular permeability by extending the drug action time (Abdelkader and Alany 2012). The most notable ocular delivery systems developed to prolong the therapeutic concentrations of ophthalmic drugs within the anterior and/or posterior segments which have been investigated are polymeric gels and hydrogels, biodegradable and non-biodegradable implants, ophthalmic emulsions, micro / nanocapsules, liposomes, micro/nanoparticulate systems (Maurice 2001; Patel et al. 2010). These ophthalmic drug forms are significant in the treatment of eye diseases, and they can be prepared from biodegradable or non-biodegradable, biocompatible, natural or synthetic polymers. Among the natural and biodegradable polymers that are used for designing ophthalmic formulations, chitosan or its derivatives are suitable materials, which possess good biological behavior, such as mucoadhesiveness; permeabilityenhancing properties both in vitro and in vivo; excellent ocular tolerance; antibacterial activity and interesting physico-chemical characteristics (biodegradability, biocompatibility, nontoxicity) (Baranowski et al. 2014; Ibrahim et al. 2015; Alhalafi 2017). Below are illustrated some examples of hydrogels, liposomes and micro/nano carriers-based chitosan used as ophthalmic drug delivery systems. Although several types of drugs were successfully entrapped in different chitosanbased delivery systems, a major drawback is the reduced capability to interact in hydrophilic environments and the relatively low swelling.

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Chitosan has been conveniently exploited for the development of gels, hydrogels for ophthalmic drug delivery due to his cationic nature. Gels and hydrogels basedchitosan offers particular properties such as biocompatibility, hydrophilicity, transparency, mechanical flexibility and elasticity, high water content. Thereby, these properties lead to an improved adhesion to the mucin which coats the conjunctiva and corneal surface of the ocular globe, and increase precorneal drug residence times, avoiding drug disposal by the lachrymal flow (Fathi et al. 2015). Various application of hydrogels based-chitosan in ophthalmology have been investigated such as: in situ forming hydrogels for ophthalmic drug delivery (Agrawal et al. 2012); adhesive material for ocular wound repair (Zignani et al. 1995); corrective soft contact lenses (Nicolson and Vogt 2001); intraocular lenses (Lloyd et al. 2001); potential vitreous substitutes (Swindle and Ravi 2007) or intravitreal drug delivery systems (Turturro et al. 2011), or cell-based therapeutic approaches (Ozcelik et al. 2013). The temperature-sensitive gel formation is possible due to changes in the physical state of chitosan induced by changes in hydrogen bonds or hydrophobic interactions. In situ thermosensitive hydrogels based on chitosan in combination with disodium α-D-glucose 1-phosphate (DGP) for ophthalmic drug delivery was evaluated by Chen et al. (2011a). The crosslinked network was obtained via a sol-gel transition at 35  C, the polysaccharide formed a gel which was able to enhance the cornea penetration of levocetirizine dihydrochloride (LD) an anti-allergic agent and allow sustained drug release. Cheng et al. developed a thermosensitive latanoprost-loaded hydrogel as a topical eye drop formulation for the sustained release of latanoprost to control ocular hypertension (2016). The gelling temperature used for the developed hydrogel was 34.2  C. Authors demonstrated by in vitro and in vivo studies that the developed chitosan-based formulation possesses promising properties which contribute to a sustained release of latanoprost and may provide a non-invasive alternative to traditional eye drops for long-term intraocular pressure (IOP) control. So far also, chitosan derivatives have been used to devise different types of hydrogel applied for the treatment of different ophthalmic affections, including poly(ethylene glycol)-stabilized collagen chitosan crosslinked systems for corneal tissue engineering (Rafat et al. 2008); poly(N-isopropylacrylamide)–chitosan for reducing the intraocular pressure (Cao et al. 2007); chitosan-carboxymethyl temperature-sensitive gel loaded with levofloxacin chitosan microspheres as ophthalmic drug delivery (Kong et al. 2018); thiolated quaternary ammonium chitosan a thermosensitive hydrogel for transcorneal administration (Fabiano et al. 2017); genipin crosslinked chitosan (Grolik et al. 2012) for corneal tissue engineering; oxidized alginate and glycol chitosan a crosslinked hydrogel as potential ocular drug delivery to treat posterior segment diseases (Xu et al. 2013). The evolution of nanoscience and nanotechnology has led to a rapid development of new nano type strategies for ocular disease therapy. Micro/nanoparticulate systems-based chitosan or its derivatives are promising as ocular drug delivery devices being capable of providing a controlled release, ensuring low eye irritation, improving drug bioavailability or enhancing the precorneal retention. The mucoadhesive property is higher in the chitosan suspension than in solution, due

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to the attraction between its positively charged amino groups and the negatively charged residues of sialic acid in the mucus, thus a prolong the contact time of the drug with the organ (Alonso and Sánchez 2003). Cationic core-shell liponanoparticles (DLCS-NP) were designed by enveloping the plasmid-laden chitosan nanoparticle (CSNP) for ocular gene delivery by Jiang et al. (2012). The fabricated DLCS-NP showed an improved DNA protecting effect, good cellular uptake efficiency, and endolysosome escaping ability. Biocompatible gelatin/ chitosan microparticles loaded adrenalin suitable for ocular drug delivery were prepared by double crosslinking process performed in a reverse emulsion system by Peptu et al. (2010). Clinical tests made on animals and a voluntary human patient showed that the microparticles presented good adherent properties and were effective as anti-inflammatory agents. In order to further increase drug permeability, prolonged drug contact time with ocular tissues, delivering the active principle to a specific tissue site in a controlled or/and sustained manner, for the preparation of new drug delivery systems-based chitosan, scientists used an oligomer or a second polymer such as poly(ethylene glycol), N-acetyl cysteine, dextran, cyclodextrins, sodium alginate, gelatine, hyaluronic acid, carbopol or lecithin (Janagam et al. 2017) (Table 7.1). Shi et al.’s study highlights an improved drug bioavailability of a nanosuspension based on functionalized chitosan with a poly(ethylene glycol)-co-poly(ε-caprolactone) copolymer developed for the administration of diclofenac (Shi et al. 2015). Thus, the obtained nanosuspension showed stability without any change of physical properties after storage at 4  C or 25  C for 20 days, but was unstable when introduced into the aqueous humour solution 24 h after incubation. In vitro release profile showed a sustained release of diclofenac for 8 h. The in vivo pharmacokinetic studies showed an increased retention and penetration of the drug into the cornea. Poly(lactic-co-glycolic acid) (PLGA) microparticles, entrapping chitosan based-nanoparticles, in a composite system loaded with ranibizumab for age-related macular degeneration treatment were developed by Elsaid et al. (2016). The in vitro study showed a sustained release for up to 120 days. The blank PLGA microparticles had a ranibizumab encapsulation efficiency of 29  4%, whereas the addition of chitosan nanoparticles leads to a decrease of drug entrapment efficiency to 13  2%.

7.3.3

Nervous System

Central nervous system is a highly intricate a sensitive organization, which is vulnerable to any changes that can affect its molecular mechanism and regular function; it includes brain, cranial nerves, spinal cord, peripheral nerves, nerve roots etc. There are many neurological diseases which affect central nervous system, such as Parkinson’s disease, Alzheimer’s disease, epilepsy, cerebrovascular diseases, brain tumors etc; they are produced by physical injuries, infections, ageing, lifestyle, nutrition and environmental factors (Aderibigbe 2018) It is not easy to access the central nervous system due to the existence of two physical barriers that

Other component N-acetyl cysteine (NAC)

–

Hyaluronic acid

Polyethyleneimine or hyaluronic acid

Poloxamer 188

Primary polymer Chitosan (CS)

Chitosan oligosaccharide lactate (COL)

Chitosan

Glycol chitosan

Chitosan

Nanoparticles

Nanoparticles

Nanoparticles

Nanostructured lipid carriers

Drug delivery system Nanostructured lipid carrier

Emulsification solvent diffusion method

Amphiphilic self-assembly

Ionotropic gelation

Micro-emulsion method

Preparation method Reverse emulsion

Table 7.1 Examples of ocular drug delivery-based chitosan or its derivatives

Brimonidine

–

Timolol maleate (TM)

Ofloxacin

Drug encapsulated Curcumin Proprieties Enhanced transcorneal penetration; The clearance of the formulations was significantly delayed in the presence of CS-NAC COL improved the preocular residence time, controlled the drug release and enhanced the corneal bioavailability. Provides sustained and local delivery of drugs to the ocular sites; reduction in IOP level; enhanced mucoadhesiveness Ability to penetrate into the deeper retinal structures Nanoparticles provide a great improvement in topical ocular brimonidine Posterior segment diseases Intraocular pressure

Glaucoma treatment

Bacterial keratitis

Application Intraocular disorders

(continued)

Ibrahim et al. (2015)

Koo et al. (2012)

Wadhwa et al. (2010)

Üstündağ-Okur et al. (2014)

References Liu et al. (2016)

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Nanoparticles

–

Poloxamer

Oxidized alginate

Gelatin

Poly(ethylene glycol)

Chitosan

Chitosan

Glycol chitosan

Chitosan

Chitosan

Hydrogel loaded liposomes Ultrathin hydrogel films

3D Hydrogels

Hydrogels

Nanoparticles

Lecithin

Chitosan

Drug delivery system

Other component

Primary polymer

Table 7.1 (continued)

Crosslinking

Double crosslinking

Physical mixture

Physical mixture

Ionotropic gelation

Ionic gelation method

Preparation method

–

Calcein

Avastin

Fluconazole (FLU)

5-fluorouracil (5-FU)

Amphotericin-B

Drug encapsulated Proprieties

Enhanced ocular bioavailability; sustained release of FLU; permeationenhancing effect Drug sustained release; controllable degradation rate Better controlled release of watersoluble drugs Display desirable mechanical, optical and degradation

delivery; a single drop was sufficient to provide extended IOP reduction Pronounced mucoadhesive properties; improved bioavailablity and precorneal residence time Diffusion controlled release of 5-FU

Ocular drug delivery Injectable depot systems Corneal tissue engineering

Anterior segment diseases Fungal keratitis treatment

Fungal keratitis

Application

Ozcelik et al. (2013)

Ciobanu et al. (2014)

Xu et al. (2013)

Gratieri et al. (2011)

Nagarwal et al. (2011)

Chhonker et al. (2015)

References

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Poly (ɛcaprolactone)/poly (ɛ–caprolactone)

Chitosan

Chitosan

Chitosan

Egg phosphatidylcholine

Soybean phosphatidylcholine and cholesterol

CS-coated liposomes

CS-coated liposomes

Nanofibrous scaffolds

Homogeneous suspensions

Homogeneous suspensions

Electrospinning

Timolol maleate (TM)

Flurbiprofen

Retinal progenitor cells

properties; promoted attachment and proliferation of ovine corneal endothelial cell Easily fabricated; hydrophilicity; favored mice retinal progenitor cells (mRPC) proliferation Prolonged pre-corneal retention and improve transcorneal penetration; Solutol HS-15, could potentiate the flexibility and penetrability effective in reducing the IOP; potentially useful carrier for ocular drug delivery; improved efficacy of TM Ocular drug delivery

Ocular drug delivery

Retinal tissue engineering

Tan et al. (2017)

Chen et al. (2016)

Chen et al. (2011b)

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protect it from the external environments. The first one is the bony structure which surrounded both the brain and the spinal cord such as skull and vertebral columns respectively; and the second one is the blood-brain barrier which is formed by a layer of endothelial cells (Liu-Snyder and Webster 2006). The drug administration for the treatment of neurological diseases is carried out on the usual ways, such as: topically, orally and intravenously. Some approaches involve the direct delivery of the drug via injection into the brain, cerebrospinal fluid or intranasal delivery. Some of these techniques are unsafe, invasive, local and short lasting. One of the most challenging problems in the treatment of neurological diseases is to manage the distribution of drugs to the central nervous system across the blood-brain barrier. In order to achieve this aim, two ways have been outlined: development of chemically derivatives of drugs or chemically modified nanoparticulate vectors of drugs, capable of crossing biological barriers, in particular the blood-brain barrier. So, nanotechnology offers solutions for overcoming the blood-brain barrier. Working inside the body, and especially in its most complex and sensitive organ, the polymers used to obtain the nanoparticles must perform a number of requirements from which biocompatibility and biodegradability are the most important. For this reason, the ideal candidates are natural polymers, especial polysaccharides, and very few synthetic polymers (Peptu et al. 2014). It is well known that blood-brain barrier penetration is possible by compounds that contain a positive charge due to their interaction with the negatively charged glycocalyx such heparan sulphate proteo-glycans and phospholipid head groups of the outer leaflet of the cell membrane facilitates their entry. Consequently, cationic nanoparticles have been recognized as an effective approach to increase their permittivity across the blood-brain barrier. However, there are only a few cationic polysaccharides. Chitosan being the most important among them is used as such, in the form of derivatives or in combinations with other polysaccharides, or some synthetic polymers. There are many reviews in the literature that present the methods for the synthesis of chitosan gels, nanoparticles, self-aggregates and micelles, and their applications as drug delivery to the brain (Barbu et al. 2009; Pathan et al. 2009; Wolfhart et al. 2012; Victor et al. 2013; Alyautdin et al. 2014; Peptu et al. 2014). The most widely used route for the administration of polymer-based formulations is intranasal one as it is non-invasive for drugs that are active in low doses and show no or minimal oral bioavailability (Aderibigbe and Naki 2018). Drugs gain access directly from the nasal mucosa to the brain and spinal cord utilizing pathways along olfactory and trigeminal nerves (Mittal et al. 2016). Nasal solution formulations of morphine containing chitosan glutamate were tested. The plasma profiles after nasal administration were similar to those obtained after intravenous administration of drug, and a bioavailability of 60% was obtained. The formulation was well tolerated and well accepted by volunteer subjects (Illum et al. 2002). Mucoadhesive thermosensitive in situ gel was developed from chitosan, Pluronic F127, hydroxypropyl methylcellulose, carbopol 934 and sodium carboxymethyl cellulose for brain delivery of rivastigmine tartrate (Abouhussein et al. 2018). In vivo tests on normal albino mice revealed 84% intranasal permeation with a good

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distribution to the brain (0.54% ID/g) when compared to intravenous administration. Thermoreversible gels were prepared using chitosan and glycerophosphate or poly (ethylene glycol) (PEG) for the intranasal delivery of doxepin. In vivo studies in Swiss albino mice showed a good increase in activity count and a decrease in immobility time, suggesting good antidepressant activity. The administration of the gel formulation caused mild swelling of glands, but there was no symptom of sluffing of the mucosal epithelium. The drug from the formulation prepared from chitosan, glycerophosphate or PEG permeated at a lower rate when compared to the formulation prepared from chitosan and glycerophosphate (Naik and Naik 2014). As it was stated, chitosan has the potential of serving as an absorption enhancer across epithelial membranes for its mucoadhesive and permeability enhancing property. Also, it has been pointed out previous that the intranasal route of drug delivery is a promising route of drug delivery into the brain, which might be augmented using suitable carrier systems like nanoparticles, which enhance central nervous system penetration of drugs and also deliver drugs in a sustained manner. The most used method to obtain chitosan based nanoparticles is the ionic gelation; the method is based on crosslinking chitosan chains bearing positive charge (ammonium ions) with polyvalent anions (sulphate, tripolyphosphate). Tripolyphosphate was often used to prepare chitosan nanoparticles, because tripolyphosphate is nontoxic, multivalent and the ionic interaction can be controlled by the charge density of tripolyphosphate and chitosan which is dependent on the pH of solution. Nanoparticles based on chitosan ioncally crosslinked with tripolyphosphate for improving nasal absorption and brain targeting of estradiol (Wang et al. 2008). Chitosan nanoparticles were prepared by the same way (with and without drug, respectively Levodopa) in the presence of Tween 80 to prevent particle aggregation (Saranya et al. 2012). The loading efficiency of the drug ranges between 88% and 60% and decreases with the increasing of the concentration of chitosan solution subjected to crosslinking. Ex vivo and in vivo were performed, which stated that release of drug followed zero order kinetics and that the drug reached the target and showed better action than the standard. Gels prepared from chitosan nanoparticles obtained by ionic gelation and included in a Pluronic and hydroxylpropylmethyl cellulose (HPMC) – based mucoadhesive thermoreversible gel was tested for the brain delivery of tramadol hydrochloride (Kaur et al. 2015). This system enhanced the drug delivery of drug to the brain and significantly increased locomotor activity and body weight of the rat model in vivo. Couvreur’s group described a nanocarrier system that can transfer chitosan and chitosan conjugated with PEG nanospheres loaded with either small peptides (caspase inhibitor Z-DEVD-FMK) or a large peptide (basic fibroblast growth factor) across blood-brain barrier (Aktas et al. 2005). The nanoparticles are selectively directed to the brain and are not measurably taken up by liver and spleen. The penetration kinetics of nanoparticles loaded with a marker was studied, and demonstrated that this nanomedicine formulation is rapidly transported across the bloodbrain barrier. The nanospheres conjugated bearing the OX26 monoclonal antibody which has a affinity for the transferrin receptor r(TfR) -, may trigger receptormediated transport across the blood-brain barrier.

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Another study reveals that this type of surface PEG-ylated chitosan based nanoparticles has the ability of to deliver siRNA to the brain, following an intranasal route (Malhotra et al. 2013). Nanoparticles based on depolymerized chitosan, grafted by alkylation with PEG and followed by Schiff base formation, proved the ability to cross the blood-brain barrier and specifically target brain tumors in a genetically engineered mouse model (Veiseh et al. 2009). The nanoparticles containing a tumor targeting agent, chlorotoxin, show an innocuous toxicity profile and sustained retention in tumors, confirmed by the in vivo tests. Thiolated chitosan hydrogel nanoparticles for the nasal delivery of an anti-depression drug (selegiline hydrochloride) were prepared, too, by ionic gelation method. The particle size was found to be 215 nm, and the entrapment efficiency was 70%. The formulation significantly attenuated oxidative stress and restored the activity of the mitochondrial complex, in vivo tests revealing its potential as a carrier for delivery of anti-depressant drug (Singh et al. 2016). Low molecular weight chitosan mixed with poly(glutamic acid) (PLGA) was used for obtaining nanoparticles by ionic gelation. The nanoparticle size and zeta potential could be controlled by their constituent components. The application of the nanoparticles to paracellular transport was investigated in an in vitro design (Lin et al. 2005). The authors successfully verified the passive diffusion of nanoparticles through the paracellular pathway, which means that their work is applicable to the field of targeted drug delivery through the bloodbrain barrier. Chitosan glutamate nanoparticles (CG-NPs) crosslinked with tripolyphosphate were prepared in order to encapsulate the rasagiline, a drug which is inhibitor of monoamine oxydase type B, with dopamine receptor antagonist activity (Mittal et al. 2016). In vivo biodistribution studies demonstrated the superiority of the nanoparticles when compared with the results of intravenous and nasal solution of the drug. Chitosan glutamate was used, too, to obtain coated niosomes for nose-to-brain delivery (Rinaldi et al. 2018). The nanoparticles show in vitro mucoadhesive properties and the capacity to gradually release in time the pentamidine. Chitosan nanoparticles were fabricated by ionic interaction with dextran sulfate prior to determination of their storage stability (Katas et al. 2013). An entrapment efficiency of 98% was achieved when BSA/siRNA was loaded into the nanoparticles. The results showed that particle size and surface charge of nanoparticles were slightly changed up to 2 weeks when stored at 4  C. With increasing the concentration of dextran sulfate greater particle size and surface charge were obtained. The release of siRNA occurs in two stages, the cumulative efficiency of BSA being greater than 85%.

7.3.4

Digestive System

The digestive system represents an ensemble of organs which ensure food digestion and nutrient absorption, as well as disposal of the residues resulting after digestion. The component parts of the digestive system are the digestive tract or the gastrointestinal tract and the accessory digestive organs: teeth, tongue, salivary glands, liver,

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gallbladder and pancreas. The digestive tract, a muscular tube with a length of approximately 10–12 m consists of several segments with different structure, diameter and function. Drug administration at the gastrointestinal tract level can be done by the oral route (sublingual, buccal and gastrointestinal ways) or by the rectal route, the absorption of the active agent being achieved at any gastrointestinal tract level: Oral cavity: absorption via oral mucosa is rapid and the first pass effect is avoided. The surface area is approximately 215 cm2 (Collins and Dawes 1987), pH ¼ 6 and the relative absorption capacity of drugs is high. Stomach: as a component of the digestive tract, it communicates in its superior part with the esophagus, and in its inferior part with the duodenum. The surface area is approximately 0.1–0.2 m2 (Cox 1952; Naik et al. 1971), pH ¼ 1.5–3 and the relative absorption capacity of drugs is high. Small intestine: the majority of drugs are absorbed at this level. The mucosa of the small intestine develops an area between 120 and 200 m2, the pH being 5.3 in the epithelium and 7 in the lumen. Large intestine: due to the presence of an important microbial population, drug absorption is significantly reduced. The surface area of large intestine is situated between 0.5 and 1 m2 and the pH being in the range 6–8. Rectum: the surface of the rectal mucosa is reduced (200–400 cm2) and the absorption is slow, the pH being in the range 5–7. The thickness of the mucus layer varies between 50 and 450 μm in the stomach and less than 1 μm in the oral cavity. Compared to other ways of drug administration, the oral one has a higher utilisation rate due to the fact that it is comfortable and not painful. The successful preparation of controlled drug delivery systems administered orally requires understanding the following aspects: gastrointestinal physiology, physicochemical properties of the drug and the characteristics of the dosage forms. Oral administration is achieved by placing the system in the oral cavity and swallowing it. The oral route may be used for: local treatment (gastrointestinal protectors of the digestive tract, intestinal infection and parasitic disease treatment) or general treatment during which the drug absorption at the digestive mucosa level takes place, followed by their diffusion in the body. The oral cavity is the initial part of the digestive system which is limited to the upper part by the palate, to the lower part by the buccal floor, laterally by the cheeks, to the anterior part by the lips and to the posterior part it continues with the pharynges. The oral cavity is coated with a mucosa consisting of several layers of cells being named, according to the place it is situated: sublingual (26.5 cm2), lingual, gingival, soft palatal (20.1 cm2) and buccal mucosa (Patel et al. 2011). Buccal and sublingual tissues are the first envisaged for drug transport by means of the buccal mucosa, since they are more permeable than the tissues from other regions of the mouth. The area of the buccal surface (200 cm2) is small compared to that of the gastrointestinal tract (350,000 cm2) or that of the skin (20,000 cm2). Nevertheless, the buccal mucosa is highly vascularized and as a result, any diffusion of the drug through the membrane of the mucosa has direct access to the systemic

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circulation via capillaries and venous drainage. Thus, the drugs which are absorbed through the buccal mucosa reach the systemic circulation directly, avoiding the gastrointestinal tract and their metabolizing through the first hepatic passage. The environment in the oral cavity presents some important changes with respect to the systemic drug delivery. The drug is released from the system to the place of action (buccal or sublingual) and then passes through the mucosa to enter in systemic circulation. The penetration rate depends on the physicochemical properties of the drugs as well as the type of tissue to be crossed. It suggests that during the absorption process, the active agents may use one or several simultaneous ways to pass through the mucosa, but only one is dominant, being dependent on the physical and chemical properties of the drugs. The drug delivery systems based on polymers used for oral administration may take different presentation forms: tablets, capsules, syrups, powders, suspensions, oils, granules and sprays (Sudhakar et al. 2006). When formulating a bucco-adhesive drug delivery systems, the following aspects must be taken into consideration: to be easily applied, non-obstructive and have a pleasant taste; to maintain their cohesion against salivary and mechanical erosion during the administration; the excipients used to obtain the dosage form do not irritate or destroy the mucosa and are not toxic; the release of the active substance to be achieved quickly. Drug administration in the oral cavity may be achieved in two ways: the sublingual way and the buccal way where the drug administration is done through the mucosa membrane which covers the cheeks (Shojaei 1998). The transmucosal systems with oral administration are designed in such a way that drug release can be achieved in the following ways: quick for immediate action; pulsatile, with the fast occurrence of the drug in the systemic circulation and appropriate maintenance of the active agent concentration in the therapeutic field; controlled for a longer period of time. The constant flow of saliva and tissue mobility may influence the drug delivery in the oral cavity. Generally, the retention time of drug in the oral cavity is lower than 5–10 minutes (Lee et al. 2000b). In order to prevent this drawback, several mucoadhesive systems based on polymers have been developed. Systems with sizes from 1 to 3 cm2 which may provide a daily dose of 25 mg of the drug are preferable for oral administration. The maximal duration for oral drug delivery with such systems is approximately 4–6 h (Reddy et al. 2013). Buccal mucoadhesive drug delivery systems may be classified as follows: • by use: local and systemic • based on presentation form: solids (tablets, microparticles), semi-solids (gels, films, ointments), liquids (solutions, syrups, emulsions or suspensions); • based on the geometry of dosage forms: type I - consisting of a single layer that due to swelling loses a large amount of drug; type II – consisting of an impermeable layer overlying a layer of bioadhesive polymer that has included the drug. Thus, a double layer device is created in order to prevent the loss of drug from the surface of the system in the oral cavity; type III - unidirectional delivery system of which the loss of drug is minimal because the biologically active principle is released into the oral cavity only by the side. This can be achieved by covering all faces of the system except of the part that comes into contact with the oral mucosa.

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• based on drug distribution: matrix-when the drug is uniform distributed in the polymer matrix and drug release is controlled by diffusion; reservoir- the drug core is externally covered by a polymeric membrane. In this case the drug release rate is controlled by several parameters such as, the polymer composition, molecular weight of polymers, the thickness of the polymeric membrane, the solubility of the drug, particle size and molecular weight of drugs (Yang and Pierstorff 2011). Systems used in oral therapy are in the form of tablets, gels, patches or films. Tablets are the most used drug dosage forms. They are small, flat, oval or round with a diameter of approximately 5–8 mm (Rathbone et al. 1994; Missaghi et al. 2010). Gel type systems were designed in such a way that they adhere to the surface of the mucosa for a longer period of time, finally resulting in the controlled release of the drug. The advantages of using gels in the oral cavity consist in their ability to determine an intimate contact with the mucosa membrane and release a certain amount of drug. For this reason, these gels are used for those drugs which have a narrow therapeutic range. The bioadhesive buccal patches are comprised of the following components: active pharmaceutical ingredients (5–30% w/w), adhesive layer (mucoadhesive polymers), diluents (lactose), sweetening agents (mannitol, aspartame), flavoring agents (menthol, vanillin), backing layer (ethyl cellulose), penetration enhancer (cyanoacrylates) and plasticizers [polyethylene glycol (PEG 100), PEG 400] (Kuldeep and Shiv 2015). Several methods of preparation are known: a) Solvent casting. With this method bioadhesive patch drug delivery systems are obtained by casting the polymer solution that contains drug to a support followed by evaporation of the solvent. This method is simple, but also presents some drawbacks such as long processing time, high costs and possible pollution of the environment due to the use of the solvents. These drawbacks can be prevented if, in the preparation of bioadhesive patch systems, the melt extrusion method is used (Repka et al. 2002); b) Direct milling, whereby the components of the dosage form are mixed and then compressed until the desired thickness is obtained, after which they are cut after a certain size and shape (Sharma et al. 2013); c) Solid dispersion extrusion d) Semisolid casting e) Hot melt extrusion is an attractive technique that can be classified as follows: (1) ram extrusion, (2) screw extruders (single screw extruders and twin-screw extruders) (Kuldeep and Shiv 2015). Bioadhesive semi-solid systems in the form of films have to fulfil several conditions in order to be used in oral therapy: to be flexible and soft; to be tear resistant because they are submitted to the tension exercised by the movements of the mouth; have good bioadhesiveness so that they can be kept in the mouth as long as necessary; the swelling degree of the film should be moderate so that is does not create discomfort to the patients. Due to its remarkable physicochemical and

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Table 7.2 Tablets and gels based on chitosan used in buccal therapy Drug Tablets propranolol hydrochloride nicotine

Molecular formula C16H22ClNO2 C10H14N2

carvedilol

C24H26N2O4

repaglinide

C27H36N2O4

bupivacaine

C18H28N2O

omeprazole

C17H19N3O3S

ibuprofen

C13H18O2

salbutamol

C13H21NO3

Gels celecoxib

C17H14F3N3O2S

ondansetron

C18H19N3O

nystatin

C47H75NO17

triamcinolone acetonid

C24H31FO6

Therapeutic domain

References

treatment of high blood pressure, atrial fibrillation, tremor smoking cessation

Abruzzo et al. (2015) Lewis et al. (2006) Yedurkar et al. (2012) Patel et al. (2012) Shivashankar and Mandal (2013) Choudhury et al. (2010) Sogias et al. (2012) Arya et al. (2011)

treatment of hypertension, management of congestive heart failure blood sugar control in type 2 diabetes mellitus local anesthetic

treatment of gastroesophageal reflux disease, peptic ulcers treatment of pain, fever and inflammation management of asthma and other chronic obstructive airway disease treatment of osteoarthritis and rheumatoid arthritis treatment of emesis treatment of Candidiasis of the skin and mucous membranas treatment of oral mucosal ulceration

Cid et al. (2012) Park et al. (2012) Abdul Rasool et al. (2010) Amasya et al. (2012)

biological properties, chitosan was used in different strategies for the development of oral drug delivery with good results in the treatment of some gastrointestinal diseases. In Tables 7.2 and 7.3 are presented some examples of bioadhesive systems based on chitosan used in buccal therapy. The stomach, the next component of the GIT is a digestive organ of great importance which is situated between the esophagus and the small intestine. From an anatomical point of view, the main regions of the stomach are: the cardia where the esophagus is connected to the stomach; the superior part of the stomach named fundus; the largest part of the stomach – the stomach body; the antrum or the pyloric region (Mandal et al. 2016). Structurally, the walls of the stomach resemble other portions of the intestines, but also presenting some differences. Numerous drugs have an increased therapeutic effect when they are released in the stomach, especially when the release is achieved in a controlled manner. The controlled drug delivery systems to the gastrointestinal tract represent a significant therapeutic option presenting advantages as well as disadvantages. The advantages

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Table 7.3 Films and patches based on chitosan used in buccal therapy Molecular formula

Therapeutic domain

References

C17H17ClO6

topical treatment of fungal infections

miconazole

C18H14Cl4N2O

treatment of oral and vaginal Candidiasis

ondansetron

C18H19N3O

acyclovir

C8H11N5O3

control of nausea and vomiting associated with cancer therapy treatment of Herpex simplex diseases

flufenamic acid lidocaine

C14H10F3NO2

valdecoxib

C16H14N2O3S

Bavarsad et al. (2016) Abdul Rasool and Khan (2010) Koland et al. (2011) Rossi et al. (2003) Mura et al. (2010) Varshosaz and Karimzadeh (2007) Averineni et al. (2009)

metoprolol

C15H25NO3

candesartan

C24H20N6O3

tramadol

C16H25NO2

Patches carvedilol

C24H26N2O4

verapamil

C27H38N2O4

granisetron

C18H24N4O

losartan

C22H23ClN6O

bisoprolol

C18H31NO4

metoprolol

C15H25NO3

furosemide

C12H11ClN2O5S

catechin

C15H14O6

amilodipine besylate

C20H25ClN2O5

Drug Films griseofulvin

C14H22N2O

COX inhibitor and prevent formation of prostaglandins local anesthetic agent, treatment of ventricular tachycardia treatment of oral submucous fibrosis, treatment of osteoarthritis, rheumatoid arthritis treatment of high blood pressure treatment of hypertension and congestive heart failure treatment of moderate to moderately severe pain treatment of hypertension, management of congestive heart failure treatment of high blood pressure, angina and supraventricular tachycardia treatment of nausea and vomiting following chemotherapy and radiotherapy treatment of high blood pressure treatment of blood pressure and cardiac diseases treatment of high blood pressure treatment of fluid build-up due to heart failure, liver scarring or kidney disease antioxidant treatment of hypertension and coronary artery disease

Gorle et al. (2015) Malpere and Deore (2016) Li et al. (2017a)

Kaur and Kaur (2012) Deshmane et al. (2009) Khobragade et al. (2013) Bansal et al. (2013) Sarath Chandran et al. (2013) Furtado et al. (2010) Singh and Sharma (2017) Sankar et al. (2015) Marabathuni et al. (2017)

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are: improvement of biodistribution and therapeutic efficiency of drugs as well as the possibility of reducing the administration frequency of the dosage forms; maintaining a constant therapeutic level for a longer period of time; reducing the resistance risk to antibiotics; extending the gastric stasis period that is desired for some types of drugs (Kawashima et al. 1992). Regarding to the disadvantages of controlled drug delivery systems for gastrointestinal administration, they are not appropriate for: drugs which cause gastric lesions or drugs like nifedipine which are well absorbed during the whole GIT and are metabolized through the first hepatic passage. Also, these systems require a high fluid level in the stomach and should be administered with a full glass of water (200–250 mL). When designing systems intended to release drug in the GIT it must take into account the anatomy and physiology of the stomach. Indeed, the particle sizes of the dosage forms must be within the 1–2 mm range in order to pass through the pyloric orifice to the small intestine (Soni et al. 2011). The gastrointestinal transit time depends on the floatability of the dosage form and implicitly on its density. Lower density systems (ρ < 1 g/cm3) can float on surface of gastric fluid, while the dosage form with higher density immerse in the bottom of the stomach. Generally, the density of the dosage form should be between 1 and 2.5 g/cm3 (Timmermans and Moes 1990). The gastric retention time of the non-floatable dosage forms depends on their size, which may vary from large dimensions to small dimensions (El-Kamel et al. 2001). For example, the systems with a diameter larger than 7.5 mm present a higher gastric retention time and a higher absorption capacity (Arora et al. 2005). Presence or absence of food within the gastrointestinal tract influences the gastric retention time of the dosage forms. Generally, the gastric retention time of the dosage forms increases when: there are foods present in the stomach; increases the acidity and caloric content of foods; foods rich in protein and fat are administered; foods are administered successively. Increasing of the gastric retention time leads to the increase of drug absorption, because the therapeutic system will stay longer at the place of absorption (Whitehead et al. 1998). The gastrointestinal tract offers a diverse physiological environment due to the presence of some factors (anatomic characteristics, physiological phenomena, nature of the gastrointestinal environment) which may affect the oral administration of drugs. For this reason, variations may occur with respect to the intestinal permeability of the drugs, resulting in their preferential absorption only in a certain GIT region, a phenomenon known as “absorption window”. Physical and chemical factors, as well as physiological factors may influence the bioavailability of drugs administered by oral route. The main goal of the pharmaceutical forms is to extend the retention time of the active biological compound in the absorption region for the desired period of time. In order to achieve the desired therapeutic goal, namely increasing the gastric retention time of the dosage forms, researchers were developed various systems that could be divided into: a) systems controlled by density: low density systems (Nur and Zhang 2000; Bhavsar et al. 2012) and high density systems (Clarke et al. 1995); b) bio mucoadhesive systems (Arora et al. 2012);

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c) systems that increase their size: swellable/expandable/unfondable systems (Deshpande et al. 1997) and superporous hydrogels systems (Chen et al. 2000); d) magnetic systems (Ito et al. 1990) Nohemann et al. (2017) have developed the gastro-retentive floating microparticles based on chitosan and hydroxypropyl methylcellulose. The microparticles with mean diameter in the range between 1.05 and 2.20 μm were prepared by spray drying technique and were evaluated for controlled release of metronidazole for eradication of Heliobacter pylori. Chitosan-poly(acrylic) acid polyelectrolyte complexes were investigated for stomach-controlled antibiotic delivery (Torrado et al. 2004; De la Torre et al. 2005) and the results were suggested that these systems are potential candidates for oral administration. Vasiliu et al. (2008) obtained core-shell microparticles based on chitosan and sodium hyaluronan. The studies were designed to analyze the retention and release processes of two antibiotics such as chloramphenicol succinate sodium salt and cefotaxime sodium salt. Among the two used antibiotics, the amphoteric drug (cefotaxime sodium salt) was retained in greater quantity. Also, superporous hydrogel composite based on chitosan and acrylic monomers loaded with ranitidine hydrochloride were studied as stomach-specific drug delivery. The components of superporous hydrogel composites have been selected either for biocompatibility (chitosan) or for their higher water retention capacity and fast copolymerization velocity (acrylic acid and acrylamide) (Chavda and Patel 2010). Among the mathematical models (zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Weibull and Hopfenberg models) used to study the kinetics of drug release, the Korsmeyer-Peppas was fitted well the experimental data. The diffusion coefficient values indicate an anomalous non-Fickian transport of ranitidine and the release mechanism is controlled by the diffusion and erosion processes. The superporous hydrogel composites present good swelling capacity, the floating behaviour and delivery of ranitidine is reached in about 17 h. Another component of GIT is the large intestine that is positioned between the ileocecal valve and the anal orifice, consisting of three main parts: colon, rectum and the anal canal. The colon is a significant part of the digestive system and has a great importance in the absorption of minerals, nutrients and water in the body, performing four important functions, namely: creating a proper environment for developing an adequate microbial flora; reservoir for storing the faeces; expulsion of the contents an appropriate period of time; absorbing potassium and water from the lumen. Millions of people are affected annually by digestive tract disorders such as, Crohn’s disease, ulcerative colitis and irritable bowel syndrome. The field of controlled release systems for different biologically active principles in the treatment of specific diseases of the large intestine is in full expansion, a proof being that the specialists continue to develop and improve the existing technologies, in order to achieve a targeted, pulsatile or self-regulating release which may adapt to the biologic rhythm of the patient, as well as to the specific conditions of his/her disease. A growing concern was noticed lately to obtain the dosage forms that can be used in

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systemic administration or as colon targeted drug delivery systems (Sowmya et al. 2012). In order to realize different drug delivery systems in the colon, several conditions must be met: the drug must not be absorbed in other parts of the GIT and suffer only a mild degradation in the small intestine; the drug release in the colon must to take place in the lumen of the large intestine and be achieved with controlled rate. The colon offers the following therapeutic advantages: the possibility of reducing side effects in the treatment of colon disease; reduces gastric irritation caused by drugs; reduced dose frequency and thus a lower cost of the treatment; the colon is an ideal place for drugs which are difficult to adsorb and whose bioavailability must be improved; it may present delayed release of the drugs, useful in treating angina pectoris, asthma and polyrheumathoid arthritis; improved patient comfort; the colon represents a more friendly environment for peptide and protein administration compared to the superior GIT (Jose et al. 2009; Sarasija and Hota 2000). Considering the disadvantages, they require many stages in the manufacturing process; a decrease of the drug bioavalability is noticed due to the interaction with the intestinal content; an incomplete release of the drug takes place; the intestinal microflora may affect the performance of the colon due to the metabolic degradation of the drug (Mandhu et al. 2011). Lorenzo-Lamosa et al. (1998) developed a novel multiparticulate system consisting in using chitosan microcores (1.8–2.9 μm) containing sodium diclofenac that were entrapped within acrylic microspheres (Eudragit L-100 and Eudragit S-100) using an oil-in-oil solvent evaporation method. The drug release process took place due to the dissolution of the acrylic coating, the swelling of the chitosan microcores, dissolution of drug and its diffusion through the chitosan cores. Nanoparticles based on chitosan-hyaluronic acid containing 5-fluorouracil were prepared by ionotropic gelation method and were studied as potential drug delivery systems for the treatment of colorectal cancer (Jain and Jain 2008). Nanoparticles loaded with 5-fluorouracil showed enhanced uptake in HT29 cell lines compared to chitosan nanoparticles, as well as an increase in cytotoxicity of loaded nanoparticles compared to 5-fluorouracil solution. In conclusion, the chitosan-hyaluronic acid nanoparticles can be used in treatment of colorectal cancer. The chitosan capsules containing 5-aminosalicylic acid (5-ASA) as model of antiinflammatory drug were coated with enteric coating material, namely hydroxypropyl methylcellulose phthalate (Tozaki et al. 2002). For the treatment of colitis in rats, the chitosan capsules and a carboxy methyl cellulose (CMC) suspension were administered by oral route. It was observed that capsules reached the large intestin of rats in 3.5 h after oral administration. Also, the healing of colitis by anti-inflammatory drug was accelerated when chitosan capsules were used. Based on the myeloperoxidase activities, colon wet weight/body weight and the damage score, it was found a better therapeutic effect with 5-ASA chitosan capsules than with 5-ASA CMC suspension, indicating that the chitosan capsules can be used as carriers for colon-specific delivery of anti-inflammatory drugs. Varshosaz et al. (2006) prepared coated chitosan microspheres by emulsion-solvent evaporation technique based on multiple w/o/w emulsion in order to use them as drug carriers for colon-specific delivery of 5-ASA. The chitosan microparticles were coated

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with cellulose acetate butyrate (CAB). The release data indicate that in the acid medium the drug is not released due to the good protecting effect of CAB. After 3 h the maximum drug release was 12.3% indicating that about 90% of the 5-ASA remains in the microparticles and therefore will be released into the colon. Drugs may be administered rectally when the other administration ways are not available. Rectal administration may be achieved in the following situations: when oral administration has drug intolerance, nausea, emesis or gastric pain as a result; when the patients do not cooperate or are unconscious; when access to the intravenous way is difficult; to the patients within the outpatient unit for which painful intramuscular administration is not well tolerated (De Boer et al. 1982). From the anatomical point of view, the rectum represents the last part of the large intestine (12–19 cm), with an area of 200–400 cm2 (Bergogne-Berezin and Bryskier 1999). Drug adsorption mechanism in the rectum does not differ much from that in the superior part of the GIT. Depending on the chemical structure of the drug, the absorption may be achieved by a transcellular or a paracellular mechanism (Van Hoogdalem et al. 1991). Drug adsorption at the rectum level depends on a series of characteristics of the active biologic principles such as: partition coefficient and molecular size. For example, the factors which determine a weak drug absorption capacity are: a low partition coefficient, large size molecules and increased capacity of forming hydrogen bonds. Other factors which may influence drug absorption are: liquefaction time of suppositories, the volume of liquid in the rectum and the pH of the rectal content. Currently, there are numerous types of rectal administration systems on the market, namely: solutions, suspensions, suppositories and capsules. Mucoadhesive catechol modified-chitosan hydrogels were used as injectable rectal delivery system of sulfasalazine a drug used in the treatment of ulcerative colitis. Compared to oral sulfasalazine delivery system, the rectal hydrogel was more effective and safe as well as it reduces the risk of side effects associated with oral dosage form (Xu et al. 2017). Also, chitosan can be considered as a suitable polymeric support for preparation of sustained release system of ketoprofen in the form of suppository (Tarimci and Ermis 1997).

7.3.5

Respiratory Systems

Respiratory drug delivery offers a noninvasive route to deliver either topically active medications or systemic drugs. Nose and lung are target organs which provide opportunities for drug delivery. Main advantages of the delivery of drugs via the respiratory tract are a reduction of side effects and an immediate onset of action. Inhalation presents a strong interest as an alternative route of systemic drug administration. Either nose or lung offer a number of distinctive advantages such as a large surface area for drug absorption, a rapid attainment of therapeutic drug levels in the blood, avoidance of harsh environmental and gastrointestinal conditions, the absence of first pass metabolism characteristic, potential direct drug delivery to the brain

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along the olfactory nerves (when nose is considered) and a direct contact site for vaccines with lymphatic tissues. However some limitations come from possible nasal irritation, risks of local side effects and damage of nasal mucosa (especially the cilia) both from substance and from constituents added to the dosage form as well as the presence of surfactants able to disrupt membrane when in high concentration. Nasally administered drugs will be deposited on the respiratory epithelium. From the site of deposition the drug can either be absorbed through the epithelium and reach the systemic circulation, or be cleared via the nasopharynx down to the gastrointestinal tract by the mucociliary clearance system (Casettari and Illum 2014). Main delivery respiratory systems consider particles as materials and their dimensions depend on the considered organ, 40–80 μm for the nose and 2–5 μm for the lung. In complement with the general properties of chitosan, its ability to adhere to mucosal surfaces and transiently open epithelial cell tight junctions potentiate the interest of chitosan-based nanoparticles for nasal or pulmonary transmucosal delivery of drugs. The glucosamine components provide amine groups that facilitate the mucoadhesiveness of chitoan, as well as its mucopermeable properties. This can prolong the contact time of the drug with the organ. The interactions between chitosan and mucin are at origin of mucoadhesive properties of chitosan. They are complex but electrostatic attraction appears to be the major mechanism for chitosan mucoadhesion and is also accompanied by contributions from hydrogen bonding and hydrophobic effects (Sogias et al. 2008). The electrostatic attraction is between the positively charged amine groups on the polymer chain (pKa~6, Rinaudo et al. 1999) and the negative sialic acid acid residues on the glycoprotein (Russo et al. 2016). Moreover, chitosan can mediate the opening of tight junctions between epithelial cells reversibly, thus, facilitating the paracellular transport of hydrophilic macromolecules (Sonaje et al. 2012). Chitosan, or its derivatives, is used either for human or veterinary treatments and they are generally used as nanoparticular materials for nasal and/or pulmonary delivery but also as microspheres, or sometimes under emulsion or solution form (Casettari and Illum 2014). Illum et al. (1994) were among the first to show the ability of chitosan to enhance the absorption of small molecular drugs as well as the larger peptides and proteins across the nasal epithelial membrane. When chitosan is used under gel form, the thermosensitive character is usually looked for. The prepared product would benefit from being able to be applied as a liquid formulation and then after gelling add the benefit of increased mucoadhesiveness resulting in prolonged residence in the nasal cavity and potential for increased absorption. Indeed, when applied as drops or a spray into the nose at 37  C, the polysaccharide forms a gel which is able to decrease the nasal mucociliary clearance rate and, to some extent, allow sustained drug release. Chitosan derivative such as N-[(2-hydroxy-3-trimethylammonium)propyl]chitosan was used by Wu et al. (2007) with PEG. Trimethylchitosan was considered with PEG and glycerophosphate with a sol-gel transition at 32.7  C (Nazar et al. 2013). But some drawbacks were pointed out such as congestion or sensitivity of the nasal mucosa or the obstruction of air flow (Kaplan et al. 2018). To overcome these problems liposomes were successfully tested with chitosan gels including ovalbumin.

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In emulsions chitosan plays the role of an absorption enhancer as mentioned by Bahadur and Pathak (2012). Specific chitosan-based formulations were elaborated as conjugates. Curcuminchitosan nanoparticle complex was prepared according to a method based on selfassembly drug-polysaccharide complexation (Yu et al. 2016). The complex is formed by electrostatic attractive interactions between curcumin and oppositely charged chitosan; soluble complex was obtained. Due to hydrophobic interactions among the bound curcumin molecules, aggregates of the complex were formed after which they precipitated upon reaching a critical concentration to form the final materials. This will allow developing dry powder aerosol formulation of this complex exhibiting strong aerosolization efficiency. Another concept of drug-polymer conjugate is characterized by a hydrophilic polymer backbone as a vehicle and a bioactive agent that is usually bound to the polymeric scaffold via a biological response linker (Marasini et al. 2017). One advantage is the ability to change the pharmacokinetic and biodistribution behavior of the loaded drug (Larson and Ghandehari 2012). Different examples of such conjugates are published during the last years. L-leucine was conjugated to chitosan to provide a potentially improved pulmonary delivery system for the model drug diltiazem (Mushin et al. 2014). Isoniazid was conjugated to chitosan derivatives as N-(2-carboxyethyl)chitosan or to N-(3-chloro-2-hydropxypropyl)chitosan (Berezin and Skorik 2015). Such complex may be formed using two oppositely charged polysaccharides such as chitosan and chondroitin sulfate (Rodrigues et al. 2015). They may form nanoparticles as carriers for transmucosal delivery of biopharmaceuticals. Associated with insulin as a therapeutic protein, the results suggest good indications on their application in respiratory transmucosal protein delivery. Combination of chitosan, presenting mucoadhesive properties, and chondroitin sulfate, endogenous of the lung, shows a great interest of theses formulations for pulmonary and, generally, respiratory drug delivery applications. Chitosan can help in preparing vaccines either against respiratory diseases such as caused by influenza virus (Dehghan et al. 2014; Spinner et al. 2015) or nasal vaccines such as against hepatitis B virus (Jesus et al. 2016). One of the promising and successful steps toward amendment of nasal vaccines is the incorporation of the antigen into mucoadhesive, biocompatible nano- or microparticles and antigen delivery in the form of powder. The dry powder nanoparticles contain bioadhesive polymers which absorb water on the surface of mucosa, swell and become gel-like, increasing the residence time of the drug entrapped inside formulation on the mucus layer. Dehghan et al. (2014) prepared chitosan nanospheres by ionic gelation with tripolyphosphate and they were intranasally administrated. Jesus et al. (2016) prepare poly(ε-caprolactone) (PCL)/chitosan nanoparticles as a mucosal vaccine delivery system against hepatitis B virus. In vitro studies demonstrated that these nanoparticles were retained in a mucus-secreting pulmonary epithetial cell line and were able of entering into differentiated epithetial cells. These nanoparticles were prepared by the nanoprecipitation of a PCL solution into a chitosan solution. It was demonstrated that the zeta potential of the vaccine formulation has a great influence on the generation of the immune response.

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Delivery of drug directly to brain is a requirement in the intervention of various central nervous system diseases and problems like Parkinson’s or Alzheimer’s disease, meningitis (Phukan et al. 2016). But one of the main problems is the impervious nature of the blood-brain barrier which does not allow easy transport of hydrophilic and large molecules (Pardridge 1999). Direct transfer of drugs from nose to brain allows overcoming this problem. Wang et al. (2008) prepared chitosan nanoparticles loaded with estradiol using ionic gelation. Experiments proved that intranasal administration leads to higher drug concentration than after intravenous administration. Similar results were obtained by Fazil et al. (2012) with rivastigmine for treatment of Alzheimer’s disease. Other drugs were considered with similar efficiency due to the mucoadhesion of chitosan. Chitosan was also used to treat animals. Mokhtar et al. evaluated hydrophobic chitosan based particulate formulations of porcine reproductive and respiratory syndrome virus vaccine candidate T cell antigens (2017). The hydrophobic derivative was octanylchitosan and use of chitosan was due to the fact that it may offer an inherent adjuvant effect through binding the innate immune sensor. In the same domain, N-2-hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) and N,O-carboxymethyl chitosan (CMCh) were considered as adjuvant and delivery carrier for vaccine antigens (Zhao et al. 2017). Encapsulation of infectious bronchitis vaccine into the nanoparticles was performed with a polyelectrolyte complex method between N-2-HACC and CMCh and they were intranasally administered to chickens. They induce humoral, cellular and mucosal immune responses.

7.3.6

Cardiovascular System

The circulatory system is responsible for the flow and distribution of blood, nutrients, hormones throughout the body, allowing oxygenation of cells and elimination of residues. The cardiovascular system consists of the following components: 1. the heart – that is similar to a pump that provides the blood irrigation of the entire body allowing the distribution of oxygen and nutrients in all body tissues; 2. a vast network of vessels: arteries, veins and capillaries that irrigate the body. The diameter of the vessels decrease progressively from the heart to the extremities of the body; 3. blood – a special tissue of human body which is in liquid form. The blood consists of blood cells (red blood cells, white blood cells and platelets) and plasma, a watery portion of blood that represents about 55% of the blood volume. The heart may be affected by many diseases, the mortality rate of cardiovascular diseases being extremely high. Thus, every year more than 17.5 million people die of cardiovascular diseases (Huang et al. 2018). The effect of chitosan on cardiovascular diseases is manifested by:

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• activation of vascular cells by restoring the elasticity of blood vessels and repairing the walls of damaged vessels; • activation of the red blood cells that are responsible for the oxygen transportation to the body cells and delivery of carbon dioxide to the lungs; • to promote the cholesterol decomposition. Chitosan is a special source of fibres, which contains carbohydrates and proteins of animal origin. Chitosan binds to dietary fats and can block the fat absorption leading to lowering cholesterol levels and weight loss. The presence of high cholesterol levels in the body can cause the development of the plaques in the arteries that can inhibit the blood flow and thus increasing the risk of cardiovascular diseases. The hypercholesterolaemic effect of chitosan has been studied with chitosan having different physicochemical properties such as, degree of deacetylation, particle size and molecular weight. Based on the obtained results it was observed that the chitosan samples with higher degree of deacetylation and molecular weight possess the ability to reduce plasma triglyceride, total cholesterol and low-density-lipoprotein cholesterol (know as “bad” cholesterol) level and increase the high-densitylipoprotein cholesterol (called “good” cholesterol) level. Also, the chitosan with smaller particle size had better cholesterol binding capacity. From the point of view of the hypercholesterolaemic mechanism it has been found that it occurs by adsorption, electrostatic forces and entrapment (Liu et al. 2008). Hypertension is one of the major risk factors that is responsible for the development of cardiovascular disease, myocardial infarction, stroke, peripheral artery disease and renal failure. It is well known that a high level of sodium chloride in food leads to increase the blood pressure in humans causing the appearance of hypertension. Kato et al. (1994) examined the effect of dietary fibres containing alginic acid and chitosan on the hypertensive action of NaCl. Oral administration of chitosan inhibits and prevents the increase in the systolic blood pressure of humans as well as inhibits intestinal adsorption of chloride that is an activator of angiotensin converting enzyme. Moreover, to control hypertension, the polymeric nanoparticles based on chitosan offer the opportunity to protect the pH-sensitive antihypertensive drugs enhancing their oral bioavailability by preventing first-pass metabolism (Alam et al. 2017). Niaz et al. (2016a, b) developed the antihypertensive nano-carrier systems based on hydrophilic carriers of natural origin (chitosan) in order to improve drug solubility, their protection and sustained release of drugs. The drugs employed in this study were: captopril (angiotensin converting enzyme inhibitor), amlodipine (calcium channel blocker) and valsartan (angiotensin II receptor antagonist). Among these drugs, captopril presents a very good compatibility with chitosan and has shown high encapsulation efficiency in chitosan nanoparticles. From FT-IR spectra it was observed that captopril and valsartan were reacted with chitosan through interactions between OH groups belonging to drugs and NH group of chitosan, while amlodipine interact only with OH group of chitosan. The chitosan nanoparticles can be a solution to increase of oral bioavailability of antihypertensive drugs. The captopril, valsartan and amlodipine were encapsulated by the same authors in polyionic hybrid nanoparticles based on chitosan and sodium alginate (Niaz et al.

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2016a, b). These systems can help in the treatment of hypertension by reducing the dosage frequency as well as the side-effects associated with antihypertensive drugs such as, hypotension, edema, dry cough, diarrhoea and nausea. Atherosclerosis, diabetes mellitus, osteoporosis, rheumatoid arthritis, cancer, hypercholesterolemia, cardiovascular and neurodegenerative diseases are common diseases that affect the older people in particular (Kerch 2015). In the pathology of these diseases the oxidative stress and chronic inflammation are the major risk factors. It was demonstrated that chitosan is a natural polymer that has an antioxidant effect in systemic circulation by reduction of the indices of oxidative stress (Anraku et al. 2009). The novel conjugates with different grafting ratios based on chitosan and hydroxycinnamic acids such as, caffeic, ferulic and sinapic acids were studied for their antioxidant activities. The antioxidant activity of conjugates has been improved compared to the unmodified chitosan, leading to the conclusion that the antioxidant property of chitosan was improved via the conjugation with hydroxycinnamic acids (Lee et al. 2014; Liu et al. 2014). A macromolecular hydrogel carrier in the bead form based on N-succinyl chitosan and alginate was prepared by Dai et al. (2008b) using the ionic gelation method. The drug chosen for this study was nifedipine, a medication used in the treatment of angina, high blood pressure and Raynaud’s phenomenon. The influence of various parameters on the swelling process was studied in order to find and select the suitable nifedipine delivery system.

7.3.7

Vaginal System

The vaginal cavity has a low permeability to the absorption of drug substances compared to other mucous membranes. It is commonly used to administer drugs directly into the vagina and generally performs a local action, but at the same time it allows the substance to pass through the walls of the mucosa, causing a systemic and sometimes even toxic, unexpected action, inducing significant side effects, especially in the event of local injuries (Hussain and Ahsan 2005; Popovici and Lupuleasa 2017). Currently, the vaginal lumen is used as a route of drug administration to obtain a local effect for the treatment of vaginally localized diseases (e.g., sexually transmitted diseases, fungal and bacterial infections, hormonal imbalances and even cancer), and a systemic effect. Drugs absorbed into the vaginal mucosa bypass the first hepatic passage, therefore, by metabolism, avoiding a series of inactivations. These particular properties of vaginal absorption make this way interesting also for peptidic drugs such as calcitonin, oxytocin, insulin, human growth hormone and its derivatives. Moreover, some enzymatic degradation due to endopeptidases and aminopeptidases can occur at the mucosal surface further reducing bioavailability. However, obtaining a locally effective therapeutic concentration in the vagina is a challenge due to the high permeability of the vaginal epithelium. (Nappi et al. 2006; Ensign et al. 2014). In addition, conventional vaginal formulations such as solutions, creams, foams, and pessaries can migrate from the

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vaginal lumen, a phenomenon that produces large variations in the drug delivery kinetics of the drug at the specific location. The vaginal discharge occurs involving endometrial fluids, Bartholin glands secretions and transudates through the epithelium, and contributes to the removal of the formulation from the application site (Bonferoni et al. 2008). The direct transport from vagina to uterus is called “the first uterine pass effect” and represents a potential way for uterine targeting. The use of mucoadhesive polymers for the development of drug administration, carrying and releasing systems helps to reduce the risk of displacement of the intravaginal system, thus leading to optimization of therapeutic efficacy. The bioadhesive properties of the pharmaceutical forms obtained with these polymers assure a sustained in-situ drug delivery, a prolonged residence, and a more intimate contact with the vaginal mucosa. (Acarturk 2009; das Neves et al. 2014). In order to obtain bioadhesive vaginal pharmaceutical forms, there are used both natural hydrophilic polymers, among which starch, collagen, chitosan, gelatin, xanthan gum, alginates, cellulose derivatives, and some synthetic polymers such as polyethylene oxides and polyacrylic acid derivatives (Valenta 2005). Its cationic character represents a defining role in using chitosan as forming agent for a controlled-release mucoadhesive delivery system. Thus, chitosan is the first choice polymer for association with anionic drugs (e.g., naproxen) or even polyanionic ones, when the interactions between chitosan and the therapeutic agent are broader (Bhise et al. 2008). In recent years, nanoparticulate therapeutic systems have been extensively researched as intravaginal drug administration and release forms because nanoparticles can lead to prolonged and targeted release, and may exert an intrinsic antimicrobial effect favoring potentiation and increasing the therapeutic efficacy of the system, especially in the treatment of local fungal or bacterial infections (Mallipeddi and Rohan 2010). The main disadvantage of mucoadhesive nanoparticles is that they do not provide a uniform distribution throughout the vagina, and generally have a reduced residence time due to the clearance of the luminal mucus layer (Ensign et al. 2012). It has been shown that chitosan is the optimal polymer for obtaining vaginal delivery nanoparticles by maximizing mucoadhesion on vaginal epithelial cells in a study conducted by Meng et al. on development and characterization of nanoparticles with tenofovir, an antiviral agent (2011). Good results have also been obtained in the preparation of cefixime-loaded chitosan-based and alginate-based microspheres, a third generation cephalosporin antibiotic highly active against a broad range of Gram-negative and some Gram-positive aerobic bacteria clinically used in the treatment of various urogenital infections. The results have shown that the association of chitosan with alginate increases both the mucoadhesive capacity as well as the loading capacity of the particle system and the antibiotic delivery time, in virtue of the formation of interactions between alginate carboxyl groups and chitosan amine groups. Moreover, a possible antibacterial action of chitosan has been reported, which could be particularly useful giving a synergic effect with cefixime (Goy et al. 2016; Maestrellia et al. 2018). However, the use of chitosan-based mucoadhesive formulations in the treatment of chronic conditions has to be seen with caution (Bernkop-Schnürch and Dünnhaupt 2012).

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Benferoni et al. demonstrated that chitosan citrate and chitosan hydrochloride have the ability to be multifunctional polymers in vaginal formulations. Thus, both chitosan salts have been shown to act both as gel forming agents, and as absorption promoters at vaginal level, both poorly permeable drug molecules such as ayclovir and ciprofloxacin, and Fluorescein isothiocyanate dextran MW 4400 selected as a drug model for high molecular weight hydrophilic molecules. Moreover, chitosan citrate exhibited strong inhibition of Zn-dependent peptidases carboxy and amino peptidases. The chelating properties of the citrate molecule are enhanced after interaction with the chitosan chains. These interactions are dependent on the pH of the environment. Thus, the pH of the mildly acidic vaginal mucosa of about 4–5 is favorable for the ionization of both chitosan and citric acid molecules, thus creating favorable conditions for maximizing these interactions (Shu et al. 2001; Bonferoni et al. 2008). The effect of the chitosan-based gel absorption promoter along with 5% dimethyl-β-cyclodextrin was also demonstrated for the insulin molecule within a research performed in vaginal mucosa rabbits. These studies support once again that insulin could be administered with good results on other alternative routes to the parenteral route (Degim et al. 2005). Biomucoadhesive tablets are commonly used to achieve a local mucosal effect because they provide prolonged release of the drug, reduce the frequency of administration, and have good compliance with the patient. Chitosan is a polymer that can be processed by direct compression, which provides it with a pharmacovigilance. Furthermore, some chitosan derivatives increase membrane permeability and act as promoters of drug absorption. Sandri et al. has shown that 5-methyl-pyrrolidinone chitosan is a chitosan derivative with optimal vaginal bioadhesive properties, also having an acyclovir absorption promoter effect. The capability to enhance the permeation/ penetration of acyclovir was reduced by partial depolymerization of chitosan and disappeared after partial reacetylation (Sandri et al. 2004). The strong mucoadhesive properties of 5-methyl-pyrrolidinone chitosan have also been demonstrated in the gel pharmaceutical form. Perioli et al. (2008) in a study evaluating the mucoadhesive performance of vaginal gels, have shown that the chitosan gel has a mucoadhesion superior to the gel prepared with hydroethylcellulose, and the mucoadhesion strength of 5-methylpyrrolidinone chitosan increases directly proportional to the concentration of the polymer from the formula. Mucoadhesive chitosan lactate gels, based on medium and high chitosan viscosity grades, were developed for the controlled release of lactic acid onto vaginal mucosa for the maintenance of acidic vaginal pH. Chitosan medium molecular weight showed better mucoadhesive properties, likely due to the less rigid structure of the gel. This study evidenced an interaction between polymer molecular weight and lactic acid concentration both for mucoadhesion and lactic acid release response. Lactic acid release occurred partly by diffusion and partly by a displacement mechanism. The release of lactic acid from these gels occurred over 7 h. Increasing chitosan molecular weight retarded release, while increased lactic acid loading accelerated release rates from the pharmaceutical dosage form (Caramella et al. 2015).

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In local vaginal therapy, chitosan has shown efficacy by using clotrimazole coated liposomes as coating agents. Ex vivo tests on the pregnant sheep vaginal tissue have shown that chitosan coated liposomes versus uncoated liposomes showed a better vaginal retention time, a prolonged release, but low penetration compared to the control (Jøraholmen et al. 2014). In conclusion, although chitosan and its derivatives are relatively poorly studied in vaginal formulations, considering the bioadhesive and absorption promoter properties of this polymer, it is to be understood in the future that chitosan is one of the most important multifunctional biopolymers used to obtain vaginal pharmaceutical forms with an increased local bioavailability and an improved therapeutic effect.

7.3.8

Renal System

The main components of the renal system, also known as urinary system are: two kidneys, two ureters, the bladder, two sphincter muscles and the urethra. The functions of the renal system are: • to regulate blood volume, blood pressure and pH of the blood; • to controls levels of water and minerals (sodium, potassium, calcium and phosphorus) in blood; • to remove the urea and uric acid from the body; • an important role in the production of red blood cells in the bone marrow by secretion of erythropoietin; • contribution to the synthesis of calcitriol, the hormonally active metabolite of vitamin D. Chronic kidney diseases also, called chronic kidney failure affect more than 36% of patients over 65 years of age (Ketteler et al. 2013) and represent gradual deterioration of kidney functions. The major metabolic dysfunctions that contribute to the development of chronic kidney diseases are: hyperphosphatemia, hyperazothemia, metabolic acidosis, hyperkalemia, renal anemia, renal osteodystrophy, cardiovascular disease, dialysis-related amyloidosis, hyperhomocysteinemia and endothelial dysfunction (Cibulka and Racek 2007). Hiperphosphatemia represents the increase of phosphate levels in plasma due to the reduction of glomerular filtration rate. Chitosan can reduce phosphatemia by reducing the phosphorous absorption at intestinal level. Chitosan-loaded chewing gum (HS219) is three layer system containing 40 mg chitosan that has the role to bind salivary phosphorus in the mouth (Akizawa et al. 2014). This system was administered in haemodialysis patients with hyperphosphatemia for 30 minute, three times a day for 3 weeks and was compared with traditional phosphate binders such as calcium carbonate or sevelamar hydrochloride. The authors were showed that the HS 219 system does not affect serum and salivary phosphorus level in haemodialysis patients with hyperphosphatemia.

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Zhi et al. (2015) investigated the effects of low molecular weight chitosan on the adenine-induced chronic renal failure in rats. Based on in vitro and in vivo experiments it was found that chitosan with low molecular weight can promote the proliferation of renal tubular epithelial cells as well as slow down adenine-induced renal tissue damage, leading to the conclusion that chitosan can be applied to repair renal failure. Because chitosan oligosaccharide has antioxidant activity and anti-inflammatory effect it can have an influence on renal function, renal oxidative stress and inflammatory response in the glycerol – induced acute renal failure (Yoon et al. 2008). The chitosan can be administered as 30 tablets/day containing 45 mg chitosan/ tablet in diet of patients with chronic renal failure undergoing haemodialysis treatment. After treatment the following conclusions can be drawn: – the total serum cholesterol and lipoprotein levels were significantly reduced; – the serum urea and creatinine levels were also reduced; – the increase of the level of serum hemoglobin (Jing et al. 1997). The diseases affecting the urinary bladder are cystitis, urinary incontinence, overactive bladder, interstitial cystitis and bladder cancer. Intravesical drug delivery is a more effective drug administration technique comparative with the conventional treatment via systemic administration (GuhaSarkar and Banerjee 2010; Erman and Veranic 2018). This method consists of instillation of drugs through a catheter directly into the bladder and presents some advantages such as, high concentration level of drugs at the disease site and reducing the risk of systemic side-effects (Hsu et al. 2013). Chitosan has excellent properties that recommend it to be used in intravesical delivery: biocompatibility, biodegradability, polycationic nature, presence of amine and hydroxyl groups in its structure and mucoadhesive properties (Eroglu et al. 2002; Kolawole et al. 2017). Chitosan-thioglycolic acid conjugate nanoparticles were incorporated in 2% chitosan gel or poloxamer gel in order to obtain intravesical delivery system of gemcitabine hydrochloride (Senyigit et al. 2015). The nanoparticles were showed superior mucoadhesion, higher stability and sustainable release for an extended period of time compared to chitosan particles. A combination between mucoadhesive polymer (chitosan) and thermosensitive polymer (poloxamer 407) was used to obtain an in-situ gel formulation for intravesical administration of ketorolac tromethamine, a nonsteroidal antiinflammatory drug. The optimized formulation adheres to the mucous membrane of the bladder tissue, allowed a continuous flow of urine and has the ability to sustain drug release for 12 h (Sherif et al. 2018). Burjak et al. (2001) prepared microspheres based on Eudragit that were coated with different mucoadhesive polymers (chitosan, carboxymethylcellulose, polycarbophil). Based on the mucoadhesive tests performed on the bladder wall it has been observed that microspheres coated with chitosan exhibits better mucoadhesive properties than those coated with carboxymethylcellulose and polycarbophil.

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Resveratrol, a phytoalexin polyphenolic compound with anti-inflammatory, antioxidant, anti-tumor, antiproliferative and anti-anging effects (Jang and Surh 2003; Alarcon de la Lastra and Villegas 2005) has been utilized to treat the kidney disease. The encapsulation of resveratrol in crosslinking chitosan loaded with phospholipid (Jeong et al. 2016) or in ionically crosslinked chitosan-tripolyphosphate nanoparticles (Wu et al. 2017) can solve the problems arising in clinical applications due to the degradability, low solubility and poor oral bioavailability of resveratrol. The studies indicate that resveratrol crosslinked chitosan nanoparticles modified with phospholipid can be used as delivery systems of neutraceutical and functional food ingredients while the resveratrol loaded chitosan-tripolyphosphate nanoparticles can preserve high antioxidant and anti-cancer activity being used in chemotherapy. Chitosan along with dimethylsulfoxide, nystatin and protamine sulfate have been used as medication for increase bladder urothelial permeability (Giannantoni et al. 2006). Relaxing the ureteral smooth muscle prior endourologic procedures is very important. Thus, by chitosan treatment of the intraluminal surface of the ureter, the following improvements can be observed: • the increase of the nefidipine diffusion across the urothelial barrier; • the increase of urothelial permeability without barrier disruption; • no effect on ureteral contraction (Pick et al. 2011). Tissue engineering scaffolds represents a useful tool in the reconstruction of bladder wall that can be affected either by congenital abnormalities or by other disorders such as, cancer, infection, trauma and inflammation (Atala 2004). Chitosan-poly (glycolic acid) grafts (Drewa et al. 2008) and hydrogels based on chitosan and gelatin (Hajiabbas et al. 2015) were used as scaffolds for reconstruction of bladder wall. It was observed that chitosan improves the poly (glycolic acid) abilities as a cell matrix and enhances nerve regeneration within the bladder wall while chitosan-gelatin hydrogel with intermediate stiffness presents the higher attachment, expansion and proliferation rate of seeded muscle-derived cells. A treatment protocol based on repeated administration of a combination between chitosan and ciprofloxacin was proposed by Erman et al. (2017) in order to eradicate uropathogenic Escherichia coli from infected mouse urinary bladder. The injected mice were treated with 80 μL of 0.5% chitosan solution or 0.5% chitosan and ciprofloxacin solution by transurethral cauterization at 1, 4, 7 and 11 days after inoculation of urophatogenic Escherichia coli cystitis in mouse. The authors showed that repeated administration of chitosan in combination with ciprofloxacin eradicate uropathogenic Escherichia coli from urinary system, presents a fast urothelial regeneration and does not cause the damage of the urothelium.

7.3.9

Bone System

The bone system is the passive part of the locomotor system that performs the movement. The skeletal system is complex, comprising bones, ligaments, cartilage

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which are providing protection and support for the soft parts of the body, and at the same time form tight, hard connections with the skeletal muscles. Defects in any component of this system can negatively impact human life. There are numerous diseases that can affect the skeletal system; the most common comprise rheumatoid arthritis, muscular dystrophy, osteoporosis, osteomyelitis, spondylitis, metastatic bone cancer, metabolic skeletal dysplasia, and infectious bone disease. Generally, due to the complicated anatomical nature and complex network formed by different types of cells, the bone system can be difficult to treat. The design of bone-targeting drugs involves two methods of targeted drug delivery: the first implies the entire skeletal system and the second targets drugs to specific cellular locations within the skeletal system (osteoclasts, bone resorption cells, or osteoblasts, bone formation cell) (Soundarya et al. 2018). However, in spite of recent advances, the drug delivering to its target (in our case the bone) without losing activity and avoiding adverse local effects remain a challenge for scientists. In generally, a material can be any implantable construct or scaffold, intended at providing the microenvironment necessary to promote the replication of natural tissue function. Materials/biomaterials used for potential bone targeted drug delivery system involve synthetic and/or natural, biological components including negatively-charged amino acid peptides or bisphosphonates. Naturally derived polymer such as chitin, chitosan, collagen, gelatin, alginate, hyaluronic acid, dextran, xanthan; respectively synthetic polymers, ceramics, silk fibres, poly(acrylic acid) are used in bone tissue engineering. The use of natural polymers like chitosan or its derivatives for tissue engineering has received a great importance, becoming a promising approach especially for repairing damaged cartilage and bone tissue, due to the fact that are safe, biocompatible, osteoconductive, antibacterial, immune modulator, and promotes bone formation in vivo. Since this date, hydrogels-based chitosan and/or chitosan derivatives continue to interest scientists and are widely investigated and improved through the inclusion of nanoparticles and/or polymers and bioactive molecules (Kamoun et al. 2015). Chitosan based hydrogels display characteristics like softness, bendable and the most important is the fact that implantation of this scaffolds does not initiate remarkable injuries to the surrounding tissues. Thus, chitosan hydrogels have been used as scaffolds for tissue replacements, and drug and growth factor delivery (Dash et al. 2011). Powders, beads, micro-spheres/particles, nanoparticles, gels, films, tablets, capsules, sponges, nanofibrils, textile fibers, and inorganic composites are different forms of chitosan hydrogels for hard tissue regeneration, as in the case of bone and cartilage. Several examples of hydrogels-based chitosan or its derivatives used in tissue engineering will be mentioned below. Chitosan/glycerophosphate (CS/GP) based thermoresponsive hydrogel containing graphene oxide (GO) for healing and regeneration of bone tissue was prepared by Saravanana et al. (2018). The results of this study show that the addition of GO to CS/GP hydrogel improved: gelation time, hydration (swelling abilities), protein adsorption and other biological properties. Moreover, the prepared hydrogel (CS/GP/GO) enables amenable environment for the growth and differentiation of mouse mesenchymal stem cells (mMSCs) and subsequent calcium deposition on mMSCs.

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In another study, Moreira et al. (2018) used chitosan/gelatin/bioactive glass in situ forming hydrogels as matrix for bone tissue engineering. The hydrogels were prepared without the use of crosslinking agents, in aqueous media, and presented a potential as materials able to support drugs or cell encapsulation. The addition of gelatin and bioactive glass into hydrogels lead to better properties such as higher mechanical properties and a short gelation time. The in situ injectable systems were tested from the cytotoxicity point of view, the results of MTT assay indicated that are non-toxic with a cell viability varying from approximately 88  6% to 103  4%. The antibacterial activity and role of N-(2-hydroxyl) propyl-3trimethylammonium chitosan chloride (HTCC) in tissue regeneration was studied. HTCC presented capacity to accelerate the proliferation of human periodontal ligament cells (HPDLCs) even at the lower concentration as compared to pristine chitosan (Ji et al. 2010). As a potential drug delivery system with applications in tissue engineering, an in-situ gelling system composed of glycol chitosan conjugated with 3-(4-hydroxyphenyl) propionic acid was evaluated by Lu et al. (2018) regarding its tissue-adhesive, anti-bacterial and hemostatic properties. In vitro study showed that 70% of amoxicillin incorporated in hydrogel was released in a controlled, slow and prolonged manner during 700 minutes, fact which confirmed the ability of the hydrogel as drug delivery system. By encapsulation of gentamycin, the authors demonstrated that the hydrogel presents antibacterial ability. In vivo hemostatic evaluation demonstrated that the hydrogel applied to a wound in a mouse liver model had the capacity to reduce the bleeding very quickly. The results of the study are very promising and shows that the photo-chemically cross linkable glycolchitosan hydrogel could be used as a tissue adhesive, controlled drug release, and a hemostat material. A copolymer scaffold comprising of poly(vinyl alcohol) (PVA), N-O carboxymethyl chitosan (N-O-CMC) and poly(ethylene glycol) (PEG), physically crosslinked by 50 KGy e-beam radiation, with desirable properties for chondrocyte cultivation was prepared by Lee and Kamarul (2014). Also, the strong crosslinking mediated by the e-beam radiation enhanced the physical properties of the scaffold such as porosity, pore size, and conferred superior swelling properties. Furthermore, the study showed that the incorporation of N-O-CMC into PVA-PEG co-polymers promotes cell adhesion, growth and biosynthesis of cartilage-like extracellular matrix (ECM). In another study, a composite photo-polymerizable gelatin hydrogel incorporating rhBMP-2 loaded 2-N, 6-O-sulfated chitosan nanoparticles (S-NP) to repair critical-sized bone defect of rabbit radius was successfully developed by Cao et al. (2014). Furthermore, the in vivo effect of rhBMP-2-loaded scaffolds in a rabbit radius critical defect was investigated: the treatment significantly increased both peripheral and new vessel formation. Thus, vascularization contributed by BMP-2/ S-NP in the critical defect site and controlled release of BMP-2 led to increased bone augmentation. An et al. (2009) successfully developed nanocomposites-based chitosan graft methyl methacrylate containing silver (Ag) nanoparticles in order to avoid an

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implant-associated infection, and the result showed excellent antimicrobial properties (up to 93–98%) with increased mechanical strength. Other examples of drug delivery systems-based chitosan for tissue engineering are presented below in Table 7.4. All, this perspective allows us to understand the great potential properties of chitosan composites in tissue engineering.

7.3.10 Immune System Since the beginning of its existence, mankind has been confronted with the struggle against disease. In immune-based therapeutic methods, the property that an organism has in order to fight and withstand the effects of pathogens that cause infectious disease, vaccines and sera are used (Popovici and Lupuleasa 2017). These are bio-preparations designed primarily to prevent various infections, and used rarely in therapy to treat infections. The general principle of immunity is explained by the fact that some foreign substances, called antigens and more recently immunogens, introduced into the body, generate in the blood the secretion of some antibodies, which specifically react against them, forming the antigen-antibody complex. Antibodies, specific protein substances, are immunoglobulins (Ig) of the classes: IgG, Ig A, Ig D, Ig M, or Ig F. Antibodies formed lead to an active immunization. On the other hand, pathogenic microorganisms secrete toxic organic substances, called bacterial toxins, causing the formation of antitoxins in the body, also called antitoxic antibodies, in order to neutralize bacterial toxins. Modified microbial toxins may become non-toxic, but preserving antigenic properties, being called anatoxins or toxoids, which will cause the production of specific antibodies in the body leading to passive immunization. It is known that anatomical barriers, such as epithelial and protective skin treatments, provide the body with the first line of defense against invading pathogens. When these barriers are destroyed, the immune response occurs by migrating the immune cells to the invasion site (Flannagan et al. 2009; Moran et al. 2018). These cells secrete a number of cytokines and chemokines that act as messengers and activate the immune response. Myeloid cells, including dendritic cells (DCs) and macrophages, play an essential role in inducing the immune response. These cells use germline coding model recognition to preserve molecular structures on the surface of the microbial cell, known as pathogenic associated molecular patterns or endogenous danger signals, known as molecular models associated with danger when initiating complex signal pathways, leading to inflammation and host defense. An ideal vaccine should be able to induce a reverse response, and provide a fairly long protection against infectious agents, while being safe and well tolerated. The first vaccine formulations were composed of totally inactivated pathogens or attenuated virulence. To avoid virulence and reactogenicity, it has been proposed to use vaccine subunits containing recombinant or purified antigens from the microbe. However, they also have pathogenic characters and after the microbe has been removed, these antigens tend to be less immunogenic.

Hyaluronic acid/ β-sodium glycerophosphate Halloysite nanotubes

Chitosan

Carboxymethyl chitosan

Aldehyde-xanthan

Acid-labile crosslinker

Chitosan

Chitosan

Other component –

Primary polymer Chitosan

Hydrogel

Hydrogel

Hydrogel

Hydrogel

Drug delivery system Nanoparticles

Schiff’s base reaction

Physical mixing

Gelation process

Crosslinking

Preparation method Aggregation method

Bovine serum albumin

Doxorubicin

Doxorubicin

Doxorubicin

Drug encapsulated

Table 7.4 Examples of tissue engineering drug delivery-based chitosan or its derivatives Properties Cytocompatibility; osteochondral bilayered scaffolds can be also developed. Excellent mechanical properties and biodegradability, biocompatibility; pH-triggered drug release at mildly acidic conditions pH sensitive drug release and good affinity to cancer cell Improvement strength; swelling capacity and pore size is decreased after halloysite nanotubes. Biocompatible. Self-healing, cytocompatibility, selfcrosslinking, anti-enzymatic hydrolysis; prevent drug outburst in liquids over the commercial fibrin gel, thus benefitting for wet wounds Regeneration of the abdominal wall defect

Tissue engineering

Cancer treatment

Application Cartilage and osteochondral tissue engineering Drug delivery system

(continued)

Huang et al. (2018)

Huang et al. (2017a)

Zhang et al. (2018a, b)

Hu et al. (2017)

References Malafaya et al. (2006)

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Other component Poly(3-sulfopropyl methacrylate)

Maleic anhydride and thiolterminated poly (vinyl alcohol)

Poly(ethylene glycol)diacrylate

Sodium alginate and polyurethane

Arginine glycine aspartic acid

Primary polymer Chitosan

(methacryloyloxy) ethyl carboxyethyl chitosan

Chitosan-graftedglycidyl methacrylate

Chitosan

Chitosan / hydroxyapatite

Table 7.4 (continued)

Scaffold

Scaffold

Hydrogel

Hydrogel

Drug delivery system Hydrogel

In situ, lyophilization and physical adsorption

Freeze drying

Photopolymerization

Photopolymerization

Preparation method Free radical polymerization

–

–

Amoxicillin

–

Drug encapsulated Bovine serum albumin Properties Efficient template to induce sponge like hydroxyapatite formation; superabsorbent; pH-responsive; used to release BSA. Rapid gelation behavior (under UV), cytocompatibility and supported growth of cells well Improved mechanical properties obtained by encapsulation of bone ash; higher swelling ratio at pH 1.2; cytocompatibility Blended scaffold promoted a higher cell proliferation compared to crude CS when checked in vitro using L6 cell line The osseo integrative ability and biomechanical properties of the scaffold were comparable to that of normal bone tissue. Promoted cell attachment and proliferation. Bone defect repair

Skeletal muscle graft substitute

Tissue engineering and regenerative

Bone tissue engineering

Application Bone tissue engineering

Chen et al. (2015)

Yuvarani et al. (2015)

Aycan and Alemdar (2018)

Zhou et al. (2011)

References Salama (2018)

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Poly(vinyl alcohol) and laponite Fe3O4 nanoparticles

Poly(ethylene oxide)

Chitosan

Chitosan

Nanofibers

Hydrogel beads

Electrospinning

Physicallycrosslinked

–

Bovine serum albumin

Magnetic-responsive beads, high adsorption capacity of BSA between isoelectric point (pI) of BSA and pH of points zero charge of hydrogel beads (pHpzc) of hydrogel beads Good structural integrity in water and exhibited better adhesion of chondrocytes compared to cast film counterpart; Promote the attachment of human cells, while preserving their morphology and viability; Bone tissue engineering

Bone tissue engineering

Bhattarai et al. (2005)

Mahdavinia et al. (2018)

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In order to avoid this inconvenience, the vaccines are often associated with an adjuvant, the substance added to the vaccine increasing the immunogenicity of the purified antigens. Additionally, adjuvants can induce strong immune responses to antigens and reduce both the dosage and the manufacturing price of the vaccine in those who respond poorly to vaccination (Mbow et al. 2010; Wei et al. 2012; Li and Wang 2015; Sun et al. 2018). The use of adjuvants in vaccine formulations dates back to 1925 when Gaston Ramon observed that the toxoid immune response increased much by co-administering agents such as oils, starch and breadcrumbs with titanium and diphtheria toxin (Moran et al. 2018). At the same time, Alexander Glenny is the first to use aluminum salts as an adjuvant, approved in 1932, and currently being the most widely used adjuvant (Moran et al. 2018). Adjuvants that are in use or are in development include aluminum salts, oily emulsions, saponins, immunostimulators, liposomes, microparticles, non-ionic block-copolymers, polysaccharides, cytokines and bacterial derivatives. In recent years, it has been observed that aluminum salts are not good for inducing the mucosal immune system, and mineral oils can cause serious side effects, such as local granuloma, lesions and fever (Heegaard et al. 2011). Many viscous oils are not suitable for injections. More recently, as adjuvants, polysaccharides can increase the immune effect of the vaccine, resulting in specific or non-specific immunity, to cellular, humoral, and mucosal immunity. Natural polysaccharides have immunomodulating properties, biocompatibility, biodegradability, poor toxicity and safety, indicating a great potential for vaccine use. These include chitosan, a cationic polymer derived from the crustacean shell, which shows good biological properties in vivo, low toxicity, good biocompatibility and good degradability (Wang et al. 2014; Saikia et al. 2015); it is a potential material that increases the effectiveness of vaccines. Among the quaternary chitosan derivatives, N-trimethylchitosan is more interesting because it has a permanent cationic charge, it is soluble at different pH values, and it has proved its high mucoadhesive properties and those of penetration promoter. But these last two properties depend on the degree of substitution or quaternization in chitosan. Thus, the mucoadhesive property of chitosan is primarily given by the electrostatic interaction between the positive charge of the polymer and the negative charge of the cell surface of the mucus, which contains significant proportions of sialic acid with physiological pH. Chitosan may activate macrophages and induce cytokine secretion from natural killer (NK) cells (Moran et al. 2018). A newly investigated mechanism indicates the involvement of dendritic cells in the activation of type-I interferon (IFN), resulting in TH1 cellular immune response (Carroll et al. 2016). Chitosan activates the latter downstream pathway, characterized by the absence of pro-inflammatory cytokines; also favors the activation of inflamazom, a multiprotein cytosolic complex, and induces type-I interferon secretion. It effectively stimulates the humoral immune response and that of cell mediator; moreover, it induces natural and adapted immune response; it exposes controlled and sustained

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release effects, which may extend the role of antigens or drug into the gastrointestinal tract. From the immunological point of view, the most effective route of administration of the vaccines is similar to the natural penetration and action of the pathogen, against which we seek specific protection. It is known that the most common routes of entry of pathogens (viruses and bacteria) for infections are mucosal surfaces: nasal, respiratory, oropharyngeal, gastrointestinal, urogenital. As a result, mucosal immune responses play an important role in protecting the body against invading agents. The easiest way to increase immunity is vaccination. Contrary to parenteral vaccination, mucosal vaccination favors not only humoral and cell-mediated immune protection at mucosal sites, but also confers systemic immunity. In addition, mucosal vaccination is carried out easily, with a high compliance of the patient, being possible in a large population (Singh et al. 2018). Generally, vaccines are administered by parenteral routes, by intramuscular, subcutaneous or intradermal injection. In parallel, alternative routes of administration have been developed to avoid discomfort, pain and stress in the patient, and the need for protection against bioterrorism at international level. These methods are also known under the derivation of “needle-free vaccination”. The administration of the vaccines is carried out in the four main ways: – – – –

parenteral routes: intramuscular, subcutaneous, intravenous oral route mucosal routes: nasal, sublingual, pulmonary, ocular, vaginal transcutaneous route (Pavot et al. 2012).

Among all these routes, the research is focused on the mucosal pathways, non-invasive pathways, and mainly via the nasal and oral mucosa, being most effective to induce immunity to sites distant from the mucosal sites. Compared to the oral route, the release of antigens does not confront the pH and enzymes, as such it requires a lower dose of antigens for release. However, the release of vaccines via the nasal route is compromised by rapid mucociliary cleansing, insufficient vaccine intake and poor patient acceptability. A mucosal intake pharmaceutical system of a vaccine must be formulated to provide antigen stability, to have sufficient retention time in the mucosa to interact with the lymphatic system, to ensure controlled release to the cells associated to the immune system and, last but not least, to provide prolonged immunoprotection against the pathogen. Critical aspects in selecting the pharmaceutical form and an adjuvant consist not only in inducing an optimal immune response, but also in maintaining the integrity of physiological functions in the mucosa and avoiding reactogenicity. Chitosan and its derivatives are used in various release systems, depending on the role of the active agent to be released.

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Such release systems include: microspheres, nanoparticles, tablets, capsules, hydrogels and conjugates. The preparation of each releasing system varies, but generally involves precipitation methods or electrostatic or cross-linking interactions (Ali and Ahmed 2018). Mucoadhesive formulations, liposomes and micro- and nanoparticulate systems are the most studied. Chitosan-based particulate systems were prepared by ionic crosslinking between the chitosan derivatives and the anionic molecules of the crosslinking agents. This results in self-assemblies of microparticles or nanoparticles, depending on the molecular weight of the polymers and crosslinkers. Thus, chitosan nanoparticles loaded with insulin and tetanus toxoid for nasal delivery (Singh et al. 2018) were prepared; also for the same pathway and for the subunit influenza vaccine, with good results (Singh et al. 2018). Another pathway consists in chemical crosslinking of antigens with chitosan derivatives to obtain antigen conjugates for mucosal delivery. Crosslinked and non-cross-linked chitosan microspheres were prepared by the spray drying method. To increase water solubility, poly(ethylene glycol) (PEG) was used through a process called PEGylated. It resulted in microspheres which were loaded with Bordetella brochiseptica dermoceratoxin (BBD) antigens and used for nasal vaccination. Other research has been focused on obtaining pluronic F-127 chitosan microspheres for BBD, which have proven a successful release of the vaccine. Also for BBD, mucoadhesive chitosan microspheres were studied for nasal or oral vaccination. Mucoadhesive nanoparticles based on glycol-chitosan have been used for hepatitis B closure and researched compared to plagile-chitosan nanoparticles, having shown a superior response to the latter. For target release, there were used mannosyllated chitosan microspheres prepared using triphenyl phosphate gels and loaded with BBC antigens for the nasal route. Chitosan nanoparticles were prepared for mucosal release of bovine herpesvirus (HBV) and for raising cellular immunity by increasing solubility and bioavailability (Günbeyaz et al. 2010; Sun et al. 2018). To increase encapsulation capacity of hydrophilic drugs, there were used chitosan derivatives with quaternary ammonium groups and amino groups as well as glucuronidated chitosan in order to prepare nanoparticles including hepatitis B virus (Pawat et al. 2013). Chitosan N, O-carboxymethyl (CMCS) is soluble in water, but has negative charges and cannot be associated with antigens. By microsphere encapsulation and crosslinking with amino group carriers, it was used to produce nanoparticles with Vibrio anguillarum. Carbomazepine carboxymethyl chitosan nanoparticles have shown good bioavailability and brain targeting through the nasal route (Pawat et al. 2013). Other studies have published research into nanoparticles based on chitosan against avian infectious bronchitis virus (IBV) (Lopes et al. 2018). Chitosan nanoparticles were prepared by gelling methods in which albumin was incorporated as antigen model and were tested in vitro on Coco-2 cells, and their ability to produce the immune response was tested in vivo (Cole et al. 2018).

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Recent researches evaluate parenteral and mucosal (intranasal and pulmonary) vaccines with chitosan used as carrier, encapsulating BCG vaccine (against Mycobacterium tuberculosis) (Khademi et al. 2018). In the chitosan stimulating effect on the immune response of patients undergoing lung cancer therapy, orally administrated chitosan solutions (Ma et al. 2015; Patil and Nanduri 2017) were investigated. Nasal administrated nanogels for drugs used in the treatment of Alzheimer’s disease, migraine, schizophrenia and depression, as well as vaccines for protection against infections such as influenza, meningitis, pneumonia, and veterinary carrier vaccines are proposed and studied, having chitosan and derivatives as polymers (Aderibigbe and Naki 2018). In conclusion, to improve the efficacy of mucosal delivery, a number of polymerbased formulations have been developed to protect degradation antigens, to increase their residence time on the mucosal surface, to release antigens at specific sites, to target M cells (from the epithelial tissue) and to enter the immune compartments. Of the variety of researched polymers, natural and synthetic, chitosan stood out due to its unique properties.

7.3.11 Auditory System Hearing impairment is the most prevalent sensory disability affecting over 5% of the world’s population, and more than 30% of people over the age of 65, according to statistics in the year 2016. This disease can be caused by some factors such as: genetic defects, environmental factors or a combination of both. These factors induce the damage and death of hair cells and neurons in the cochlea, therefore cellular loss and concomitant hearing loss cannot be reversed. So far, no treatment exist to restore hearing impairment, but only therapies that partially prevent or restore hearing loss. As a consequence, the management of many inner ear diseases remains a challenge for the otolaryngologist. Systemic therapies to the inner ear are ineffective due to physiological and anatomical barriers (e.g round window membrane – RWM) that limit access. The volume of drug that eventually reaches the cochlea after systemic administration is reduced; therefore, high doses are required, but which are at risk of undesirable side effects or toxicity. A breakthrough in the treatment of hearing disorders has been recorded with the understanding of the RWM diffusion properties, and with advances in biomedical nanotechnology. The intratympanic (IT) approach is currently the most effective and promising route for non-invasive delivery of drugs to the inner ear as it allows for the diffusion of various agents, including drugs and NPs through the RWM (Zhang et al. 2011; Buckiova et al. 2012; Roy et al. 2012). In order to increase the effectiveness of the treatment and the safety of drug release, delivery systems based on biodegradable polymers both natural (gelatin, hyaluronic acid, alginate, chitosan, etc.) and synthetic nanoparticles or hydrogels were prepared. The involvement of nanomedicine in the treatment of inner ear diseases is the subject of recent papers (Dong-Kee 2017; Agraharti 2018). Physicochemical

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properties, intrinsic biological activity and lack of immunogenicity and of activation of local inflammatory reactions of chitosan, allowed its use in various formulations (gels, nanoparticles, films) in the treatment of hearing system disorders. A gel based on chitosan glycosilated derivative was proved to be a safe and efficient carrier for inner ear therapy, although it causes the RWM to swell (Saber et al. 2010). A thermosensitive gel composed of chitosan and β-glycerophosphate (CGP), biodegradable by lysozymes, was prepared in order to release drugs in the middle ear. (Paulson et al. 2008; Xu et al. 2010). The hydrogel was loaded with dexamethasone (92%), as a model drug, and was surgical placed in the round window niche of mice. Elevated levels of dexamethasone were detected in perilymph for 5 days. Auditory function testing revealed a temporary hearing loss in the immediate postoperative period, which resolved by the tenth postoperative day. Based on the same type of hydrogel, a formulation containing chitosanase (the enzyme that digests the CGP-hydrogel) was prepared. The result was the rerouting of the loaded drug away from the RWM, effectively downregulating its delivery to the inner ear. The system thus obtained stops the ototoxic effects, providing a novel and salient approach for safe and effective delivery to the inner ear (Lajud et al. 2013). A (CGP) and Ringer’s Lactate buffer (RL) were used, too, as a biocompatible vehicle for local drug delivery; it is a viscous liquid at room temperature but it congeals to a semi solid phase at body temperature. A small volume of this vehicle was precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The authors proved that this procedure is suitable as drug delivery methods into the mouse middle ear (Murillo-Cuesta et al. 2017). Nanohydrogel systems based on CGP containing fluorescein-labeled liposomes have been tested in vivo from the point of view of their release ability (Shayanne et al. 2015). It was proved that the liposomal stability is maintained for over two weeks under physiologic in vitro conditions. For the first time it was demonstrated that CGP-hydrogel-nanoparticle system (nanohydrogel) releases these stable liposomes across the RWM into the perilymph, ultimately delivering their payload to inner ear structures. In a recent published patent (Simons et al. 2014), it is mentioned the possibility of use in various embodiments of some polyelectrolyte complexes such as chitosanchondroitin sulfate complexes as thermo-responsive gelling agents for the inclusion, transport and delivery of drugs specific to the treatment of some inner ear disorders. Besides the criticisms related to injectability, the technological properties of a hydrogel formulation should be also rationalized to minimize any side effects due to a direct interference of hydrogel with the movements of the three ossicles after deposition in the tympanic cavity. Generally, auditory function is recovered within 7–10 days because of formulation washout from the middle ear. In addition to hydrogel systems, nanoparticles can be used as drug delivery through the RWM to the inner ear, because they can offer targeted drug delivery to specific cells in the cochlea, providing certain advantages over conventional drug delivery methods. Nanoparticles (NPs) have been created from a variety of materials, generally

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ranging from tens to several hundred nanometers in diameter. Local administration of nanoparticles charged with drugs has been shown to successfully deliver the active principle into the inner ear via the RWM. Many NP systems have been developed for inner ear drug delivery, including poly(D,L-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs), magnetic NPs, lipid NPs, liposomes, polymersomes, hydroxyapatite NPs, and silica NPs. (Li et al. 2017b). Nanoparticles such as cationic polymers and cationic liposomes offer non-viral vector options for gene therapy delivery, which reduces the immunogenicity, inflammatory responses, and risk of insertional mutagenesis. The literature does not mention the preparation of chitosan-based nanoparticles, its derivatives or its association with other polymers, in order to treat the affections of the auditory system.

7.3.12 Stomatology The oral cavity is the first segment of the digestive system being composed of several anatomic structures, such as: lips, teeth, gingiva (gum), tongue, hard and soft palate, supportive tissues, mucosal membrane lining the inner surface of the cheek; it is constantly flushed by saliva, and is inhabited by diverse microorganisms often existing in resistant biofilms. Being the most important way of accessing the body, good oral health is of major importance for general health and well-being. Diseases specific to oral cavity can be classified into two categories: odontogenic (that originate in the tooth or the closely surrounding structures, such as dental caries or periodontitis) and non-odontogenic (such as mucosal infections) (Nguyen and Hiorth 2015). The most common odontogenic issues are periodontitis and dental carries. Periodontitis is a local inflammation in the periodontal pockets and is caused by dental plaque, and consists in an inflammation in the periodontal pockets, caused by over 800 species of microorganisms existing in the oral cavity while some of them are capable to directly adhere to the oral cavity tissues. Obviously, suppressing the risk of producing periodontitis can be accomplished by canceling the cause or destroying the dental plaque. Chitin and chitosan have long been used with respect to their bacteriostatic and bactericidal actions against a variety of oral microorganisms. These polymers have low toxicity and antimicrobial activity against Porphyromonas gingivalis and Staphylococcus mutans, levels ranging from 100 to 100,000 mg/l and100 to 1250 mg/l (De Carvalho et al. 2011; Shehriar et al. 2017). The authors reveal the antimicrobial effect of chitosan against Staphylococcus mutans, which plays an important role in the cavity, highlighting that chitosan inhibits the bacterial plaque formation and stimulates salivation in vivo. It has been established that low molecular weight chitosan prevents colonization of pathogenic strains (such as S. mutans) on tooth surfaces without disrupting normal oral flora (Tarsi et al. 2007). High molecular weight chitosan it forms a film around the bacterial cells and choking the entry of nutrients to the central metabolic sites. The effect of chitosan against five periodontal pathogens, Porphyromonasgingivalis, Prevotellaintermedia, Prevotellabuccae,

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Tanerella-forsythensis and Aggregatibacter actinomycetemcomitans biofilm formation was studied (Costa et al. 2014) The authors stated that both high molecular weight and low molecular weight chitosan were capable of inhibiting biofilm formation and biofilm associated phenomena. Sub-MIC concentrations of chitosan inhibited single species biofilm formation up to 90% and dual species biofilms formation up to 80%. Furthermore analysis of the effect of chitosan upon quorum sensing showed inhibition values that reached 70% after 24 h exposure to chitosan. Chitosan can be used in different formulations, such as toothpastes, mouthwash solutions and chewing gums. In all these forms, the chitosan has shown antibacterial activity on Streptococcus bacteria groups. It inhibits the bacterial plaque formation and stimulates salivation in vivo, effects that suggest the application of chitosan as preventive and therapeutic agent to control dental caries (Miao et al. 2009; Verkaik et al. 2011; Liu et al. 2006). The classic antimicrobial treatment of periodontitis is the systemic administration of drugs. But the impact of this approach is reduced by the fact that the antibiotic is normally difficult to be maintained in therapeutic concentrations at the site over the course of the treatment period. Therefore, the use of local drug delivery devices containing antibiotics which can maintain therapeutic concentrations at the site of infection is an increasingly exploited approach. A chitosan based film formulation containing ciprofloxacin and diclofenac was proposed (Ahmed et al. 2009). The films are obtained by drying the polymer solution containing the drugs followed by crosslinking with glutaric aldehyde in the vapor state and are characterized in view of their spectral, morphological and mechanical properties. These films were flexible, possessed good tensile strength and demonstrated satisfactory physicochemical characteristics. Although the films showed an initial burst release of drug of more than 40%, release was sustained for days. The authors highlight the advantage of intra-pocket delivery are that administration is less time-consuming than mechanical debridement and a lower dose of drug would be required to achieve effective therapeutic concentration at the site of action. In order to achieve high local bioactivity and low systemic side effects of antibiotics in the treatment of periodontal infections, Khan et al. (2016) proposed a biodegradable system based on chitosan capable to assure a localized controlled delivery system. The physical characteristics of the film depend on the concentration of the solution of chitosan, the plasticizer used (propylene glycol) and the crosslinking agent (glutaraldehyde). The release of drugs (metronidazole and levofloxacin) from crosslinked films showed sustained release for 7 days. The use of combination of drugs has proven to surpass the potential over single drug film and placebo film during antibacterial study and clinical study. The local delivery of both drugs in a sustained release formula enhances the therapeutic effect of SRP as demonstrated by the measured clinical parameters. Physiologically activated in situ gel for local periodontal application were obtained by Gupta et al. (2009). The gel is formed by electrostatic interactions of chitosan and Pluronic F-127, which initial solutions contain procaine hydrochloride. In-vitro drug release profile of the formulation in simulated fluid (pH 7.4) proved a 35.2% cumulative drug release after 2 h, 79.9% after 6 h and 98.6% after 24 h. The

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system gives a stiff gel at mucous pH and body temperature with prolong action that may be helpful against conventional painful periodontal application, where surgical procedure and systemic delivery is required; in addition, the system can be easily packaged and sterilized with method tested with shelf life of 2 years. The polymer/drug systems for treating periodontitis can also be formulated as microparticles, directly administered in the periodontal pocket. Clindamycin is one of the preferred, broad spectrum antibiotics for dental and periodontal therapies, with a bacteriostatic action against gram-positive aerobes. It present an efficient intracellular penetration, efficacy to periodontal disease, and its potential to prevent severe side effects. Spray-dried chitosan microparticles loaded with clindamycin were prepared, and the effect of formulation variables on obtained microparticles was investigated (Kilicarsla et al. 2014). Using glutaraldehyde as a crosslinker increased the viscosity and affected the preparation conditions, mean particle size, and size distribution, but the drug release rate did not significantly change by increasing the amount of crosslinker. It was established that a delayed drug release of more than one week could be obtained despite the high water solubility of clindamycin. For a ratio chitosan/clindamycin of 4/1, antimicrobial efficacy studies indicated that a minimum of 7 days’ sustained antimicrobial activity of drug could be obtained. Among odontogenic disorders, one of the most common diseases that affect the health of teeth is dental caries, which can even lead to their loss if the adequate treatment is not provided. Tooth pastes have for decades been the most important delivery system of fluoride in the combat against dental caries, but other administration systems can also be found such as mouth rinses, varnishes, gels and tablets (Selwitz et al. 2007). Ganss et al. (2011) reported on the commercially available chitosan-based dentifrice (Chitodent®), a non-fluoride formulation, which significantly reduces the tissue loss. Similar results attributed to the cationic nature of chitosan coupled with a low pH, and high affinity for binding to structures with negative zeta potentials such as enamel and salivary pellicles.have been reported while using Sn-based dentifrices (Schlüter et al. 2014). The problem of using fluorinated derivatives is the short action time because of the saliva that dilutes and even removes the active product from the oral cavity thus reducing their bioavailability. The use of bioadhesive drug delivery systems will therefore have a prominent advantage compared with conventional fluoride delivery systems. Microparticles composed of the bioadhesive polymer chitosan, the crosslinking agent glutaraldehyde and fluoride have been investigated (Keegan et al. 2012). The total release time of fluoride was of 6 h, with a fast burst effect. Bioadhesive polymers appear to be particularly attractive for the development of alternative etches free dentin bonding system with an added advantage of additional therapeutic delivery systems to improve intradental administration of therapeutic and prophylactic agents if necessary. Chitosan has been proposed as a bioadhesive polymer due to its unique properties and flexibility in broad range of oral applications. Chitosan based gels with resveratrol, β-carotene or propolis as potential substrate for bonding to dentine were obtained (Perchyonok et al. 2012). The antioxidant-chitosan hydrogels significantly improved bonding to dentine with or

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without phosphoric acid treatment. The pH of the growth medium had a high influence on the cell survival rate of Balb/c mouse 3 T3 fibroblast cells. The release of the antioxidant β-carotene would not have an influence on the pulp cells (Perchyonok et al. 2013). Chitosan has been evaluated for its ability to contribute to dental bone repair. It eases the vascularization of blood vessels and stimulates budding issue (tissue comprising of budding capillaries and fibroblasts) (Chevrier et al. 2007). Spongy chitosan supports the proliferation of osteoblastic cells (Lee et al. 2000b). Zhang and coworkers used chitosan along with mannitol and calcium phosphate cement for bone healing. This new formulation can be used in improving the macroporosity of apatite frameworks, in order to help in reduction of the stress shielding in an implantbone complex, and also in implant life expectancy (Zhang et al. 2006). Chitosan thermosensitive hydrogel loading rhBMP-2 can facilitate regeneration of the periodontal tissue and simplify the surgical operation (Ma et al. 2008). Chitosan scaffold containing an adenovirus vector was used for regeneration of alveolar bone in dental implant defects, and proved to be a good mediator in bone regeneration (Zhang et al. 2007; Ezoddini-Ardakani et al. 2011). Degradation of the dental pulp is a serious condition of the oral cavity, resulting in inevitable loss of teeth. The most currently applied therapy consists of replacing the infected or damaged tissue of the dental pulp with a biological inert material that can attenuate the pain and control the infection. Often, this therapy may fail because of the re-infection of the chamber or the destruction of the tooth, which requires resumption of treatment, usually in the same manner. Moreover, this procedure increases the fragility of the tooth and loss of its vitality due to the fact that the role of the dental pulp is to provide nutrition and to detect potential pathogens. In order to recover these features, the dental pulp needs to be submitted to an effective treatment. Tissue engineering may be an alternative to partial or total resolution of such disorders by creating a biological substitute capable of maintaining, restoring, and improving the functions of dental pulp tissue. The combination of nanotechnology, which allows the preparation of advanced materials with predefine characteristics, and stem cell biology, has opened infinite possibilities in regenerative endodontics (Nakashima et al. 2017). Yang et al. reported the use of dental pulp stem cells cultured on a collagen– chitosan complex and were also able to form a dentine–pulp complex (2012). Moreover, stem cell technology for regenerative therapies is already available as mesenchymal stem/stromal cells (MSCs) already have been introduced in the clinic for alveolar bone augmentation (D’Aquino et al. 2009).

7.4

Conclusions

Considering the structural properties of chitosan and its derivatives, the consequent physico-chemical or applied properties, they are potential candidates for many applications in the domain of drug delivery materials as shown in this chapter. However they are not still developed at a large scale and the steps to be overcome

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are first to be available as reproducible and well characterized compounds as well as the sources (crustaceans, insects or fungi), and second all the biological properties have to be demonstrated. More work will be then performed to extend their domain of applications but their potential as drug delivery device was already clearly shown as versatile characteristics of chitosan are being understood.

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Zhang Y, Thomas Y, Kim E, Payne GF (2012) pH- and voltage-responsive chitosan hydrogel through covalent cross-linking with catechol. J Phys Chem B 116:1579–1585. https://doi.org/ 10.1021/jp210043w Zhang W, Jin X, Li H, Zhang R, Wu C (2018a) Data on the experiments of temperature-sensitive hydrogels for pH-sensitive drug release and the characterizations of materials. Data Brief 17:419–423. https://doi.org/10.1016/j.dib.2018.01.042 Zhang W, Jin X, Li H, Zhang R, Wu C (2018b) Injectable and body temperature sensitive hydrogels based on chitosan and hyaluronic acid for pH sensitive drug release. Carbohydr Polym 186:82–90. https://doi.org/10.1016/j.carbpol.2018.01.008 Zhao J (2012) Chitosan-based gels for the drug delivery system. In: Yao K, Li J, Yao F, Yin Y (eds) Chitosan-based hydrogels functions and applications. CRC Press Taylor & Francis Group, Boca Raton, FL, pp 232–314 Zhao K, Li S, Li W, Yu L, Duan X, Han J, Wang X, Jin Z (2017) Quaternized chitosan nanoparticles loaded with the combined attenuated live vaccine against Newcastle disease and infectious bronchitis elicit immune response in chicken after intranasal administration. Drug Deliv 24:1574–1586. https://doi.org/10.1080/10717544.2017.1388450 Zhi X, Han B, Sui X, Hu R, Liu W (2015) Effects of low-molecular-weight chitosan on the adenineinduced chronic renal failure rats in vitro and in vivo. J Ocean Univ China 14:97–104. https:// doi.org/10.1007/s11802-015-2320-y Zhou J, Lee JM, Jiang P, Henderson S, Lee TDG (2010) Reduction in postsurgical adhesion formation after cardiac surgery by application of N,O-carboxymethyl chitosan. J Thorac Cardiovasc Surg 140:801–806. https://doi.org/10.1016/j.jtcvs.2009.11.030 Zhou Y, Ma G, Shi S, Yang D, Nie J (2011) Photopolymerized water-soluble chitosan-based hydrogel as potential use in tissue engineering. Int J Biol Macromol 48:408–413. https://doi.org/ 10.1016/j.ijbiomac.2010.12.015 Zignani M, Tabatabay C, Gurny R (1995) Topical semi-solid drug delivery: kinetics and tolerance of ophthalmic hydrogels. Adv Drug Deliv Rev 16:51–60. https://doi.org/10.1016/0169-409X (95)00015-Y

Chapter 8

Design of Nano-Chitosans for Tissue Engineering and Molecular Release Sheriff Adewuyi, Iriczalli Cruz-Maya, Onome Ejeromedoghene, and Vincenzo Guarino

Abstract The design of biopolymers such as chitosan is currently a major activity in biomedicine and nanomedicine to fabricate innovative medical devices suitable for therapeutic, diagnostic and orteranostic use. Indeed, the peculiar properties of chitosan such as mucoadhesivity and pH sensitivity make chitosan suitable for drug delivery systems. Chitosan can also be manipulated at the nanoscale, in terms of characteristic size, surface morphology and composition, for the fabrication of nanodevices or nanochitosans with improved properties in comparison with bulk materials of micrometric size. This chapter reviews current uses of chitosan for the fabrication of nanodevices suitable for biomedical applications. We describe the main processing routes used to fabricate smart devices at the nanometric size. Recent applications of nano-chitosans in the form of fibres, particles or capsules for in tissue engineering and drug delivery are then presented. We emphasize the role of additive materials such as magnetic particles with specific functionalities that are able to improve, to control and to guide molecular release in vitro and in vivo. Keywords Nanofibers · Nanoparticles · Electrofluidodynamics · Magnetic Response · Biomedical applications

S. Adewuyi · O. Ejeromedoghene Department of Chemistry, College of Physical Sciences, Federal University of Agriculture Abeokuta, Abeokuta, Ogun, Nigeria e-mail: [email protected] I. Cruz-Maya · V. Guarino (*) Institute for Polymers, Composites and Biomaterials, National Research Council of Italy, Naples, Italy e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_8

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Abbreviations NFs NPs NDs DDA LMW NCs TPP EDFs DNA BMPs MFC-7 MNPs CPA DDS β-CD

8.1

Nanofibres Nanoparticles Nanodevices Degree of Deacetylation Low Molecular Weight Nanochitosans Tripolyphosphate Electrofluidodynamic Deoxyribonucleic Acid Bone Morphogenetic Proteins Michigan Cancer Foundation-7 Magnetic Nanoparticles Cyclophosphamide Drug Delivery Service β-Cyclodextrin

Introduction

The development of nanodevices in the form of nanoparticles and/or nanofibers currently represents one of the most active areas for the applied sciences in biomedicine and nanomedicine. In the form of particles 1–100 nm in size or fibres diameters lower than 500 nm, nanodevices present peculiar properties namely high surface area to volume ratio able to influence significantly physical, chemical and biological properties, and, ultimately, their functionalities in vitro and in vivo (Bronstein et al. 2000). Nanofibres are generally composed of organic, inorganic materials or composites of them, and their confinement at the sub-microscale allows improving specific functional properties (i.e., mechanical response, water permeability, electrical conductivity, etc.) (Elsabee et al. 2012). Likewise, nanoparticles could be formed using metallic or polymeric compounds. In this case, metallic nanoparticles are obtained by the fabrication of metal ions (iron, zinc, silver, platinum etc.) with other materials while polymeric nanoparticles are made of synthetic polymers or biopolymers (Al-Remawin 2012; Adewuyi et al. 2012). In both cases, intrinsic nanodevices properties are mainly determined by characteristic sizes, surface morphology and composition, crystallinity, compared to those of the corresponding bulk materials at the micrometric size scale. Chitosan is a unique cationic amino polysaccharide copolymer of glucosamine and N-acetyl glucosamine obtained by the alkaline N-deacetylation of chitin which is the most important and abundant polysaccharide not including cellulose (Acharyulu et al. 2013; Adewuyi et al. 2017). It is edible, biodegradable, non-toxic, and biocompatible natural polymer. These properties of chitosan make

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it a preferential candidate to receive great attention for numerous applications, i.e., in agriculture, food industry, pharmacy and bio-nanotechnology (Zivanovic et al. 2015).The properties of chitosan are mainly dictated by pH. This is due to the presence of free hydroxyl and amino group in the polymer backbone. At pH lower than 6, the amino groups are protonated and become positively charged, making chitosan a water-soluble cationic polyelectrolyte allowing ionic cross-linking with multivalent anions (Ejeromedoghene et al. 2018). On the other hand, as the pH is increased above 6, chitosan amino groups become deprotonated and the free amino groups are readily available for cross-linking (Akinremi et al. 2016). This inherent physicochemical property of chitosan made it suitable for peroral drug delivery purpose. Ionic interactions between positively charged amino groups in chitosan and the negatively charged mucus gel layer make it mucoadhesive (Assa et al. 2017). The solubility of chitosan is also dictated by the degree of deacetylation, molecular weight and ionic strength of the solution. Low molecular weight (LMW) chitosan which are more soluble are gaining attention in the field of nanotechnology due to their ability to form nanoparticles with amplified properties (Qandil et al. 2009; Obaidat et al. 2010).This affords material with novel characteristics of large surface-to-volume proportion as the key factor to physical, chemical and mechanical properties. Ohya et al. (1993) were the first to describe chitosan in the form of nanoparticles as a drug delivery material when they proposed an anticancer drug based on 5-flurouracil carried by nano-chitosan obtained by emulsification and cross-linking. In furtherance, many researchers have developed new formulations of nano-chitosans including secondary matrix forming materials, employing different preparation methods as depicted in Table 8.1 (Du et al. 2004; Sarmento et al. 2006; Grenha et al. 2010; Grenha 2012). In this chapter, an overview of current technological approaches to designing nano-chitosans is looked into, followed by an extended description of recent applications of nano-chitosans in the form of fibres or particles in tissue engineering and drug delivery.

8.2

Processing Routes

There are several different processing routes for the preparation of nano-chitosans in the form of particles or fibers. Among them, the most significant and diffused ones include gelification, emulsification, and electrofluidodynamics techniques, i.e., electrospraying and electrospinning. Polymer gels or hydrogels have become attractive for biomedical applications, control drug release, cell encapsulation and tissue engineering scaffolds. Chemical or physical methodologies have been used to fabricate chitosans gels at micro sub micrometric size scale (Croisier and Jérôme 2013). Physical gelation of chitosan could be obtained by different techniques based on ionic complexation, pH or temperature variation. In this context, compounds such as β-glycerolphosphate may be successfully used to address the gel formation under controlled thermal conditions. This process is due to the chitosan-chitosan

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Table 8.1 Methods used for the synthesis of chitosan- and composition of the carriers’ matrix Production method Nanoparticles Emulsification and cross-linking Emulsion droplet coalescence Emulsion solvent diffusion Reverse micellization Ionic gelation Polyelectrolyte complexation

Modified ionic gelation with radical polymerization Desolvation

Electrospraying

Nanofibres Electrospinning

Phase separation/ gelation

Matrix composition

References

Chitosan, glutaraldehyde

Songjiang and Lixiang (2009)

Chitosan

Anto et al. (2011)

Chitosan

El-Shabouri (2002)

Chitosan, glutaraldehyde

Manchanda and Nimesh (2010), Tang et al. (2007) Wang et al. (2008), Fan et al. (2012), Sreekumar et al. (2018) Sarmento et al. (2006), Liu et al. (2007), Lin et al. (2008), Bayat et al. (2008), Teijeiro-Osorio et al. (2009), Avadi et al. (2010), Kaihara et al. (2011), Yeh et al. (2011)

Chitosan, tripolyphosphate Chitosan, alginate, arabic gum, carboxymethyl Cellulose, carrageenan, chondroitin sulfate, cyclodextrins, dextran sulfate, polyacrylic acid, poly-γ-glutamic acid, insulin, DNA Chitosan, acrylic acid, methacrylic acid, polyethylene glycol, polyether Chitosan

Chitosan, cellulose derivatives, gellan, haluronan derivatives, dextran sulfate, aliphatic polyesters Chitosan, chitin, cellulose derivatives, haluronanderivates, aliphatic polyesters, polyurethanes Chitosan, gelatin, collagen, cellulose

Hu et al. (2002), Sajeesh and Sharma (2006) Borges et al. (2005), Agnihotri and Aminabhavi (2007), Atyabi et al. (2009) Guarino et al. (2012), Khodir et al. (2013), Guarino et al. (2017)

Guarino et al. (2015), Guarino et al. (2018) Anderson and Jones (2001), Chen et al. (2011)

hydrophobic association in the presence of local increase in temperature. In this case, hydrogen bondstend to be easily formed and the multivalent ionization of β-glycerolphosphatecatalyzes the ion bindings (Chenite et al. 2002; Benamer et al. 2018). Ionic gelation is based on the interaction between positively charged chitosan and polyanions, as sodium tripolyphosphate (TPP). Ionic gelation by dropping TPP to crosslink chitosan nanoparticles creates inter and intramolecular cross-linkages without using high temperatures or toxic crosslinkers as other processes (Mohamed et al. 2017). In comparison with physical mechanisms, covalently crosslinked chitosan stend to form more stable gels, without losing their mechanical and transport properties.

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Different aldehyde crosslinkers can be used to replace hydrogen bonds by stable covalent bonds. The effect of aldehydes is the formation of Schiff’s base with the primary amino group of chitosan D-units. Glutaraldehyde –as reported in several studies (Huang et al. 2011). However, the only partial removal of this chemical compound could induce toxic responses, also decreasing bio-adhesive properties of substrates. Genipin from natural source – i.e., fruits of gardenia plant – is an alternative covalent crosslinker which is often preferred, due to their proved biocompatibility in comparison with glutaraldehyde (Muzzarelli 2009; Karnchanajindanun et al. 2010). As well as aldehydes, genipin reacts with primary amino groups of polymers, forming intermediate aldehyde groups able to react with amino groups of chitosan, so forming a covalently bound network, stable in a basic environment. Noteworthy, Chitosan is a pH sensitive polymer so that the crosslinking reactions among adjacent polymer chains may be drastically influenced by local pH conditions (Mi et al. 2005). An alternative approach to process nano-chitosans involves the use of emulsion process which is based on the creation of two phases at the equilibrium – the aqueous phase, which consists on water and hydrophilic surfactant; and the organic phase which is a homogenous solution of oil, lipophilic surfactant and water-miscible solvent. Single Emulsion has been just widely used to encapsulate essential oils by chitosan nanoparticles in food industry; in the biomedical area. Double or multiple emulsion has been widely explored to encapsulate drugs since an aqueous phase composed of chitosan and bioactive molecules, i.e., for wound dressing and oral delivery applications (Ye et al. 2010; Hasheminejad et al. 2018). Emulsion technique should be optimized using appropriate solvents, oils and surfactants, obtention of nanodroplets depends on the solubility of the organic solvent in water, surface tension, and viscosity (Bouchemal et al. 2004; Shimanovich et al. 2011). However, the main reason of the limited use of emulsion methods is due to the interface between the organic and aqueous phases. Indeed, it plays a relevant role to protect molecules, thus preserving their chemical stability. Moreover, modification of local interfaces by using different surfactants may also contribute to the encapsulation efficiency, influencing the transport mechanisms via diffusion of drugs from one to another phase (Soppimath et al. 2001).Chitosan nanoparticles have been developed by multistep processes based on oil-in-water-emulsion followed by ionic gelation to avoid the use of high temperatures to encapsulate ascorbylpalmitate that can be used as source of vitamin C, cosmetics or in food industry as antioxidant (Yoksan et al. 2010). More recently, electrofluidodynamic techniques (Fig. 8.1), including electrospinning and electrospraying have been used to develop nano-chitosans for tissue engineering and drug release applications (Chakraborty et al. 2009; Altobelli et al. 2016). In the last years, nanofibrous scaffolds have demonstrated to be attractive for tissue engineering, due to the similarity with the structure of the natural extracellular matrix and the possibility to encapsulate molecules or drugs via different functionalization strategies. Electrospinning process is widely using to fabricate fibers from polymer solutions since natural, synthetic polymers, or mixture of two or more polymers in solution.

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Fig. 8.1 Electrofluiodynamic techniques to fabricate nano-chitosan devices. By an accurate setting of process conditions and setup configuration it is possible to fabricate nanofibers via electrospinning or nanoparticles via electrospraying

Electrospinning apparatus consists of a high voltage power supply, a syringe with a steel needle, a syringe pump, and a grounded collector (Altobelli et al. 2016). The process is based on overcoming the surface tension of the droplet at the tip of the needle-syringe to form the Taylor cone, from the polymer solution is ejected to the grounded collector. Electrospinning could be influenced by process parameters, these include voltage, distance, syringe pump flow rate, environment, namely temperature and relativity humidity; and polymer solution properties e.g. molecular weight, solvent, polymer concentration, viscosity, etc. The peculiar chemical features of chitosan make it difficult to dissolve in water solution, but it is required the use of acid solvents as acetic, trifluoracetic, formic, and lactic acids to promote the solubility at neutral pH, as required to process it by electrospinning technique (Ohkawa et al. 2004). Trifluoracetic acid is the best solvent to process chitosan fibers, being able to disrupt the interaction among macromolecular chitosan chains, however it is highly toxic for cells, thus excluding its use for biomedical applications (Hasegawa et al. 1992). Alternatively, acetic acidwater solutions may be successfully used to form fibres minimizing the problems of toxicity. The morphology and average diameters of fibers can be influenced by acid acetic concentration (Geng et al. 2005; Homayoni et al. 2009). Indeed, as the acetic acid concentration increase in the solution, surface tension of chitosan solution drastically decreases while charge density rises up, resulting in the formation of defect-free fibers in the nanometric range. The final morphology of electrospun fibers, is close to those of collagen fibers composing the native extracellular matrix.

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This open interesting scenario for the use of nano-chitosanfibres to form 3D networks able to work as extracellular matrix analogues (Xu et al. 2009). Electrospray technique is widely used to encapsulate drugs into the medium. The technique is based, as electrospinning in apply voltage to a polymer solution until form the Taylor cone. Once formed the droplet, the excess of charge into, is dissipated forming smaller charged droplets that are collected in micro- or nanoscale. As electrospinning, this technique is influenced by the polymer solutions, process parameters and the environment. Chitosan nanoparticles by electrospray have been developed to encapsulate molecules as antibacterial drugs, to avoid infection during healing. Chitosan nanoparticles by electrospray technique are proposed as a good option due to their better efficiency of encapsulation of hydrophilic or hydrophobic molecules, differently to emulsion-based methods and the kinetic release from the particles (Guarino et al. 2016).

8.3

Applications of Chitosan Nanofibers

Nano-chitosans are safe, biodegradable and can work as carriers of molecules, resulting suitable for different biomedical applicative areas i.e., degenerative, inflammatory, and infective diseases, cancer treatments, wound healing and tissues regeneration (Fig. 8.2). In particular, chitosan nanofibers have intrinsic properties as antimicrobial, anti-inflammatory, mucoadhesive, which make attractive for its use in tissue engineering and drug delivery. They have been used to design different innovative devices such as wound dressing, drug release systems or scaffolds for in vitro tissue growth. The high biocompatibility with fibroblasts assures an optimal performance of chitosan nanofibers for wound healing applications (Li et al. 2012). Chitosan nanofibers have demonstrated to be able to inhibit bacterial, algae and fungi growth (Torres-Giner et al. 2008). However, a drastic improvement of chitosan antibacterial properties may solely occur with the addition of selective agents such as poly(hexamethylenebiguanide) hydrochloride into chitosan/poly(ethylene oxide) fibers (Dilamian et al. 2013). Indeed, taking into account the polycationic nature of chitosan able to hinder the polar interactions among ionic groups, it is required the use of more complex setups – i.e., co-axial or dual-electrospinning – for the fabrication highly controlled drug delivery systems (Yuan et al. 2018). Chitosan nanofibers processed by electrospinning can be successfully used in tissue engineering as a function of peculiar chemical features that influence fibre morphology and, ultimately, biological response of cells, as proliferation(Xu et al. 2009; Sarukawa et al. 2011). This is mainly ascribable to the relative amount of amino and hydroxyl groups, and their interactions with native macromolecules like glycosaminoglycans into the extracellular matrix of native tissues. The interaction between cells and chitosan has been confirmed by atomic force microscopy, where other studies confirm a strong affinity between fibroblasts and osteoblast in vitro seeded onto chitosan films (Hsiao et al. 2010). For these purposes, chitosan nanofibers prepared by electrospinning, can be treated via simulated body fluid to

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Fig. 8.2 Main applications of nano-chitosans in biomedical area: nanofibers and nanoparticles can be successfully used for different applications involving cells and/or bioactive molecules

encourage hydroxyapatite to improve the fiber surface osteoconductivity (Van Hong Thien et al. 2013). The increasing interest to bone regeneration has lead search biomaterials with adequate bulk and surface properties. For instance, recent studies confirm the attitude of chitosan nanofibers to incorporate growth factors as bone morphogenetic proteins (BMPs) for bone regeneration. Immobilization of rhBMP-2 in chitosan nanofibers promoted cell attachment and could be suitable for local and prolongate delivery of factors for localized bone formation (Park et al. 2006). Another similar approach involved the encapsulation of simvastatin in chitosan nanofibers to guide in vitro bone regeneration, without adverse reactions(Ghadri et al. 2018). Besides, scaffolds for tissue engineering have to provide topographical cues to regulate the cell interaction, so inducing specific cell behavior towards selected tissue phenotypes. For instance, aligned chitosan/polycaprolactone fibers have been developed to support skeletal muscle cells (Cooper et al. 2010). The muscle cell attachment and proliferation were influenced by the composition and differentiation promoted by nanofiber orientation. A similar approach for nerve tissue engineering have been also explored, resulting on better mechanical properties and hydrophilicity, ascribable to the anisotropic spatial organization of fibres (Karimi et al. 2018). As for drug release systems, primary amino groups of chitosan confer the peculiar cationic character which is required to control the release of anionic drugs (BernkopSchnürch and Dünnhaupt 2012). In this context, the mucoadhesive properties of chitosan may represent a further advantage to design drug delivery systems able to more efficiently retain the drugs at the site of action. Recent studies have focused on the delivery of tetracycline and triamcinolone from chitosan nanofibers as carrier,

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showing an increase of mucoadhesive properties at pH 6, and ultimately, an increase of the drug absorption rate (Behbood et al. 2018).

8.4

Applications of Chitosan Nanoparticles

Nanoparticles do not only have potential as drug delivery carriers, they also offer non-invasive routes of administration such as oral, nasal and ocular routes. Recently, research on chitosan-based nanoparticles for non-parenteral drug delivery is based on the understanding of chitosan properties and methods of chemical or physical modification, which are applied to the optimization of nanoparticle drug loading and release features (Munawar et al. 2017). Studies have shown that the efficacy of many drugs is often limited by their potential to reach the site of therapeutic action. In most conventional dosage forms, only a small amount of administered dose reaches the target site, while the majority of the drug distributes throughout the rest of the body in accordance with its physicochemical and biochemical properties(Tiyaboonchai 2003). Chitosan and its corresponding nanoparticles have been thoroughly investigated broadly in two biomedical fields. Its haemostatic and quickening wound healing properties have been explored in the treatment of wounds, ulcers and burns. In the same vein, its cell affinity and biodegradability have been exploited in tissue regeneration and restoration, as structural material (Vivek et al. 2013). Researchers have shown the application of chitosan nanoparticles as a matrix in drug-release systems, basically in two forms as beads and granules (Fig. 8.3).

Fig. 8.3 Chitosan nanoparticles in drug-release systems. As a function of the peculiar strategies used for the crosslinking of magnetic species, it is possible to design granules or beads – with different size scale and architecture – for different applications in drug delivery

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Beads for Drug Release

This refers to glassy drop of nano-chitosan drug matrix to form a small roundish or spherical material. Chitosan nanoparticles in beaded form are known to possess improved physical and thermal properties. Generally, they can be prepared by blowing chitosan solution through nozzles of predetermined diameter into NaOHmethanol solution by compressed-air (Chandy and Sharma 1992). The generated porous beads can then be washed in water to remove the excess NaOH. In forming chitosan nanoparticles beads, the diameter of the nozzle determines the diameter of the produced beads. For instance, 0.15 mm diameter nozzle can generate 0.18–0.8 mm bead. Several chitosan nanoparticles in beaded form have been used for effective drug delivery. Barreiro-Iglesias et al. (2005),have shown that the amount of loaded metronidazole strongly depends on the composition of the medium and the thermal-hydration history of the beads. Also, pH sensitive chitosan-g-poly(acrylic acid)/attapulgite/sodium alginate composite hydrogel beads was used for the controlled release of diclofenac sodium by Wang et al. (2009). More so, hollow chitosan/poly(acrylic acid) nanospheres have been reported as drug carrier system for doxorubicin by Hu et al. (2007). Recently, a novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels bead was developed for prolonged and sustained controlled drug release (Chang and Xiao 2010). Significantly, the release rate of chitosan nanoparticles bead loaded drug has been found to be slower that its counterpart granular form (Chandy and Sharma 1992). In addition, Saha et al. (2010) prepared chitosan nanoparticles containing ampicillin trihydrate and sodium tripolyphosphate as crosslinking agent using ionic gelation method assisted by sonication produced nanoparticles with good stability. It was inferred that, nanoparticles prepared by incorporating chitosan are usually characterized by polymeric chains that are electrostatically linked as a result of ionic interactions. Entrapment of the drug within the gel network of the chitosan matrix may have made the formulation more stable. Thus, the prepared material was reported to have good compatibility with the entrapped ampicillin trihydrate as there was no clear evidence of interaction between the two compounds. In another study, chitosan nanoparticles and perindopril erbumine loaded chitosan nanoparticles were prepared using the ionic gelation method with tripolyphosphate as a crosslinking agent (Hussein-Al-Ali et al. 2016). The results obtained from the study demonstrated a good combination of perindopril erbumine with chitosan nanoparticles. The nanocomposite exhibited a suitable drug-loading capacity. Moreover, the release kinetics of the nanocomposites show controlled release properties, indicating a good combination of perindopril erbumine with chitosan nanoparticles.

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Granules for Drug Release

Chitosan nanoparticles drug matrixes are free flowing particles produced by spraydrying and/or reverse micellar methods (Kosta et al. 2012). Basically, chitosan along with the drug substance and suitable cross linker are suspended in 1–2% acetic acid and about 5–6% NaOH solution. The matrix is then mixed at high revolution of approximately 600 revmin 1 for 1 h before the addition of CaCl2 solution to coagulate the paste. The resulting mixture can be air dried, ground and sieved to desired particle size (Chandy and Sharma 1992). In reverse micellar method however, surfactant is first dissolved in a suitable organic solvent as reported by Kosta et al. (2012), to produce reverse micelles. Aqueous solution of chitosan and the drug substance are added to the micelles with constant vortexing followed by addition of crosslinker. The chitosan nanoparticles drug matrix can be obtained by evaporating the organic solvent and dispersing the dry mass in water, followed by addition of suitable salt to precipitate the surfactant. The granular form of chitosan nanoparticles drug matrix has been explored for fast release of loaded drugs. The granular form of chitosan nanoparticles loaded nifedipine was shown to release the drug in acidic medium at a faster rate following a first-order release profile (Kosta et al. 2012). This property is attributable to the ionic bond formed between calcium and the hydroxyl groups on the polysaccharide molecule which toughens the granules and provide texture. The textural granules can swell very fast in drug media causing a burst of drugs. Tamoxifen-loaded chitosan nanoparticles were formulated by solvent evaporation and emulsification cross linking method (Vivek et al. 2013). The study revealed a pH-responsive drug release from the chitosan which was significantly accelerated by decreasing pH from 7.4 to 4.0. This mechanism has a particular interest in cancer therapy due to the acidic extracellular tumor environment in the cancer cells. It was also observed that blank chitosan nanoparticles had almost no cytotoxicity, besides, the inhibiting rate of drug loaded chitosan nanoparticles to MCF-7 (Michigan Cancer Foundation-7) breast cancer cells increased with high concentration of the drug. Chitosan-copper-loaded nanoparticles have been prepared and their antimicrobial properties explored (Qi et al. 2004). The nanoparticles obtained were reported to have small particle size and positive surface charges, which may improve their stability in the presence of biological cations and improved antibacterial activities due to the interaction with negatively charged biological membranes and sitespecific targeting in vivo. In order to compare the molecular weight of chitosan with respect to drug delivery property of chitosan nanoparticles, two drug delivery systems of chitosan nanoparticles and ammonium-quaternary derivative of chitosan nanoparticles-doxorubicin matrix of hydrodynamic diameter below 200 nm nanoparticles, have been synthesized (Soares et al. 2016). Evidently, the release of this chemotherapeutic drug used in the treatment of various solid tumors, is independent of the molecular weight. In another study, the smart pH-responsive drug delivery system based on chitosan nanoparticles for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of

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Tamoxifen was explored (Soares et al. 2016). Comparing the pH, tamoxifen was found to be released from the chitosan nanoparticles more rapidly at slightly acidic pH (4.0 and 6.0) than at pH slightly above 7 as a desired characteristic for tumortargeted drug delivery.

8.4.3

Magnetic Systems

Chitosan magnetic nanoparticles are new trend in the field of chemotherapeutics. In terms of constituent, it contains magnetic nucleus used for the delivery of a carrier to a specific site under external magnetic field. Outside the nucleus is the chitosan shell, which basically provides surface functional groups for binding of drug molecules and protects the air oxidation of the magnetic core (Fig. 8.4). With conventional chemotherapeutic agents, there are challenging difficulties ranging from rapid burst, non-specificity and selectivity to aggregation of particles (Honary et al. 2013; Unsoy et al. 2014). However, the emergence of chitosan magnetic nanoparticles has succeeding resolved these entire draw backs. The major parameters in the behavior of are related to surface chemistry, size (magnetic core, hydrodynamic volume and size distribution) and magnetic properties (magnetic moment, remanence and coercivity) (Felton et al. 2014). The magnetic core especially ferrite-based ones (magnetite (Fe3O4), maghemite (Fe2O3), cobalt ferrite (Fe2CoO4)) are of much importance in chitosan magnetic nanoparticles, allowing channeling of the drug towards specific target cells under the influence of external magnetic field (Dresco et al. 1999). The role of chitosan as a result of its important functionalities has been established, especially, its ability to chelate metal ions. This property of chitosan has been explored in magnetic nanoparticles allowing the use of different magnetic cores. Several studies have used iron oxide coated with chitosan for drug delivery. Fig. 8.4 Scheme of chitosan nanoparticles with magnetic core: as a function of the peculiar composition of the magnetic core (Fe3O4, Fe2O3, Fe2CoO4, PtFe3O4 and AuFe3O4), it is possible to guide the transport of drugs or other bioactive species on to the target by the support of external magnetic forces

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Fe3O4nanoparticles coated by alginate/chitosan was fabricated and used for insulin encapsulation by extrusion method (Assa et al. 2017). Also, magnetite nanoparticles coated with chitosan and poly(vinyl alcohol) as cross linker has been synthesized, invariably used in clinical application and drug delivery. Magnetic nanoparticles using chitosan as the encapsulating material for embedding Fe3O4 nanoparticles were prepared in situ in the biopolymer (Galhoum et al. 2015). The composite material was chemically modified and functionalized through successive treatments with epichlorohydrin and cysteine. Mohapatra et al. (2018) reported chitosan microbeads embedded with magnetic nanoparticles, loaded with the antibiotic vancomycin and stimulated by a high frequency alternating magnetic field. Three such stimulation sessions separated by 1.5 h were applied to each test sample. The chromatographic analysis of the supernatant from these stimulated samples showed more than approximately 200% higher release of vancomycin after the stimulation periods compared to non-stimulated samples. Further results demonstrated that the chitosan magnetic nanoparticles responded to stimulus by discharging significant amount of drug compared to control non-simulated samples. It was also observed that they did not respond to general hyperthermia, indicating that any in vivo thermal fluctuations will not affect drug elution. In a special design, Anirudhan et al. (2015) reported the synthesis and characterization of novel drug delivery system using modified chitosan-based hydrogel grafted with cyclodextrin to release curcumin for anti-tumor application. In the study, chitosan coated magnetic nanoparticles with acrylic acid were obtained, after grafting with ethylenediamine derivate of β-cyclodextrin which contains both hydrophilic and hydrophobic moieties in order to encapsulate maximum amount of curcumin. The hydrophilic groups like amide and carboxylic acid groups were used to encapsulate drug through H-bonding interaction and β-cyclodextrin cavities were employed to encapsulate drug through host-guest interactions. It is worth noting the use of metal-magnetite nanohybrid as the magnetic core in drug delivery devices. Glycolic acid functionalized chitosan-Au-Fe3O4 hybrid nanoparticles based nanohybrid scaffold has been successfully synthesized for drug delivery (Kumari and Singh 2013). In this preparation, chitosan-g-glycolic acid and Au-Fe3O4nanoparticle nanocomposite film was initially prepared before the loading of cyclophosphamide drug. This system showed faster and higher drug release as a result of the porosity of the nanohybrid. In the same vein, Pt-Fe3O4nanohybrids has been used as the magnetic core(Kumari and Singh 2012). The inclusion of the nanohybrid particles was proved as viable additive and sustained the molecular release systems.

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Conclusion

Chitosan-based nanodevices or nano-chitosans are largely based on the understanding of chitosan properties and methods of chemical or physical modification, applied to the optimization of nanoparticles drug loading and release features. Studies on nano-chitosans in the form of particles or fibres, confirmed their ability to efficiently encapsulate and release active molecules, such as growth factors, drugs, often limited by their potential to reach specific sites. As for the nanofibers, several studies have demonstrated that chitosan processed in the form of fibres at the nanometric size scale, can be successfully used as scaffolds with multiple functionalities as stiffness, antimicrobial response, pH sensitivity, for cell guidance in vitro and in vivo. As for the nanoparticles, researchers have shown the application of chitosan nanoparticles as smart matrix to release molecules, either in the form of beads and granules as a function of the preparation method, with differences in terms of release kinetics and administration modalities. In this context, the discoveries of new chitosan magnetic nanoparticles – with highly customizable surface chemistry, size, magnetic core, hydrodynamic volume and size distribution, and magnetic properties – is facing the draw backs of conventional chemotherapeutic agents, mainly related to lacks in specificity/selectivity.

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Chapter 9

Chitosan for Direct Bioflocculation Processes Eric Lichtfouse, Nadia Morin-Crini, Marc Fourmentin, Hassiba Zemmouri, Inara Oliveira Carmo do Nascimento, Luciano Matos Queiroz, Mohd Yuhyi Mohd Tadza, Lorenzo A. Picos-Corrales, Haiyan Pei, Lee D. Wilson, and Grégorio Crini

Abstract Coagulation-flocculation is a major process allowing to remove suspended particles from municipal and industrial wastewater. This process commonly involves metal salts as coagulants and synthetic organic polymers as flocculants. Although those chemicals are cheap, efficient, available and easy to use, they have drawbacks such water pollution by metals, and production of large amounts of toxic sludges. Therefore, safer biocoagulants and bioflocculants of biological origin are currently developed. For instance, the direct flocculation process involves water-soluble, ionic organic polymers, and thus do not need the addition of metal E. Lichtfouse (*) Aix-Marseille Université, CNRS, IRD, INRA, Coll France, CEREGE, Aix-en-Provence, France e-mail: [email protected] N. Morin-Crini (*) Laboratoire Chrono-environnement, UMR 6249, UFR Sciences et Techniques, Université Bourgogne Franche-Comté, Besançon, France e-mail: [email protected] M. Fourmentin Université du Littoral Côte d’Opale, Laboratoire de Physico-Chimie de l’Atmosphère (LPCA, EA 4493), ULCO, Dunkerque, France e-mail: [email protected] H. Zemmouri Laboratoire des Sciences et du Génie des Procédés Industriels, Faculté de Génie Mécanique et Génie des Procédés, Université des Sciences et de la Technologie Houari Boumediene, Alger, Algeria I. O. C. do Nascimento · L. M. Queiroz Department of Environmental Engineering, Federal University of Bahia, Polytechnic School, Salvador, Bahia, Brazil e-mail: [email protected] M. Y. M. Tadza Faculty of Civil Engineering & Earth Resources, Universiti Malaysia Pahang, Gambang, Kuantan, Malaysia e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_9

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coagulants. In particular, chitosan and byproducts have been recently designed as bioflocculants to remove particulate matter and dissolved pollutants. Chitosan is a partially deacetylated polysaccharide obtained from chitin, a biopolymer extracted from shellfish sources. Chitosan exhibits various physicochemical and functional properties of interest for many environmental applications. Key achievements of chitosan applications include the removal of more than 90% of solids and 95% of residual oil from palm oil mill effluents. Chitosan highly reduces the turbidity of agricultural wastewater and seawater. Comparison of raw chitosan with modified chitosan, such as 3-chloro-2-hydroxypropyl trimethylammonium chloride grafted onto carboxymethyl-chitosan, to treat a solution of high turbidity (400 mg/L kaolinite) and phosphate (25 mg/L), shows that the modified chitosan decreases the turbidity by 99% and the phosphate content by 97% at all pH, whereas those abatements are below 80% for the raw chitosan. Chitosan also removes toxic Microcystis aeruginosa cyanobacterial cells by 99% and microcystins by 50%. This chapter discusses advantages and drawbacks of using chitosan for direct flocculation for water and wastewater treatment, sludge dewatering, and post-treatment of sanitary landfill leachates. Keywords Chitosan · Bioflocculant · Direct bioflocculation · Wastewater treatment · Sludge dewatering

9.1

Introduction

Coagulation and flocculation are two frequently applied processes in the water treatment industry for solids removal, water clarification, drinking water treatment, decontamination of wastewaters, solids dewatering, sludge thickening, and lime softening (Bratby 2006; Oladoja 2015; Morin-Crini and Crini 2017; Wei et al. 2018). Chemical reagents are often used at the first stage of solids-liquids separation in a wastewater treatment plant to facilitate the removal of suspended and colloidal particles. During wastewater treatment, coagulation and flocculation occur in two main successive steps (Fig. 9.1), namely a destabilization step and an aggregation step L. A. Picos-Corrales Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Blvd. de las Américas y Josefa Ortiz de Domínguez, Ciudad Universitaria, Culiacán, Sinaloa, Mexico e-mail: [email protected] H. Pei School of Environmental Science and Technology, Shandong University, Jinan, China L. D. Wilson Department of Chemistry, University of Saskatchewan, Saskatoon, Canada e-mail: [email protected] G. Crini (*) Chrono-Environnement, UMR 6249, Université Bourgogne Franche-Comté, Besançon, France e-mail: [email protected]

9 Chitosan for Direct Bioflocculation Processes coagulant

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treated wastewater

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filter press

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Fig. 9.1 The coagulation-flocculation process in a physicochemical wastewater treatment plant. An inorganic coagulant such as a metal salt is added at step 1 to alter the physical state of dissolved and suspended solids, in order to obtain complex precipitates of metal hydroxides at the desired pH for precipitation at step 2, and to facilitate further sedimentation at step 4. Precipitation at step 2 is is followed by the addition of flocculants or coagulant aids at step 3 to enhance the treatment efficiency and sedimentation rate by aggregation of microflocs into visible, dense, and rapid settling flocs. The filter press at step 5 allows to filtrate the sludge under pressure in order to separate the liquid phase (filtrate) from the solid phase: the cake

(Bratby 1980; Cox et al. 2007). These processes combine insoluble particles such as solids and colloids, dissolved organic matter, organics, inorganics and microorganisms into large aggregates, thereby facilitating their removal in subsequent stages of sedimentation and filtration. Additional operations include the removal of target substances, i.e. phosphates and oils, color and odor, and recovery of valuable products such as proteins and microalgae. Coagulation-flocculation is also an important phenomenon during sludge dewatering to extract water from the solids. Actually, the disposal or recycling of wastewater sludge, in particular the minimization of sludge volume, is a major challenge for the water treatment industry. Sludge dewatering separates sludge into liquid and solid components, with the aims of waste minimization and cost efficiency of disposal and recycling. Coagulation using a chemical coagulant is a chemical-driven process whereby a given system, solution or suspension, is transformed from a stable into an unstable state. The destabilization step involves charge neutralization. The coagulation aim is indeed to counter the factors that promote the system stability. This step usually involves the addition of chemical reagents, e.g. a coagulant, which destabilizes the suspended solids and pollutants and, in turn, allows their agglomeration, leading to the formation of micro-flocs (Bratby 1980, 2006). Then, bonding these micro-flocs together by the addition of a flocculant, forms larger, denser aggregates that settle rapidly and are easier to separate. Flocculation is the aggregation step. Then, a simple separation step, e.g. settling, flotation or filtration, separates the flocs and produces a clarified water. Overall, flocculation used in conjunction with coagulation is the process whereby the manifestation of destabilization is realized in

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practicable terms (Bratby 1980, 2006). A flocculant aid is a chemical substance added to a coagulated system to bridge the particles together, to form bigger aggregates or flocs in size, to accelerate the rate of flocculation and to strengthen flocs formed during flocculation. This process strongly influences the physical characteristics of flocs, e.g. their size, strength and density. Coagulation and flocculation are sequential processes distinguished primarily by the types of chemicals used and the size of the particles formed. There are two major classes of commercial chemicals used (Fig. 9.2): (1) inorganic and organic coagulants including mineral additives, hydrolyzing metal salts, pre-hydrolyzed metals and polyelectrolytes; and (2) organic flocculants including cationic and anionic polyelectrolytes, non-ionic polymers, amphoteric and hydrophobically modified polymers, and naturally occurring flocculants (Bratby 2006; Bolto and Gregory 2007). Coagulation is mainly induced by metal salts. Common metal coagulants fall into two general categories: aluminium and iron salts. The most common coagulants are aluminium sulfate, generally known as alum, polyaluminium chloride (PAC), ferric chloride, ferric sulfate, and polyferric sulfate (PFS). The addition of these cations contribute to colloidal destabilization, as they specifically interact with, and neutralize the negatively charged colloids (Stechemesser and Dobiáš 2005; Bratby 2006). Their popularity arises not only from their effectiveness but also from their ready availability and low-cost. Flocculants are classified into polymeric inorganic-based products and polymeric organic-based materials (Fig. 9.2). Polyelectrolyte flocculants are mainly linear or branched organic macromolecules. Flocculants can be of synthetic or natural origin. Synthetic macromolecules are based on monomers such as acrylamide, acrylic acid, or dimethyldiallylammonium chloride. Naturally occurring products include starches, celluloses, alginates, gums and other plant derivatives (Levine 1981). The most frequently used flocculants in industrial applications are polyacrylamide-based products such as nonionic polyacrylamides, anionic acrylamide-acrylate copolymers, partially hydrolyzed polyacrylamides, cationic dimethyldiallylammonium chlorides and copolymers of the dimethyldiallylammonium ion with acrylamide. The main advantage is their ability to produce large, dense, compact flocs that are stronger and have good settling characteristics compared to those obtained by coagulation. Polymeric organic flocculants are also easy to handle and immediately soluble in aqueous systems. They can reduce the sludge volume. However, the use of synthetic coagulants and flocculants poses serious environmental and health problems and debates. For instance, the problems often cited are: production of large volumes of toxic sludge, low biodegradability, water pollution by toxic metals, e.g. aluminum salts are connected to Alzheimer’s disease, and dispersion of acrylamide oligomers, which is also a health hazard because the acrylamide monomer is carcinogenic and neurotoxic to humans (Salehizadeh et al. 2018). For these reasons, alternative natural materials, named biocoagulants and bioflocculants, have been developped for wastewater treatment. Among them, chitosan, a partially deacetylated polysaccharide obtained from chitin, deserves particular attention.

- polyaluminium chloride - polyferric sulfate - cationic polyacrylamides - poly(alkylamines) - epichlorohydrin/dimethyl amine polymers - poly(dimethyldiallyl ammonium chloride) - poly(styrene) derivatives - cationic starches

- anionic polyacrylamides - polycarboxylic acids - phosphonic acid polymers - sulphonic acid polymers - sulfated polysaccharides - modified lignin sulfonates - alginates

Anionic Polyelectrolytes

Cationic Polyelectrolytes

Pre-hydrolyzed polyelectrolytes

- coagulant aids

Polyelectrolytes

Polymeric Organic-Based Products

FLOCCULANTS

- polyaluminium chloride - polyaluminosilicate sulfate - polyferric sulfate

Pre-hydrolyzed metals

Organic-Based Products

Polymeric InorganicBased Products

- aluminium sulfate - ferric chloride - ferric sulfate - sodium aluminate

Hydrolyzing metal salts

Fig. 9.2 Major coagulants and flocculants used in water and wastewater treatment

- lime - calcium salts - magnesium carbonate

Mineral Additives

Inorganic-Based Products

COAGULANTS

- polyacrylamides - starches derivatives - cellulose derivatives - tannins

Non-Ionic Polymers

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Chitin is a linear long-chain homo-polymer composed of N-acetyl-glucosamine, characterized by its average degree of acetylation or degree of deacetylation and molecular weight. Chitin is commercially extracted from marine crustaceans, and is considered as a low-cost by-product of the seafood processing industry. Chitosan is a partially deacetylated polysaccharide obtained from chitin and is also characterized by its degree of deacetylation and molecular weight. Chitosan is an aminopolysaccharide which is non-toxic, biocompatible, biodegradable and classified as a green product. Chitosan exhibits a variety of physicochemical and functional properties resulting in numerous practical applications in medicine, pharmacy, cosmetology, food and nutrition, agriculture, agrochemistry, beverage industry, biotechnology, textile and paper industries, packaging, catalysis, and wastewater treatment (Onsoyen and Skaugrud 1990; Peters 1995; Goosen 1997; Kurita 1998, 2006; No and Meyers 2000; Ravi Kumar 2000; Dutta et al. 2004; Rinaudo 2006; Crini and Badot 2008; Crini et al. 2009a, b; Sudha 2011; Ujang et al. 2011; Vakili et al. 2014; Crini 2015; Vandenbossche et al. 2015; Yong et al. 2015; Bhalkaran and Wilson 2016; Agbovi et al. 2017; Arfin 2017; Bonecco et al. 2017; Dima et al. 2017; Wang and Zhuang 2017; de Andrade et al. 2018). Most applications rely on the cationic nature of chitosan in acidic media, e.g. allowing its dissolution in water as a polyelectrolyte, which is unique among abundant polysaccharides and natural polymers. Table 9.1 describes the practical applications of chitosan for environmental purposes, including in water and wastewater treatment. The water-insoluble form of chitosan can be used as biosorbent for the removal of pollutants such as metals and metalloids, dyes, fluorides, pesticides, and endocrine Table 9.1 Practical applications of chitosan for environmental purposes Coagulation of suspended solids, mineral and organic suspensions Reduction of turbidity Flocculant to clarify water, drinking water, pools and spas Flocculation of bacterial suspensions Chelation and elimination of metals Recovery of precious metals Dye removal, elimination of color Removal of pollutants: pesticides, phenols, fluorides, rare earth elements Recovery of valuable products such as proteins Microalgae harvesting Reduction of odors Antifouling agent Polymer-assisted ultrafiltration Sludge treatment, sludge dewatering References: Lee et al. (2014), Liu and Bai (2014), Vakili et al. (2014), Crini (2015), Vandenbossche et al. (2015), Yong et al. (2015), Azarova et al. (2016), Barbusinski et al. (2016), Yang et al. (2016), Crini et al. (2017), Kanmani et al. (2017), Kyzas et al. (2017), Sudha et al. (2017), Desbrières and Guibal (2018), El Halah et al. (2018), Nechita (2017), Pakdel and Peighambardoust (2018), Van Tran et al. (2018)

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disruptors. Biosorption is a process of separation based on the selective complexation of the pollutant molecules by the solid biosorbent. Effective sorption is controlled by specific interactions between the surface of the amino-polysaccharide and the adsorbed pollutants. The main interaction force is chemisorption, i.e. electrostatic attraction, ion-exchange or chelation. Further information can be found in the reviews by Crini (2015), Yong et al. (2015), Bhalkaran and Wilson (2016), Kanmani et al. (2017), Kyzas et al. (2017), Nechita (2017), Wang and Zhuang (2017), Desbrières and Guibal (2018), Pakdel and Peighambardoust (2018), and Van Tran et al. (2018). The water-soluble form of chitosan can be used as a complexing agent in membrane filtration processes such as polymer-assisted ultrafiltration (Ang et al. 2016; Crini et al. 2017; Mohamed et al. 2018). This process involves a step of pollutant complexation by chitosan, then a step of filtration by an ultrafiltration membrane. Here, the macroligand-pollutant complex is held back, allowing purified water to go through the membrane. Crini et al. (2017) recently reviewed the advantages gained from the use of cationic chitosan in the process of complexation-ultrafiltration. The cationic biopolymer chitosan has also drawn particular attention as a flocculating agent for application in water industries due to its biological origin, non-toxicity, eco-friendly character, low cost, and outstanding performances. In this chapter, after a brief description of the main advantages and possible drawbacks of using chitosan as bioflocculant, we highlight selected works on the use of chitosan products for target applications.

9.2 9.2.1

Application of Chitosan as Bioflocculant Coagulation and Flocculation in Wastewater Treatment

Coagulation/flocculation is a common method for the decontamination of industrial and urban wastewaters and for water purification. The advantages are: – technological simplicity, e.g. simple equipment, integrated physicochemical process, well established procedure, easy control and maintenance, – economically advantageous, e.g. inexpensive initial capital cost, relatively low-cost in maintenance, – rapid and efficient, – adaptable to many treatments formats such as primary clarification, pretreatment, and/or final treatment and to high pollutant loads, including sludge treatment, – very efficient for suspended solids, colloidal particles, and turbidity, efficient for biochemical oxygen demand and chemical oxygen demand removal, – significant reduction of the dissolved organic content, total organic carbon, and pollutants such as metals, dyes, pigments, and fluorides, and also efficient for color and odor removal.

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Coagulation and flocculation occur in successive steps (Fig. 9.1). For wastewater treatment, the coagulation-flocculation process can be used at different stages. For instance, coagulation-flocculation as pretreatment consists of eliminating the floating, solid particles and all suspended substances from the effluents. As secondary treatment, coagulation/flocculation may be necessary to remove remaining pollutants produced during the physicochemical or biological treatments. For the treatment of pulp and paper industry wastewaters, chemicals addition is typically done at one or more locations within the wastewater treatment plant, as shown in Fig. 9.3 (Renault et al. 2009a, b, c). For instance, the dosage points are as follows: 1. pretreatment: to remove much of the solids and fibers before the chemical and biological steps; 2. physicochemical primary treatment: coagulation, precipitation and/or oxidation; 3. flocculation and sedimentation using a primary clarifier; 4. biological treatment to treat both biochemical oxygen demand and chemical oxygen demand; 5. flocculation of biomass using a secondary clarifier; and 6. tertiary treatment. Over the range of wastewater pH, of about 7–8, particles nearly always carry a negative surface charge and, as a consequence, are often colloidally stable and resistant to aggregation. A metal salt as coagulant is thus needed to destabilize the particles. Destabilization can be brought about by: – either increasing the ionic strength, giving some reduction in the zeta potential and a decreased thickness of the diffuse part of the electrical double layer, – or specifically adsorbing counterions to neutralize the particle charge. Renault et al. (2009a, c) showed that the coagulation process is not always perfect as it may result in small flocs when coagulation takes place at low temperatures, or produce fragile flocs that break up when subjected to physical forces. To overcome these problems and also to improve the process in order to obtain good quality effluent and rapid sedimentation of the flocs formed, the industry uses a polymeric additive that permits association and agglomeration of the flocs formed by the coagulant. This flocculant can act either by polymer bridging or by charge neutralization, enhancing the formation of larger floc, and improving the rate of sedimentation. Such processes can be done by chitosan because chitosan has specific macromolecular structures with a variety of functional groups, i.e. amino and hydroxyl groups, which can interact with pollutants. From the end of the 2000s, Crini’s group proposed direct bioflocculation using low cost chitosan as a novel approach to treat wastewater from pulp and paper plant (Crini et al. 2009a, b; Renault et al. 2009a, b, c, d). Their works demonstrated that chitosan was able to combine the two functions of coagulation and flocculation in industrial wastewater treatment. Crini thus spoke of ‘two-in-one’ materials (Crini and Badot 2007; Crini et al. 2009a, b).

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Fig. 9.3 Treatment of wastewater from pulp and paper industry. This scheme shows the locations where the coagulant, ‘metal salt’, and the flocculant, ‘polymer’, are added. Noteworthy, a part of the clarified water and all of the sludge formed are reused in the pulp for paper production

Production

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Coagulation-Flocculation Versus Direct Flocculation

Polymeric flocculants such as cationic polymers can be used in direct flocculation processes because they possess dual functions of coagulation and flocculation, i.e. neutralizing the negative charges and bridging the aggregated destabilized particles. Indeed, the direct flocculation using ionic polymers – without addition of coagulants – allows to completely replace inorganic coagulants by water-soluble organic polymers during chemical pretreatments, main treatments or posttreatments. The selection between conventional coagulation-flocculation and direct flocculation is highly depending on the type of wastewater. In general, the applications of direct flocculation using only polymeric flocculants are mainly limited to organic-based wastewater having high concentration of suspended and colloidal solids such as food, paper and pulp, and textile effluents.

9.2.3

Direct Bioflocculation Using Chitosan

In last decade there has been a rapid increase of the use of chitosan as bioflocculant and the development of new chitosan-based materials for direct bioflocculation process, e.g. grafted chitosans, composites and hybrid materials. Table 9.2 refers to reviews on the synthesis, characterization and properties of chitosan-based flocculants and their applications for bioflocculation. Table 9.3 presents selected examples of potential applications of chitosan in water and wastewater treatment, sludge dewatering, harvesting of microalgae and dissolved air flotation. All reports demonstrated that direct bioflocculation is an effective and competitive approach, and that chitosan is a promising bioflocculant for environmental and purification purposes (Chong 2012; Lee et al. 2014; Yang et al. 2016).

9.2.4

Advantages of Using Chitosan as Bioflocculant

Table 9.4 describes the main characteristics and properties of chitosan in relation to its use in flocculation application. They can be summarized as follows: – Chitosan may be produced at relatively low cost. In many countries, fishery wastes are used as excellent sources to produce chitin and chitosan. For applications in wastewater treatment, chitosans are usually offered as flakes or powders with prices that range from 10 to 50 US$/kg, depending mainly on the degree of deacetylation (70% < value < 90%), molecular weight and purity (technical grade) parameters. – Chitosan is a non-toxic, biocompatible and biodegradable resource, and a possible alternative to synthetic polymers as an ecofriendly product. It has also the advantage of being non corrosive and safe to handle, i.e. non-hazardous product, not irritating.

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Table 9.2 Reviews on chitosan-based bioflocculants for bioflocculation-oriented processes Pollution/Pollutant(s) SS, COD, metals, dyes SS, turbidity, COD, TOC, color

Dyes, color Turbidity, COD, color, phosphate, nitrogen SS, turbidity, DOC Arsenic, metals, turbidity

SS, dissolved matter

SS, dissolved matters, TOC Metals SS, turbidity, COD, dyes, color, metals, harvesting and cell recovery, sludge dewatering Harvesting of microalgae Microalgae

Topics Products, mechanism, performance, wastewater treatment Structure-activity relationship, chitosan characteristics, process variables, mechanism, performance, wastewater treatment Products, process variables, mechanism, interactions, performance Chemical modification, hybrid materials, preparation, characterization, operating parameters Products, mechanism, performance Products, chemical modification, chitosan characteristics, self-assembly processes, process variables, mechanism, performance, wastewater treatment Products, chemical modification, structure-activity relationship, chitosan characteristics, process variables, mechanism, performance, water treatment, wastewater treatment, toxicity, cost performance Products, performance, papermaking industry Products, composites, wastewater treatment, performances Chemical modification, preparation, biosynthesis, operating parameters, mechanisms, performances Flotation, operating parameters, performance Products, flocculation strategies, process variables, mechanism, interactions, performance

Reference Crini et al. (2009a) Renault et al. (2009d) Verma et al. (2012) Lee et al. (2012) Oladoja (2015) Bhalkaran and Wilson (2016) Yang et al. (2016)

Song et al. (2018) Kanmani et al. (2017) Salehizadeh et al. (2018) Laamanen et al. (2016) Ummalyma et al. (2017)

SS suspended solids, COD chemical oxygen demand, TOC total organic content, DOC dissolved organic content

– Besides being natural and plentiful, this amino-polysaccharide also possesses other useful characteristics such as hydrophilicity, polyfunctionality, reactivity, complexing and adsorption properties. – Due to their structure, e.g. high molecular weight, and chemical properties, e.g. high cationic charge, chitosan macromolecules promote both chemical coagulation, subsequent floc formation and sedimentation of colloidal particles and/or dissolved pollutants in the effluents through established processes such as charge neutralization, inter-particle bridging, and also adsorption.

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Table 9.3 Applications using bioflocculation by chitosan Potential application Drinking water Municipal wastewater Sanitary landfill leachate Drinking water sludge Municipal activated sludge Lake restoration River water Sea water Fishmeal industry

Algal removal

Chitosan/Flocculation condition(s) Modified: hydrochloride, acetate, lactate Raw powder dissolved in HCl solution Chitosan dissolved in HCl solution at 960 mg/L; pH 8.5 Chitosan (DD 95%)-aluminum chloride in acetic acid solution; pH 8.4 Powder (DD > 75%) dissolved in acetic acid solution; pH 4 Raw powder dissolved in acetic acid solution DD 75–85%; dosage of 1 mg/L; pH 6.7 Powder dissolved in acetic acid solution; 18 mg/L; pH 8.1 Chitosan: pH 6.5, dose 300 mg/L

Algal removal

Quaternized carboxymethyl chitosan pH 8.5

Algal removal

Chitosan-graft-polyacrylamide

Harvesting of microalgae Harvesting of microalgae Harvesting of microalgae Flocculation of microalgae in seawater Aquaculture wastewater from catfish farming Bacterial suspensions Wastewaters from a yeast factory

Flakes (DD: 80%) dissolved in acetic acid solution Raw powder dissolved in HCl solution Chitosan: dose 100 mg/L; pH 7–10 Chitosan (DD: > 75%, dissolved in HCl solution): pH > 7.5, dose 75 mg/L Raw powder dissolved in HCl solution (1 g/L) Raw powder (DD: 86.3%) dissolved in HCl solution Modified chitosan; dose 2 or 3 g/L; pH 3 and 7

Pollution/Pollutant(s) Turbidity, viruses, bacteria Cu, Pb, Ni, Zn, turbidity, organic matter Turbidity, SS, COD, TOC, nitrite, nitrate, color, phosphorus Dewatering, extracellular organic matter Dewatering, SS, VSS, turbidity Cyanobacteria Pb, Mn, turbidity Turbidity SS, VSS

Microalgae, cyanobacterium species Algal colloid particles Microalgae Microalgae suspension, COD BOD, COD Marine microalgae, Mg

Reference Abede et al. (2016) Hargreaves et al. (2018) Nascimento et al. (2016) Ma et al. (2016a, b) Zemmouri et al. (2015) Mucci et al. (2017) Ruelas-Leyva et al. (2017) Altaher (2012) AriasLizarraga and MendezGomez (2014) Dong et al. (2014) Lama et al. (2016) Lu et al. (2017) Gerchman et al. (2017) Sajjad et al. (2017) Gupta et al. (2018) Blockx et al. (2018)

Microalgae

Yunos et al. (2017)

Cyanobacteria

Lürling et al. (2017) Momemi et al. (2018)

Turbidity, SS, COD, color

(continued)

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Table 9.3 (continued) Potential application Agricultural wastewaters Tanning effluents

Chitosan/Flocculation condition(s) DD 75–85%; dosage of 10 mg/L; pH 6.6 Raw product (DD: 85%)

Effluents from the sugar industry

Powder dissolved in HCl solution (138 mg/L); pH 5

Palm oil mill effluent

Chitosan dissolved in acetic acid solution

Palm oil mill effluent Emulsified oily wastewater

Powder (DD: 90.1%) dissolved in acetic acid solution Flakes (DD: 82.9%) dissolved in acetic acid solution, dose 0.793 g/L, pH 4 or 7 Powder dissolved in HCl solution

Effluents containing diesel oil and gasoline Brackish water

Clay suspensions Effluents containing humic substances Effluents containing dyes Effluents containing dyes Solutions containing dyes Plating wastewater Effluents containing metals Effluents containing palladium Solutions containing Cr(VI) Effluents containing dyes and metals

Pollution/Pollutant(s) Turbidity, conductivity SS, COD, TOC, BOD SS, color, COD

BOD, COD, ammonium nitrogen, Phosphate, potassium Turbidity, COD, hydrocarbon content

Turbidity, COD

SS, turbidity

Powder dissolved in acetic acid solution Raw product (DD: 90%) in acetic acid solution; pH 7

Cu, Zn, turbidity

Composite

Color, dyes

Copolymer with starch

Dyes

Powder dissolved in HCl solution (1 g/L) Chitosan dianhydride

Dyes

Mercaptoacetyl chitosan (DD: 80%); pH 4.5; time 2.5 h Sulphur-chitosan; pH 2–5.5, dose 0.8 g/L

Copper, turbidity

Copolymer with starch

Cr(VI)

Carboxylate-rich magnetic chitosan

Dyes, metals

Humic acid, turbidity

Cu, Pb, Zn, Ni, Cr

Pd, metals

Reference Ruelas-Leyva et al. (2017) Sila et al. (2014) Pambi and Musonge (2015) Tadza et al. (2016) Adnan et al. (2017) PérezCalderón et al. (2018) de Oliveira et al. (2016) Lamia and Abdelghani (2017) Ferhat et al. (2016) Chen et al. (2015) Lou et al. (2018) Sami et al. (2017) Wang et al. (2017) MartinezQuiroz et al. (2018) Zhang et al. (2015) Xie et al. (2018) You et al. (2016) Liu et al. (2018) (continued)

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Table 9.3 (continued) Potential application Effluents containing plastics Solutions containing antibiotics Dissolved air flotation process for river water treatment

Chitosan/Flocculation condition(s) Powder (DD: 60%) dissolved in HCl solution (0.1 g/L)

Pollution/Pollutant(s) Polystyrene

Reference Ramirez et al. (2016)

Amino-acid-modified chitosan

Antibiotics, SS, organic matter

Jia et al. (2016)

Powder (DD: 87.8, 76.5 and 75.9%; low and high MW) dissolved in HCl solution (1 g/L; pH 7)

Turbidity, SS, TOC, organic matter

Shi et al. (2017)

DD degree of deacetylation, SS suspended solids, COD chemical oxygen demand, BOD biochemical oxygen demand, TOC total organic carbon, VSS volatile suspended solids, MW molecular weight Table 9.4 Main characteristics and properties of chitosan in relation to its use for flocculationbased application Main characteristics and properties Raw chitosan for water treatment applications: low-cost product (chitin: renewable resource obtained from byproducts) Non-toxic, biocompatible and biodegradable substance Ecofriendly biopolymer; ecologically acceptable product Linear amino-polysaccharide with high nitrogen content; weak base and powerful nucleophile Hydrophilic biopolymer with high reactivity Reactive amino and hydroxyl groups for modification Polyelectrolyte at acidic pH with high charge density: polycationic biopolymer Ionic conductivity Gelation ability; adhesivity; film-forming ability Ability to form hydrogen bonds and other noncovalent interactions Ability to encapsulate; entrapment properties Chelation, ion-exchange and adsorption properties Removal of pollutants or pollutions (color, odor) with outstanding performance Strong adsorption to negative microalgae cells; since the products work as a function of surface charge, the required dosage increases proportionately to microalgae concentration Formation of salts with organic and inorganic acids Efficient against bacteria, viruses and fungi Chitosan is less sensitive to pH changes than metal salts Chitosan has been shown to coagulate microalgae cells very effectively and to produce larger flocs than polyaluminium chloride References: Skjåk-Braek et al. (1989), Roberts (1992), No and Meyers (1995), Peters (1995), Goosen (1997), Kurita (1998, 2006), Ravi Kumar (2000), Domard and Domard (2001), Dutta et al. (2004), Vårum and Smidsrød (2004), Rinaudo (2006), Li et al. (2008), Crini et al. (2009a, b), de Alvarenga (2011), Sudha (2011), Nwe et al. (2011), Teng (2016), Nechita (2017)

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– Chitosan has demonstrated outstanding performance, not only for the elimination of particulate pollutants, i.e. suspended solids and colloids, but also for the removal of dissolved pollutants, even at ultra-trace levels. This product is efficient towards very fine particles. The cationic amino groups on the chitosan chains facilitate their chemical interaction (attraction phenomenon, adsorption) with negatively charged colloids, such as viruses, bacteria and clay turbidity, thereby promoting their coagulation-flocculation and sedimentation, and also pollutant removal by adsorption. Chitosan produces a high-quality pretreated or treated effluent. The alkalinity is also maintained. – Chitosan can be used over a wide range of temperatures. It is efficient in cold water and at much lower concentration than metal salts. – The lower concentration reduces the volume of sludge production compared to sludge obtained with polyaluminium chloride. The sludge can be degraded by microorganisms. – Compared with conventional chemical reagents, chitosan produces no secondary pollution. There are no residuals or metals added such as Al(III) and Fe(III).

9.2.5

Limitations of Using Chitosan as Bioflocculant

Table 9.5 describes the main disadvantages of chitosan used as bioflocculants. They can be summarized as follows: – Despite a large number of studies on the use of chitosan for bioflocculation in the literature, this research field has failed to find practical applications on the Table 9.5 Disadvantages of chitosan-based bioflocculants for water and wastewater treatments applications Technologies are still being developed: to be confirmed at scale up levels The cost limitations still exist: chitosan is considered cost prohibitive to purchase for use as an microalgae bioflocculant Chitosan is not water-soluble: it requires a weak acid treatment to be dissolved; the solubility depends on the degree of deacetylation and molecular weight parameters Variability in the chitosan characteristics and in the materials used; performances depend on type of raw chitosan, chitosan activation and chitosan-based materials Chitosan is a very efficient flocculant but at low pH; pH-dependent behavior The dosage used is in general high; chitosan concentration should be monitored to avoid restabilization (due to excess cationic charge if a high concentration is used) Possible clogging of filters when the doses of chitosan are high Chitosan requires chemical modification to improve its performance, to decrease its pH sensitivity, and to enlarge the field of its potential applications; results depend on the functional groups grafted Bioflocculation using chitosan is not universal to all pollutant types; e.g. it was found effective for green microalgae but gave poor results for cyanobacteria References: Crini et al. (2009a, b); Renault et al. (2009a, b, c, d); Ujang et al. (2011); Lee et al. (2014); Yang et al. (2016); Sudha et al. (2017)

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industrial scale. Indeed, aside from a few pilot studies in aquaculture or in target applications, e.g. recovery of precious metals, bioflocculation using chitosan is at the stage of laboratory-scale study in water and wastewater treatments. It is difficult to get reproducible initial chitosan, i.e. product quality control, and there is a need for a better standardization of the production process. Chitosan is a polysaccharide composed by macromolecules of D-glucosamine and N-acetyl glucosamine. The chitosan label generally corresponds to products with less than 40% acetyl content. So, each commercial chitosan is a copolymer characterized by its average degree of acetylation or degree of deacetylation. Both parameters vary with the source of the raw materials and the preparation method. The degree of deacetylation and molecular weight parameters are important factors because they influence the physical and chemical properties of chitosan, particularly its solubility. Changes in the specifications, e.g. degree of deacetylation, molecular weight, of the chitosan may significantly change flocculation performance. The higher the quality, the greater the cost. A direct comparison of data obtained using different chitosans is difficult to make because of inconsistencies in the data presentation, e.g. specifications of chitosan, used experimental conditions of the effluents treated. Performance is dependent on the characteristics of the wastewater. In particular, uptake is strongly pH-dependent. Chitosan is a very efficient flocculant but it works at low pH. For target applications such as in the microalgae culture fields where pH is generally high, it requires chemical modification. Chitosan also requires chemical derivatization such as grafting reactions or modifications (composite or hybrid materials) to improve its performance, to decrease its pH sensitivity or to enlarge the field of its practical applications. The flocculation performance depends on the different types of material used. For grafted polymer materials, the performance results were found to be a function not only of the nature of the ligands but also of the degree of attachment of the polyfunctional groups. So, the properties of the materials can be varied extensively.

All these reasons can explain why it is difficult to transfer the flocculation process to industrial scale. In addition, a direct comparison of data obtained in the literature using different chitosan-based materials is not possible since experimental conditions are not systematically the same. Comparisons among different commercial flocculants are also scarce. Cost is also an important parameter for comparing the materials. Due to scarcity of consistent information, cost comparisons are also difficult to make.

9.2.6

Mechanism

Similar to classical flocculation, bioflocculation by chitosan involves combining insoluble particles and dissolved organic matter into larger aggregates which can

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Fig. 9.4 Bioflocculation mechanism; (a) charge neutralization, (b) bridging, (c) electrostatic patch and (d) sweeping

be removed in subsequent sedimentation and filtration stages. Chitosan chains first destabilize suspended and colloidal particles in wastewater by forming micro-flocs in the coagulation step. These are then aggregated in the flocculation step, which consists of an agitation procedure that encourages particles to clump allowing their removal in subsequent treatment stages. The mechanism is well-known (Fig. 9.4), mainly driven by charge neutralization and bridging mechanisms. Other mechanisms such as electrostatic patch and sweeping mechanisms adsorption, entrapment, and complexation, chelation, and precipitation processes may also contribute to bioflocculation. Charge neutralization refers to the interaction of two particles with opposite charged ions, whereas sweep flocculation entails the enmeshment of particles in a growing precipitate. Polymer chains agglomerate particles by inter-particle bridging. This phenomenon involves the adsorption of particles onto polymer chains by forming particle-polymer-particle complexes. The loops and tails of adsorbed polymer chains can protrude and attach to other particles in the medium, allowing bridging of particles to occur. This accounts for the fact that chitosan has the ability

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to enhance dissolved pollutant removal such as metal ions. Electrostatic patch is caused by polymer chains of high charge density interacting with oppositely charged colloidal particles of low charge density. The net residual charge of the polymer patch on one colloidal particle surface can adsorb onto the oppositely charged colloidal particle. Chitosan forms a bulky precipitate that enmeshes the colloidal particles (sweeping mechanism). These particles are then settled out or they flocculate together with the precipitate.

9.2.7

Control of Bioflocculation Performance of Chitosan

The main factors that affect coagulation are the characteristics of the solid materials, e.g. particle size and surface charge, the polyelectrolyte, e.g. charge density, molecular weight and hydrophobicity, the water chemistry, in particular pH and ionic strength, and the coagulation regime, e.g. concentration and agitation. Factors affecting flocculation are primarily polymer type, e.g. molecular weight, degree of deacetylation and charge density, ionic strength, water pH, slurry solids, flocculant dilution, shear, and process conditions such as flocculation behavior, e.g. sedimentation velocity, packing density of the sludge and particle size distribution (Stechemesser and Dobiáš 2005; Abebe et al. 2016). Bioflocculation is a time-dependent process that directly affects clarification efficiency by providing multiple opportunities for particles suspended in aqueous solutions to collide through gentle and prolonged agitation. Similar to flocculation that uses conventional polymers, the process is complex that involves several steps or sub-processes that occur sequentially or concurrently, where its behavior is critically dependent on the physicochemical characteristics of the reagents used. During the process, the mixing of particles and polymers in solution, adsorption of the polymer on the surface of particles, re-conformation of adsorbed polymer chains on the surface, aggregate formation, breakage of flocs by shear, restructuring of flocs, re-flocculation of broken flocs, desorption of polymer under high shear and sedimentation or creaming of flocs take place simultaneously. Agitation should be thorough enough to encourage inter-particle contact but gentle enough to prevent disintegration of existing flocculated particles or flocs. Flocs grow by colliding with other particles, and sticking together. Time is an important factor for the formation of flocs. The longer the time, the larger the floc. Solution pH is another important variable in flocculation because it affects the electrochemical nature of both the components. A comprehensive discussion on these topics can be found in the book by Stechemesser and Dobiáš (2005).

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Chitosan for Direct Bioflocculation: Potential Applications Palm Oil Mill Effluent

The main problem with palm oil producing countries are commonly associated with the production of palm oil mill effluent. In Malaysia alone, it is estimated that approximately, 50–75 million tons of palm oil mill effluent were produced annually (Ding et al. 2016). The effluent is a thick brownish colloidal mixture of different element including water, oil and suspended particles (Bala et al. 2015). Freshly generated palm oil mill effluent is usually discharged at temperature between 80 and 90
C and is acidic in nature, having an average pH value of about 4.5. The dark liquid typically contains substantial amount of suspended solids, oil and grease and have high concentrations of biochemical oxygen demand as well as chemical oxygen demand. Table 9.6 presents typical characteristics of raw and treated palm oil mill effluent. Illegal discharge of raw or partially treated palm oil mill effluent into nearby water bodies or land is common and still being practiced, as this is the easiest and cheapest option for disposal (Tadza et al. 2015). However, due to strict regulatory discharge limits and increasing environmental awareness, palm oil mill effluent is now treated prior to being discharged into the environment. Currently, integrated biological with physicochemical methods are commonly used for the treatment of raw effluent. Since the effluent is largely biodegradable, biological treatment appears to be the most viable treatment method. In this case, open aerobic or anaerobic ponding systems are opted over the years. Ironically, the final discharged effluents

Table 9.6 Typical characteristics of raw and treated palm oil mill effluent and discharge limits Parameters pH Temperature COD BOD Oil, grease TS TSS NH4-N PO43 Turbidity Color

Unit


C mg/L mg/L mg/L mg/L mg/L mg/L mg/L NTU (PtCo)

Raw effluent 4.2 85–90 50,000 35,000 6000 40,000 18,000 180 210 430 32,000

Treated effluent 8.4 25–30 4500 450 – – 130 20 – 100 250

Discharge limits 5.0–9.0 45 – 100 50 1500 400 100 – – –

References: Wu et al. (2010), Chan et al. (2011), MPOB (2012), Bello et al. (2013), Bala et al. (2015), Tadza et al. (2015, 2016), Saeed et al. (2016) COD chemical oxygen demand, BOD biochemical oxygen demand, TSS total suspended solids

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from these conventional ponding systems often failed to conform to regulatory discharge limits (Rushdy et al. 2014; Bello and Raman 2017). Furthermore, removal of compound, i.e. lignin-tannin, that is responsible for the dark coloration of palm oil mill effluent, is recalcitrant to biological treatment and should be further treated using different secondary treatment or polishing methods. To date, the use of chitosan in the treatment of palm oil mill effluent appears to be very limited. Chitosan and its derivatives have been tested to be effective coagulation agents in treating raw and treated palm oil mill effluents. For instance, Ahmad et al. (2005a, b) noted that powdered and flake chitosan is effective in removal of solids (> 90%) and residual oil (> 95%) from palm oil mill effluent. The results showed that chitosan performed better compared to other natural absorbents such as bentonite, zeolite and activated carbon. The performance of chitosan was better than that of alum and polyaluminum chloride. The removal of residual oil and reduction in the total solid concentrations in palm oil mill effluent is pH dependent. The removal efficiency is reduced with increasing pH values. Palm oil mill effluent strong acidic conditions enhances the coagulation of the oil residue in the effluent. Under acidic conditions, chitosan provokes a physico-chemical effect, serves as a demulsifying agent and enhances the adsorption of oil and grease (Ahmad et al. 2005a). It is believed that the availability of proton increased to protonate amine groups of chitosan molecules. On the other hand, adsorptive removal of heavy metals using chitosan alone has not been very successful. Apart from powdered and flakes of chitosan, the derivatives of chitosan were also used to treat palm oil mill effluents. This involves dissolving powdered chitosan with an acidic solution (Ahmad et al. 2006; Torres et al. 2018). In some cases, chitosan is mixed with other oxidative chemicals such as ferric chloride, ferrous sulfate and hydrogen peroxide (Parthasarathy et al. 2016; Tadza et al. 2016). These studies showed improved solids removal and significant increase in the removal efficiency of chemical oxygen demand compared to using powdered chitosan alone. Based on these studies, chitosan coagulation coupled with hydrogen peroxide proves to be a better alternative for the post-treatment of anaerobically digested palm oil mill effluent due to its improved treatment efficiency, environmental safety and availability. Although no explanation was made on the possible reasons for this observation, it is anticipated that the neutral pH considered or the possible interaction between iron and chitosan which might lead to the reduction of active sites of the iron (Bello and Raman 2017). Although chitosan has shown remarkable performance in treating palm oil mill effluents, the palm oil mills have been complaisant with the ponding system due to its simplicity and cost effectiveness. Consequently, almost all studies mentioned were conducted under small scale laboratory conditions. Feasibility studies are yet to be put to large scale applications. Despite chitosan reported potentials, a lot of effort is required in upscaling these technologies to the industrial level. Another challenge would be dealing with sludge generated as by-product of coagulation process using chitosan. Tadza et al. (2016) showed that the sludge displayed good fertility characteristics and may be considered as fertilizer or soil conditioners in the future.

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355

Effluents from the Sugar Industry

Pambi and Musonge (2015) studied the efficiency of chitosan as a coagulant in the treatment of the effluents from the sugar industry to remove both suspended solids, color and chemical oxygen demand. The sugar refinery consumes large amounts of water daily and approximately 47% of this water is discharged as wastewater. The treatment of effluents by chitosan was investigated under varying chitosan dosage with a study of the effect of pH on impurity removal performance. It was found that an increase in the chitosan dosage increased the impurity removal efficiency for the response variables investigated. However, beyond the optimum coagulant concentration, no further improvement was observed. The optimum chitosan loading was found to be 138 mg/L. The impurity content in the effluent was found to influence the amount of chitosan loading required. High removal efficiencies were achieved under acidic conditions, due to the cationic nature of chitosan. However, the removal of chemical oxygen demand was very low due to the fact that most of the matter present in the effluent was related to dissolved organics. The performance of the chitosan was found to be pH-dependent. Using sodium hydroxide to adjust the pH to higher values strongly affected the performance of the chitosan in a negative way, due to its possible gelation at such alkaline conditions. Overdosing the coagulant destabilized the neutralized flocs and impeded their settling. The mechanism was explained in further detail as follows: firstly the cationic charge of the protonated macromolecule destabilized and neutralized the anionic charges of the impurities; secondly, there was bridging of the macromolecules with the particles leading to flocs formation; and finally electrostatic patch occurs, as described above. Chitosan serves a dual role, both as a coagulant and flocculant by virtue of its charge density and relatively high molecular weight. The authors concluded that chitosan as low-cost biodegradable material was an ideal candidate to substitute conventional synthetic materials.

9.3.3

Agricultural Wastewater

Chitosan can be an alternative for the treatment of effluents containing residual fertilizers and pesticides such as herbicides that trigger the pollution of diverse segments of the environment, including rivers used for drinking water production. Specially, for pesticides that persist for many years, where it is necessary for the removal of these chemicals from contaminated water bodies. As an example, organochlorines pesticides are highly hazardous and have reluctant chemical structures to exhibit degradation. In this field, there is still a demand for efficient methods to be developed and applied at an industrial scale, as recently pointed out by Rani et al. (2017). Rahmanifar and Moradi-Dehaghi (2014) carried out interaction tests among chitosan and permethrin, an organochlorine pesticide. Batch trials were performed

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at pH 7, under shaking at 150 rpm for time of 45 min, with prescribed amount of chitosan within the range from 0.01 to 1.5 g added to 25 mL of a prepared permethrin solution (0.1 ppm). The adsorption efficiency increased with the higher adsorbent concentration up to 0.5 g. Thereafter, the adsorbent dose did not play an important role, and nearly 50% removal was reached for dosages between 0.5 and 1.5 g. The entrapment of the model pesticide was markedly improved (near to 98%) when a nanocomposite form of chitosan-AgO was the adsorbent. In another contribution (Shankar et al. 2018), the removal of pentachlorophenol, a common pesticide, from aqueous solutions was assessed by comparing chitosan versus modified chitosan: [chitosan-(2-hydroxy-1-naphthaldehyde)]. The effect of contact time on pesticide adsorption was studied, based on experiments in batch mode, under stirring, where 0.2 g of adsorbent were added to 200 mL of a synthetic solution containing pesticide (150 mg/L). Data showed fast initial removal, which was related to the availability of vacant sites for adsorbent-pesticide interactions. From 60 min, the maximum adsorption capacity was practically reached for both of the biosorbents. The adsorption capacity exhibited by chitosan (24.4 mg/g) at neutral pH was enhanced by 94% using the modified form. The adsorption capacity decreased with rising the pH from 3.0 to 8.0 (higher contaminant solubility; pKa ¼ 4.7), as well as for higher temperatures in the range of 293–313 K for the unmodified and modified forms of chitosan. In the case of other chemical families, model wastewaters containing the commercial pyrethroid and dithiocarbamate pesticides were selected to be treated for removal by employing chitosan (Ghimici et al. 2016). These tests led to a similar maximum removal efficiency (nearly 90%), irrespective of the pesticide type. Chitosan showed good flocculation at low doses from 1 to 3.4 mg/L for α-cypermethrin, deltamethrin and mancozeb as active ingredients, and the analysis of zeta potential measurements suggested that the flocculation of particles took place mainly via the charge neutralization mechanism. Naturally, the behavior of the treatment process can be significantly different when synthetic samples are compared with samples taken from agricultural effluents, because of the wide variety of pollutants deposited in raw water. Nevertheless, Ruelas-Leyva et al. (2017) proved the high efficiency of chitosan in turbidity removal using samples of raw agricultural wastewater with 36 NTU and pH conditions close to 7.5. Experiments involved the direct bioflocculation process starting with stirring at 100 rpm for 5 min, afterward 60 rpm for 30 min, and then 30 min of undisturbed settling; the pH of samples was not manipulated. From the results, it was found that an increase in the chitosan dosage resulted in higher turbidity reduction, and after a given dosage (10 mg/L) the remaining turbidity was constant ( chitosan > carboxymethyl-chitosan, in accordance with the trends in the relative zeta-potential of the biopolymers. In the presence of turbidity (400 mg/L kaolinite) and initial orthophosphate Pi (25 mg/L), 3-chloro-2hydroxypropyl trimethylammonium chloride grafted onto carboxymethyl-chitosan showed greater orthophosphate Pi removal versus chitosan and carboxymethylchitosan at all pH conditions, where optimal turbidity removal (99.2%) and orthophosphate Pi removal (97.8%) was demonstrated at pH 4, according to the experimental results shown in Fig. 9.5. Based on these selected examples of coagulant-flocculant systems, it can be concluded that enhanced removal of orthophosphate can be achieved through synthetic modification of chitosan, especially in conjunction with Fe(III) coagulants at industrially relevant wastewater conditions. The performance of amphoteric chitosan flocculants can be tuned for optimal performance at variable pH conditions in response to the type of waterborne contaminant species. Thus, the overview provided herein and elsewhere (Bhalkaran and Wilson 2016) reveals the utility of such biopolymer-flocculants for wider applications aimed at oxoanion removal in water and wastewater treatment.

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Fig. 9.5 Effect of pH on the removal of orthophosphate Pi at variable flocculant dosage; (a) 3-chloro-2-hydroxypropyl trimethylammonium chloride grafted onto carboxymethyl-chitosan (b) chitosan and (c) carboxymethyl-chitosan, where the initial concentration of Pi is 25 mg/L. (Reproduced with permission; Agbovi and Wilson 2018)

9.3.6

Treatment of Cyanobacteria-Laden Source Water

The proliferation of harmful cyanobacteria in river, lake and reservoir is considered as a serious environmental issue since its ability to produce toxins as well as taste and odor compounds which adversely affect aquatic ecosystems and humans (Schindler et al. 2012). Cyanobacteria will threaten the safety of drinking water when such forms of contaminated water is used for drinking water purposes. Microcystins produced by Microcystis aeruginosa, which is the most notorious species in eutrophic surface waters, are hepatotoxins which pose a health threat on humans. Other algal organic matters could also compromise the safety of drinking water since they are precursors leading to the development of disinfection by-products during chlorination. Generally, most algal organic matters including microcystins are contained within healthy cyanobacteria cells except Cylindrospermopsis raciborskii, which contains around 50% or less toxin in cells (Newcombe 2009). Its removal in

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dissolved form is more difficult than those in the cells of cyanobacteria. Therefore, an efficient method to remove cyanobacteria cells without damaging the membrane is significant to drinking water treatment. Coagulation using conventional coagulants is considered as the most important process for algal removal in conventional drinking water treatment due to short detention time and low capital cost. Even though the traditional coagulants, such as polymeric aluminium and ferric chloride, could remove cyanobacteria cells without causing cell lysis (Xu et al. 2016), excess Al and Fe will affect the water quality when plenty of traditional coagulant is used to remove cyanobacteria. Furthermore, the traditional coagulant is ineffective at the removal of extracellular microcystins. Recently, increasing demand for environmental-friendly technologies has led to the search for natural, available and efficient materials to be used as coagulants. Chitosan, as a non-toxic and biodegradable coagulant/flocculant, has been extensively applied in water treatment and may be a suitable flocculant for cyanobacteria cells removal in drinking water treatment plants. For instance, Pei et al. (2014) studied the effects of chitosan on treatment of cyanobacteria-laden source water, where the results showed that chitosan can remove Microcystis aeruginosa cell efficiently without damage the cells. Meanwhile, chitosan can absorb an amount of extracellular microcystins due to the presence of amino and hydroxyl groups in chitosan which give it powerful adsorptive capacity. The impacts of chitosan dosage and flocculation stirring were systematically investigated on Microcystis aeruginosa and microcystins removal. Under optimized conditions, i.e. chitosan concentration: 7.31 mg/L, rapid mix speed: 227 rpm, rapid mix time: 2 min, slow mix speed: 19 rpm, and slow mix time: 12 min, 99% of Microcystis aeruginosa cells and 46.5% microcystins were removed. Despite there are many desired properties of the chitosan as a coagulant and its relatively low cost, the cost of chitosan is still high compared with the traditional inorganic coagulants used as coagulants in drinking water treatment plants. To address issues of cost, research efforts were directed at finding ways to reduce the dosage of chitosan. Pan et al. (2006) prepared a composite coagulant containing chitosan-modified local soils (chitosan: soil ¼ 1:10; weight), where it was found that a loading of 0.025 g/L chitosan-modified local soils removed 99% Microcystis aeruginosa cells (cell intensity: 4.86  109 cells/L) within 16 h for a field enclosure of Taihu Lake. Pei et al. (2016) used a novel hydrogen-terminated porous Si wafer to enhance Microcystis aeruginosa removal by chitosan at a low dosage. It was found that moderate pre-oxidation by this wafer not only could avoid the damage of Microcystis aeruginosa cell but also can decrease the level of dissolved organic matter, hence, this led to a method for reducing the dosage of chitosan during coagulation. Another solution to reduce the dosage of chitosan during coagulation is to prepare a coagulant combining the advantages of bioflocculant with inorganic coagulant in water treatment. Ma et al. (2016a, b) studied the effect of a composite coagulant chitosan-aluminum chloride on removal of Microcystis aeruginosa cells in cyanobacteria-laden drinking water for treatment. Results showed that the composite

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coagulant can remove algal cells effectively for stronger entrapment and bridging ability, where negligible cell lysis was observed during the coagulation process. The optimal coagulation performance was obtained when the composite coagulant was set as 2.6 mg/L chitosan plus 7.5 mg/L aluminum chloride, under which 97.8% of intact cells, 53.1% of extracellular microcystins and almost all extracellular organic matters were simultaneously removed. Even though the dosage of chitosan was reduced during coagulation as above, its water insolubility (chitosan is soluble in weak acid solution) restricts its application in drinking water treatment processes. Recently, some water-soluble chitosan derivatives have been synthesized. Jin et al. (2017), for example, studied the chitosan quaternary ammonium salt, a water-soluble chitosan derivative, on removal of Microcystis aeruginosa cells during coagulation. It was found that Microcystis aeruginosa cells can be removed efficiently without damage under optimum coagulation conditions: coagulant dosage 1.5 mg/L, rapid mixing for 0.5 min at 5.04 g and slow mixing for 30 min at 0.20 g. Overall, as shown in Table 9.8, because chitosan and chitosan derivatives are non-toxic and biodegradable, they may be the promising coagulant for treatment of the cyanobacteria-laden source water. However, it is worth to note that their use on cyanobacteria removal is still at the laboratory research phase. The field pilot study on cyanobacteria removal by chitosan or chitosan derivatives should be done to obtain relevant operating parameters in the drinking water treatment plant. It will be helpful in this application to treat the cyanobacteria-containing source water in the drinking water Table 9.8 Comparison between chitosan and chitosan derivatives on Microcystis aeruginosa cell removal

Coagulant Chitosan

Dose (mg/L) 7.31

Cell density (cells/mL) 2  106

Advantage(s) Degradability

Chitosan-modified local soils (chitosan: soil ¼ 1:10; weight) H-PSi wafer preoxide plus chitosan

25 (chitosan dose: 2.27)

4.86  106

Degradability; low dosage of chitosan

0.75

2  106

Degradability; low dosage of chitosan

CTSAC (chitosan: aluminum chloride ¼1:3; weight) HTCC

10.1 (chitosan dose:2.6) 1.5

2  106

Degradability; low dosage of chitosan Degradability; water solubility

1  106

Problem(s) Water insolubility Water insolubility of chitosan

References Pei et al. (2014) Pan et al. (2006)

High cost of H-PSi wafer; water insolubility of chitosan Water insolubility of chitosan

Pei et al. (2016)

High cost

Jin et al. (2017)

Ma et al. (2016a, b)

H-PSi hydrogen-terminated porous Si, CTSAC chitosan-aluminum chloride, HTCC chitosan quaternary ammonium salt

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treatment plant. In addition, cheaper and better performance chitosan derivatives should be developed in the future. This also contributes to the wide range of applications of chitosan derivatives in drinking water treatment plant.

9.3.7

Sludge Dewatering

One of the major environmental problems facing wastewater treatment is the high volume of sludge produced by sewage treatment. Sludge treatment or dewatering, disposal and management are major challenges in the water industries, in particular to reduce the costs of final disposal including transportation. Typically, dewatering is focused on reducing the weight and volume of the sludge. For this, the primary means of volume reduction (before sludge waste) is water removal. Depending on the operation and process used, sludge can be very dilute suspension which generally contain a heterogeneous mixture of 50–80% of pollution in form of a high-organic load, colloids, pathogenic germs, mineral particles, captions and metals (Zhai et al. 2012). That is why, if they are inadequately managed, they can pose a serious environmental consequence. Hence, the main target of sludge treatment is (i) to dewatering as high a solids level as possible (in the most economical manner), (ii) to eliminate smell by reducing the quantity of the organic solids, and (iii) to reduce number of disease-causing microorganisms present in the solids. All these treatments are important for both economical and environmental reasons. Sludge dewatering separates sludge into liquid and solid components for waste minimization. This requires an efficient conditioning step and there are various technologies involving biological, chemical and/or physical treatments. It is important to point out that, after treatment, both the liquid and solid components may contain contaminants. Indeed, the dewatering step is not intended to treat the liquid of sludge. Generally, chemical methods are used to enhance sludge filtration and final dewatering efficiency. They consists in the addition of chemicals, e.g. acids, alkalis, surfactants, coagulants and/or flocculants, to the sludge to change its nature and to improve dewatering performance. Coagulation/flocculation is one of the most commonly used sludge conditioning approaches when cost and efficiency are considered (Wei et al. 2018). In this treatment, colloidal particles present in the sludge form large flocs and compacted cakes for the improvement of sedimentation and dewatering performance by increasing the sludge dewatering rates and solid content (Qi et al. 2011; Suopajärvi et al. 2003; Wei et al. 2018). The additives used can be classified into two main groups: mineral additives such as metal salts and organic polymer (synthetic products or natural polymers). The synthetic ones may be cationic, anionic or non-ionic. In most cases, they are derived from oil-based and non-renewable raw materials (Suopajärvi et al. 2003). Some of these products often lead to secondary pollution and new environmental problems (Renault et al. 2009a). So, the sludge formed has a limited potential for recycling due to its non-biodegradability (Zahrim et al. 2011). Natural

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polymers, such as starches, celluloses and chitosan, and microbial materials, such as bacteria, fungi and yeast, can reduce such environmental problems, reuse sludge as fertilizer with environment respect and encourage sludge proper handling and disposal (Bolto and Gregory 2007). Depending on the nature of the solids to be treated, chemical conditioning can reduce the 90–99% incoming moisture content to 65–85% (Yu et al. 2008). Moisture content in sludge directly corresponds to the dewatering extent. Other parameters can be also used such as the capillary suction time (in s) and specific resistance in filtration (in m/kg) (Christensen et al. 1985; Ripperger et al. 2012). These parameters are popular in evaluating sludge dewaterability. In a capillary suction time test, a filtration force generated by the capillary action of an absorbent filter paper is applied to the sample. The lower the capillary suction time the higher the dewatering rate, i.e. the better sludge filtration properties. This test is simple, rapid and inexpensive because it does not require an external source of pressure or suction. The specific resistance in filtration test requires the application to be in a vacuum. It is important to note that the capillary suction time and specific resistance in filtration parameters are empirical and lacking in accuracy. However, they rapidly provide an indication of a sample filtration capability which is usually sufficient for operational controls. Figures 9.6, 9.7, 9.8 and 9.9 show a typical example of obtained results. The raw sludge originates from a municipal waste water treatment plant (Beni-Messous, 15 km west of Algiers, Algeria). Its characteristics are described in Table 9.9. The following conditions were used: sludge conditioning was carried out by flocculation using a conventional Jar Test with six ramps; samples of 100 mL in a 500 mL beaker were mixed with solutions containing different amounts of conditioners calculated on the basis of chemical mass per unit mass of dry solids contents of the sludge

60 50

Sed CF802

Chitosan

FeCl3

CST (s)

40

30 20 10 0 0

1

2 3 4 Polymer dosage (kg/t ds)

5

6

Fig. 9.6 Capillary suction time (CST) versus flocculant dosage. Flocculants: commercial cationic polymer Sedipur CF802 abbreviated Sed CF802, chitosan and ferric chloride FeCl3; the capillary suction time parameter was evaluated according to the Standard Method 2710G (APHA, AWWA and WEF 1995) with a portable apparatus (Triton 304B, chromatography paper Whatman n
17)

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8

SRF (10 12 m/kg)

7

FeCl3

Chitosan

Sed CF802

6 5 4 3

2 1

0 0

1

2 3 Polymer dosage (kg/t ds)

4

5

Cake dry solid content (%)

Fig. 9.7 Specific resistance to filtration (SRF) versus flocculant dosage. Flocculants: ferric chloride FeCl3, chitosan and a commercial cationic polymer Sedipur CF802 abbreviated Sed CF802

20 18 16 14 12 10 8 6 4 2 0

Chitosan

0

1

FeCl3

2 3 4 Polymer dosage (kg/t ds)

Sed CF802

5

6

Fig. 9.8 Cake dry solid content vs. flocculant dosage. Flocculants: chitosan, ferric chloride FeCl3 and a commercial cationic polymer Sedipur CF802 abbreviated Sed CF802

(expressed in kilogram per ton of dry solids); the jar test was operated at 140 rpm for 20 s for intense mixing of the polyelectrolyte into the sludge, and then stirring speed was reduced to 28 rpm for 2 min to promote floc growth. Dewatering sludge was processed using laboratory-scale pressure filtration cell standardized (APHA, AWWA and WEF 1995). After flocculation, conditioned sludge is immediately transferred into the filtration cell. An appropriate pressure (10 kg/cm2) was applied. During the introduction of the piston, a certain amount of filtrate can flow under the effect of gravity without pressing. The filtration time was set to 1 hour. Collected filtrates were measured as function of time. Dry solids content (ds in %) of the recuperated cake and filtrate turbidity were determined according to procedures

Turbidity removal (%)

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100 90 80 70 60 50 40 30 20 10 0 Chitosan

SedCF802 Polymer

FeCl3

Fig. 9.9 Turbidity removal versus flocculant dosage. Flocculants: chitosan ferric, a commercial cationic polymer Sedipur CF802 abbreviated Sed CF802 and chloride FeCl3 Table 9.9 Characteristics of raw sludge before conditioning

Parameter pH Total suspended solids Volatile suspended solids Dry solid content Capillary suction time Specific resistance to filtration Temperature

Unit g/L g/L % s 1012 m/kg
C

Value 8.3 3.3 17 3.22 48 6.78 25

given in Standard Methods (APHA, AWWA and WEF 1995). Chitosan efficiency was compared to synthetic cationic polymer Sedipur CF802 abbreviated Sed CF802, and ferric chloride FeCl3. The capillary suction time is an empirical measure of the resistance offered by the sludge to the withdrawal of water. In Fig. 9.6, the results show that the capillary suction time value has been reduced from 48 s obtained in the raw sludge case to 5 s and 6 s with optimal dosage, in the range of 2–3 and 1.5–3 kg/t ds of Sed CF802 and chitosan, respectively. Beyond the optimal dosage, the capillary suction time value increases again. Otherwise, with sludge conditioned with 6 kg/t ds as optimal dose of FeCl3, capillary suction time value was around 9 s. Indeed, the two cationic polyelectrolytes showed a good dewaterability. The low capillary suction time obtained using cationic polyelectrolytes is due to smaller flocs and sludge containing less bound water. The sludges are therefore dewatered faster than those obtained with FeCl3. However, further increase in polyelectrolyte concentration increased the capillary suction time. This is associated with the overdosing phenomena caused by excess polyelectrolyte remaining in the liquid phase leading to the viscosity increase and then deteriorating the sludge dewaterability. Otherwise, saturation of

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the colloidal surface with polymer is usually accompanied by a reversal of the surface charge. The optimal polymer dosage is commonly associated with partial coverage of the colloidal surface, accompanied by a minimum surface charge (Lee and Liu 2000). Figure 9.7 depicts the evolution of specific resistance in filtration data as a function of dosage of each flocculant. Initially, the specific resistance in filtration value of unconditioned sludge was 6.78  1012 m/kg. The value is decreased when both cationic polyelectrolytes and FeCl3 were added. The optimum doses for Sed CF802 and chitosan were about 1.5–2 kg/t ds for both polyelectrolytes. Beyond the optimum value, the SRF increased again. SRF values of sludge conditioned with Sed CF802 and chitosan at the respective optimum doses were 0.634  1012 m/kg and 0.932  1012 m/kg, respectively. On the other hand, 4.5 kg/t ds of FeCl3 has reduced specific resistance in filtration to 2  1012 m/kg. Through these results, the objective of this study was accomplished; adding flocculating agents improved the dewaterability of sludge, i.e. reduced the specific resistance in filtration. Chitosan as well as Sed CF802 and FeCl3 helped to increase the sludge particle size by agglomerating the small fines of the sludge colloids (causing blinding) and to form large flocs (which are easily separated from the water). This flocs agglomeration is translated by the specific resistance in filtration decrease and consequently the filterability improvement. The evolution of the cake dryness according to the dose of each flocculant is presented in Fig. 9.8. A significant increase in dryness to 17.31% with 3 kg/t ds of chitosan has been recorded and 2 kg/t ds of Sed CF802 increased cake dryness to 18.65%. The cakes formed with application of both polyelectrolytes were uniform, with thicknesses of 0.5 cm. These results led to the conclusion that the performance of these two polymers was substantially similar, with a slight difference. Otherwise, 15.78% of cake dryness was obtained using 4 kg/t ds of FeCl3. Obtaining large flocs after flocculation was conducive to good settle ability and filterability. However, the filterability did not depend on the size of the flocs. It essentially depended on floc cohesion or their mechanical and bond strengths uniting the elementary particles that make up the formed cluster. The weakness of these links may result in a change in the structure of the filter cake which becomes less porous, and consequently a decrease in the rate of filtration. Figure 9.9 depicts the filtrate turbidity after filtration tests of flocculated sludges with different polymers. It shows that both chitosan and SedCF802 with 94.68% and 87.85% respectively, a maximum filtrate cleaning (minimum nephelometric turbidity unit, NTU, values) have been achieved. By cans, 54.18% of turbidity abatement has been obtained using FeCl3. A better capture efficiency of some fine dispersed particles in the aqueous phase translates the lower residual turbidity of filtrate when both cationic polyelectrolytes were used. These fine, dispersed particles of sludge were flocculated to form primary flocs due to electrostatic attraction. Lee and Liu (2000) have shown that knowing that the fine particles should cause a decrease in cake porosity, flocculation of sludge particles by the cationic polyelectrolyte could prevent fine particles from clogging up the filter. This also contributes to the enhanced dewaterability of sludge.

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The sludge particles are most frequently known to be positively or negatively charged. Chemical conditioners, often with opposite charges, are used to coagulate or flocculate sludge colloids by charge neutralization, leading to the establishment of interactions between charged particles. It is well known that the two main mechanisms of flocculation using organic polymers are the destabilization of the colloidal system by charge neutralization and the bridging intra-particles. Polymer can adsorb on the surface of a colloidal particle due to a chemical strength (chemical bonding) or physical force (e.g. van der Waals forces), or both. Some parts of the polymer chains can then be determined by bare paths on another particle and therefore closest to form bridges. So, destabilization of sludge is interpreted as a neutralization charge and/or particles bridging during the application of polyelectrolytes. The combined action of the mass and charge of the polymer helps to implement both phenomena bridging and charge neutralization (Gregory and Barany 2011). The bridge allows the polymer to set a large number of particles and to include them in large flocks. Since chitosan is a cationic polyelectrolyte, in our case, the clotting mechanism is essentially borne by a double effect: charge neutralization and bridging flocs. Chitosan is adsorbed on the surface of the colloidal particles by attractive electrostatic interactions between the negative charges of the surface of the colloidal particles and the amine groups of the chitosan (Renault et al. 2009a, b). These also promote adsorption (Gregory and Barany 2011) and this explain the fact that the adsorbed amount of chitosan increases with the increase of the dose of added chitosan. According to results related to the effect of the chitosan dose, the general trend showed that each increase of chitosan above its optimum concentration increased specific resistance in filtration and decreased cake dry solid contents. One hypothesis for this phenomenon would be the reversal of load and re-stabilization of colloidal particles which have been coagulated. This re-stabilization of loads depends on the zeta potential of the solution (Gregory and Barany 2011). In fact, chitosan, by its constitution, has a surplus of electrical charges and is solvated by water trapping colloidal particles causing turbidity. Indeed, these authors have reported that the excessive addition of polymer creates hyperconductive water where collisions between particles due to electric forces are so intense; they disrupt completely the balance of the solution (Gregory and Barany 2011). In conclusion, compared to a commercial synthetic polymer, chitosan has shown the same efficiency in terms of sludge conditioning. Chitosan, as a natural organic flocculant, may be a promising substitute for conventional flocculants used so far in the field of sludge conditioning. Its sole inconvenience is its relatively high cost, which could be minimized by future technological developments.

9.3.8

Post-Treatment of Sanitary Landfill Leachate

The landfill leachate presents high concentrations of ammonia nitrogen, organic matter biodegradable, recalcitrant compounds, such as humic substances, heavy metals and xenobiotic organic compounds (Kjeldsen et al. 2002). Biological

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treatment, is commonly used to remove the bulk of organic matter biodegradable and ammonia nitrogen, due to its reliability, simplicity and high cost-effectiveness. As a complementary alternative to the biological treatment, the coagulation-flocculation process has been employed to reduce the concentration of recalcitrant organic matter and toxicity present in the landfill leachate (Renou et al. 2008; Ziyang et al. 2009). Nevertheless, chemical coagulants may have adverse effects on the environment. Hence, it is suggested that chitosan could be a better alternative (Verma et al. 2012; Ramli and Aziz 2015; Nascimento et al. 2016). Nascimento et al. (2016) carried out a determination of the optimum dosage and pH values for coagulation-flocculation of biologically-treated leachate using chitosan as biocoagulant for the removal of recalcitrant organic matter. The performance of chitosan was compared to aluminum sulfate which is a metal coagulant widely used in wastewater treatment plants. The coagulant dosage investigated ranged from 700 to 1100 mg/L for chitosan and from 1300 to 1700 mg/L for alum; the pH value was varied from 6.0 to 9.0 for chitosan and from 8.0 to 10.0 for alum. The gradient for rapid mixing, time for rapid mixing, gradient for flocculation mixing, and flocculation time were held constant. Their values for chitosan and alum were: 400 s1 and 869 s1 (gradient for rapid mixing), 30 s and 10 s (time for rapid mixing), 30 s1 and 30 s1 (gradient for flocculation), and 10 min and 10 min (flocculation time), respectively. Based on a mathematical model and graphical optimization, the results showed that chitosan dosages below 700 mg/L and pH values between 6.0 and 6.5 or chitosan dosage near 900 mg/L and pH values between 8.0 and 8.5 lead to greater removal efficiencies of recalcitrant organic matter (50–80%) and the highest turbidity removal (90%) was obtained at a lower dosage, less than 900 mg/L, with a pH between 6.5 and 9.5; and an alum dosage between 1542 and 1762 mg/L with a pH between 8.5 and 10.0 lead to greater removal efficiency values. Employing the Response Optimizer function (Minitab® 16 software), the maximum efficiency removal of true color (80%) and the turbidity removal (91%) were found using 960 mg/L of chitosan at pH 8.5; and using 1610 mg/L of alum at pH 9.5, the true color removal efficiency was 87% and the turbidity removal reached 81% (Nascimento et al. 2016). The authors explained that with decreasing solution pH, part of the humic substances in the leachate became insoluble, resulting in a reduced level of remaining organic matter. Consequently, the dosage of chitosan required for the destabilization of the colloidal system is less and lower pH (acidic) conditions. Moreover, at a pH of 6.0 or less, more than 90% of the amine groups are protonated. Thus, the lower dosage of chitosan required for efficient coagulation-flocculation at lower pH. This can be explained by the acid-base properties of chitosan and the degree of dissociation of the polyelectrolyte (Guibal and Roussy 2007). The pKa of the amine groups is close to 6.3–6.4 for fully dissociated chitosan (with a deacetylation degree of close to 90%). The authors concluded that the high sensitivity of the performance of chitosan in removing true color and turbidity levels opens up possibilities for its use as a coagulant to aid in the removal of recalcitrant contaminants in landfill leachate.

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Conclusion

Chitosan, a partially deacetylated polysaccharide obtained from chitin, has received considerable attention in recent years as a versatile bioflocculant. Its potential application as an efficient and eco-friendly material for environmental purposes has been well investigated. As reported in this chapter, chitosan can be used for water and wastewater treatment, sludge dewatering and post-treatment of sanitary landfill leachate. In general, the data published have shown comparable or better flocculation efficiency compared to the current commercial ones, and thus chitosan has strong potential in the near future. However, although its performance was satisfactory and pilot plants were designed, the economic feasibility to design large scale treatment plants still need to be carried out. Moreover, attention should be given towards investigating the intrinsic characteristics of the biopolymer, i.e. degree of deacetylation and molecular weight, and the various operating parameters, e.g. dosage, initial pH, settling time, etc., which could significantly affect the viability and effectiveness of chitosan and its derivatives. In addition, more research is still needed to understand the mechanisms of flocculation in order to control flocs density and removal ability of pollutants.

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Chapter 10

Cross-Linked Chitosan-Based Hydrogels for Dye Removal Grégorio Crini, Giangiacomo Torri, Eric Lichtfouse, George Z. Kyzas, Lee D. Wilson, and Nadia Morin-Crini

Abstract Synthetic dyes are a major class of recalcitrant organic compounds, often occurring in the environment as a result of their wide industrial use. More than 100,000 dyes are commercially available. Synthetic dyes are common contaminants, many of them being toxic or carcinogenic. Colored effluents from industrial plant are also perceived by the public as an indication of the presence of a dangerous pollution. Even at very low concentrations, dyes are both highly visible, inducing an esthetic pollution, and impacting the aquatic life and food chain, as a chemical pollution. Dye contamination of water is a major problem worldwide and the treatment of wastewaters before their discharge into the environment is a priority. Dyes are difficult to treat due to their complex aromatic structure and synthetic origin. In general, a combination of different physical, chemical and biological processes is often used to obtain the desired water quality. However, there is a need to develop new removal strategies and decolorization methods that are more effective, acceptable in industrial use, and ecofriendly. Currently, there is an increasing interest G. Crini (*) Chrono-Environnement, UMR 6249, Université Bourgogne Franche-Comté, Besançon, France e-mail: [email protected] G. Torri Istituto di Chimica e Biochimica G. Ronzoni, Milano, Italy e-mail: [email protected] E. Lichtfouse Aix-Marseille Université, CNRS, IRD, INRA, Coll France, CEREGE, Aix-en-Provence, France G. Z. Kyzas Hephaestus Advanced Laboratory, Eastern Macedonia and Thrace Institute of Technology, Kavala, Greece e-mail: [email protected] L. D. Wilson Department of Chemistry, University of Saskatchewan, Saskatoon, Canada e-mail: [email protected] N. Morin-Crini (*) Laboratoire Chrono-environnement, UMR 6249, UFR Sciences et Techniques, Université Bourgogne Franche-Comté, Besançon, France e-mail: [email protected] © Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9_10

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for biological materials as effective adsorbents for dye removal. In particular, crosslinked chitosan-based hydrogels are popular biosorbents. Between 2013 and 2017, 18,430 chitosan-related publications have been published. In this chapter, we describe technologies for color removal, chitosan-based hydrogels and biosorption basics. Then we highlight cases studies published over the last 5 years. We found that chitosanbased hydrogels display outstanding removal capabilities for some dyes. Keywords Chitosan · Hydrogels · Dyes · Biosorption · Batch

10.1

Introduction

Water pollution by dyes remains a serious environmental and public problem (Sharma 2015; Khalaf 2016; Morin-Crini and Crini 2017; de Andrade et al. 2018; Karimifard and Moghaddam 2018; Katheresan et al. 2018). Many industries such as chemicals, textiles, pulp and paper, metallurgy, leather, paint and coatings industry, food, packaging, pharmacy, and plastics consume considerable amounts of water and chemical reagents during processing, dyeing and finishing operations. Due to their high solubility, dyes are common water pollutants and may frequently be found in trace quantities in their industrial discharge waters. More than 700,000 tons of synthetic dyes are produced worldwide every year, e.g. in India, it is close to 80,000 tons, and 5–10% of them are discharged in wastewater (Sinha et al. 2016; Karimifard and Moghaddam 2018; Katheresan et al. 2018; Piaskowski et al. 2018). The textile industry (54%) in releases the highest amount of dye wastewater, contributing to more than half of the existing dye effluents seen in the environment around the world (Katheresan et al. 2018). The presence of very small amounts of dyes is highly visible and the public perception of water quality is greatly influenced by color. This generates an increasing number of complaints and concern. Environmental contamination by dyes also pose a severe ecological problem which is enhanced by the fact that most dyes are difficult to degrade using standard biological treatments. Moreover, since the last two decades, concerns are expressed about the potential toxicity of dyes and of their precursors, and this poses a serious hazard to aquatic living organisms (Liu and Liptak 2000; Khalaf 2016; Katheresan et al. 2018). The removal of pollutants including dyes and pigments from wastewaters is a matter of great interest in the field of water pollution. Amongst the numerous techniques of pollutant removal, adsorption using solid materials – named adsorbents or biosorbents depending on their origin – is a simple, useful and effective process (Crini 2005, 2006). The adsorbent may be of mineral, organic or biological (biosorbent in this case) origin. Activated carbon is the preferred adsorbent at industrial scale. However, its widespread use is restricted due to high cost. In the last three decades, numerous approaches have been studied for the development of cheaper, ecofriendly and more effective biosorbents capable to eliminate pollutants present in synthetic solutions contaminated with a single type of pollutant (Onsoyen and Skaugrud 1990; Peters 1995; Allen 1996; Goosen 1997; Hirano 1997; Ramakrishna and Viraraghavan

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1997; Cooney 1999; Blackburn 2004; Gavrilescu 2004; Varma et al. 2004; Crini 2005, 2006; Bhatnagar and Minocha 2006; Oliveira and Franca 2008; Qu 2008; Gadd 2009; Wang and Chen 2009; Elwakeel 2010; Park et al. 2010; Ali 2012; Michalak et al. 2013; Katheresan et al. 2018; Piaskowski et al. 2018). Among the various materials proposed for water and wastewater treatment by biosorption, cross-linked chitosan hydrogels are by far the most widely studied materials, owing not only to their efficiency at eliminating a broad range of pollutants but also to their synthesis that is straightforward and facile (Ravichandran and Rajesh 2013; Liu and Bai 2014; Vandenbossche et al. 2015; Yong et al. 2015; Muya et al. 2016; Nechita 2017; Pakdel and Peighambardoust 2018). In this chapter, after a brief description of technologies for color removal, chitosan-based hydrogels and biosorption basics, we chose to highlight selected works on the use of cross-linked chitosan hydrogels for dye removal published over the last 5 years. The main objectives are to provide a summary of recent information concerning the use of chitosan-based hydrogels as biosorbents and to discuss the main interactions involved in the biosorption process. Recent reported biosorption capacities are also noted to give some idea of biosorbent effectiveness.

10.2

Principal Technologies for Color Removal

In Europe, since 2000s, water pollution by chemicals has become a major source of concern and a priority not only for both society and public authorities but also for the whole industrial world. Indeed, due to increasingly stringent restrictions on the organic and metallic content of industrial effluents, the industrial sector has taken significant efforts to reduce their consumption of water and energy, and to improve their wastewater discharges by installing treatment plants in a context of sustainable development. In general, conventional wastewater treatment consists of a combination of mechanical, physical, chemical, and biological processes and operations to remove insoluble particles and soluble pollutants from effluents to reach the decontamination objectives established by legislation. At the present time, there is no single method capable of adequate treatment, mainly due to the complex nature of industrial wastewaters (Crini and Lichtfouse 2018). Table 10.1 shows the main technologies available for color removal. Each technology has its own constraints not only in terms of cost, but also in terms of feasibility, efficiency, practicality, environmental impact, sludge production, operation difficulty, pre-treatment requirements and the formation of potentially toxic byproducts. Readers interested in a detailed discussion of the advantages and drawbacks of each method should refer to the following references: Berefield et al. 1982; Henze 2001; Forgacs et al. 2004; Pokhrel and Viraraghavan 2004; Aksu 2005; Anjaneyulu et al. 2005; Chuah et al. 2005; Bratby 2006; Crini 2006, 2015; Cox et al. 2007; Hai et al. 2007; Mohan and Pittman 2007; Wojnárovits and Takács 2008; Gupta and Suhas 2009; Barakat 2011; Sharma and Sanghi 2012; Sharma 2015; Khalaf 2016; Rathoure and Dhatwalia 2016; Morin-Crini and Crini 2017; Alaba et al. 2018; Crini and Lichtfouse 2018; Katheresan et al. 2018; Piaskowski et al. 2018.

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Table 10.1 Principal technologies available for dye removal at industrial scale Technology Physicochemical treatments Coagulation/ flocculation Oxidation/ coagulation Oxidation/coagulation/ precipitation Coagulation/ precipitation Coagulation/precipitation/ flocculation Precipitation/ flocculation

Oxidation Ozone

Advantages Conventional treatment: simple, rapid and technological simple Both economically feasible and efficient Integrated physicochemical process Adapted to high contaminant loads

Physicochemical monitoring of the effluent: pH High sludge production, handling and disposal problems

Rapid and efficient for insoluble dyes Not dye selective

Significant reduction of the COD Used as an efficient primary treatment in the textile and paper industries Established removal method: simple, rapid and efficient process

Hypochlorite treatment Hydrogen peroxide

Integrated physicochemical process

Electrochemical treatments

Conventional treatment process; economically feasible

Electrocoagulation Electroflotation Electrolysis

Disadvantages Requires adjunction of non-reusable chemicals: lime, oxidants, coagulants, flocculants, aidchemicals

Generation of ozone on-site (no storage-associated dangers) Good elimination of color and odor Increases biodegradability of the effluent and favors precipitation Initiates and accelerates azo-bond cleavage

Adaptation to different contaminant loads and different flow rates Useful for post-clarification Significant reduction of the COD Moderately dye selective

Ineffective in removal of dyes at low concentration Requires an oxidation step if the dye molecules are complexed Energy cost and chemicals required Production, transport and management of the oxidants (other than ozone) Efficiency strongly depends on the type of oxidant Short half-life (ozone) Problems with certain recalcitrant dye molecules; certain dyes are more resistant to treatment and necessitate high ozone doses Pre-treatment indispensable (to remove suspended solids) Formation of intermediates; release of aromatic amines (hypochlorite treatment) No effect on the COD Initial cost of the equipment Chemical consumption

Increased sludge volume generation: management, treatment, cost Formation of iron hydroxide sludge Filtration process for flocs (continued)

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Table 10.1 (continued) Technology Incineration

Biological methods Bioreactors Biological activated sludge Microbiological treatments

Adsorption on activated carbons

Ion-exchange

Advantages Established removal method: destruction by combustion Simple technology and highly efficient Elimination of all organics including dyes Useful for concentrated effluents Production of energy Simple technology Economically attractive and well accepted by the public Large number of species used in mixed cultures or pure cultures Good elimination of color and also significant reduction of biodegradable organic matter Used as final treatment in the pulp and paper industry

Conventional treatment process: technological simple and adaptable to many treatment formats Large range of commercial products Produces a high-quality treated effluent Highly effective for various dyes with high capacity and rapid kinetics Coupled with a precipitation/flocculation process: very good elimination of suspended matter, organic load and color Can be applied to different flow regimes: batch, continuous Established removal method Large range of commercial products Technological simple: simple equipment, well established

Disadvantages Economic constraints Transport and storage of the effluents Formation of pollutants and byproducts: dioxins

Necessary to create an optimally favorable environment Maintenance and nutrition requirements Low biodegradability of certain (recalcitrant) dyes Slow process: problems of kinetics

Generation of biological sludge with uncontrolled degradation products Complexity of the microbiological mechanisms Relatively high initial investment; cost of carbons Performance depends on type of materials Ineffective against disperse and vat dyes Rapid saturation and clogging of the reactors: pre-treatment indispensable Regeneration is expensive and results in loss of capacity Elimination of the carbons Economically non-viable for certain industries (textile, pulp and paper): incapable of treating large volumes (economic constraints) Economic constraints; initial investment costs; high maintenance costs Large volume require large columns (continued)

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Table 10.1 (continued) Technology

Advantages procedures, Easy control and maintenance Good elimination of color; dye selective process

Membrane filtration

Advanced oxidation processes

Biosorption Biopolymers Biomass Agricultural byproducts Industrial wastes

High regeneration; no loss of resin on regeneration Established removal method: simple, rapid and efficient Small space requirement Large range of commercial membranes Remove all types of dyes: produces a high-quality treated effluent Dye selectivity possible Elimination of salts, dyes and auxiliaries: surfactants, chelating chemicals Emerging recovery technology No sludge production Little or no consumption of chemicals Very good elimination of soluble and insoluble dyes Efficient for recalcitrant dyes Significant reduction of the COD and TOC Emerging recovery technology Economically feasible Outstanding biosorption capacities towards anionic and cationic dyes Efficient at trace levels High selectivity Regeneration is not necessary

Disadvantages Rapid saturation and clogging of the reactors: requires a physicochemical pretreatment Performance sensitive to pH of effluent Not effective for disperse dyes Elimination of the resins High initial capital cost; high maintenance and operation costs High pressure processes Incapable of treating large volumes; limited flow rates Fouling with high concentrations Concentrated sludge production

Laboratory scale Technical constraints Economically unfeasible Formation of by-products

Requires physical and chemical modification Important role of the pH of the solution Variables differences in materials uses Elimination of the materials

COD chemical oxygen demand, TOC total organic carbon

Among the various treatment processes currently cited for dye removal, only a few are commonly employed by the industrial sector for technological and mostly economic reasons (Morin-Crini and Crini 2017; Crini and Lichtfouse 2018). In practice, a combination of different physical and chemical processes is often used

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to achieve the desired water quality in the most economical way. Indeed, the main approach used by industry to treat their wastewater containing dyes involves physicochemical methods with, for instance, oxidation, coagulation, precipitation and flocculation of the pollutants by applying chemical agents, then separation by physical treatment of the sludge formed to leave clarified water (Berefield et al. 1982; Henze 2001). The use of physicochemical treatment generally enables the legislation concerning liquid industrial effluent to be respected but this conventional treatment does not completely remove pollution. However, as it has to cope with an increasingly strict framework, the industrial sector continues to look into new treatment methods to decrease the levels of pollution still present in the effluent, the aim being to tend towards zero pollution outflow. In theory, many methods could be suitable to finish off the work done during the physicochemical treatment. These include adsorption on activated carbons, ionexchange on resins, membrane filtration, electrodialysis, membrane bioreactors, biological activated sludge, electrocoagulation, electrochemical oxidation, electrochemical reduction, incineration, advanced oxidation, photolysis, catalytic or noncatalytic oxidation, liquid-liquid extraction or evaporation. Currently, because of the high costs, disposal problems and technical constraints, many of these methods for treating dyes in pretreated effluent have not been widely applied on a large scale. There is a need to develop new removal strategies and decolorization methods that are effective, acceptable in industrial use, and ecofriendly (Crini and Lichtfouse 2018). It is now well-accepted that, amongst the numerous techniques of dye removal proposed as secondary or tertiary (final) step in a treatment plant, liquid-solid adsorption-oriented processing is the procedure of choice and gives the best results as it can be used to remove different types of coloring materials (Ravi Kumar 2000; Crini 2006; Gérente et al. 2007; Li et al. 2008; Kyzas et al. 2013a, b; Sanghi and Verma 2013; Dolatkhah and Wilson 2016, 2018; Udoetok et al. 2016). Most commercial systems currently use activated carbon as adsorbent to remove dyes mainly due to its excellent adsorption ability. This technology is also simple, adaptable to many treatment formats, and a large range of commercial products are available from several manufacturers. Activated carbon is extensively used at industrial scale not only for removing dyes from wastewaters streams but also for adsorbing pollutants from drinking water sources, e.g. rivers, lakes or reservoirs. However, although activated carbon is a preferred material, its widespread use is restricted due to the high material and regeneration cost, in particular for small and medium-size enterprises. Moreover, this conventional process is not competitive when faced with very dilute effluents and waters. To overcome this, numerous approaches have been studied for the development of cheaper and effective new materials such as chitosan-based materials (Kyzas and Kostoglou 2014; Crini 2015; Kos 2016; Kanmani et al. 2017; Kyzas et al. 2017; Nechita 2017; de Andrade et al. 2018; Desbrières and Guibal 2018; El Halah et al. 2018; Pakdel and Peighambardoust 2018; Wilson and Tewari 2018).

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Chitosan for Wastewater Treatment

Since the 1990s, chitosan and its derivatives have practical applications in food industry, agriculture, pharmacy, medicine, cosmetology, textile and paper industries, beverage industry, biotechnology and chemistry (Rauh and Dornish 2006; Peniche et al. 2008; Cheba 2011; Davis 2011; Ferguson and O’Neill 2011; Khor and Wan 2014; Pokhrel et al. 2015; Hamed et al. 2016; Annu et al. 2017; Arfin 2017; Dima et al. 2017; Philibert et al. 2017; Pellá et al. 2018; Shariatinia and Jalali 2018). For instance, in beverage industry, chitosan is used as eco-friendly coagulant for passion fruit clarification, natural flocculant for beer clarification, or for elimination of undesired substances, e.g. metals and pesticides. In the last two decades, chitosan as biosorbent has also received much attention in water and wastewater treatment, mainly for metal chelation and dye removal (Muya et al. 2016; Nechita 2017). Indeed, chitosan has an extremely high affinity for metals and metalloids and for many classes of dyes, including direct, acid, mordant and reactive. In their comprehensive reviews, Crini (2015), Yong et al. (2015), Kyzas et al. (2017), Wang and Zhuang (2017), Desbrières and Guibal (2018), El Halah et al. (2018) and Pakdel and Peighambardoust (2018) recently indicated that biosorption onto chitosan was a promising alternative to replace conventional adsorbents used for decolorization purposes, metal chelation or recovery, and organic removal. With nutraceuticals and cosmeceuticals, the water and wastewater treatment field seems to be the next market in the development of chitosan. Chitosan represents an alternative as ecofriendly complexing agent because of its low cost, its intrinsic characteristics, e.g. renewable, non-toxic and biodegradable resource, and hydrophilicity, and its chemical properties, e.g. polyelectrolyte at acidic pH, high reactivity, coagulation, flocculation and biosorption properties, resulting from the presence of reactive hydroxyl and mostly amine groups in the macromolecular chains (Roberts 1992; Sandford 1989; Skjåk-Braek et al. 1989; de Alvarenga 2011; Teng 2016). These groups allow chemical modifications yielding different derivatives for specific domains of application (Bhatnagar and Sillanpää 2009; Sudha 2011; Azarova et al. 2016; Arfin 2017; Ahmed and Ikram 2017; Sudha et al. 2017; Wang and Zhuang 2017). In wastewater treatment, its use is also justified by two other important advantages: firstly, its outstanding pollutant-binding capacities and excellent selectivity, and secondly, its versatility (No and Meyers 1995, 2000; Peters 1995; Hirano 1997; Houghton and Quarmby 1999; Blackburn 2004; Crini 2005; Crini and Badot 2008; Honarkar and Barikani 2009). Indeed, chitosan possesses strong affinity to interact with pollutants present in concentrated or diluted solutions, and even at trace levels. One of the most important properties of chitosan is its cationic nature. This aminopolysaccharide is the only natural cationic polymer in the nature (Roberts 1992; Kurita 1998, 2006; Ujang et al. 2011; Teng 2016). At low pH, usually less than about 6.3, chitosan’s amine groups are protonated conferring polycationic behavior to polymer while at higher pH (above 6.3), chitosan’s amine groups are deprotonated and reactive. The protonation reaction is useful because, after

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dissolution, chitosan can be conditioned under different physical forms. It can be precipitated into beads, cast into films and membranes, spun into fibers, and also cross-linked to produce gels, fibers or sponges (No and Meyers 2000; Kurita 2006; Pillai et al. 2009; Salehi et al. 2016; Shen et al. 2016; Teng 2016; Nechita 2017). The material can be used in solid form for the removal of pollutants from water and wastewater by filtration or adsorption processes or in liquid state, i.e. dissolved in acidic media, for applications in coagulation, flocculation, and membrane filtration (polymer assisted ultrafiltration) technologies. In the last two decades, application of chitinous products as complexing materials in water and wastewater treatment for pollutant removal has received considerable attention not only for dye removal but also for other pollutants (Table 10.2). Among these treatments, biosorption onto cross-linked chitosan hydrogels is one of the more popular method for dye removal (Pakdel and Peighambardoust 2018).

10.4

Chitosan-Based Hydrogels

The chitosan-based derivatives can be classified into four main classes of materials (Crini 2005; Crini and Badot 2008): modified polymers, cross-linked chitosans, chitosan-based composites and membranes. An important class of chitosan derivatives are cross-linked gels/hydrogels (Ahmed 2015; Ullah et al. 2015; Akhtar et al. 2016; Mittal et al. 2016; Shen et al. 2016; Xiao et al. 2016; Yao et al. 2016; Aminabhavi and Dharupaneedi 2017; Caccavo et al. 2018; Van Tran et al. 2018). Gels are physically or chemically cross-linked three dimensional hydrophilic polymeric networks capable of swelling and absorbing large amounts of water (hydrogels), solvent (organogels) or biological fluids (gels/hydrogels) in their swollen state. They also have the ability to interact with a wide range of ions, molecules, oligomers and polymers. Hydrogels are also versatile materials as they can selfassemble into a variety of forms including microgels/microspheres, beads, nanoparticles/nanogels, films and membranes, fibers/nanofibers, and sponges/ nanosponges, thereby resulting in the formation of 2D and 3D networks, e.g. spheres, scaffolds, ribbons, and sheets. Once freeze-dried or supercritically dried, hydrogels can also become cryogels or aerogels, respectively. The different classifications of hydrogels can be found in the reviews by Ahmed (2015) and Ullah et al. (2015). Hydrogels are mainly divided into two classes depending on the types of cross-linking and the nature of their network, namely physical gels and chemical gels. Physical hydrogels are formed by various reversible links and chemical hydrogels are formed by irreversible covalent links. Physical hydrogels are reversible due to the presence of noncovalent interactions and conformational changes. The hydrogels interconnected by covalent bonds cannot be redissolved (they are permanent) and are thermally irreversible. Hydrogels are also divided into two categories according their natural or synthetic origin: biopolymerbased or synthetic (Ullah et al. 2015). Due to their hydrophilicity, biocompatibility, biodegradability, “intelligent” swelling behavior, i.e. as responsive materials, and

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Table 10.2 Recent reviews on chitosan-based materials used for pollutant removal Material/Form Solution

Technology Coagulation Flocculation

Pollutant Metals, dyes

Reference(s) Sudha et al. (2017)

Solution, hybrid materials

Coagulation Flocculation

Color, turbidity, SS, COD

Lee et al. (2012)

Solution

Coagulation

Metals, dyes

Oladoja (2015)

Solution

Flocculation

Metals, dyes

Nechita (2017)

Solution

Flocculation

Color, turbidity, SS, COD

Lee et al. (2014)

Solution, grafted materials

Flocculation

Color, turbidity, SS, COD

Salehizadeh et al. (2018)

Solution, grafted materials

Flocculation

Color, turbidity, SS, COD, microorganisms

Yang et al. (2016a)

Solution

Polymerassisted ultrafiltration

Metals

Crini et al. (2017)

Beads

Biosorption

Metals, metalloids

Azarova et al. (2016)

Flakes, hydrogels, beads

Biosorption

Ammoniac

Bernardi et al. (2018)

Topics Mode of application, modification, mechanisms, performance, industrial wastewater Synthesis, characterization, mode of application, mechanisms, performance, industrial wastewater Mode of application, modification, mechanisms, performance Mode of application, mechanisms, performance, industrial wastewater Synthesis, characterization, modification, mechanisms, performance, industrial wastewater Synthesis, modification, mechanisms, performance, industrial wastewater Synthesis, modification, mechanisms, performance, industrial wastewater Mode of application, regeneration, mechanisms, performance, industrial wastewater Synthesis, characterization, modification, biosorption capacity, kinetics, modeling, regeneration, biosorption mechanisms, performance Synthesis, characterization, mode of application, biosorption mechanisms, performance, industrial wastewater (continued)

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Table 10.2 (continued) Material/Form Hydrogels

Technology Biosorption

Pollutant Dyes

Reference(s) Sharma (2015)

Hydrogels

Biosorption

Metals

Muya et al. (2016)

Hydrogels

Biosorption

Metals

Gupta et al. (2015)

Hydrogels

Biosorption

Metals

Boamah et al. (2015)

Hydrogels, beads

Biosorption

Desbrières and Guibal (2018)

Hydrogels, beads

Biosorption

Metals, dyes, drugs, endocrine disruptors, mineral suspensions, herbicides Metals

Hydrogels, beads

Biosorption

Metals

Zhang et al. (2016)

Hydrogels, beads

Biosorption

Metals

Vandenbossche et al. (2015)

Hydrogels, beads

Biosorption

Metals, dyes

Barbusinski et al. (2016)

Hydrogels, beads

Biosorption

Phenols, PAHs, pesticides

Tran et al. (2015)

Hydrogels, beads

Biosorption

Uranium

Muzzarelli (2011)

Ahmad et al. 2017

Topics Biosorption capacity, kinetics, thermochemistry, modeling, regeneration, biosorption mechanisms Synthesis, modeling, biosorption mechanisms, performance, industrial wastewater Modification, biosorption capacity, kinetics, thermochemistry, modeling, biosorption mechanisms, performance Synthesis, characterization, modification, biosorption capacity Mode of application, biosorption mechanisms, industrial wastewater Modification, polyfunctionality, biosorption capacity, biodegradability Synthesis, characterization, modification, modeling Synthesis, characterization, mode of application, modification, biosorption capacity, biosorption mechanisms Biosorption capacity, kinetics, thermochemistry, modeling, biosorption mechanisms, performance Biosorption capacity, mechanisms, performance Biosorption capacity, mechanisms, performance (continued)

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Table 10.2 (continued) Material/Form Hydrogels, beads, composites

Technology Biosorption

Pollutant Boron

Reference(s) Nasef et al. (2014)

Hydrogels, beads, composites

Biosorption

Dyes, metals

Reddy and Lee (2013)

Hydrogels, beads, composites

Biosorption

Fluoride

Miretzky and Cirelli (2011)

Hydrogels, composites

Biosorption

Dyes

Vakili et al. (2014)

Hydrogels, beads, bifunctional products

Biosorption

Dyes

Crini (2015)

Hydrogels, aerogels, composites, semiinterpenetrating networks

Biosorption

Dyes, metals, pharmaceuticals, PAHs, PCBs

Kyzas and Bikiaris (2015) and Kyzas et al. (2017)

Hydrogels, nanomaterials

Biosorption

Dyes

Tan et al. (2015)

Nanocomposites

Biosorption

Metals, dyes, phosphorus

Alaba et al. (2018)

Topics Synthesis, mode of application, modification, mechanisms, performance, industrial wastewater Biosorption capacity, kinetics, thermochemistry, modeling, mechanisms, performance Synthesis, modification, biosorption capacity, mechanisms, performance, industrial wastewater Synthesis, characterization, modification, biosorption capacity, performance, industrial wastewater Synthesis, characterization, modification, biosorption capacity, regeneration, biosorption mechanisms, performance, industrial wastewater Synthesis, modification, grafting, biosorption capacity, kinetics, thermochemistry, modeling, biosorption mechanisms, performance, industrial wastewater Synthesis, biosorption capacity, mechanisms, performance Synthesis, modification, industrial wastewater

SS suspended solids, COD chemical oxygen demand, PAHs polycyclic aromatic hydrocarbons, PCBs polychlorinated biphenyls

modifiability, i.e. in their structure, functionality, appearance, and electrical charge, biopolymer-based hydrogels have acquired increasing attention and have found extensive applications ranging from biomaterials to sensors (Ullah et al. 2015).

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Natural polymers such as cellulose, hemicellulose, starch, gelatin, proteins, hyaluronate and alginates have been proposed and studied (Jing et al. 2013; Khan and Lo 2016). Chitosan and chitin also deserved particular attention (Pakdel and Peighambardoust 2018). As semi-flexible, hydrophilic, versatile and reactive biopolymer, chitosan is able to formulate hydrogels in a variety of physical forms from micro- to nano-scale superstructures. Its hydrophilicity is due to the presence of hydroxyl groups. Chitosan-based hydrogels are held together by either physical interactions such as chain entanglements, van der Waals forces, hydrogen bonds, crystallite associations and/or ionic interactions, or chemical cross-links, i.e. covalent bonding, or a combination of both (Varma et al. 2004; Crini 2005; Tang et al. 2007; Pereira et al. 2017; Sudha et al. 2017). Cross-linking drastically reduces segment mobility in the polymer and a number of chains are interconnected by the formation of new interchain linkages. If the degree of cross-linking is sufficiently high, the product becomes insoluble but swellable in water. Its structure is directly dependent on the degree of cross-linking: the higher the degree, the greater proportion of cross-links, making the material rigid, and this decrease the ability of the material to swell in water and/or to interact with pollutants. Crini (2005, 2015), Akhtar et al. (2016) and Khan and Lo (2016) pointed out that the cross-linking density and hydrophilicity of the polymeric chains mainly control the degree of swelling and their ability to absorb and retain a large amount of water or pollutants. Covalent cross-linking, and therefore the crosslinking density, is influenced by various parameters, but mainly dominated by the concentration of cross-linker. It is favored when chitosan molecular weight and temperature increased. Moreover, since cross-linking requires mainly deacetylated reactive units, a high degree of deacetylation of chitosan is favorable. Due to their reactivity, chitosan-based hydrogels can be prepared under different chemical and physical forms for target applications. Their networks can be nonionic, ionic, or amphoteric in nature and their structure amorphous, semi-crystalline or crystalline (Crini 2005; Jing et al. 2013). These materials have gained relevance for practical applications in pharmacy, e.g. drug carriers, medicine and biomedicine, e.g. wound dressings and tissue engineering scaffolds, cosmetology, hygiene and personal care (superabsorbents), and agriculture e.g. for pesticide delivery or water retention) (Zhang et al. 1993; Dash et al. 2009; Luna-Bárcenas et al. 2011; van Vliergerghe et al. 2011; Ahmadi et al. 2015; Nilsen-Nygaard et al. 2015; Shen et al. 2016; Yao et al. 2016; Zhao 2016; Xiao et al. 2016; Wang et al. 2016; Aminabhavi and Dharupaneedi 2017; Pereira et al. 2017; Pakdel and Peighambardoust 2018; Pellá et al. 2018; Shariatinia and Jalali 2018). They have potential applications in the biotechnology, bioseparation, oil recovery, and biosensor fields. Cross-linked chitosan materials, from gel/hydrogel types to bead types or particles, have also received much attention in wastewater treatment as biosorbents for the removal of metals, dyes, pesticides, phenols, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, pharmaceuticals or fluorides from aqueous solutions (Table 10.2). The abundant literature data showed that they exhibited superior performance in the adsorptive removal of a wide range of aqueous pollutants (Pakdel and Peighambardoust 2018; Van Tran et al. 2018). The major advantages and

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drawbacks of biosorption technology using cross-linked chitosan are listed in Table 10.3 (Varma et al. 2004; Crini 2005, 2006; Gérente et al. 2007; Crini and Badot 2009; Liu and Bai 2014; Rhazi et al. 2012; Sudha et al. 2017). Table 10.3 Advantages and drawbacks of using chitosan-based hydrogels for dye removal by biosorption-oriented process Advantages Emerging recovery technology, publicly acceptable (ecofriendly and non-toxic polymer) Economically feasible: low-cost resource for applications in pollutant removal Raw chitosan: renewable, biodegradable and environmentally friendly resource; hydrophilic biopolymer with high reactivity and cationic properties in acidic medium Bifunctional materials: easy physical and chemical modifications Versatile materials: can be conditioned under different forms (powders, gels, beads, fibres)

Technological simple: simple equipment (batch), adaptable to many treatment formats; can be applied to different flow regimes: batch, continuous; capable of treating large volumes; useful technology in combination with physicochemical (coagulation, precipitation, flocculation) pretreatments Outstanding dye-binding capacities; also useful for the recovery of (valuable) metals Highly effective for various dyes: acids, direct, mordant, reactive, disperse, and vat dyes High efficiency and selectivity in detoxifying both very dilute or concentrated effluents with rapid kinetics Real effluents: a high-quality treated effluent is obtained with simultaneous elimination of color, organic load (COD, BOD, TOC) and metals Easy regeneration if required (while keeping its initial properties); regeneration is possible but not necessary; no loss of resin on regeneration Certain materials are biodegradable Chemisorption mechanism clearly established: complexation, electrostatic attraction, ionexchange, complex formation

Disadvantages Technologies are still being developed; laboratory stage Nonporous materials with low surface area (except nanostructures, hyper-cross-linked beads, composites) Poor chemical stability (except for hypercross-linked beads); low mechanical strength Variability in the chitosan characteristics and in the materials used; performances depend on type of materials and DD A high affinity for water; a tendency to shrink and/or swell; not appropriate for column systems (except for hyper-cross-linked beads): hydrodynamic limitations, column fouling, technical constraints Requires chemical modification to improve both its performance and stability Important role of the pH of the solution on the biosorption performance; influence of salts and sensitive to particle, suspended solids, and oils

Ineffective against basic (cationic) dyes (except for modified functional materials) Functional hydrogels: results depend on the functional groups grafted Hyper-cross-linked systems: possible clogging of the reactors: requires physicochemical pretreatment to remove suspended solids Elimination of the materials after use

DD degree of deacetylation, COD chemical oxygen demand, BOD biochemical oxygen demand, TOC total organic content

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Various methods have been developed for the chemical cross-linking of chitosan, which commonly result in gel formation. Recent information can be found in the reviews by Ahmed (2015), Akhtar et al. (2016) and Khan and Lo (2016). These methods are generally divided into three main classes: (i) crosslinking with chemicals, e.g. single emulsion reaction, multiple emulsion, and precipitation/cross-linking; (ii) cross-linking and interactions with charged ions, molecules or polymers, e.g. ionotropic gelation, wet-phase inversion, emulsification and ionotropic gelation and iii) miscellaneous methods including thermal cross-linking, solvent evaporation method, spray drying or freeze drying. Generally, cross-linking with chemicals is an easy method to prepare chitosan-based hydrogels with relatively inexpensive reagents (Crini 2005). Indeed, the main approach in the conversion of chitosan into derivatives capable of interacting with dyes from aqueous solutions involves the direct chemical modification of macromolecules by cross-linking using a chemical agent to form gel/hydrogel systems. This reaction involves creating covalent chemical bonds in all directions in space during a co-polymerization reaction that generates a three-dimensional network. In this chemical type of reaction, the cross-linking agents are molecules with at least two reactive functional groups that allow the formation of bridges between polymer chains. To date, the most common cross-linkers used with chitosan are dialdehydes such as glutaraldehyde and epoxides such as epichlorohydrin. Glutaraldehyde and epichlorohydrin are the most frequently used crosslinked agent in chitosan chemistry and their reactions are very well documented (Crini 2005; Kurita 2006; Akhtar et al. 2016). Indeed, they are not expensive and their mode of action is well understood. They react with chitosan chains and crosslink in inter and intramolecular fashion through the formation of covalent bonds with the amino and/or hydroxyl groups of the polymer (Fig. 10.1). Epichlorohydrin is highly reactive with hydroxyl groups. Another advantage is that it does not eliminate the cationic amine function of chitosan, which is the major adsorption site attracting the pollutant during biosorption process. The main drawback of these two cross-linker agents are that they are considered to be toxic (glutaraldehyde contains cytotoxic chemical species and it is known to be neurotoxic; epichlorohydrin is also considered to hazardous environmental pollutant and potential carcinogen), even if the presence of free unreacted glutaraldehyde and epichlorohydrin is improbable since the materials are purified before use. Other cross-linkers of chitosan are other epoxides such as ethyleneglycol diglycidyl ether, carboxylic acids such as citric acid, isocyanates, polyanions such as tripolyphosphate, and genipin (Crini 2005; Jing et al. 2013; Shukla et al. 2013; Ahmed 2015; Ullah et al. 2015; Akhtar et al. 2016; Khan and Lo 2016). Recently, silicon oxide polymeric precursors, e.g. tetraethoxysilane, sodium silicates, aminopropyltriethoxysilane, have been proposed. These precursors are interesting because they can form interpenetrated polymers with chitosan after polymerization. The active sites of the biopolymer remain intact while its solubility is diminished and its biosorption capacity is maintained. Nevertheless, most of these approaches involve the obtaining of a hybrid material whose main

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Fig. 10.1 Schematic representation of cross-linked chitosan hydrogels: (a) epichlorohydrin EPI and (b) glutaraldehyde GLU

component is SiO2. Therefore, the overall biosorption capacity of these materials is, in general, lower than that of pure chitosan but these materials have the advantages of high stability, recoverability and reutilization. In view of industrial developments, these advantages are also of utmost importance. Generally, a cross-linking step is required to improve mechanical resistance and to reinforce the chemical stability of the chitosan in acidic solutions, modifying hydrophobicity and rendering it more stable at drastic pH, which are important features to define an efficient biosorbent (Crini 2005). However, this reaction can decrease the number of free and available amino groups on the chitosan backbone, and hence the possible ligand density and the polymer reactivity. It also decreases the accessibility to internal sites of the material and leads to a loss in the flexibility of the polymer chains. Moreover, when the cross-linking degree is high, the material is mostly amorphous. So, the chemical step may cause a significant decrease in dye uptake efficiency and biosorption capacities, especially in the case of chemical reactions involving amine groups, since the amino groups of the polymers are much more active than the hydroxyl groups that can be much more easily attacked by cross-linkers. Consequently, it is important to control and characterize the conditions of the cross-linking reaction since they determine and allow the modulation of the cross-linking density, which is the main parameter influencing properties of gels (Ahmed 2015; Ullah et al. 2015; Akhtar et al. 2016; de Luna et al. 2017a, b). Indeed, the conditions of preparation of hydrogels used as biosorbents for dye removal play a crucial role in the determination of their performances and in the better comprehension of the

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biosorption mechanisms (Crini 2005, 2015). However, this aspect is often neglected in the literature (Ahmed 2015; Crini 2015; Mohamed et al. 2015; Ullah et al. 2015; Akhtar et al. 2016; de Luna et al. 2017a, b; Pakdel and Peighambardoust 2018; Van Tran et al. 2018).

10.5

Biosorption-Oriented Processes Using Batch Methods

10.5.1 Biosorption Technology Liquid-solid biosorption has received a great attention in the last three decades as an alternative process for the recovery of toxic pollutants present in aqueous solutions, e.g. industrial effluents, groundwater and drinking water (Gadd 1990; Volesky 1990, 2004; McKay 1996; Fomina and Gadd 2014; Crini and Lichtfouse 2018). Biosorption is a process of separation which utilizes inexpensive biological materials to sequester pollutants. These materials used as biosorbents are abundant and often widely available that possess complexing and chelating properties. This technology is particularly feasible to use for removal of these pollutants from dilute effluents and waters, and for treating large volumes. Indeed, conventional processes such as chemical precipitation, ion-exchange or chelation onto organic resins, or adsorption onto activated carbons are not competitive with dilute solutions. In a biosorptionoriented process, the separation is based on the selective adsorption – i.e. thermodynamic and/or kinetic selectivity – of the pollutants by the biosorbent owing to specific interactions between the surface of the material and the adsorbed pollutants (Yang 2003; Allen and Koumanova 2005; Ahmaruzzaman 2008; Gadd 2009). This is a simple mass transfer from the liquid phase towards the solid phase, involving similar separation and mechanism than those used in a conventional adsorption process using commercial products such as carbons, alumina, silica or zeolites. However, in the case of biosorption, the origin of the material is biological. Moreover, biosorption includes several mechanisms, ranging from physical to chemical binding. In general, the affinity between the biosorbent and the pollutant is the main interaction force controlling the process (Wase and Forster 1997; Dąbrowski 2001; Crini 2005; Bhatnagar and Minocha 2006; Michalak et al. 2013).

10.5.2 Batch Methods There are several types of contacting systems available to obtain experimental data and for industrial applications including batch methods, fixed-bed type processes, pulsed beds, moving mat filters and fluidized beds (Morin-Crini and Crini 2017; Crini and Lichtfouse 2018). The most frequently used system applied in biosorption process for dye removal is the batch-type contact (Fig. 10.2). This decontamination approach involves mixing a known volume of water with known concentrations of

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biosorbent

separation treated effluent

raw effluent

spent biosorbent Industrial scale

Fig. 10.2 Schematic representation of batch process used for dye removal from wastewaters

dye to be processed with a given quantity of biosorbent, in previously established conditions of stirring rate, stirring duration, concentration, pH, ionic strength, and temperature. The mixture is stirred for a given contact time, then separated by a physical step involving centrifugation, sedimentation or filtration. By determining the concentrations in the supernatant and in the initial solution it is possible to calculate the efficiency of the material, i.e. its performance in terms of dye elimination. In wastewater treatment, the batch method is widely used because this technology is cheap, simple, quick, and easy to set up and, consequently often favored for small and medium size process applications using simple and readily available mixing tank equipment (Morin-Crini and Crini 2017).

10.5.3 Langmuir Equation In batch systems, the parameters of the solution such as dye concentration, contact time, pH, strength ionic, temperature, etc. can be controlled and/or adjusted. For instance, by varying the quantity of biosorbent, the concentration of the dye(s) or the contact time, it becomes possible to experimentally determine various isotherms (biosorption capacity), kinetics, and the thermochemistry of the process, and also to model them (Al-Duri 1996; Ho and McKay 1998; Wong et al. 2003, 2004; Ho 2006; Hamdaoui and Naffrechoux 2007a, b). Indeed, batch studies use the fact that the biosorption phenomenon at the solid/liquid interface leads to a change in the concentration of the solution. Biosorption isotherms are then constructed by measuring the concentration of dye in the medium before and after biosorption at a fixed temperature. The amount of dye adsorbed at time t by the biosorbent (qt) is obtained from the differences between the concentrations of dye added to that in the supernatant. qt is calculated from the mass balance equation given by Eq. (10.1) where Co and Ct are the initial and final dye concentrations in liquid phase (mg L
1), respectively, V is the volume of dye solution (L) and m the mass of biosorbent used (g). When t is equal to the

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equilibrium time (i.e. Ct ¼ Ce, qt ¼ qe), then the amount of dye adsorbed at equilibrium, qe, can be calculated by using Eq. (10.2) where Ce is the liquid phase dye concentration at equilibrium (mg L
1). qt ¼

V ðC o
C t Þ m

ð10:1Þ

qe ¼

V ðC o
C e Þ m

ð10:2Þ

By plotting solid phase concentration against liquid phase concentration graphically, it is possible to depict an equilibrium adsorption isotherm. This isotherm represents the relationship existing between the amount of pollutant adsorbed and the pollutant concentration remaining in solution. Equilibrium is established when the amount of pollutant being adsorbed onto the material is equal to the amount being desorbed. Among the numerous theories relating to adsorption equilibrium, the Langmuir adsorption isotherm is the best known of all isotherms describing adsorption (Wong et al. 2003, 2004; Hamdaoui and Naffrechoux 2007a, b; Crini and Badot 2009; Morin-Crini and Crini 2017). Using an empirical equation introduced by the American chemist and physicist Irving Langmuir in 1916 (Nobel Prize in Chemistry in 1932), it is possible to obtain an interesting parameter widely used in the literature to promote a solid material as adsorbent, i.e. the theoretical monolayer capacity or the maximum adsorption capacity of an adsorbent (qmax in mg/g). Indeed, the Langmuir isotherm incorporates an easily interpretable constant which corresponds to the highest possible adsorbate uptake in terms of performance. It is important to point out that, although this theory is the most popular, the model was initially developed for the modeling of the adsorption of gas solutes onto metallic surfaces and is based on the hypothesis of physical adsorption (Langmuir 1916, 1918). The Langmuir equation is represented by Eq. (10.3) where x is the amount of dye adsorbed (mg), m is the amount of biosorbent used (g), Ce (mg/L) and qe (mg/g) are the liquid phase concentration and solid phase concentration of dye at equilibrium, respectively, and KL (L/g) and aL (L/ mg) are the Langmuir isotherm constants. The Langmuir isotherm constants, KL and aL are evaluated through linearisation of Eq. (10.3). By plotting Ce/qe against Ce, it is possible to obtain the value of KL from the intercept which is 1/KL and the value of aL from the slope which is aL/KL (Eq. 10.4) Using these constants, it is then possible to obtain qmax. Its value, numerically equal to KL/aL, permits to evaluate the maximum biosorption capacity of a material for the biosorption of a target pollutant. Of course, the uptake of a contaminant by two material biosorbents must be compared not only at the same equilibrium concentration but also in the same experimental conditions (particularly pH). qe ¼

x K L Ce ¼ m 1 þ aL C e

ð10:3Þ

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Ce 1 aL ¼ þ Ce KL KL qe

10.6

ð10:4Þ

Removal of Dyes from Solutions by Chitosan-Based Hydrogels

10.6.1 Biosorption Capacity Since the 1990s, a large variety of biosorbents have been proposed and studied for their ability to remove organic contaminants, in particular dye molecules (Gadd 2009). Some of the reported materials include agricultural wastes, industrial byproducts, biomass and biopolymers. However, biosorbent materials with high adsorption capacities are still under development to reduce the biosorbent dose and minimize disposal problems (Crini and Lichtfouse 2018). Among the numerous biosorbents proposed, much attention has been focused on various chitin-based (Peters 1995; Goosen 1997; Hirano 1997; Li et al. 2008; Bhatnagar and Sillanpää 2009; Sudha 2011; Khor and Wan 2014; Anastopoulos et al. 2017; Sudha et al. 2017) and chitosan-based (Table 10.4) materials for pollutant removal. Recent results in terms of biosorption capacities using values of the monolayer capacity (qmax in mg/g) obtained from batch studies were compiled in Table 10.4. These reported biosorption capacities must be taken as an example of values that can be achieved under specific conditions since biosorption capacities of the biosorbents presented vary, depending on the characteristics of the material, the experimental conditions, and also the extent of chemical modifications. The reader is encouraged to refer to the original articles for information on experimental conditions. Crini (2015), Kyzas et al. (2017), and Wang and Zhuang (2017) demonstrated that biosorption using non-conventional cross-linked chitosan hydrogels is an effective and economic method for water decolorization. These materials had an extremely high affinity for many classes of dyes commonly used in industry with outstanding biosorption capacities, in particular anionic dyes such as acid, reactive and direct dyes (Table 10.4). For instance, 1 g of material can adsorb 2498 mg of Reactive Blue 2 present in aqueous solution. In comparison with commercial activated carbons, these non-conventional materials exhibited excellent performance for removal of anionic dyes and the performances were 3–15 times higher at the same pH (Crini 2015; Hadi et al. 2015; Mohamed et al. 2015; Udoetok et al. 2016). The only class for which chitosan have low affinity is basic (cationic) dyes. Moreover, it is well-known that, the uptake is strongly pH-dependent when natural sorbents are used. This is due to the presence of chemical functions on the materials. In general, for anionic dye molecules removal by cross-linked chitosan hydrogels, the highest biosorption effectiveness were achieved at low pH values, whereas an opposite tendency was observed for cationic dyes removal where an increase in pH

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Table 10.4 Maximum adsorption capacities qmax (in mg/g) for dye removal obtained on different cross-linked chitosan hydrogels using batch studies Cross-linked hydrogel Nanoparticles Cyclodextrin-chitosan nanoparticles EPI-chitosan Hydrogel composite Hydrogel composite EPI-chitosan Edetate-chitosan (pH 4) Hydrogel microbeads Urea diammonium tartrate modified chitosan Chitosan granules Diammonium tartrate modified chitosan Edetate-chitosan (pH 4) Powder Tripolyphosphate-chitosan (pH 4) Hydrogel composite Quaternary chitosan Chitosan nanodispersion Polyacrylic acid-chitosan GLU-chitosan Aerogel Semi-IPN hydrogel EPI-chitosan Hydroxyapatite-based nanocomposite IPN hydrogel (pH 7) IPN hydrogel (pH 7) GLU-chitosan (pH 5)

Dye Eosin Y Methyl blue Reactive blue 2 Methylene blue Methylene blue Reactive yellow 86 Reactive yellow 84 Acid Orange 7 Congo red

qmax 3333 2780 2498 1968

Reference Du et al. (2008) Fan et al. (2012) Crini (2015) Melo et al. (2018)

1952

Vaz et al. (2017)

1911

Crini (2015)

1883.6

Jóźwiak et al. (2015)

1670 1597

Kuroiwa et al. (2017) Zahir et al. (2017)

Reactive black 5 Congo red

1559

Jóźwiak et al. (2017a)

1447

Zahir et al. (2017)

Reactive black 5 Reactive red

1296.6

Jóźwiak et al. (2015)

1250

Reactive black 5 Methylene blue Reactive orange Reactive red 120 Methylene blue Reactive black 5 Methylene blue Methylene blue Metanil yellow Congo red

1125.7

Subramani and Thinakaran (2017) Filipkowska et al. (2016)

1134

Liu et al. (2018)

1060

Crini (2015)

Methyl violet Congo red Reactive black 5

910

Momenzadeh et al. (2011)

990

Li et al. (2017)

846.9

Filipkowska et al. (2016)

785

Yang et al. (2016b)

750

Drăgan et al. (2012)

722 769

Crini (2015) Hou et al. (2012)

411 621 538

Mandal and Ray (2014) Mandal and Ray (2014) Jóźwiak et al. (2013) (continued)

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Table 10.4 (continued) Cross-linked hydrogel GLU-chitosan (pH 3) Semi-IPN hydrogel Graphene oxide/chitosan sponge GLU-chitosan (pH 9) Powder Cyanoguanidine-chitosan Chitosan-Fe Semi-IPN hydrogel Cyanoguanidine-chitosan GLU-chitosan (pH 9) Powder Hyper-cross-linked hydrogel Hyper-cross-linked hydrogel Hyper-cross-linked hydrogel N-maleyl chitosan cross-linker N-maleyl chitosan cross-linker GLU-chitosan (pH 5) Oxide-based nanoparticles Acrylamide-chitosan Terephthaloyl-thiourea-chitosan GLU-chitosan (pH 3) Semi-IPN hydrogel Magnetic hydrogel

Dye Reactive black 5 Acid red 18 Methylene blue Reactive black 5 Direct yellow Food yellow 4 Acid red 73 Methyl Orange Food blue 2 Basic green 4 Malachite green Indigo carmine Rhodamine 6G Sunset yellow Methylene blue Crystal violet Basic green 4 Acid black 26 Astrazone blue Congo red Basic green 4 Rhodamine B Methyl Orange

qmax 514

Reference Jóźwiak et al. (2013)

342.5 275

Zhao et al. (2012) Qi et al. (2018)

254

Jóźwiak et al. (2013)

250

Subramani and Thinakaran (2017) Gonçalves et al. (2015) Zhou et al. (2017a) Zhao et al. (2012) Gonçalves et al. (2015) Jóźwiak et al. (2013) Subramani and Thinakaran (2017) de Luna et al. (2017a, b) de Luna et al. (2017a, b) de Luna et al. (2017a, b) Nakhjiri et al. (2018)

210 206 185.2 180 137 166 118 78 72 66.89 64.56 56 52.6 47 44 19 17.5 6.936

Nakhjiri et al. (2018) Jóźwiak et al. (2013) Salehi et al. (2010) Aly (2017) El-Harby et al. (2017) Jóźwiak et al. (2013) Al-Mubaddel et al. (2017) Wang et al. (2018)

EPI epichlorohydrin, GLU glutaraldehyde, IPN interpenetrating network

value facilitated enhanced removal of dye. To overcome, these problems, several workers suggested the chemical modification of chitosan in order to decrease the sensitivity of biosorption to environmental conditions, e.g. pH and ionic strength. The grafting of carboxyl groups, amine functions and sulfur compounds has been regarded as an interesting method for these purposes (Varma et al. 2004; Crini 2005; Bhatnagar and Sillanpää 2009; Sudha 2011). Other examples can also be found in the reviews by Ahmad et al. (2017), Ahmed and Ikram (2017), Arfin (2017), Sudha et al. (2017), Azarova et al. (2016), Liu and Bai (2014), and Vakili et al. (2014). The grafting of various functional groups onto the hydrogel network or the chitosan backbone can also improve chitosan’s removal performance and selectivity for dye molecules, and also used for controlling diffusion properties. Indeed, these modifications can increase the density of biosorption sites. The presence of new functional

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groups on the surface of the materials results in an increase of surface polarity and hydrophilicity and this enhances the biosorption of polar sorbates and improves the biosorption selectivity for the target dye. The conditions of preparation of hydrogels and their post-functionalization play a crucial role in the determination of their performances. These performances exhibited by each material relates primarily not only to its chemical properties, e.g. type of functional groups and degree of grafting but also to textural properties (from microspheres to nanoparticles). An overview of the literature data shows that performances strongly depend on the type of material used (Crini 2015; Yong et al. 2015; Kyzas et al. 2017; Wang and Zhuang 2017; Desbrières and Guibal 2018). Indeed, each material has its specific application as well as inherent advantages and disadvantages in dye removal. These problems can explain why it is difficult to develop chitosan-based materials at an industrial scale.

10.6.2 A Recent Review of the Literature on Dye Removal by Chitosan-Based Hydrogels Chitosan-based hydrogels are competitive against conventional sorbents or other biosorbents as recently reported by Li et al. (2017). The authors proposed a versatile low-cost material prepared by simple thermal cross-linking chitosan in presence of polyacrylic acid. This material (1 g) was able to remove 990.1 mg of Methylene Blue dye which was higher than most of conventional materials, in parallel agreement with a report by Guo and Wilson (2012). The biosorption properties were reproducible for a wide range of experimental conditions. The interaction between the dye molecules and material was driven mainly by electrostatic attractions. It also presented high selectivity and permitted to separate dye mixtures. The materials were stable and can be recycled for 10 times with negligible reduction of efficiency. The biosorption results were reproducible. In view of industrial development, these features are also of utmost importance. The regeneration of saturated commercial carbon by thermal or chemical procedure is known to be expensive, and results in loss of the material. The authors concluded that chitosan complexation was a procedure of choice for dye removal in terms of cost, efficiency and reusability. Zahir et al. (2017), El-Sayed et al. (2017), and Lin et al. (2017) also reported that cross-linked chitosan hydrogels were very efficient for the removal of dyes at different concentrations and competitive against commercial systems. The materials exhibited high biosorption capacities toward various dyes present in monocontaminated solutions and possessed a high rate of biosorption, high efficiency and selectivity in detoxifying either very dilute or concentrated solutions. Indeed, chitosan hydrogels are more selective than traditional materials and can reduce dye concentrations to ppb levels. Zahir et al. (2017), El-Sayed et al. (2017), and Lin et al. (2017) concluded that the use of cross-linked chitosan hydrogels as biosorbents was a promising tool for the purification of dyecontaining textile wastewaters.

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However, the choice of the cross-linking agent has a significant influence on the biosorption properties because the chemical structure of the synthesized beads depends on the nature of the cross-linking agent and the degree of cross-linking. Despite the large number of papers dedicated to the removal of dyes by hydrogels, most of them focus on the evaluation of biosorption performance and only a few of them aim at gaining a better understanding of the role of the cross-linking agent. Copello et al. (2014) proposed chitosan hydrogel beads modified by three different cross-linking treatments, glutaraldehyde and epichlorohydrin and tetraethoxysilane. The authors studied and characterized the behavior of hydrogel cross-linked using a tetraethoxysilane/chitosan ratio of 1 mmol/g. At this ratio, chitosan was in excess compared to tetraethoxysilane, which contrasted with the developments described in literature where the alcoxysilane was the main component of the composite. The three different hydrogels were used as biosorbent for the removal of an anionic dye, namely Remazol Black. The tetraethoxysilane cross-linking lead to a safer and environmentally friendly hydrogel stable in acidic media and with desirable biosorption characteristics. Their results showed that none of the treatments affected the expected biosorption tendency in regard of media pH. The uptake rate of Remazol Black showed that the three types of beads followed a similar kinetic behavior. The pseudo-first-order model fitted the best for almost all cases, followed by pseudo-second-order model. The model which showed to have a good fitting for all systems was the Sips model. The performances were strongly pH-dependent. The tetraethoxysilane cross-linked beads demonstrated the higher maximum biosorption capacity, followed by epichlorohydrin and glutaraldehyde cross-linked beads. Crini (2015) reported that glutaraldehyde interaction with chitosan required the consumption of two glucosamine units to form the corresponding Schiff bases, which leads to a loss of biosorption sites. Moreover, polymerization of glutaraldehyde also occurred forming a greater cross-linking chain which diminished biosorption capacity in terms of dye-mass/biosorbent-mass ratio. Filipkowska et al. (2016) and Udoetok et al. (2016) reported similar conclusions. The experimental data published demonstrated that, compared with glutaraldehyde, the use of a tripolyphosphate-based cross-linking agent increased color removal. The comparison of the maximum biosorption capacity at the same experimental conditions for Reactive Red 5 dye by glutaraldehyde-chitosan and tripolyphosphate-chitosan showed 846.9 mg/g for glutaraldehyde and 1125.7 mg/g for pentasodium tripolyphosphate. However, the mechanisms need to be explored. de Luna et al. (2017a, b) recently developed new composite chitosan based hydrogels containing hyper-cross-linked polymer particles to be used as broadspectrum biosorbents. The hydrogels were obtained by phase inversion method in order to efficiently combine the dye biosorption ability of chitosan and the capacity of the porous particles of trapping pollutant molecules. The particles exhibited improved mechanical properties with possible use in batch or column procedures (de Luna et al. 2017a, b). Batch biosorption experiments revealed a synergistic effect between chitosan and hydrogels, and the samples are able to remove both anionic and cationic dyes such as Indigo Carmine (qmax ¼ 118 mg/g), Rhodamine 6G (qmax ¼ 78 mg/g) and Sunset Yellow (qmax ¼ 72 mg/g) from water (de Luna et al.

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2017a, b). The maximum dye uptakes were higher than those of comparable biosorbents. However, dependencies in relation to the chemical structure of the dye molecules were not identified. The mechanical properties of hydrogels were enhanced respect to pure chitosan, and the samples can be regenerated and reused keeping their adsorption ability unaltered over successive cycles of biosorption, desorption, and washing. The authors, focusing on the structure-property relationships of chitosan hydrogels, also showed that the conditions of preparations played a crucial role in their performances. The concentration of the starting solution determined the density and strength of intermolecular interactions, and that the gelation kinetics dictated the hydrogel structure at the microscale. Consequently, even subtle changes in the preparation protocol can cause significant differences in the performances of chitosan hydrogels in terms of mechanical properties and dye biosorption capacity. The observed trends can be interpreted looking at the chitosan network structure, which can be inferred by rheological measurements. In a series of works, Jóźwiak et al. (2013, 2015, 2017a, b) also focused on the structure-property relationships of chitosan hydrogels. Their works compared properties of hydrogel chitosan biosorbents cross-linked with nine agents (Jóźwiak et al. 2017b), including five ionic ones (sodium citrate, sodium tripolyphosphate, sodium edetate, sulfosuccinic acid, and oxalic acid) and four covalent ones (glutaraldehyde, epichlorohydrin, trimethylpropane triglycidyl ether, and ethylene glycol diglycidyl ether). The effect of cross-linking process conditions (pH, temperature) and dose of the cross-linking agent on material stability during biosorption and on the effectiveness of Reactive Black 5 dye biosorption were examined. The influence of chemical nature of chitosan, e.g. degree of deacetylation, was also studied (Jóźwiak et al. 2017a). The optimal parameters of cross-linking ensuring biosorbent stability in acidic solutions and high biosorption capability were established for each crosslinking agent tested. The susceptibility of cross-linked biosorbents to mechanical damages was analyzed as well. The process of ionic cross-linking was the most effective at the pH value below which hydrogel chitosan biosorbent began to dissolve (pH 4). The cross-linking temperature ranging from 25 to 60  C had no effect upon biosorbent stability. The higher temperature during ionic cross-linking, however, slightly decreased Reactive Black 5 biosorption effectiveness. The ionic cross-linking significantly decreased the susceptibility of hydrogels to mechanical damages. In the case of covalent cross-linking of chitosan hydrogel beads, the effect of process conditions, e.g. pH and temperature, on the properties of the cross-linked biosorbent depended on the type of cross-linking agent. The biosorbents crosslinked with covalent agents were usually harder but also more fragile, and therefore more susceptible to mechanical damages. The authors showed that increasing the degree of deacetylation, ranging from 75% to 90%, involved an increase in the relative proportion of amine groups, which were able to be protonated, favoring dye biosorption. The higher degree of deacetylation chitosan provided a better biosorption. The highest biosorption capacity (qmax ¼ 1559.7 mg/g) was obtained for the hydrogel in the form of granules (degree of deacetylation ¼ 90%). Due to a loose structure and an easy access to biosorption centers, chitosan hydrogel granules may ensure up to 224% higher biosorption capacity (for degree of

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deacetylation ¼ 75%, qmax ¼ 1307.5 mg/g) than chitosan in the form of flakes (for degree of deacetylation ¼ 75%, qmax ¼ 403.4 mg/g). The results were also found to be strongly dependent of the pH of the solution. The authors concluded that biosorption onto hydrogels was a promising alternative to replace conventional materials used for decolorization purposes. These materials were efficient in dye removal with the additional advantage of being cheap and non-toxic. However, their performances were strongly depended on their structure. In particular, the extent of cross-linking was accompanied by a decrease in dye uptake. Moreover, which crosslinking agent is better? There is no direct answer to this question. El-Harby et al. (2017) investigated the biosorption capacity of three antimicrobial terephthaloyl thiourea cross-linked chitosan hydrogels for Congo Red dye removal. The hydrogels were prepared by reacting chitosan with various amounts of terephthaloyl diisothiocyanate cross-linker in order to study the structure-property relationships of chitosan hydrogels. The results showed that the cross-linking ratio slightly affected the equilibrium biosorption capacity and the performance decreased with an increase in cross-linking density under the range studied. An optimum terephthaloyl thiourea/amine ratio was found for dye biosorption. This decrease in biosorption was interpreted in terms of the decrease in hydrophilicity and accessibility of complexing groups. The cross-linking reaction also decreased the availability of amine groups for the complexation of dyes. The biosorption isotherms and kinetics showed that the experimental data were better fitted by the Langmuir equation and the pseudo-second-order equation, respectively. Isotherms were characterized by a steep increase in the biosorption capacity, indicating a great affinity of the hydrogel for the dye, followed by a plateau representing the maximum capacity at saturation of the monolayer (qmax ¼ 44.248 mg/g). The biosorption phenomena were most likely to be controlled by chemisorption process. It was spontaneous in nature, indicated by the negative value for the Gibbs energy change ΔG, more favorable at lower concentrations of dye molecules compared with higher concentrations, and was most likely to be controlled by chemisorption. The positive values of enthalpy change ΔH and entropy change ΔS suggested the endothermic nature of biosorption and increased randomness at the solid/solution interface during the biosorption of dye on chitosan derivatives. The authors concluded that cross-linked chitosan hydrogels may be promising biosorbents in wastewater treatment. Recently, some novel procedures such as irradiation-based techniques, e.g. ionizing radiation, gamma rays and electron beam, have been reported for cross-linking polysaccharides. The preparation of gels by radiation treatment carries some advantages over the conventional methods. The reaction can be initiated at ambient temperature and, in certain cases, it does not require the presence of cross-linking agents. The method is also relatively simple and the process control is easy. The degree of cross-linking, which strongly determines the extent of properties in gels, can be easily controlled by varying the irradiation dose. In the synthesis of gels by chemical methods, cross-linking density is controlled by the concentration of the cross-linker, reaction time, temperature and other factors. While for the radiation method it is determined by the absorbed dose, which means by the irradiation time. Moreover, cross-linking by the chemical methods is generally performed mainly in

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the liquid state. Since the ionizing radiation is highly penetrating, it is possible to initiate chemical reactions in liquid or in solid state. Piątkowski et al. (2017) recently proposed a novel, waste-free method for obtaining multifunctional chitosan hydrogels under microwave irradiation without the presence of a cross-linking agent. Their chemical and morphological structure, swelling properties, and biosorption capability of a model dye were described. Bifunctional materials containing both negative and positive surface charges were fully biodegradable, and capable to absorb high amounts of water, as well as to remove various water contaminants. Wach’s group have applied electron beam irradiation to prepare gels from chitosan. They synthesized a series of novel gels of carboxymethylated chitosan derivatives by electron beam for biomedical applications and their characteristics are being studied in detail (Mozalewska et al. 2017; Czechowska-Biskup et al. 2016). Solutions of chitosan and carboxymethyl-chitosan were subjected to irradiation by electron beam in presence of poly(ethylene glycol) diacrylate in order to produce carboxymethyl-chitosan- and chitosan-based hydrogels. Poly(ethylene glycol) diacrylate monomer itself undergoes simultaneous polymerization and cross-linking either in neutral water or in acidic medium. Acidic solutions of chitosan of 0.5, 1 and 2% can be effectively cross-linked with poly(ethylene glycol) diacrylate to form a gel. Although carboxymethyl-chitosan undergoes radiation-initiated cross-linking only at high concentration in water (over 10%), the presence of poly(ethylene glycol) diacrylate in solution facilitated hydrogel formation even at lower concentration of carboxymethyl-chitosan. The formation of chitosan and carboxymethyl-chitosan hydrogels required irradiation doses lower than those needed for sterilization, i.e. 25 kGy, in some cases even as low as 200 Gy. Sol-gel analysis revealed relatively high gel fraction of obtained hydrogels, up to 80%, and good swelling ability. Both parameters can be easily controlled by composition of the initial solution and irradiation dose. Possible mechanisms of cross-linking reactions were proposed, involving addition of the polysaccharide macro-radicals to a terminal double bond of poly(ethylene glycol) diacrylate. Even though the polymer chains may be partly degraded during irradiation, the authors concluded that ionizing radiation was a convenient tool to synthetize hydrogels based on chitosan for potential applications not only in the biomedical field but also in water and wastewater treatment. Practical industrial applications of hydrogels in column-based biosorption processes are limited due to hydrodynamic limitations (Esquerdo et al. 2014, 2015). Certain hydrogels are also too soft and degrade at fast rates which can pose major handling difficulties during their applications. Various hyper-cross-linked chitosan gels/beads, chitosan scaffolds, sponges, and chitosan-based composites have been designed to overcome these problems. Different techniques such as blending between two or more polymers, copolymerization with (hydrophobic) synthetic monomers, synthesis of interpenetrating network and semi-interpenetrating network have been proposed. These techniques are useful because they improve the mechanical strength, enhance swelling/deswelling response and avoid the loosening of their structure in wet environments. Dragan (2014) reviewed the main synthesis strategies of fully- and semi-interpenetrating network hydrogels and their potential applications.

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Hyper-cross-linked hydrogel beads were prepared from monodisperse water-inoil emulsions using a microchannel emulsification technique for the first time, and proposed for Acid Orange 7 removal by Kuroiwa et al. (2017). Monodisperse emulsion droplets can be generated spontaneously via an interfacial tension-driven process without generating severe shear force and heat by a two-step gelation process. They were formed by physical gelation of chitosan-containing water droplets by alkali treatment followed by chemical cross-linking treatment using ethylene glycol diglycidyl ether. To clarify the effect of various process parameters such as chitosan concentration and flow rate of chitosan solution on the emulsification, microchannel emulsification was performed under various conditions. The mean diameter and diameter distribution were affected by the viscosity and flow rate of the chitosan solution pressed into microchannels. The biosorption results showed that chitosan gel microbeads exhibited high biosorption capacities toward Acid Orange 7 (qmax ¼ 1670 mg/g). Electrostatic attractions between the positively charged polymer chains (-NH3+ groups) and the negatively charged anionic dye molecules (-SO3
groups) were the most prevalent mechanism with the pH as the main factor affecting performances. Although these properties were pH-responsive, the microbeads can be applied under acidic and neutral pH conditions. The high value of qmax suggested that the molar ratio of -NH3+/-SO3
was 1.0/0.82 at maximum biosorption, i.e. 82% of -NH3+ groups in chitosan hydrogel would be bound to SO3
. This result indicated that the biosorption was achieved by electrostatic interactions. The microbeads were also stable for more than 120 days and could be reused in repetitive adsorption-desorption cycles (at least 10 times) without decrease of performance. The authors concluded that these new hydrogels would be interesting in wastewater treatment for the removal of anionic organic dyes due to their intrinsic properties (small diameter 5. The removal efficiency was higher than 90% for all samples. The dye biosorption onto the composite material was spontaneous in nature and the kinetic measurements showed that the process was rapid (the equilibrium time was found to be 60 min in all the experiments). The biosorption system obeyed the pseudo-second-order kinetic model for the entire

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biosorption period studied. Using kinetic studies, the authors also showed that the mechanism of action was chemisorption rather than physisorption. After saturation, the hydrogels are easily regenerated in acidic solution and after five cycles of biosorption/desorption, they maintained their dye removal efficiency (> 91%). Zhou et al. (2017b) proposed new nano-TiO2/chitosan/poly(Nisopropylacrylamide) composite hydrogels by using a two-step polymerization synthetic method. The hydrogels exhibited both high biosorption capacity and efficiency of photocatalytic degradation for Acid Fuchsin dye. The mechanism was clearly established for the interpretation of experimental data. Dye elimination is assumed to occur through chemisorption with the pH as the main factor affecting the process. Amine sites were the main reactive groups for dyes even though hydroxyl groups may also contribute to the biosorption process. The biosorption performance was observed to be pH-dependent. An accurate mathematical description of biosorption capacity at equilibrium was indispensable for reliable prediction of biosorption parameters and quantitative comparison of adsorption behavior for different materials and/or for varied experimental conditions. Liu et al. (2018) synthesized a three-dimensional porous beta-cyclodextrin/ chitosan functionalized graphene oxide hydrogel by a simple and facile chemical reduction method in the presence of sodium ascorbate which acted as a reducing agent. This new hydrogel was used as biosorbent to remove Methylene Blue from aqueous solutions. The material showed an ultrahigh biosorption capacity (1134 mg/g) for this dye. The unique 3D structure enabled the rapid reuse and recyclability of hydrogel without a complicated filtration system. The biosorption process was well fitted with the pseudo-second-order equation and Freundlich model. The simulation of the intra-particle diffusion model illustrated that both film diffusion and intraparticle diffusion were involved in the process. The characteristics of hydrogels were expressed in thermodynamic parameters, indicating that the biosorption process was spontaneous and endothermic. The authors concluded that this new material could be a cost-effective and promising biosorbent for dye removal. Recently, graphene oxide-based materials were proposed for potential application in water treatment. Although these materials exhibited high performances both in concentrated or diluted solutions, their separation from water for reuse remains a challenge. Qi et al. (2018) investigated the self-assembly of graphene oxide sheets in the presence of chitosan into sponges. The results showed that about 93% of added chitosan could be combined with graphene oxide, regardless of the chitosan concentration. Upon freeze-drying, a stable sponge was generated only at a chitosan content of 9%. The qmax for Methylene Blue was determined to be 275.5 of dye per gram of material. The performances increased with the chitosan content between 9% and 41%. From X-ray diffraction, scanning electron microscopy and transform infrared spectroscopy data, both electrostatic attraction and hydrophobic interactions were responsible for Methylene Blue biosorption by sponges. Another advantage was the use of fixed-bed column and the easy recycling of the materials after biosorption. Indeed, desorption can be carried out in the same column using an alkaline solution. This regeneration step restored the material close to the original

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condition for effective reuse with undiminished dye uptake and no physical change or damage. Sabzevari et al. (2018) similarly demonstrated the utility of cross-linking chitosan with graphene oxide to yield adsorbent materials with greater adsorption over that of colloidal graphene oxide with methylene blue. The facile cross-linking strategy of graphene oxide reveals that such polymer composites display tunable physicochemical properties and functional versatility for a wider fields of application versus graphene oxide, especially for contaminant removal over multiple adsorptiondesorption cycles. Melo et al. (2018) proposed the use of cellulose nanowhiskers to enhance the biosorption capacity of chitosan-g-poly(acrylic acid) hydrogel. The composites contained up to 20 w/w-% cellulose nanowhiskers showed an improved biosorption capacity towards Methylene Blue as compared to the pristine hydrogel. At 5 w/w-% cellulose nanowhiskers, the biosorbent presented the highest performance (qmax ¼ 1968 mg/g). The maximum removal of Methylene Blue (>98% of initial concentration 2 g/L) was achieved at the following conditions: contact time 60 min, pH 6, ionic strength 0.1 M, and room temperature. The biosorption mechanism was explained with the Langmuir type I model suggesting the formation of a Methylene Blue monolayer on the material surface. Using kinetic data, the interaction between the biosorbent and dye molecules was explained by chemisorption. The regeneration step was easy and the materials were regenerated at low cost by a simple immersion with an acidic solution. They were reusable more than 5 cycles without any loss of mechanical or chemical efficacy. This change in the pH of the solution reversed the biosorption because the electrostatic attraction mechanism was very sensible to pH. Yang et al. (2016b) developed a novel green biopolymer-based aerogel by freezedrying a hydrogel from cross-linking bifunctional hairy nanocrystalline cellulose and carboxymethylated chitosan through a Schiff base reaction. The authors used a sequential periodate and partial chlorite oxidation of cellulose, followed by a hot water treatment. The nanocelluloses, bearing aldehyde and carboxylic acid groups, facilitated the cross-linking with chitosan through imine bond formation while providing negatively charged functional groups, where chitosan was modified to accommodate carboxylic acid. The material was highly porous (pore size in the range of 35–70 μm) and negatively charged (the carboxyl group content was 3.2 mmol/g). It showed excellent biosorption performance over a wide range of pH. At pH ¼ 7.5, the maximum Methylene Blue dye biosorption capacity of the aerogel was 785 mg/g, obtained by fitting the equilibrium data to the Langmuir isotherm, yielding the highest biosorption capacity for any reported reusable biosorbents prepared from biopolymers. The performance was also comparable to commercial activated carbon (980.3 mg/g) and an as-received starch microparticle (716.3 mg/g), reported by Karoyo et al. (2018). The maximum biosorption is about of 86% of the amount calculated from charge stoichiometry, i.e. in reference to the chitosan carboxylated materials. The mechanism was explained by electrostatic complexation between acidic groups on the anionic aerogel with the cationic dye. At pH ¼ 3, the qmax was about 192 mg/g, which was about 25% of the maximum biosorption at pH ¼ 7.5. This decrease was due to the protonation of carboxylic acid

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groups. Dynamics of biosorption was modeled by numerically solving the unsteadystate diffusion-sorption mass balance in a 1D spherical coordinate, which attested to a diffusion-controlled process. The aerogel can be regenerated using acidic solution (pH < 2) in 60 min. Successful biosorption-regeneration cycles proved an excellent reusability (at least six cycles), and the biosorption capacity remained constant over a wide pH range.

10.6.3 Biosorption Mechanisms In the context of adsorption technology, the major challenge is to select the most promising types of adsorbent, mainly in terms of high capacity, often expressed by the qmax value. The next real challenge is to clearly identify the mechanism. For chitosan hydrogels used for the removal of dyes, the mechanisms have been demonstrated (Crini and Badot 2008; Elwakeel 2010; Sudha 2011). Biosorption involves similar binding mechanisms than those used with commercial synthetic organic resins, where dye binding takes place essentially on amine groups, although the contribution of hydroxyl groups is also possible. In general, dye elimination by chitosan involves two different mechanisms, complexation versus ion-exchange, depending on the pH since this parameter may affect the protonation of the macromolecule chains. Amine groups are susceptible to ionization as a function of pH (pka values in the range 6.3–6.5), that allow chitosan to form a polycation species. Hence, the protonated amine groups can form complexes with anionic species by electrostatic attractions and/or ion-exchange (Guo and Wilson 2012; Olivera et al. 2016; Salehi et al. 2016; Kyzas et al. 2017; Subramani and Thinakaran 2017; Wang and Zhuang 2017; Karimi et al. 2018). Figure 10.3 illustrates the mechanism of anionic dye adsorption by a cross-linked chitosan hydrogel under acidic conditions. In this case, the main interaction is electrostatic attraction. It is also possible that these two interactions can occur simultaneously depending on the composition of the material, the dye structure and its properties, and the solution conditions, e.g. pH, ionic strength and temperature. In neutral or alkaline solutions, chitosan is a weakly alkaline material due to the fact that amino groups are deprotonated. These reactive groups can bind dye species by complexation including chelation and coordination. Some of other reported interactions cited in other studies also include surface adsorption, physical adsorption and diffusion in the macromolecular network, hydrogen bonding (hydroxyl groups contribute to stabilizing dye binding on amine groups), and acid-base interactions.

10.6.4 Personal Comment Future research needs to explore some of the following aspects. To date, despite the large number of papers devoted to the biosorption of dyes onto chitosan hydrogels,

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Fig. 10.3 Mechanism of anionic dye adsorption by a cross-linked chitosan hydrogel under acidic conditions

the outstanding removal capabilities reported reveal unquestionable progress. However, biosorption processes of such materials are often limited by laboratory-based studies (Crini 2015). As industrial production of cross-linked chitosan hydrogels has not started, the biosorbents produced at lab-scale suffer from variability in their characteristics and lack of reproducibility, e.g. difficulty to produce materials at the same cross-linking density. Indeed, although various laboratories and a few companies can synthesize these materials to order, it is very difficult to find commercial sources of cross-linked hydrogels with guaranteed reproducible properties. Yet, the performance can vary depending on the conditions and the mode of preparation of hydrogels. However, this aspect is often neglected in the literature (Ahmed 2015; Ullah et al. 2015; Akhtar et al. 2016; de Luna et al. 2017a, b; Pakdel and Peighambardoust 2018; Van Tran et al. 2018). A more detailed study appears to be necessary to show how the chemical structure of the hydrogels affects the biosorption performance. Most studies focused on solutions contaminated with a single type of dye using standard conditions. Studies involving treatment of polycontaminated solutions and real effluents are indeed scarce. The experimental conditions should be chosen to simulate real wastewater on the basis of thermodynamics and studies of reaction kinetics. Much work in this area is necessary to demonstrate the possibilities on an industrial scale. Moreover, in spite of the abundance of literature reports, there is yet little information that detail comprehensive studies that compare various biosorbents and conventional commercial adsorbents at similar conditions. Comparisons of different materials are however difficult

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because of inconsistencies in the manner of data presentation. Due to scarcity of consistent cost information, cost comparisons are also difficult to make. This economic aspect is often neglected. Moreover, there is no systematic and comparative study taking into account the physicochemical properties of the different kind of dyes. Recently, some investigators have focused on studying the influence of the chemical structure of dyes on biosorption capacity. These studies would help in optimizing the type and amount of chitosan, i.e. in reference to material dosage and/ or the manner in which composite materials are prepared. The development of mechanistic and mathematical models in order to simulate the biosorption process are also important aspects in future studies that should be further developed. Finally, most studies have focused on the evaluation of biosorption performance, where only a few aim at gaining a greater understanding of the desorption strategy. On this topic, Kyzas et al. (2014) developed a phenomenological model which was capable of describing the data for all the initial dye concentrations. The model was extended to repeated batch biosorption/desorption cycles. Results showed that the decrease in biosorption efficiency during the cycles can be attributed to the requirement for total adsorbate mass conservation during each step, rather than thermodynamic irreversibility of the process. The inherent irreversibility cannot be identified by the biosorption/desorption cycle only, but requires advanced diagnostic tools such as spectroscopic techniques to show any changes in the structure and functional groups of the biosorbent.

10.7

Conclusion

The past two decades have shown an explosion in the development of new hydrogels that contain chitosan for use as biosorbents in dye removal from solution. Their potential use in biosorption-oriented processes is now recognized. However, in spite of numerous results, publications, and patents, cross-linked chitosan hydrogels are not yet produced on an industrial scale and are still not widely used for water treatment. Nevertheless, they will find industrial environmental applications due to their outstanding biosorption capacities and efficiency to treat either concentrated or diluted solutions of contaminants in aqueous media. In Europe, the tightening of regulations concerning effluent implies a better level of treatment of waste to tend towards zero pollution. With most types of conventional water treatment, it is difficult to remove pollutants including dyes present at low or very low levels in heterogeneous and variable effluents. Cross-linked chitosan hydrogels are shown to have efficacy to remove pollution present at trace levels. Further efforts will be necessary to convince industry to use these materials as part of the treatment strategy in their wastewater treatment plants.

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Index

A Active food packaging, 106, 110, 115 Agriculture, 3, 32, 125–140, 151, 178, 317, 340, 388, 393 Antimicrobial, 14, 18, 31–33, 47, 49–56, 58, 60, 62–70, 83, 92–95, 99, 106, 108–115, 132, 138, 139, 195, 197, 212, 249, 250, 275, 282, 291, 293, 321, 325, 328, 406 Antioxidant, 18–20, 24–32, 47–50, 56, 58, 60–70, 95, 99, 108, 109, 113–115, 178, 205, 265, 274, 278, 294, 319

B Barrier properties, 56, 90, 92, 94, 102, 105, 113 Batch, 355, 356, 385, 394, 397–401, 404, 414 Biocide elicitor, 128, 131, 132, 140 Biocompatible, 17, 69, 82, 159, 161, 163–165, 177, 181, 183, 184, 252, 254, 271, 280, 283, 290, 316, 340, 344, 348 Biodegradable, 15, 17, 69, 82, 86, 90, 95, 96, 98, 102, 108, 115, 152, 154, 157, 164, 177, 181, 184, 198, 208, 219, 221, 252, 289, 290, 292, 316, 321, 324, 340, 344, 348, 353, 355, 362, 363, 369, 370, 385, 388, 394, 407 Bioflocculant, 338, 341–352, 362, 371 Biomaterial, 2, 70, 148, 152–155, 157, 158, 162–164, 167, 280, 322, 392 Biomedical application, 243, 317, 320, 407 Bone system, 279–282

C Capsules, 3, 8, 177, 178, 182, 183, 192, 193, 208, 211, 214, 217, 218, 221, 243–245, 252, 262, 268, 269, 280, 288 Cardiovascular system, 272–274 Chitin, 1–33, 46, 83, 125–140, 148, 175–225, 242, 316, 338, 393 Chitin fertilizer, 129–131 Chitosan, 1–33, 45–69, 81–115, 127, 148, 175–224, 243, 316, 335–370, 383 Cross linked, 6, 13, 14, 148, 152–157, 160, 161, 163, 166, 183, 184, 187, 192, 198, 246, 247, 253, 259, 260, 279, 281, 284, 288, 292, 318, 381–414

D Dietary fibers, 3, 6 Diffusion, 98, 99, 103, 108, 164, 185–187, 190, 194, 196, 208, 248, 255, 256, 260, 261, 263, 267, 268, 276, 279, 289, 318, 319, 402, 410, 412 Digestive system, 32, 260–269, 291 Direct bioflocculation, 335–371 3D networks, 148, 389 Drug delivery, 12, 15, 148, 153, 158, 161–164, 175–225, 241–295, 317, 321–327 Drug delivery systems (DDS), 15, 158, 161, 162, 177, 182–185, 194, 225, 242–244, 248, 251–256, 261–264, 266, 268, 280–284, 293, 321, 322, 327

© Springer Nature Switzerland AG 2019 G. Crini, E. Lichtfouse (eds.), Sustainable Agriculture Reviews 36, Sustainable Agriculture Reviews 36, https://doi.org/10.1007/978-3-030-16581-9

427

428 Dyes, 57, 137, 152, 153, 156, 161, 162, 166, 340, 341, 345, 347, 359, 381–414

E Electrofluidodynamics, 317, 319

F Film, 25, 31, 49, 59, 82, 86, 90, 95, 107, 110, 136, 148, 178, 185, 197, 201, 247, 249, 291, 292, 321, 389 Fining agents, 16 Flexible, 95, 98, 154, 159, 163, 165, 178, 183, 185, 263, 393 Food additive, 16, 46, 49, 58, 82 Food preservation, 82 Functional compounds, 48, 49

G Gastritis, 12, 15

H Hydrogel, 12, 147–167, 177, 243, 317, 381–414

I Immune system, 286, 287

L Lipid binding, 5–9

M Mechanical properties, 56, 57, 69, 83–89, 95–108, 115, 148, 153, 156, 162–165, 194, 247, 249, 281, 283, 284, 292, 321, 404, 405 Modification, 13, 18, 52, 54, 83, 95, 98, 99, 102, 103, 115, 148, 152, 155, 156, 158, 166, 167, 201, 247, 319, 323, 328, 345, 348–350, 358, 360, 386, 388, 390–392, 394, 395, 400, 402

Index P Particles, 2, 7, 13–15, 21, 25, 27, 28, 50, 58, 59, 62, 84, 133, 151, 157, 177, 184, 191, 200, 201, 203, 204–206, 208–212, 214, 216, 243, 245–247, 259, 260, 263, 266, 270, 273, 275, 278, 280, 293, 316, 317, 321, 325–328, 337, 338, 341, 342, 344–346, 349–353, 355, 356, 364, 368, 369, 383, 393, 394, 404, 410 Plant growth regulator, 126, 127, 135, 139, 140 Polysaccharide, 2, 3, 46, 50, 52, 55, 59, 82, 83, 90, 99–104, 115, 148, 149, 153, 242, 243 Porosity, 18, 154, 161, 163, 166, 167, 182, 201, 281, 327, 368, 408 Prebiotic, 3–5

R Renal system, 277–279 Respiratory system, 269–272

S Scaffold, 133, 148, 152, 154, 159–165, 167, 195, 198, 199, 218, 219, 225, 257, 271, 279–281, 283, 284, 294, 317, 319, 321, 322, 327, 328, 389, 393, 407, 408 Seafood processing, 45–70 Sludge dewatering, 336, 337, 340, 345, 364–369, 371 Solubility, 2, 5, 12, 48, 52, 56, 65, 68, 84, 93, 127, 138, 139, 148, 149, 152, 159, 178–180, 188, 195, 200, 212, 216, 225, 243, 249, 263, 273, 279, 288, 293, 317, 319, 320, 349, 350, 356, 363, 382, 395 Stabilizers, 3, 17, 22 Sustainable development, 383

U UV protect, 81

V Vaginal system, 274–277 N Nanofibers, 69, 130, 134, 135, 207, 247, 285, 316, 320–323, 389 Nanoparticles, 8, 15, 28, 50, 152, 155, 177, 191, 203, 211, 246, 260, 279, 281, 316, 327, 389, 402

W Wastewater treatment, 153, 158, 162, 336–345, 349, 350, 358, 360, 364, 365, 370, 371, 383, 388–389, 393, 398, 406–408, 414