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Tissue Engineering Strategies for Organ Regeneration Editors Naznin Sultana Medical Academy, Prairie View A&M University, Texas, USA Sanchita Bandyopadhyay-Ghosh Department of Mechanical Engineering Manipal University Jaipur Rajasthan, India Chin Fhong Soon Biosensor and Bioengineering Laboratory Microelectronics and Nanotechnology-Shamsuddin Research Centre (MiNT-SRC) AND Faculty of Electrical and Electronic Engineering Universiti Tun Hussein Onn Malaysia Batu Pahat, Johor, Malaysia p, A SCIENCE PUBLISHERS BOOK Cover credit: Cover illustrations reproduced by kind courtesy of Dr. Mohd. Izzat Hassan and Mr. Kapender Phogat. CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2020 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20191003 International Standard Book Number-13: 978-1-138-39154-3 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the valid- ity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or uti- lized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopy- ing, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Names: Sultana, Naznin, editor. | Bandyopadhyay-Ghosh, Sanchita, 1971- editor. | Soon, Chin Fhong, 1974- editor. Title: Tissue engineering strategies for organ regeneration / editors, Naznin Sultana, Sanchita Bandyopadhyay-Ghosh, Chin Fhong Soon. Description: Boca Raton : CRC Press, Taylor & Francis Group, [2020] | Includes bibliographical references and index. Identifiers: LCCN 2019036051 | ISBN 9781138391543 (hardback) Subjects: LCSH: Tissue scaffolds. | Guided tissue regeneration. | Tissue engineering. | Biomedical materials. | Regeneration (Biology) Classification: LCC R857.T55 T574 2020 | DDC 610.28--dc23 LC record available at https://lccn.loc.gov/2019036051 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Preface Tissue Engineering Strategies for Organ Regeneration addresses the multidisciplinary tissue engineering approaches in regenerating different types of tissues and organs. This book provides a comprehensive summary of the recent improvements of biomaterials used in scaffold-based tissue engineering and describes the different protocols for the manufacture of scaffolds. In addition, it describes the mechanisms behind cell-biomaterials interactions. In addition, this book focuses on advanced technologies such as microfabrication techniques for tissue engineering approaches. Several in vitro and in vivo functions of tissue engineering scaffolds for several applications are provided. Tissue engineering scaffolds with multifunctional properties such as biocompatibility, conductivity and antibacterial characteristics are addressed in the book. This book not only addresses the present constraints in tissue engineering applications but also highlights the future directions of tissue engineering applications. This book is written by experts from around the world in tissue engineering field. Chapter 1 focuses on designing biomaterials for regenerative medicine: state-of-the-art and future perspectives. Chapter 2 deals with new generation materials for applications in bone tissue engineering and regenerative medicine. Chapter 3 discusses enhanced scaffold fabrication techniques for optimal characterization. Chapter 4 describes next generation tissue engineering strategies by combination of organoid formation and 3D bioprinting. Chapter 5 provides a strategy for regeneration of three- dimensional (3D) microtissues in microcapsules: aerosol atomization technique. Chapter 6 highlights BioMEMS devices for tissue engineering. Chapter 7 focuses on injectable scaffolds for bone tissue repair and augmentation. Chapter 8 presents the details associated with bio-ceramics for tissue engineering. Chapter 9 reviews stimulus-receptive conductive polymers for tissue engineering. Chapter 10 delivers PCL /Chitosan/Nanohydroxyapatite/Tetracycline composite scaffolds for bone tissue engineering. All the chapters of this book are self-contained and focused on current tissue engineering strategies for organ restoration. It is expected that the book will be a great resource and reference for the multidisciplinary societies such as the Researchers, Advanced Undergraduate and Postgraduate students in Biomedical Engineering, Materials Engineering, Chemical Engineering, and Clinical investigators. Naznin Sultana Sanchita Bandyopadhyay-Ghosh Chin Fhong Soon Contents Preface iii 1. Designing Biomaterials for Regenerative Medicine: State-of-the-Art and Future Perspectives 1 Zohreh Arabpour, Mansour Youseffi, Chin Fhong Soon, Naznin Sultana, Mohammad Reza Bazgeir, Masoud Mozafari and Farshid Sefat 2. New Generation Materials for Applications in Bone Tissue Engineering and Regenerative Medicine 10 Ravikumar K, Ashutosh Kumar Dubey and Bikramjit Basu 3. Enhanced Scaffold Fabrication Techniques for Optimal Characterization 23 Tshai Kim Yeow, Lim Siew Shee, Yong Leng Chuan and Chou Pui May 4. Next Generation Tissue Engineering Strategies by Combination of Organoid Formation and 3D Bioprinting 51 Shikha Chawla, Juhi Chakraborty and Sourabh Ghosh 5. A Strategy for Regeneration of Three-Dimensional (3D) Microtissues in Microcapsules: Aerosol Atomization Technique 63 Chin Fhong Soon, Wai Yean Leong, Kian Sek Tee, Mohd Khairul Ahmad and Nafarizal Nayan 6. BioMEMS Devices for Tissue Engineering 81 Tao Sun and Chao Liu 7. Injectable Scaffolds for Bone Tissue Repair and Augmentation 91 Subrata Bandhu Ghosh, Kapender Phogat and Sanchita Bandyopadhyay-Ghosh 8. Bio-Ceramics for Tissue Engineering 126 Hasan Zuhudi Abdullah, Te Chuan Lee, Maizlinda Izwana Idris and Mohamad Ali Selimin 9. Stimulus-Receptive Conductive Polymers for Tissue Engineering  144 Naznin Sultana 10. Evaluation of PCL / Chitosan/Nanohydroxyapatite / Tetracycline Composite Scaffolds for Bone Tissue Engineering 157 Rashid Bin Mad Jin, Naznin Sultana, Chin Fhong Soon and Ahmad Fauzi Ismail Index 171 Color Plate Section 173 1 Designing Biomaterials for Regenerative Medicine: State-of- the-Art and Future Perspectives Zohreh Arabpour1, Mansour Youseffi2, Chin Fhong Soon3, Naznin Sultana4, Mohammad Reza Bazgeir5, Masoud Mozafari6, 7 and Farshid Sefat2, 8* 1.1  INTRODUCTION The complexity of the human body can be simplified when stating the matter from which it is composed. To expand, the body is known to be made up of four tissue types, including epithelial tissue, neural tissue, muscle tissue and connective tissue. Each tissue type is created from a varying physiology, which contributes to the functionality of the matter. For example, the muscle tissue is rich in mitochondria due to the excessive need for oxygen in order for it to function with great exertion of energy. Table 1.1 demonstrates the four tissue types, and clarifies both the functionality of the matter alongside the cells within the tissue which allows the tissue type to work as it should. 1 Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2 Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, UK. 3 Biosensor and Bioengineering Lab, MiNT-SRC, Faculty of Electrical and Electronic Engineering, Universiti Tun Hussein Onn Malaysia, 86400 Parit Raja, Batu Pahat, Johor, Malaysia. 4 Medical Academy, Prairie View A&M University, TX 77446, USA. 5 Royal National Orthopaedic Hospital, Brockley Hill, London, UK. 6 Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran. 7 Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. 8 Interdisciplinary Research Centre in Polymer Science & Technology (IRC Polymer), University of Bradford, Bradford, UK. * Corresponding author: [email protected] 1 2 Tissue Engineering Strategies for Organ Regeneration TABLE 1.1  The four main tissue types in the human body Tissue Type Location Functions Subtype Epithelial Cover inner and outer organ and Protection, secretion, absorption Squamous, columnar, cuboidal, body surfaces simple, pseudostratified, stratified Connective Between other tissues Support and protect body Loose and dense Muscle Attached to skeletal system, Movement Skeletal or striated, cardiac digestive system and smooth Nervous Distributed in the body Regulates and controls physical Central and peripheral system functions 1.2  ORGAN SYSTEMS There are 11 main organ systems in the human body, composed of different variations of the main tissue types. These organ systems are vital to quality of life, and if one organ within a system fails to carry out its purpose, fatality could occur, hence the need of tissue engineering intervention. Trauma is one of the main causes for organ failure, and the body responds through expressing genes, growth factors and activating cells as a healing process. Unfortunately, humans do not possess the capability to regrow limbs, such as the salamander; however in terms of natural tissue growth, the extracellular matrix for some tissues (such as simple connective) can be rebuilt to a certain extent (Krafts 2010, Zadpoor 2015). As technology has advanced, novel methods have been developed and tested, portraying that synthetic tissues can exponentially increase the duration of a life cycle, by allowing continuity of functioning organ systems. Examples of beneficial tissue regeneration include creation of blood vessels for cardiac patients, bone scaffolds for amputees, skin grafts for burn patients and many more, to be discussed further in the chapter. 1.3  ESSENTIAL REQUIREMENTS IN DESIGNING BIOMATERIALS FOR TISSUE  ENGINEERING AND REGENERATIVE MEDICINE APPLICATIONS 1.3.1  Mechanical Requirements The chemical and physical optimization of new biomaterials in order to interact with living cells are being studied by many research groups (Khan and Tanaka 2017). Synthetic or hybrid biomaterials should be developed to adapt for living systems or live cells in vitro and in vivo. The selection and design of an appropriate biomaterial is determined by specific application of scaffold. Some of the mechanical properties that are of utmost importance are hardness, plasticity, elasticity, tensile strength and compressibility. For example, ceramics such as hydroxyl apatite (HAp), and tricalcium phosphate (TCP) are appropriate for bone regeneration (Khan and Tanaka 2017). The scaffold of the bioceramic should mimic mechanical properties of the anatomical location that will be planted and the degradation rate should be consistent with bioactive surface for suitable tissue regeneration. Since the regeneration rates of bone are different for different age groups, this must be taken into consideration when designing scaffolds because the rate of regeneration in older adults is slower than young individuals (O’Brien 2011). Maintaining the mechanical behavior of implanted scaffolds structure and tolerance of stress and loads during the reconstruction is very important. The stability of scaffolds in biological systems depends on some factors such as stress, strength, elasticity, temperature and absorption of the material associated with chemical degradation. Therefore, in order to select an appropriate biomaterial, it is important to assess some of the following properties: (1) Elastic behavior—measurement of Designing Biomaterials for Regenerative Medicine: State-of-the-Art and Future Perspectives 3 pressure in response to tensile or compressed stress during the force. This reversible behavior could be assessed by linear relation between stress and strain. Stress is a measure of load and strain is a measure of displacement; (2) Plastic behavior—when (or compression) uniaxial tensile stress reaches yield strength, permanent deformation occurs; (3) Tensile strength—the highest stress that material can endure before breakdown; (4) Ductility—the plastic strain at failure. Plasticity before breaking; (5) Toughness—the energy needed to break a unit volume of material; (6) Flexural behavior— the relationship between a flexural stress and strain in response to a tensile or compressive stress perpendicular to the bar. The mechanical behavior of materials can be equated by some factors. Swelling, porosity pore size, shape, orientation, and connectivity are some of these factors that directly impacts mechanical properties of the biomaterial (Olson et al. 2011). The balance between mechanical behaviors and porous pattern allowing cell penetration and vascularization is necessary to ensure success of scaffolds in tissue engineering. The mechanical stiffness as well as the roughness of materials and the physical stimulation of the three-dimensional microstructure of the scaffold significantly influence the cellular regeneration, cellular polarization and balanced intracellular signaling (Olson et al. 2011). 1.3.2  Biological Requirements Production of appropriate scaffolds to support the proliferation and differentiation of cells to mimic biological function of extracellular matrix proteins is another essential step to generate appropriate 3D biomimetic scaffolds in tissue engineering (Chiono et al. 2009). Biocompatibility of scaffolds must be ensured, to avoid undesirable immune responses to the implant and ectopic calcifications in vivo. The surface of biomaterials should have excellent chemical properties to improve attachment, migration, proliferation, and differentiation of cells (Mandal et al. 2009). Biomaterials used as scaffold in tissue engineering should be non-toxic to eliminate inflammatory or allergic reactions in the human body (Moztarzadeh et al. 2018). The human body’s response to the implant determines the success of the implanted biomaterial, and assesses the degree of biocompatibility of a substance. The tissue response to the materials and materials’ degradation in the body system are two major factors that affect the biocompatibility of biomaterial (Sefat et al. 2018). In this context, biodegradability should be controllable to support the formation of new tissue (Grayson et al. 2003). After a biomaterial implant is exposed to the body, tissues start to react to the implant surface. The body responses to implants are: (1) Thrombosis or coagulation of blood after platelets are attached to the surface of implant and, (2) Formation of fibrous capsule around the surface of implant (Chiono et al. 2009). The kind of reactions depends on type of biomaterial that is used in the implants. Biomaterials based on the body responses can be classified into three main groups: bioinert, bioactive and bioresorbable. The bioresponses and examples of each classified biomaterials are as shown in Table 1.2 (Geetha et al. 2009). TABLE 1.2  Biomaterials classification and interaction with tissue Classification Response Examples Bioinert materials Minimal interaction with tissue. Zirconia, polymethyl metha acrylate Formation of connective tissue capsules (PMMA), alumina, titanium, etc (0.1-10 lm) around the implant, without any attachment to the implant surface Bioactive materials Interaction with tissue. Bioglass, glass ceramic, synthetic, Formation of new tissue around the implant and hydroxyl apatite (HAP) strongly merges with the implant surface Bioresorbable materials Dissolved and replaced by the advanced tissue Polyglycolic acid and Polylactic, tricalcium phosphate, composites of proteins

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