Published by Pan Stanford Publishing Pte. Ltd.

Penthouse Level, Suntec Tower 3 8 Temasek Boulevard Singapore 038988 Email: editorial@panstanford.com Web: www.panstanford.com British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

Handbook of Intelligent Scaolds for Tissue Engineering and Regenerative Medicine Copyright c 2012 Pan Stanford Publishing Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.

ISBN 978-981-4267-85-4 (Hardcover) ISBN 978-981-4267-86-1 (eBook)

Printed in the USA

I would like to dedicate this handbook to my wife, Isabella Seong Hee Koh; my children, Jerome Taeuk and Daniel Taehoon; and my mother. G.K.

Contents

Preface I. INTRODUCTION 1 Biomaterials and Manufacturing Methods for Scaold in Regenerative Medicine Gilson Khang 1.1 Introduction 1.2 Biomaterials for Regenerative Medicine and Tissue Engineering 1.2.1 Importance of Scaold Matrices in Regenerative Medicine and Tissue Engineering 1.2.2 Bioceramic Scaolds 1.2.2.1 Calcium phosphate 1.2.2.2 Tricalcium phosphate 1.2.2.3 Hydroxyapatite 1.2.2.4 Bioglass 1.2.2.5 Demineralized bone particle 1.2.3 Synthetic Polymers 1.2.3.1 Poly(-hydroxy ester)s 1.2.3.2 Polyanhydride 1.2.3.3 Poly(propylene fumarate) 1.2.3.4 PEO and its derivatives 1.2.3.5 Polyvinylalcohol 1.2.3.6 Oxalate-based polyesters (polyoxalate) 1.2.3.7 Polyphosphazene 1.2.3.8 Biodegradable polyurethane 1.2.3.9 Other synthetic polymers

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1.2.4 Natural Polymers 1.2.4.1 Fibrin 1.2.4.2 Collagen 1.2.4.3 Alginate 1.2.4.4 Small intestine submucosa 1.2.4.5 Silk 1.2.4.6 Hyaluronan 1.2.4.7 Chitosan 1.2.4.8 Agarose 1.2.4.9 Acellular dermis 1.2.4.10 Polyhydroxyalkanoates 1.2.4.11 Other natural polymers 1.2.5 Bioactive Molecules Release System for the Regenerative Medicine and Tissue Engineering 1.3 Scaold Fabrication and Characterization 1.3.1 Fabrication Methods of Scaolds 1.3.1.1 Electrospinning method 1.3.1.2 PGA nonwoven sheet 1.3.1.3 Porogen-leaching methods 1.3.1.4 Gas-foaming method 1.3.1.5 Phase separation method 1.3.1.6 Rapid prototyping 1.3.1.7 Injectable gel method 1.3.2 Physicochemical Characterization of Scaolds 1.3.3 Sterilization Method for Scaolds 1.4 Conclusions II. CERAMIC AND METAL SCAFFOLD 2 Innovative Bioinspired SIC Ceramics from Vegetable Resources M. Lopez-Alvarez, P. Gonzalez, J. Serra, A. de Carlos, S. Chiussi, and B. Leon 2.1 Introduction 2.2 Bioinspired SiC Ceramics 2.3 Biocompatibility Studies 2.4 Conclusions and Outlook

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3 Production of Three-Dimensional Hierarchical Nano Ti-Based Metals Scaolds for Bone Tissue Grafts Shuilin Wu, Xiangmei Liu, Paul K. Chu, Tao Hu, Kelvin W. K. Yeung, Jonathan C. Y. Chung, and Zushun Xu 3.1 Introduction 3.2 Fabrication and Characteristics of Macroporous Ti-Based Alloys 3.3 Natural Growth and Characterization of 1D Nano Titanates 3.4 Conclusions and Outlook 4 Bioceramic ScaoldBone Tissue Engineering Willi Paul and Chandra P. Sharma 4.1 Introduction 4.2 Bioceramics 4.3 Bone Tissue Engineering 4.4 Research Perspective 4.5 Basic Questions in Bone Tissue Engineering 4.6 Conclusion III. INTELLIGENT HYDROGEL 5 Induction of Soft-Tissue Regeneration Using Hydrogels Optimized for Inammatory Response Nicholas P. Rhodes and John A. Hunt 5.1 Introduction 5.2 Hyaluronan as a Base Polymer for Regenerative Therapies 5.2.1 Experience with Esteried Hyaluronan 5.2.2 Strategies for Controlling Inammation 5.2.3 Amidated Hyaluronan Biomaterials 5.3 Results of Implantation of Amidated Gels 5.4 Conclusions and Outlook 6 Enzymatically Triggered in situ Gel-Forming Biomaterials for Regenerative Medicine Yoon Ki Joung, Kyung Min Park, and Ki Dong Park 6.1 Introduction

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6.2 In situFormed Hydrogels as Injectable Scaolds 6.3 Enzyme-Triggered Hydrogels 6.3.1 HRP-Catalyzed Systems 6.3.2 TGase-Catalyzed Systems 6.3.3 Other Enzyme-Catalyzed Systems 6.4 Conclusions and Outlook 7 Thermo-Sensitive Injectable Scaolds for Regenerative Medicine Moon Suk Kim, Jae Ho Kim, Gilson Khang, and Hai Bang Lee 7.1 Introduction 7.2 In situForming Hydrogels Formed by Electrostatic Interactions 7.2.1 In situForming Chitosan Hydrogel Scaolds 7.2.2 In situForming Alginate Hydrogel Scaolds 7.3 In situForming Hydrogels Formed by Hydrophobic Interactions 7.3.1 PEGPPG Block Copolymers as in situ Forming Hydrogel Scaolds 7.3.2 PEGOther Degradable Polyesters as in situForming Hydrogel Scaolds 7.3.3 Other Polymers as in situForming Hydrogel Scaolds 7.4 Conclusions and Outlook

113 114 115 120 121 122 127 128 129 129 132 132 134 135 136 137

8 Photocurable Hydrogel for Tissue Regeneration 143 Min Soo Bae and Il Keun Kwon 8.1 Introduction 143 8.2 Photopolymerization of Hydrogels 146 8.2.1 Photoinitiators of Photocurable Hydrogel 147 8.3 Photopolymerizable Materials 147 8.3.1 Photocurable Hydrogel from Natural Polymers 149 8.3.1.1 Photo-cross-linkable collagen and gelatin 149 8.3.1.2 Photo-cross-linkable hyaluronic acid 151 8.3.1.3 Photo-cross-linkable chitosan 151 8.3.2 Photocurable Hydrogel from Synthetic Polymers 152 8.3.2.1 Photo-cross-linkable poly(ethylene glycol) 153

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8.3.2.2 Transition in theoretical work 8.3.2.3 Photo-cross-linkable poly(hydroxyl esters) 8.4 Summary and Outlook 9 Hyaluronan-Based Hydrogel Scaolds Insup Noh 9.1 Introduction 9.2 Characteristics of Hyaluronic Acid in Biomedical Engineering 9.3 HA Derivatives 9.3.1 Ester Derivatives 9.3.2 Carbodiimide (R1 N=C=NR2 ) 9.3.3 Sulfydrylation (HASH) 9.3.4 Sulfation 9.3.5 Acrylates 9.4 Fabrication of Hyaluronic Acid Hydrogels 9.4.1 Hydrogel Formation by Direct Cross-Linking Methods 9.4.1.1 Diepoxy cross-linking method 9.4.1.2 Bifunctional amine cross-linkers 9.4.1.3 Divinyl sulfone 9.4.1.4 In situ HA hydrogels 9.4.1.5 HAaldehyde hydrogels 9.4.1.6 Azaide 9.5 Hyaluronic Acid-Based Hybrid Hydrogels 9.5.1 HACollagen/Oligopeptide Hydrogels 9.5.2 HANatural Polymer Hybrid Hydrogels 9.5.3 HASynthetic Polymer Hybrid Hydrogels 9.6 Conclusions and Outlook IV. ELECTROSPINNING NANOFIBER 10 Guidance of Cell Adhesion, Alignment, Inltration, and Dierentiation on Electrospun Nanobrous Scaolds Sang Jin Lee and James J. Yoo 10.1 Introduction 10.2 Electrospinning Technology

155 156 157 165 165 167 169 169 169 170 171 172 172 173 173 173 176 177 184 187 188 188 190 191 192

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10.3 Cellular Interactions with Electrospun Fibrous Scaolds 10.3.1 Cell Adhesion 10.3.2 Cell Alignment 10.3.3 Cell Inltration 10.3.4 Cellular Dierentiation 10.4 Summary 11 Fabrication of Tissue Engineering Scaolds by Electrospinning Techniques Jiang Chang, Wenguo Cui, Yue Zhou, and Lei Chen 11.1 Introduction 11.2 Electrospun Nanobers 11.3 One-Dimensional Electrospun Fibrous Bundle 11.4 Two-Dimensional Electrospun Fibrous Membranes 11.5 Three-Dimensional Electrospun Fibrous Scaolds 11.6 Conclusions and Outlook

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219 220 222 224 225 227 229

12 Biodegradable Tunable Nanobrous Matrix for Regenerative Medicine 233 Shanta Raj Bhattarai, Madhab Prasad Bajgai, and Hak Yong Kim 12.1 Introduction 234 12.2 Electrospun Nanober Matrices 237 12.3 Electrospun Nanober Matrices as Tissue Regenerative Matrices 239 12.3.1 Skin Grafts 240 12.3.2 Blood Vessel (Vascular and Cardiac) Grafts 241 12.3.3 Ligament Grafts 244 12.3.4 Nerve Grafts 245 12.3.5 Skeletal Muscle Grafts 247 12.3.6 Bone Tissue Grafts 248 12.3.7 Articular Cartilage Tissue Grafts 249 12.3.8 Drug, DNA, Protein, and Enzyme Delivery 250 12.4 Conclusions 252

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13 PHBV/Proteins Composite Nanobrous Scaolds for Tissue Engineering K. M. Kamruzzaman Selim, Zhi-Cai Xing, and Inn-Kyu Kang 13.1 Introduction 13.2 Electrospinning Technique 13.3 Nanocomposite Preparation 13.3.1 Principle of the Blending Method 13.4 Typical PHBV/Protein Nanocomposite Preparation 13.4.1 Electrospun PHBV/Collagen Composite Nanobrous Scaolds 13.4.2 Electrospun PHBV/Gelatin Composite Nanobrous Scaolds 13.5 Interaction of As-Prepared Nanocomposites with Cells and Results Obtained Thereby 13.5.1 PHBVCol Nanocomposites 13.5.2 PHBV/Gelatin Nanocomposites 13.6 Conclusions 14 Nanobrous Scaolding for Bone Tissue Engineering Hae-Won Kim 14.1 Introduction 14.2 Nanober Production Tools and Electrospinning 14.2.1 Phase Separation 14.2.2 Self-Assembly 14.2.3 Electrospinning 14.3 Nanobrous Materials for Bone Tissue Engineering 14.3.1 Biodegradable Polymers 14.3.2 Bioactive Inorganics 14.3.3 Composite Nanobers 14.4 Functionalization of Nanobers for Bone Tissue Engineering 14.4.1 Surface Modications 14.4.2 Incorporation of Biomolecules 14.5 Concluding Remarks 15 Strategies to Engineer Electrospun Scaold Architecture and Function Aaron S. Goldstein, Christopher A. Bashur, and Joel Berry 15.1 Overview

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15.2 Design of Fiber Topography to Aect Cell Function 15.2.1 Eect of Electrospun Fiber Alignment on Cell Morphology 15.2.2 Eect of Fiber Diameter on Cell Morphology 15.2.3 Eect of Fiber Roughness 15.3 Creation of Larger Pores to Facilitate Cell Entry into Scaolds 15.3.1 Co-Electrospinning of a Sacricial Polymer 15.3.2 Incorporation of Extruded Fibers 15.3.3 Incorporation of Porogens into Electospun Meshes 15.3.4 Chemotaxis and other Considerations Regarding Cell Inltration into Electrospun Meshes 15.3.5 Electrospraying or Electrospinning of Cells 15.4 Creation of Three-Dimensional Architectures for Tissue-Specic Applications 15.4.1 Processing Techniques for Tube- and Cord-Shaped Structures 15.4.2 Variations on the Tube Structure for Blood Vessel and Annulus Fibrosis Applications 15.5 Composite Scaolds and the Spatial Heterogeneity 15.6 Mechanics of Scaold Deformation and Failure Under Strain 15.7 Conclusions V. NOVEL BIOMATERIALS FOR SCAFFOLD 16 Synthetic/Natural Hybrid Scaold for Tissue Regeneration Gilson Khang, Soon Hee Kim, Su Hyun Jung, and Yun Sun Yang 16.1 Introduction 16.2 Fibrin/PLGA Hybrid Scaolds 16.2.1 Fibrin/PLGA Hybrid Scaolds for Cartilage Regeneration in vivo and in vitro

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16.2.2 Fibrin/PLGA Hybrid Scaolds for IVD in vitro 16.3 The Eect of DBPs on the Reduction of Inammatory Reaction of the PLGA/DBP Hybrid Scaold 16.3.1 Cell Viability 16.3.2 Inammatory Cytokine Expression 16.3.3 In vivo Tissue Response 16.4 The Eect of SIS on the Host Tissue Response to PLGA/SIS Hybrid Scaolds 16.5 Conclusions and Outlook

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323 324 325 326 330 333

17 Articial Binding Growth Factors 337 Takashi Kitajima and Yoshihiro Ito 17.1 Introduction 337 17.2 Diusible and Nondiusible Actions of Growth Factors 338 17.3 Gene-Engineered Binding Growth Factors 340 17.3.1 Collagen-Binding Growth Factors 341 17.3.2 Fibrin-Binding Growth Factors 344 17.3.3 Cell-Binding Fusion Proteins 345 17.3.4 Other Binding Growth Factors 346 17.4 Application of Engineered Binding Growth Factors 346 17.4.1 Skin Wound Repair 347 17.4.2 Repair of Cardiovascular Tissues 347 17.4.2.1 Materials that induce angiogenesis 348 17.4.2.2 Articial blood vessel and heart valve 348 17.4.3 Nerve Regeneration 349 17.4.4 Bone Regeneration 349 17.5 Concluding Remarks 350 18 Porous Poly(Lactic-Co-Glycolic Acid) Microsphere as Cell Culture Substrate and Cell Transplantation Vehicle Byung-Soo Kim 18.1 Introduction

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18.2 Fabrication of Macroporous PLGA Microspheres 18.3 Macroporous PLGA Microsphere as an ASC Culture Substrate 18.4 Macroporous PLGA Microsphere as an ASC Transplantation Vehicle 18.5 Concluding Remarks 19 Suppression of Inammatory Reactions on MPC Polymer Surfaces Yasuhiko Iwasaki and Kazuhiko Ishihara 19.1 Introduction 19.2 Molecular Design and Fundamental Property of MPC Polymers 19.3 Secretion of HSP mRNA from Adherent Cells on MPC Copolymers 19.4 Reduction of in vivo Host Responses to MPC Polymer Hydrogels 19.5 Newly Extracellular Matrices Generated from MPC Polymers 19.6 Conclusion 20 Extracellular MatrixBased Scaolds from Scratch Willeke F. Daamen, Kaeuis A. Faraj, Martin J. W. Koens, Gerwen Lammers, Katrien M. Brouwer, Peter J. E. Uijtdewilligen, Suzan T. M. Nillesen, Luc A. Roelofs, Jody E. Nuininga, Paul J. Geutjes, Wouter F. J. Feitz, and Toin H. van Kuppevelt 20.1 Introduction 20.2 Scaolds with a Specic Three-Dimensional Structure 20.2.1 Flat Films 20.2.2 Porous Scaolds 20.2.2.1 Unidirectional scaolds 20.2.3 Tubular Porous Scaolds 20.3 Scaolds with Dened Molecular Composition 20.3.1 Purication of Scaold Components 20.3.2 Cross-Linking and Covalent Attachment of Glycosaminoglycans 20.3.3 Binding of Growth Factors

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365 365 367 369 373 376 380 385

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20.4 Acellular Scaolds for in vivo Tissue Regeneration 20.5 Future Outlook 21 Design of Biomimetic Scaolds for Liver Tissue Engineering Chong-Su Cho, Hu-Lin Jiang, Takashi Hoshiba, and Toshihiro Akaike 21.1 Introduction 21.2 Specic Interaction between Galactose Residue and ASGPR 21.3 Bulk Modication of Biomaterials 21.4 Surface Modication of Biomaterials 21.5 Criteria to Design Biomimetic Scaolds for Liver Tissue Engineering 21.5.1 Topology of the ECM 21.5.2 Coculture 21.5.3 Cell Sources 21.6 Summary 22 Hybrid Porous Scaolds of Biodegradable Synthetic Polymers and Collagen for Tissue Engineering Guoping Chen, Naoki Kawazoe, and Tetsuya Tateishi 22.1 Introduction 22.2 PLGA-Collagen Hybrid 22.3 PLGA-Collagen Hybrid Mesh 22.4 PLLA-Collagen Hybrid Braid 22.5 Biphasic Hybrid Porous Scaold 22.6 Leak-Proof Hybrid Scaolds 22.7 Conclusions 23 Chitin and Chitosan for Tissue Engineering Application Sang Jun Park and Chun-Ho Kim 23.1 Introduction 23.2 Chitin and Chitosan 23.3 Chitosan Sponge Scaolds 23.3.1 Preparation of Chitosan Sponge Scaolds 23.3.2 Cell Culture on Chitosan Sponge Scaolds 23.4 Chitosan Bead Scaolds

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23.4.1 Preparation of Chitosan Bead Scaolds 23.4.2 Cell Culture on Chitosan Bead Scaolds 23.5 Chitosan Hydrogels 23.5.1 Preparation of Chitosan Hydrogels 23.5.2 Cell Culture on Chitosan Hydrogels 23.6 Conclusions and Outlook VI. NOVEL FABRICATION METHODS FOR SCAFFOLD 24 Controlling a Cellular Niche in Scaold Designs for Epithelial Tissue Engineering Zhilian Yue, Yan-Ru Lou, Nur Aida Abdul Rahim, and Hanry Yu 24.1 Introduction 24.2 Native Extracellular Microenvironment for Epithelial Cells 24.2.1 Extracellular Matrix and Growth Factors 24.2.2 Epithelial Polarity, Dierentiation, and Function 24.2.3 Other Physical Factors: Biomechanics and Microuidics 24.3 Engineering an Extracellular Microenvironment for Epithelial Cells 24.3.1 The State of Art 24.3.1.1 2D plastic substrata 24.3.1.2 3D polymeric scaolds 24.3.2 Spatial and Temporal Presentation of Extracellular Cues in Scaolds for Liver Tissue Engineering 24.3.3 Biomechanical Issues 24.3.4 Fluid Dynamics and Mass Transfer 24.4 Applications and Outlook 25 Biological Implications of Polymeric Scaolds for Bone Tissue Engineering Developed via Solid Freeform Fabrication Andrew B. Yeatts and John P. Fisher 25.1 Introduction 25.1.1 The Need for Bone Tissue Engineering

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25.2

25.3

25.4

25.5

25.6

25.1.2 Benets of Scaolds Developed via Solid Freeform Fabrication Stereolithography 25.2.1 Scaold-Manufacturing Process 25.2.2 Biological Implications Three-Dimensional Printing 25.3.1 Scaold-Manufacturing Process 25.3.2 Biological Implications Selective Laser Sintering 25.4.1 Scaold-Manufacturing Process 25.4.2 Biological Implications Fused Deposition Modeling 25.5.1 Scaold-Manufacturing Process 25.5.2 Biological Implications Conclusions

485 486 486 488 490 490 491 494 494 496 498 498 499 502

26 Considerations on the Structure of Biomaterials for Soft- and Hard-Tissue Engineering Hideaki Kagami, Hideki Agata, Makoto Satake, and Yuji Narita 26.1 Introduction 26.2 Material Design for Soft-Tissue Engineering: Small-Caliber Vascular Grafts 26.2.1 Tissue Engineering for Cardiovascular Surgery 26.2.2 Decellularized Tissue Scaolds for Tissue-Engineered Small-Caliber Vascular Grafts: Methodology, Biocompatibility, and Mechanical Properties 26.2.3 Biodegradable Synthetic Polymer Scaolds for Tissue-Engineered Small-Caliber Vascular Grafts 26.2.4 How to Create Scaolds for Tissue-Engineered Small-Diameter Vascular Grafts Using Electrospun Nanobers 26.2.5 Biocompatibility and Mechanical Properties of Electrospun Synthetic Scaolds

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26.2.6 Prospects of Designing a Scaold for Cardiovascular Tissue Engineering 26.3 Scaold Design for Hard-Tissue Engineering: Alveolar Bone 26.3.1 Bone Reconstruction/Regeneration in Orthopedic and Oral Applications 26.3.2 Ideal Ceramic Scaolds for Bone Tissue Engineering from a Clinical Point of View 26.3.3 Fate of Transplanted Scaolds in the Human Body: A Clinical Study of Alveolar Bone Tissue Engineering Using Bone Marrow Stromal Cells and -TCP 26.3.4 Considerations for Designing Scaolds for Clinical Bone Tissue Engineering 26.3.5 Prospective Novel Biomaterials for Hard-Tissue Engineering 26.3.5.1 Composite and combined materials 26.3.5.2 Growth factor incorporation into scaolds 26.4 Conclusions and Outlook 27 Mechano-Active Scaolds Sang-Heon Kim, Youngmee Jung, Young Ha Kim, and Soo Hyun Kim 27.1 Introduction 27.2 Mechano-Active Scaolds 27.2.1 Elastic Biodegradable PLCL Copolymer 27.2.2 Tubular PLCL Scaold 27.2.3 Seamless Double-Layered Scaold 27.2.4 Sheet-Form PLCL Scaold 27.3 Mechano-Active Tissue Engineering 27.3.1 Vascular Tissue Engineering 27.3.2 Cartilage Tissue Engineering 27.4 Conclusions and Outlook 28 Reinforced Scaold for Tissue Engineering Young-Kwon Seo and Jung-Keug Park 28.1 Introduction

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28.2 Biocompatibility of Reinforced Composite Scaolds 28.3 Reinforced Composite Scaold for Bioarticial Tissue 28.3.1 Bioarticial Ligament and Tendon 28.3.2 Bioarticial Bone 28.3.3 Bioarticial Vessel 28.3.4 Bioarticial Tracheae 28.3.5 Bioarticial Skin 28.4 Conclusion and Outlook 29 Three-Dimensional Shape Control of Implant Devices Ung-il Chung, Hideto Saijoh, Kazuyo Igawa, Yuki Kanno, Yoshiyuki Mori, and Tsuyoshi Takato 29.1 Introduction 29.2 Current Status of Articial Bones 29.3 3D Fabrication Technologies and Their Comparison 29.4 Inkjet Printing Technology 29.5 Conclusions and Outlook 30 Novel Fabrication and Characterization of Pore-SizeGradient Scaolds by a Centrifugation Technique Se Heang Oh and Jin Ho Lee 30.1 Introduction 30.2 Fabrication of Pore-Size-Gradient Scaolds 30.2.1 Materials 30.2.2 Pore-Size-Gradient Alginate Scaolds 30.2.3 Pore-Size-Gradient Chitosan Scaolds 30.2.4 Pore-Size-Gradient PCL Scaolds 30.3 Characterization of Pore-Size-Gradient Scaolds 30.3.1 Measurements of Pore Sizes and Porosity 30.3.2 Measurements of Mechanical Properties 30.3.3 Evaluation of Wettability 30.3.4 In vitro Cell Interactions 30.3.5 In vivo Tissue Interactions 30.4 Conclusions

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589 590 592 592 593 594 594 595 595 597 600 600 603 606

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31 Solid Freeform Fabrication Method Applied to Tissue Scaolds Dong-Woo Cho, Jin Woo Lee, Jong Young Kim, and Tae-Yun Kang 31.1 Introduction 31.2 SFF Methods Applied to Scaolds 31.2.1 Stereolithography 31.2.1.1 Photopolymer scaold 31.2.1.2 Biopolymer scaold 31.2.2 Fused Deposition Modeling 31.2.3 3D Printing 31.2.4 Selective Laser Sintering 31.3 Summary 32 Novel Microspheres for Prolonged Cell Survival Sing Muk Ng, Jeung Soo Huh, Syed Izhar Haider Abdi, and Jeong Ok Lim 32.1 Introduction 32.2 Current Status and Development in Supplying Oxygen for Tissue Engineering 32.2.1 The Use of Articial Oxygen Carriers 32.2.2 Induction and Enhancement of Vascularization 32.2.3 The Utilization of Oxygen-Generating Biomaterials 32.3 Oxygen-Releasing Microspheres (ORMs) 32.3.1 The State of the Art 32.3.2 Materials as Building Blocks of Microspheres 32.3.3 Techniques for Producing ORMs 32.3.3.1 Double-emulsion and solvent evaporation technique 32.3.3.2 Functionalization of matrices selected as building blocks 32.3.3.3 Instrumentations for the preparation of microspheres 32.3.4 Evaluation of the Oxygen-Releasing Prole 32.3.4.1 Direct observation

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32.3.4.2 Quantitative analytical approach 32.3.4.3 Biologically related study 32.4 ORMs in Applications for Ecient Cell Survival 32.4.1 Direct Integration in Scaolds 32.4.2 Oxygen-Generating Reservoir 32.4.3 Medicine to Oxygenate Tissues 32.5 Conclusion 33 Emulsion Templating Elizabeth Cosgri-Hernandez 33.1 Introduction 33.2 Bone Tissue Engineering 33.3 Scaold Fabrication 33.4 PolyHIPEs as Bone Scaolds 33.4.1 Nondegradable: Styrene-Based PolyHIPEs 33.4.2 Semidegradable: Polyester-Based PolyHIPEs 33.4.3 Fully Degradable: Fumarate-Based PolyHIPEs 33.5 New Synthesis Routes 33.6 Conclusions and Outlook VII. SCAFFOLD FOR TARGET ORGAN 34 PGA Fiber for Soft Tissue Engineering Wei Liu and Yilin Cao 34.1 Introduction 34.2 PGA Fibers for Tendon Engineering 34.3 PGA Scaold for Cartilage Engineering 34.4 PGA Fibers for Skin Engineering 34.5 PGA Fibers for Corneal Stroma Engineering 34.6 PGA Fibers for Blood Vessel Engineering 34.7 PGA Fibers for Engineering Peripheral Nerve Tissue 34.8 Conclusion 35 Tissue Engineering and Anti-Aging Minoru Ueda 35.1 Introduction

654 656 657 657 659 659 660 665 665 667 668 671 671 672 674 675 676

681 681 683 689 694 698 701 705 707 711 711

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35.2 Materials and Method 35.2.1 Tissue Preparation 35.2.2 Cell Culture 35.2.3 Medium and Autologous Serum Preparation 35.2.4 Preparation of Cell Suspension and HA Admixture 35.2.5 Safety Tests 35.2.6 Clinical Assessment of Aesthetic Improvement 35.2.7 Skin Replica and Analysis 35.3 Result 35.3.1 Single-Case Report 35.4 Discussion 35.4.1 Fibroblast and HA for Skin Rejuvenation 35.4.2 Wrinkle Treatment in Dentistry 35.5 Conclusion 36 Matrices for Zonal Cartilage Tissue Engineering Daisy Irawan, Dietmar Hutmacher, and Travis Klein 36.1 Introduction 36.2 Carbohydrate-Based Matrices 36.2.1 Alginate 36.2.2 Agarose 36.3 Protein-Based Matrices 36.3.1 Collagen or Gelatin 36.3.2 Fibrin 36.4 Synthetic and Semisynthetic Matrices 36.4.1 Poly(Ethylene Glycol) 36.4.2 Extracel 36.5 Conclusions and Outlook 37 Collagen-Based Scaold for Bone Tissue Regeneration Fu-Zhai Cui, Zong-Gang Chen, and Xue Xia 37.1 Introduction 37.2 Compositional and Structural Characteristics of Natural Bone

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37.2.1 Composition of the Natural Bone Matrix 37.2.2 Hierarchical Structure of the Natural Bone Matrix by Self-Assembly 37.3 Biomimetic Fabrication with Self-Assembled Collagen Mineralization 37.3.1 Mineralization Mechanism of Hydroxyapatite Crystals on Collagen Fibers 37.3.2 Assembly of the Nano-Fibril of Mineralized Collagen 37.4 Synthesis and Application of Collagen-Based Scaolds in Bone Tissue Regeneration 37.4.1 Synthesis of Nano-HA/Collagen-Based Scaolds 37.4.2 Applications and Development of Nano-HA/Collagen Scaolds for Bone Tissue Engineering 37.5 Conclusions and Outlook 38 Scaold Considerations for Osteochondral Tissue Engineering Eric Farrell, Fergal J. OBrien, and Gerjo J. V. M. van Osch 38.1 Introduction 38.1.1 Tissue Engineering of the Bone Cartilage Interface 38.2 Joint Homeostasis 38.3 Current and Recent Approaches to the Field of Osteochondral Tissue Engineering 38.4 Functional Properties of Bone and Cartilage and the Important Dierences Between Them 38.5 Vascularization and its Absence in Cartilage 38.6 Scaold Considerations for Osteochondral Tissue Engineering 38.7 Endochondral Ossication, a More Logical Approach for Osteochondral Tissue Engineering 39 Application of Scaolds for Articial Skin in Regenerative Medicine Hyun Ju Lim and Ho Yun Chung 39.1 Introduction

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39.2 Scaolds: Biomaterials as One of Important Factors for Regeneration of Skin Tissue 806 39.3 Clinical Applications of Tissue-Engineered Skin Products 808 39.4 Conclusions and Outlook 813 40 Biodegradable Scaolds for Bone Regeneration Yoichi Yamada 40.1 Introduction 40.2 Biodegradable Scaolds 40.2.1 Biodegradable Ceramic Composite (-TCP) 40.2.2 Nanobers Hydrogel Peptide 40.2.3 Injectable Tissue-Engineered Bone 40.3 Clinical Application 40.3.1 Preparation and Clinical Application of MSCs, PRP, and Injectable TEB 40.4 Conclusions and Outlook 817 818 819 819 821 824 827 827 830

41 An Ecient ex vivo Expansion of Adult Mesenchymal Stem Cells in Scaolds 833 Eui Kyun Park, Hong-In Shin, and Shin-Yoon Kim 41.1 Introduction 834 41.2 The Use of Growth Factors and Glucocorticoids for the Propagation of Adult MSCs 836 41.2.1 Growth Factors 836 41.2.1.1 Fibroblast growth factors 837 41.2.1.2 Epidermal growth factor 837 41.2.1.3 Platelet-derived growth factor 839 41.2.1.4 Other growth factors 840 41.2.2 Glucocorticoids 840 41.2.3 Combination of Growth Factors and Steroids 841 41.3 Growth of MSCs in Scaolds 843 41.4 Conclusions and Outlook 846 42 Nanoparticles for Bioimaging in Regenerative Medicine Dongwon Lee, John M. Rhee, and Gilson Khang 42.1 Introduction

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42.2 Fluorescent Probes for Imaging of Hydrogen Peroxide 42.3 Luminescent Probes for Imaging of Hydrogen Peroxide 42.4 Fluorescent Probes for Other ROS 42.5 Conclusions and Outlook 43 Eect of Scaolds with Bone Growth Factors on New Bone Formation Hae-Ryong Song, Swee-Hin Teoh, Jun-Ho Wang, Hak-Jun Kim, Ji-Hoon Bae, Sung Eun Kim, Jerry Chan, Zhi-Yong Zhang, and Chang-Wug Oh 43.1 Introduction 43.2 Bone Lengthening in Preclinical Animal Studies 43.2.1 Calcium Sulfate in Tibial Lengthening 43.2.2 Cord Blood Stem Cells and rhBMP-2 in Tibial Lengthening 43.3 Growth Factor/Stem CellsMediated Scaolds for Bone Tissue Engineering 43.3.1 Use of Fibrin and Stem Cells for Bone Defect Healing in Rabbits 43.3.2 Use of Bioreactors, Human Fetal Stem Cells, and 3D Scaolds for Bone Tissue Engineering 43.3.3 The Use of Scaolds with or without Growth Factors and Cells for Clinical Trials 44 Temperature-Responsive Culture Surfaces for Regenerative Medicine Yoshikazu Kumashiro, Yoshikatsu Akiyama, Masayuki Yamato, and Teruo Okano 44.1 Introduction 44.2 The Basic Mechanism of Cell Attachment to and Detachment 44.3 Temperature-Responsive Cell Culture Surfaces that Enable Anity Control 44.4 Applications of Cell Sheet Technology 44.5 Corneal Surface Reconstruction

858 861 866 868

871

872 873 873 877 881 881

888 896

903

903 905 908 912 913

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44.6 Periodontal Ligament Cell Sheets 44.7 Endoscopic Esophageal Epithelial Transplantation 44.8 Sealing of Lung air Leaks 45 Customized Nanocomposite Scaolds Fabricated via Selective Laser Sintering for Bone Tissue Engineering Bin Duan and Min Wang 45.1 Introduction 45.2 Application of Rapid Prototyping Technologies to Scaold Fabrication 45.3 Design of Scaolds and the Nanocomposite Strategy 45.4 Fabrication of Nanocomposite Scaolds via SLS and Characteristics of the Scaolds 45.5 Nanocomposite Scaolds as Delivery Vehicles for Biomolecules 45.6 Conclusions Index

916 918 920

925 926 930 934 938 941 949 955

Preface

It has been recognized that regenerative medicine and tissue engineering oer an alternative technique to whole-organ and tissue transplantation for diseased, failed, or malfunctioning organs. Millions of patients suer from end-stage organ failure or tissue loss annually. The only way to solve this problem might be organ transplantation and biomaterials transplantation. However, in order to avoid the shortage of donor organs and other problems caused by poor biocompatibility of biomaterials, a new hybridized method combined with cells and biomaterials had been introduced as regenerative medicine and tissue engineering around 20 years ago. The specialty of regenerative medicine and tissue engineering continues to grow and change rapidly. This area saw major advances in the past few years. This eld for academic research and commercialization is needed in multidisciplinary areas such as adult, embryoinic, and induced pluripotent cells, genetic programming, nuclear transfer, cloning, genomics, proteomics, nanotechnology, biomaterials, etc. Thanks to the latest 20 years endeavor, several tissue-engineered products (TEMPS) and regenerative medicinal products (RMP) are on the boundary of the translation of benchside discoveries to clinical therapies. For the reconstruction of a neotissue by regenerative medicine and tissue engineering, triad components such as (i) cells that are harvested and dissociated from the donor tissue, including nerve, liver, pancreas, cartilage, and bone, as well as embryonic stem cells, adult stem cells, induced pluripotent cells (iPS), or precursor cells; (ii) biomaterials as scaold substrates whose cells are attached and cultured, resulting in the implantation at the desired site of the functioning tissue; and (iii) growth factors that are promoting and/or preventing cell adhesion, proliferation, migration, and dierentiation by up-regulating or down-regulating

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Preface

the synthesis of protein; growth factors; and receptors must be needed. This handbook has concentrated on all the things for scaolds among triad components, especially intelligent scaolds from basic science, industries, to clinical applications. This textbook is organized into seven major areas. Part I, Introduction, reveals some of fundamentals of the biomaterials, scaolds, and manufacturing methods. Part II covers ceramic and metal scaolds. Part III, Intelligent Hydrogel, deals with various types of hydrogels for tissue regenerations. In Part IV, topics of scaolds from electrospinning nanobers have been covered. In Part V, novel biomaterials for scaolds have been introduced, especially to mimic Mother Nature. The sixth part covers the recent novel fabrication methods for smart scaolds. The last part, Part VII, of this handbook deals with the recent clinical trial of specic target organs using intelligent scaolds. The authors have tried to dedicate the 45 chapters to the whole area of the recent topic of smart scaolds for regenerative medicine and tissue engineering. I am indebted to the authors for their willing acceptance, devotion, and contribution to each recent topic. I express my thanks to my students Mrs. Yong Ki Kim, Jung Bo Shim, and Young Un Kim for editing all manuscripts. Finally, I really appreciate our publisher, Mr. Stanford Chong. Without his trust and guidance, this huge work could not have been accomplished. Also, I would like to give special appreciation to Mr. Sarabjeet Garcha and Ms. Archana Ziradkar for the hard work. Gilson Khang, PhD