Biomedical Materials and Diagnostic Devices

Scrivener Publishing 100 Cummings Center, Suite 541J

Beverly, MA 01915-6106

Publishers at Scrivener Martin Scrivener (martin@scrivenerpublishing.com)

Phillip Carmical (pcarmical@scrivenerpublishing.com)

Biomedical Materials and Diagnostic Devices

Edited by

Ashutosh Tiwari Biosensors & Bioelectronics Center,

Linköping University, Sweden

Murugan Ramalingam University of Strasbourg, France

Hisatoshi Kobayashi National Institute for Materials Science, Japan

and

Anthony P.F. Turner Biosensors & Bioelectronics Center,

Linköping University, Sweden

&

Scrivener

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Illustration on front cover depicts interaction of stem cells into the nanobiomaterials for tissue engineering.

Cover design by Russell Richardson with illustration by Murugan Ramalingam and used with his permission

Library of Congress Cataloging-in-Publication Data:

Tiwari, Ashutosh, 1945-Biomedical materials and diagnostic devices / edited by Ashutosh Tiwari... [et al.]

p. cm. Includes bibliographical references and index. ISBN 978-1-118-03014-1 (hardback)

[DNLM: 1. Biocompatible Materials. 2. Drug Delivery Systems. 3. Nanotechnology. 4. Tissue Engineering. QT37]

610.28'4-dc23

2012025753

ISBN 978-1-118-03014-1

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Contents

Preface xv List of Contributors xvii

Part I: Biomedical Materials

1. Application of the Collagen as Biomaterials 3 Kwangwoo Nam and Akio Kishida 1.1 Introduction 3 1.2 Structural Aspect of Native Tissue 5

1.2.1 Microenvironment 5 1.2.2 Decellularization 6 1.2.3 Strategy for Designing Collagen-based Biomaterials 7

1.3 Processing of Collagen Matrix 8 1.3.1 Fibrillogenesis 8 1.3.2 Orientation 10 1.3.3 Complex Formation and Blending 11 1.3.4 Layered Structure 13

1.4 Conclusions and Future Perspectives 14 References 15

2. Biological and Medical Significance of Nanodimensional and Nanocrystalline Calcium Orthophosphates 19 Sergey V. Dorozhkin 2.1 Introduction 19 2.2 General Information on "Nano" 21 2.3 Micron- and Submicron-Sized Calcium Orthophosphates

versus the Nanodimensional Ones 23 2.4 Nanodimensional and Nanocrystalline Calcium

Orthophosphates in Calcified Tissues of Mammals 26 2.4.1 Bones 26 2.4.2 Teeth 27

2.5 The Structure of the Nanodimensional and Nanocrystalline Apatites 28

2.6 Synthesis of the Nanodimensional and Nanocrystalline Calcium Orthophosphates 34 2.6.1 General Nanotechnological Approaches 34 2.6.2 Nanodimensional and Nanocrystalline Apatites 34

v

CONTENTS

2.6.3 Nanodimensional and Nanocrystalline TCP 43 2.6.4 Other Nanodimensional and Nanocrystalline Calcium

Orthophosphates 44 2.6.5 Biomimetic Construction Using

Nanodimensional Particles 46 2.7 Biomedical Applications of the Nanodimensional and

Nanocrystalline Calcium Orthophosphates 47 2.7.1 Bone Repair 47 2.7.2 Nanodimensional and Nanocrystalline Calcium

Orthophosphates and Bone-related Cells 51 2.7.3 Dental Applications 53 2.7.4 Other Applications 54

2.8 Other Applications of the Nanodimensional and Nanocrystalline Calcium Orthophosphates 58

2.9 Summary and Perspectives 58 2.10 Conclusions 61

Closing Remarks 62 References and Notes 62

Layer-by-Layer (LbL) Thin Film: From Conventional To Advanced Biomedical and Bioanalytical Applications 101 Wing Cheung Mak 3.1 State-of-the-art LbL Technology 101 3.2 Principle of Biomaterials Based Lbl Architecture 102 3.3 LbL Thin Film for Biomaterials and

Biomedical Implantations 103 3.4 LbL Thin Film for Biosensors and Bioassays 105 3.5 LbL Thin Film Architecture on Colloidal Materials 107 3.6 LbL Thin Film for Drug Encapsulation and Delivery 108 3.7 LbL Thin Film Based Micro/Nanoreactor 110

References 111

Polycaprolactone based Nanobiomaterials 115 Narendra K. Singh and Pralay Maiti 4.1 Introduction 115 4.2 Preparation of Polycaprolactone Nanocomposites 118

4.2.1 Solution Casting Method 118 4.2.2 Melt Extrusion Technique 118 4.2.3 In Situ Polymerization 119

4.3 Characterization of Poly(caprolactone) Nanocomposites 119 4.3.1 Nanostructure 120 4.3.2 Microstructure 121

4.4 Properties 123 4.4.1 Mechanical Properties 123

CONTENTS vii

4.4.2 Thermal Properties 126 4.4.3 Biodegradation 130

4.5 Biocompatibility and Drug Delivery Application 141 4.6 Conclusion 150

Acknowledgement 150 References 150

Bone Substitute Materials in Trauma and Orthopedic Surgery -Properties and Use in Clinic 157 Esther M.M. Van Lieshout 5.1 Introduction 158 5.2 Types of Bone Grafts 159

5.2.1 Autologous Transplantation 159 5.2.2 Allotransplantation and Xenotransplantation 159 5.2.3 Alternative Bone Substitute Materials for Grafting 160

5.3 Bone Substitute Materials 161 5.3.1 General Considerations 161 5.3.2 Calcium Phosphates 161 5.3.3 Calcium Sulphates 166 5.3.4 Bioactive Glass 168 5.3.5 Miscellaneous Products 169 5.3.6 Future Directions 170

5.4 Combinations with Osteogenic and Osteoinductive Materials 171 5.4.1 Osteogenic Substances 172 5.4.2 Osteoinductive Substances 173

5.5 Discussion and Conclusion 173 References 174

Surface Functionalized Hydrogel Nanoparticles 191 Mehrdad Hamidi, Hajar Ashrafi and Amir Azadi 6.1 Hydrogel Nanoparticles 192 6.2 Hydrogel Nanoparticles Based on Chitosan 193 6.3 Hydrogel Nanoparticles Based on Alginate 194 6.4 Hydrogel Nanoparticles Based on Poly(vinyl Alcohol) 195 6.5 Hydrogel Nanoparticles Based on PolyCethylene Oxide) and

Poly(ethyleneimine) 197 6.6 Hydrogel Nanoparticles Based on Poly (vinyl Pyrrolidone) 198 6.7 Hydrogel Nanoparticles Based on

Poly-N-Isopropylacrylamide 198 6.8 Smart Hydrogel Nanoparticles 199 6.9 Self-assembled Hydrogel Nanoparticles 200 6.10 Surface Functionalization 201 6.11 Surface Functionalized Hydrogel Nanoparticles 205

References 209

viii CONTENTS

Part II: Diagnostic Devices

7. Utility and Potential Application of Nanomaterials in Medicine 217 Ravindra P. Singh, Jeong -Woo Choi, Ashutosh Tiwari and Avinash Chand Pandey 7.1 Introduction 217 7.2 Nanoparticle Coatings 220 7.3 Cyclic Peptides 222 7.4 Dendrimers 223 7.5 Fullerenes/Carbon Nanotubes/Graphene 229 7.6 Functional Drug Carriers 231 7.7 MRI Scanning Nanoparticles 235 7.8 Nanoemulsions 237 7.9 Nanofibers 238 7.10 Nanoshells 241 7.11 Quantum Dots 242 7.12 Nanoimaging 250 7.13 Inorganic Nanoparticles 250 7.14 Conclusion 252

Acknowledgement 253 References 253

8. Gold Nanoparticle-based Electrochemical Biosensors for Medical Applications 263 Ülkü Anik 8.1 Introduction 263 8.2 Electrochemical Biosensors 264

8.2.1 Gold Nanoparticles 264 8.3 Conclusion 274

References 275

9. Impedimetric DNA Sensing Employing Nanomaterials 279 Manel del Valle and Alessandra Bonanni 9.1 Introduction 279

9.1.1 DNA Biosensors (Genosensors) 280 9.1.2 Electrochemical Genosensors 282

9.2 Electrochemical Impedance Spectroscopy for Genosensing 282 9.2.1 Theoretical Background 283 9.2.2 Impedimetric Genosensors 286

9.3 Nanostructured Carbon Used in Impedimetric Genosensors 288 9.3.1 Carbon Nanotubes and Nanostructured Diamond 288 9.3.2 Graphene-based Platforms 290

CONTENTS ix

9.4 Nanostructured Gold Used in Impedimetric Genosensors 292 9.4.1 Gold Nanoelectrodes 293 9.4.2 Gold Nanoparticles Used as Labels 294

9.5 Quantum Dots for Impedimetric Genosensing 295 9.6 Impedimetric Genosensors for Point-of-Care Diagnosis 295 9.7 Conclusions (Past, Present and Future Perspectives) 296 Acknowledgements 298 References 298

Bionanocomposite Matrices in Electrochemical Biosensors 303 Ashutosh Tiwari, Atul Tiwari and Ravindra P. Singh 10.1 Introduction 303 10.2 Fabrication of Si02-CHIT/CNTs Bionanocomposites 305 10.3 Preparation of Bioelectrodes 306 10.4 Characterizations 307 10.5 Electrocatalytic Properties 309 10.6 Photometric Response 317 10.7 Conclusions 318 Acknowledgements 318 References 319

Biosilica - Nanocomposites - Nanobiomaterials for Biomedical Engineering and Sensing Applications 323 Nikos Chaniotakis and Raluca Buiculescu 11.1 Introduction 323 11.2 Silica Polymerization Process 325 11.3 Biocatalytic Formation of Silica 327 11.4 Biosilica Nanotechnology 329 11.5 Applications 330

11.5.1 Photonic Materials 330 11.5.2 Enzyme Stabilization 330 11.5.3 Biosensor Development 332 11.5.4 Surface Modification for Medical Applications 334

11.6 Conclusions 336 References 336

Molecularly Imprinted Nanomaterial-based Highly Sensitive and Selective Medical Devices 339 Bhim Bali Prasad and Mahavir Prasad Tiwari 12.1 Introduction 339 12.2 Molecular Imprinted Polymer Technology 342

12.2.1 Introduction of Molecular Recognition 342 12.2.2 Molecular Imprinting Polymerization: Background 342 12.2.3 Contributions of Polyakov, Pauling and Dickey 343

x CONTENTS

12.2.4 Approaches Toward Synthesis of MIPs 344 12.2.5 Optimization of the Polymer Structure 347

12.3 Molecularly Imprinted Nanomaterials 362 12.4 Molecularly Imprinted Nanomaterial-based

Sensing Devices 364 12.4.1 Electrochemical Sensors 365 12.4.2 Optical Sensors 373 12.4.3 Mass Sensitive Devices 376

12.5 Conclusion 381 References 381

Part III: Drug Delivery and Therapeutics

13. Ground-Breaking Changes in Mimetic and Novel Nanostructured Composites for Intelligent-, Adaptive- and In iwo-responsive Drug Delivery Therapies 395 Dipak K. Sarker 13.1 Introduction 395

13.1.1 Diseases of Major Importance in Society 400 13.1.2 Types of Cancers and Diseases Requiring Specific

Dosage Delivery 403 13.2 Obstacles to the Clinician 404 13.3 Hurdles for the Pharmaceuticist 412 13.4 Nanostructures 415

13.4.1 Key Current Know-how 418 13.5 Surface Coating 419 13.6 Cell Promoting, Toxicity and Clearance 420 13.7 Formulation Conditions and Parameters 423 13.8 Delivery Systems 424

13.8.1 State-of-the-Art Technological Innovation 426 13.9 Evaluation 427

13.9.1 Future Scientific Direction 429 13.10 Conclusions 431

References 432

14. Progress of Nanobiomaterials for Theranostic Systems 435 Dipendra Gyawali, Michael Palmer, Richard T. Tran and Jian Yang 14.1 Introduction 435

14.1.1 Nanomaterials and Nanomedicine 435 14.1.2 Drug Delivery, Imaging, and Targeting 437 14.1.3 Theranostic Nanomedicine 438

14.2 Design Concerns for Theranostic Nanosystems 440 14.2.1 Size and Stability 440 14.2.2 Surface Area and Chemistry 441

CONTENTS xi

14.2.3 Drug Loading and Release 441 14.2.4 Imaging 442 14.2.5 Targeting 442

14.3 Designing a Smart and Functional Theranostic System 443 14.3.1 Tailoring Size and Shape of the Particles 443 14.3.2 Degradation and Drug Release Kinetics 444 14.3.3 Surface Properties and Placement of

Targeting Molecules 445 14.4 Materials for Theranostic System 446

14.4.1 Polymeric Systems 446 14.4.2 Diagnostic and Imaging Materials 449

14.5 Theranostic Systems and Applications 458 14.5.1 Polymeric Nanoparticle-based Theranostic System 458 14.5.2 QD-based Theranostic System 459 14.5.3 Colloidal Gold-particle-based Theranostic System 462 14.5.4 Iron-oxide-based Theranostic Systems 463

14.6 Future Outlook 465 References 466

15. Intelligent Drug Delivery Systems for Cancer Therapy 477 Mousa Jafari, Bahram Zargar, M. Soltani, D. Nedra Karunaratne, Brian Ingalls and P. Chen 15.1 Introduction 477 15.2 Peptides for Nucleic Acid and Drug Delivery

in Cancer Therapy 478 15.2.1 Self-assembling Peptides as Carriers for

Anticancer Drugs 478 15.2.2 Different Classes of Peptides Used in

Gene Delivery 479 15.2.3 Protein-derived and Designed CPPs 481 15.2.4 Cell Targeting Peptides 482 15.2.5 Nuclear Localization Peptides 483

15.3 Lipid Carriers 483 15.3.1 Liposomes 483 15.3.2 Modified Liposomes 484 15.3.3 Targeted Lipid Carriers 485 15.3.4 Bolaamphiphiles 487 15.3.5 Solid Lipid Nanoparticles (SLNs) and

Nanostructured Lipid Carriers (NLCs) 488 15.3.6 MixedSystems 489

15.4 Polymeric Carriers 490 15.4.1 Polymeric Nanoparticles 492 15.4.2 Dendrimers 492 15.4.3 Polymer-Protein/Aptamer Conjugates 493 15.4.4 Polymer-Drug Conjugates 494

xii CONTENTS

15.4.5 NoncovalentDrug Conjugates 494 15.4.6 Cationic Polymers 495 15.4.7 Polymers for Triggered Drug Release 495 15.4.8 Polymerosomes 496 15.4.9 Other Applications 497

15.5 Bactria-Mediated Cancer Therapy 498 15.5.1 The Tumor Microenvironment 498 15.5.2 Salmonella-mediated Cancer Therapy 499 15.5.3 Clostridium-mediated Cancer Therapy 500

15.6 Conclusion 503 References 503

Part IV: Tissue Engineering and Organ Regeneration

16. The Evolution of Abdominal Wall Reconstruction and the Role of Nonobiotecnology in the Development of Intelligent Abdominal Wall Mesh 517 Cherif Boutros, Hatty F. Sobhi and Nader Hanna 16.1 The Complex Structure of the Abdominal Wall 518 16.2 Need for Abdominal Wall Reconstruction 519 16.3 Failure of Primary Repair 519 16.4 Limitations of the Synthetic Meshes 520 16.5 Introduction of Biomaterials To Overcome

Synthetic Mesh Limitations 521 16.6 Ideal Material for Abdominal Wall Reconstruction 522 16.7 Role of Bionanotechnology in Providing the

Ideal Material 523 16.8 Future Directions 526

References 526

17. Poly(Polyol Sebacate)-based Elastomeric Nanobiomaterials for Soft Tissue Engineering 529 Qizhi Chen 17.1 Introduction 529 17.2 Poly(polyol sebacate) Elastomers 531

17.2.1 Synthesis and Processing of Poly(polyol sebacate) 531 17.2.2 Biocompatibility of PPS 533 17.2.3 Biodegradation of PPS 538 17.2.4 Mechanical Properties of PPS 542 17.2.5 Applications of PPS in Tissue Engineering 544 17.2.6 Poly(polyol sebacate)-based Copolymers 544 17.2.7 Summary of PPS 546

17.3 Elastomeric Nanocomposites 546 17.3.1 Introduction to Elastomeric Nanocomposites 546

CONTENTS xiii

17.3.2 Thermoplastic Rubber-based Nanocomposites 547 17.3.3 Crosslinked Elastomer-based Nanocomposites 549

17.4 Summary 553 References 555

Electrospun Nanomatrix for Tissue Regeneration 561 Debasish Mondal and Ashutosh Tiwari 18.1 Introduction 561 18.2 Electrospun Nanomatrix 562 18.3 Polymeric Nanomatrices for Tissue Engineering 564

18.3.1 Natural Polymers 564 18.3.2 Synthetic Polymers 565

18.4 Biocompatibility of the Nanomatrix 565 18.5 Electrospun Nanomatrices for Tissue Engineering 566

18.5.1 Bone Tissue Engineering 567 18.5.2 Cartilage Tissue Engineering 568 18.5.3 Ligament Tissue Engineering 570 18.5.4 Skeletal Muscle Tissue Engineering 570 18.5.5 Skin Tissue Engineering 571 18.5.6 Vascular Tissue Engineering 572 18.5.7 Nerve Tissue Engineering 575

18.6 Status and Prognosis 576 References 577

Conducting Polymer Composites for Tissue Engineering Scaffolds 581 Yashpal Sharma, Ashutosh Tiwari and Hisatoshi Kobayashi 19.1 Introduction 582 19.2 Conducting Polymers 582 19.3 Synthesis of Conducting Polymers 583 19.4 Application of Conducting Polymer in Tissue Engineering 584 19.5 Polypyrrole 584 19.6 Poly(3,4-ethylene dioxythiophene) 586 19.7 Polyaniline 587 19.8 Carbon Nanotube 589 19.9 Future Prospects and Conclusions 591

Acknowledgements 592 References 592

Cell Patterning Technologies for Tissue Engineering 595 Azadeh Seidi and Murugan Ramaltngam 20.1 Introduction 595 20.2 Patterned Co-culture Techniques 596

20.2.1 Substrate Patterning with ECM Components 597

xiv CONTENTS

20.2.2 Microfluidic-based Patterning 598 20.2.3 Switchable Surface-based Patterning 599 20.2.4 Mechanical and Stencil-based Patterning 599 20.2.5 3D Patterned Co-cultures 601

20.3 Applications of Co-cultures in Tissue Engineering 602 20.4 Concluding Remarks 603

Acknowledgements 603 References 604

Index 607

Preface

Engineering of advanced biomaterials has resulted in striking solutions to multifarious biomedical and diagnostic conudrums, including cell separa-tion, stem-cell scaffolds, targeted drug delivery, treatments for hyperthermia, automated DNA extraction, gene targeting, resonance imaging, biosensors, tissue engineering and organ regeneration. The biomedical materials with the most promising potential combine biocompatibility with the ability to precisely adjust biological phenomenon in a controlled manner. The world market for biomedicals and diagnostic devices is expanding rapidly and is currently valued over US$1000 trillion. Likewise, academic research has kept pace with the market demand with over 50,000 papers being published in the field last year. While the field of diagnostic devices has achieved consider-able success, commercial returns in this sector are dominated by glucose sens-ing, despite the myriad of other possibilities for novel and useful analytical devices. Key areas such as drug delivery and regenerative medicine, not only represent huge opportunities to improve longevity and quality of life, but will also benefit from the fusion of ideas occurring within the emerging modern field of biomaterials. Molecular design for one application is finding utility across the field in a synergistic combination of solutions that brings together sensing, imaging, therapy and reconstruction in a plethora of exciting medical applications.

This book aims to provide an up-to-date overview of the fascinating field of biomedical materials and devices. This large volume includes twenty chapters divided into four main areas: biomedical materials, diagnostic devices, drug delivery and therapeutics, and tissue engineering and organ regeneration. It covers the latest research and developments in biomedical materials and medical devices: fabrication, performance and uses.

The chapters seek to address progress in successful design strategies for biomedical materials and devices such as the use of collagen, crystalline cal-cium orthophosphates, amphiphilic polymers, polycaprolactone, biomimetic assembly, bio-nanocomposite matrices, bio- silica, theranostic nanobiomateri-als, intelligent drug delivery systems, elastomeric nanobiomaterials, electros-pun nano-matrices, metal nanoparticles and a variety of biosensors. This book is intended to be suitable for a wide readership including university students and researchers from diverse backgrounds such as chemistry, materials sci-ence, physics, pharmacy, biological science and bio-medical engineering. It can

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be used not only as a text book for both undergraduate and graduate students, but also as a review and reference book for researchers in the materials science, bioengineering, pharmacy, biotechnology and nanotechnology.

Editors

Ashutosh Tiwari, PhD Murugan Ramalingam, PhD

Hisatoshi Kobayashi, PhD Anthony PR Turner, PhD, DSc

List of Contributors

Ülkü Anik graduated from Ege University (Izmir,Turkey) in chemistry (BSc) in 1995, in analytical chemistry (MSc) in 1998, in analytical chemistry (PhD) in 2003. She is an associate professor of analytical chemistry in Mugla Sitki Kogman University (Mugla, Turkey). She has published 30 articles mainly on nanstructure modified electrochemical biosensors.

Hajar Ashrafi PhD student of pharmaceutics, Shiraz University of Medical Sciences, Shiraz, Iran. Research interests include hydrogel nanoparticles in drug delivery; bioconjugation; surface-modified nanoparticles. Published 5 articles, 1 book, 1 book chapter and 15 research abstracts.

Amir Azadi PhD student of pharmaceutics, Tehran University of Medical Sciences, Iran. Research interests include hydrogel nanoparticles in drug delivery; surface-modified nanoparticles; pharmacokinetic evaluation of drug delivery systems. Published 15 articles, 1 book chapter and 30 research abstracts.

Alessandra Bonanni received her PhD in chemistry from Universität Autonoma de Barcelona, Spain in 2008. After a post-doctoral experience at the National Institute for Materials Science (NIMS, Japan) she joined Nanyang Technological University in Singapore as senior researcher. Her cur-rent research is focused on the characterization and use of nanomaterials for the development of disposable electrochemical devices for next generation diagnostics.

Cherif Boutros obtained the Diploma of General Surgery and Master degree of Surgical Science from Paris University, France. He completed intern-ship and residency in general surgery at New York Presbyterian Hospital in New York and Monmouth Medical Center in New Jersey. He also com-pleted a Surgical Oncology fellowship at Roger Williams Medical Center in Providence, Rhode Island. Dr Boutros published and presented more than thirty papers in surgical oncology as well as in abdominal wall recon-struction in cancer patients. Dr Boutros is assistant professor of surgery at the University of Maryland School of Medicine and the Chief of Surgical Oncology at Baltimore Washington Medical Center.

Raluca Buiculescu obtained her MSc in biotechnology in 2006 from the "Politehnica" University of Bucharest. She completed her PhD in 2011 in the Laboratory of Analytical Chemistry of Prof. Chaniotakis. During these years

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xviii LIST OF CONTRIBUTORS

she earned important experience in the synthesis and characterization of gold nanoparticles, semiconductor quantum dots and carbon nanomaterials and their conjugation with biomolecules with the purpose of constructing new biosensors systems. Her work gave rise to a significant number of refereed journal publications and poster or oral conference presentations. She currently works as a post doc scientist in the Laboratory of Analytical Chemistry of the University of Crete.

Nikos Chaniotakis is professor of analytical chemistry at the University of Crete, Greece. He studied at the University of Michigan (thesis with Prof. M. Meyerhoff) and then did his post-doctoral studies at Laboratorium für Organishe Chemie, Eidgenossische Technische Hochschule (ETH) Zentrum, Zurich, Switzerland under the supervision of Prof. W. Simon. He then started working at the University of Crete where he established the Laboratory of Analytical Chemistry. His research interest are focused in the area of the design of chemical sensors and biosensors, with emphasis in the utilization of opto-electrochemical nanomaterials, and nanostructures.

Pu Chen is a professor of chemical engineering and physics at the University of Waterloo, Canada. As Canada Research Chair in Nano-Biomaterials, Dr. Chen will continue to develop new engineering principles for molecular building block design and its applications in drug and gene delivery. He and his colleagues will strive for advancing the emerging fields in nanomedicine and bio-nanotechnology.

Qizhi Chen received her PhD degree in biomaterials from Imperial College London. She is currently an academic in the Department of Materials Engineering at Monash University, Australia. Previously she was employed by the National Heart and Lung Institute in London and the University of Cambridge. She has published more than 100 peer-reviewed journal articles and book chapters. Her research interests broadly cover polymeric, ceramic, metallic and composite materials for applications in biomedical engineering.

Jeong-Woo Choi received his PhD from the Department of Chemical & Biochemical Engineering, Rutgers University, USA (1990), DEng from the Department of Biomolecular Engineering, Tokyo Institute of Technology, Japan (2003), and MBA from the University of Durham, UK (2007). He is professor in the Department of Chemical and Biomolecular Engineering, and Director of Interdisciplinary Program of Integrated Biotechnology of Sogang University in Korea. He has done research in the fields of nanobioelectronics, especially bio-memory, protein chip, and cell chip. He has published more than 300 journal papers in the bioelectronics and biotechnology field.

Sergey V. Dorozhkin received his MS in chemical engineering in 1984 and PhD in chemistry in 1992. From 1996 to 2004, he held post-doctoral positions on calcium orthophosphates at five universities of four countries (France, Portugal, Germany, and Canada). Dr. Dorozhkin has authored more than 60 research papers, about 15 reviews, more than 10 book chapters, and 2 monographs.

LIST OF CONTRIBUTORS xix

Dipendra Gyawali is a faculty research associate at the University of Texas at Arlington. He obtained his BSc and MSc degrees (2009) in biomedical engineering from the University of Texas at Arlington. He has authored more than 10 publications, 2 book chapters, 10 abstracts, and 2 pending patents.

Mehrdad Hamidi professor of pharmaceutics and Dean School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran. His research interests are hydrogel nanoparticles in drug delivery; surface-modified nanoparticles; pharmacokinetic evaluation of drug delivery systems. He has published more than 50 articles, 1 book, 3 book chapters and 130 research abstracts.

Nader Hanna received his medical degree from Ain Shams University in Cairo, Egypt and completed his surgical residency at Tufts University. He also completed two fellowships at the University of Chicago. Dr. Hanna was featured in multiple news reports and was selected as one of "America's Top Doctors for Cancer" in 2009. He was named on the "Top Doctors" List and was included in the "Guide to America's Top Oncologists" by the Consumers' Research Council of America. Dr Hanna has more than 50 publications in sur-gical oncology practice and research. Dr. Hanna is a professor of surgery at the University of Maryland and Director of Clinical Operations at the division of General and Oncologic Surgery.

Brian Ingalls is an associate professor in the Department of Applied Mathematics at the University of Waterloo, Canada. His research program is focused on applying tools from systems and control theory to study the regula-tion of intracellular networks.

Mousa Jaf ari is a PhD candidate in the Department of Chemical Engineering at the University of Waterloo, Canada. He is currently working on design and potential application of peptides for gene and drug delivery and tissue engineering purposes. He has published 2 book chapters, and 8 papers in peer-reviewed journals and documented 2 US patents.

D.N. Karunaratne obtained her PhD from the University of British Columbia, Vancouver, Canada. Currently she is a professor of chemistry at the University of Peradeniya, Sri Lanka. Her research interests are in the applications of carbohydrate liquid crystals in emulsion stabilization, and drug delivery through nanoencapsulation with polymers and liposomes. Dr. Karunaratne has authored 7 book chapters, 22 research articles in peer reviewed journals and obtained 6 US patents and 3 provisional US patent applications.

Akio Kishida obtained his PhD from Kyoto University in Polymer Chemistry. He is currently a professor in the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University where his main research interests are polymer chemistry, surface chemistry, and regenerative medicine. He has published 158 peer-reviewed articles, 35 book chapters, and 24 review articles.

Hisatoshi Kobayashi is a group leader of WPI Research center MAN A, National Institute for Material Science, Tsukuba Japan. Currently, he is President of

xx LIST OF CONTRIBUTORS

International Association of Advanced Materials(IAAM). He has published more than 150 publications, books, and patents in the field of biomaterial science and technology. His current research interest is cell-nano-materials interac-tion and the design and development of highly functionalized biodegradable scaffold for tissue engineering and nano-composites for medical devices.

Martin Wing Cheung Mak received his PhD in bioengineering in 2004 from The Hong Kong University of Science and Technology (HKUST). Currently, he is a senior research fellow jointly in the "Biosensors and Bioelectronics Centre" of the Department of Physics, Chemistry and Biology (IFM) and the "Integrative Regenerative Medicine (IGEN) Center" of the Faculty of Health Sciences at the Linköping University in Sweden. He has authored more than 30 articles, patents and conference proceedings in the field of colloidal mate-rials and interfaces. Dr. Mak has developed various unique scientific skills and has pioneered new technologies to create functional colloidal materials as microencapsulated analytical system, advanced signal amplified biolabel system and transdermal drug carriers.

Pralay Maiti is professor and coordinator of the School of Materials Science and Technology, Institute of Technology at Banaras Hindu University. Pralay earned his PhD from the Indian Association for the Cultivation of Science, Kolkata. After spending 7 years at Cornell University, Toyota Technological Institute and Hiroshima University, he joined Central Leather Research Institute, Chennai and then moved to Banaras Hindu University in 2004 as a associate professor. His research expertise is in designing polymers for self-assembled thermoplastics, controlled biodegradation, polymer gels, radiation resistant electro active polymers, and application of polymeric materials for biomedical arena. His laboratory has synthesised novel nanoparticle induced piezoelectric polymeric materials, radiation resistant polymer, nanochan-nel conducting membrane, media for sustained drug release, and polymeric biocompatible materials for tissue engineering. He has published 65 papers mostly in high impact journals. He is the recipient of Prof. M. Santappa Silver Jubilee award by the Society of Polymer Science, India.

Debasish Mondal is a visiting post-doctoral researcher at the Department of Clinical and Experimental Medicine, Linkoping University, Sweden. He completed his PhD from School of Materials Science and Engineering at Nanyang Technological University (NTU), Singapore in 2010. He worked as a research associate and research fellow at NTU. His areas of research inter-est are bioengineering, nanobiomaterials, gene delivery, cell & tissue engineer-ing, drug delivery and controlled release. Debasish has published more than 10 articles and conference proceedings.

Kwangwoo Nam earned a PhD in metallurgy from the University of Tokyo. He is currently an assistant professor at the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University. His main research inter-ests are in polymer physics, surface chemistry, and regenerative medicine. He has published more than 30 peer-reviewed articles and 9 book chapters.

LIST OF CONTRIBUTORS xxi

Michael Palmer is a graduate student at the University of Texas at Arlington. He received his BSc degree from the University of California at San Diego.

Avinash Chandra Pandey holds four masters degrees namely MSc (Physics, 1984), MBA (Marketing, 1993) and MSc (Mathematics, 1996) from the University of Allahabad, India and MTech (Computer Science) from the Motilal Nehru National Institute of Technology, Allahabad, India as well as a DPhil from the University of Allahabad in 1995. Dr. Pandey is working as professor in atmospheric and oceanic sciences, University of Allahabad, India. He has more than 150 scientific papers in international and national conferences and Journals to his credit.

Bhim Bali Prasad is currently a professor at Banaras Hindu University, India where he has mentored 20 PhD students and published 90 research papers. He received his BSc degree in 1972, MSc degree in 1974, and PhD degree in 1978 from Banaras Hindu University, India. He is a recipient of several national awards including IAAM medal-2011. At present, he is leading a research group working in the field of MIP.

Murugan Ramalingam is an associate professor of biomaterials and tissue engi-neering at the Institut National de la Sante et de la Recherche Medicale, Faculte de Chirurgie Dentaire, Universite de Strasbourg (UdS), France. Concurrently he holds an adjunct associate professorship at Tohoku University (Japan). He received his PhD (biomaterials) from the University of Madras. His research interests are focused on the development of multiphase biomaterials, through conventional to nanotechnology to biomimetic approaches, cell patterning, stem cell differentiation and tissue engineering. He has authored more than 125 publications and is Editor-in-Chief of Journal of Bionanoscience and Journal of Biomaterials and Tissue Engineering.

Dipak Sarker gained a PhD in physics in 1995. He has worked at universities and research institutes in the UK, France and Germany and now working in the School of Pharmacy at the University of Brighton (UK). His research involves medical nanotechnology. He has published a specialist book, two book chapters and more than 60 scientific papers.

Azadeh Seidi is a biochemist at Okinawa Institute of Science and Technology, Japan. Since earning her PhD from Tokyo Institute of Technology in 2007, she has focused her activities on biomedical researches on biochemical and engineering.

Yashpal Sharma graduated in chemistry from the G. J. University of Science and Technology, Hisar, India in 2012. He has been awarded a NIMS intern-ship fellowship, Japan to carry out research in bio-functional materials group at the National Institute for Materials Science, Japan under the super-vision of Dr. Hisatoshi Kobayashi and Dr. Ashutosh Tiwari on temperature responsive biomaterials for tissue regeneration. He is the recipient of the Young Scientist Award from the International Association of Advanced Materials (IAAM) in 2011. His research interests include smart micro and

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nano materials for supercapacitors, fuel cells, batteries and biological applications.

Narendra Kumar Singh earned his MSc degree (2005) in chemistry from Purvanchal University, India. In 2007 he joined the School of Materials Science and Technology, BHU, Varanasi as a junior research fellow in DBT sponsored project for his PhD Degree in material science and technology. He became a senior research fellow in 2009. He has visited the University of Guelph, Canada as visiting researcher through the Canadian Commonwealth scholar-ship programme. He was awarded the Senior Research Fellow Award in 2011 from the Council of Scientific & Industrial Research (CSIR), Human Resource Development Group, India. He has published five research papers in peer-reviewed journals and one book chapter. His current research interest includes the fabrication of biodegradable polymer nanobiohybrid scaffolds for targeted drug delivery and biomedical applications.

Ravindra P. Singh, earned his MSc and PhD in biochemistry from Lucknow University, India. Currently, he is working as a scientist at the Nanotechnology Application Centre, Allahabad University. He has been credited with several national and international awards and is the author of more than 30 research articles and 12 book chapters.

Hany Sobhi obtained his PhD in clinical bioanalytical chemistry at Cleveland State University, USA in 2008. He was appointed as an assistant professor of organic and clinical chemistry at Coppin State University Baltimore in 2010. Dr. Sobhi is an active researcher in translational research, and development of strategies for synthesis bioorganic molecules for clinical diagnosis and under-stands the pathogenetic mechanisms underlying the clinical manifestations of mitochondrial and cancer diseases. He has published sixteen research articles, and in 2011 he was awarded Faculty Scholar in Cancer Research from The American Society for Cancer Research AACR.

Madjid Soltani is a PhD student in the Waterloo Institute for Nanotechnology and Chemical Engineering Department, University of Waterloo, Canada. He studied mechanical engineering with the focus on numerical and computa-tional modeling of transport phenomena for his undergraduate and Master degrees. He is currently working on a mathematical model of interstitial fluid behavior in physiological systems containing a solid tumor. He has published more than 20 journal and conference papers.

Ashutosh Tiwari is an assistant professor at the Biosensors and Bioelectronics Centre, IFM-Linkoping University; Editor-in-Chief of Advanced Materials Letters; a materials chemist and graduate from University of Allahabad, India. Dr. Tiwari is also honoured as a visiting professor in many presti-gious institutions worldwide. Just after he completed his doctorate degree, he joined as a young scientist at National Physical Laboratory, India and later moved to University of Wisconsin, USA for postdoctoral research. He is actively engaged as reviewer, editor and member of scientific bodies around

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the world. Dr. Tiwari obtained various prestigious fellowships including JSPS, Japan; SI, Sweden; and Marie Curie, England/Sweden. In his aca-demic carrier, he has published more than 175 articles, patents and confer-ence proceedings in the field of materials science and technology. He has also edited/authored ten books on the advanced state-of-the-art of mate-rials science with many publishers. Dr. Tiwari has been honoured by the prestigious 'The Nano Award' and 'Innovation in Materials Science Award and Medal'in 2011.

Atul Tiwari is an associate research faculty at the Department of Mechanical Engineering in the University of Hawaii, USA. He received his Master degree in organic chemistry and PhD in polymer science from universities in India. He earned the Chartered Chemist and Chartered Scientist status from the Royal Society of Chemistry, UK. His areas of research interest include the develop-ment of silicones and graphene materials for various industrial applications. Dr. Tiwari has invented several international patents pending technologies that have been transferred to industries. He has been actively engaged in vari-ous fields of polymer science, engineering, and technology and has published more than 50 scientific peer-reviewed journal papers, book chapters and books related to material science.

Mahavir Prasad Tiwari has worked for his PhD degree under the supervision of Professor Bhim Bali Prasad at Banaras Hindu University, India. He received his BSc in 2005 and MSc in 2007 from Purvanchal University. His research interests lie in the field of solid phase extraction/microextraction, molecular ly imprinted polymers, and electroanalytical chemistry.

Richard T. Tran is a post-doctoral research fellow at the University of Texas at Arlington. He obtained a BSI in bioinformatics at Baylor University and a PhD in bioengineering at the University of Texas at Arlington. He has authored more than 10 publications, 3 book chapters, 25 abstracts, and has 3 pending patents.

Manel del Valle received his PhD in analytical chemistry (1992) from the Universität Autonoma de Barcelona, Spain. He is currently a professor of ana-lytical chemistry at UAB, member of the Sensors and Biosensors group, and head of chemistry studies. He has authored more than 160 research papers in the field of electrochemical sensors. He is the leader of research lines of sensor arrays and electronic tongues, as well as the use of Electrochemical Impedance Spectroscopy for biosensing.

E. M.M. Van Lieshout graduated in medical biology at the University of Nijmegen, the Netherlands and obtained a PhD in 1998. She is head of research at the Trauma Research Unit of Erasmus MC in Rotterdam, the Netherlands. Her research interests include bone healing biology and efficacy of inter-ventions in trauma care. Dr. Van Lieshout (co)authored more than 100 peer-reviewed articles and two book chapters.

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Jian Yang is an associate professor of bioengineering at the University of Texas at Arlington. He was the recipient of NSF CAREER award in 2010 and out-standing young faculty award at UTA College of Engineering in 2011. Dr. Yang has authored more than 50 journal articles, 15 issued/pending patents, and 4 book chapters.

Bahram Zargar is a PhD candidate in the Department of Chemical Engineering at the University of Waterloo, Canada. His Bachelor and Masters degrees were in Mechanical Engineering. His research programme is focused on synthetic biology and bacteria mediated cancer therapy.

PARTI BIOMEDICAL MATERIALS

1

Application of the Collagen as Biomaterials Kwangwoo Nam and Akio Kishida

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan

Abstract Collagen is the protein of connective tissue in mammals. The content of collagen in the total protein is approximately 30% of the mammalian tissues. Due to its good cyt-ocompatibility, researchers use this material for the biomedical research application. However, the control of its physical and biological properties is difficult. There are two obstacles in collagen application: 1) difficulty in regeneration of the collagen properties, and 2) difficulties in controlling the properties of the collagen products. The collagen is easily denatured and affected by the environment, which leads to unexpected results. On the other hand, the crosslinker to suppress the denaturation may cause the stiffness of the collagen product. So the researchers are investigating new ways to prepare a col-lagen product which can be used as a biomaterial for biomedical research application. An important component of the research is the structure and the function of extracel-luar matrix (ECM). That is, there is biorelevant structure-function-property relation-ship, which alters its function as an ECM. Recent studies on decellularized tissue is also based on the fact that the native structure of the ECM can be preserved, and therefore may perform the function of the original tissue. So, by replicating its microstrutcure and producing a collagen fiber complex, it is expected that the function of ECM can be replicated. In this chapter, we will be introducing recent studies on the preparation of a collagen matrix based on fibrillogenesis, orientation, complex formation and layered structure, and how these structures alter the physical and biological properties.

Keywords: Collagen, decellularization, extracellular matrix, fibrillogenesis, microen-vironment, regenerative medicine

1.1 Introduction

Collagen is an extracellular-matrix (ECM) protein that plays an important role in the formation of tissues and organs and is involved in various functional expressions of cells [1]. A native ECM is a complex fiber-composite material in which collagen fibrils are a major component [2]. The function of an ECM is to provide support, tensile strength, and scaffolding for the tissue and cells. In addition, it should serve as a three-dimensional structure for cell adhesion

Ashutosh Tiwari, Murugan Ramalingam, Hisatoshi Kobayashi and Anthony P.F. Turner (eds.) Biomedical Materials and Diagnostic Devices, (3-18) © 2012 Scrivener Publishing LLC

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4 BlOMEDICAL MATERIALS AND DIAGNOSTIC DEVICES

and movement and as a storage depot for growth factors, chemokines, and cytokines; and it should provide signals for morphogenesis and differentiation [3]. Approximately 30% of all vertebrate body protein is composed of collagen. Among these, the highest collagen composition can be found for the tendon, bone and cornea where 90% of ECM is collagen. Mainly, the collagen can be distinguished into two types; fibrillar and non-fibrillar. There are 28 types of collagen and the collagen types I, II and III are the classical fibril-forming col-lagens and account for 80-90% of all collagens in the human body. Collagen fibril is very important from the aspect that its properties and the morphol-ogy provide the key to the scaffolding structures in the body according to the location.

It has been shown that the collagen possesses non-immunogenicity and good cell compatibility, and can be obtained from various sources. These make collagen popular among biomaterials researchers, and diverse methods have been adopted for its application in the biomedical fields. The collagen is puri-fied after being treated with pH adjustment or pepsin digestion. Either way, the collagen should be water soluble in order to process it for use as a collagen matrix for biomaterial applications. There are several kinds of collagen matrix; gel, film, micropartices, conjugate, minipellets or sponge [1,4]. However, there are still many problems to overcome. For example, the collagen which is avail-able in the marketplace is hydrophilic, which absorbs water at a high rate. So, the uncross-linked collagen matrix possesses low mechanical strength and fast degradation rate in aqueous solution. The collagen matrix degrades by the collagenase, so this makes the collagen applicable in some biomedical prod-ucts where the biodegradation in the living body is required. However, con-trol of the biodegradation is not easy. The properties of the collagen matrix can be controlled by cross-linking. The cross-linking is executed chemically or physically. Furthermore, using the same cross-linking process, the collagen matrix can be functionalized by immobilization or, blend of a second com-ponent. The collagen is composed of amino acid groups where the chemical reaction can be executed. Mainly, the cross-linking is executed using ε-amino groups of lysine or hydrolysine, and aspartic acid or glutamic acid residues. These residues are highly reactive and can be easily functionalized. The cross-linking can change physical and biological properties of the collagen matrix and can be applied for the loading of the drugs. For the chemical cross-link, glutaraldehyde, formaldehyde, hexamethyelenediisocynate, polyepoxy com-pounds, carbodiimides, and acyl azides are commonly used [1, 4-14]. These show a good result in vivo, such as suppressing the inflammatory response and promoting the healing response. However, there are still several problems to be overcome. Although the collagen gels, sponges or films that have been cross-linked show an increase in the mechanical strength, the cross-link which consumes the functional groups are consumed for the cross-linking site, which may affect the biological properties. Moreover, the stiffness of the ECM is also a very important parameter, but it is not easy to control the stiffness of the col-lagen gel by cross-linking or a change in the collagen solution. That is, a stiff collagen gel can be prepared, but a gel with viscoelasticity cannot be prepared.