Biomaterials Fabrication and Processing Handbook

Biomaterials Fabrication and Processing HANDBOOK CRC_7973_FM.indd i 2/26/2008 2:29:23 PM CRC_7973_FM.indd ii 2/26/...

Author: Paul K. Chu | Xuanyong Liu

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Biomaterials Fabrication and Processing HANDBOOK

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Biomaterials Fabrication and Processing HANDBOOK Edited by

Paul K. Chu Xuanyong Liu

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

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CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2008 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 Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-13: 978-0-8493-7973-4 (Hardcover) 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 validity 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 utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, 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 Biomaterials fabrication and processing handbook / [edited by] Paul K. Chu and Xuanyong Liu. p. ; cm. “A CRC title.” Includes bibliographical references and index. ISBN 978-0-8493-7973-4 (alk. paper) 1. Biomedical materials. 2. Biomedical engineering. I. Chu, Paul K. II. Liu, Xuanyong. III. Title. [DNLM: 1. Biocompatible Materials. 2. Biosensing Techniques. 3. Nanotechnology--methods. 4. Tissue Engineering--methods. QT 37 B61413 2008] R857.M3B5696 2008 610.284--dc22

2007042613

Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

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Contents Preface..............................................................................................................................................ix Editors ..............................................................................................................................................xi Contributors ................................................................................................................................. xiii

PART I Tissue Engineering Scaffold Materials Chapter 1

Inorganic and Composite Bioactive Scaffolds for Bone Tissue Engineering ..............3 Qi-Zhi Chen, Oana Bretcanu, and Aldo R. Boccaccini

Chapter 2

Design, Fabrication, and Characterization of Scaffolds via Solid Free-Form Fabrication Techniques............................................................................................... 45 Dietmar W. Hutmacher and Maria Ann Woodruff

Chapter 3

Control and Monitoring of Scaffold Architecture for Tissue Engineering ................ 69 Ying Yang, Cassilda Cunha-Reis, Pierre Olivier Bagnaninchi, and Halil Murat Aydin

Chapter 4

Rapid Prototyping Methods for Tissue Engineering Applications ............................ 95 Giovanni Vozzi and Arti Ahluwalia

Chapter 5

Design and Fabrication Principles of Electrospinning of Scaffolds ........................ 115 Dietmar W. Hutmacher and Andrew K. Ekaputra

PART II Chapter 6

Drug Delivery Systems Nanoparticles in Cancer Drug Delivery Systems .................................................... 143 So Yeon Kim and Young Moo Lee

Chapter 7

Polymeric Nano/Microparticles for Oral Delivery of Proteins and Peptides .......... 171 S. Sajeesh and Chandra P. Sharma

Chapter 8

Nanostructured Porous Biomaterials for Controlled Drug Release Systems........... 193 Yang Yang Li, Jifan Li, and Bunichiro Nakajima

Chapter 9

Inorganic Nanostructures for Drug Delivery ........................................................... 217 Ying-Jie Zhu v

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Contents

PART III Nano Biomaterials and Biosensors Chapter 10 Self-Assembly of Nanostructures as Biomaterials.................................................. 237 Hua Ai, Yujiang Fan, and Zhongwei Gu Chapter 11 Electrohydrodynamic Processing of Micro- and Nanometer Biological Materials ................................................................................................................. 275 Yiquan Wu and Robert Lewis Clark Chapter 12 Fabrication and Function of Biohybrid Nanomaterials Prepared via Supramolecular Approaches ............................................................................. 335 Katsuhiko Ariga Chapter 13 Polypyrrole Nano- and Microsensors and Actuators for Biomedical Applications ............................................................................................................ 367 Yevgeny Berdichevsky and Yu-Hwa Lo Chapter 14 Processing of Biosensing Materials and Biosensors ............................................... 401 Yingchun Zhu, Yu Yang, and Yanyan Liu

PART IV Other Biomaterials Chapter 15 Synthetic and Natural Degradable Polymeric Biomaterials ................................... 457 Sanjukta Deb Chapter 16 Electroactive Polymers as Smart Materials with Intrinsic Actuation Properties: New Functionalities for Biomaterials ................................................... 483 Federico Carpi and Danilo De Rossi Chapter 17 Blood-Contacting Surfaces ..................................................................................... 505 Menno L.W. Knetsch Chapter 18 Improving Blood Compatibility of Biomaterials Using a Novel Antithrombin–Heparin Covalent Complex ............................................................. 535 Leslie Roy Berry and Anthony Kam Chuen Chan Chapter 19 Surface Modification of Biomaterials Using Plasma Immersion Ion Implantation and Deposition ................................................................................... 573 Xuanyong Liu, Ricky K.Y. Fu, and Paul K. Chu

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Contents

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Chapter 20 Biomaterials for Gastrointestinal Medicine, Repair, and Reconstruction ............. 633 Richard M. Day Chapter 21 Biomaterials for Cartilage Reconstruction and Repair........................................... 659 Wojciech Swieszkowski, Miroslawa El Fray, and Krzysztof J. Kurzydlowski Index .............................................................................................................................................. 679

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Preface Biomaterials are used in the biomedical industry to replace or repair injured and nonfunctional tissues. The worldwide biomaterials market was worth over $300 billion in 2005. This market is projected to grow at a rate of 20% per year, and a growing number of scientists and engineers are engaged in fabrication and research of biomaterials. Recognizing the ever increasing importance of biomaterials, a number of books on biomaterials were published in the past 20 years. The Biomaterials Fabrication and Processing Handbook is different from these published books in that it brings together the various aspects of fabrication and processing of the latest biomaterials, including tissue engineering scaffold materials, drug delivery systems, and nanobiomaterials and biosensors. Some common implant materials including hard tissue materials, blood-contacting materials, and soft tissue materials are also described in this book. Tissue engineering involves the development of new materials or devices capable of interacting specifically with biological tissues. The key to tissue engineering is the preparation of scaffolds using materials with the appropriate composition and structure. In the drug industry, advances in drug delivery systems are very important. Controlled release can be obtained by selecting the appropriate materials to produce the drug delivery system. Attempts have been made to incorporate drug reservoirs into implantable devices for sustained and preferably controlled release. Nanotechnology also plays an important role in the biomedical and biotechnology industries and has been used in the preparation of drugs for protein delivery, tissue engineering, bones, cardiovascular biomaterials, hard tissue replacements, biosensors, and biological microelectromechanical systems (Bio-MEMS). This book covers the latest information pertaining to tissue engineering scaffold materials, drug delivery systems, and nanobiomaterials and biosensors. The book has 21 chapters describing different types of biomaterials, and is divided into four sections, namely tissue engineering scaffold materials, drug delivery systems, nanobiomaterials and biosensors, and other biomaterials. The section on tissue engineering describes inorganic and composite bioactive scaffolds for bone tissue engineering, design, fabrication, and characterization of scaffolds via solid free-form fabrication techniques, control and monitoring of scaffold architecture for tissue engineering, rapid prototyping methods for tissue engineering applications, as well as design and fabrication principles of electrospinning of scaffolds. The section on drug delivery systems discusses nanoparticles in cancer drug delivery systems, polymeric nano/microparticles for oral delivery of proteins and peptides, nanostructured porous biomaterials for controlled drug release systems, and inorganic nanostructures for drug delivery. The section on nanobiomaterials and biosensors includes self-assembly of nanostructures as biomaterials, electrohydrodynamic processing of micro- and nanometer biological materials, fabrication and functions of biohybrid nanomaterials prepared via supramolecular approaches, polypyrrole nano- and microsensors and actuators for biomedical applications, as well as processing of biosensing materials and biosensors. The last section, which deals with other biomaterials, includes synthetic and natural degradable polymeric biomaterials, electroactive polymers as smart materials with intrinsic actuation properties such as new functionalities for biomaterials, blood-contacting surfaces, improvement of blood compatibility of biomaterials using a novel antithrombin–heparin covalent complex, surface modification of biomaterials using plasma immersion ion implantation and deposition, biomaterials for gastrointestinal medicine, repair, and reconstruction, and biomaterials for cartilage reconstruction and repair. These chapters have been written by renowned experts in their respective fields, and this book is valuable to the biomaterials and biomedical engineering community. It is intended for a broad and diverse readership including bioengineers, materials scientists, physicians, surgeons, research students, practitioners, and researchers in materials science, bioengineering, and medicine.

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Preface

Readers will be able to familiarize themselves with the latest techniques in biomaterials and processing. In addition, each chapter is accompanied by an extensive list of references for readers interested in pursuing further research. The outstanding cooperation from contributing authors who devoted their valuable time and effort to write excellent chapters for this handbook is highly appreciated. We are also indebted to all our colleagues who have made this book a reality. Paul K. Chu Xuanyong Liu

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Editors Paul K. Chu is a professor (chair) of materials engineering at the City University of Hong Kong. He received a BS in mathematics from The Ohio State University in 1977 and an MS and a PhD in chemistry from Cornell University in 1979 and 1982, respectively. Professor Chu’s research activities are quite diverse, encompassing plasma surface engineering and various types of materials and nanotechnology. He has published over 550 journal papers and has been granted eight U.S. and three Chinese patents. He is a fellow of the IEEE, AVS, and HKIE, senior editor of IEEE Transactions on Plasma Science, associate editor of International Journal of Plasma Science and Engineering, and a member of the editorial board of Materials Science & Engineering: Reports, Surface and Interface Engineering, and Biomolecular Engineering. He is a member of the Plasma-Based Ion Implantation and Deposition International Committee, Ion Implantation Technology International Committee, and IEEE Plasma Science and Application Executive Committee. Xuanyong Liu is an associate professor of materials engineering at the Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS), and a professor at Hunan University. He received a BS and an MS in materials science and engineering from Hunan University in 1996 and 1999, respectively, and a PhD in materials science and engineering from SICCAS in 2002. His doctoral dissertation was awarded the National Excellent Doctoral Dissertation of People’s Republic of China in 2004. Professor Liu’s primary research focus is on surface modification of biomaterials. He has founded the Surface Engineering of Biomaterials Group in SICCAS and has published over 70 journal papers, including 14 papers on biomaterials.

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Contributors Arti Ahluwalia Interdepartmental Research Center “E. Piaggio” and Department of Chemical Engineering University of Pisa Pisa, Italy Hua Ai National Engineering Research Center for Biomaterials Sichuan University Chengdu, China Katsuhiko Ariga WPI Center for Materials Nanoarchitectonics National Institute for Materials Science Tsukuba, Japan Halil Murat Aydin Institute for Science and Technology in Medicine Keele University Staffordshire, U.K. Pierre Olivier Bagnaninchi Institute for Science and Technology in Medicine Keele University Staffordshire, U.K. Yevgeny Berdichevsky Electrical and Computer Engineering Department University of California San Diego, California, U.S.A.

Oana Bretcanu Department of Materials Imperial College London, U.K. Federico Carpi Interdepartmental Research Centre “E. Piaggio” University of Pisa Pisa, Italy Anthony Kam Chuen Chan Henderson Research Centre Hamilton, Ontario, Canada Qi-Zhi Chen Department of Materials Imperial College London, U.K. Paul K. Chu Department of Physics and Materials Science City University of Hong Kong Hong Kong, China Robert Lewis Clark Center for Biologically Inspired Materials and Material Systems Pratt School of Engineering Duke University Durham, North Carolina, U.S.A.

Leslie Roy Berry Henderson Research Centre Hamilton, Ontario, Canada

Cassilda Cunha-Reis Institute for Science and Technology in Medicine Keele University Staffordshire, U.K.

Aldo R. Boccaccini Department of Materials Imperial College London, U.K.

Richard M. Day Department of Medicine University College London, U.K.

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Contributors

Danilo De Rossi Interdepartmental Research Centre “E. Piaggio” University of Pisa Pisa, Italy

Menno L.W. Knetsch Centre for Biomaterials Research University of Maastricht Maastricht, The Netherlands

Sanjukta Deb Department of Biomaterials Dental Institute, King’s College London, U.K.

Krzysztof J. Kurzydlowski Division of Materials Design Faculty of Materials Science and Engineering Warsaw University of Technology Warsaw, Poland

Andrew K. Ekaputra Graduate Program in Bioengineering National University of Singapore Singapore Miroslawa El Fray Division of Biomaterials and Microbiological Technologies Szczecin University of Technology Polymer Institute Szczecin, Poland Yujiang Fan National Engineering Research Center for Biomaterials Sichuan University Chengdu, China Ricky K.Y. Fu Department of Physics and Materials Science City University of Hong Kong Hong Kong, China Zhongwei Gu National Engineering Research Center for Biomaterials Sichuan University Chengdu, China

Young Moo Lee School of Chemical Engineering Hanyang University Seoul, South Korea Jifan Li Hitachi Chemical Research Center Irvine, California, U.S.A. Yang Yang Li Hitachi Chemical Research Center Irvine, California, U.S.A. and Department of Physics and Materials Science City University of Hong Kong Hong Kong, China Xuanyong Liu Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai, China and Department of Physics and Materials Science City University of Hong Kong Hong Kong, China

Dietmar W. Hutmacher Division of Regenerative Medicine Institute of Health and Biomedical Innovation Queensland University of Technology Brisbane, Australia

Yanyan Liu Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai, China and Laboratory of Special Functional Materials Henan University Kaifeng, China

So Yeon Kim Division of Engineering Education College of Engineering Chungnam National University Daejeon, South Korea

Yu-Hwa Lo Electrical and Computer Engineering Department University of California San Diego, California, U.S.A.

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Contributors

Bunichiro Nakajima Hitachi Chemical Research Center Irvine, California, U.S.A. S. Sajeesh Division of Biosurface Technology Sree Chitra Tirunal Institute for Medical Sciences and Technology Thiruvananthapuram, India Chandra P. Sharma Division of Biosurface Technology Sree Chitra Tirunal Institute for Medical Sciences and Technology Thiruvananthapuram, India Wojciech Swieszkowski Division of Materials Design Faculty of Materials Science and Engineering Warsaw University of Technology Warsaw, Poland Giovanni Vozzi Interdepartmental Research Center “E. Piaggio” and Department of Chemical Engineering University of Pisa Pisa, Italy Maria Ann Woodruff Division of Regenerative Medicine Institute of Health and Biomedical Innovation Queensland University of Technology Brisbane, Australia

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Yiquan Wu Center for Biologically Inspired Materials and Material Systems Pratt School of Engineering Duke University Durham, North Carolina, U.S.A. Ying Yang Institute for Science and Technology in Medicine School of Medicine Keele University Staffordshire, U.K. Yu Yang Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai, China Yingchun Zhu Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai, China Ying-Jie Zhu State Key Laboratory of High Performance Ceramics and Superfine Microstructures Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai, China

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Part I Tissue Engineering Scaffold Materials

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Inorganic and Composite Bioactive Scaffolds for Bone Tissue Engineering Qi-Zhi Chen, Oana Bretcanu, and Aldo R. Boccaccini

CONTENTS 1.1 Introduction ...............................................................................................................................4 1.2 Design of 3-D Scaffolds ............................................................................................................4 1.3 Scaffold Materials for Bone Tissue Engineering ......................................................................6 1.3.1 Bioceramics: Calcium Phosphates ................................................................................6 1.3.1.1 Biocompatibility ..............................................................................................6 1.3.1.2 Degradability ..................................................................................................6 1.3.1.3 Mechanical Properties ....................................................................................7 1.3.2 Bioceramics: Bioactive Silicate Glasses ........................................................................8 1.3.2.1 Biocompatibility ..............................................................................................8 1.3.2.2 Biodegradability ..............................................................................................9 1.3.2.3 Mechanical Properties ....................................................................................9 1.3.3 Bioceramics: Glass-Ceramics ..................................................................................... 10 1.3.3.1 A-W Glass-Ceramics .................................................................................... 10 1.3.3.2 Ceravital Glass-Ceramics ............................................................................. 11 1.3.3.3 Bioverit Glass-Ceramics ............................................................................... 11 1.3.3.4 45S5 Bioglass-Derived Glass-Ceramics ....................................................... 11 1.3.4 Naturally Occurring Biopolymers ............................................................................... 11 1.3.4.1 Collagen and ECM-Based Materials ............................................................ 11 1.3.4.2 Chitosan ........................................................................................................ 12 1.3.5 Synthetic Polymers ...................................................................................................... 12 1.3.5.1 Bulk Degradable Polymers ........................................................................... 13 1.3.5.2 Surface Bioeroding Polymers ....................................................................... 15 1.3.6 Biocomposites.............................................................................................................. 16 1.3.7 Summary ..................................................................................................................... 18 1.4 Fabrication of Tissue-Engineering Scaffolds.......................................................................... 19 1.4.1 Fabrication of Inorganic Scaffolds .............................................................................. 19 1.4.1.1 Powder-Forming Processes ........................................................................... 19 1.4.1.2 Sol–Gel Techniques ...................................................................................... 23 1.4.1.3 Solid Free-Form Techniques .........................................................................24 1.4.1.4 Comparison of Fabrication Techniques for Ceramic or Glass Scaffolds ......25 1.4.2 Fabrication of Composite Scaffolds ............................................................................28 1.4.2.1 Solvent Casting.............................................................................................. 30 1.4.2.2 Solvent Casting or Particle Leaching and Microsphere Packing.................. 30 1.4.2.3 Thermally Induced Phase Separation or Freeze-Drying .............................. 31

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Biomaterials Fabrication and Processing Handbook

1.4.2.4 Microsphere Sintering ................................................................................... 31 1.4.2.5 Foam Coating ................................................................................................ 31 1.5 Surface Functionalization ....................................................................................................... 32 1.5.1 Protein Adsorption ...................................................................................................... 32 1.5.2 Silane-Modified Surfaces (Silanization Technique) .................................................... 32 1.5.3 Topography (Roughness) Modification ....................................................................... 33 1.5.4 Polymer Coatings ........................................................................................................ 33 1.6 Conclusions ............................................................................................................................. 33 References ........................................................................................................................................34

1.1

INTRODUCTION

Being a modern discipline, tissue engineering encounters various challenges, such as the development of suitable scaffolds that temporarily provide mechanical support to cells at an early stage of implantation until the cells are able to produce their own extracellular matrix (ECM) [1]. Numerous biomaterials and techniques to produce three-dimensional (3-D) tissue-engineering scaffolds have been considered; biomaterials include polymers, ceramics, and their composites, as discussed in the literature [1–3]. In this chapter, we present an up-to-date summary of the fabrication technologies for tissue-engineering scaffolds, including the choice of suitable materials and related fabrication techniques, with a focus on the development of synthetic scaffolds based on bioceramics, glasses, and their composites combined with biopolymers for bone regeneration. Being one of the most promising technologies, the replication method for the production of highly porous, biodegradable, and mechanically competent Bioglass®-derived glass-ceramic scaffolds is highlighted. The enhancement of scaffold properties and functions by surface modification is also discussed, and examples of novel approaches are given.

1.2 DESIGN OF 3-D SCAFFOLDS In an organ, cells and their ECM are organized into 3-D tissues. Therefore, in tissue engineering a highly porous 3-D matrix (i.e., scaffold) is necessary to accommodate cells and to guide their growth and tissue regeneration in 3-D structures. This is particularly relevant in the field of bone tissue engineering and regeneration, bone being a highly hierarchical 3-D composite structure. Moreover, the structure of bone tissue varies with its location in the body. So the selection of configurations as well as appropriate biomaterials depends on the anatomic site for regeneration, the mechanical loads present at the site, and the desired rate of incorporation. Ideally, the scaffold should be porous enough to support cell penetration, tissue ingrowth, rapid vascular invasion, and nutrient delivery. Moreover, the matrix should be designed to guide the formation of new bones in anatomically relevant shapes, and its degradation kinetics should be such that the biodegradable scaffold retains its physical (e.g., mechanical) properties for at least 6 months (for in vitro and in vivo tissue regeneration) [1,3]. Important scaffold design parameters are summarized in Table 1.1. The design of highly porous scaffolds involves a critical issue related to their mechanical properties and structural integrity, which are time dependent. For example, it has been reported that the compressive strength of hydroxyapatite scaffolds increases from ∼10 to ∼30 MPa because of tissue ingrowth in vivo [5]. This finding leads to a conclusion that it might not be necessary to have a starting scaffold with a mechanical strength equal to that of a bone, because cultured cells on the scaffold in vitro will create a biocomposite and increase the strength of the scaffold significantly. Another factor that affects scaffold design is the need for vascularization and angiogenesis in the constructs [6]. In vitro engineering approaches face the problem of critical thickness while regenerating tissue in the absence of true vascularization: mass transportation into tissue is difficult beyond a thin peripheral layer of a tissue construct even if artificial means are used to supply nutrients and oxygen [7]. Diffusion barriers that are present in vitro are most likely to become more


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Inorganic and Composite Bioactive Scaffolds for Bone Tissue Engineering

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TABLE 1.1 Scaffold Design Parameters for Bone Tissue Engineering [4] Parameters Porosity Pore size Pore structure Mechanical properties of the cancellous bone Tension and compression Mechanical properties of the cortical bone Tension Compression

Degradation properties Degradation time Degradation mechanism Biocompatibility Sterilizability

Requirements Maximum possible without compromising mechanical properties 200–400 µm Interconnected Strength: 5–10 MPa Modulus: 50–100 MPa Strength: 80–150 MPa Modulus: 17–20 GPa Strength: 130–220 MPa Modulus: 17–20 GPa __ Fracture toughness: 6–8 MPa√ m Must be tailored to match the application in patients Bulk dissolution in medium No chronic inflammation Sterilizable without altering material properties

deleterious in vivo due to lack of vascularization. Once the engineered tissue construct is placed in the body, vascularization becomes a key issue for further remodeling in the in vivo environment. Thus, angiogenesis is an essential step in the colonization of macroporous biomaterials during osteointegration. Capillaries bring osteoprogenitor cells and the nutriments that are required for their growth. They transport especially numerous angiogenic growth factors [8]. The main critical factors affecting bone formation are the pore size and pore interconnection of the scaffold. Pore size is related to the in vivo bone tissue ingrowth, allowing migration and proliferation of osteoblasts and mesenchymal cells, and matrix deposition in the empty spaces [9]. Pore interconnection provides the channel for cell distribution and migration allowing efficient in vivo blood vessel formation. An incomplete pore interconnection could limit blood vessels invasion. Small pore size could obstruct cell adhesion and bone ingrowth. Bone vascularization, besides providing nutrients essential for tissue survival, plays also a crucial role in coordinating the activity of bone cells and their migration for new bone formation [10]. Several studies have investigated the minimum pore size required to regenerate mineralized bone. The minimum requirement for pore size is considered to be around 100 µm due to cell size, migration requirements, and transport. However, pore sizes >300 µm are recommended due to enhanced growth rate of a new bone and the formation of capillaries [3,4,11]. Pore size in the range of 300–500 µm would promote vascularization and mass transportation of nutrients and waste products, while the scaffold would maintain good mechanical integrity during in vitro culture and in vivo transplantation [12]. It is equally important to notice that tissue-engineering scaffolds should have enhanced biological functions. Therefore, the incorporation of growth factors, such as bone growth factors (BGF) and vascularization growth factors (VGF), or specific peptide sequences into the scaffolds or on their surface is being considered as part of the integral design of scaffolds. Moreover, to improve cell attachment and growth, the surface of scaffolds’ struts needs to be pretreated (a process called surface functionalization) [13–15]. The design of the surface properties of scaffolds is an important step to achieve their successful in vitro and in vivo applications. A few approaches to surface modification of scaffolds are discussed below.


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1.3 SCAFFOLD MATERIALS FOR BONE TISSUE ENGINEERING The first step in achieving a successful scaffold is to choose a suitable biomaterial. Natural bone matrix is a composite of biological ceramic (a natural apatite) and biological polymer. Carbonated hydroxyapatite Ca10(PO4)6(OH)2 accounts for nearly two-thirds of the weight of a bone. The inorganic component provides compressive strength to the bone. Roughly one-third of the weight of a bone is from collagen fibers. Collagen fibers are tough and flexible, and thus tolerate stretching, twisting, and bending. It is not surprising that polymers, ceramics, or their composites have been chosen for bone repair [16]. They can be either synthetic or naturally occurring ones. Table 1.2 lists synthetic and natural scaffold biomaterials that have been most widely investigated for bone regeneration, some of which are well-established and clinically applicable. In this section, the biocompatibility, biodegradability, and mechanical properties of these scaffold materials, which are the most essential factors to be considered in the fabrication of bone regeneration scaffold, are reviewed concisely. Particular attention is paid to a key issue that remains with almost all existing scaffold biomaterials, that is, mechanically strong materials (in crystalline structure) tend to be bioinert, and biodegradable materials (in amorphous structure) are, in general, mechanically weak. An exception, 45S5 Bioglass-derived glass-ceramic, is considered in more detail because the issue associated with the two apparently irreconcilable properties (mechanical strength and biodegradability) have been successfully addressed in this material [17].

1.3.1

BIOCERAMICS: CALCIUM PHOSPHATES

1.3.1.1 Biocompatibility Since almost two-thirds of the weight of a bone is hydroxyapatite Ca10(PO4)6(OH)2, it seems logical to use this ceramic as a major component of scaffold materials for bone tissue engineering. Actually, hydroxyapatite and related calcium phosphates (e.g., β-tricalcium phosphate [β-TCP]) have been intensively investigated [16,18,21]. As expected, calcium phosphates have an excellent biocompatibility due to their close chemical and crystal resemblance to bone mineral [19,20]. Although they have not shown osteoinductive ability, they certainly possess osteoconductive properties as well as a remarkable ability to bind directly to bone [32–35]. A high number of in vivo and in vitro assessments have concluded that calcium phosphates, no matter which forms (bulk, coating, powder, or porous) and which phases (crystalline or amorphous) they are in, always support the attachment, differentiation, and proliferation of cells (such as osteoblasts and mesenchymal cells), with hydroxyapatite being the best among these scaffold materials [36]. Although the excellent biological performance of hydroxyapatite and related calcium phosphates has been welldocumented, the slow biodegradation of their crystalline phases and the weak mechanical strength of their amorphous states limit their application in engineering of new bone tissue, especially at load-bearing sites. 1.3.1.2 Degradability Typically, crystalline calcium phosphates have a long degradation time in vivo, often of the order of years [37]. The dissolution rate of synthetic hydroxyapatite depends on the type and concentration of the buffered or unbuffered solutions, pH of the solution, degree of the saturation of the solution, solid and solution ratio, length of suspension in the solution, as well as composition and crystallinity of the hydroxyapatite. In the case of crystalline hydroxyapatite, the degree of micro and macroporosities, defect in the structure, and amount and type of other phases present also have significant influence [39]. Crystalline hydroxyapatite exhibits the slowest degradation rate, compared with other calcium phosphates. The dissolution rate decreases in the following order [38]: Amorphous hydroxyapatite > all other calcium phosphates (e.g., TCP) >> crystalline hydroxyapatite.


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TABLE 1.2 List of Promising Scaffold Biomaterials for Bone Regeneration Biomaterials Ceramics [16,18] Calcium phosphates [19–21] Hydroxyapatite Tricalcium phosphate Biphasic calcium phosphate: HA and TCP Bioactive glasses [22–25] Bioglass Phosphate glasses Bioactive Glass-Ceramics [26,27] Apatite-Wollastonite Ceravital Polymers [28–31] Synthetic degradable polymers Bulk biodegradable polymers Aliphatic polyester Poly(lactic acid) Poly(d-lactic acid) Poly(l-lactic acid) Poly(d,l-lactic acid) Poly(glycolic acid) Poly(lactic-co-glycolic acid) Poly(ε-caprolactone) Poly(hydroxyalkanoate) Poly(3- or 4-hydroxybutyrate) Poly(3-hydroxyoctanoate) Poly(3-hydroxyvalerate) Polydioxanone Poly(propylene fumarate) Surface bioerodible polymers Poly(ortho esters) Poly(anhydrides) Poly(phosphazene) Natural degradable polymers Polysaccharides Hyaluronan Alginate Chitosan Proteins Collagen Fibrin Composites [12] Composed of the above-mentioned ceramics and polymers

Abbreviation CaP HA TCP BCP

A/W

PLA PDLA PLLA PDLLA PGA PLGA PCL PHA PHB PHO PHV

Application

Dental Drug delivery Scaffolds Dental Drug delivery Scaffolds Dental Drug delivery Scaffolds

Sutures Dental Orthopedic Drug delivery Scaffolds

PPF Drug delivery POE PPHOS

HyA

1.3.1.3 Mechanical Properties The properties of synthetic calcium phosphates vary significantly with their crystallinity, grain size, porosity, and composition (e.g., calcium deficiency). In general, the mechanical properties of synthetic calcium phosphates decrease significantly with increasing content of amorphous phase, microporosity, and grain size. High crystallinity, low porosity, and small grain size tend to give


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TABLE 1.3 Comparison of Mechanical Properties of Calcium Phosphates and Human Bone

Ceramics Calcium phosphates Hydroxyapatite Cortical bone

Compressive Strength (MPa)

Tensile Strength (MPa)

Elastic Modulus (GPa)

Fracture Toughness __ (MPa√ m )

References

20–900 >400 130–180

30–200 ∼40 50–151

30–103 ∼100 12–18

8 (called region E), soft tissue bonding occurs. Apatite-wollastonite glass-ceramic (A-WGC) has higher P2O5 content [22].


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TABLE 1.4 Mechanical Properties of Hydroxyapatite, 45S5 Bioglass, Glass-Ceramics, and Human Cortical Bone

Ceramics 45S5 Bioglass A-W Parent glass of A-W Bioverit I Cortical bone

Compression Strength (MPa)

Tensile Strength (MPa)

Elastic Modulus (GPa)

Fracture Toughness __ (MPa√ m )

References

500 1080 NA 500 130–180

42 215 (bend) 72 (bend) 140–180 (bend) 50–151

35 118 NA 70–90 12–18

0.5–1 2.0 0.8 1.2–2.1 6–8

42,73 26 26 74 28,43–46

and even turn a bioactive glass into an inert material [71]. This is one of the disadvantages that limit the application of bioactive glasses as scaffold materials, as full crystallization occurs prior to significant densification upon heat treatment (i.e., sintering) [72]. Extensive sintering is necessary to densify the struts of a scaffold, which would otherwise be made up of loosely packed particles and thus the structure would be too fragile to handle. Most recently, Boccaccini’s group at Imperial College London [17] reported on a phase transformation from a mechanically competent crystalline phase to a biodegradable amorphous calcium phosphate in 45S5 Bioglass-derived scaffolds. This phase transition, which takes place in a biological environment at body temperature, couples the two required properties (mechanical strength and biodegradability) in a single scaffold. A detailed characterization of this material is given in Section 1.3.3.4. In summary, like hydroxyapatite and related calcium phosphates, bioactive glasses exhibit good biocompatibility and osteoconductivity. At the same time, all these materials, except 45S5 Bioglassderived glass-ceramics, encounter a similar disadvantage, that is, a mechanically strong scaffold has to be achieved through crystallization, which unfortunately hampers the biodegradability of these materials.

1.3.3

BIOCERAMICS: GLASS-CERAMICS

Glasses can be strengthened by the formation of crystalline particles in the glass matrix upon heat treatment in the relevant glass-crystal region of its phase diagram. The resultant glass-ceramics usually exhibit better mechanical properties than both the parent glass and sintered crystalline ceramics (e.g., sintered hydroxyapatite) (Table 1.4). There are many biomedical glass-ceramics available for the repair of damaged bones. Among them, apatite-wollastonite (A-W), Ceravital, and Bioverit glass-ceramics have been intensively investigated [16,18]. Recently, a 45S5 Bioglass-derived glass-ceramic showed a great potential as a tissue-engineering scaffold material, as mentioned above (Section 1.3.2.3). 1.3.3.1

A-W Glass-Ceramics

In A-W glass-ceramic, the glass matrix is reinforced by β-wollastonite (CaSiO3) crystals and a small amount of apatite phase, which precipitate successively at 870°C and 900°C, respectively [75]. Some mechanical properties of this glass-ceramic have been listed in Table 1.4. The high bending strength (215 MPa) of A-W glass-ceramic is due to the precipitation of wollastonite as well as apatite. These two precipitates also give the glass-ceramic a higher fracture toughness than that of both the glass and ceramic phases. It is believed that wollastonite effectively prevents straight propagation of cracks, causing them to deflect or branch out [26,75–77]. A-W glass-ceramic is capable of binding tightly to a living bone in a few weeks after implantation, and the implants do not deteriorate in vivo [78]. The excellent bone-bonding ability of A-W


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11

glass-ceramic is attributed to the glass matrix and apatite precipitates, whereas the in vivo stability as a whole is due to the inertness of β-wollastonite. Although the long-term integrity in vivo is desirable in the application of nonresorbable prosthesis, the material does not match the goal of tissue engineering, which demands biodegradable scaffolds. 1.3.3.2 Ceravital Glass-Ceramics [79] “Ceravital” was coined to mean a number of different compositions of glasses and glass-ceramics and not only one product. Their basic network components include SiO2, Ca(PO2)2, CaO, Na2O, MgO, and K 2O, with ceramic additions being Al2O3, Ta2O5, TiO2, B2O3, Al(PO3)3, SrO, La2O3, or Gd2O3. This material system was developed as solid fillers in the load-bearing conditions for the replacement of bone and teeth. It turned out, however, that their mechanical properties do not serve the purpose, and there has been virtually no research on the application of this material in tissueengineering scaffolds. 1.3.3.3 Bioverit Glass-Ceramics [74] Bioverit products are mica-apatite glass-ceramics. Mica crystals (aluminum silicate minerals) give the materials good machinability, and apatite crystals ensure the bioactivity of the implants. The mechanical properties of Bioverit materials (Table 1.4) allow them to be used as fillers in dental application. As regards bioreactivity, Bioverit implants show a hydrolytic stability in vivo. As for Ceravital glass-ceramics, no significant research has been carried out regarding the use of this glass-ceramic in tissue engineering. 1.3.3.4

45S5 Bioglass-Derived Glass-Ceramics

In 2005, Chen et al. [80] fabricated a 3-D, highly porous, mechanically competent, bioactive and biodegradable scaffold for the first time by the replication technique using 45S5 Bioglass powder. Under an optimum sintering condition (1000°C/h), nearly full densification of the foam struts occurred and fine crystals of Na2Ca2Si3O9 are formed, which conferred the scaffolds the highest possible compressive and flexural strength for this foam structure. Important findings in this work are that the mechanically strong crystalline phase Na2Ca2Si3O9 can transform into an amorphous calcium phosphate phase after immersion in simulated body fluid (SBF) for 28 days and that the transformation kinetics can be tailored by controlling the crystallinity of the sintered 45S5 Bioglass. As such, it was demonstrated that the goal of an ideal scaffold that provides good mechanical support temporarily while maintaining bioactivity and that can biodegrade at later stages at a tailorable rate can be achieved with these Bioglass-based scaffolds [17].

1.3.4

NATURALLY OCCURRING BIOPOLYMERS

Much research effort has been focused on naturally occurring polymers such as demineralized bone ECM [81], purified collagen [82,83], and chitosan [84] for tissue engineering applications. Theoretically, naturally occurring polymers should not cause response of foreign materials when implanted. They provide a natural substrate for cellular attachment, proliferation, and differentiation in their native state. For these reasons, naturally occurring polymers could be a favorite substrate for tissue engineering [28]. Table 1.5 provides a list of some of the naturally occurring polymers, their sources, and applications. Among them, collagen and chitosan are most widely investigated for bone engineering and are briefly discussed here. 1.3.4.1 Collagen and ECM-Based Materials The most commonly used naturally occurring polymer is the structural protein collagen. Biomaterials derived from ECM include collagen and other naturally occurring structural and functional


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12


TABLE 1.5 List of Naturally Occurring Polymers, Their Sources, and Applications [85] Polymers

Source

Collagen

Tendons and ligament

Collagen-Glycosaminoglycan (GAG) (alginate) copolymers Albumin

In blood

Hyaluronic acid

In the ECM of all higher animals

Fibrinogen–Fibrin

Purified from plasma in blood

Chitosan

Shells of shrimps and crabs

Application Multiapplications, including bone tissue engineering Artificial skin grafts for skin replacement Transporting protein used as coating to form a thromboresistant surface An important starting material for preparation of new biocompatible and biodegradable polymers that have applications in drug delivery, tissue engineering, and viscosupplementation Multiapplications, including bone tissue engineering Multiapplications, including bone tissue engineering

proteins. Natural polymers must be modified and sterilized before clinical use. All methods of stabilization and sterilization can moderately or severely alter the rate of in vivo degradation and change the mechanical and physical properties of the native polymers. Each method has certain advantages and disadvantages, and thus should be selectively utilized for scaffolds of specifically sited bone tissue engineering [86]. 1.3.4.2 Chitosan The use of chitosan for bone tissue engineering has been widely investigated [84,87]. This is in part due to the apparent osteoconductive properties of chitosan. Mesenchymal stem cells cultured in the presence of chitosan have demonstrated an increased differentiation to osteoblasts compared with cells cultured in the absence of chitosan [88]. It is also speculated that chitosan may enhance osteoconduction in vivo by entrapping growth factors at the wound site [89].

1.3.5

SYNTHETIC POLYMERS

Although naturally occurring polymers possess the above-mentioned advantages, their poor mechanical properties and variable physical properties with different sources of protein matrices have hampered their progress in broad applications in tissue engineering. Concerns have also been expressed regarding immunogenic problems associated with the introduction of foreign collagen [37]. Following the developmental efforts regarding the use of naturally occurring polymers as scaffolds, much attention has been paid to synthetic polymers. Synthetic polymers have high potential in tissue engineering not only because of their excellent processing characteristics, which can ensure their off-the-shelf availability, but also because of their advantage of being biocompatible and biodegradable [37,90]. Synthetic polymers have predictable and reproducible mechanical and physical properties (e.g., tensile strength, elastic modulus, and degradation rate) and can be manufactured with great precision. Although they are unfamiliar to cells and many have some shortcomings, such as eliciting persistent inflammatory reactions, being eroded, not being compliant or able to


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13

integrate with the host tissues, they may be replaced in vivo in a timely fashion by native constructs built by the cells seeded into them. It has been widely accepted that an ideal tissue-engineered bone substitute should be a synthetic scaffold, which is biocompatible and provides for cell attachment, proliferation and maturation, has mechanical properties to match those of the tissues at the site of implantation, and degrades at rates to match tissue replacement. Table 1.6 lists selected properties of synthetic, biocompatible, and biodegradable polymers that have been intensively investigated as scaffold materials for tissue engineering, type I collagen fibers being included for comparison. 1.3.5.1

Bulk Degradable Polymers

1.3.5.1.1 Saturated Poly-α-Hydroxyesters (PLA, PGA, and PCL) The biodegradable synthetic polymers most often utilized for 3-D scaffolds in tissue engineering are the poly(α-hydroxyacids), including poly(lactic acid) (PLA) and poly(glycolic acid) (PGA), as well as poly(lactic-co-glycolide) (PLGA) copolymers [91]. PLA exists in three forms: l-PLA (PLLA), d-PLA (PDLA), and racemic mixture of d,l-PLA (PDLLA). These polymers are popular for various reasons, among which biocompatibility and biodegradability stand out. These materials have chemical properties that allow hydrolytic degradation through de-esterification. After the process of degradation is over, the monomeric components of each polymer are removed through natural pathways: PGA can be converted to other metabolites or eliminated by other mechanisms, and PLA can be cleared through tricarboxylic acid cycle. The body already contains highly regulated mechanisms for completely removing monomeric components of lactic and glycolic acids. Due to these properties, PLA and PGA have been used in products such as degradable sutures and have been approved by the U.S. Food and Drug Administration (FDA) [28]. Other significant properties of these polymers are their very good processability, and their ability to exhibit a wide range of degradation rates, physical, mechanical, and other properties, which can be achieved by PLA and PGA of various molecular weights and their copolymers. However, these polymers undergo a bulk erosion process in contact with body fluids such that they can cause scaffolds to fail prematurely. In addition, abrupt release of these acidic degradation products can cause a strong inflammatory response [92,93]. In general, PGA degrades faster than PLA, as listed in Table 1.6. Their degradation rates decrease in the following order. PGA > PDLLA > PLLA Degradation rates decrease Table 1.6 also lists the mechanical properties of type I collagen, which is the major organic component of ECM in bone. The strength and ductility (e.g., ultimate elongation) of PLA and PGA are comparable to those of type I collagen fibers. PDLLA has been extensively investigated as a biomedical coating material because of its excellent features with respect to implant surface [28,104]. In addition to its high mechanical stability [105], PDLLA also shows excellent biocompatibility in vivo and good osteoinductive potential [106]. PDLLA of low molecular weight can be combined with drugs like growth factors [106], antibiotics [107], or thrombin inhibitors [108] to establish a locally acting drug-delivery system. It is due to these desirable features that much more attention has recently been paid to PDLLA for applying it as a scaffold material for tissue engineering. Highly porous 3-D scaffolds made of Bioglass-filled PDLLA and PLGA were fabricated by Boccaccini et al. [59]. Since then an increasing number of publications have emerged on this subject, as reviewed recently [12]. Porous PDLLA foams and Bioglass-filled PDLLA composite foams have both been fabricated, using thermally induced–phase separation (TIPS) technique [109,110]. Bioglassfilled PDLLA composite foams exhibit high bioactivity, assessed by the formation of hydroxyapatite


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Poly(ortho-esters) Polyphosphazene Type I collagen

−72

58

30–100 −66–50

150–200

35–40 45–55

225–230 Amorphous

PGA PLGA PPF PCL Surface erosive polymers Poly(anhydrides)

242

60–65

173–178

PLLA

55–60

Amorphous

Glass Transition Point, Tg (°C)

Bulk degradable polymers PDLLA

Polymers

Melting Point, Tm (°C)

Surface Surface Bulk

Surface

Uncross-linked fiber: 0.91–7.2 Cross-linked fiber: 46.8–68.8

25–27 30–40* 4–16*

Fiber: 340–920 41.4–55.2 2–30*

Pellet: 40–120 Film or disk: 28–50 Fiber: 870–2300

>24

6–12 Adjustable Bulk Bulk

Pellet: 35–150* Film or disk: 29–35

Tensile or Compressive* Strength (MPa)

12–16

Degradation Time (months)

Uncross-linked fiber: 1.8–46×10 –3 Cross-linked fiber: 0.383–0.766

2.5–4.4

0.14–1.4

Fiber: 7–14 1.4–2.8

Film or disk: 1.2–3.0 Fiber: 10–16

Film or disk: 1.9–2.4

Modulus (GPa)

Uncross-linked fiber: 24.1–68.0 Cross-linked fiber: 11.6–15.6

700

Pellet: 0.5–8.0 Film or disk: 5.0–6.0 Pellet: 2.0–10.0 Film or disk: 2.0–6.0 Fiber: 12–26 Fiber: 15–25 3–10

Ultimate Elongation (%)

TABLE 1.6 Physical Properties of Synthetic, Biocompatible, and Biodegradable Polymers Investigated as Scaffold Materials

28,100 101,102 103

28,30,99

90,96,97 28 28,30 98

90,94

90,94,95

References

14 Biomaterials Fabrication and Processing Handbook

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15

on the strut surfaces upon immersion in SBF [111]. It has also been shown that the foams support the migration, adhesion, spreading, and viability of MG-63 cells (osteosarcoma cell line) [112]. Poly(ε-caprolactone) (PCL) is also an important member of the aliphatic polyester family. It has been used to effectively entrap antibiotic drugs and thus a construct made with PCL can be considered as a drug-delivery system, being used to enhance bone ingrowth and regeneration in the treatment of bone defects [113]. The degradation of PCL and its copolymers involves similar mechanisms to PLA, proceeding in two stages: random hydrolytic ester cleavage and weight loss through the diffusion of oligometric species__ from the bulk. It has been found that the degradation of PCL system with a high molecular weight (Mn of 50,000) is remarkably slow, requiring 3 years for complete removal from the host body [114]. 1.3.5.1.2 Polyhydroxyalkanoates (PHB, PHBV, P4HB, PHBHHx, PHO) Recently, polyhydroxyalkanoates (PHAs), another type of polyesters, have been suggested for tissue engineering because of their controllable biodegradation and high biocompatibility [115]. They are aliphatic polyesters as well, but produced by microorganisms under unbalanced growth conditions [116,117]. They are generally biodegradable (via hydrolysis) and thermoprocessable, making them attractive as biomaterials for application in medical devices and tissue engineering. Over the past years, PHA, particularly poly-3-hydroxybutyrate (PHB), copolymers of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV); poly 4-hydroxybutyrate (P4HB), copolymers of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx); and poly 3-hydroxyoctanoate (PHO) were demonstrated to be suitable for tissue engineering and are reviewed in detail in Refs. 115,116. Depending on the property requirement of different applications, PHA polymers can be either blended, surface modified, or composed with other polymers, enzymes, or inorganic materials to further adjust their mechanical properties or biocompatibility. The blending among the several PHA themselves can dramatically change their material properties and biocompatibility [115,116]. PHB is of particular interest for bone tissue application as it was demonstrated to produce a consistent favorable bone tissue adaptation response with no evidence of an undesirable chronic inflammatory response after an implantation period of up to 12 months [116]. The bone is formed close to the material and subsequently becomes highly organized, with up to 80% of the implant surface lying in direct apposition to the new bone. The materials showed no evidence of extensive structural breakdown in vivo during the implantation period of the study [118]. However, a drawback of some PHA polymers is their limited availability and the time-consuming extraction procedure from bacterial cultures that is required for obtaining sufficient processing amounts as described in the literature [115,119]. Therefore, the extraction process might be a challenge to a cost-effective industrial upscale production for large amounts of some PHA polymers. 1.3.5.1.3 Polypropylene Fumarate Poly(propylene fumarate) (PPF) is an unsaturated linear polyester. Similar to PLA and PGA, the degradation products of PPF through hydrolysis (i.e., propylene glycol and fumaric acid) are biocompatible and readily removed from the body. The double bond along the backbone of the polymer permits cross-linking in situ, which causes a moldable composite to harden within 10–15 min. Mechanical properties and degradation time of the composite may be controlled by varying the PPF molecular weight. Therefore, preservation of the double bonds and control of molecular weight during PPF synthesis are critical issues [120]. PPF has been suggested for use as scaffold for guided tissue regeneration, often as part of an injectable bone replacement composite [121], and has been used as a substrate for osteoblast culture [122]. 1.3.5.2

Surface Bioeroding Polymers

There is a family of hydrophobic polymers that undergo a heterogeneous hydrolysis process, which is predominantly confined to the polymer–water interface. This property is referred to as surface eroding as opposed to bulk degrading behavior. These surface bioeroding polymers have been


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16


intensively investigated as drug-delivery vehicles. The surface-eroding characteristic offers three key advantages over bulk degradation when used as scaffold materials: (1) retention of mechanical integrity over the degradative lifetime of the device, owing to the maintenance of mass to volume ratio; (2) minimal toxic effects (i.e., local acidity), owing to lower solubility and concentration of degradation products; and (3) significantly enhanced bone ingrowth into the porous scaffolds, owing to the increment in pore size as the erosion proceeds [123]. 1.3.5.2.1 Poly(anhydrides) Poly(1,3-bis-p-carboxyphenoxypropane anhydride) [124] and poly(erucic acid dimer anhydride) [125] are biodegradable polymers for controlled drug delivery in a form of implant or injectable microspheres. Studies in rabbits have shown that the osteocompatibility of poly(anhydrides) that undergo photocuring are comparable to PLA and that the implants of poly(anhydrides) show enhanced integration with the surrounding bones in comparison to PLA controls [126]. 1.3.5.2.2 Poly(ortho-esters) Poly(ortho-esters) (POE) scaffolds were coated with cross-linked acidic gelatine to improve surface properties for cell attachment. Preliminary in vitro and in vivo results revealed that POE did not show any inflammation and had little or no effect on bone formation while PLA provoked a chronic inflammatory response and inhibited bone formation [127,128]. 1.3.5.2.3 Polyphosphazenes These polymers seem to be potential bioerodible materials capable of controlled degradation and sustained drug delivery for therapeutic use [101,129] and bone regeneration [130]. Their tailored side groups enable a wide variety of hydrolytic properties to be designed into selected polymers for application in biological environments without the release of harmful degradation products at physiological concentration.

1.3.6

BIOCOMPOSITES

From a biological perspective, it is a natural strategy to combine polymers and ceramics to fabricate scaffolds for bone tissue engineering because native bone is the combination of a naturally occurring polymer and a biological apatite. From the point of view of materials science, a single material type does not always provide the necessary mechanical and chemical properties desired for a particular application. In these instances, composite materials designed to combine the advantages of both components may be most appropriate. Polymers and ceramics that degrade in vivo should be chosen for designing biocomposites for tissue-engineering scaffolds. While massive release of acidic degradation from polymers can cause inflammatory reactions [4,92,131], the basic degradation of calcium phosphate or bioactive glasses would buffer the acidic by-products of polymers and may thereby help to avoid the formation of an unfavorable environment for cells due to a decreased pH level. Mechanically, bioceramics are much stronger than polymers and play a critical role in providing mechanical stability to constructs prior to the synthesis of a new bone matrix by cells. However, ceramics and glasses are very fragile because of their intrinsic brittleness and flaw sensitivity. To capitalize on their advantages and minimize their shortcomings, ceramic and glass materials have been combined with various biopolymers to form composite biomaterials for osseous regeneration. Table 1.7 lists selected ceramic/glass–polymer composites, which were designed as biomedical devices or scaffold materials for bone tissue engineering, and their mechanical properties. In general, all these synthetic composites have good biocompatibility. Kikuchi et al. [132], for instance, combined TCP with PLA to form a polymer–ceramic composite, which was found to possess the osteoconductivity of β-TCP and the degradability of PLA [132]. The research team led by Laurencin [147] synthesized porous scaffolds containing PLGA and hydroxyapatite, which were reported to combine the degradability of PLGA with the bioactivity of hydroxyapatite, fostering cell proliferation and differentiation as well as mineral formation


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Human cancellous bone

Phosphate glass A/W

Bioglass

Porous composites Amorphous CaP β-TCP HA

A/W Ca3(CO3)2 Human cortical bone

β-TCP

HA

Dense composites HA fiber

Ceramic

40 (wt.) 20–40 (wt.)

0.1–1 (wt.) 5–29 (wt.)

PLGA PDLLA

PLA–PDLLA PDLLA

75 (wt.) 20–50 (wt.)

28–75 (wt.) 10–70 (wt.) 50 (wt.) 60–75 (wt.)

2–10.5 (vol.) 10–70 (wt.) 40–85 (vol.) 40–85 (vol.) 40–85 (vol.) 85–95 (wt.) 50–72 (wt.) 75 (wt.) 25 (wt.) 10–50 (vol.) 30 (wt.)

Percentage of Ceramic (%)

PLGA Chitosan–Gelatin PLLA PLGA PLGA PLGA PLLA

PDLLA PLLA PLGA Chitosan Chitosan+PLGA PPhos Collagen PLLA-co-PEH PPF PE PLLA

Polymer

Biocomposites

93–97 85.5–95.2

94

85–96 81–91 30–40 43 77–80

75

Pore Size (µm)

98–154

>100 322–355 100×300 800–1800 110–150 89 ∼100 ∼10 50–300 ∼100 10–50

Not applicable

Porosity (%)

TABLE 1.7 Biocomposites Designed for Bone Tissue Engineering

4–12 (C)

0.017–0.020 (C)

0.07–0.08 (C)

0.42 (C) 1.5–3.9 (T)

0.32–0.88 (C) 0.39 (C) 0.07–0.22 (C)

51 (F) 7.5–7.7 (C) 18–28 (F) 50 (C) 50–150 (T) 130–180 (C)

45 (F) 50–60 (F) 22 (F) 12 (F) 43 (F)

Compressive (C), Tensile(T), Flexural Strength (F) (MPa)

100–500

0.075–0.12

0.65–1.2

65 3.94–10.88 10–14 2–7.5 337–1459 51 137–260

5.18×103 191–134 0.9–5.7×103 3.5–6×103 12–18×103

1.75–2.47×103 6.4–12.8×103 1.1×103 2.15×103 2.6×103

Modulus (MPa)

1.65–2.11

7.21–13.3

1.1–13.7

0.7–2.3

Ultimate Strain (%)

5.29 0.092 9.77

Toughness (kJ/m2)

153 154 155,156

151 111,112,152

142,143 144 145 146 147 64,148,149 150

133 134 135,136 136 136 137 138 132 139 140 141 28,43–46

References

Inorganic and Composite Bioactive Scaffolds for Bone Tissue Engineering 17

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[147,157,158]. Similarly, composites of bioactive glass and PLA were observed to form calcium phosphate layers on their surfaces and support rapid and abundant growth of human osteoblasts and osteoblast-like cells when cultured in vitro [109–112,148–154]. A comparison between the dense composites and cortical bone indicates that the most promising synthetic composite seems to be hydroxyapatite fiber–reinforced PLA composite [134], which, however, exhibit mechanical property values close to the lower values of the cortical bone. Other promising composite scaffolds reported in literature are those from Bioglass and PLLA or PDLLA [149–152]. They have a well-defined porous structure, for example obtained by thermally induced phase separation [151], at the same time their mechanical properties are close to (but lower than) those of cancellous bone.

1.3.7

SUMMARY

To design an ideal scaffold, which is bioresorbable, biocompatible, provides for cell attachment, proliferation, and maturation, and which disappears whenever a new bone forms allowing the new bone to undergo remodeling, it is necessary to weight up the pros and cons of the potential precursor materials, as summarized in Table 1.8. Among the bioactive ceramics and glasses listed in Table 1.8, bioactive (silicate) glasses have remarkable advantages. The ability to enhance vascularization, the role of silicon in upregulating TABLE 1.8 Advantages and Disadvantages of Synthetic Scaffold Biomaterials in Bone Tissue Engineering Biomaterials

Positive

Calcium phosphates (e.g., HA, TCP, and BPCP)

1. Excellent biocompatibility 2. Supporting cell activity 3. Good osteoconductivity

Bioactive glasses and glass-ceramics

1. Excellent biocompatibility 2. Supporting cell activity 3. Good osteconductivity 4. Vascularization 5. Upregulation of gene expression 6. Tailorable degradation rate 1. Good biocompatibility 2. Biodegradable with a wide range of degradation rates 3. Bioresorbable 4. Good processability 5. Good ductility 1. Good biocompatibility 2. Retention of mechanical integrity over the degradative life of the device 3. Significantly enhanced bone ingrowth into the porous scaffolds, owing to the increment in pore size 1. Excellent biocompatibility 2. Supporting cell activity 3. Good osteconductivity 4. Tailorable degradation rate 5. Improved mechanical properties

Bulk biodegradable polymers (e.g., PLA, PGA, PLGA, PPF)

Surface bioerodible polymers (e.g., POE, poly(anhydrides), poly(phosphazene))

Composites


Negative 1. Too fragile in amorphous structure 2. Nearly bioinert in crystalline phase 1. Mechanically brittle and weak in the glass state 2. Degrade slowly in crystalline structures, except for 45S5 Bioglass-derived glass-ceramics 1. Inflammation caused by acid degradation products 2. Accelerated degradation rates cause collapse of scaffolds

1. They cannot be completely replaced by new bone tissue

1. Fabrication techniques can be complex

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19

gene expression, and the tailorable degradation rate make bioactive glasses promising scaffold materials over others, and so they could be the material of choice as the inorganic component of composite scaffolds. Although bioactive glasses are brittle with low fracture toughness (Table 1.4), they can be used in combination with polymers to form composite materials. The ability to couple mechanical strength with tailorable biodegradability makes 45S5 Bioglass-derived glass-ceramics advantageous over calcium phosphates (including hydroxyapatite), as well as other bioactive glasses and related glass-ceramics. Between the two types of polymers, the bulk degradable type is more promising than the surface-erosive group, considering that being replaced by new bone tissue is one of the important criteria of an ideal scaffold material (Table 1.1). Finally, it is obvious that composites can be considered ideal scaffolding materials for bone tissue engineering if fabrication processes suitable for the production of 3-D structures of the required size and shape and amenable to commercialization are further developed and optimised.

1.4 FABRICATION OF TISSUE-ENGINEERING SCAFFOLDS 1.4.1

FABRICATION OF INORGANIC SCAFFOLDS

Porous ceramics can be produced by a variety of different processes [2,159], which may be classified into two main categories: (1) manual-based processing techniques and (2) computer-controlled fabrication processes, such as solid free-form (SFF) technology, which is also commonly known as rapid prototyping (RP) [160]. Most manual-based processing techniques can further be divided into two groups: conventional powder-forming processes and sol–gel techniques [161]. 1.4.1.1 Powder-Forming Processes A flowchart that is common to all powder-forming processes is shown in Figure 1.2, and the different steps involved in these processes are discussed in this section. 1.4.1.1.1 Preparation of Slurries Slurry is a suspension of ceramic particles in a suitable liquid (e.g., water or ethanol) used to prepare green bodies. The inherent mechanism of pore formation in a powder compact is illustrated in Figure 1.3. Attractive forces that consist of hydrogen bonds, van der Waals forces, Coulomb’s forces, and physical friction between particles cause agglomeration of particles. Addition of fillers to the

Start with a ceramic powder

Prepare slurry from the powder

Add

Additives (e.g., porogen, binder)

Form a green body from the slurry

Heat treatment of the green body to sinter the ceramic structure

Porous ceramic

FIGURE 1.2


Flowchart of the powder-sintering method to produce porous ceramic scaffolds.

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20

Biomaterials Fabrication and Processing Handbook Primary particle Pore among agglomerates Pore among primary particles

Agglomerate of primary particles

FIGURE 1.3

Schematic illustration of pores among agglomerates and particles [159].

TABLE 1.9 Methods for Obtaining Ceramic Bodies for 3-D Porous Ceramics [159] Dry processes Loose packing Compaction Uniaxial pressing Cold isostatic pressing (CIPing) Wet processes Slip casting Injection molding Phase separation/freeze-drying Polymer replication Gelcasting

slurry, such as sucrose, gelatine, and PMMA microbeads, and a wetting agent (i.e., a surfactant) can increase porosity. These chemicals, which are called porogens, are evaporated or burned out during sintering, and as a result pores are formed [2,159]. One successful formulation has been the use of hydroxyapatite powder slurries (dispersed with vegetable oil) added with gelatine solution [162], which has led to porous scaffolds with interconnected pore structure with pore diameters of ∼100 µm. A similar process has been used to prepare melt-derived Bioglass scaffolds using camphor (C10H16O) as the porogen [163]. Binders are also added to slurries. The most important function of a binder is to improve the strength of the green body in order to provide structural integrity for handling (green strength) before the product is sintered [164]. Polysaccharides [165], polyvinyl alcohol (PVA) [166], and polyvinyl butyl (PVB) [167] are the frequently added binders in bioceramic slurries. 1.4.1.1.2 Formation of Green Bodies In ceramic production, a green body is always porous, and its structure largely determines that of the sintered product. Table 1.9 lists different methods of obtaining green bodies for 3-D porous ceramics. These methods can be classified into two categories: dry and wet processes [159]. They lead to different porous structures and pore volume fractions. Certain techniques, such as tape casting, extrusion, slurry dipping, and spraying, are not included here; because they aim at achieving a predetermined geometric shape of ceramic parts (such as rods, tubes, sheets, and coating on films), instead of a given porous structure. Except injection molding, all conventional processes listed in Table 1.9 have been applied to synthesize ceramic scaffolds for tissue engineering as discussed below.


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21

Dry methods. The simplest way to prepare ceramic green bodies is the dry powder method where powders are directly compressed by pressing (uniaxially or isostatically) into molds, thereby forming green bodies. Pore diameters decrease and mechanical properties increase as the packing density of the particles in the green bodies increases. A densification step by sintering at high temperature is required (see Section 1.4.1.1.3). Mechanical properties can be increased further by hotisostatic pressing (HIP) [168] or by uniaxial hot pressing. These pressure-assisted methods decrease the pore diameter as well. The addition of porogens, such as sucrose and camphor, enhances the formation of pores [159]. Slip casting. Slip is a creamy (relatively thick) slurry. In this method, the slurry is cast into a porous mold. The liquid of the slurry is absorbed into the porous mold, and as a result the particles in the slurry are filtered, which adhere to the mold surface. After this process, a porous green body is obtained through further drying [161,169]. Phase separation/freeze-drying. In this method, a ceramic slurry is poured into a container, which is immersed in a freezing bath. Thus, ice is stimulated to grow and ceramic particles are piled up between the columns of the growing ice. After the slurry is completely frozen, the container is dried in a drying vessel, usually under vacuum [170]. The pores are created by the ice crystals that sublimate at a reduced pressure. Freeze-drying removal of ice crystals creates 3-D interconnected pore channels with complex structures. The porous structure can be customized by the variation of the slurry concentration, freezing temperature, and pressure. Replication technique. This method, which is also called the polymer-sponge method, was patented for the manufacturing of ceramic foams [171]. In the polymer-replication process, the green bodies of ceramic foams are prepared by coating a polymer (e.g., polyurethane) foam with a ceramic slurry. The polymer foam, which already has the desired macrostructure, simply serves as a sacrificial template for the ceramic coating. The polymer template is immersed in the slurry, which subsequently infi ltrates the structure, and so the ceramic particles adhere to the surface of the polymer substrate. Excess slurry is squeezed out leaving a ceramic coating on the foam struts. After it is dried, the polymer is slowly burned out in order to minimize damage to the porous ceramic coating. After the removal of the polymer, the ceramic is sintered to the desired density. The process replicates the macroporous structure of the polymer foam and results in a rather distinctive microstructure within the struts. A flowchart of the process is given in Figure 1.4 [172]. This method has been applied for the preparation of foam-like scaffolds for tissue engineering, including porous calcium phosphates [173], Bioglass [80], and other inert bioceramics [172,174].

Ceramic powder

Prepare slurry from the powder

Add

Binder

Coat a polymer foam with the slurry

Dry, burn out the polymer substrate, and sinter the green body

Ceramic foam

FIGURE 1.4


Flowchart of the replication process to produce a ceramic foam.

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22


Apart from the slurry-immersion coating, electrospray coating techniques have also been applied together with the polymer-sponge process to produce ceramic foams, for example, Al2O3 [175] and ZrO2 foams [176]. Unlike the foams produced by the slurry-immersion method, the struts of the ceramic foams produced by the process of electrospray coating contain fewer holes and cracks. This microstructure can lead to improved mechanical properties of the foams [176]. Another possibility investigated to improve the mechanical properties of foams made by the replication method is to apply a thin polymer coating on the porous structure. For example, to improve the mechanical stability of highly porous Bioglass-derived scaffolds produced by the replication technique [80], a polymer coating, such as poly(d,l-lactic acid) (PDLLA), was applied [177]. The coating thickness was approximately 3 µm on an average. Although the thin coating layer did not increase the mechanical strength of the foams considerably, it significantly improved the mechanical stability of the structure. The fracture energy of the coated foams was ∼20 times higher than that of uncoated foams. More importantly, upon immersion in SBF, nanofibers of hydroxyapatite deposited within the PDLLA coating layer, eventually a nanocomposite layer, formed biomimetically on the strut surfaces. This method has remarkably improved the mechanical performance of the scaffolds in a biological environment [177]. Gelcasting. This method adopts one of the direct-foaming techniques mentioned in Table 1.10 to achieve highly porous green bodies. The foamed suspension is set through a direct-consolidation technique, listed in Table 1.10, that is, polymerization of organic monomers (i.e., gelation), in which the particles of the slurry are consolidated through polymerization reaction. A green body is formed after the gel is cast in a mold [178–180]. Figure 1.5 gives the flowchart of the gelcasting process. Two factors are critical in the gelcasting process: (1) the gelation speed must be fast enough to prevent foam collapse, and (2) the gel rheology is important because the process involves casting. Systems of high fluidity are required in order to enable easy filling of small details in molds to allow production of high-complexity shapes. Gelcasting techniques have been applied to produce hydroxyapatite foams [181–183]. Gelcasting has also been combined with the replication process (described above in this section) to produce hydroxyapatite scaffolds with interconnected pores [184]. 1.4.1.1.3 Sintering The final step in the production of a ceramic foam is the densification of the green bodies by conducting a high temperature sintering process. Foams are normally dried at room temperature for at least 24 h prior to sintering. In this step, controlled heating is important to prevent collapse of the ceramic network. The heating rate, sintering temperature, and holding time depend on the ceramic starting materials. For example, values are in the range of 0.5–2°C/min, 1200–1350°C, and 2–5 h,

TABLE 1.10 Techniques of Direct Foaming and Direct Consolidation Techniques Direct foaming 1. Injection of gases through the fluid medium 2. Mechanically agitating particulate suspension 3. Blowing agents 4. Evaporation of compounds 5. Evaporation of gas by in situ chemical reaction Direct consolidation 1. Gelcasting 2. Direct coagulation consolidation (DCC) 3. Hydrolysis-assisted solidification (HAS) 4. Freezing (quick set)


References 20

178

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23

Ceramic powder

Prepare suspension from the powder

Add

Dispersant, surfactant, monomer, cross-linker

Foam the suspension using one of the foaming techniques in Table 2.16 Add

Initiator, catalyst

While the foamed suspension is poly merized to form a gel, cast the gel

Dry and sinter the green body

Ceramic foam

FIGURE 1.5

Flowchart of the gelcasting method to produce a ceramic foam.

respectively, in the case of porous hydroxyapatite [173,181,183,185]. It is worthwhile noticing that there is a narrow time–temperature window for densification of foams made from bioactive glasses, which are prone to crystallize while sintering by viscous flow. Hence the production of bioactive glass foams by powder-based methods presents difficulties [80]. 1.4.1.2 Sol–Gel Techniques 1.4.1.2.1 Sol–Gel Process and Synthesis of Aerogel Ceramics The sol–gel process is a well-developed, robust, and versatile “wet” technique for the synthesis of ceramics and glasses. By applying the sol–gel process, it is possible to fabricate inorganic materials in various forms: ultrafine or spherical shaped powders, thin film coatings, ceramic fibers, microporous inorganic membranes, monolithic ceramics and glasses, and extremely porous aerogel materials [186]. The processing path of aerogel ceramics starts with an alkoxide precursor. Alkoxide precursors, such as tetraethyl orthosilicate (TEOS) and triethoxyl orthophosphate (TEP), undergo hydrolysis and condensation reactions to form a sol. In case of silicate precursors, polymerization of –Si–OH groups continues after hydrolysis is complete, beginning the formation of the silicate (–Si–O–Si–) network. The network connectivity increases until it spans throughout the solvent medium. Eventually a wet gel forms. The wet gel is then subjected to controlled thermal processes of aging to strengthen the gel, drying to remove the liquid by-product of the polycondensation reaction, and thermal stabilization (or sintering) to remove organic species from the surface of the material; and as a result, a porous aerogel forms [2,187]. 1.4.1.2.2 Production of Highly Porous Glasses Highly porous glasses (or glass foams) have been developed by a slightly modified sol–gel process [188]. The sol–gel process is based on the polymerization reactions of metal alkoxide precursors (usually TEOS and TEP). These precursors are dissolved in a solvent, and a gel is formed by hydrolysis and condensation reactions. The gel is then subjected to controlled thermal processes of aging to strengthen the gel, drying to remove the liquid by-product of the polycondensation reaction, and thermal stabilization/sintering to remove organic species from the surface of the material (500–800°C). Sol–gel derived glass scaffolds are obtained by directly foaming the sol with the use


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24

Biomaterials Fabrication and Processing Handbook Alkoxides: TEOS and TEP

Prepare a sol from the alkoxides and Ca(NO3)2 in deionized water solvent

Add

Add

Catalysis (HNO3) to speed up hydrolysis Surfactant for foaming, catalyst (HF) for gelation

Foam the sol by vigorous agitation

When the gelation of the foamed sol is nearly completed, cast the gel in molds

Age, dry, and sinter the gel

Glass foam

FIGURE 1.6

Flowchart of the production of bioactive glass foams using sol–gel technology.

of a surfactant and catalysts [188–190]. Therefore, after sol hydrolysis, the surfactant (e.g., Teepol, a detergent containing a low-concentration mixture of anionic and nonionic surfactants), water (improves foamability of surfactant), and the catalyst for polycondensation (e.g., HF) are added by vigorous agitation. A flowchart of the process is given in Figure 1.6. Porosity of the foam scaffolds is influenced by the foaming temperature, water content, and catalyst content. Sol–gel derived bioactive glass foams [191,192] and gelcast hydroxyapatite scaffolds [181,183] have shown favorable results in both in vitro and in vivo tests for bone regeneration. 1.4.1.3

Solid Free-Form Techniques

SFF techniques, also known as RP, are computer-controlled fabrication processes. They can rapidly produce highly complex 3-D objects using data generated by computer-aided design (CAD) systems. In a typical case, an image of a bone defect in a patient can be taken, which is used to develop a 3-D CAD model. The computer can then reduce the model to slices or layers. The 3-D objects are constructed layer-by-layer using RP techniques such as fused deposition modeling (FDM), selective laser sintering (SLS), 3-D printing (3-DP), or stereolithography [160]. Calcium phosphate scaffolds have been produced using the FDM process [193,194], SLS, 3-DP processes [160], stereolithography [195,196], and RP combined with replication technique [197]. The typical process chain for all SFF techniques is presented in Figure 1.7. To date, only a small number of SFF techniques, such as 3-DP, FDM, and SLS, have been adopted for tissue-engineering scaffolds. The following paragraphs give brief descriptions of the principles on which these three techniques are based. Comprehensive technical details can be found in previous detailed reviews [160,198–201]. 1.4.1.3.1 Three-Dimensional Printing Three-dimensional printing employs ink-jet printing technology for processing materials from powders. Therefore, this technique is a combination of SFF and powder sintering. During fabrication, a printer head is used to print a liquid binder onto thin layers of powder following the object’s profile being generated by the system computer. The subsequent stacking and printing layer recreates the full structure of the desired object.


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25

Medical imaging • CT, MRI, etc.

3-D solid model creation in CAD • Pro /engineer (PTC)

SFF system computer • Generation of slice data, etc.

SFF fabrication • SLS, FDM, etc.

Post-processing • Finishing and cleaning

FIGURE 1.7

Flowchart of the typical rapid prototyping (RP) process [160].

1.4.1.3.2 Fused Deposition Modeling FDM employs the concept of melt extrusion to deposit a parallel series of material rods that forms a material layer. In FDM, filament material stock (generally thermoplastic) is fed and melted inside a heated liquefier head before being extruded through a nozzle with a small orifice. Indirect fabrication methods involving FDM have been applied for producing porous bioceramic implants. In this method, FDM was employed to fabricate wax molds containing the negative profiles of the desired scaffold microstructure. Ceramic scaffolds were then cast from the mold through a lost mold technique [193,194]. 1.4.1.3.3 Selective Laser Sintering SLS employs a CO2 laser beam to selectively sinter polymer, ceramic, or polymer-ceramic composite powders to form material layers. The laser beam is directed onto the powder bed by a high precision laser scanning system. The fusion of material layers that are stacked on top of one another replicates the object’s height [202,203]. 1.4.1.4

Comparison of Fabrication Techniques for Ceramic or Glass Scaffolds

Table 1.11 lists the porosity, pore size, and mechanical properties of several porous ceramics produced by different techniques. Figure 1.8 shows typical pore structures produced by different techniques. Comparing the pore structures of ceramic scaffolds shown in Figure 1.8 with the structure of cancellous bone, it is evident that the pore morphology produced by the replication technique is the most similar one, containing completely interconnecting pores and solid material forming only the struts. The ceramic foams synthesized by gelcasting and sol–gel techniques come next in terms of structural similarity to cancellous bone, however, it is expected that these foams exhibit lower pore interconnectivity than foams made by the replication method. The advantages of replication method over other ceramic foaming techniques are summarized in Table 1.12. In brief, the replication technique meets all criteria posed on the fabrication process of tissue-engineering scaffolds: suitable for commercialization, reproducible, cost-effective, safe, and capable of producing irregular or complex shapes. Contemporary authors consider the replication technique as the optimal technique for production of novel bioactive glass-ceramic scaffolds for bone tissue engineering [204].


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Electrospray Gelcasting/foamed by Starch

Phase separation/ freeze-drying Replication technique/coated by Slurry-immersion

Powder forming–sintering Dry process with porogens

Technique

30–60

87 74 85–97.5 69–86 69–86 >90 96 23–70

Al2O3 TiO2 Glass-reinforced HA Hydroxyapatite HA coated by PLGA Bioglass Al2O3 Al2O3

NA 67 21 42

Porosity (%)

Al2O3

Hydroxyapatite Hydroxyapatite 45S5 Bioglass

Materials

10–80

C

O O O O O O O

O

∼50 in width, 300–500 in length Up to 800 385–700 Average size 420–560 490–1130 490–1130 400–800 ∼800

C O C C

Closed (C) or Open (O)

Varying between 40 and 100 250–400 200–300 80

Pore Size (µm)

TABLE 1.11 Porous Structures and Mechanical Properties of Porous Bioceramics Produced by Different Techniques

NA

0.01–0.175 0.03–0.29 0.31–4.03 0.4–0.5

NA

NA

NA

Compressive/Flexural Strength (MPa)

178

169 165 185 173 173 80 175

166 205 163 206 69 170

References

26 Biomaterials Fabrication and Processing Handbook

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SLS

Solid free-form (SFF) FDM

Sol–gel/foamed by Burning PMMA beads Decomposition of H2O2 Burning EO-PO-EO blocks Vigorous stirring

Replication technique

Vigorous stirring

Al2O3 β-TCP CaO-Al2O3 PP-TCP composite Calcium phosphates

29–44 29–44 29–44 36–52 30

70–95

NA 76.7–80.2 48 NA 70–77 73

Al2O3 Hydroxyapatite Hydroxyapatite Hydroxyapatite Hydroxyapatite β-TCP+HA

CaO–SiO2 glass (CH3O)4Si SiO2 glass Bioactive glasses

70–92

Al2O3

305–480 305–480 300 160 200

∼0.5 1070 (no break)

60–80

39–75

Source: Adapted from Kurtz, S.M., in Total Joint Replacement, Elsevier Science & Technology, San Diego, CA, 2004. With permission.

TABLE 21.2 Physical Properties of Cross-Linked Ultra High–Molecular Weight Polyethylene Property Melting temperature (°C) Tensile modulus of elasticity* (MPa) Tensile yield strength* (MPa) Tensile ultimate strength* (MPa) Tensile elongation at fracture (%) Degree of crystallinity (%)

Cross-Linked UHMWPE 135.8 ± 5.6 860 ± 206 321.1 ± 2.5 29.3 ± 7.7 212 ± 61 245.3 ± 5.3

Source: Adapted from Lewis, G., Biomaterials, 22, 371–401, 2001. With permission.

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For convex side of the artificial joint, metals (titanium or CoCr alloys) or ceramic (aluminum ceramic) components are used. These components are equipped with short or long stems, which can be fixed to the trabecular bone by means of bone ingrowth to a porous surface with or without porous hydroxyapatite (HA) coating or by means of poly(methyl methacrylate) (PMMA) cement [67]. To fixate the prosthetic components, a surgeon has to remove not only affected and painful joint surfaces but also much of the healthy bone [68]. Although millions of TJRs are performed annually to improve quality of life of the patients, despite the early and mid-range follow-up good results of the human load–bearing joint replacement, the complications of artificial joint are inevitable, with an incidence of approximately 14% in 12–15 years after shoulder replacement and up to 70% of the total hip replacements (THR) after 10 years or less. The complications result in pain, reduction of the range of joint movements, loosening of components, and finally in a revision operation [33]. One of the main reasons of these complications is the failure or degradation of the implant biomaterials. The biomaterials such as metals and polymers (synthetic or natural), ceramics and their composites degrade and lose their original properties due to exposure to in vivo conditions [67]. The implant biomaterials subjected to highly demanding conditions such as high stresses and high cyclic loadings, coupled with aggressive body environment, degrade in time, losing their properties such as strength and wear or corrosion resistance. The undesirable degradation takes place in the form of wear, corrosion, deformation, creep, fatigue, fractures, and oxidation of the biomaterials. Despite all the progresses made in regenerative medicine, these phenomena are recognized as major factors limiting the success of the TJR. Abrasion, burnishing, pitting, erosion, and delamination were found to be the most predominant modes of in vivo degradation (wear and cold flow) of polyethylene in TJR. From the scanning electron micrographs of the exposed surfaces of the retrievals, it was found that fine multidirectional scratches were dominant (Figure 21.16a). In addition to the scratches, flakes and rim erosion are also observed. Two implants revealed pitting areas and surface microcracks, which most likely resulted from subsurface fatigue. Polyethylene delamination was observed for metal-backed component. Some of the implants were completely worn out, in some places, to the metal backing. In vivo degradation products such as particulate and ionic wear and corrosion debris cause aggressive biologic response that can lead to synovitis, periprosthetic bone loss, and aseptic loosening of the implants [67]. The polyethylene wear particles migrate into the periprosthetic spaces and stimulate the activity of the macrophages by the release of cytokines, which activate the osteoclasts,

(a)

(b)

FIGURE 21.16 Atomic force microscope (AFM) image of (a) the polyethylene surface with multidirectional scratches and (b) degradation and wear of the glenoid component.

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and these osteoclasts lead, in the long term, to the bone resorption around the prosthesis [68]. Increased concentrations of circulating metal-degradation products of fretting corrosion of the metallic implants may also induce the bone resorption and have deleterious biological effects over the long term [69]. Additionally to these negative biological effects, deformation and damage of the implant materials disturb the stabilizing function of the implant. It was found, for instance, that glenohumeral instability after arthroplasty was associated with the wear of the glenoid component [70] (Figure 21.16b). There are many factors that influence the material wear and degradation in TJRs (Figure 21.17). Design and manufacturing process takes into account geometry of the prostheses, surface roughness, loading characteristics, and lubrication condition. By comparing anatomical and artificial joints, it can be concluded that while healthy human joints are lubricated by fluid film, all current artificial joints with relatively hard-bearing surfaces are lubricated by the boundary and mixed lubrication, which results in wear, and consequently wear debris from articulating surfaces [71]. Among the material factors, the material properties are crucial. However, details of manufacturing process, sterilization, and handling may profoundly alter these properties. Design of the artificial joints is of paramount importance. Insufficient thickness of the polyethylene component influences wear of the TJRs. Bartel et al. [72] indicated that in order to minimize wear, a minimum thickness of 8–10 mm should be chosen for tibia component and 6–8 mm for acetabular components. Contact surface geometry described by radial clearance (or degree of conformity) between the radii of curvature of the articulating surfaces of components is another geometrical factor affecting the wear of implants. Low joint conformity might result in high contact stresses and could contribute to faster implant wear and failure. Swieszkowski et al. [73] reported that the peak stress generated in nonconforming glenoid components under conditions of normal living can be as high as 25 MPa; since this exceeds the polyethylene yield strength deformation, wear of the components can be expected. The major factor responsible for the failure of polyethylene implants is oxidative degradation of polymer induced by sterilization with γ-irradiation. The irradiation results in the generation of free radicals in polyethylene. These free radicals may react with oxygen that could diffuse into polyethylene during shelf storage or in vivo, causing the polymeric chain scission, which in turn, will lower the molecular weight of PE, increase the density, stiffness, and brittleness, and reduce the fracture strength and elongation to failure. Any of these changes could dramatically affect the wear resistance [63]. Material fatigue could be the reason of the subsurface cracking in the polyethylene components of the knee implants. These cracks very often propagate to the surface of the implants, causing the fracture of the polymeric components. The fatigue and structure defects of the biomaterials may

(a)

FIGURE 21.17

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(b)

Wear, oxidation, and fracture of the (a) tibia and (b) acetabular components.

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result in the fracture of the metallic stem in the THR. Aggressive fatigue loading of cemented artificial joints is responsible for the formation of microcracks in bone cement and stem/bone micromotions [67]. Another issue is related to the fact that after insertion of prosthesis–a bone, prosthesis structure is a composite one. It consists of bonded elements with different elastic and geometrical properties. These differences result in an altered load distribution in the artificial joint, as compared to the natural one [67]. In natural joints, the loads are distributed over the entire cross-section of the proximal part of the bone (i.e., femur). In the case of an artificial joint, the load is partially transformed by shear forces across the bone–cement–prosthesis interfaces. This altered load transfer leads to increased stresses at the cement–prosthesis interface and unloading of the bone away from prosthesis. The interface shear stresses are further increased due to the stiffness ratio between the prosthesis and the bone, typically at the order of 10:1 and higher. In addition, the bending displacements in the bone surrounding the stem are reduced because of relatively high flexural stiffness of the prosthesis. The change in load distribution increases the stress in some regions and reduces it in other regions. Areas with higher loads may experience an increase in bone mass, while areas with reduced load may experience a decrease. Moreover, for an inadequate proximal fit of the stem, either initially as an effect of bone preparation, or gradually postoperatively as the effect of stem subsidence, the proximal load transfer is bypassed in favor of distal one. This bypass mechanism as well as stress shielding causes failure of the arthroplasty [67]. To improve joint replacement in terms of long-term component fixation and wear properties, future work should also be concentrated on the design of advanced prosthetic materials, which will better mimic AC properties [33], such as water content, stiffness, shock absorption, promoting fluid film lubrication, and low coefficient of friction. One of the biomaterial design conflicts is between mechanical and biological compatibilities. Many load-bearing implants require materials with a strength and durability stronger than bone, because the implant lacks the ability of living bone to repair localized damage due to fatigue or overloading. Strong materials should • distribute high static and repetitive dynamic loads (up to 2500 N); • protect the cancellous bone from high stresses; and • allow to obtain a firm attachment to the underlying bones, leading to a long-term fixation. On the other hand, soft material for bearing is needed to • • • •

improve wear properties of bearing surfaces in TJR; provide a smooth, lubricated surface with fluid film and low coefficient of frictions; reduce nominal contact pressure; and increase joint congruence.

The soft material and its elastic deformation have been found to be the most significant factor in the prediction of the film fluid and low friction capability in artificial joints [71]. Cushion articulating surfaces consisting of low elastic modulus materials, which can articulate with full fluid film lubrication, are needed to mimic the natural lubrication of the joint where synovial fluid lubricates the bone cartilage interface [74]. Moreover, when the fluid film breaks down, such as during periods of heavy loading with little movement or at the start of movement, this biomaterial must give low friction and a low wear rate in these conditions of mixed or boundary lubrication. Recent studies have shown that polyurethane as a soft bearing material, which is articulated against a highly polished metallic surface, provides a lower coefficient of friction as compared with standard polyethylene versus metal bearings [75]. When polyurethane was replaced with water-swollen hydrogel, the friction was considerably reduced [76].

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It can be concluded that the most appropriate design for load-bearing artificial joints would be an advanced material, which will be soft as well as strong enough. In comparison with homogeneous materials, composites offer a variety of advantages, which can be useful during the design of the advanced material. These include the possibility for engineers to exercise considerable control over material properties. By varying the type and distribution of the reinforcing phase in the composite, it is possible to obtain a wide range of elastic properties to enable better mechanical compatibility with bone and the other tissue while maintaining high strength and durability.

21.6

SUMMARY

The human body is generally adoptive to the articular joints; however, these joints must satisfy a long list of requirements that can be met with the application of several materials formed into composite structures. By gradually changing the material combinations, volume fractions and anisotropy at different locations, very effective and efficient structures can be produced. Articular cartilage can be modeled as a fiber-reinforced, porous, permeable composite material. Fluid-filled, porous engineering materials can be used to reconstruct the subchondral bone properties. Presently, it is not possible to replace these structures with the same effectiveness by engineering materials and designs. When the AC and subchondral bone layers are resected in human joint arthroplasty, the biomaterials (i.e., metal and polyethylene) used to replace and mimic them do not fulfill properties and functions of natural composite structures. Existing differences between natural and artificial materials can be the reason for unsatisfactory results of TJRs. Complications occur over several years, as a result of the introduction of interfaces, decreased lubrication properties, and changed load distribution. Structure and properties of the cartilage and subchondral bone should be restored in prosthesis design. Currently, most of the repair strategies meet the aim to regenerate defected AC, although, many fail to prevent future degeneration of the repaired surrounding host tissues. The repair tissue is often of a fibrocartilaginous nature without the zonal organization of AC. Where hyaline cartilage is produced, it is often of an immature nature and does not have a true articular surface. Future research may need to focus on the combination of biodegradable scaffolds and autologous cells to produce a mechanically functional hyaline repair tissue. The advanced materials (i.e., fiber-reinforced composites or other hybrid materials) fabricated using modern, rapid manufacturing techniques and nanotechnologies may offer new opportunities. These materials should better mimic the functional, physical, and mechanical behavior of tissues in anatomical joints.

ACKNOWLEDGMENTS We would like to thank Prof D. Hutmacher for his inspiration and sharing his knowledge in tissue engineering with us.

REFERENCES 1. Reis R.L., Biodegradable Materials in Tissue Engineering and Regenerative Medicine, John Andrews, New York, 2004. 2. Temenoff J.S., Mikos A.G., Review: tissue engineering for regeneration of articular cartilage, Biomaterials, 2000 (21), 431–440. 3. Zdebiak P., El Fray M., The perspectives of polymeric hydrogels and thermoplastic elastomers as cartilage–like materials, Inżynieria Biomateriałów, 2006 (54–55), 27–35. 4. Mow V.C., Ratcliffe A., Structure and function of articular cartilage and meniscus. In: Mow V.C., Hayes W.C., eds. Basic Orthopaedic Biomechanics, Lippincott-Raven Publisher, Philadelphia, PA, 1997, 113–177. 5. Chen A.C., Bae W.C., Schinagl R.M., Sah R.L., Depth- and strain-dependent mechanical and electromechanical properties of full-thickness bovine articular cartilage in confined compression, J. Biomech., 2001 (34), 1–12.

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Index A acetylcholinesterase (AChE), biosensor applications, 407, 409 actuator devices electroactive polymers classification and examples, 485–486 conducting polymers, 490–496 dielectric elastomers, 496–498 future research issues, 498 gels, 486–489 ionic metal-polymer composites, 489–490 overview, 483–484 high-density polypyrrole nanowires, 389 polypyrrole nanomaterials, 369–378 conductivity, 369–370 DBS ion doping, 370–372 electrochemistry, 369–374 electropolymerization, 369 nanowire electropolymerization, 383–387 nanowire time response, 389–393 optically controlled microstructure fabrication, 377 reversible electrochemical redox reaction, 372–373 silicon device integration, 376–378 test line microfabrication, 374 thickness change measurement, 374–376 time response, 373–374 adenosine triphosphate (ATP)-binding cassette family, chemotherapy multidrug resistance, 145 adsorption process, biosensor applications, biomoleculefilm attachments, 431–432 adult stem cells (ASCs), scaffold-based tissue engineering, 70–71 aerogel ceramics, inorganic tissue-engineering scaffolds, 23–24 aerosolization, electrospraying of biomaterials, 321–329 DNA/protein biomolecule, 321–324 living cells and drugs, 324–329 affinity interaction, biosensor applications, biomoleculefilm attachments, 431–432 air-water interface, biohybrid nanomaterials, small bioactive molecules, 341–349 albumin nanoparticles biomaterials from, 472 chemotherapy applications, 152 phosphorus-doped diamond like carbon films, 612 alginates biomaterials, 469–470 cell-encapsulated biomaterials, electrospray fabrication of, 319–321 colon-targeted drug delivery systems, 645–646 gastrointestinal tissue engineering, 652–653 nano/microparticles, oral peptide delivery, 182–183 aliphatic polyesters amphiphilic block copolymers, 261–263 biomaterials from, 459–463

alkoxysilanes, lipid-based biohybrid nanomaterial fabrication, 338–341 Amadori rearrangement, covalent antithrombin/heparin in vitro activity, 551–553 surface coatings, in vivo activity, 558–559 amperometric biosensors glucose oxidase, structure and properties, 404–405 lactate dehydrogenase, structure and properties, 414 amphiphilic molecules aliphatic polyesters, 261–263 biohybrid nanomaterials, small bioactive molecules, 341–349 cancer drug targeting, 259–261 lipid-based biohybrid nanomaterial fabrication, 338–341 AND-type logic gates, biohybrid nanomaterials, protein hybridization, 357–359 angiogenesis gastrointestinal tissue engineering scaffolds, 651–653 nanoparticle inhibition, 162–163 scaffold design, 4–5 annealing parameters diamond like carbon (DLC) films, electrical property and blood behaviors, 608–610 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 596–601 antibodies biohybrid nanomaterials, small bioactive molecules, 342–349 biosensor applications, 422, 424 nanoparticles, 435–437 targeted drug delivery, 157–158 antigens, biosensor applications, 422, 424 nanoparticles, 435–437 antimicrobial reagents, polyethylene biomaterials, 622–623 antithrombin (AT). See also covalent antithrombin/ heparin (ATH) basic properties of, 636–637 chemical structure, 538–539 covalent antithrombin/heparin (ATH) complexes, surface coatings from, 556–559 functional biochemistry, 538–539 architecture, scaffold-based tissue engineering control and monitoring, 70 case study, 78–88 processing techniques, 71–73 design criteria, 51–52 tailoring techniques, 78–79 Arrhenius plots, lipid-based biohybrid nanomaterial fabrication, 338–341 arthritis, articular cartilage repair, biomaterials for, 661–662 articular cartilage chondrocytes, tissue engineering, electrospun scaffolds, 133–134 structure and properties, 659–661

679

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680 artificial tissue, cell microencapsulation, immune protection, 267 Arxula adeninivorans, biosensor applications, 420–421 atomic force microscopy (AFM), electrospun scaffolds, 130 autologous chondrocyte transplantation (ACT), articular cartilage repair, biomaterials for, 662 A-W glass-ceramic, bone tissue scaffold materials, 10–11

B Bacillus licheniformis, biosensor applications, 416 Bacillus subtilis, biosensor applications, 416 basic fibroblast growth factor, angiogenesis inhibition, 162 beam-line ion implantation, plasma immersion ion implantation vs., 581 beclomethasone dipropionate, electrospray fabrication, 291–297 Bessel function, polypyrrole nanowire time response, 392–393 betamethasone phosphate, calcium carbonate nanostructured drug carriers, 224–226 beta-TCP products, rapid prototyping applications, 110–111 BET gas absorption method, electrospun scaffold analysis, 130 bias voltage, diamond like carbon (DLC) films, platelet adhesion and bilayer actuators, polypyrrole nanomaterials, 378–379 bioactive coatings and films, electrospray fabrication, 297–307 bioactivity index, bioactive silicate glasses, 9 bioceramics bone tissue scaffold materials bioactive silicate glasses, 8–10 calcium phosphates, 6–8 coatings and films, electrospray fabrication, 298–301 glass-ceramics, 10–11 plasma immersion ion implantation and deposition, 587 titanium dioxide coatings, 587–590 porous bioceramics, 26–28 biochip manufacturing, electrospraying techniques, 311–314 biocompatibility bioactive silicate glasses, 8–9 calcium phosphate bioceramics, 6 diamond like carbon (DLC) films, flow ratios and, 602–605 gastrointestinal tract biomaterials, 634–635 multilayered biofilms, layer-by-layer nanostructure self-assembly, 244 titanium-oxide thin films, 614–618 bioinert materials, blood-contacting devices, 518 biomaterials. See also biopolymers; biosensors aerosolization, 321–324 antigens-antibodies, 422, 424 biohybrid nanomaterials fabrication technologies, 335–336 future research issues, 359–361 lipid-based materials, 336–341 proteins, 349–359 small bioactive molecules, 341–349


Index biosensor applications, 402 carbon nanotube coupling, 428 diamond film tethering, 440 electropolymerized film entrapment of, 430 film attachment, 431–432 monomer electrosynthesis, 430 bone tissue scaffold materials, 16–18 cartilage reconstruction and repair articular cartilage structure and properties, 659–661 artificial cartilage materials, 662–666 disease and damage mechanisms, 661–662 future research issues, 675 synthetic polymers, 667–668 tissue engineering approach, 668–670 total joint replacement, 670–675 covalent antithrombin/heparin (ATH) complexes, surface coatings from, 556–559 DNA, 422–243 encapsulation techniques, biomaterial electrospraying, 315–318 enzymes, 402–415 acetylcholinesterase/choline oxidase, 407, 409 cholesterol esterase/cholesterol oxidase, 405, 407–408 glucose oxidase, 402–406 glutamate oxidase, 415 horseradish peroxidase, 409–413 lactate dehydrogenase, 410, 414 pyruvate oxidase, 414–415 gastrointestinal medicine applications bulking materials, 637–641 fistula repair, 636–637 future research issues, 653 gastroesophageal reflux disease, 635–636 laparotomy procedures, 641–644 overview, 634–635 targeted drug delivery, 644–647 tissue engineering, 647–653 hollow polyelectrolyte loading, 250–254 pH-controlled macromolecules, 252 protection devices, 254 protein encapsulation, porous particles, 253–254 switch on/off capsule, external magnetic field opening, 252–253 microorganisms, 415–421 plasma immersion ion implantation and deposition, 581–582 biomimetic techniques biohybrid nanomaterials, 335–336 controlled-release drug delivery, siliceous nanocapsules, 206–207 bioplotter device rapid prototyping, 111 scaffold tissue fabrication, 54–55 biopolymers applications, 473–475 drug delivery, 475 orthopedics, 473 tissue engineering, 473–475 chemotherapy nanoparticles, 148–149 coatings and films, electrospray fabrication, 301–304

1/28/2008 11:41:39 AM

Index controlled drug release systems, nanostructured porous materials biomimetic siliceous nanocapsules, 206 future research issues, 209–210 inorganic porous materials, 197, 200 matter-41 porous silica, 200–205 overview, 193–196 photonic crystals, 207–209 porous silicon, 206–209 soft porous materials, 196–199 degradable polymers albumin, 472 alginates, 469–470 chitosan, 470–471 collagen, 472 hyaluronic acid, 472–473 poly(α-amino acids), 467 poly(alkyl 2-cyanoacrylates), 467–468 polydioxanone, 465 polyesters, 459–465 polyethylene glycol, 465–466 polyurethanes, 468–469 tissue engineering, 473–475 trimethylene carbonate, 466–467 electroactive smart materials classification and examples, 485–486 conducting polymers, 490–496 dielectric elastomers, 496–498 future research issues, 498 gels, 486–489 ionic metal-polymer composites, 489–490 overview, 483–484 future research issues, 475–476 naturally-occurring compounds, bone tissue scaffold materials, 11–12 overview, 437–438 pharmaceutical products from, 171–172 targeted drug delivery, electrospray fabrication, 295–297 biosensors biorecognition materials, 402–422 antigens-antibodies, 422, 424 DNA, 422–243 enzymes, 402–415 microorganisms, 415–421 intermedia materials, 422–423, 425–440 carbon nanotubes, 423, 425–429 diamond thin films, 439–440 functionalized monolayers, 438–439 nanomaterials, 433–438 polymers, 429–433 polypyrrole nanomaterials, 393–398 bioverit glass-ceramics, bone tissue scaffold materials, 11 block copolymers amphiphilic micelles, drug/gene delivery, 259–261 chemotherapy nanoparticles, 148–149 nanostructured porous materials, controlled drug release systems, 196 poly (l-amino acid), 263–265 targeted drug delivery, folate receptors, 160–161


681 blood compatibility with biomaterials, 523–530 antithrombin structure, 538–541 cell compatibility/endothelialization, 529–530 complement activation, 529 covalent antithrombin-heparin complexes, 544–559 future research issues, 560 hemolysis, 529 heparin, 541–544 leukocyte adhesion/activation, 528–529 overview, 535–537 platelet adhesion/activation, 526–528 structure and composition, 506–508 vessel structure and properties, 508–509 blood-contacting surfaces and materials coagulation, 510–514 complement system, 516–517 covalent antithrombin/heparin (ATH) complexes, surface coatings from, 556–559 devices, 509 bioinert materials, 518 living cell boundary layer, 521–522 polymeric coatings, 519–521 tissue engineering, 522 future research issues, 530 leukocytes, 517 medical implants and, 505–506 plasma immersion ion implantation and deposition and surface modification, 601–618 annealing temperature, 608–610 bias voltage and platelet adhesion, 605–608 calcium-doped DLC films, 612–614 diamond like carbon thin films, 601–602 flow ration and hemocompatibility, 602–605 phosphorus-doped DLC films, 610–612 titanium-oxide thin films, 614–618 platelet adhesion and activation, 515–516 protein adsorption, 510 BODIPY ligands, targeted drug delivery, electrospray fabrication, 295–297 bone growth factors (BGF), bone tissue engineering, 5 bone marrow stromal cell sheet scaffolds, extrusion/ direct wiring fabrication, 58–62 bone morphogenetic protein (BMP) articular cartilage biomaterials, scaffold-based tissue engineering, 668–670 electrospun scaffolds, bone tissue engineering, 133 bone tissue engineering calcium sulfate nanostructured drug carriers, 225–226 electrospun scaffolds, 132–133 extrusion/direct wiring fabrication and, 58–62 plasma immersion ion implantation and deposition, 584–587 calcium/sodium deposition on titanium, 590–595 titanium dioxide coatings, 587–590 scaffold design parameters, 4–5 scaffold materials, 6–19 total joint replacement, polyethylene biomaterials, 673–675 bone volume to total volume ration (BV:TV), scaffold architecture monitoring, 80–81

1/28/2008 11:41:40 AM

682 bottom-up processing biohybrid nanomaterial fabrication, 336 carbon nanotubes, biosensor applications, 426–427 Bragg reflections, layer-by-layer nanostructure self-assembly, 242–244 bronopol antimicrobial reagent, polymer biomaterials, 622–623 bulk degradable polymers, bone tissue scaffold materials, 13–15 bulking biomaterials, gastrointestinal disease, 637–641 collagen materials, 640–641 fecal incontinence management, 637 polymer microspheres, 637–639 zirconium dioxide microspheres, 641

C cadmium sulfide nanoparticles Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 silica nanoparticle drug carriers, 219–224 calcium carbonate nanostructured drug carriers, 224–226 plasma immersion ion implantation and deposition, calcium/sodium deposition on titanium, 592–595 porous polymer microparticles, protein encapsulation, 253–254 calcium-deficient hydroxyapatite (CDHA)/chitosan nanocomposite, controlled-release drug system, 226 calcium-doped diamond like carbon (Ca-DLC) films, plasma immersion ion implantation and deposition surface modifications, 612–614 calcium hydroxide, plasma immersion ion implantation and deposition, calcium/sodium deposition on titanium, 592–595 calcium ions, plasma immersion ion implantation and deposition calcium/sodium deposition on titanium, 590–595 titanium dioxide coatings, 590 calcium phosphate bioceramic coatings and films, electrospray fabrication, 298–301 bioceramics, bone tissue scaffold materials, 6–8 nanostructured drug carriers, 224–226 plasma immersion ion implantation and deposition, titanium alloys, 590–595 calcium sulfate, nanostructured drug carriers, 225–226 cancer drug delivery alphatic polyesters, amphilic block copolymers, 261–263 nanotechnology active targeting, 156–157 albumin nanoparticles, 152 angiogenesis inhibition, 162 ceramic nanoparticles, 151 chemotherapy, 144–145 dendrimers, 150 drug targeting, 156 future research issues, 164 liposomes, 147


Index magnetic nanoparticles, 150–151 metal nanoparticles, 151 overview, 144 particulate drug carriers, 145–147 passive targeting, 156 polymeric structures, 148–149 tumor-specific targeting, 157–162 vascular targeting, 162–163 in vivo biodistribution, 152–155, 163–164 pluronic block copolymer targeting, 260–261 poly (l-amino acid) block copolymers, 263–264 carbohydrate-deficient glycoprotein syndrome, antithrombin chemical structure, 538–539 carbon nanocage structures, biohybrid nanomaterials, proteins, 352–359 carbon nanotubes (CNTs), biosensor applications, 423, 425–429 biomolecule coupling, 428 multiwall CNT wire attachments, 427–428 nanoelectrode ensemble/array microfabrication, 426–427 paste electrode packing, 428 solution casting, glass-carbon electrodes, 425–426 cardiomyocytes, electrospun scaffolds, 135 cardiovascular devices, biopolymers for, 474–475 carrier surface functionalization, polyelectrolyte shells, 258–259 cartilage reconstruction and repair, biomaterials applications articular cartilage structure and properties, 659–661 artificial cartilage materials, 662–666 disease and damage mechanisms, 661–662 future research issues, 675 synthetic polymers, 667–668 tissue engineering approach, 668–670 total joint replacement, 670–675 cartilage tissue engineering, electrospun scaffolds, 133–134 catalytic defense, polyelectrolyte capsule protection, 254 Cath.a-differentiated (CAD) cell, electrospray fabrication of, 328–329 catheterization covalent antithrombin/heparin surface coatings, 556–559 thrombus formation and, 535–537 cathodic arc discharge, plasma production, 575–577 cell adhesion multilayered polyelectrolyte films for, 244–246 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 600–601 cell compatibility endotheliazation, blood-contacting devices, 529–530 cell-encapsulated biomaterials, electrospray fabrication of, 318–321 drug delivery and, 324–329 cell/organ printing, scaffold tissue fabrication, 63–64 cell pellet (CP) protocol, electrospun scaffolds, cartilage tissue engineering, 134 cells electrospun scaffolds, 136 microencapsulation, 267–268 cellulose acetate (CA) membranes, coatings and films, electrospray fabrication, 301–304

1/28/2008 11:41:40 AM

Index ceramic scaffolds chemotherapy nanoparticles, 151 extrusion/direct wiring fabrication, 58–62 fabrication techniques, 25–28 cerasome assembly, lipid-based biohybrid nanomaterial fabrication, 338–341 ceravital glass-ceramics, bone tissue scaffold materials, 11 chemical vapor deposition (CVD) carbon nanotubes, biosensor applications, 426–427 diamond films, 439–440 chemotherapy calcium phosphate nanostructured carriers, 225–226 magnetic targeting drug delivery systems, 226–231 nanotechnology, 144–145 problems of, 145 Child-Law sheath, plasma immersion ion implantation and deposition, 578–579 chitosans biomaterials from, 470–471 colon-targeted drug delivery systems, 644–645 dual pore modes, 79 electrospinning techniques, 125 cartilage tissue engineering, 133–134 nano/microparticles, oral peptide delivery, 182–183 scaffolds architectural control, 84–88 bone tissue engineering, 12 wet spinning technology, 79 cholesterol esterase/cholesterol oxidase (CEH/COD), biosensor applications, 405, 407–408 cholesterol microspheres, drug delivery systems, electrospray fabrication, 294–297 choline oxidase (ChOD), biosensor applications, 407, 409 chondrocytes, articular cartilage repair, biomaterials for, 661–662 chronoamperometry polypyrrole actuator films, 373–374 polypyrrole nanowires, 391–393 circular dichroism (CD) biohybrid nanomaterials, small biomolecules, 349 polyelectrolyte microencapsulation for gene delivery, 255 cisplatin, calcium phosphate nanostructured carriers, 225–226 clotting mechanisms, blood-biomaterials compatibility thrombin generation/thrombus formation, 524–526 thrombus formation, 535–537 coagulation antithrombin functional biochemistry, 538–539 blood-synthetic surface interactions, 510–514 thrombus formation and, 536–537 thrombin generation/thrombus formation, 524–526 coating materials blood-contacting devices, 519–521 covalent antithrombin/heparin (ATH) complexes, 556–558 chemistry and in vitro characterization, 556–558 in vivo performance, 558–559 plasma immersion ion implantation and deposition nickel-titanium alloy surface modification, 595–601 titanium dioxide coatings, 587–590


683 collagen articular cartilage structure and properties and, 659–661 biomaterials from, 472 electrospun scaffolds, 119–125 bone tissue engineering, 132–133 gastrointestinal tissue engineering, scaffold structures, 650–651 injectable bulking biomaterials, 640–641 naturally-occurring biopolymers, 11–12 platelet adhesion and activation, 515–516 scaffold materials from, 71 collection systems, electrospun scaffolds, 123 colon, targeted drug delivery biomaterials for, 644–647 complementary determining region (CDR), targeted drug delivery, 158 complement system, activation, 516–517, 529 complex coacervation, nano/microparticles, preformed polymers, 186–187 composite scaffolds extrusion/direct wiring fabrication, 57–62 fabrication of, 28–30 gastrointestinal tissue engineering, 653 compressive stress analysis, articular cartilage hydrogels, 664–666 computer-aided design and manufacture (CAD/CAM) architecture, scaffold-based tissue engineering control and monitoring, 70 case study, 78–88 processing techniques, 71–73 design criteria, 51–52 tailoring techniques, 78–79 rapid-prototyping microfabrication, laser sintering, 106–107 scaffold architecture control, 73 three-dimensional printing, scaffold tissue fabrication, 54–57 concanavalin A (Con A), soft nanostructured porous materials, controlled drug release systems, 197, 202 conductivity parameters electroactive polymers, 490–496 polymer membranes, biosensor applications, 428–432 polypyrrole electrochemistry, 369–370 cone-jet electrospraying system aerosolization, 324–329 basic properties, 276–277 biochip manufacturing, 311–314 forces and mechanisms, 280–283 jet breakup theory and modeling, 285–287 liquid cone jet model, 283–285 confocal microscopy (CM) electrospun scaffolds, 130 layer-by-layer nanostructure self-assembly, 243–244 pH-controlled macromolecule encapsulation, 252 scaffold architecture monitoring, 75–76 conjugation mechanisms, covalent antithrombin/heparin (ATH), 547–548 contact activation pathway, blood coagulation, 513–514 contact angle measurement biomaterials and plasma proteins, diamond like carbon (DLC) films, 613–614 layer-by-layer nanostructure self-assembly, 243–244

1/28/2008 11:41:40 AM

684 controllable deposition, patterned nanostructured biomaterials, 308–311 controlled drug release systems biopolymers for, 475 electroactive polymers conducting polymers, 494–496 gel systems, 487–489 porous nanostructured biomaterials biomimetic siliceous nanocapsules, 206 future research issues, 209–210 inorganic porous materials, 197, 200 matter-41 porous silica, 200–205 overview, 193–196 photonic crystals, 207–209 porous silicon, 206–209 soft porous materials, 196–199 silica nanoparticle drug carriers, 219–224 copper-implanted polymers, antibacterial enhancement, surface modification, 618–622 covalent antithrombin/heparin (ATH) chemical structures and in vitro activities, 548–553 formation of, 537 future research issues, 560 overview and evolution of, 544–545 potential advantages of, 545–547 surface coating applications, 556–559 chemistry and in vitro characterization, 556–558 in vivo performance, 558–559 synthesis concepts, 547–548 covalent bonding biohybrid nanomaterials, small biomolecules, 349–350 biosensor applications, biomolecule-film attachments, 431–432 critical micelle concentration (CMC), chemotherapy nanoparticles, 148–149 cryogels, articular cartilage hydrogels, 664–666 cyanogen bromide (CNBr), covalent antithrombin/ heparin, in vitro activity, 548–553 cyclic voltammography polypyrrole biosensors, 394–398 polypyrrole electrochemical cycling, 371–372 polypyrrole nanowire actuation, 386–387 polypyrrole nanowire time response, 391–393 cytochrome c protein, coatings and films, electrospray fabrication, 305–307 cytokines, angiogenesis inhibition, 162

D degradability bioactive silicate glasses, 9 biopolymers albumin, 472 alginates, 469–470 chitosan, 470–471 collagen, 472 hyaluronic acid, 472–473 poly(a-amino acids), 467 poly(alkyl 2-cyanoacrylates), 467–468 polydioxanone, 465 polyesters, 459–465


Index polyethylene glycol, 465–466 polyurethanes, 468–469 tissue engineering, 473–475 trimethylene carbonate, 466–467 calcium phosphate bioceramics, 6–7 multilayered biofilms, layer-by-layer nanostructure self-assembly, 244 polymeric nano/microparticles, oral protein delivery, 173 scaffold architecture control, 79 synthetic polymeric nano/microparticles, 175–178 dendrimers chemotherapy nanoparticles, 150 Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 deoxyribonucleic acid (DNA), biosensor applications, 422–423 deposition processes, plasma immersion ion implantation and deposition, 580–581 depth profiles, plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 596–601 dialkylorganosilane, lipid-based biohybrid nanomaterial fabrication, 337–341 diamond like carbon (DLC) films biosensor applications, 439–440 blood-contacting materials, plasma immersion ion implantation and deposition modification annealing temperature and electrical properties, 608–610 bias voltage and platelet adhesion, 605–608 calcium-doped films, 612–614 flow ratio and hemocompatibility, 602–605 overview, 601–602 phosphorus-doped films, 610–612 dielectric elastomers, smart materials from, 496–498 differential pulse stripping voltammetry (DPSV), polypyrrole biosensors, 397–398 differential pulse voltammetry (DPV), polypyrrole biosensors, 394–398 digital light processing (DLP), scaffold tissue fabrication, 56 digital mirror devices (DMDs), scaffold tissue fabrication, 56 dihydrolipoic acid (DHLA), magnetic targeting drug delivery systems, 228–231 dispersion polymerization, nano/microparticles from monomers, 184–185 dithiothreitol (DTT) magnetic targeting drug delivery systems, 228–231 silica nanoparticle drug carriers, 219–224 dodecylbenzenesulfonate (DBS). See also sodium dodecylbenzenesulfonate polypyrrole, ion doping with, 370–372 polypyrrole nanodevices nanowire actuation, 383–387 overview, 368 reversible electrochemical redox reaction, 372–374 time response, 373–374 polypyrrole nanomaterials, direct-mode PPy/PDMS structures, 379–380

1/28/2008 11:41:40 AM

Index doping effects, diamond like carbon (DLC) films calcium-doped films, 612–614 phosphorus-doped films, 610–612 doxorubicin nanoparticulate micelles for chemotherapy, 163–164 poly (L-amino acid) delivery system, 263–265 silica nanoparticle drug carriers for, 218–224 “smart” micelle delivery systems, 265–267 droplet size, electrospraying systems, 282–283 drop on demand printing (DDP), extrusion/direct wiring fabrication, 61–62 drug delivery structures biopolymers for, 475 colon-targeted delivery, 644–647 electrospray fabrication techniques, 288–297 liquid flow rate, drug concentration, and particle size, 293–294 living cells, 324–329 targeted drug delivery, 295–297 inorganic nanomaterials calcium carbonate/calcium phosphate drug carriers, 224–226 future research issues, 231 magnetic targeting delivery systems, 226–231 overview, 217–218 silica drug carriers, 218–224 microencapsuled polyelectrolyte films, 250–259 biomacromolecules, hollow shell loading, 250–254 pH-controlled macromolecule encapsulation, 252 protection devices, 254 protein encapsulation, porous particles, 253–254 switch on/off capsule, external magnetic field opening, 252–253 carrier surface functionalization, 258–259 direct coating, protein aggregates, 255–256 microencapsulation techniques, 254–255 overview, 250 small molecule encapsulation, 256 oral protein/peptide delivery, polymeric nano/microparticles emulsion polymerization, 184 natural- and protein-based polymers, 182–183 nonbiodegradable synthetic polymers, 179–181 oral delivery barriers, 172 oral peptide-delivery system, 173–187 oral protein delivery techniques, 173 overview, 171–172 precipitation/dispersion polymerization, 184–185 preformed polymer particles, 186–187 preparation, 183–184 protein-based polymers, 183 suspension polymerization, 185 synthetic biodegradable compounds, 175–178 drying methods nano/microparticles, preformed polymers, 186 powder-forming process, inorganic tissue-engineering scaffolds, 21 dual plasma deposition, plasma immersion ion implantation, 581 dual pore molds, chitosan scaffolds, 79


685

E elastomers, articular cartilage biomaterials, 667–668 electroactive polymers (EAPs) classification and examples, 485–486 conducting polymers, 490–496 dielectric elastomers, 496–498 future research issues, 498 gels, 486–489 ionic metal-polymer composites, 489–490 overview, 483–484 electrochemistry conducting polymer membranes biosensor applications, 429–432 electroactive polymers, 492–496 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 599–601 polypyrrole actuators, 374–378 nanowire time response, 389–393 polypyrrole biosensors, 394–398 polypyrrole-dodecylbenzenesulfonate, 369–374 polypyrrole nanowires, 383–387 electrodes, polypyrrole electropolymerization, 369 electrohydrodynamic processing electrospray mechanisms, 279–280 nanomaterials, 275–276 electromagnetic waves, plasma and, 576–578 electron micrograph, electrospun scaffolds, melt polymers, 127–128 electropolymerization, polypyrrole nanomaterials, 369 nanowire evaluation, 383–387 electrospinning of scaffolds basic principles, 117–123 bone tissue engineering, 132–133 cartilage tissue engineering, 133–134 cells, 136 chitosans, 125 collagen/gelatin, 124–125 collection systems, 123 future research issues, 136–137 hyaluronic acid, 125 mechanical testing, 131 melt properties, 127 microscopic analysis, 130 nanotechnology overview, 115–116 natural polymers, 124–125 neural tissue engineering, 135–136 physical characterization, 127–131 polymer solutions, 123–124 porosity, surface roughness, surface energy, 127–129 rapid prototyping, 108–110 solution spinning, 126–127 synthetic polymers, 125–127 tissue engineering principles, 116–117 vascular tissue engineering, 134–135 electrospraying controllable deposition techniques, 308–311 future research issues, 329 nano/micro biomaterials background, 277–279 definition, 276 fabrication, 288–328, 288–329

1/28/2008 11:41:40 AM

686 electrospraying (contd.) aerosolization, 321–329 bioactive coating/film deposition, 297–307 bioceramics, 298–301 biochip manufacturing, 311–314 biomolecule encapsulation, 315–318 biopolymers, 301–304 cell encapsulation, 318–321 controllable deposition, 308–311 drug delivery carriers, 288–297 encapsulation techniques, 314–321 native biomaterials, 304–307 patterned nanostructures, 308–314 future research issues, 329 jet breakup theory and modeling, 285–287 liquid cone jet model, 283–285 mechanisms and modes of, 279–280 processing parameters, 280 system properties, 287–288 electrosynthesis, biomolecular monomers, biosensor applications, 430 emission spectroscopy, plasma diagnostics, 577–578 emulsion polymerization injectable bulking biomaterials, 637–639 nano/microparticles from monomers, 184 encapsulation techniques biomaterial electrospraying, 314–321 biosensor applications, nanoconducting polymers, 432 hot melt polymers, 186 layer-by-layer nanostructure self-assembly, 239 polyelectrolyte films, drug/gene delivery, 250–259 biomacromolecules, hollow shell loading, 250–254 pH-controlled macromolecule encapsulation, 252 protection devices, 254 protein encapsulation, porous particles, 253–254 switch on/off capsule, external magnetic field opening, 252–253 carrier surface functionalization, 258–259 direct coating, protein aggregates, 255–256 microencapsulation techniques, 254–255 overview, 250 small molecule encapsulation, 256 endothelial progenitor cells (EPC), boundary layers from, blood-contacting devices, 521–522 enzymes, biosensor applications, 402–415 acetylcholinesterase/choline oxidase, 407, 409 carbon nanotube coupling, 428 cholesterol esterase/cholesterol oxidase, 405, 407–408 diamond films, 440 electropolymerized biomolecule entrapment, 430 glucose oxidase, 402–406 glutamate oxidase, 415 horseradish peroxidase, 409–413 lactate dehydrogenase, 410, 414 monomer electrosynthesis, 430 pyruvate oxidase, 414–415 erythrocytes, structure and properties, 507 erythropoietin calcium carbonate nanostructured drug carriers, 224–226 erythrocytes, 507


Index Escherichia coli biosensor applications, 416 polyethylene biomaterials, antibacterial enhancement, surface modification, 621–622 ethylene vinyl acetate (EVA), biomaterials electrospraying production of, 315–318 gastroesophageal reflux disease, 635–636 extracellular matrix (ECM) electrospun scaffolds, 117 neural tissue engineering, 135–136 naturally-occurring biopolymers, 11–12 scaffold architecture control, CAD/CAM techniques, 73 three-dimensional tissue scaffolds, 4–5 tissue-engineering scaffolds, 4 extrusion/direct wiring techniques, scaffold tissue fabrication, 57–62

F fabrication system schematic, biohybrid nanomaterials, supramolecular assembly, 359–360 face-centered cubic mesoporous silica materials (KIT-5), biohybrid nanomaterials, proteins, 352–355 failure analysis, total joint replacement, polyethylene biomaterials, 673–675 fecal incontinence, bulking biomaterials for management of, 637 fiber actuators, conducting polymers, 493–496 fibrin glue, gastrointestinal fistula repair, 636–637 fibroblast growth factor-2 (FGF2), gastrointestinal tissue engineering scaffolds, 652–653 fibrous scaffolds architecture control, 84–88 electrospinning techniques, 123–124 Fick’s law of diffusion, polyethylene biomaterials, antibacterial enhancement, surface modification, 621–622 film deposition process, layer-by-layer nanostructure self-assembly, 238–239 finite element method (FEM), articular cartilage hydrogels, 664–666 fistula repair, gastrointestinal, biomaterials fo, 636–637 FITC dye, electrospun scaffolds, 123 flavin adenine dinucleotide (FAD) biohybrid nanomaterials, small bioactive molecules, 341–349 glucose oxidase and, biosensor applications, 403–406 flow-limited field-injection electrostatic spraying (FFESS), biopolymer coatings and films, 302–304 flow ratios, diamond like carbon (DLC) films, structure and hemocompatibility, 602–605 fluid-based rapid-prototyping microfabrication, 100–104 fused deposition modeling, 102–103 organ printing, 103–104 pressure-assisted microsyringe system, 101–102 fluorescein isothiocyanate (FITC) magnetic targeting drug delivery systems, 228–231 polyelectrolyte drug/gene delivery, switch on/off capsule, 252–253 5-fluorouracil (5-FU), silica nanoparticle drug carriers, 223–224 foam coating, tissue engineering scaffolds, 31

1/28/2008 11:41:41 AM

Index folate receptors alphatic polyesters, amphilic block copolymers, 262–263 targeted drug delivery, 160–161 follicle-associated epithelium (FAE), synthetic polymeric nano/microparticles, 176–178 Fourier transform infrared attenuated total internal reflection (FTIR-ATR) technique, layer-by-layer nanostructure self-assembly, 243–244 45S5 bioglass-derived glass-ceramics, bone tissue scaffold materials, 11 freeze-drying, tissue engineering scaffolds, 31 functionalized monolayers, biosensor applications, 438–439 fused deposition modeling (FDM) articular cartilage biomaterials, tissue engineering, 670 extrusion/direct wiring fabrication and, 57–62 fluid-based rapid prototyping microfabrication, 102–103 inorganic tissue-engineering scaffolds, 24 scaffold architecture control, 73 scaffold tissue fabrication, 54–55

G gastroesophageal reflux disease (GERD), biomaterials applications in, 635–636 gastrointestinal medicine, biomaterial applications in bulking materials, 637–641 fistula repair, 636–637 future research issues, 653 gastroesophageal reflux disease, 635–636 laparotomy procedures, 641–644 overview, 634–635 targeted drug delivery, 644–647 tissue engineering, 647–653 gated drug delivery system, Mobil Composition of Matter-41 porous silica (MCM-41), 200–205 gelcasting, powder-forming process, inorganic tissueengineering scaffolds, 22 gel materials. See also hydrogels electroactive polymers, 486–489 electrospun scaffolds, 124–125 gene delivery, polyelectrolyte microencapsulation for, 254–255 gentamicin, calcium sulfate nanostructured drug carriers, 225–226 glass-carbon electrodes, carbon nanotube casting, 425–426 glass-ceramics bone tissue scaffold materials, 10–11 fabrication techniques, 25–28 plasma immersion ion implantation and deposition, 587 glow discharge, plasma production, 575 glucoamylase (GA), biohybrid nanomaterials, protein hybridization, 355–359 Gluconobacter oxydans, biosensor applications, 417 glucose nanochannel release systems covalent antithrombin/heparin, in vitro activity, 551–553 schematic of, 223–224


687 glucose oxidase (GOD) solutions biohybrid nanomaterials, protein hybridization, 354–359 biosensor applications, 402–406 amperometric glucose biosensor, 404–405 biomolecular monomer electrosynthesis, 430 diamond films, 440 optical glucose biosensor, 405 porous composites, 437–438 potentiometric glucose biosensor, 405 glutamate oxidase (GLOD), biosensor applications, 415 glutaraldehyde biomaterials articular cartilage hydrogels, 663–666 injectable bulking biomaterials, 640–641 glycoproteins, electrospun scaffolds, bone tissue engineering, 132–133 glycosaminoglycans (GAGs) antithrombin chemical structure, 538–541 covalent antithrombin/heparin and, 545–547 synthesis concepts, 547–548 electrospun scaffolds, bone tissue engineering, 132–133 heparin biochemistry, 542–544 good manufacturing practice (GMP) conditions, scaffold tissue fabrication, 65–66 graft materials articular cartilage repair, biomaterials for, 661–662 covalent antithrombin/heparin, surface coatings, 556–559 polyethylene biomaterials, antibacterial reagents, 622–623 green body formation, powder-forming process, inorganic tissue-engineering scaffolds, 20 green fluorescent protein (GFP) Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 targeted drug delivery, electrospray fabrication, 295–297 guided bone regeneration (GBR), electrospun scaffolds, bone tissue engineering, 133 gut-associated lymphoid tissue (GALT), synthetic polymeric nano/microparticles, 176–178

H haloperidol, soft nanostructured porous delivery system for, 197–199 hardness properties, plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 596–601 hematite nanoparticles, magnetic targeting drug delivery systems, 227–231 hemocompatibility. See biocompatibility hemolysis, basic properties of, 529 hemopoiesis, basic principles of, 506 heparin. See also covalent antithrombin/heparin (ATH) antithrombin cofactor activity, 538–539 chemical structure, 541–542 functional biochemistry, 542–544 limitations of, 544–545 ultrathin coatings, medical implants, 247–248

1/28/2008 11:41:41 AM

688 1,1,1,3,3,3-Hexafluoro-2-propanol (HFP), electrospun scaffolds, 124–125 highly porous glasses, inorganic tissue-engineering scaffolds, 23–24 high-molecular-weight kininogen (HMWK), blood coagulation pathways, 513 histidine adsorption, biohybrid nanomaterials, small biomolecules, 347–349 histology, scaffold architecture monitoring, 74–75 “hollow shell” micro/nanocarrier system, polyelectrolyte drug/gene delivery, 250–259 horseradish peroxidase, biosensor applications, 409–413 one-dimensional nanomaterials, 435 host functional groups, biohybrid nanomaterials, small bioactive molecules, 344–349 human cervical cancer (HeLa) cells, magnetic targeting drug delivery systems, 229–231 hyaline cartilage, structure and properties, 659–661 hyaluronic acid (HA) articular cartilage hydrogels, 664–666 biomaterials from, 472–473 electrospun scaffolds, 125 intra-abdominal adhesion prevention, 641–642 nanocomposite drug delivery system, 226 targeted drug delivery, 161–162 ultrathin coatings, medical implants, 247–248 hybridization, biohybrid nanomaterials, basic principles, 335–336 hydrogels articular cartilage repair, 662–666 drug delivery systems, 475 electroactive polymers, 486–489 soft nanostructured porous materials, controlled drug release systems, 197, 202 hydrogen bonding biohybrid nanomaterials, small bioactive molecules, 341–349 plasma immersion ion implantation and deposition, 582–587 titanium dioxide coatings, 587–590 hydrophobicity particular drug carriers, 153–154 synthetic polymeric nano/microparticles, 176–178 hydroxyapatite scaffolds bioactive silicate glasses, 9–10 bioceramic coatings and films, electrospray fabrication, 300–301 calcium sulfate nanostructured drug carriers, 225–226 electrospinning of, 132–133 extrusion/direct wiring fabrication, 58–62 plasma immersion ion implantation and deposition, 585–587 titanium alloys, 590–595 total joint replacement, polyethylene biomaterials, 672–675

I ibuprofen model biohybrid nanomaterials, small biomolecules, 348–349 magnetic targeting drug delivery systems, 227–231


Index nanostructured drug carriers calcium phosphate, 224–226 silica nanoparticle, 219–224 immobilization techniques biohybrid nanomaterial fabrication, 335–336 biosensor applications biomolecule-film attachments, 431–432 nanoconducting polymers, 432 immunoassays, nanoparticle biosensors, 435–437 inductively coupled plasma mass spectrometry plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 599–601 polyethylene biomaterials, antibacterial enhancement, surface modification, 620–622 inhalant pharmaceuticals, electrospray fabrication, 291–297 injury, articular cartilage repair, biomaterials for, 661–662 “in-oil” microsphere fabrication, injectable bulking biomaterials, 637–639 inorganic nanomaterials biohybrid nanomaterials, small bioactive molecules, 344–349 drug delivery structures calcium carbonate/calcium phosphate drug carriers, 224–226 future research issues, 231 magnetic targeting delivery systems, 226–231 overview, 217–218 silica drug carriers, 218–224 layer-by-layer nanostructure self-assembly, 241–242 inorganic tissue-engineering scaffolds fabrication of, 19–28 powder-forming process, 19–23 sol-gel techniques, 23–24 nanostructured porous materials, controlled drug release systems, 197, 200 insulin delivery systems electroactive polymers, gel systems, 488–489 electrospray fabrication techniques, 324–329 nano/microparticles naturally-occurring polymers, 182–183 synthetic polymers, 177–178 nanostructured porous materials, phase-reversible glucose hydrogels, 197, 202 integrated methodologies, rapid prototyping, 110 interfacial tentions, biomaterials and plasma proteins, diamond like carbon (DLC) films, 610–614 intermedia materials, biosensor applications, 422–423, 425–440 carbon nanotubes, 423, 425–429 diamond thin films, 439–440 functionalized monolayers, 438–439 nanomaterials, 433–438 polymers, 429–433 internal reflective element (IRE), layer-by-layer nanostructure self-assembly, 243–244 intra-abdominal adhesions, biomaterials and, 641–643 in vitro activity biopolymers, tissue engineering, 473–475 blood compatibility testing, 523 covalent anthithrombin-heparin complexes, 548–553 surface coatings, 556–558 electrospun scaffolds, 117–123

1/28/2008 11:41:41 AM

Index mechanical testing, 131 melt polymers, 127–128 neural tissue engineering, 135–136 vascular tissue engineering, 135 mechanoactive scaffolds, 71 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 601 polyester biomaterials, 462–463 polypyrrole biosensors, 393–398 second-generation scaffolds, 58–62 solid free-form systems, 63 tissue engineering, 46–48, 70 cell seeding, 50 extrusion/direct wiring fabrication, 57–62 unfractionated heparin structure, 542 in vivo activity blood compatibility testing, 523 covalent antithrombin/heparin, 553–555 surface coatings, 558–559 electrospun scaffolds, 117–123 magnetic targeting drug delivery systems, 227–231 nanoparticulates for chemotherapy, 163–164 particulate drug carriers, 152 long-circulating nanoparticles, 154–155 particle size, 153 surface charge, 154 surface hydrophobicity, 153–154 polypyrrole biosensors, 393–398 rapid prototyping, 111 targeted drug delivery, 157–164 total joint replacement, polyethylene biomaterials, 672–675 unfractionated heparin structure, 542 “in-water” microsphere fabrication, injectable bulking biomaterials, 637–639 ionic polymer-metal composites (IMPCs), electroactive polymers, 489–492 ion-solid interactions, plasma immersion ion implantation and deposition, 579–580 calcium/sodium deposition on titanium, 591–595 irradiation-enhanced diffusion, plasma immersion ion implantation and deposition, 579–580

J jet breakup theory and modeling, electrospraying systems, 285–287 joint repair, articular cartilage repair, biomaterials for, 661–662 Jurkat cell suspension, electrospraying of, 324–329

K keto-amine formation, covalent antithrombin/heparin surface coatings from, 556–559 in vitro activity, 551–553 Kiessig fringes, layer-by-layer nanostructure selfassembly, 242–244 Klebsiella oxytoca, biosensor applications, 418 Kokubo method, plasma immersion ion implantation and deposition, titanium alloys, 590–595


689

L a-lactalbumin, coatings and films, electrospray fabrication, 305–307 lactate dehydrogenase (LDH) biohybrid nanomaterials, protein hybridization, 357–359 biosensor applications, 410, 414 Langmuir-Blodgett (LB) technique biohybrid nanomaterials protein hybridization, 353–359 small bioactive molecules, 341–349 biosensor applications, 438–439 lipid-based biohybrid nanomaterial fabrication, 336–341 Langmuir probe, plasma diagnostics, 577–578 laparotomy procedures, biomaterials and, 641–643 laser sintering inorganic tissue-engineering scaffolds, 24 rapid-prototyping microfabrication, 106–107 scaffold architecture control, 73 scaffold tissue fabrication, 54–56 layer-by-layer self-assembly biohybrid nanomaterials, protein hybridization, 355–359 lipid-based biohybrid nanomaterial fabrication, 340–341 nanostructured biomaterials, 238–244 characterization of, 242–244 materials, 239–242 methods for, 238 multilayered biofilms, 244–250 overview, 238 leaching techniques, electrospun scaffolds, 123 lectins, synthetic polymeric nano/microparticles, 177–178 leukocytes adhesion/activation, 528–529 structure and properties, 507–508 synthetic interactions, 517 lidocaine hydrochloride, silica nanoparticle carriers, 223–224 light and fluorescence microscopy, scaffold architecture monitoring, 74–75 lipids biohybrid nanomaterials, fabrication techniques, 336–341 layer-by-layer nanostructure self-assembly, 241–242 Liposil nanocapsules, controlled-release drug delivery, 206–207 liposomes chemotherapy nanoparticles, 147 lipid-based biohybrid nanomaterials, fabrication techniques, 336–341 MCC465 liposome, 163–164 liquid cone jet model, electrospraying systems, 283–285 liquid-crystal templates, controlled-release drug delivery Mobil matter-41 porous silica, 203–205 porous silicon photonic crystals, 208–209 liquid flow rate, drug delivery systems, electrospray fabrication, 293–297 live-death assay, electrospun scaffolds, melt polymers, 127–128 living cell layers, blood-contacting devices, 521–522

1/28/2008 11:41:41 AM

690 lizard templating method, biohybrid nanomaterials, small biomolecules, 349–350 localized surface plasmon resonance (LSPR), nanoparticles in biosensors, 435 long-circulating nanoparticles, particulate drug carriers, 154–155 low-molecular-weight heparin (LMWH) biochemistry, 542–544 covalent antithrombin/heparin surface coatings from, 556–559 in vitro activity, 549–553 in vivo effects, 553–555 limitations of, 544–545 low-temperature isotropic-pyrolitic carbon (LTIC) phosphorus-doped diamond like carbon films, plasma immersion ion implantation and deposition surface modifications, 611–612 titanium-oxide thin films, plasma immersion ion implantation and deposition surface modifications, 614–618 lyophilization, polyelectrolyte encapsulation, 250 lysozyme adsorption, biohybrid nanomaterials, supramolecular fabrication, 350–359

M magnetic drug targeting chemotherapy nanoparticles, 150–151 nanostructured materials, 226–231 polyelectrolyte drug/gene delivery, switch on/off capsule, 252–253 magnetic nanoparticles, Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 materials for scaffolds electrospun scaffolds, vascular tissue engineering, 135 natural origin polymers, 72 rapid-prototyping microfabrication, 98–99 synthetic polymers, 71–72 MCC465 liposome, nanoparticulates for chemotherapy, 163–164 M-cells, synthetic polymeric nano/microparticles, 177–178 mechanical lapping, polypyrrole nanowires, 383–384 mechanical testing, electrospun scaffold analysis, 131 mediators, lactate dehydrogenase biosensor technology, 410, 414 medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP) composite scaffold, structure and properties, 46–47 medical implants, ultrathin coatings on, 246–248 melts electrospinning techniques and principles, 127–128 microencapsulation, 186 membrane lamination technique, scaffold microfabrication, 104 mercaptoethanol (ME), silica nanoparticle drug carriers, 219–224 mesenchymal stem cells (MSCs), electrospun scaffolds bone tissue engineering, 132–133 cartilage tissue engineering, 133–134 mesoporous carbon (CMK-3), biohybrid nanomaterials proteins, 351–359 small biomolecules, 347–349


Index mesoporous silica nanospheres (MSNs) biohybrid nanomaterials, 346–349 proteins, 350–359 magnetic targeting drug delivery systems, 227–230 Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 silica nanoparticle drug carriers, 218–224 metal ion affinity, biomolecule-film attachments, biosensor applications, 431–432 metal nanoparticles, chemotherapy applications, 151–152 methylparahydroxybenzoate (MPHB), electrospray fabrication, 291–297 micelles, drug/gene delivery, 259–267 amphiphilic block copolymers, 259–261 aliphatic polyesters, 261–263 overview, 259 poly l-amino acid block copolymers, 263–265 “smart micelles,” 265–267 microactuators, polypyrrole nanomaterials, 378–382 bilayer structures, 378–379 direct-mode polypyrrole-PDMS microvalve, 379–380 microfabrication techniques, 380–381 microvalve operation, 382 passive microfluidic component, 381–382 microarrays carbon nanotubes, biosensor applications, 426–427 electrospray fabrication, 311–314 microcomputed tomography (micro-CT) BMSC scaffolds, extrusion/direct wiring fabrication, 58–61 scaffold architecture monitoring, 76–77, 79–81 self-assembled structures, micropatterning, 249–250 microfabrication process carbon nanotubes, biosensor applications, 426–427 conducting polymers, 493–496 injectable bulking biomaterials, 637–639 polypyrrole actuators, 374 isolated nanowires, 389–393 optically controlled microstructures, 377 silicon device integration, 376–378 polypyrrole biosensors, 395–398 polypyrrole microvalves, 380–382 rapid-prototyping techniques, three-dimensional scaffold structures, 96–98 microfluidic systems, polypyrrole nanomaterials bilayer actuators, 378–379 direct-mode microvalves, 379–380 microfabrication techniques, 380–382 passive component microfabrication, 381–382 microorganisms, biosensor applications, 415–421 Arxula adeninivorans, 420–421 B. licheniformis, 416 B. subtilis, 416 E. coli, 416 Gluconobacter oxydans, 417 Klebsiella oxytoca, 418 Pichia methanolica, 421 Pseudomonas aeruginosa, 417 Pseudomonas fluorescens, 417–418 Pseudomonas putida, 418 Rhodococcus erythopolis, 419 Saccharomyces cerevisiae, 419–420 Serratia marcescens, 419

1/28/2008 11:41:41 AM

Index Torulopsis candida, 421 Trichosporon cutaneum, 419 microparticles. See nanomaterials micropatterning, self-assembled structures, 248–250 microscopy layer-by-layer nanostructure self-assembly, 243–244 platelet adhesion and activation, 526–528 scaffold architecture monitoring, 74–76 microsphere packing colon-targeted drug delivery systems, 644–647 gastrointestinal tissue engineering scaffolds, 652–653 injectable bulking biomaterials, 637–641 tissue engineering scaffolds, 30–31 microsphere sintering, tissue engineering scaffolds, 31 microvalves electroactive polymers, 487–489 polypyrrole nanomaterials direct-mode PPy/PDMS structures, 379–380 microfabrication techniques, 380–382 operating principles, 382 Mobil Composition of Matter-41 porous silica (MCM-41) biohybrid nanomaterials proteins, 350–359 small biomolecules, 346–349 controlled drug release systems, 200–201, 203–205 silica nanoparticle drug carriers, 219–224 molecular recognition, biohybrid nanomaterials, small bioactive molecules, 341–349 monitoring techniques, scaffold architecture, 79–80 monoclonal antibodies, targeted drug delivery, 157–158 monolayer assemblies, biosensor applications, 438–439 monomer polymerization biosensor applications, 430 nano/microparticles, 184–185 mononuclear phagocytic system (MPS), particulate drug carriers, 152–154 morphology drug delivery particles, electrospray fabrication, 292–297 electrospun scaffolds, 127–130 polypyrrole nanowires, 387–389 scaffold architecture control, 79 scaffold-based tissue engineering, 51–52 mucoadhesion, nonbiodegradable nano/ microparticles, 179–181 multidrug resistance chemotherapy, 145 pluronic block copolymer targeting, 261 multienzyme reactors, biohybrid nanomaterials, protein hybridization, 356–359 multilayered biofilms, layer-by-layer self-assembly, 244–250 micropatterning, 248–250 overview, 244 polyelectrolyte films, cell adhesion, 244–246 polyelectrolyte films, drug incorporation, 248 ultrathin medical implant coatings, 246–248 multiphoton confocal microscopy (MCM), scaffold architecture monitoring, 76 multiwall carbon nanotubes (MWCNTs), biosensor applications, 425–429, 432 solution casting, glass-carbon electrodes, 425–426 wire attachments, 427


691

N nanomaterials biohybrid structures fabrication technologies, 335–336 future research issues, 359–361 lipid-based materials, 336–341 proteins, 349–359 small bioactive molecules, 341–349 biosensor applications, 433–438 conducting polymers, 432 nanoparticle structures, 435–437 nanoporous materials, 437–438 one-dimensional structures, 434–435 cancer drug delivery active targeting, 156–157 albumin nanoparticles, 152 angiogenesis inhibition, 162 ceramic nanoparticles, 151 chemotherapy, 144–145 dendrimers, 150 drug targeting, 156 future research issues, 164 in vivo biodistribution, 152–155, 163–164 liposomes, 147 magnetic nanoparticles, 150–151 metal nanoparticles, 151 overview, 144 particulate drug carriers, 145–147 passive targeting, 156 polymeric structures, 148–149 tumor-specific targeting, 157–162 vascular targeting, 162–163 colon-targeted drug delivery, 646–647 controlled drug release systems biomimetic siliceous nanocapsules, 206 future research issues, 209–210 inorganic porous materials, 197, 200 matter-41 porous silica, 200–205 overview, 193–196 photonic crystals, 207–209 porous silicon, 206–209 soft porous materials, 196–199 electrohydrodynamic processing, 275–276 electrospraying background, 277–279 biomaterials fabrication, 288–328 definition, 276 future research issues, 329 jet breakup theory and modeling, 285–287 liquid cone jet model, 283–285 mechanisms and modes of, 279–280 processing parameters, 280 system properties, 287–288 electrospun scaffolds basic principles, 117–123 bone tissue engineering, 132–133 cartilage tissue engineering, 133–134 cells, 136 chitosans, 125 collagen/gelatin, 124–125 collection systems, 123 future research issues, 136–137

1/28/2008 11:41:42 AM

692 nanomaterials (contd.) hyaluronic acid, 125 mechanical testing, 131 melt properties, 127 microscopic analysis, 130 nanotechnology overview, 115–116 natural polymers, 124–125 neural tissue engineering, 135–136 physical characterization, 127–131 polymer solutions, 123–124 porosity, surface roughness, surface energy, 127–129 rapid prototyping, 108–110 solution spinning, 126–127 tissue engineering principles, 116–117 vascular tissue engineering, 134–135 inorganic drug delivery structures calcium carbonate/calcium phosphate drug carriers, 224–226 future research issues, 231 magnetic targeting delivery systems, 226–231 overview, 217–218 silica drug carriers, 218–224 intra-abdominal adhesion prevention, nanofibrous sheets, 642–643 magnetic targeting drug delivery systems, 230–231 plasma immersion ion implantation and deposition, titanium dioxide coatings, 587–590 polymeric nano/microparticles emulsion polymerization, 184 natural- and protein-based polymers, 182–183 nonbiodegradable synthetic polymers, 179–181 oral delivery barriers, 172 oral peptide-delivery system, 173–187 oral protein delivery techniques, 173 overview, 171–172 precipitation/dispersion polymerization, 184–185 preformed polymer particles, 186–187 preparation, 183–184 protein-based polymers, 183 suspension polymerization, 185 synthetic biodegradable compounds, 175–178 polypyrrole polymers actuators, 369–378 biosensors, 393–398 device fabrication, 383 microactuators, 378–382 nanowire electropolymerization, 383–389 nanowire time response, 389–393 overview, 368 self-assembly mechanisms biological cell encapsulation, 267–268 future research issues, 268–269 layer-by-layer self-assembly, 238–244 multilayered biofilms, 244–250 polyelectrolyte encapsulation, drug/gene delivery, 250–259 polymeric micelles, drug/gene delivery, 259–267 silica nanoparticle drug carriers, 223–224 naturally-occurring biopolymers articular cartilage tissue engineering, 668–670 biohybrid nanomaterials, fabrication technologies, 335–336


Index biomaterials from, 469–473 albumin, 472 alginates, 469–470 chitosan, 470–471 collagen, 472 hyaluronic acid, 472–473 bone tissue scaffold materials, 11–12 colon-targeted drug delivery systems, 644–647 electrospun scaffolds, 124–125 extrusion/direct wiring fabrication based on, 57–62 gastrointestinal tissue engineering collagen scaffolds, 650–651 three-dimensional printing scaffolds, 652–653 injectable bulking biomaterials, collagen, 640–641 layer-by-layer nanostructure self-assembly, 239–242 multilayered biofilms, 244 nano/microparticles, oral peptide delivery, 182–183 scaffold materials, 72 small-molecule drug micro/nanoparticles, encapsulation of, 257–258 neo-tissue formation, scaffold tissue engineering, 48–49 neovascularization, gastrointestinal tissue engineering scaffolds, 651–652 neural stem cells (NSC), electrospun scaffolds, neural tissue engineering, 135–136 neural tissue engineering biopolymers, 473–475 electrospun scaffolds, 135–136 neurotransmitters, polypyrrole biosensors, 394–398 neutron reflectivity, layer-by-layer nanostructure self-assembly, 243–244 nickel-titanium alloys, plasma immersion ion implantation and deposition, surface modification, 595–601 nonconducting polymers, biosensor applications, 433 nonheparinoid anticoagulants, development of, 544–545

O ocular refractive errors, ionic polymer-metal composites, 489–492 one-dimensional nanomaterials, biosensor applications, 434–435 optical coherence tomography (OCT), scaffold architecture monitoring, 77, 79–83, 85–88 optical glucose biosensor, structure and properties, 405 optical microscopy polypyrrole actuators, 374–376 polypyrrole nanowire actuation, 385–387 oral protein/peptide delivery, polymeric nano/ microparticles emulsion polymerization, 184 natural- and protein-based polymers, 182–183 nonbiodegradable synthetic polymers, 179–181 oral delivery barriers, 172 oral peptide-delivery system, 173–187 oral protein delivery techniques, 173 overview, 171–172 precipitation/dispersion polymerization, 184–185 preformed polymer particles, 186–187 preparation, 183–184 protein-based polymers, 183

1/28/2008 11:41:42 AM

Index suspension polymerization, 185 synthetic biodegradable compounds, 175–178 organic matrices, extrusion/direct wiring fabrication based on, 58–62 organic nanoparticles, layer-by-layer nanostructure self-assembly, 241–242 organotypic antigens, targeted drug delivery, 157–158 organ printing, fluid-based rapid prototyping microfabrication, 103–104 oriented fibers, electrospun scaffolds, 117–123 orthopedics biomaterial applications in, 473 plasma immersion ion implantation and deposition diamond like carbon (DLC) films, 601–602 titanium dioxide coatings, 587–590 oxidative degradation, total joint replacement, polyethylene biomaterials, 673–675

P paclitaxel, polyelectrolyte films, drug incorporation in, 248 PAM-fabricated scaffolds, rapid prototyping, 110–111 particle leaching, tissue engineering scaffolds, 30–31 particle size drug delivery systems, flow rate and drug concentration, 293–297 electrospraying systems, 283 particular drug carriers, 153 particle uptake pathway, polymeric nano/microparticles, oral protein delivery, 173–174 particulate drug carriers chemotherapy nanoparticles, 145–147 electrospray fabrication, 291–297 in vivo biodistribution, 152 paste electrodes, carbon nanotube packing, biosensor applications, 428 patterned nanostructured biomaterials, electrospray fabrication, 308–314 PCL/TCP-Coll scaffolds, extrusion/direct wiring fabrication, 58–62 penetration barrier, polyelectrolyte capsule protection, 254 peptide-based biotechnology biohybrid nanomaterials, small bioactive molecules, 344–349 polymeric nano/microparticles emulsion polymerization, 184 natural- and protein-based polymers, 182–183 nonbiodegradable synthetic polymers, 179–181 oral delivery barriers, 172 oral peptide-delivery system, 173–187 oral protein delivery techniques, 173 overview, 171–172 precipitation/dispersion polymerization, 184–185 preformed polymer particles, 186–187 preparation, 183–184 protein-based polymers, 183 suspension polymerization, 185 synthetic biodegradable compounds, 175–178 permeation control, lipid-based biohybrid nanomaterial fabrication, 336–341


693 pesticide detection, acetylchholinesterase/choline oxidase (AchE/ChOD) detection, 407, 409 phagocytosis, particulate drug carriers, 152 phase separation/freeze-drying, powder-forming process, inorganic tissue-engineering scaffolds, 21 pH-controlled macromolecule encapsulation colon-targeted drug delivery systems, 644–647 polyelectrolyte drug/gene delivery, 252 “smart” micelle delivery systems, 265–266 phosphate buffered saline (PBS) optical coherence tomography, scaffold architecture monitoring, 82–83 polypyrrole biosensors, 396–398 scaffold tissue fabrication, cell/organ printing, 63–64 phosphorus-doped diamond like carbon (P-DLC) films, plasma immersion ion implantation and deposition surface modifications, 610–612 photodynamic therapy chemotherapy nanoparticles, dendrimers, 150 silica nanoparticle carriers, 222–224 photoisomerization, biohybrid nanomaterials, protein hybridization, 356–359 photonic crystals, controlled-release drug delivery, porous silicon, 207–209 photopolymerization, rapid-prototyping microfabrication, 107–108 Pichia methanolica, biosensor applications, 421 piezoelectric technology, scaffold tissue fabrication, cell/organ printing, 63–64 plasma (blood) covalent antithrombin/heparin, in vivo clearance mechanisms, 553–555 structure and properties, 508 plasma enhanced chemical vapor deposition (PECVD), polypyrrole microvalve fabrication, 380–382 plasma immersion ion implantation and deposition (PIIID) applications, 581–582 basic principles, 578–579 blood-contacting materials modification, 601–618 annealing temperature, 608–610 bias voltage and platelet adhesion, 605–608 calcium-doped DLC films, 612–614 diamond like carbon thin films, 601–602 flow ration and hemocompatibility, 602–605 phosphorus-doped DLC films, 610–612 titanium-oxide thin films, 614–618 calcium/sodium PIIID of titanium, 590–594 conventional beam-line ion implantation vs., 581 deposition process and dynamics, 580–581 future research issues, 623 hydrogen PIII, 583–590 ion-solid interactions, 579–580 nickel/titanium alloy modification, 595–601 overview, 574–578 plasma sources and properties, 574–578 polymer surface modification, 618–622 antimicrobial reagent grafts, 621–623 copper-implanted polymers, 618–622 plasmid DNA (pDNA), electrospraying of biomaterials, 321–324 platelet-derived growth factor (PDGF), angiogenesis inhibition, 162

1/28/2008 11:41:42 AM

694 platelet rich plasma (PRP), diamond like carbon (DLC) films annealing temperatures and, 608–610 bias voltage and platelet adhesion, 605–608 platelets adhesion and activation, 515–516 determination of, 526–528 diamond like carbon (DLC) films annealing temperatures, 608–610 bias voltage and, 605–608 calcium-doped diamond like carbon films, 612–614 flow ratios and biocompatibility, 604–605 phosphorus-doped diamond like carbon films, 610–612 titanium-oxide thin films, 614–618 structure and properties, 508 pluripotent hematopoietic stem cells (PHSC), properties of, 506 pluronic block copolymers, drug/gene delivery, 259–261 poly(a-amino acids) (PAA), biomaterials from, 467 polyacrylic acid (PAA) nonbiodegradable nano/microparticles, 179–181 targeted drug delivery, electrospray fabrication, 295–297 poly(a-hydroxyacids) (PHA), biomaterials from, 459–463 poly(alkyl cyanoacrylate) biomaterials from, 467–468 synthetic polymeric nano/microparticles, 177–178 polyamidoamine (PAMAM) chemotherapy nanoparticles, 150 Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 poly(anhydrides), bone tissue scaffold materials, 16 polyaniline (PANI) biosensor applications biomolecule-film attachments, 431–432 conducting polymer membranes, 429–432 nanoconducting polymers, 432 conducting polymers, 493–496 poly(butylene terephthalate) (PBT), articular cartilage biomaterials, 667–668 polycaprolactone (PCL) articular cartilage biomaterials, tissue engineering, 670 biomaterials from, 463 copolymers, 463–465 drug delivery systems, electrospray fabrication, 288–297 electrospinning parameters, 119–123 mechanical testing, 113 extrusion/direct wiring fabrication, 57–62 properties of, 71–72 rapid-prototyping microfabrication, 98–99 synthetic polymeric nano/microparticles, 177–178 polydimethylsiloxane (PDMS) multilayered polyelectrolyte films, cell adhesions, 245–246 polypyrrole nanomaterials bilayer actuators, 378–379 direct-mode microvalves, 379–380 microvalve fabrication, 380–382 polydioxanone (PDS), biomaterials from, 465 polyelectrolyte films cell adhesion applications, 244–246 drug incorporation in, 248


Index encapsulation, drug/gene delivery, 250–259 biomacromolecules, hollow shell loading, 250–254 pH-controlled macromolecule encapsulation, 252 protection devices, 254 protein encapsulation, porous particles, 253–254 switch on/off capsule, external magnetic field opening, 252–253 carrier surface functionalization, 258–259 direct coating, protein aggregates, 255–256 microencapsulation techniques, 254–255 overview, 250 small molecule encapsulation, 256 multilayer research, metal nanoparticles, 151 polyesters articular cartilage biomaterials, 667–668 biomaterials from, 459–465 polyethylene biomaterials antibacterial enhancement, surface modification, 618–622 total joint replacement, 670–675 poly(3,4-ethylenedioxythiophene) (PEDOT) biosensor applications, nanoconducting polymers, 432 conducting polymers, 494–496 soft nanostructured porous materials, controlled drug release systems, 197–201 poly(ethylene glycol) diacrylate (PEGDA), electrospun scaffolds, 125 polyethylene glycol (PEG) biomaterials from, 465–466 chemotherapy nanoparticles block copolymers, 149 dendrimers, 150 liposomes, 147 long-circulating design, 154–155 polyelectrolyte shells, carrier surface functionalization, 258 polymeric nano/microparticles, oral protein delivery, 173 polyethylene oxide (PEO) alphatic polyesters, amphilic block copolymers, 261–263 biomaterials from, 465–466 coatings and films, electrospray fabrication, 302–304 electrospinning parameters, 121–123 pluronic block copolymers, 260–261 targeted drug delivery, electrospray fabrication, 295–297 poly(fumaric-co-sebacic) system, synthetic polymeric nano/microparticles, 177–178 poly(glycolic acid) (PGA) articular cartilage biomaterials, tissue engineering, 669–670 biomaterials from, 459–463 copolymers, 463–465 gastrointestinal tissue engineering, 647 scaffold materials, 71–72 polyhydroxyalkanoates, bone tissue scaffold materials, 15 polyions layer-by-layer nanostructure self-assembly, 239–242 multilayered polyelectrolyte films, cell adhesions, 244–246

1/28/2008 11:41:42 AM

Index poly(lactic acid ) (PLA) articular cartilage biomaterials, tissue engineering, 669–670 biomaterials from, 459–463 copolymers, 463–465 drug delivery systems, electrospray fabrication, 290–297 mechanoactive scaffolds, 71 nanostructured porous materials, controlled drug release systems, 196 soft nanostructured porous materials, 197–201 rapid-prototyping microfabrication, 98–99 scaffold materials, 71–72 synthetic polymeric nano/microparticles, 177–178 polylactide/glycolide copolymers (PLGA) biomaterials and toxicity of, 462–463 colon-targeted drug delivery systems, 646–647 drug delivery systems, electrospray fabrication, 291–297 gastrointestinal tissue engineering fibrous synthetic scaffolds, 647 foam synthetic scaffolds, 647–650 injectable bulking biomaterials, 639 intra-abdominal adhesion prevention, 642–643 nanostructured porous materials, controlled drug release systems, 196 soft nanostructured porous materials, 197–201 rapid-prototyping microfabrication, 98–99 synthetic polymeric nano/microparticles, 177–178 poly(L-amino acid) (PLAA) scaffold architectural control, 84–88 block copolymers, 263–265 optical coherence tomography, architecture monitoring, 81–83 poly (L-lactic acid) (PLLA), biomaterials from, 461–463 polymeric biomaterials. See biopolymers applications, 473–475 drug delivery, 475 orthopedics, 473 tissue engineering, 473–475 articular cartilage repair, 662–668 hydrogels, 662–666 synthetic polyesters/polyurethanes, 667–668 blood-contacting devices bioinert materials, 518 coatings, 519–521 degradable polymers albumin, 472 alginates, 469–470 chitosan, 470–471 collagen, 472 hyaluronic acid, 472–473 poly(a-amino acids), 467 poly(alkyl 2-cyanoacrylates), 467–468 polydioxanone, 465 polyesters, 459–465 polyethylene glycol, 465–466 polyurethanes, 468–469 tissue engineering, 473–475 trimethylene carbonate, 466–467


695 future research issues, 475–476 gastrointestinal tissue engineering fibrous synthetic scaffolds, 647 foam scaffolds, 647–650 microspheres, injectable bulking biomaterials, 637–639 overview, 437–438 plasma immersion ion implantation and deposition, 618–622 antimicrobial reagent grafts, 621–623 copper-implanted polymers, 618–622 polymeric micelles, drug/gene delivery, self-assembly mechanisms, 259–267 amphiphilic block copolymers aliphatic polyesters, 261–263 PEO-PPO-PEO micelles, 259–261 overview, 259 poly l-amino acid block copolymers, 263–265 “smart micelles,” 265–267 polymeric nano/microparticles. See also nanomaterials; specific types of polymers and polymer compounds biosensor applications, 428–433 biomolecule-functionalized monomer electrosynthesis, 430 conducting polymer membrane, 428–432 electropolymerized film, biomolecule entrapment, 430 film-biomolecule attachment, 431–432 nanoconducting polymers, 432 nonconducting polymers, 433 chemotherapy nanoparticles, 148–149 electrospun scaffolds, 117–123 melt electrospinning, 127–128 solution properties, 123–124 naturally-occurring compounds, 11–12, 72 oral protein/peptide delivery emulsion polymerization, 184 natural- and protein-based polymers, 182–183 nonbiodegradable synthetic polymers, 179–181 oral delivery barriers, 172 oral peptide-delivery system, 173–187 oral protein delivery techniques, 173 overview, 171–172 precipitation/dispersion polymerization, 184–185 preformed polymer particles, 186–187 preparation, 183–184 protein-based polymers, 183 suspension polymerization, 185 synthetic biodegradable compounds, 175–178 polypyrrole biosensors, 395–398 scaffold tissue fabrication coatings, 33 overview, 28–31 stereolithography, 55 surface bioeroding polymers, 15–16 synthetic polymers, 12–16, 72–73 targeted drug delivery, electrospray fabrication, 295–297 poly(m-phenylenediamine) (PMPD), biosensor applications, 433 poly(N-isopropylacrylamide) (PNIPAAm), “smart” micelle delivery systems, 266–267

1/28/2008 11:41:42 AM

696 poly(ortho-esters) (POE), bone tissue scaffold materials, 16 polyphosazenes, bone tissue scaffold materials, 16 polypropylene fumarate (PPF) bone tissue scaffold materials, 15 extrusion/direct wiring fabrication, 61–62 material properties, 72 polypropylene oxide (PPO), pluronic block copolymers, 260–261 polypyrrole (PPy) nanomaterials actuators, 369–378 conductivity, 369–370 DBS ion doping, 370–372 electrochemistry, 369–374 electropolymerization, 369 optically controlled microstructure fabrication, 377 reversible electrochemical redox reaction, 372–373 silicon device integration, 376–378 test line microfabrication, 374 thickness change measurement, 374–376 time response, 373–374 biosensors, 393–398 nonconducting membranes, 433 conducting polymer membranes, biosensor applications, 429–432 device fabrication, 383 microactuators, 378–382 bilayer structures, 378–379 direct-mode polypyrrole-PDMS microvalve, 379–380 microfabrication techniques, 380–381 microvalve operation, 382 passive microfluidic component, 381–382 nanowire electropolymerization, 383–389 actuation, real-time optical microscopy, 385–386 mechanical lapping, 383–384 optical microscopy/cyclic voltammetry data, 386–387 time response, 389–393 volume change, 384–385 nanowire morphology, 387–389 nanowire time response, 389–393 overview, 368 polysaccharides layer-by-layer nanostructure self-assembly, 241–242 nano/microparticles, oral peptide delivery, 182–183 ultrathin coatings, medical implants, 247–248 polythiophene, conducting polymer membranes, biosensor applications, 429–432 polyurethanes articular cartilage biomaterials, 667–668 biomaterials from, 468–469 poly(vinyl alcohol) (PVA) articular cartilage hydrogels, 662–666 injectable bulking biomaterials, 639 polyvinyl chloride, antimicrobial reagents, 622–623 pore interconnectivity bone tissue engineering, 5 scaffold architecture control, 78–79 scaffold design, 52 silica nanoparticle drug carriers, 218–224


Index pore size bone tissue engineering, 5 silica nanoparticle drug carriers, 218–224 porogen techniques, scaffold pore interconnectivity control, 78–79, 82–88 porosity articular cartilage hydrogels, 664–666 electrospun scaffolds, 127–128 scaffold design and, 52 quantitative estimation of, 87–88 silica nanoparticle drug carriers, 218–224 porous composites bioceramics, fabrication techniques, 26–28 biohybrid nanomaterials, 346–349 biosensor applications, 437–438 fabrication methods, 29–30 nanostructured biomaterials, controlled drug release systems biomimetic siliceous nanocapsules, 206 future research issues, 209–210 inorganic porous materials, 197, 200 matter-41 porous silica, 200–205 overview, 193–196 photonic crystals, 207–209 porous silicon, 206–209 soft porous materials, 196–199 porous hollow silica nanoparticles (PHSNs), drug carriers, 222–224 porous polymer microparticles, protein encapsulation, 253–254 porous silicon biosensor applications, 437–438 controlled-release drug delivery, 206–209 potentiometric glucose biosensor, structure and properties, 405 powder-based microfabrication laser sintering, 106–107 membrane lamination, 104 photopolymerization, 107 three-dimensional printing, 105–106 powder-forming process, inorganic tissue-engineering scaffolds, 19–23 precipitation polymerization, nano/microparticles from monomers, 184–185 precision extrusion deposition (PED) fluid-based rapid prototyping microfabrication, 103 scaffold fabrication, 58–62 precision extrusion manufacturing (PEM), fluid-based rapid prototyping microfabrication, 103 preformed polymers, nano/microparticles, 186–187 pressure-assisted microsyringe (PAM) fluid-based rapid prototyping microfabrication, 101–102 scaffold architecture control, 73 printing head microfabrication laser sintering, 106–107 membrane lamination, 104 photopolymerization, 107 three-dimensional printing, 105–106 protein adsorption blood-synthetic surface intractions, 510 diamond like carbon (DLC) films, annealing temperatures and platelet adhesion, 609–610

1/28/2008 11:41:43 AM

Index gastrointestinal tissue engineering scaffolds, 652–653 tissue engineering scaffolds, 32 ultrathin coatings on medical implants, 247–248 protein-based polymers aerosolization, 321–324 biochip manufacturing, 311–314 coatings and films, electrospray fabrication, 304–307 direct coating for, 255–256 nano/microparticles, oral peptide delivery, 182–183 proteins, biohybrid nanomaterials, supramolecular fabrication, 349–359 Proteosilica film, biohybrid nanomaterials, small biomolecules, 348–349 Pseudomonas aeruginosa, biosensor applications, 417 Pseudomonas fluorescens, biosensor applications, 417–418 Pseudomonas putida, biosensor applications, 418 pyruvate oxidase, biosensor applications, 414–415

Q quality control, scaffold architecture monitoring, 73–77 quartz crystal microbalance (QCM) biohybrid nanomaterials, protein hybridization, 355–359 layer-by-layer nanostructure self-assembly, 242–244 lipid-based biohybride nanomaterial fabrication, 340–341

R radio frequency discharge diamond like carbon (DLC) films, bias voltage and platelet adhesion, 605–608 plasma production, 574–575 Raman spectra, diamond like carbon (DLC) films annealing temperatures and, 608–610 bias voltage and platelet adhesion, 605–608 flow ratios and biocompatibility, 603–605 random mat-like structure, electrospun scaffolds, 117–123 rapid prototyping (RP) commercial systems, 110–111 electrospinning, 108–110 extrusion/direct wiring fabrication and, 58–62 fabrication principles, 53 fluid-based microfabrication, 100–104 fused deposition modeling, 102–103 organ printing, 103–104 pressure-assisted microsyringe system, 101–102 future research issues, 112 integrated techniques, 110 limitations and critiques, 111–112 materials, 98–99 overview, 95–96 printing head and powder-based microfabrication, 104–107 resolution and resolution/time of manufacture ratio and geometry, 99–100 sacrificial molds, 107–108 three-dimensional structures, microfabrication, 96–98 Rayleigh scattering electrospray systems, 277–279 electrospun scaffolds, 124


697 real-time optical microscopy, polypyrrole nanowire actuation, 385–387 regenerative medicine, scaffold-based tissue engineering, 45–47 replication technique, powder-forming process, inorganic tissue-engineering scaffolds, 21–22 resolution, rapid-prototyping, 99–100 resolution/time of manufacture ratio, rapid-prototyping, 99–100 reticuloendothelial system (RES) chemotherapy nanoparticles, 147 layer-by-layer nanostructure self-assembly, 241–242 particulate drug carriers, 152 polymeric nano/microparticles, oral protein delivery, 173 reversible electrochemical redox reaction, polypyrroledodecylbenzenesulfonate, 372–374 Rhodococcus erythopolis, biosensor applications, 419 robot-assisted construct fabrication, scaffold tissue, 64–65 roughness properties, tissue engineering scaffolds, 33

S Saccharomyces cerevisiae, biosensor applications, 419–420 sacrificial molds, rapid prototyping, 107–108 salt-leaching techniques, scaffold architecture control, 83–88 saturated poly-a-hydroxyesters, bone tissue scaffold materials, 13–15 scaffold-based tissue engineering articular cartilage biomaterials, 668–670 bioactive silicate glass bioceramics, 8–10 biocomposites, 16–19 bone tissue engineering materials, 6–19 calcium phosphate bioceramics, 6–8 design principles, 50–52 electrospun scaffolds, basic principles, 117–123 extrusion/direct writing systems, 57–62 fabrication, 19–31 composite scaffolds, 28–31 inorganic scaffolds, 19–28 solid free-form technique, 53–56 surface functionalization, 32–33 future directions, 62–65 cell/organ printing, 63–64 gastrointestinal disease, biomaterials for, 647–653 collagen-based scaffolds, 650–651 fibrous synthetic polymer scaffolds, 647 foam synthetic polymer scaffolds, 647–650 indirect three-dimensional printed scaffolds, 651 neovascularization, 651–653 glass-ceramic bioceramics, 10–11 limitations of, 46–47 morphology/architecture, 51–52 naturally occurring biopolymers, 11–12 overview, 4 repair and regeneration of, 45–49 requisite conditions, 70–71 robot-assisted construct fabrication, 65 synthetic polymers, 12–16 three-dimensional design, 4–5 printing technology, 56–57

1/28/2008 11:41:43 AM

698 scaling laws, electrospraying systems, 281–283 scanning electron microscopy (SEM) drug delivery systems, electrospray fabrication, 288–297 electrospun scaffolds, 123–124 interfiber distance and fiber diameter measurement, 130 surface roughness analysis, 129 scaffold architecture monitoring, 74, 84–88 Schiff base complex, covalent antithrombin/heparin surface coatings, in vivo activity, 558–559 in vitro activity, 551–553 second-generation scaffolds, extrusion/direct wiring fabrication based on, 58–62 selective laser sintering (SLS) inorganic tissue-engineering scaffolds, 24 scaffold architecture control, 73 scaffold tissue fabrication, 54–56 self-assembled monolayers (SAMs), biosensor applications, 439 self-assembly of nanostructures biogical cell encapsulation, 267–268 biohybrid nanomaterials, small bioactive molecules, 342–349 biosensor applications, 439 conducting polymers, 494–496 electrospun scaffolds, 117 future research issues, 268–269 layer-by-layer self-assembly, 238–244 characterization of, 242–244 materials, 239–242 methods for, 238 multilayered biofilms, 244–250 overview, 238 multilayered biofilms, 244–250 micropatterning, 248–250 overview, 244 polyelectrolyte films, cell adhesion, 244–246 polyelectrolyte films, drug incorporation, 248 ultrathin medical implant coatings, 246–248 polyelectrolyte encapsulation, drug/gene delivery, 250–259 biomacromolecules, hollow shell loading, 250–254 carrier surface functionalization, 258–259 direct coating, protein aggregates, 255–256 microencapsulation techniques, 254–255 overview, 250 small molecule encapsulation, 256 polymeric micelles, drug/gene delivery, 259–267 amphiphilic block copolymer aliphatic polyesters, 261–263 amphiphilic block copolymer micelles, 259–261 overview, 259 poly l-amino acid block copolymers, 263–265 “smart micelles,” 265–267 semiconductor devices plasma immersion ion implantation and deposition, 581–582 polypyrrole actuator integration with, 376–377 quantum dots, nanoparticle biosensors, 435–437 semi-interpenetrating polymer (SIPN), articular cartilage hydrogels, 666


Index serpin family antithrombin chemical structure, 538–539 covalent antithrombin/heparin and, 545–547 Serratia marcescens, biosensor applications, 419 shape memory effects electroactive polymer gels, 486–489 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 595–601 signal-to-noise ratio (SNR), optical coherence tomography, scaffold architecture monitoring, 81–83 silane-modified surfaces (silanization), tissue engineering scaffolds, 32–33 silica nanoparticle chemotherapy applications, 151 drug carriers, 218–224 magnetic targeting drug delivery systems, 227–231 porous silicon, controlled-release drug delivery, 206–209 silicon devices plasma immersion ion implantation and deposition and, 581–582 hydrogen implants, 582–587 polypyrrole actuator integration with, 376–378 silk-like polymer with fibronectin functionality (SLPF), electrospray fabrication, 307–308 single-wall carbon nanotubes (SWCNTs), biosensor applications, 425–429, 432 solution casting, glass-carbon electrodes, 425–426 sintering inorganic tissue-engineering scaffolds, selective laser techniques, 25 microsphere sintering, 31 powder-forming process, inorganic tissue-engineering scaffolds, 22–23 selective laser sintering, scaffold tissue fabrication, 54–56 slip casting, powder-forming process, inorganic tissueengineering scaffolds, 21 slurry preparation, powder-forming process, inorganic tissue-engineering scaffolds, 19–20 small-molecule drug micro/nanoparticles biohybrid nanomaterials, 341––349 encapsulation of, 256–258 smart materials, electroactive polymers classification and examples, 485–486 conducting polymers, 490–496 dielectric elastomers, 496–498 future research issues, 498 gels, 486–489 ionic metal-polymer composites, 489–490 overview, 483–484 “smart” micelles, targeted drug delivery, 265–267 smooth muscle cells (SMCs), electrospun scaffolds copolymer electrospinning, 136 microscopic analysis, 130 synthetic polymers, 125–126 vascular tissue engineering, 135–136 sodium beam-line ion implantation, plasma immersion ion implantation and deposition, titanium alloys, 590–595

1/28/2008 11:41:43 AM

Index sodium dodecylbenzenesulfonate (NaDBS), polypyrrole, ion doping with, 370–372 polypyrrole nanowires, 384–387 silicon device integration, 377–378 sodium nitroprusside (SNP), polyelectrolyte films, drug incorporation in, 248 soft-landing instrumentation, controllable deposition, electrospraying, 308–311 soft nanostructured porous materials, controlled drug release systems, 196–201 soft-tissue scaffolds, rapid-prototyping microfabrication, 96–98 sol-gel techniques electrospray fabrication, bioceramic coatings and films, 300–301 inorganic tissue-engineering scaffolds, 23–24 magnetic targeting drug delivery systems, 230–231 silica nanoparticle drug carriers, 218–224 solid free-form (SFF) techniques inorganic tissue-engineering scaffolds, 24–25 scaffold tissue fabrication, 48–49, 53 extrusion/direct writing, 57–62 selective laser sintering, 55–56 solid ground curing, 56 stereolithography, 53–55 three-dimensional printing, 56–57 solid ground curing, scaffold tissue fabrication, 56 solid-liquid phase separation, scaffold architecture control, 72–73 solution casting, carbon nanotubes, glass-carbon electrodes, biosensor applications, 425–426 solution properties, electrospun scaffolds, 123–124, 126–127 solvent casting, tissue engineering scaffolds, 30–31 solvent evaporation/particulate leaching nano/microparticles, preformed polymers, 186 scaffold pore interconnectivity control, 78–79 solvent properties electrospun scaffolds, 121–123, 126–127 scaffold architecture control, 72–73, 83–84 specific surface energy, electrospun scaffolds, 127–128 sphincter augmentation (GERD), biomaterials for, 635 spray drying, nano/microparticles, preformed polymers, 186 Staphylococcus aureus, polymer biomaterials, antimicrobial reagents, 622–623 stent implants biopolymers for, 474–475 ultrathin coatings, 247–248 stereolithography (SL) rapid-prototyping microfabrication, 107–108 scaffold tissue fabrication, 53–55 stimuli-responsive controlled release system magnetic targeting drug delivery systems, 228–231 silica nanoparticle drug carriers, 219–224 superconducting quantum interference device (SQUID), nanoparticle biosensors, 437 superelasticity, plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 595–601 superparamagnetic nanoparticles, magnetic targeting drug delivery systems, 231


699 supramolecular fabrication techniques, biohybrid nanomaterials future research issues, 359–361 lipid-based materials, 336–341 overview, 335–336 proteins, 349–359 small bioactive molecules, 341–349 surface-cross-linked nanoparticles (SCNPs), alphatic polyesters, amphilic block copolymers, 261 surface modification, biomaterials bone tissue scaffold materials, 15–16 electrospun scaffolds, 127–128 hydrophobicity, particular drug carriers, 153–154 layer-by-layer nanostructure self-assembly, 243–244 particulate drug carriers, 154 plasma immersion ion implantation and deposition applications, 581–582 basic principles, 578–579 blood-contacting materials modification, 601–618 calcium/sodium PIIID of titanium, 590–594 conventional beam-line ion implantation vs., 581 deposition process and dynamics, 580–581 enhanced antibacterial polymers, 618–622 future research issues, 623 hydrogen PIII, 583–590 ion-solid interactions, 579–580 nickel/titanium alloy modification, 595–601 overview, 574–578 polymeric biomaterials, 618–622 tissue engineering scaffolds, 32–33 suspension polymerization, nano/microparticles from monomers, 185 switchable enzyme reactor biohybrid nanomaterials, protein hybridization, 356–359 polyelectrolyte drug/gene delivery, 252–253 synthetic polymers articular cartilage biomaterials, 667–668 tissue engineering, 669–670 bone tissue scaffold materials, 12–16 electrospinning, 125–126 gastrointestinal tissue engineering fibrous scaffolds, 647 foam scaffolds, 647–650 layer-by-layer nanostructure self-assembly, 238–240 materials for, 239–242 nonbiodegradable nano/microparticles, 179–181 polymeric nano/microparticles, 175–178 scaffold materials from, 71–72

T targeted drug delivery chemotherapy nanoparticles, 156–164 active targeting, 156–157 antibodies, 157–158 drug targeting, 156 folate, 160–161 hyaluronic acid, 161–162 passive targeting, 156 transferrin, 158–159

1/28/2008 11:41:43 AM

700 targeted drug delivery (contd.) colon-targeted delivery, biomaterials for, 644–647 electrospray fabrication techniques, 295–297 polyelectrolyte shells, carrier surface functionalization, 258–259 “smart” micelles for, 265–267 TAT peptides, liposomes, chemotherapy nanoparticles, 147 Taylor cone, electrospun scaffolds, 119–123 temperature-programmed desorption (TPD) analysis, biohybrid nanomaterials, small biomolecules, 349–350 temperature-sensitive micelles, “smart” micelle delivery systems, 266–267 template synthesis, polypyrrole biosensors, 395–398 tetrahydrofuran (THF), scaffold pore interconnectivity control, 79 Texas Red-loaded G2-PAMAM dendrimer, Mobil Composition of Matter-41 porous silica (MCM-41), 201–205 tgolylene-2,4-diisothiocyanate (TDTC), covalent antithrombin/heparin, in vitro activity, 549–553 thermal denaturation, nano/microparticles, preformed polymers, 187 thermally induced phase separation/freeze-drying electrospun scaffolds, 117 gastrointestinal tissue engineering, foam synthetic scaffolds, 647–650 tissue engineering scaffolds, 31 thermoplastic elastomers, articular cartilage biomaterials, 667–668 tissue engineering, 669–670 thickness changes, polypyrrole actuators, electrochemical measurement, 374–376 thiomers, nonbiodegradable nano/microparticles, 180–181 three-dimensional printing architecture control, 73 gastrointestinal tissue engineering, indirect scaffolds, 651 inorganic tissue-engineering scaffolds, 24 rapid-prototyping microfabrication, 105–106 sacrificial molds, 107–108 scaffold tissue fabrication, 54–57 three-dimensional scaffold structures design of, 4–5 rapid-prototyping microfabrication, 96–98 regenerative medicine, 47–49 thrombin/thrombus formation. See also antithrombin blood-biomaterial compatibility coagulation pathways, 510–513 diamond like carbon (DLC) films, 609–610 overview, 535–537 testing, 524–526 titanium-oxide thin films, 614–618 time response polypyrrole actuator films, 373–374 polypyrrole nanowire actuation, 386–387, 389–393 tissue culture plastic (TCP) control, electrospun scaffolds, cartilage tissue engineering, 134 tissue-engineered constructs (TECs) basic properties, 46–48 scaffold design, 50–51


Index tissue engineering articular cartilage biomaterials, 668–670 biopolymers, 473–475 blood-contacting devices, 522 gastrointestinal disease, biomaterials for, 647–653 collagen-based scaffolds, 650–651 fibrous synthetic polymer scaffolds, 647 foam synthetic polymer scaffolds, 647–650 indirect three-dimensional printed scaffolds, 651 neovascularization, 651–653 tissue factors, blood coagulation pathways, 513–514 tissue repairs, layer-by-layer self-assembled thin films, 248 titanium alloys plasma immersion ion implantation and deposition calcium/sodium deposition, 590–595 nickel-titanium surface modification, 595–601 titanium dioxide coatings, 587–590 titanium-oxide thin films, 614–618 titania porous microspheres, silica nanoparticle drug carriers, 223–224 titanium dioxide nanomaterials, biosensor applications, 435 total joint replacement, polyethylene biomaterials, 672–675 topography modification, tissue engineering scaffolds, 33 Torulopsis candida, biosensor applications, 421 total joint replacement, biomaterials for, 670–675 transferrin, targeted drug delivery, 158–160 Trichosporon cutaneum, biosensor applications, 419 triclosan antimicrobial reagent, polymer biomaterials, 622–623 trifluoroacetic acid (TFA), electrospinning techniques, 125 2,2,2-trifluoroethanol (TFE), electrospun scaffolds, 124–125 trimethylene carbonate, biomaterials from, 466–467 tumor-associated antigens (TAAs), targeted drug delivery, 157–158 tumor-specific antigens, targeted drug delivery, 157–158 tumor tissues alphatic polyesters, amphilic block copolymers, 261–263 chemotherapy, nanotechnology, 144 pluronic block copolymer targeting of, 260–261 targeted drug delivery, 156–164 active targeting, 156–157 antibodies, 157–158 drug targeting, 156 folate, 160–161 hyaluronic acid, 161–162 passive targeting, 156 transferrin, 158–159

U ultra high-molecular weight polyethylene (UHMWPE), total joint replacement materials, 670–675 ultrathin coatings, medical implants, 246–248 ultraviolet-laser technology, stereolithography, scaffold tissue fabrication, 53–55 unfractionated heparin (UFH). See also covalent antithrombin/heparin (ATH) antithrombin chemical structure, 538–541 chemical structure, 541–542

1/28/2008 11:41:43 AM

Index covalent antithrombin/heparin and, 545–547 in vitro activity, 548–553 in vivo effects, 553–555 functional biochemistry, 542–544 limitations of, 544–545 thrombin inhibition by, 636–637 unimorph bilayer bender actuator, conducting polymers, 492–496

V vancomycin calcium sulfate nanostructured drug carriers, 225–226 silica nanoparticle drug carriers for, 219–224 vascular endothelial growth factor (VEGF) angiogenesis inhibition, 162 bone tissue engineering, 5 gastrointestinal tissue engineering scaffolds, 652–653 vascular tissue engineering electrospun scaffolds, 134–135 scaffold design, 4–5 targeted drug therapy, 162–163 vesicle structures, biohybrid nanomaterials, fabrication techniques, 336–341 vitamin-functionalized electrode, biohybrid nanomaterials, small bioactive molecules, 344–349 voltage-liquid flow rate, electrospray systems, 278–279 voltage range diamond like carbon (DLC) films, platelet adhesion and, 605–608 polypyrrole electrochemical cycling, 370–372


701 volume of interest (VOI), scaffold architecture monitoring, 81 von Willebrand factor, platelet adhesion and activation, 515–516

W wax printing, scaffold tissue fabrication, 54–55 wet spinning technology, chitosan scaffolds, 79

X xerogels, silica nanoparticle drug carriers, 223–224 x-ray reflectivity measurements, layer-by-layer nanostructure self-assembly, 242–244

Y Young’s modulus electrospun scaffolds, surface properties, 129 plasma immersion ion implantation and deposition, nickel-titanium alloy surface modification, 596–601

Z zeolite particles, magnetic targeting drug delivery systems, 230–231 zinc oxide, one-dimensional nanomaterials, biosensor applications, 434–435 zirconium dioxide microspheres, injectable bulking biomaterials, 641

1/28/2008 11:41:43 AM


1/28/2008 11:41:44 AM

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