An Introduction To Tissue- Biomaterial Interactions pot

geneti-Synthetic materials currently used for biomedical applications include metalsand alloys, polymers, and ceramics.. The main considerations inselecting metals and alloys for biomedi

Copyright ( 2002 John Wiley & Sons, Inc.

ISBNs: 0-471-25394-4 (Hardback); 0-471-27059-8 (Electronic)

An Introduction To

Biomaterial Interactions

Tissue-Kay C Dee, Ph.D.

Tulane UniversityDepartment of Biomedical Engineering

New Orleans, Louisiana

David A Puleo, Ph.D.

University of KentuckyCenter for Biomedical Engineering

Lexington, Kentucky

Rena Bizios, Ph.D.

Rensselaer Polytechnic InstituteDepartment of Biomedical Engineering

Troy, New York

A John Wiley & Sons, Inc., Publication

Copyright 6 2002 by John Wiley & Sons, Inc All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Bizios, Rena.

An introduction to tissue-biomaterial interactions / Rena Bizios, Kay

C Dee, David A Puleo.

To students

—of the past, present and future—

who have shared our fascination with the tissues, cells, and molecules

of the human body

Contents Preface xiii

1.3.1 Basis of Structure-Property Relationships 6

3.9 Study Questions/Discovery Activities 52

4 Blood-Biomaterial Interactions and Coagulation 53

4.2 The Blood Cell Source: Marrow and Stem Cells 53

4.4.2 Platelet Aggregation and the Process of

4.5.2 Control Points 79

4.6 Anticoagulants and Fibrinolysis 80

4.7 Biomaterials, Devices, and Thrombosis 81

5.4.1 Chemotaxis and Cell Migration 94

6.5.1 B Cell Subpopulations and Functions 117

6.6 Generating Specificity 120

6.6.1 Clonal Selection Theory 120

6.6.2 ‘‘Self ’’ Versus ‘‘Non-self ’’? 121

7.3.7 An Example of Wound Healing Tissue: Skin 137

7.6 Complications Related to Wound Healing Around

8.2.1 Contact Angle Analysis 150

8.2.2 X-Ray Photoelectron Spectroscopy (XPS) 1518.2.3 Fourier Transform Infrared (FTIR) Spectroscopy 1538.2.4 Secondary Ion Mass Spectroscopy (SIMS) 1558.2.5 Scanning Electron Microscopy (SEM) 159

8.3 Surface Responses to the Wound Healing Process 1618.3.1 Protein Fouling 161

8.3.2 Degradation and Dissolution 163

Example 2 Replacing Joints and Teeth 191

Answers to Quiz Questions 197

Glossary 205

Index 219

Undergraduate biomedical engineering programs and curricula are being rapidlydeveloped across the United States We perceive a correspondingly increasingneed for biomedical engineering textbooks specifically designed for under-graduate readers Many educators have come to appreciate that physiology andbiology are not narrow, specialized applications to be ‘‘tacked onto’’ an en-gineering curriculum, but are instead rich subjects that can naturally elicit andbenefit from the kinds of creative problem-solving and quantitative analysesthat are hallmarks of engineering However, integrating life sciences within thestructured and rigorous framework of fundamental knowledge required for

an undergraduate engineering degree—especially early in the undergraduatecurriculum, before the senior year or a ‘‘capstone’’ course—is still a challengefor educators

We believe that providing undergraduates with an opportunity to learn medically oriented material early in their academic careers establishes a vividframework of ‘‘vocational relevance’’ (i.e., showing students that the basicscience and engineering skills they are learning are crucially important to bio-medical science) that is often otherwise lacking We also believe that helpingstudents see connections between seemingly disparate course materials—fluidmechanics and cell biology, for example, connected by understanding both howred blood cells flow through capillaries and why altered flow characteristics may

bio-be of clinical importance—can help students develop creative thinking andproblem-solving skills The fields of biomaterials and cell/tissue engineeringpresent excellent opportunities to integrate life sciences and engineering, bycapitalizing on the inherently interdisciplinary interface between cells/tissuesand biomaterials (whether man-made or biologically-derived)

In accordance with the principles and needs described above, we have signed this textbook, which focuses on the wound healing process and inter-actions between the human body and implanted biomaterials or devices Thisbook is short, accessible, and we hope a¤ordable, because it is intended foruse in a one-semester, undergraduate-level course by students who have com-pleted some science/engineering course work (introduction to materials, statics,and perhaps mechanics of materials or a fundamental fluid mechanics course)with minimal chemistry or biology (general chemistry and one semester of cell

de-xiii

biology would be su‰cient) Although this book is particularly appropriate foruse in biomedical engineering curricula, especially those with a focus on cell ortissue engineering, we intended it to be an accessible and useful resource forother programs of study as well (premedical students with little or no engineer-ing background, for example, or first-year engineering graduate students withlittle or no biomedical background) Therefore, skills in advanced mathematicsand computational modeling are not required for use of this text.

This book is not intended to be a comprehensive or advanced reference (otherexcellent reference texts are currently available) This book is instead intended

to be a resource for exploration and discovery by undergraduate students Wewould encourage instructors to supplement the core material presented in thistext—as we ourselves do when we teach—with relevant quantitative analyses/models, current ideas and results from recent peer-reviewed research articles,information from current events and the popular media, and advanced coursework

An Introduction To Tissue-Biomaterial Interactions xiv

We thank our colleagues and students for their support and encouragement andespecially thank the following: Amanda Filanowski (Tulane University) fordrafting the intimal hyperplasia and osseointegration sections of this text; LunaHan and Colette Bean (John Wiley & Sons, Inc.) for constructive suggestions,understanding, and gentle insistence regarding deadlines; Glen A Livesay, Ph.D.(Tulane University) for advice on schematic illustrations and for allowing his

‘‘Bezier Man’’ figure to appear in some of the illustrations; John David LarkinNolen, M.D., Ph.D., MSPH (Emory University) and Joel Bumgardner, Ph.D.(Mississippi State University) for reviews and helpful comments; and Sue, Nick,and Angela Puleo for their patience, support, and love Most importantly, wethank the students of Rensselaer Polytechnic Institute Course 31.4240/BMED-

4240 (and earlier versions under various titles), of Tulane University CourseBMEN 340/740, and of University of Kentucky Course BME 662 for theirpatience and good will as the concepts and material in this book were developedand refined

A portion of the material included in this book is based on work supported by the National Science Foundation under Grant No 9983931 Any opinions, findings and conclusions or rec- ommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation (NSF).

xv

The interactions of tissues and body fluids with biomaterials or medical devices

is an area of crucial importance to all kinds of medical technologies For ample, electrical sensors or drug delivery patches applied externally, on the skin,must be designed to function optimally without causing skin irritation or hy-persensitivity responses Many kinds of reconstructive medical implants (hip re-placements, for example, or dental implants) need to integrate with surroundingtissues to restore adequate function, without releasing harmful chemical prod-ucts or significantly modifying the local electrical and mechanical environment.Pacemaker leads, arterial grafts, and dialysis machines are all further examples

ex-of devices that involve man-made materials interacting with tissues and/or bodyfluids like blood This textbook is intended to help students discover how many

of the macroscopic, tissue-level events (bone resorption or growth, blood ting, fibrous tissue encapsulation, etc.) that often determine the success or failure

clot-of the medical devices listed above are, ultimately, derived from cellular andmolecular level interactions with the tissue-implant interface

A crucial concept to understand about the tissue-biomaterial interface is that

a lot of things happen there! The environment inside the body is chemically,electrically, and mechanically active, and the interface between an implantedbiomaterial and the body is the location of a variety of dynamic biochemicalprocesses and reactions For example, Figure 0.1 shows some of the atomic andmolecular level events that happen when a metallic implant is placed in thebody Oxygen di¤uses from the surface oxide into the bulk metal, and metalions can di¤use from the bulk into the surface oxide as well Biological ions canalso be incorporated into the surface oxide Interactions of biological molecules(proteins, enzymes, etc.) with the implant surface can cause transient or perma-nent changes in the conformation—and thus the function—of these molecules.Chapters 1 through 3 of this book provide more detail about the molecular levelevents that happen at the tissue-implant interface, whereas Chapters 4 through 7explore selected biological and physiological consequences of these events Spe-cifically, because virtually all implantation procedures create wounds (i.e., someform of surgery is required to implant a device), tissue-implant interactions will

be largely influenced by the body’s wound healing response From the first tact of biological molecules with an implant surface to the final tissue remodel-

con-xvii

ing around an implant, understanding the temporal progression of wound ing (Fig 0.2) is a necessary part of understanding tissue-implant interactions.Although the interface between a man-made, synthetic biomaterial and thebody is complex enough (Fig 0.3), tissue-engineered products that incorporateliving cells within a biomaterial matrix make things even more complicated.These tissue-engineered products have three distinct interfaces to consider: be-tween the body and the biomaterial, between the body and the living cells, andbetween the cells and the biomaterial (Fig 0.4) Each interface presents uniqueopportunities and potential problems related to the long-term viability of thetissue-engineered product Researchers have been working on understandingand controlling events at these interfaces for years; some of the ‘‘classic’’ studiespublished ten or twenty years ago are still fresh and very relevant to current re-search e¤orts As more is learned about the clinically desirable and undesirableevents that can occur at the tissue-biomaterial interface, new ideas are sparkedabout designing biomaterial surfaces to control subsequent cell and tissue func-tions and making novel biomaterials or cell/biomaterial constructs that trulyintegrate with the body’s natural tissues (Chapters 8, 9, and 10 of this text).Controlling cell-biomaterial interactions is an important goal for the devel-opment of tissue-engineered products However, influencing even the most fun-damental cellular functions (such as adhesion or migration) requires an ability

heal-to link and utilize concepts from a variety of scientific/engineering and ical disciplines The main purpose of this textbook is, therefore, to provide a

biomed-Figure 0.1 Molecular level events at the surface of a metal implant On a macroscopic level, the surface of a metal implant may appear to be smooth, uniform, and inert On the microscopic level, such a surface probably varies in chemical composition and topology and is the location of

a number of dynamic molecule-surface interactions A number of these molecule-surface actions can have far-reaching physiological e¤ects (initiating the process of coagulation, for example) that are relevant to the wound healing process and to the long-term viability of the implant.

inter-An Introduction To Tissue-Biomaterial Interactions xviii

fundamental, physiology-oriented, and interdisciplinary overview of key cepts in tissue-biomaterial interactions, with the hope of motivating the nextgeneration of scientists and engineers to extend this rapidly growing field of re-search.

con-Figure 0.2 Fundamental stages of the wound healing process This textbook outlines mechanisms

by which the wound healing process is initiated by injury and by the presence of synthetic materials, and discusses why these stages are linked in a natural progression This book also notes some of the major problems that can arise during the wound healing process and how these problems can a¤ect the utility of an implanted material or device.

bio-Figure 0.3 The interface between a biomaterial and the body In this figure, a hip implant is used

as an example Whereas the bulk biomaterial is metallic (titanium, for example) the surface of the implant is probably comprised of a oxide layer (e.g., titanium oxide) The interface between this surface oxide and the biological environment is the location for ions, proteins, enzymes, and other biomolecules to interact with the biomaterial, as well as the location where stages of the body’s wound healing processes (Fig 0.2) will occur.

An Introduction To Tissue-Biomaterial Interactions xx

American Association for Accreditation of

Laboratory Animal Care, 177

American Association for Laboratory Animal

Science, 177

American Society for Testing and Materials

(ASTM), 175, 177

Amino acid groups, 15–16

Amino acid hydrophilicity, 37

Amino acids, 15–19, 205 See also Derived amino acids

abbreviations for, 18 polymerization of, 16 Amphipathic proteins, 43 Anaphylactic shock, 205 Anastomoses, 188, 205 Anastomotic sites, 83 Anergic cells, 122, 205 Angiogenesis, 134–135, 205 Animal models, 176–180 Animal tests, classification of, 178 Animal Welfare Act of 1985, 177 Antibiotics, 104–105

Antibodies, 112, 118, 205 Antibody-antigen binding, 112, 118 Antibody screening tests, 123 Anticoagulants, 80–81, 82 systemic, 84

Antigenic determinant, 112, 206 Antigen-presenting cells, 116–117, 206 Antigens, 111–112, 206

Antithrombin III, 81, 206 Apoptosis, 121–122, 187, 206 See also Cell death

Arachidonic acid cascade, 68, 74, 206 Arginine-glycine-aspartic acid (Arg-Gly-Asp, RGD) peptide, 67, 131–132 See also RGD-containing peptide

Arginine-glycine-aspartic acid sequence, 32,

169, 193, 206, 216 Arterial grafts, 188 Arteriosclerosis, 185 Artery wall, cross section, 67 ASTM See American Society for Testing and Materials (ASTM)

Atherosclerosis, 185 Atomic force microscopy (AFM), 160–161,

205 See also AFM images

219

An Introduction to Tissue-Biomaterial Interactions Kay C Dee, David A Puleo, Rena Bizios.

Copyright ( 2002 John Wiley & Sons, Inc.

ISBNs: 0-471-25394-4 (Hardback); 0-471-27059-8 (Electronic)

Atomic level structure, 3

B cells, 118, 120, 206 See also Memory B cells

humoral immunity and, 118

methods for testing and evaluating, 175–181

tests prerequisite to evaluation of, 174–175

cell-tissue interactions with, 3–4

ceramic and glass, 6–7

Biomaterials Science: An Introduction to

Materials in Medicine (Didisheim and

Watson), 82

Biomaterial surface engineering, 166–171

Biomaterial surfaces

central role of, 124

physiological environment and, 149–172

Blood, 46 constituents of, 54 viscosity of, 61 whole, 60–61 Blood-biomaterial compatibility, 82–83 Blood-biomaterial interactions, 53–88 Blood cells

formation of, 53–54 source of, 53–55 trauma to, 84 Blood clots, 81, 128 See also Clot formation formation of, 68

Blood clotting, 32, 74 adsorption of proteins in, 50 interstitial, 103

Blood clotting factors, 80 See also Clotting factors

Blood coagulation, 73–80 See also Blood clots; Coagulation

Blood compatibility tests, 175 Blood-contact applications, biomaterials for, 76–77

Blood-derived cells, 55 Blood flow, 80 Bloodletting, 90 Blood oxygenators, 83–84 Blood-surface interactions, 49–50 Blood vessels

damage, injury, or trauma to, 68, 73–79, 128–129

occluded, 185–190

B lymphocytes, 110, 111, 207 See also B cells

Body fluids, 45–46 interaction with biomaterials or medical devices, xvii

Bone growth factors, 193 Bone marrow, 53–55 rat, 55

Bone matrix, 127 Bone resorption, 5 Bradykinin, 93 Bubble oxygenators, 84 Bulk solution concentration, altered conformation and, 45

Bypass surgery, 84, 186

Index 220

Calcification, 165–166

Calcium ions, 32

coagulation and, 79

Calcium phosphate ceramic coatings, 169

Calcium phosphate ceramics, 164–165

Cell adhesion, integrin-mediated, 131

Cell-biomaterial interactions, xviii

Cell-cell adhesion, 131

Cell culture techniques, 176

Cell death, 128 See also Apoptosis

Cells, regenerative capacity of, 128

Cellular functions, influencing, xviii

Cellular in vitro models, 176

Chemical bonds, 4 See also CaN bond;

Covalent bonds; Covalent disulfide

bonds; Disulfide bond; Hydrogen

bonding; Ionic bond; Metallic bonding;

Peptide bond

‘‘Chemical environment,’’ of blood-contacting

device, 85

Chemical events, intracellular, 132

Chemical surface properties, 40–41

Clonal selection theory, 120–121, 122

Clot formation, 73, 82 See also Blood clots

Clotting factors, 74, 80

Cluster of di¤erentiation (CD), 114, 207 See also CD3 proteins

CaN bond, 20 Coagulation, 53, 68–73, 128, 207 See also Blood coagulation

control points for, 79–80 explanations for the cardinal signs of, 102– 103

Coagulation cascades, 73–80 chart of, 78

Coatings, porous, 166–167 Cobalt-chromium-molybdenum alloys, 2, 5 Codons, 15, 207

Collagen, 207 structure of, 27, 29 Collagen fibrils, 28 Collagen helices, 28 Collagen protein family, 26–29 Common pathway, 76, 207 Complement cascade, 142 Complement system, 102, 118–120, 207 Compliance mismatch, 188

Conformation, 207

of proteins, 25–26 Conformational changes, 45, 47 Contact angle analysis, 150–151 Contact guidance, 167, 193 Contractile proteins, 67 Controlled degradation, 9 Corrosion, 4, 163, 207 Covalent bonds, 208 See also Chemical bonds Covalent disulfide bonds, 22

Cross-linking, 9

in elastin, 30–31 intra- and intermolecular, 29 Cross-matching tests, 123 Cyclooxygenase, 68–69 Cytokines, 129, 208 Cytotoxic T cells, 115–116, 208

Dacron, 83 Dalton (Da), 208

‘‘Dead space,’’ 105 Deep immediate infection, 104 Deep late infection, 104 Degradation, 163–165

of ceramics and glasses, 6–7

of polymers, 9 Degranulation, 68

of platelets, 208 Delivery agents, 2

Demarcation membranes, 65, 208

Denaturation, 208

Dental implants, 7 See also Teeth

Derived amino acids, 16, 18

Drug delivery patches, xvii

Drug delivery systems, 8

Dynamic loading conditions, 10

Dynamic SIMS, 156 See also Secondary ion

mass spectroscopy (SIMS)

ECM See Extracellular matrix (ECM)

EDTA (ethylenediaminetetraacetic acid),

Erythrocyte shape, changes in, 62 Erythropoietin, role of, 58–59 ESCA See Electron spectroscopy for chemical analysis (ESCA)

Expanded polytetrafluoroethylene (ePTFE), 185

Extracellular matrix (ECM), 209 formation of, 133–134 Extrinsic coagulation pathway, 73, 74–75, 209

Ex vivo tests, 178

Factor X, 80 Factor XII, 50, 76–77, 102 Factor XIII, 72

Fatigue strength, 209 FDA See Food and Drug Administration (FDA)

FDA/ISO test matrix, 179 Fetal wound healing, 145 Fibrin, 68, 81

Fibrin degradation products, 96 Fibrin monomers, 70

Fibrinogen, 32–34, 50, 70, 72 structure of, 34

Fibrinolysis, 80–81, 209 Fibrinolytic agents, 81 Fibrin threads, 75 Fibroblast cells, 99, 128 Fibronectin, 31–32, 133 adsorbing to a biomaterial, 43–44 modular architecture of, 32 structure of, 33

Fibrous encapsulation, 141–142, 144 Fluid, shear deformation in, 60 Focal adhesion point, 133 Focal adhesions, 132, 209 Food and Drug Administration (FDA), 173,

180 See also FDA/ISO test matrix Foreign-body carcinogenesis/tumorigenesis,

144, 209 Foreign body giant cells, 94, 138, 209 evolution of, 95

Foreign body reaction, 141, 142, 209 Fourier transform infrared (FTIR) spectroscopy, 153–155, 210 FTIR spectra, 157, 164

Index 222

Human blood, percentages of leukocytes in,

93 See also Blood entries

Human leukocyte antigen (HLA), 123, 210

Human platelets, micrograph of, 65–66 Humoral immunity, 110, 117–120, 210 Hydrogen bonding, 22, 27, 42, 211 Hydrolysis, 164, 211

Hydrophilic biomaterials, 82 Hydrophobic amino acids, 30 Hydrophobic interactions, 22–25 Hydrophobic surfaces, 41 Hydroxyapatite, 7 Hydroxyproline assays, 27 Hyperplasia, 128, 211 Hypersensitivity, 211 responses, 144 Hypertonic solution, 62 Hypertrophy, 128, 211 Hypotonic solution, 63 Hypoxia, 63, 211

IACUC See Institutional Animal Care and Use Committee (IACUC)

IgG See Immunoglobulin G (IgG) Immune reactions, 144

Immune system, 97 inflammation and, 109–126 Immunity

cell-mediated, 114–117 humoral, 117–120 kinds of, 109 Immunogen, 211 Immunogenicity, degree of, 112 Immunogens, 111

Immunoglobulin classes, 113 Immunoglobulin G (IgG), 49–50 molecule, 112, 114

Immunoglobulins (Igs), 111–112, 211 Immunosuppressive drugs, 123 Implantation

in animals, 178–180 infection and, 104 Implant devices, 11, 82, 138 Implant failure, 181 Implants

biomedical metals used for, 5 ceramics and glasses in, 6 load-bearing, 7

mechanical properties of, 5 porous coatings on, 166–167 wound healing around, 138–142, 142–144

Infection, 89–106, 211

types of, 104

Inflammation, 89–106, 128–129, 211

cardinal signs of, 90

chemical products of, 101

chronic, 142

immune system and, 109–126

leukocyte functions and, 94–102

Inflammatory response

acute, 139

implant size and, 140

Inhomogeneous biomaterial surfaces, 41

International Organization for

Standardization (ISO), 175 See also

FDA/ISO test matrix

inflammatory, 129, 143 movement of, 101 nonlymphatic, 90–94 Lumen, 185, 212 Lymphatic leukocytes, 212 Lymphocytes, 55, 110–111, 212 di¤erentiation between ‘‘self ’’ and ‘‘non- self,’’ 121–123

production of, 121 Lymphocyte surface receptors, 120 Lymphoid stem cells, 55, 212 Lymphokines, 97, 102, 115, 124, 212 Lysis, 63, 212

Lysozyme, 24

MAC See Membrane attack complex (MAC) Macromolecule grafting, 168

Macrophages, 58, 94, 99, 100, 116, 129, 138, 212

wound healing and, 136–137 Major histocompatibility complex (MHC),

123, 212, 210 proteins, 116 Mammalian cell models, in vitro, 176 Margination, 101, 212

Marrow, 53–55 Mass transport, 49–50 Mast cells, 92–93 Material plasticity, 8 Materials

biological versus synthetic, 173–174 chemical properties of, 3

choice of, 10–11 durability of, 10

in vitro characterization of, 174–175 wettability of, 150

Material strength, 10 Matrix formation, extracellular, 133–134 Matrix metalloproteinases (MMPs), 131, 213

‘‘Mechanical environment,’’ of contacting device, 85

blood-Mechanical properties, 4–6

of ceramics and glasses, 7

of polymers, 9–10 Media, 186

Medical Device Amendment to the U.S Food and Drug Act of 1976, 173

Medical devices, 1 Medical implants, xvii

Index 224

Megakaryoblasts, 64

Megakaryocytes, 64–65

Membrane attack complex (MAC), 119, 213

Membrane oxygenators, 84

Memory B cells, 118, 213 See also B cells

Memory T cells, 116, 213 See also T cells; T

Molecular biology, advances in, 145

Molecular spreading, time-dependent, 45, 46

Molecule transport mechanisms, 41

Multipotent stem cells, 54

Myeloid stem cells, 55, 213

Myofibroblasts, 135

National Institutes of Health (NIH), 175, 177

National Institutes of Health Consensus

NIH See National Institutes of Health (NIH)

NK cells See Natural killer (NK) cells

Noncollagenous adhesive proteins, 31

Nonfunctional tests, 178 Nonhealing wounds, 137–138 Nonlymphatic leukocytes, 90–94, 214 Non-Newtonian fluid, 61

Nonpolar amino acids, 17 Nonpolar molecules, 214 Nonsteroidal anti-inflammatory drugs (NSAIDs), 214

Opsonins, serum-derived, 138 Opsonization, 97, 214 Organ transplant, 123 Orthochromatic erythroblast stage, 56 Orthopedic/dental applications, 176 Orthopedics, 169

Osmolarity, 62–63, 214 Osseointegration, 191–193, 214 Osteoblasts, 159, 214

Osteoclasts, 214 Osteogenesis, 193 Oxidation, 214 Oxide surface film, 4

Paracrine manner, 129 Paracrine substance, 214 Parenchymal tissue, 214 Passivated surfaces, 4 Passivation, 214 Pathogens, 92, 111, 214 Peptide bond, 19, 214 Peptides, 67, 169, 214 Percent elongation, 214 Phagocyte, 214 Phagocytosis, 94, 97–100, 214 frustrated, 138

process of, 98 Phagosomes, 97–99, 215 Pharmaceuticals, controlled delivery of, 2 Phenotype, 215

Phosphorylcholine, 170, 171 PHSCs See Pluripotent hematopoietic stem cells (PHSCs)

Physicochemical surface modifications, 167– 169

Physiological environment, biomaterial surfaces and, 149–172

Plaque formation, 187 Plasma, 53, 59, 215 Plasma cells, 118, 215 Plasma proteins, 32–33, 49 exchange hierarchy of, 50 Plasma treatment, 168

Polar amino acids, 17

Polyetherurethane, surface cracking of, 165

Polyurethane, calcification of, 166

Positively charged amino acids, 17

tertiary structure of, 22–25, 216 unfolding of, 39–40

Protein size, e¤ect on interaction with a surface, 39

Protein structure, levels of, 20 Protein-surface interactions, 37–52 See also Tissue-implant interactions

Proteoglycan, 215 Proteolytic enzymes, 76, 136 Prothrombin, 70, 80 Prothrombin activator, 76 Pseudointima, 185 Pseudopodia, 68, 215 Pus, 103–104 Pyrogens, 102, 215

‘‘Quarter-stagger’’ array, 28 Quaternary structure, 25, 215

Rat bone marrow, 55 Red blood cells, 55–64 See also Blood; Erythrocytes

Red marrow, 53 Regulations, international, 180 Regulatory-agency approval, 173 Residue, 215

Resorption, 215 Reticulocytes, 57 lineage of, 56 production of, 58 Review boards, 180 RGD See Arginine-glycine-aspartic acid (Arg-Gly-Asp, RGD) sequence RGD-containing peptide, 170 Rouleaux, 61–62, 216

Safe Medical Devices Act of 1990, 173 Saphenous vein grafts, 188

Scanning electron microscopy (SEM), 159–

160, 216 Scar tissue, 136 Secondary ion mass spectroscopy (SIMS), 155–159, 216 See also SIMS spectra; Static SIMS

Secondary structure, 19–22, 216

Index 226

‘‘Self-knowledge,’’ 109–110

‘‘Self-recognition,’’ 116

‘‘Self ’’ versus ‘‘non-self,’’ 121–123

SEM See Scanning electron microscopy

Skin, 128 See also Wound healing

wound healing in, 137, 145

Synthetic vascular grafts, 83

T cells, 120, 216 See also Memory T cells T-cell subpopulations, 114–116

Teeth, replacing, 191–196 Tertiary structure, 22–25, 216 Testing laboratories, commercial, 173 Thermal behavior, of polymers, 8 Thrombi (thrombus), 216 formation of, 82 Thrombin, 70, 72, 75, 79 Thromboembolism, 216 Thymus, rat, 110 Thymus tissue, rat, 111 Time-dependent molecular spreading, 45, 46 Tissue-biomaterial interface, xvii, xviii Tissue-engineered products, xviii interface with the body, xx Tissue heart valves, 84–85 Tissue-implant interactions, xvii, 192–193 See also Protein-surface interactions

Tissue injury, 127–128 Tissue macrophages, 94, 100 Tissue plasminogen activator, 81, 96 Tissue repair, 53

mechanisms, 127 Tissues

interaction with biomaterials or medical devices, xvii

trauma to, 79 Tissue thromboplastin, 74–76 Tissue typing, 123, 217 Titanium alloys, 2, 5 Titanium (Ti)-based metals, 5

T lymphocytes, 110, 111, 217 See also T cells Totipotent cells, 217

Totipotent stem cells, 54 Triple helix, 27

Trypsin, 25, 27 Type I collagen, 27

Ultimate compressive strength, 217 Ultimate tensile strength, 217

Vascular grafts, 83, 185–190 Vascularized connective tissue, wound healing

of, 128–137 Vascular spasm, 73–74, 77, 217 Vasoconstrictors, 74

Vasodilation, 77 Venous graft structure, remodeling of, 188 Viral infections, 116

‘‘Virgin’’ lymphocytes, 121

‘‘Vocational relevance,’’ xiii

von Willebrand factor, 67–68

Vroman e¤ect, 47

Wear debris, 142–144, 217

Whole biomolecules, in biological surface

modification, 169–170

Whole blood, 60–61 See also Blood entries

Wound care products, 145

Wound contraction, 135

Wound healing, 53, 127–147 See also

Nonhealing wounds; Wound healing

around implants

extracellular matrix components and, 134

inflammation phase of, 76

remodeling phase of, 135–136

response, xvii–xviii

stages of, xix

surface responses to, 161–166

timing aspects of, 136–137

of vascularized connective tissue, 128–737

Wound healing around implants, 138–142 complications related to, 142–144 Wound healing outcome, factors a¤ecting, 137

Wounds, infection in, 103–105

Xenografts, 84, 217 XPS See X-ray photoelectron spectroscopy (XPS)

XPS spectrum, 153 X-ray analysis, energy- or wavelength- dispersive, 160

X-ray photoelectron spectroscopy (XPS), 151–

153, 217 See also XPS spectrum

Young’s modulus, 217

Zisman analysis, 150 Zisman plot, 151 Zwitterions, 15

Index 228

Biomaterials 1.1 INTRODUCTION

In the past, there was no targeted development of biomaterials based on

scien-tific criteria Instead, devices consisting of materials that had been designed,

synthesized, and fabricated for various industrial needs (for example, the textile,

aerospace, and defense industries) were tested in a trial-and-error fashion in the

bodies of animals and humans These unplanned and sporadic attempts had (at

best) modest success Most frequently, the results were unpredictable, mixed,

and confounding both in success and in failure

Because of the continuous and ever-expanding practical needs of medicine

and health care practice, there are currently thousands of medical devices,

diag-nostic products, and disposables on the market Estimated annual sales of such

products in the United States alone are in the order of one hundred billion

dol-lars In fact, the range of applications continues to grow In addition to

tradi-tional medical devices, diagnostic products, pharmaceutical preparations, and

health care disposables, now the list of biomaterial applications includes smart

delivery systems for drugs, tissue cultures, engineered tissues, and hybrid organs

To date, tens of millions of people have received medical implants

Undoubtedly, biomaterials have had a major impact on the practice of

con-temporary medicine and patient care in both saving, and improving the quality

of lives of humans and animals Modern biomaterial practice still takes

advan-tage of developments in the traditional, nonmedical materials field but is also

(actually, more so than ever) aware of, and concerned about, the biocompatibility

and biofunctionality of implants

1.1.1 Definition

Biomaterials is a term used to indicate materials that constitute parts of

medi-cal implants, extracorporeal devices, and disposables that have been utilized in

medicine, surgery, dentistry, and veterinary medicine as well as in every aspect

of patient health care The National Institutes of Health Consensus

Develop-1

An Introduction to Tissue-Biomaterial Interactions Kay C Dee, David A Puleo, Rena Bizios.

Copyright ( 2002 John Wiley & Sons, Inc.

ISBNs: 0-471-25394-4 (Hardback); 0-471-27059-8 (Electronic)

ment Conference defined a biomaterial as ‘‘any substance (other than a drug) orcombination of substances, synthetic or natural in origin, which can be used forany period of time, as a whole or as a part of a system which treats, augments,

or replaces any tissue, organ, or function of the body’’ (Boretos and Eden,1984) The common denominator in all the definitions that have been proposedfor ‘‘biomaterials’’ is the undisputed recognition that biomaterials are distinctfrom other classes of materials because of the special biocompatibility criteriathey must meet The biocompatibility aspects of biomaterials are addressed inChapter 9

Admittedly, any current definition of biomaterials is neither perfect nor plete but has provided an excellent reference or starting point for discussion Itwas inevitable that such a definition would need updating to reflect both the evo-lution of, and revolution in, the dynamic biomedical field For example, there is

com-an increased emphasis on developing nontraditional clinical methodologies,such as preventing and curing major genetic diseases These trends in medicinepresent unique challenges for the biomaterials field Applications such as con-trolled delivery of pharmaceuticals (drugs and vaccines), virally and nonvirallymediated delivery agents for gene therapy, and engineered functional tissuesrequire vision, nontraditional thinking, and novel design approaches Most im-portantly, to meet the present and future biomaterials challenges successfully,

we need materials scientists and engineers who are familiar with and sensitive

to cellular, biochemical, molecular, and genetic issues and who work e¤ectively

in teams of professionals who include molecular biologists, biochemists, cists, physicians, and surgeons

geneti-Synthetic materials currently used for biomedical applications include metalsand alloys, polymers, and ceramics Because the structures of these materialsdiffer, they have di¤erent properties and, therefore, di¤erent uses in the body.These three classes of materials are reviewed in the remainder of this chapter

1.2 METALLIC BIOMATERIALS

Metals have been used almost exclusively for load-bearing implants, such as hipand knee prostheses and fracture fixation wires, pins, screws, and plates Metalshave also been used as parts of artificial heart valves, as vascular stents, and aspacemaker leads Although pure metals are sometimes used, alloys (metals con-taining two or more elements) frequently provide improvement in material prop-erties, such as strength and corrosion resistance Three material groups dominatebiomedical metals: 316L stainless steel, cobalt-chromium-molybdenum alloy,and pure titanium and titanium alloys (Table 1.1) The main considerations inselecting metals and alloys for biomedical applications are biocompatibility, ap-propriate mechanical properties, corrosion resistance, and reasonable cost

An Introduction To Tissue-Biomaterial Interactions 2

1.2.1 Basis of Structure-Property Relationships

The properties of materials are governed by their structure At the atomic level,metals consist of positively charged ion cores immersed in a ‘‘cloud’’ of looselybound electrons This atomic level structure is responsible for the characteristicand distinct properties of metals Metallic bonding allows the atoms to organizethemselves into an ordered, repeating, three-dimensional crystalline pattern,which can be visualized as the packing of hard spheres into cubic or hexagonalarrangements The delocalized electrons are responsible for the electrical andthermal conductivity of metals Because the interatomic bonds are not spatiallydirected in metals, planes of atoms can ‘‘slip’’ over one another to allow plastic(permanent) deformation

The chemical properties of materials also are related to the nature of theiratomic bonding The more resistant the constituent atoms/ions are to being sep-arated, the more inert the material will be In metals, the loose, nondirectionalway in which the electrons are bonded allows the atoms/ions to be parted moreeasily Consequently, although their mechanical properties make metals the ap-propriate choice for many biomedical applications, susceptibility to chemicaldegradation is an aspect that must be considered

Because the interactions between cells and tissues with biomaterials at thetissue implant interface are almost exclusively surface phenomena, surface prop-erties of implant materials are of great importance A surface is the termination

TABLE 1.1 Surgical Implant Alloy Compositions (wt %)

Element

316L Stainless Steel

(ASTM F138,139)

CoaCraMo (ASTM F799)

Grade 4 Ti (ASTM F67)

Ti-6Al-4V (ASTM F136)

of the normal three-dimensional structure of a material Lack of near neighboratoms on one side of the surface alters the electronic structure and consequentlythe way these atoms interact with other atoms Chemical bonds will ‘‘dangle’’into the space outside the solid material and will result in the surface atomshaving higher energy than do atoms in the bulk As a result, surface atoms willattempt to reduce free energy by rearranging and/or bonding to any availablereactive molecules to reach a more favorable energy state.

1.2.2 Corrosion

The physiological environment is typically modeled as a 37C aqueous solution,

at pH 7.3, with dissolved gases (such as oxygen), electrolytes, cells, and proteins.Immersion of metals in this environment can lead to corrosion, which is deteri-oration and removal of the metal by chemical reactions During the electro-chemical process of corrosion, metallic biomaterials can release ions, which mayreduce the biocompatibility of materials and jeopardize the fate of implants Forexample, the type and concentration of released corrosion products can alter thefunctions of cells in the vicinity of implants as well as of cells at remote loca-tions after transport of the corrosion by-products to distant sites inside the body.These circumstances become stronger possibilities in the bodies of sick andelderly patients, who are the largest group of recipients of prostheses

Even before implantation, through chemical reaction of metals with the gen in ambient air or by oxidation in an acidic solution, an oxide surface filmforms on their surface Because oxides are ceramics (see Section 1.3), which areelectrical and thermal insulators, the electrochemical reactions that lead to cor-rosion are reduced or prevented In other words, the oxidized metallic surfacesare ‘‘passivated.’’ In fact, the stability of the oxides present on di¤erent metalsdetermines their overall corrosion resistance For example, even though 316Lstainless steel implants perform satisfactorily in short-term applications, such asfracture fixation, they are susceptible to crevice corrosion and pitting when im-planted for longer periods Titanium and its alloys, as well as cobalt-chromiumalloys, have more favorable corrosion resistance for long-term implant applica-tions such as joint and dental prostheses

oxy-1.2.3 Mechanical Properties

The mechanical properties of materials are of great importance when designingload-bearing orthopedic and dental implants Some mechanical properties ofmetallic biomaterials are listed in Table 1.2 With a few exceptions, the hightensile and fatigue strength of metals, compared with ceramics and polymers,make them the materials of choice for implants that carry mechanical loads

It should be noted that, in contrast to the nanophase, composite nature of

An Introduction To Tissue-Biomaterial Interactions 4

tissue such as bone, the biomedical metals used for implants are conventional,homogeneous materials The elastic moduli of the metals listed in Table 1.2are at least seven times greater than that of natural bone This mismatch ofmechanical properties can cause ‘‘stress shielding,’’ a condition characterized bybone resorption (loss of bone) in the vicinity of implants This clinical compli-cation arises because preferential distribution of mechanical loading through themetallic prosthesis deprives bone of the mechanical stimulation needed to main-tain homeostasis.

The mechanical properties of a specific implant depend not only on the type

of metal but also on the processes used to fabricate the material and device.Thermal and mechanical processing conditions can change the microstructure

of materials For example, in ‘‘cold-working’’ a metal, such as by rolling orforging, the resulting deformation makes the material stronger and harder Un-fortunately, as the metal becomes harder and stronger it also becomes less duc-tile (undergoes less deformation before failure) and more chemically reactive.Compared with the elastic moduli of either stainless steel or cobalt-chromiummolybaenum alloys, Ti and Ti-6Al-4V have much lower (approximately half )moduli that are still almost an order of magnitude higher than that of bone.Another advantage of Ti-based metals as a bone implant material is theirfavorable strength-to-density ratio Stainless steel and CoaCr alloys have den-sities of approximately 8.8 g/cm3 and 7.8 g/cm3, respectively Because Ti has adensity of only 4.5 g/cm3, its strength-to-density ratio is larger Disadvantages

of titanium for medical use include a relatively low shear strength, poor wearresistance, and di‰culties in fabrication The stable, coherent titanium oxide(TiO2) film that forms on titanium and its alloys gives them superior corrosionresistance compared with stainless steel and CoaCr alloys The oxidized surface

is also believed to be responsible for Ti implants becoming osseointegrated invivo, a process whereby bone is aposed to the implant without chronic inflam-mation and without an intervening fibrous capsule

TABLE 1.2 Select Properties of Metallic Biomaterials*

Material

Young’s Modulus, E (GPa)

1.3 CERAMIC AND GLASS BIOMATERIALS

Ceramics and glasses are used as components of hip implants, dental implants,middle ear implants, and heart valves Overall, however, these biomaterials havebeen used less extensively than either metals or polymers Some ceramics thathave been used for biomedical applications are listed in Table 1.3

1.3.1 Basis of Structure-Property Relationships

Ceramics are materials composed of metallic and nonmetallic elements heldtogether by ionic and/or covalent bonds As with metals, the interatomic bonds

in ceramics result in long-range three-dimensional crystalline structures; glasses

do not have long-range order In contrast to metallic bonding, the electrons inionic and covalent bonds are localized between the constituent ions/atoms Con-sequently, ceramics are typically electrical and thermal insulators The strongionic and covalent bonds also make ceramics hard and brittle, because the planes

of atoms/ions cannot slip past one another Ceramics and glasses typically failwith little, if any, plastic deformation, and they are sensitive to the presence ofcracks or other defects The ionic and/or covalent nature of ceramics also influ-ences their chemical behavior

1.3.2 Degradation

Although they do not undergo corrosion, ceramics and glasses are susceptible toother forms of degradation when exposed to the physiological environment The

TABLE 1.3 Ceramics Used in Biomedical Applications

Pyrolytic carbon

Definitions:

Bioinert refers to a material that retains its structure in the body after implantation and does not

induce any immunologic host reactions.

Bioactive refers to materials that form bonds with living tissue.

Biodegradable refers to materials that degrade (by hydrolytic breakdown) in the body while they are being

replaced by regenerating natural tissue; the chemical by-products of the degrading materials are absorbed and released via metabolic processes of the body.

An Introduction To Tissue-Biomaterial Interactions 6

mechanism and rate of degradation, however, depend on the particular type ofceramic Even alumina, which is generally considered a bioinert ceramic, expe-riences a time-dependent decrease in strength during immersion in saline in vitroand after implantation This process may result from a preferential dissolution

of impurities that results in crack propagation Bioactive ceramics and glassesare also degraded in the body Not only can they undergo slow or rapid disso-lution (depending on the composition and processing history of the material),but because of the similarity of calcium phosphates to the mineral component ofbone, they may also be resorbed by osteoclasts (the cells that break down bone)

1.3.3 Mechanical Properties

The major drawbacks to the use of ceramics and glasses as implants are theirbrittleness and poor tensile properties (Table 1.4) Although they can have out-standing strength when loaded in compression, ceramics and glasses fail at lowstress when loaded in tension or bending Among biomedical ceramics, aluminahas the highest mechanical properties, but its tensile properties are still belowthose of metallic biomaterials Additional advantageous properties of aluminaare its low coe‰cient of friction and wear rate Because of these properties,alumina has been used as a bearing surface in joint replacements

The mechanical properties of calcium phosphates and bioactive glasses makethem unsuitable as load-bearing implants Clinically, hydroxyapatite has beenused as a filler for bone defects and as an implant in load-free anatomic sites(for example, nasal septal bone and middle ear) In addition, hydroxyapatite hasbeen used as a coating on metallic orthopedic and dental implants to promotetheir fixation in bone In these cases, the underlying metal carries the load,whereas the surrounding bone strongly bonds to hydroxyapatite Delamination

of the ceramic layer from the metal surface, however, can create serious lems and lead to implant failure

prob-TABLE 1.4 Mechanical Properties of Ceramic Biomaterials*

Young’s Modulus,

E (GPa)

Compressive Strength,

Tensile Strength,

1.4 POLYMERIC BIOMATERIALS

Polymers are the most widely used materials in biomedical applications Theyare the materials of choice for cardiovascular devices as well as for replacementand augmentation of various soft tissues Polymers also are used in drug deliverysystems, in diagnostic aids, and as a sca¤olding material for tissue engineeringapplications Examples of current applications include vascular grafts, heartvalves, artificial hearts, breast implants, contact lenses, intraocular lenses, com-ponents of extracorporeal oxygenators, dialyzers and plasmapheresis units, coat-ings for pharmaceutical tablets and capsules, sutures, adhesives, and blood sub-stitutes Examples of polymers and their uses are given in Table 1.5

1.4.1 Basis of Structure-Property Relationships

Polymers are organic materials consisting of large macromolecules composed ofmany repeating units (called ‘‘mers’’) These long molecules are covalentlybonded chains of atoms Unless they are cross-linked, the macromolecules in-teract with one another by weak secondary bonds (hydrogen and van der Waalsbonds) and by entanglement Because of the covalent nature of interatomic bond-ing within the molecules, the electrons are localized, and consequently polymerstend to be poor thermal and electric conductors

The mechanical and thermal behavior of polymers is influenced by severalfactors, including the composition of the backbone and side groups, the struc-ture of the chains, and the molecular weight of the molecules Plastic deforma-tion occurs when the applied mechanical forces cause the macromolecularchains to slide past one another Changes in polymer composition or structurethat increase resistance to relative movement of the chains increase the strengthand decrease the plasticity of the material Substitutions into the backbonethat increase its rigidity hinder movement of the chains Bulky side groupsalso make disentanglement more di‰cult Increasing macromolecule length(molecular weight) also makes the chains less mobile and hinders their relativemovement

TABLE 1.5 Examples of Biomedical Applications of Polymers

poly(ethylene terephthalate); polytetrafluoroethylene

An Introduction To Tissue-Biomaterial Interactions 8

1.4.2 Degradation

Degradation of polymers requires disruption of their macromolecular structureand can occur by either alteration of the covalent interatomic bonds in thechains or alteration of the intermolecular interactions between chains Theformer can occur by chain scission (cleavage of chains) or cross-linking ( joiningtogether of adjacent chains), an unlikely occurrence under physiological con-ditions The latter can occur by incorporation (absorption) or loss (leaching)

of low-molecular-weight compounds As described in Chapter 8, Section 8.2,chemical reactions, such as oxidation and hydrolysis, can also change the prop-erties of implanted polymers For polymers, the method of sterilizing the bio-material can significantly alter its properties For example, high temperatures(121–180C), steam, chemicals (ethylene oxide), and radiation can compromisethe shape and/or mechanical properties of polymeric materials

Polymers may contain various (often unspecified) additives, traces of lysts, inhibitors, and other chemical compounds needed for their synthesis.Over time in the physiological environment, these compounds can leach fromthe polymer surface As is the case with corrosion by-products released frommetallic implants, the chemicals released from polymers may induce adverselocal and systemic host reactions that cause clinical complications This release

cata-is a concern for materials, such as bone cement, that are polymerized in thebody and for flexible polymers, such as poly(vinyl chloride), that contain low-molecular-weight species (plasticizers) to make them pliable

In addition to unintentional degradation, certain polymers have been designed

to undergo controlled degradation Among biodegradable polymers, poly(lacticacid), poly(glycolic acid), and their copolymers have been the most widely used.These materials degrade into smaller fragments as well as monomers, such aslactic acid, that can be eliminated by normal metabolic processes of the body.Biodegradable polymers are used for sutures, controlled drug delivery, tissueengineering, and fracture fixation

1.4.3 Mechanical Properties

The mechanical properties of polymers depend on several factors, including thecomposition and structure of the macromolecular chains and their molecularweight Table 1.6 lists some mechanical properties of selected polymeric bio-materials Compared with metals and ceramics, polymers have much lowerstrengths and moduli but they can be deformed to a greater extent before fail-ure Consequently, polymers are generally not used in biomedical applicationsthat bear loads (such as body weight) Ultra-high-molecular-weight polyethyl-ene is an exception, as it is used as a bearing surface in hip and knee replace-ments The mechanical properties of polymers, however, are su‰cient for nu-merous biomedical applications (some of which are listed in Table 1.5)

1.5 CHOICE OF MATERIALS FOR BIOMEDICAL APPLICATIONS

In the past, success of materials in biomedical applications was not so much theoutcome of meticulous selection based on biocompatibility criteria but ratherthe result of serendipity, continuous refinement in fabrication technology, andadvances in material surface treatment

In the present and future, election of a biomaterial for a specific applicationmust be based on several criteria The physicochemical properties and durability

of the material, the desired function of the prosthesis, the nature of the logical environment at the organ/tissue level, adverse e¤ects in case of failure, aswell as cost and production issues must be considered for each specific applica-tion Biocompatibility (addressed in Chapter 9) is the paramount criterion thatmust be met by every biomaterial

physio-Mechanical requirements must also be taken into consideration when ing materials for biomedical applications Material strength (tensile or com-pressive), sti¤ness, fatigue endurance, wear resistance, and dimensional stabilityshould be considered with respect to the end use of the prosthetic device to en-sure its success For example, a rigid, strong material would be more suitable for

choos-a hip implchoos-ant, wherechoos-as choos-a flexible, less strong mchoos-aterichoos-al would be su‰cient for choos-avascular graft Moreover, the performance of materials under dynamic loadingconditions must be considered when appropriate, because many implants aresubjected to various types and magnitudes of repeated stresses in the body.Consider a hip, knee, or ligament replacement that will be subjected to approx-imately one million steps per year, while various other physical activities willexert di¤erent loads across the joints At 70 beats per minute, a prosthetic heartvalve would experience over three and a half million cycles per year Other

TABLE 1.6 Mechanical Properties of Polymers*

Polymer

Tensile Strength

Young’s Modulus, E

An Introduction To Tissue-Biomaterial Interactions 10

physical properties (such as electrical and thermal conductivity, light sion, and radiopacity) are important for specific applications, such as pace-maker electrodes, intraocular lenses, and dental restoratives, and must be con-sidered when applicable.

transmis-Because the practice of medicine and surgery requires sterile products, sions regarding choice of biomaterial(s) for a specific application should includeconsideration of sterilization of the final product(s) Moist heat and high pres-sure (typical conditions in steam autoclaves), ethylene oxide gas, and gamma ra-diation are procedures commonly used in sterilizing biomedical materials anddevices Special care should be taken with polymers that do not tolerate heat,absorb and subsequently release ethylene oxide (a toxic substance), and degradewhen exposed to radiation

deci-1.6 BIOMATERIALS FOR IMPLANTABLE DEVICES: PRESENT AND FUTURE DIRECTIONS

Unquestionably, important advances have been made in the clinical use of cal implants and other devices Presently, emphasis is placed on the design ofproactive biomaterials, that is, materials that elicit specific, desired, and timelyresponses from surrounding cells and tissues Medical research continues to ex-plore new scientific frontiers for diagnosing, treating, curing, and preventing dis-eases at the molecular/genetic level With this newfound knowledge, there will befurther need for innovative formulations and/or modifications of existing materi-als (see Chapter 8, Section 8.4), for novel materials, and for nontraditional appli-cations of biomaterials, such as in tissue engineering Promising developmentsinclude bioinspired chemical and topographic modifications of materials surfaces,current-conducting polymers, and nanophase materials In addition to new chal-lenges and opportunities, some of the unresolved issues (primarily, biocom-patibility) of the past and present will also need to be addressed in the future

medi-1.7 SUMMARY

A biomaterial is any substance (other than drugs), natural or synthetic, that

treats, augments, or replaces any tissue, organ, and body function

The properties of materials are governed by their structure, determined by

the way their constituent atoms are bonded together

Lack of near neighbor atoms, caused by creation of a surface, results in

dif-ferent surface versus bulk material properties that have major consequencesfor tissue-implant interactions

The mechanical properties (e.g., strength, modulus, and fatigue limit) of

metals makes them desirable choices for many load-bearing biomedicalprostheses applications

Metals are susceptible to degradation by corrosion, a process that can release

by-products (such as ions, chemical compounds, and particulate debris) thatmay cause adverse biological responses

Ceramics are attractive biomaterials because they can be either bioinert,

bioactive, or biodegradable; however, they have serious drawbacks becausethey are brittle and have low tensile strength

The properties of polymers depend on the composition, structure, and

ar-rangement of their constituent macromolecules

1.8 BIBLIOGRAPHY/SUGGESTED READING

Alexander H., Brunski J.B., Cooper S.L., Hench L.L., Hergenrother R.W., Ho¤man A.S., Kohn J., Langer R., Peppas N.A., Ratner B.D., Shalaby S.W., Visser S.A., and Yannas I.V., Classes of materials used in medicine In Biomaterials Science: An Intro- duction to Materials in Medicine, Ratner, B.D., Ho¤man, A.S., Schoen, F.J., Lemons, J.E., (eds.) Academic Press, New York, NY (1996), pp 37–130.

Boretos, J.W., Eden, M Contemporary Biomaterials, Material and Host Response, Clinical Applications, New Technology and Legal Aspects Noyes Publications, Park Ridge, NJ (1984), pp 232–233.

Cooke F.W., Lemons J.E., and Ratner B.D., Properties of Materials in Biomaterials Science: An Introduction to Materials in Medicine, Ratner, B.D., Ho¤man, A.S., Schoen, F.J., Lemons, J.E., (eds.) Academic Press, New York, NY (1996), pp 11–35 Peppas, N.A., Langer, R ‘‘New Challenges in Biomaterials’’, Science: 263 (1994),

pp 1715–1720.

Ratner, B.D ‘‘New ideas in biomaterials science—a path to engineered biomaterials.’’ Journal of Biomedical Materials Research: 27 (1993), pp 837–850.

1.9 QUIZ QUESTIONS

1 Define the term ‘‘biomaterial.’’

2 Define the term ‘‘metal.’’ Give an example of a metal and describe its use in a medical prosthesis.

bio-3 Define the term ‘‘ceramic.’’ Give an example of a ceramic and describe its use in a biomedical prosthesis.

4 Define the term ‘‘polymer.’’ Give an example of a polymer and describe its use in a biomedical prosthesis.

5 Why does the method of processing a material change its properties?

6 What are the potential consequences of a biomaterial degrading after implantation

of a prosthetic device?

An Introduction To Tissue-Biomaterial Interactions 12

(b) What criteria should the new material satisfy?

(c) What are the advantages of the new material?

(d) What are the disadvantages of the new material?

2 Repeat Study Question a1, but now consider the design of a novel material for

re-placement of diseased blood-vessel wall tissue (vascular grafts).

3 What are the advantages and disadvantages of using bioactive and biodegradable ceramics in bone replacement?

4 Discuss how biomaterials in the next century may di¤er from those presently used for biomedical applications.