A comprehensive yet accessible introductory textbook designed for one-semester courses in biomaterials
Biomaterials are used throughout the biomedical industry in a range of applications, from cardiovascular devices and medical and dental implants to regenerative medicine, tissue engineering, drug delivery, and cancer treatment. Materials for Biomedical Engineering: Fundamentals and Applications provides an up-to-date introduction to biomaterials, their interaction with cells and tissues, and their use in both conventional and emerging areas of biomedicine.
Requiring no previous background in the subject, this student-friendly textbook covers the basic concepts and principles of materials science, the classes of materials used as biomaterials, the degradation of biomaterials in the biological environment, biocompatibility phenomena, and the major applications of biomaterials in medicine and dentistry. Throughout the text, easy-to-digest chapters address key topics such as the atomic structure, bonding, and properties of biomaterials, natural and synthetic polymers, immune responses to biomaterials, implant-associated infections, biomaterials in hard and soft tissue repair, tissue engineering and drug delivery, and more. - Offers accessible chapters with clear explanatory text, tables and figures, and high-quality illustrations - Describes how the fundamentals of biomaterials are applied in a variety of biomedical applications - Features a thorough overview of the history, properties, and applications of biomaterials - Includes numerous homework, review, and examination problems, full references, and further reading suggestions
Materials for Biomedical Engineering: Fundamentals and Applications is an excellent textbook for advanced undergraduate and graduate students in biomedical materials science courses, and a valuable resource for medical and dental students as well as students with science and engineering backgrounds with interest in biomaterials.
Table of Contents
Preface xix
About the Companion Website xxi
Part I General Introduction 1
1 Biomaterials - An Introductory Overview 3
1.1 Introduction 3
1.2 Definition and Meaning of Common Terms 3
1.3 Biomaterials Design and Selection 8
1.3.1 Evolving Trend in Biomaterials Design 8
1.3.2 Factors in Biomaterials Design and Selection 9
1.4 Properties of Materials 11
1.4.1 Intrinsic Properties of Metals 11
1.4.2 Intrinsic Properties of Ceramics 11
1.4.3 Intrinsic Properties of Polymers 12
1.4.4 Properties of Composites 12
1.4.5 Representation of Properties 13
1.5 Case Study in Materials Design and Selection: The Hip Implant 13
1.6 Brief History of the Evolution of Biomaterials 17
1.7 Biomaterials - An Interdisciplinary Field 19
1.8 Concluding Remarks 19
Part II Materials Science of Biomaterials 21
2 Atomic Structure and Bonding 23
2.1 Introduction 23
2.2 Interatomic Forces and Bonding Energies 23
2.3 Types of Bonds between Atoms and Molecules 26
2.4 Primary Bonds 27
2.4.1 Ionic Bonding 29
2.4.2 Covalent Bonding 30
2.4.3 Metallic Bonding 33
2.5 Secondary Bonds 34
2.5.1 Van der Waals Bonding 34
2.5.2 Hydrogen Bonding 35
2.6 Atomic Bonding and Structure in Proteins 36
2.6.1 Primary Structure 36
2.6.2 Secondary Structure 37
2.6.3 Tertiary Structure 38
2.6.4 Quaternary Structure 43
2.7 Concluding Remarks 44
3 Structure of Solids 47
3.1 Introduction 47
3.2 Packing of Atoms in Crystals 47
3.2.1 Unit Cells and Crystal Systems 49
3.3 Structure of Solids Used as Biomaterials 51
3.3.1 Crystal Structure of Metals 51
3.3.2 Crystal Structure of Ceramics 52
3.3.3 Structure of Inorganic Glasses 54
3.3.4 Structure of Carbon Materials 55
3.3.5 Structure of Polymers 57
3.4 Defects in Crystalline Solids 58
3.4.1 Point Defects 59
3.4.2 Line Defects: Dislocations 59
3.4.3 Planar Defects: Surfaces and Grain Boundaries 62
3.5 Microstructure of Biomaterials 62
3.5.1 Microstructure of Dense Biomaterials 63
3.5.2 Microstructure of Porous Biomaterials 64
3.6 Special Topic: Lattice Planes and Directions 65
3.7 Concluding Remarks 67
4 Bulk Properties of Materials 69
4.1 Introduction 69
4.2 Mechanical Properties of Materials 69
4.2.1 Mechanical Stress and Strain 70
4.2.2 Elastic Modulus 72
4.2.3 Mechanical Response of Materials 74
4.2.4 Stress-Strain Behavior of Metals, Ceramics, and Polymers 78
4.2.5 Fracture of Materials 79
4.2.6 Toughness and Fracture Toughness 82
4.2.7 Fatigue 82
4.2.8 Hardness 83
4.3 Effect of Microstructure on Mechanical Properties 84
4.3.1 Effect of Porosity 84
4.3.2 Effect of Grain Size 85
4.4 Designing with Ductile and Brittle Materials 85
4.4.1 Designing with Metals 85
4.4.2 Designing with Ceramics 85
4.4.3 Designing with Polymers 87
4.5 Electrical Properties 87
4.5.1 Electrical Conductivity of Materials 87
4.5.2 Electrical Conductivity of Conducting Polymers 88
4.6 Magnetic Properties 88
4.6.1 Origins of Magnetic Response in Materials 88
4.6.2 Meaning and Definition of Relevant Magnetic Properties 89
4.6.3 Diamagnetic and Paramagnetic Materials 89
4.6.4 Ferromagnetic Materials 90
4.6.5 Ferrimagnetic Materials 91
4.6.6 Magnetization Curves and Hysteresis 91
4.6.7 Hyperthermia Treatment of Tumors using Magnetic Nanoparticles 91
4.7 Thermal Properties 92
4.7.1 Thermal Conductivity 92
4.7.2 Thermal Expansion Coefficient 93
4.8 Optical Properties 94
4.9 Concluding Remarks 95
5 Surface Properties of Materials 99
5.1 Introduction 99
5.2 Surface Energy 100
5.2.1 Determination of Surface Energy of Materials 101
5.2.2 Measurement of Contact Angle 102
5.2.3 Effect of Surface Energy 104
5.3 Surface Chemistry 104
5.3.1 Characterization of Surface Chemistry 105
5.4 Surface Charge 108
5.4.1 Surface Charging Mechanisms 108
5.4.2 Measurement of Surface Charge and Potential 109
5.4.3 Effect of Surface Charge 110
5.5 Surface Topography 110
5.5.1 Surface Roughness Parameters 112
5.5.2 Characterization of Surface Topography 112
5.5.3 Effect of Surface Topography on Cell and Tissue Response 115
5.6 Concluding Remarks 116
Part III Classes of Materials Used as Biomaterials 119
6 Metallic Biomaterials 121
6.1 Introduction 121
6.2 Crystal Structure of Metals 121
6.3 Polymorphic Transformation 122
6.3.1 Formation of Nuclei of Critical Size 123
6.3.2 Rate of Phase Transformation 123
6.3.3 Diffusive Transformations 124
6.3.4 Displacive Transformations 125
6.3.5 Time-Temperature-Transformation (TTT) Diagrams 125
6.4 Alloys 126
6.5 Shape (Morphology) of Phases 126
6.6 Phase Diagrams 127
6.7 Production of Metals 129
6.7.1 Wrought Metal Products 129
6.7.2 Cast Metal Products 130
6.7.3 Alternative Production Methods 130
6.8 Mechanisms for Strengthening Metals 131
6.8.1 Solid Solution Hardening 131
6.8.2 Precipitation and Dispersion Hardening 131
6.8.3 Work Hardening 131
6.8.4 Grain Size Refinement 132
6.9 Metals Used as Biomaterials 133
6.9.1 Stainless Steels 133
6.9.2 Titanium and Titanium Alloys 134
6.9.3 Cobalt-Based Alloys 137
6.9.4 Nickel-Titanium Metals and Alloys 141
6.9.5 Tantalum 143
6.9.6 Zirconium Alloys 144
6.9.7 Noble Metals 144
6.10 Degradable Metals 145
6.10.1 Designing Degradable Metals 145
6.10.2 Degradable Magnesium Alloys 146
6.11 Concluding Remarks 149
7 Ceramic Biomaterials 153
7.1 Introduction 153
7.2 Design and Processing of Ceramics 154
7.2.1 Design Principles for Mechanically Reliable Ceramics 154
7.2.2 Principles of Processing Ceramics 155
7.3 Chemically Unreactive Ceramics 157
7.3.1 Alumina (Al2O3) 157
7.3.2 Zirconia (ZrO2) 158
7.3.3 Alumina-Zirconia (Al2O3-ZrO2) Composites 160
7.3.4 Silicon Nitride (Si3N4) 161
7.4 Calcium Phosphates 162
7.4.1 Solubility of Calcium Phosphates 163
7.4.2 Degradation of Calcium Phosphates 164
7.4.3 Hydroxyapatite 164
7.4.4 Beta-Tricalcium Phosphate (β-TCP) 165
7.4.5 Biphasic Calcium Phosphate (BCP) 165
7.4.6 Other Calcium Phosphates 166
7.4.7 Mechanical Properties of Calcium Phosphates 167
7.5 Calcium Phosphate Cement (CPC) 167
7.5.1 CPC Chemistry 168
7.5.2 CPC Setting (Hardening) Mechanism 168
7.5.3 Microstructure of CPCs 168
7.5.4 Properties of CPCs 169
7.6 Calcium Sulfate 170
7.7 Glasses 170
7.7.1 Glass Transition Temperature (Tg) 171
7.7.2 Glass Viscosity 171
7.7.3 Production of Glasses 172
7.8 Chemically Unreactive Glasses 172
7.9 Bioactive Glasses 173
7.9.1 Bioactive Glass Composition 173
7.9.2 Mechanism of Conversion to Hydroxyapatite 174
7.9.3 Reactivity of Bioactive Glasses 175
7.9.4 Mechanical Properties of Bioactive Glasses 176
7.9.5 Release of Ions from Bioactive Glasses 177
7.9.6 Applications of Bioactive Glasses 178
7.10 Glass-Ceramics 179
7.10.1 Production of Glass-Ceramics 179
7.10.2 Bioactive Glass-Ceramics 180
7.10.3 Chemically Unreactive Glass-Ceramics 181
7.10.4 Lithium Disilicate Glass-Ceramics 181
7.11 Concluding Remarks 183
8 Synthetic Polymers I: Nondegradable Polymers 187
8.1 Introduction 187
8.2 Polymer Science Fundamentals 188
8.2.1 Copolymers 188
8.2.2 Linear and Crosslinked Molecules 189
8.2.3 Molecular Symmetry and Stereoregularity 189
8.2.4 Molecular Weight 190
8.2.5 Molecular Conformation 192
8.2.6 Glass Transition Temperature (Tg) 193
8.2.7 Semicrystalline Polymers 194
8.2.8 Molecular Orientation in Amorphous and Semicrystalline Polymers 197
8.3 Production of Polymers 198
8.3.1 Polymer Synthesis 198
8.3.2 Production Methods 199
8.4 Mechanical Properties of Polymers 199
8.4.1 Effect of Temperature 199
8.4.2 Effect of Crystallinity 200
8.4.3 Effect of Molecular Weight 200
8.4.4 Effect of Molecular Orientation 200
8.5 Thermoplastic Polymers 201
8.5.1 Polyolefins 201
8.5.2 Fluorinated Hydrocarbon Polymers 203
8.5.3 Vinyl Polymers 204
8.5.4 Acrylic Polymers 204
8.5.5 Polyaryletherketones 205
8.5.6 Polycarbonate, Polyethersulfone, and Polysulfone 206
8.5.7 Polyesters 206
8.5.8 Polyamides 206
8.6 Elastomeric Polymers 207
8.6.1 Polydimethylsiloxane (PDMS) 208
8.7 Special Topic: Polyurethanes 209
8.7.1 Production of Polyurethanes 209
8.7.2 Structure-Property Relations in Polyurethanes 210
8.7.3 Chemical Stability of Polyurethanes in vivo 211
8.7.4 Biomedical Applications of Polyurethanes 212
8.8 Water-soluble Polymers 212
8.9 Concluding Remarks 213
9 Synthetic Polymers II: Degradable Polymers 217
9.1 Introduction 217
9.2 Degradation of Polymers 217
9.3 Erosion of Degradable Polymers 218
9.4 Characterization of Degradation and Erosion 219
9.5 Factors Controlling Polymer Degradation 219
9.5.1 Chemical Structure 219
9.5.2 pH 220
9.5.3 Copolymerization 221
9.5.4 Crystallinity 222
9.5.5 Molecular Weight 222
9.5.6 Water Uptake 223
9.6 Factors Controlling Polymer Erosion 223
9.6.1 Bulk Erosion 224
9.6.2 Surface Erosion 224
9.7 Design Criteria for Degradable Polymers 225
9.8 Types of Degradable Polymers Relevant to Biomaterials 226
9.8.1 Poly(α-hydroxy Esters) 226
9.8.2 Polycaprolactone 230
9.8.3 Polyanhydrides 231
9.8.4 Poly(Ortho Esters) 233
9.8.5 Polydioxanone 234
9.8.6 Polyhydroxyalkanoates 235
9.8.7 Poly(Propylene Fumarate) 236
9.8.8 Polyacetals and Polyketals 237
9.8.9 Poly(polyol sebacate) 238
9.8.10 Polycarbonates 240
9.9 Concluding Remarks 241
10 Natural Polymers 245
10.1 Introduction 245
10.2 General Properties and Characteristics of Natural Polymers 246
10.3 Protein-Based Natural Polymers 246
10.3.1 Collagen 247
10.3.2 Gelatin 255
10.3.3 Silk 256
10.3.4 Elastin 259
10.3.5 Fibrin 260
10.3.6 Laminin 261
10.4 Polysaccharide-Based Polymers 262
10.4.1 Hyaluronic Acid 263
10.4.2 Sulfated Polysaccharides 265
10.4.3 Alginates 267
10.4.4 Chitosan 269
10.4.5 Agarose 271
10.4.6 Cellulose 272
10.4.7 Bacterial (Microbial) Cellulose 274
10.5 Concluding Remarks 275
11 Hydrogels 279
11.1 Introduction 279
11.2 Characteristics of Hydrogels 279
11.3 Types of Hydrogels 281
11.4 Creation of Hydrogels 281
11.4.1 Chemical Hydrogels 281
11.4.2 Physical Hydrogels 282
11.5 Characterization of Sol to Gel Transition 284
11.6 Swelling Behavior of Hydrogels 285
11.6.1 Theory of Swelling 285
11.6.2 Determination of Swelling Parameters 288
11.7 Mechanical Properties of Hydrogels 289
11.8 Transport Properties of Hydrogels 289
11.9 Surface Properties of Hydrogels 290
11.10 Environmentally Responsive Hydrogels 291
11.10.1 pH Responsive Hydrogels 291
11.10.2 Temperature Responsive Hydrogels 293
11.11 Synthetic Hydrogels 294
11.11.1 Polyethylene Glycol and Polyethylene Oxide 294
11.11.2 Polyvinyl Alcohol 297
11.11.3 Polyhydroxyethyl Methacrylate 298
11.11.4 Polyacrylic Acid and Polymethacrylic Acid 298
11.11.5 Poly(N-isopropyl acrylamide) 298
11.12 Natural Hydrogels 299
11.13 Applications of Hydrogels 301
11.13.1 Drug Delivery 301
11.13.2 Cell Encapsulation and Immunoisolation 302
11.13.3 Scaffolds for Tissue Engineering 302
11.14 Concluding Remarks 303
12 Composite Biomaterials 307
12.1 Introduction 307
12.2 Types of Composites 307
12.3 Mechanical Properties of Composites 307
12.3.1 Mechanical Properties of Fiber Composites 308
12.3.2 Mechanical Properties of Particulate Composites 309
12.4 Biomedical Applications of Composites 311
12.5 Concluding Remarks 313
13 Surface Modification and Biological Functionalization of Biomaterials 315
13.1 Introduction 315
13.2 Surface Modification 315
13.3 Surface Modification Methods 316
13.4 Plasma Processes 317
13.4.1 Plasma Treatment Principles 317
13.4.2 Advantages and Drawbacks of Plasma Treatment 318
13.4.3 Applications of Plasma Treatment 318
13.5 Chemical Vapor Deposition 319
13.5.1 Chemical Vapor Deposition of Inorganic Films 319
13.5.2 Chemical Vapor Deposition of Polymer Films 319
13.6 Physical Techniques for Surface Modification 322
13.7 Parylene Coating 322
13.8 Radiation Grafting 323
13.9 Chemical Reactions 323
13.10 Solution Processing of Coatings 324
13.10.1 Silanization 324
13.10.2 Langmuir-Blodgett Films 325
13.10.3 Self-Assembled Monolayers 328
13.10.4 Layer-by-Layer Deposition 329
13.11 Biological Functionalization of Biomaterials 330
13.11.1 Immobilization Methods 331
13.11.2 Physical Immobilization 331
13.11.3 Chemical Immobilization 332
13.11.4 Heparin Modification of Biomaterials 334
13.12 Concluding Remarks 337
Part IV Degradation of Biomaterials in the Physiological Environment 339
14 Degradation of Metallic and Ceramic Biomaterials 341
14.1 Introduction 341
14.2 Corrosion of Metals 342
14.2.1 Principles of Metal Corrosion 342
14.2.2 Rate of Corrosion 345
14.2.3 Pourbaix Diagrams 346
14.2.4 Types of Electrochemical Corrosion 347
14.3 Corrosion of Metal Implants in the Physiological Environment 349
14.3.1 Minimizing Metal Implant Corrosion in vivo 351
14.4 Degradation of Ceramics 351
14.4.1 Degradation by Dissolution and Disintegration 351
14.4.2 Cell-Mediated Degradation 352
14.5 Concluding Remarks 353
15 Degradation of Polymeric Biomaterials 355
15.1 Introduction 355
15.2 Hydrolytic Degradation 356
15.2.1 Hydrolytic Degradation Pathways 356
15.2.2 Role of the Physiological Environment 357
15.2.3 Effect of Local pH Changes 357
15.2.4 Effect of Inorganic Ions 358
15.2.5 Effect of Bacteria 358
15.3 Enzyme-Catalyzed Hydrolysis 358
15.3.1 Principles of Enzyme-Catalyzed Hydrolysis 359
15.3.2 Role of Enzymes in Hydrolytic Degradation in vitro 360
15.3.3 Role of Enzymes in Hydrolytic Degradation in vivo 362
15.4 Oxidative Degradation 362
15.4.1 Principles of Oxidative Degradation 363
15.4.2 Production of Radicals and Reactive Species in vivo 363
15.4.3 Role of Radicals and Reactive Species in Degradation 366
15.4.4 Oxidative Degradation of Polymeric Biomaterials 367
15.5 Other Types of Degradation 369
15.5.1 Stress Cracking 369
15.5.2 Metal Ion-Induced Oxidative Degradation 370
15.5.3 Oxidative Degradation Induced by the External Environment 370
15.6 Concluding Remarks 371
Part V Biocompatibility Phenomena 373
16 Biocompatibility Fundamentals 375
16.1 Introduction 375
16.2 Biocompatibility Phenomena with Implanted Devices 375
16.2.1 Consequences of Failed Biocompatibility 376
16.2.2 Basic Pattern of Biocompatibility Processes 377
16.3 Protein and Cell Interactions with Biomaterial Surfaces 378
16.3.1 Protein Adsorption onto Biomaterials 378
16.3.2 Cell-Biomaterial Interactions 378
16.4 Cells and Organelles 380
16.4.1 Plasma Membrane 380
16.4.2 Cell Nucleus 382
16.4.3 Ribosomes, Endoplasmic Reticulum, and the Golgi Apparatus 384
16.4.4 Mitochondria 386
16.4.5 Cytoskeleton 386
16.4.6 Cell Contacts and Membrane Receptors 388
16.5 Extracellular Matrix and Tissues 389
16.5.1 Components of the Extracellular Matrix 389
16.5.2 Attachment Factors 389
16.5.3 Cell Adhesion Molecules 390
16.5.4 Molecular and Physical Factors in Cell Attachment 391
16.5.5 Tissue Types and Origins 391
16.6 Plasma and Blood Cells 393
16.6.1 Erythrocytes 393
16.6.2 Leukocytes 395
16.7 Platelet Adhesion to Biomaterial Surfaces 396
16.8 Platelets and the Coagulation Process 396
16.9 Cell Types and Their Roles in Biocompatibility Phenomena 398
16.10 Concluding Remarks 399
17 Mechanical Factors in Biocompatibility Phenomena 401
17.1 Introduction 401
17.2 Stages and Mechanisms of Mechanotransduction 401
17.2.1 Force Transduction Pathways 401
17.2.2 Signal Transduction Pathways and Other Mechanisms 403
17.2.3 Mechanisms of Cellular Response 404
17.3 Mechanical Stress-Induced Biocompatibility Phenomena 407
17.3.1 Implantable Devices in Bone Healing 407
17.3.2 Implantable Devices in the Cardiovascular System 408
17.3.3 Soft Tissue Healing 410
17.3.4 Stem Cells in Tissue Engineering 411
17.4 Outcomes of Transduction of Extracellular Stresses and Responses 414
17.5 Concluding Remarks 414
18 Inflammatory Reactions to Biomaterials 417
18.1 Introduction 417
18.2 Implant Interaction with Plasma Proteins 418
18.3 Formation of Provisional Matrix 418
18.4 Acute Inflammation and Neutrophils 419
18.4.1 Neutrophil Activation and Extravasation 419
18.4.2 Formation of Reactive Oxygen Species 421
18.4.3 Phagocytosis by Neutrophils 421
18.4.4 Neutrophil Extracellular Traps (NETs) 421
18.4.5 Neutrophil Apoptosis 423
18.5 Chronic Inflammation and Macrophages 423
18.5.1 Macrophage Differentiation and Recruitment to Implant Surfaces 423
18.5.2 Phagocytosis by M1 Macrophages 424
18.5.3 Generation of Oxidative Radicals by M1 Macrophages 425
18.5.4 Anti-inflammatory Activities of M2 Macrophages 425
18.6 Granulation Tissue 426
18.7 Foreign Body Response 427
18.8 Fibrosis and Fibrous Encapsulation 429
18.9 Resolution of Inflammation 430
18.10 Inflammation and Biocompatibility 431
18.11 Concluding Remarks 433
19 Immune Responses to Biomaterials 437
19.1 Introduction 437
19.2 Adaptive Immune System 437
19.2.1 Lymphocyte Origins of Two Types of Adaptive Immune Defense 438
19.2.2 Antibody Characteristics and Classes 438
19.2.3 Major Histocompatibility Complex and Self-Tolerance 439
19.2.4 B Cell Activation and Release of Antibodies 440
19.2.5 T Cell Development and Cell-Mediated Immunity 440
19.3 The Complement System 443
19.4 Adaptive Immune Responses to Biomaterials 443
19.4.1 Hypersensitivity Responses 444
19.4.2 Immune Responses to Protein-Based Biomaterials and Complexes 445
19.5 Designing Biomaterials to Modulate Immune Responses 446
19.6 Concluding Remarks 447
20 Implant-Associated Infections 449
20.1 Introduction 449
20.2 Bacteria Associated with Implant Infections 450
20.3 Biofilms and their Characteristics 450
20.4 Sequence of Biofilm Formation on Implant Surfaces 451
20.4.1 Passive Reversible Adhesion of Bacteria to Implant Surface 452
20.4.2 Specific Irreversible Attachment of Bacteria to Implant Surface 452
20.4.3 Microcolony Expansion and Formation of Biofilm Matrix 452
20.4.4 Biofilm Maturation and Tower Formation 453
20.4.5 Dispersal and Return to Planktonic State 453
20.5 Effect of Biomaterial Characteristics on Bacterial Adhesion 453
20.6 Biofilm Shielding of Infection from Host Defenses and Antibiotics 454
20.7 Effects of Biofilm on Host Tissues and Biomaterial Interactions 454
20.8 Strategies for Controlling Implant Infections 456
20.8.1 Orthopedic Implants Designed for Rapid Tissue Integration 456
20.8.2 Surface Nanotopography 457
20.8.3 Silver Nanoparticles 458
20.8.4 Anti-biofilm Polysaccharides 458
20.8.5 Bacteriophage Therapy 458
20.8.6 Mechanical Disruption 459
20.9 Concluding Remarks 460
21 Response to Surface Topography and Particulate Materials 463
21.1 Introduction 463
21.2 Effect of Biomaterial Surface Topography on Cell Response 464
21.2.1 Microscale Surface Topography in Osseointegration 466
21.2.2 Microscale and Nanoscale Patterned Surfaces in Macrophage Differentiation 469
21.2.3 Microscale Patterned Surfaces in Neural Regeneration 470
21.3 Biomaterial Surface Topography for Antimicrobial Activity 471
21.3.1 Microscale Topography with Antimicrobial Activity 471
21.3.2 Nanoscale Topography with Antimicrobial Activity 477
21.4 Microparticle-Induced Host Responses 482
21.4.1 Mechanisms of Microparticle Endocytosis 482
21.4.2 Response to Microparticles 483
21.4.3 Microparticle Distribution in the Organs 487
21.4.4 The Inflammasome and Microparticle-Induced Inflammation 488
21.4.5 Wear Debris-Induced Osteolysis 488
21.5 Nanoparticle-Induced Host Responses 489
21.5.1 Mechanisms of Nanoparticle Endocytosis 489
21.5.2 Response to Nanoparticles 489
21.5.3 Cytotoxicity Effects of Nanoparticles 492
21.6 Concluding Remarks 496
22 Tests of Biocompatibility of Prospective Implant Materials 499
22.1 Introduction 499
22.2 Biocompatibility Standards and Regulations 499
22.2.1 ISO 10993 499
22.2.2 FDA Guidelines and Requirements 500
22.3 In vitro Biocompatibility Test Procedures 500
22.3.1 Cytotoxicity Tests 500
22.3.2 Genotoxicity Tests 502
22.3.3 Hemocompatibility Tests 504
22.4 In vivo Biocompatibility Test Procedures 507
22.4.1 Implantation Tests 507
22.4.2 Thrombogenicity Tests 509
22.4.3 Irritation and Sensitization Tests 510
22.4.4 Systemic Toxicity Tests 511
22.5 Clinical Trials of Biomaterials 511
22.6 FDA Review and Approval 512
22.7 Case Study: The Proplast Temporomandibular Joint 512
22.8 Concluding Remarks 513
Part VI Applications of Biomaterials 515
23 Biomaterials for Hard Tissue Repair 517
23.1 Introduction 517
23.2 Healing of Bone Fracture 518
23.2.1 Mechanism of Fracture Healing 518
23.2.2 Internal Fracture Fixation Devices 520
23.3 Healing of Bone Defects 521
23.3.1 Bone Defects 521
23.3.2 Bone Grafts 521
23.3.3 Bone Graft Substitutes 523
23.3.4 Healing of Nonstructural Bone Defects 527
23.3.5 Healing of Structural Bone Defects 532
23.4 Total Joint Replacement 535
23.4.1 Total Hip Arthroplasty 535
23.4.2 Total Knee Arthroplasty 536
23.5 Spinal Fusion 536
23.5.1 Biomaterials for Spinal Fusion 538
23.6 Dental Implants and Restorations 539
23.6.1 Dental Implants 539
23.6.2 Direct Dental Restorations 539
23.6.3 Indirect Dental Restorations 540
23.7 Concluding Remarks 543
24 Biomaterials for Soft Tissue Repair 547
24.1 Introduction 547
24.2 Surgical Sutures and Adhesives 548
24.2.1 Sutures 548
24.2.2 Soft Tissue Adhesives 549
24.3 The Cardiovascular System 550
24.3.1 The Heart 550
24.3.2 The Circulatory System 551
24.4 Vascular Grafts 551
24.4.1 Desirable Properties and Characteristics of Synthetic Vascular Grafts 552
24.4.2 Synthetic Vascular Graft Materials 552
24.4.3 Patency of Vascular Grafts 552
24.5 Balloon Angioplasty 555
24.6 Intravascular Stents 556
24.6.1 Bare-Metal Stents 556
24.6.2 Drug-Eluting Stents 557
24.6.3 Degradable Stents 557
24.7 Prosthetic Heart Valves 558
24.7.1 Mechanical Valves 558
24.7.2 Bioprosthetic Valves 559
24.8 Ophthalmologic Applications 560
24.8.1 Contact Lenses 561
24.8.2 Intraocular Lenses 563
24.9 Skin Wound Healing 566
24.9.1 Skin Wound Healing Fundamentals 567
24.9.2 Complicating Factors in Skin Wound Healing 569
24.9.3 Biomaterials-Based Therapies 569
24.9.4 Nanoparticle-Based Therapies 574
24.10 Concluding Remarks 576
25 Biomaterials for Tissue Engineering and Regenerative Medicine 581
25.1 Introduction 581
25.2 Principles of Tissue Engineering and Regenerative Medicine 582
25.2.1 Cells for Tissue Engineering 584
25.2.2 Biomolecules and Nutrients for in vitro Cell Culture 587
25.2.3 Growth Factors for Tissue Engineering 587
25.2.4 Cell Therapy 588
25.2.5 Gene Therapy 589
25.3 Biomaterials and Scaffolds for Tissue Engineering 589
25.3.1 Properties of Scaffolds for Tissue Engineering 589
25.3.2 Biomaterials for Tissue Engineering Scaffolds 591
25.3.3 Porous Solids 591
25.3.4 Hydrogels 594
25.3.5 Extracellular Matrix (ECM) Scaffolds 594
25.4 Creation of Scaffolds for Tissue Engineering 595
25.4.1 Creation of Scaffolds in the Form of Porous Solids 596
25.4.2 Electrospinning 601
25.4.3 Additive Manufacturing (3D Printing) Techniques 603
25.4.4 Formation of Hydrogel Scaffolds 608
25.4.5 Preparation of Extracellular Matrix (ECM) Scaffolds 608
25.5 Three-dimensional Bioprinting 609
25.5.1 Inkjet-Based Bioprinting 609
25.5.2 Microextrusion-Based Bioprinting 611
25.6 Tissue Engineering Techniques for the Regeneration of Functional Tissues and Organs 614
25.6.1 Bone Tissue Engineering 614
25.6.2 Articular Cartilage Tissue Engineering 615
25.6.3 Tissue Engineering of Articular Joints 618
25.6.4 Tissue Engineering of Tendons and Ligaments 621
25.6.5 Skin Tissue Engineering 624
25.6.6 Bladder Tissue Engineering 626
25.7 Concluding Remarks 629
26 Biomaterials for Drug Delivery 633
26.1 Introduction 633
26.2 Controlled Drug Release 634
26.2.1 Drug Delivery Systems 636
26.2.2 Mechanisms of Drug Release 636
26.3 Designing Biomaterials for Drug Delivery Systems 638
26.4 Microparticle-based Delivery Systems 638
26.4.1 Preparation of Polymer Microsphere Delivery Systems 639
26.4.2 Applications of Microparticle Delivery Systems 640
26.5 Hydrogel-based Delivery Systems 640
26.5.1 Environmentally Responsive Drug Delivery Systems 641
26.5.2 Drug Delivery Systems Responsive to External Physical Stimuli 644
26.6 Nanoparticle-based Delivery Systems 648
26.6.1 Distribution and Fate of Nanoparticle-based Drug Delivery Systems 649
26.6.2 Targeting of Nanoparticles to Cells 650
26.6.3 Polymer-based Nanoparticle Systems 653
26.6.4 Lipid-based Nanoparticle Systems 655
26.6.5 Polymer Conjugates 663
26.6.6 Dendrimers 666
26.6.7 Inorganic Nanoparticles 667
26.7 Delivery of Ribonucleic Acid (RNA) 668
26.7.1 Chemical Modification of siRNA 670
26.7.2 Biomaterials for siRNA Delivery 671
26.8 Biological Drug Delivery Systems 675
26.8.1 Exosomes for Therapeutic Biomolecule Delivery 675
26.9 Concluding Remarks 676
Index 681
