Materials for Biomedical Engineering

Mohamed N. Rahaman, Professor Emeritus of Materials Science and Engineering, Missouri University of Science and Technology, USA. Dr. Rahaman is a Fellow of the American Ceramic Society, the author of five textbooks, the author and co-author of over 280 reviewed journal articles and conference proceedings, and the co-inventor on three US patents in the area of medical devices. Roger F. Brown, Professor Emeritus of Biological Sciences, Missouri University of Science and Technology, USA. Dr Brown is the author and co-author of over 60 reviewed journal articles and conference proceedings, and is a co-inventor on one US patent pertaining to the use of bioactive borate glass microfibers for soft tissue repair.

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