Tissue Engineering (eBook)

Norbert Pallua is Professor, Chairman and Director of the Department of Plastic Surgery, Hand Surgery, Burn Center at the RWTH University Hospital, Aachen, Germany. Professor Pallua is recognized to be among the leading Plastic Surgeons in Germany. He is also nominated Honorary Professor and Director of several Universities. Professor Pallua is the author of numerous scientific and clinical publications and is a reviewer for several leading journals. He has been responsible for developing innovative methods of extensive facial reconstruction and has led research into tissue engineering, with a particular focus on soft tissue. Professor Christoph Suschek works in the laboratory of the Department of Plastic Surgery, Hand Surgery, Burn Center at the RWTH University Hospital in Aachen as leading biologist. Professor Suschek is the author or co-author of many journal articles presenting research related to tissue engineering approaches, such as ways in which the induction of inflammation might be used to stimulate adipose tissue formation.

Tissue Engineering 2
Copyright Page 3
Preface 4
Contents 6
Part I: Basics and Principlesof Tissue Engineering 9
1: Micro- and Nanotechnology in Tissue Engineering 10
1.1 Introduction 10
1.2 Aim of the Discipline 11
1.3 State of the Art 12
1.3.1 The Need for Micro and Nanotechnologies in Tissue Engineering Strategies 12
1.3.2 Micro and Nanofabrication Methods 13
1.3.2.1 Bottom–Up Approach 14
1.3.2.2 Top–Down Approach 15
Photolithography 15
Soft Lithography 16
Microcontact Printing 16
Microtransfer Molding 16
Molding in Capillaries (Capillary Force Lithography) 23
Scanning Probe Lithography 23
1.3.2.3 Electrospinning 23
1.4 Clinical Applications 24
1.4.1 Micro and Nanotechnologies in the Development of Enhanced Constructs for Tissue Engineering 25
1.4.2 Towards 3D Micro and Nanofabricated Structures 27
1.4.3 Towards In Vivo Microenvironment: Microbioreactors 28
1.5 Expert Opinion 29
1.6 Five-Year Perspective 30
1.7 Limitations/Critical View 30
1.8 Conclusion/Summary 31
Suggested Readings with Abstracts 31
References 32
2: Biomimetic Scaffolds in Tissue Engineering 37
2.1 Introduction 37
2.2 Aims of Biomimetics in Tissue Engineering 37
2.3 State-of-the-Art Biomimetic Materials 38
2.4 Clinical Applications 42
2.5 Expert Opinion 42
2.6 Five-Year Perspective 43
2.7 Limitations/Critical View 43
2.8 Conclusion 43
Suggested Reading 43
References 44
3: Natural and Synthetic Scaffolds 46
3.1 Introduction 46
3.2 Aim of the Discipline 46
3.2.1 Tissue Engineering ECM 46
3.2.2 Native ECM 47
3.2.3 ECM Analog Scaffolds 48
3.3 State of the Art 49
3.3.1 Synthetic Scaffolds 49
3.3.1.1 Poly(Glycolic Acid) 50
3.3.1.2 Poly(Lactic Acid) 51
3.3.1.3 Poly(Lactide-Co-Glycolide) 52
3.3.1.4 Polydioxanone 53
3.3.1.5 Polycaprolactone 53
3.3.1.6 Poly(Ethylene Glycol)/Poly(Ethylene Oxide) 53
3.3.2 Natural Scaffolds 53
3.3.2.1 Collagen 54
3.3.2.2 Gelatin 55
3.3.2.3 Elastin 55
3.3.2.4 Fibrinogen 56
3.3.2.5 Silk 57
3.3.2.6 Acellular Matrix and Submucosa 57
3.3.3 Fabrication Techniques 58
3.3.3.1 Electrospinning 58
3.3.3.2 Phase Separation 59
Liquid–Liquid Phase Separation 61
Solid–Liquid Phase Separation 62
3.3.3.3 Self-Assembly 63
3.3.3.4 Leaching Techniques 64
3.3.3.5 Computer-Aided Design Techniques 64
3.4 Clinical Application 65
3.5 Limitations/Critical View 66
3.6 Expert Opinion 66
3.7 Five-Year Perspective 67
3.8 Conclusion/Summary 68
Literature with Abstracts 68
Suggested Readings with Abstracts 69
References 69
4: Pluripotent Stem Cells: Sources and Characterization 73
4.1 Introduction 73
4.1.1 The Promise of Pluripotent Stem Cells in Tissue Engineering 73
4.1.2 Challenges Facing Implementing Human Pluripotent Stem Cells in Engineered Tissue 73
4.2 Aim of the Discipline 74
4.3 State of the Art 74
4.3.1 Human Embryonic Stem Cell Derivation 74
4.3.1.1 Derivation of Human Embryonic Stem Cells Without Embryo Destruction 75
4.3.2 Human Induced Pluripotent Stem Cell Derivation 75
4.3.2.1 Pluripotency Reprogramming Factors 75
4.3.2.2 Inducing Pluripotency Through Nonviral Methods 76
4.3.2.3 Somatic Cell Sources for Human-Induced Pluripotent Stem Cells 77
4.3.3 Characterizing Pluripotent Human Stem Cells 77
4.3.3.1 Demonstrating Self-Renewal Potential 78
4.3.3.2 Demonstrating Pluripotency 78
4.3.3.3 Differentiation Potential 78
4.3.3.4 Marker Expression 78
4.3.3.5 Epigenetics 80
4.3.4 Pluripotent Stem Cell Culture 80
4.3.4.1 Feeder Cultures 80
4.3.4.2 Defined Culture Media 80
4.4 Clinical Application 81
4.5 Expert Opinion 82
4.5.1 Cell Source 82
4.5.2 Cell Characterization 82
4.5.3 Pluripotent Stem Cell Culture 82
4.6 Five-Year Perspective 82
4.6.1 The Future of Pluripotent Stem Cell Derivation, Characterization, and Culture 82
4.6.2 Applications of Pluripotent Stem Cells in Engineered Tissues 83
4.7 Limitations 83
4.8 Conclusion 83
Suggested Reading 84
References 84
5: Adult Stem Cells: Sources and Characterization 87
5.1 Introduction 87
5.2 Aim of the Discipline 88
5.3 State of the Art 88
5.3.1 Micro-RNA (miRNA) 88
5.3.2 Aging 88
5.3.3 iPS Cells (Induced Pluripotent Stem Cells) 88
5.4 Stem Cells and Clinical Applications 90
5.4.1 HSC (Hematopoietic Stem Cells) 90
5.4.2 Umbilical Cord Blood (UCB) 90
5.4.3 MSC (Mesenchymal Stem Cell, Multipotent Stromal Cell) 90
5.4.3.1 Adipose-Derived Stem Cell (ADSC) 91
5.4.4 Stem Cells in the Epidermis and Hair Follicle 91
5.4.5 Muscle-Derived Stem Cells 91
5.4.6 Cardiac Stem/Progenitor Cells 92
5.4.7 Neural Stem Cells 92
5.5 Expert Opinions 92
5.5.1 Label-Retaining Cells 92
5.5.2 SP Cells (Side Population Cells) 92
5.5.3 The MSC Niche: The Pericyte 93
5.6 Five Year Perspective 93
5.6.1 Immunomodulation 93
5.6.2 Anticancer Therapy 94
5.6.3 iPS Cells 94
5.6.4 Engineered Skin 94
5.7 Limitations/Critical View 94
5.7.1 The Risk of Transformation 94
5.8 Conclusion/Summary 94
5.9 Literature with Abstracts 94
References 95
6: Isolation and Growth of Stem Cells 97
6.1 Introduction 97
6.2 Aim of the Discipline 97
6.3 State of the Art 97
6.3.1 Use of Human Serum, Platelet Lysates, and Serum-Free Supplements 100
6.4 Manufacturing Issues 104
6.4.1 Point of Care Generation vs. Culture-Expanded Cells: Pros and Cons 104
6.4.2 Lot Quality Assurance/Quality Control 104
6.4.3 Staff Protocols and Equipment and Reagent Certification 105
6.4.4 Cell Processing Devices 105
6.5 Clinical Applications and On-Going Human Trials 105
6.5.1 Regenerative Medical Clinicaltrials.Gov Searching Under “Mesenchymal Stem Cells” 106
6.5.2 Regenerative Medical Clinicaltrials.Gov Search Under “Adipose Stem Cells” 111
6.5.3 Regenerative Medical Clinicaltrials.Gov Searching Under “Skeletal Muscle Stem Cells” 112
6.6 Expert Opinion 112
6.7 Five Year Perspective 112
6.8 Limitations/Critical View 112
6.9 Conclusions/Summary 113
References 113
7: Differentiation and Plasticity of Stem Cells for Tissue Engineering 116
7.1 Introduction 116
7.2 Differentiation 116
7.2.1 The Role of Local Environment in Differentiation 120
7.2.1.1 Niche: Extracellular Matrix 120
7.2.1.2 Humoral Factors 120
7.2.1.3 Exchange of MicroRNA 120
7.3 Plasticity 120
7.4 Stem Cells for Tissue Engineering 121
7.4.1 Stem Cells for Cardiac Repair 121
7.4.2 Transdifferentiation 123
7.4.3 Paracrine Mechanisms 123
7.4.4 MSCs for Soft Tissue Repair 123
7.5 Future Perspectives 129
References 130
8: Animal Models for the Evaluation of Tissue Engineering Constructs 134
8.1 Introduction 134
8.2 Aim of the Discipline 136
8.3 State of the Art 137
8.3.1 Animal Models Used in Dentistry 137
8.3.2 Rodent-Mouse Model 137
8.3.3 Rodent-Rat Model 139
8.3.4 Rabbit Model 141
8.3.5 Canine (Dog) Model 143
8.3.6 Sheep and Goat Models 146
8.3.7 Porcine (Pig) Model 149
8.3.8 Primate (Monkey) Model 150
8.4 Clinical Application 151
8.5 Expert Opinion 151
8.6 5-Year Perspective 152
8.7 Limitations/Critical View 152
8.8 Conclusions/Summary 152
8.9 Literature with Abstracts 153
Suggested Readings with Abstracts 153
References 154
9: Biomedical Imaging and Image Processing in Tissue Engineering 158
9.1 Introduction 158
9.2 Light Transportation Model 159
9.2.1 Radiative Transport Equation 160
9.2.2 Diffusion Approximation 160
9.2.3 Simplified Spherical Harmonics Model 161
9.2.4 Phase Approximation for RTE 162
9.3 Bioluminescence Tomography 163
9.3.1 Overview of Bioluminescence Tomography 163
9.3.2 Bioluminescence Imaging System 166
9.3.2.1 Multiview and Multispectral Bioluminescence Imaging System 167
9.3.3 Bioluminescence Tomography Algorithm 170
9.3.3.1 Objective Function 170
9.3.3.2 Stochastic Algorithm 171
9.3.3.3 Multispectral BLT 171
9.3.3.4 Temperature-Modulated Bioluminescence Tomography 172
9.3.4 Discussion 173
9.4 Fluorescence Imaging 173
9.4.1 Fluorescence Tomography 174
9.4.1.1 Fluorescence Tomography Algorithm 174
9.4.1.2 Multispectral FMT 175
9.4.2 Discussion 176
9.5 Five-Year Perspective 177
Suggested Readings with Abstracts 177
References 179
10: Bioreactors for Tissue Engineering 182
10.1 Introduction 182
10.2 Aim of the Discipline 182
10.3 State of the Art 184
10.4 Clinical Application 191
10.5 Expert Opinion 195
10.6 Five-Year Perspective 195
10.7 Limitations/Critical View 197
10.8 Conclusion/Summary 198
Suggested Readings 198
References 198
Part II: Tissue Engineering of Organs 201
11: Issues in Bioartificial Liver Support Therapy for Acute Liver Failure 202
11.1 Introduction 202
11.2 Aim of the Discipline 203
11.2.1 Membranes and Compartmentalization 205
11.2.2 Hepatic Cell Source 205
11.2.3 Tissue Engineering with Hepatocytes 206
11.2.3.1 Monolayer Culture 206
11.2.3.2 Spheroid Suspension Culture 206
11.2.3.3 Three-Dimensional Culture 207
11.3 State of the Art 207
11.3.1 Perfusion 207
11.3.2 Mass Transport 207
11.4 Clinical Application 208
11.4.1 Medical Therapies 208
11.4.2 Extracorporeal Liver Support 208
11.4.2.1 Detoxification (Artificial Liver) Devices 209
11.4.2.2 Metabolic, Cell-Based (Bioartificial Liver) Devices 209
11.4.3 Cell Transplantation 210
11.5 Expert Opinion 210
11.5.1 Perfusion 210
11.5.2 Mass Transport 211
11.5.3 Membranes and Compartmentalization 211
11.5.4 Hepatic Cell Source 212
11.6 Five-Year Perspective 212
11.7 Limitations/Critical View 213
11.8 Conclusions/Summary 215
Suggested Readings 216
References 216
12: Central Nervous System 221
12.1 Introduction 222
12.2 Aim of the Discipline 222
12.3 State of the Art 222
12.3.1 Pathophysiology of Traumatic Spinal Cord Injury 222
12.3.1.1 Myelin-Associated Inhibitors 224
12.3.1.2 Astroglial Scarring and Axon Growth-Repulsive Molecules 224
12.3.1.3 Other Axon Growth-Inhibitory Molecules 225
12.3.1.4 Spontaneous Axon Sprouting and Regeneration 225
12.3.2 Design of Implantable Biomaterials for SCI 225
12.3.2.1 Hollow Conduits 225
12.3.2.2 Hydrogels 227
12.3.2.3 Topographical Cues and Patterning 227
12.3.2.4 Nanofibres 228
12.3.2.5 General Considerations for Implantable Biomaterials for CNS Applications 228
12.3.3 Biomaterials Developed for SCI: Natural Polymers 229
12.3.3.1 Collagen 229
12.3.3.2 Fibronectin 230
12.3.3.3 Fibrin 230
12.3.3.4 Alginate 230
12.3.3.5 Agarose 231
12.3.3.6 Chitosan 231
12.3.3.7 Poly-b-hydroxybutyrate (PHB) 231
12.3.3.8 Hyaluronic Acid 232
12.3.4 Synthetic Polymers 232
12.3.4.1 Poly(-Hydroxy Acids) 232
12.3.4.2 Poly-(Acrylonitrile-Co-Vinylchloride) 233
12.3.4.3 Poly(2-Hydroxyethyl Methacrylate) 233
12.3.4.4 Polyethylene Glycol 234
12.3.4.5 Poly[N-(2-Hydroxypropyl)Methacrylamide 234
12.3.4.6 Self-Assembling Nanofibre Scaffolds 234
12.4 Clinical Application 235
12.5 Expert Opinion 236
12.6 Five-Year Perspective 236
12.7 Limitations/Critical View 237
12.8 Conclusion/Summary 237
Suggested Readings with Abstracts 237
References 239
13: Tissue Engineering for Peripheral Nerve Regeneration 245
13.1 Introduction 245
13.1.1 Neurobiology of Peripheral Nerve Injury 246
13.1.1.1 Peripheral Nerve Anatomy 246
13.1.1.2 Injury Events: Inflammatory, Anterograde, Retrograde (including death), Phenotypic Change 246
13.1.2 Neurobiology of Nerve Regeneration After Repair 247
13.1.3 Summary of the Requirements for Optimal Nerve Repair 248
13.2 Aim of the Discipline: The Tissue-Engineered Neurosynthesis 248
13.3 State of the Art: Tissue Engineering Technologies for Peripheral Nerve Repair 249
13.3.1 Entubulation /Wraparound Repair 249
13.3.2 Gap Repair: Extending the Entubulation Concept to the Nerve Conduit Tube 250
13.3.2.1 Clinical Background: Nerve Graft Repair 250
13.3.2.2 The Nerve Conduit: Initial Experimental and Clinical Constructs 250
13.3.2.3 Refining the Nerve Conduit as a Biodynamic Construct: Matrix 251
13.3.2.4 Refining the Nerve Conduit as a Biodynamic Construct: Therapeutic Delivery of Cultured Schwann Cells 252
13.3.2.5 Refining the Nerve Conduit as a Biodynamic Construct: Therapeutic Delivery of Stem Cells 253
13.3.2.6 Refining the Nerve Conduit as a Biodynamic Construct: Therapeutic Delivery of Exogenous Growth Factors 253
13.4 Clinical Application 254
13.5 Expert Opinion and 5-Year Perspective 254
13.6 Limitations/Critical View 255
13.7 Conclusions/Summary 255
References 255
14: Tissue Engineering of Blood Vessels: How to Make a Graft 263
14.1 Introduction 263
14.2 Aim of the Discipline 263
14.2.1 Cell Sources for Vascular Tissue Engineering 265
14.2.2 Scaffolds for Vascular Tissue Engineering 266
14.2.3 Vessel Reactors for Vascular Tissue Engineering 266
14.3 State of the Art and History of Tissue-Engineered Blood Vessels 267
14.3.1 Natural Scaffolds 267
14.3.2 Permanent Synthetic Scaffolds 267
14.3.3 Biodegradable Synthetic Scaffolds 269
14.3.4 Nonscaffold-Based Tissue-Engineered Blood Vessels 270
14.4 Clinical Application: An Example 270
14.5 Expert Opinion 271
14.6 Five-Year Perspective 271
14.7 Limitations/Critical View 272
14.8 Conclusion/Summary 272
Suggested Readings with Abstracts 272
References 275
15: Biohybrid Strategies for Vascular Grafts 279
15.1 Introduction 279
15.1.1 Current Status of Vascular Grafts 279
15.1.2 Failure Mechanism 280
15.2 Aim of the Discipline 282
15.3 State of the Art: Biohybrid Strategies for Synthetic Grafts 283
15.3.1 Modification with Other Materials to Decrease Thrombogenicity 283
15.3.1.1 Coating of Grafts with Synthetic Materials 283
Carbon 283
Polyethylene Glycol 284
Phosphatidylcholine 284
Poly(Diol Citrate) (PDC) 285
15.3.1.2 Coating of Grafts with Natural Materials 285
Albumin 285
Elastin 286
15.3.2 Protein and Drug Immobilization and Release 286
15.3.2.1 Agents That Inhibit Thrombin 286
15.3.2.2 Agents That Inhibit Platelet Activation 287
15.3.2.3 Agents That Inhibit Neo-Intimal Hyperplasia 287
15.3.2.4 Nitric Oxide 288
15.3.2.5 Combinatory Approaches 289
15.3.3 Stimulation of Endothelial Cell Monolayer Formation 290
15.3.3.1 In Situ Endothelialization 290
Extracellular Matrix Components 291
Growth Factors 292
Specific EPC Capture 293
15.3.3.2 Endothelial Retention After Ex Vivo Endothelialization 293
Alternative Cell Sources 294
Genetically Engineered Cells 295
Other 296
15.3.4 Gene Therapy for Vascular Grafts 296
15.3.4.1 Current Status of Genetic Engineering for Vascular Grafts 296
15.3.4.2 Prospects 297
15.4 State of the Art: Tissue Engineering of Small-Diameter Blood Vessels 298
15.4.1 The Central Paradigm 298
15.4.2 Design Criteria 299
15.4.3 Current Status 300
15.4.3.1 In Vivo Tissue Regeneration Methods 300
15.4.3.2 In Vitro Tissue Regeneration Methods 301
15.4.3.3 Tissue Engineered Blood Vessels in the Clinical Setting 302
15.5 Clinical Applications 302
15.6 Expert Opinion and Limitations 303
15.6.1 Biohybrid Strategies for Synthetic Grafts 303
15.6.2 Stimulation of EC Monolayer Formation 305
15.6.3 Gene Therapy 305
15.6.4 Tissue Engineering of Small-Diameter Blood Vessels 306
15.7 Five-Year Perspective 307
15.8 Summary and Conclusion 307
Suggested Readings 308
References 309
16: Heart and Cardiovascular Engineering 317
16.1 Cardiac Engineering 317
16.1.1 Heart Valves 318
16.1.2 Myocardial Tissue 320
16.1.2.1 Matrix Scaffolds 322
16.1.2.2 Cell Sources 322
16.1.3 Cardiac Cell Therapy 323
16.1.3.1 Skeletal Muscle Cells 323
16.1.3.2 Bone Marrow Stem Cells 323
16.1.3.3 Cellular Therapies in Cardiac Arrhythmias 324
16.2 Blood Vessel Engineering 325
16.2.1 Biological Vessel Grafts 325
16.2.2 Alloplastic Vessel Grafts 326
16.2.3 Hybrid Vessel Grafts 327
16.2.4 Conclusion 328
References 329
17: Tissue Engineering of Organs: Eye/Retina 334
17.1 Introduction 334
17.2 Aim of the Discipline 334
17.2.1 Restoring Damaged Retina Using Embryonic Retinal Tissue 334
17.2.2 In Vitro Engineering of Retinal Cell Types 335
17.2.3 Transplantation of Cells Isolated from the Postnatal Retina of the Mouse 337
17.3 State of the art 337
17.3.1 Polymer and RPC Composites for Retinal Transplantation 337
17.3.2 In Vitro Multilayer Film and Reaggregation Approaches 339
17.4 Clinical Application 339
17.5 Five-Year Perspective 340
17.6 Limitations/Critical View 341
17.6.1 Creating Optimal Retinal Environmental Conditions for Transplantation 341
17.7 Conclusion/Summary 343
References 343
Part III: Tissue Types 346
18: Engineering of Adipose Tissue 347
18.1 Introduction 347
18.1.1 White Adipose Tissue 347
18.1.2 The Clinical Need for Adipose Tissue Engineering Applications 348
18.2 Aims of the Discipline 349
18.3 State of the Art 349
18.3.1 Cells 349
18.3.1.1 Mesenchymal Stem Cells 349
18.3.1.2 Preadipocytes and Adipocytes 350
18.3.1.3 Inflammatory Cells 350
18.3.2 Extracellular Matrix 350
18.3.2.1 Biopolymers 351
18.3.2.2 Hydrogels 351
18.3.2.3 Microspheres 352
18.3.3 Vascularization 353
18.3.4 Growth Factors and Cytokines 356
18.3.5 The Concept of Space 356
18.3.6 The Inductive Theory of Adipose Tissue Engineering In Vivo 357
18.4 Clinical Application 358
18.5 Expert Opinion 358
18.6 Five-Year Perspective 359
18.7 Limitations 359
18.8 Conclusion 360
18.9 Suggested Readings with Abstracts 360
References 363
19: Blood Substitutes 369
19.1 Introduction 369
19.2 Aim of the Discipline 370
19.3 State of the Art 371
19.3.1 Perfluorocarbons 371
19.3.1.1 First-Generation PFC 372
19.3.1.2 Second-Generation PFC 373
19.3.2 Hemoglobin Based Oxygen Carriers 374
19.3.2.1 First-Generation HBOC 375
19.3.2.2 Second-Generation HBOC 375
Crosslink of a-Subunits 375
Pyridoxylation 376
Conjugation 376
Genetically Engineered Hb 376
Polymerized Human Hb 377
Polymerized Bovine Hb 377
Maleimide-Activated PEG Modified Hb (MP4) 377
19.3.3 Liposome Encapsulated Hb 378
19.4 Clinical Application 380
19.4.1 Hemorrhagic Shock 380
19.4.1.1 PFC 380
19.4.1.2 HBOC 381
19.4.1.3 Liposome Encapsulated Hemoglobin 382
19.4.2 Treatment of Acute Intraoperative Blood Loss 382
19.4.2.1 PFC 382
19.4.2.2 HBOC 382
19.4.2.3 Liposome Encapsulated Hemoglobin 383
19.4.3 Use as a Transfusion Alternative in Hematological Disorders 383
19.4.4 Potential Transfusion Alternative for Jehovah’s Witnesses 384
19.5 Expert Opinion 384
19.6 Five-Year Perspective 385
19.7 Limitations/Critical View 386
19.8 Conclusion/Summary 387
Suggested Readings 387
Review Articles 387
Textbooks 388
References 388
20: Tissue Engineering of Blood Vessels: How to Make a Graft 392
20.1 Introduction 392
20.2 Expert Opinion 393
20.3 Biology of Neovascularization 394
20.3.1 Mechanism of Neovascularization 394
20.3.2 Angiogenic Growth Factors 396
20.3.3 Cell/Matrix Interactions in Neovascularization 399
20.4 Engineering Microvascular Networks 400
20.4.1 Cellular Patterning 400
20.4.1.1 Effects of Scaffold Materials on Neovascularization 401
20.4.1.2 Microfabrication Techniques for Engineering Microvascular Networks 404
20.4.2 Recruitment of Microvascular Networks by Application of Angiogenic Biomolecules 406
20.4.2.1 Controlled Growth Factor Administration 406
20.4.2.2 Utilization of Mesenchymal Mural Cells to Enhance Microvascular Network Formation 410
20.4.2.3 Dynamic Biomechanical Stimulation 412
20.4.2.4 Postimplantation Remodeling and In Vivo Recruitment of Microvascular Networks 414
20.4.2.5 Progenitor Cells 416
20.5 Five Year Perspective 418
20.6 Limitations/Critical Views 419
20.7 Summary 420
References 420
21: Bone Tissue Engineering 428
21.1 Introduction 428
21.2 Aim of the Discipline 432
21.3 State of the Art 433
21.4 Clinical Application 436
21.4.1 Orthopedic and reconstructive surgery 436
21.4.2 Oral and Maxillofacial Surgery 441
21.5 Expert Opinion 441
21.6 Five-Year Perspective 444
21.6.1 In Vivo Bone Engineering 444
21.6.2 Stimulation of New Candidate Pathways 445
21.6.3 Design and Fabrication of Scaffolds 446
21.6.4 Application of Bone Tissue Engineering Platforms to Study Mechanisms of Bone Metastasis 447
21.6.5 Bone Chip Model vs. Tissue Engineered Bone 448
21.7 Limitations/Critical View 450
21.8 Conclusion/Summary 451
References 451
22: Tissue Engineering of Organs: Brain Tissues 454
22.1 Introduction 454
22.2 Aim of the Discipline 456
22.2.1 The Neuronal Niche 456
22.2.2 Engineering Cellular Microenvironments 457
22.3 State of the Art 460
22.3.1 Exogenous Cell Source 460
22.3.2 Scaffold Materials 461
22.3.2.1 Hydrogels 466
22.3.2.2 Fibrous Structures 469
22.3.3 Biofunctionalization 473
22.3.3.1 Bioactive Molecules 473
22.3.3.2 Incorporation of Bioactive Molecules onto Scaffolds 475
22.3.4 Summary 476
22.4 Clinical Application 477
22.4.1 Parkinson’s Disease 477
22.4.2 Summary 480
22.5 Expert Opinion 480
22.5.1 Challenges in Tissue Engineering for Brain Repair 480
22.5.2 Current and Future Scaffolds for Brain Repair 481
22.6 Five-Year Perspective 482
22.7 Limitations/Critical Review 483
22.8 Conclusion/Summary 484
Suggested Readings 485
References 485
23: Engineering Cartilage Tissue 490
23.1 Introduction 490
23.1.1 Adult Articular Cartilage: Composition, Mechanical Properties, and Physiologic Loading 490
23.1.2 Articular Cartilage: Formation and Maturation 492
23.2 Aim of the Discipline 493
23.2.1 Overview 493
23.2.2 Cartilage Tissue Engineering Strategies 493
23.3 State of the Art 495
23.3.1 Photopolymerizable Hydrogels 495
23.3.2 Tailoring Hydrogels to Promote Cartilage Tissue Formation 496
23.3.3 Hyaluronic Acid: Biologic Relevance, Role in Cartilage, and Hydrogel Formation 498
23.3.4 Cells Used in Cartilage Repair and Tissue Engineering 498
23.3.5 Mesenchymal Stem Cells in Cartilage Regeneration 499
23.3.6 Tissue Engineering of Articular Cartilage with Mechanical Preconditioning 502
23.3.7 Mechanical Sensitivity of Mesenchymal Progenitor Cells 503
23.4 Clinical Application 504
23.4.1 Articular Cartilage Injury and Repair 504
23.4.2 Clinical Translation of Engineered Cartilage 505
23.5 Expert Opinion 506
23.6 Five-Year Perspective 509
23.7 Limitations/Critical View 509
23.8 Conclusion/Summary 510
Suggested Reading with Abstracts 511
References 512
24: Pancreatic Tissues 518
24.1 Introduction 518
24.2 Aims of Pancreatic Tissue Engineering 519
24.3 State of the Art Technologies in Pancreatic Tissue Engineering 519
24.3.1 Sources of Insulin Producing Cells 519
24.3.1.1 Pancreatic b Cells Generated from Embryonic Stem Cells (ESC) 520
24.3.1.2 Amniotic Fluid-Derived Stem Cells (AFSC) as a Source for Insulin Producing Pancreatic b Cells 521
24.3.1.3 Progenitor Cells 521
24.3.1.4 Induced Pluripotent Stem Cell (iPS cells) 522
24.3.2 Encapsulation: Strategies to Engineer Bioartificial Pancreatic Tissue 522
24.3.2.1 Pancreatic Islet Cell Encapsulation as Immunoisolation 523
24.3.2.2 Types of Islet Cell Encapsulation 523
24.3.2.3 Geometry of Capsules 524
24.4 Clinical Application 525
24.5 Expert Opinion 525
24.6 Five-Year Perspective 526
24.7 Limitations/Critical View 526
24.8 Conclusion/Summary 527
Suggested Reading with Abstract 528
Reference 531
25: Tendons: Engineering of Functional Tissues 534
25.1 Introduction 534
25.2 Cellular Composition of Tendons 534
25.3 Structural Elements of Tendons 535
25.3.1 Collagen Type I 535
25.3.2 Other Collagenous Structures of Tendons 537
25.3.3 Non-Collagenous Constituents of Tendons 537
25.4 Tendon Hierarchical Structure 538
25.5 Function of Native Tendon 540
25.6 Changes in Tendon During Maturation and Ageing 541
25.7 Vascular Supply of Tendons 542
25.8 Tendon Healing 542
25.9 Non-Invasive Strategies 543
25.10 Clinical Need and Requirements 544
25.11 Approaches Towards Tendon Repair: Autografts, Allografts and Xenografts 545
25.12 Approaches Towards Tendon Repair: Synthetic and Natural Biomaterials 546
25.13 Approaches Towards Tendon Repair: Collagen-based Biomaterials 548
25.14 Conclusions 552
References 552
26: Tissue Engineering in Oral and Maxillofacial Surgery (OMFS) 570
26.1 Introduction 570
26.2 Aim of the Discipline 570
26.2.1 From Resection to Reconstruction to Regeneration 570
26.3 State of the Art 571
26.3.1 Cell-Based Tissue Repair Strategies 571
26.3.1.1 General Principles 571
26.3.1.2 Polymer Cell System 571
26.3.2 Cell Transplantation Devices 572
26.3.2.1 Coating Technique 573
26.3.2.2 Spraying Technique 573
26.3.2.3 Framing Technique 573
26.3.2.4 Sandwich Technique 573
26.3.3 Cell Sources, Growth, and Differentiation 574
26.3.3.1 Autologous Cells for Cartilage Regeneration 574
Chondroprogenitor Cells 574
26.3.3.2 Autologous Cells for Bone Regeneration 574
Osteoprogenitor Cells 574
Mesenchymal Stem Cells 575
26.3.3.3 Autologous Cells for Oral Mucosa Regeneration 575
Dentoalveolar Tissue Progenitor Cells 575
Periodontal Progenitor Cells 575
Dental Pulp Progenitor Cells 575
Neural Crest-Derived Progenitor Cells 575
Salivary Gland Progenitor Cells 576
Skeletal Muscle Progenitor Cells 576
Placenta-Derived Multipotent Cells 576
Embryonic Stem Cells 576
26.3.4 Bioreactors for Engineering of Structural Tissue 576
26.3.4.1 Stirred Spinner Flask 576
26.3.4.2 Rotating Bioreactors 577
26.3.4.3 Perfusion Bioreactors 577
26.4 Experimental and Clinical Applications of Tissue Engineering in OMFS 577
26.4.1 Cartilage Tissue Engineering 577
26.4.1.1 Experimental Tissue-Engineered Growth of Cartilage 577
Cell Concentration Study 577
Injectable Cartilage 578
Quality Control Using Magnetic Resonance Imaging (MRI) 578
Biomechanical Testing of New Cartilage Generated by Tissue Engineering 579
Facial Implants Generated by Tissue-Engineered Growth of Cartilage 579
Transplantation of Neocartilage Created by TE Techniques 582
26.4.1.2 Clinical Applications of Cartilage Engineering in OMFS 582
Tissue-Engineered Growth of a Temporomandibular Joint (TMJ) Disk Replacement 582
26.4.2 Bone Tissue Engineering 584
26.4.2.1 Experimental Tissue-Engineered Growth of Bone 584
26.4.2.2 Clinical Application of Bone Engineering in OMFS 585
26.4.2.3 Bone Regeneration and Reformation 586
Platelet-Rich Plasma (PRP) 586
Bone Morphogenetic Proteins (BMPs) 586
26.4.2.4 Guided Tissue Regeneration 587
Guided Bone Regeneration 587
26.4.3 Periodontal Tissue Engineering 587
26.5 Expert Opinion 588
26.6 Five Year Perspective 589
26.7 Limitations/Critical View 589
26.8 Conclusion/Summary 589
Suggested Readings 590
References 590
27: Tissue Engineering of Musculoskeletal Tissue 594
27.1 Introduction and Objectives 594
27.2 Features of Musculoskeletal Tissues Which Impact Tissue Engineering 594
27.3 Bone Tissue 596
27.3.1 Bone Composition and Structure 596
27.3.2 Bone Reconstruction and State of the Art 597
27.3.3 Investigative Approaches to Advance Bone–Tissue Engineering 597
27.3.3.1 Biomaterial Scaffolds 597
27.3.3.2 Growth Factors 598
27.3.3.3 Exogenous Cells 598
27.3.4 Clinical Applications of Bone–Tissue Engineering 602
27.3.5 Limitations 603
27.3.6 Conclusions 603
27.4 Cartilage Tissue 603
27.4.1 Types of Cartilage 603
27.4.2 Cartilage Cells Isolated for Tissue Engineering 604
27.4.3 Articular Cartilage Tissue Engineering 604
27.4.3.1 Aim of the Discipline 604
27.4.3.2 State of the Art 605
27.4.3.3 Clinical Applications 609
27.4.3.4 Conclusion 609
27.4.4 Fibrocartilage 609
27.4.4.1 Meniscus 609
27.4.4.2 Intervertebral Disc, IVD 610
27.5 Synovium Tissue 610
27.5.1 Synovium Composition and Structure 610
27.5.2 Aim of the Discipline 611
27.5.3 State of the Art 611
27.5.4 Conclusion 612
27.6 Tendons and Ligaments 612
27.6.1 Introduction 612
27.6.2 Aim of the Discipline 613
27.6.3 State of the Art 613
27.6.4 Critical View 615
27.6.5 Conclusion 615
27.7 Skeletal Muscle 615
27.7.1 Introduction 615
27.7.2 Aim of the Discipline 616
27.7.3 State of the Art 616
27.7.4 Critical View 618
27.7.5 Conclusion 618
Reference 618
Index 622