Santin. / Santin Strategies in Regenerative Medicine

Integrating Biology with Materials Design
1. Auflage 2009
ISBN: 978-0-387-74660-9
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 605 Seiten

The profound transformations occurred in our modern age have been made possible by the unique combination of new technologies. Among them, me- cine has completely changed our perception of life. Longevity has been signi- cantly extended and linked to new lifestyles. The negative impact that pathologies and ageing have always had on the quality of our life is now mitigated by the availability of treatments daily applied to many individuals worldwide. For many years, pharmacological and surgical treatments have been supported by the introduction of biomedical devices. Biomedical implants have played a key role in the development of these treatments and achieved the objective of replacing tissue and organ structures and functionalities. Gra- ally, the scientific and clinical communities have understood that replacement could be improved by materials able to interact with the tissues and to parti- pate in their metabolism and functions. This approach soon led to biomedical implants with improved clinical performances, but also to a new aspiration; rather than replacing damaged tissues and organs scientists and clinicians nowadays aim at their partial or complete regeneration. As a consequence of this ambition, the disciplines of tissue engineering and regenerative medicine have recently emerged. It is the dawn of a fascinating era where scientists from various disciplines, clinicians, and industry will need to intensify their col- borative efforts to provide our society with new and affordable solutions.

Autoren/Hrsg.

Santin., Matteo

Santin, Matteo

Inhaltsverzeichnis

1;Preface;6
2;Contents;8
3;Contributors;10
4;The Editor’s Profile;15
5;Introduction: History of Regenerative Medicine;17
5.1;1.1 Introduction;17
5.2;1.2 The Pioneers;18
5.2.1;1.2.1 The Pioneers of Tissue Engineering and of Clinical Tissue Regeneration;18
5.2.2;1.2.2 The Pioneers of the Biomimicking Biomaterials Science;20
5.2.3;1.2.3 The Pioneers of the Tissue Engineering Science;23
5.3;1.3 The Birth of Regenerative Medicine;24
5.3.1;1.3.1 Early Clinical Applications;25
5.3.2;1.3.2 Commercialization Efforts;25
5.4;1.4 Challenges;27
5.5;Questions;27
5.6;References;28
6;Soft Tissues Characteristics and Strategies for Their Replacement and Regeneration;30
6.1;2.1 Composition-Structure-Properties of Soft Tissues: Introduction;31
6.2;2.2 Tendons and Ligaments;32
6.2.1;2.2.1 Composition and Structure;32
6.2.2;2.2.2 Mechanical Properties;33
6.3;2.3 Skin;35
6.3.1;2.3.1 Composition and Structure;35
6.3.2;2.3.2 Mechanical Properties;37
6.4;2.4 Arteries;40
6.4.1;2.4.1 Composition and Structure;40
6.4.2;2.4.2 Mechanical Properties;42
6.5;2.5 Cartilage;43
6.5.1;2.5.1 Composition and Structure;43
6.5.2;2.5.2 Mechanical Properties;46
6.6;2.6 Soft Tissue Replacements;49
6.6.1;2.6.1 Introduction;49
6.7;2.7 Ligament Prostheses;49
6.8;2.8 Skin Replacements;53
6.8.1;2.8.1 Skin Substitutes for Wound Cover;55
6.8.1.1;2.8.1.1 Biobranereg;55
6.8.1.2;2.8.1.2 Transcytereg;55
6.8.1.3;2.8.1.3 Apligrafreg;55
6.8.1.4;2.8.1.4 Dermagraftreg;55
6.8.2;2.8.2 Skin Substitutes for Wound Closure;56
6.8.2.1;2.8.2.1 Allodermreg;56
6.8.2.2;2.8.2.2 Integrareg;56
6.8.2.3;2.8.2.3 Cultured Epidermal Autograft (CEA);56
6.8.2.4;2.8.2.4 Cultured Skin Substitutes (CSS);57
6.9;2.9 Vascular Grafts;57
6.10;2.10 Cartilage Replacement;60
6.10.1;2.10.1 Joint Resurfacing;60
6.10.2;2.10.2 Biological Autograft;60
6.10.3;2.10.3 Total Joint Replacement;61
6.10.4;2.10.4 Tissue Engineered Constructs;61
6.11;Questions/Exercises;64
6.12;References;65
7;Biomaterials for Tissue Engineering of Hard Tissues;70
7.1;3.1 Function and Structure of Bone;71
7.2;3.2 Bone Engineering;71
7.2.1;3.2.1 Cells;72
7.2.2;3.2.2 Growth Factors;73
7.2.3;3.2.3 Scaffolds;74
7.3;3.3 Synthetic Material for Bone Repair Biodegradable Scaffolds;75
7.3.1;3.3.1 Bioactive Glass Ceramics;79
7.4;3.4 Natural Biodegradable Scaffolds for Bone Repair;81
7.5;3.5 Bio-Stable Materials;84
7.5.1;3.5.1 Natural: Hydroxyapatite;84
7.5.1.1;3.5.1.1 Bioceramic Coatings;85
7.5.1.2;3.5.1.2 Bioactive Ceramics;86
7.5.2;3.5.2 Synthetic Materials;87
7.5.2.1;3.5.2.1 Metals;87
7.5.2.1.1;Most Important Applications of SMA Devices in Biomedicine are the;90
7.5.2.2;3.5.2.2 Polymers;90
7.6;3.6 Composite Materials;92
7.6.1;3.6.1 Why Porosity is Needed?;95
7.6.2;3.6.2 PLA-Glasses;96
7.6.3;3.6.3 Collagen-Cement Composites;96
7.6.4;3.6.4 Hyaluronic Acid-collagen;96
7.6.5;3.6.5 Coated Scaffolds;97
7.6.6;3.6.6 Self Assembly Nanofibers for Biomineralization;97
7.7;3.7 Characterization Methods;98
7.7.1;3.7.1 Porosity;98
7.7.2;3.7.2 Microstructure;98
7.7.3;3.7.3 Surface Properties;99
7.7.4;3.7.4 Dynamic and Static Contact Angles Measurement;100
7.7.5;3.7.5 Mechanical Properties;100
7.7.6;3.7.6 Z Potential;100
7.7.7;3.7.7 Solubility of the Different Compounds;101
7.7.8;3.7.8 Adsorbed Protein Amount;101
7.7.9;3.7.9 Statistical Study;101
7.8;3.8 Bone Disease Society Impact and Market;102
7.8.1;3.8.1 Incidence of Bone Fractures;102
7.8.2;3.8.2 Business Market on Bone Tissue Engineering;102
7.9;Questions/Exercises;104
7.10;References;105
8;Biomimetic and Bio-responsive Materials in Regenerative Medicine;112
8.1;4.1 Introduction to Biomimetic Materials;113
8.2;4.2 Biomimetic Rationale and Design Principles;114
8.3;4.3 Mammalian Tissue and Natural ECM as Design Guides;117
8.3.1;4.3.1 ECM Composition and Structure;117
8.3.1.1;4.3.1.1 ECM Types and Function;117
8.3.1.2;4.3.1.2 ECM Structure;119
8.3.1.3;4.3.1.3 ECM Components;119
8.3.1.4;4.3.1.4 ECM Receptors;120
8.4;4.4 Tissue Dynamics;121
8.4.1;4.4.1 ECM Metabolism;121
8.4.2;4.4.2 Enzymatic Catabolism;123
8.5;4.5 Strategies for Biomimetic Tissue Regeneration;124
8.5.1;4.5.1 Matrices and Tissue Conduction;125
8.5.2;4.5.2 Growth Factors and Cellular Induction;126
8.5.3;4.5.3 Cells and Tissue Neogenesis;128
8.6;4.6 Building Biomimetic Materials;130
8.6.1;4.6.1 Starting Materials;130
8.6.2;4.6.2 Natural Biopolymers;130
8.6.3;4.6.3 Synthetic Polymers;132
8.6.4;4.6.4 Hybrid and Composite Materials;133
8.7;4.7 Biomimetic Material Synthesis;133
8.7.1;4.7.1 Macromers;133
8.7.2;4.7.2 Conjugation Methods;134
8.7.3;4.7.3 In Situ Material Synthesis;134
8.7.4;4.7.4 Free Radical Polymerization;135
8.7.5;4.7.5 Step-Growth Polymerization;135
8.7.6;4.7.6 Physical Association;136
8.7.7;4.7.7 Molecular Self-Assembly;137
8.8;4.8 Biomimetic Elements;137
8.8.1;4.8.1 Cell Adhesion Domains;137
8.8.1.1;4.8.1.1 Cellular Adhesion;137
8.8.1.2;4.8.1.2 Conjugation of Cell-Binding Motifs to Polymers;140
8.8.1.3;4.8.1.3 Self-Assembling Nanofibers Featuring Cell-Binding Motifs;142
8.8.1.4;4.8.1.4 Reactive Macromers Containing Cell-Binding Motifs;142
8.8.1.5;4.8.1.5 Parameters and Effects of Cell-Binding Motif Incorporation;143
8.8.2;4.8.2 Substrate Mechanics;146
8.8.3;4.8.3 Enzymatic Degradability;148
8.8.3.1;4.8.3.1 Engineering Degradability into Biomaterials;148
8.8.3.2;4.8.3.2 Methods of Imparting Enzymatic Degradability;150
8.8.3.3;4.8.3.3 Effects of Enzymatic Degradability;150
8.8.4;4.8.4 Growth Factor Activity;152
8.8.4.1;4.8.4.1 Considerations for Growth Factor Incorporation;152
8.8.4.2;4.8.4.2 Growth Factor Encapsulation;152
8.8.4.3;4.8.4.3 Growth Factor Conjugation;154
8.8.4.4;4.8.4.4 Heparin and Heparin-Binding Incorporation;156
8.8.4.5;4.8.4.5 Multiple Growth Factor Release Profiles;158
8.9;4.9 Neglected Topics in Biomimetic Materials;159
8.10;Questions/Exercises;160
8.11;Top Ten Original Publications from the Last Decade;161
8.12;References;161
9;Clinical Approaches to Skin Regeneration;170
9.1;5.1 Introduction;170
9.2;5.2 Normal Skin Structure and Function;171
9.2.1;5.2.1 Epidermis;172
9.2.2;5.2.2 Basement Membrane;172
9.2.3;5.2.3 Dermis;172
9.2.4;5.2.4 Cellular Component of the Dermis;173
9.3;5.3 Mechanisms of Skin Loss;174
9.3.1;5.3.1 Pathological Damage;174
9.3.1.1;5.3.1.1 Wound Depth;174
9.3.2;5.3.2 Surgical Damage;175
9.4;5.4 Healing of Wounds;176
9.4.1;5.4.1 Wound Closure Categories;176
9.4.1.1;5.4.1.1 Primary Healing;177
9.4.1.2;5.4.1.2 Secondary Healing;177
9.4.1.3;5.4.1.3 Tertiary Healing;177
9.4.2;5.4.2 Wound Healing Process;177
9.4.2.1;5.4.2.1 Hemostasis and Inflammation;178
9.4.2.2;5.4.2.2 Proliferative Phase;179
9.4.2.3;5.4.2.3 Scar Maturation or the Remodeling Phase;180
9.5;5.5 Problems of Natural Wound Healing;180
9.6;5.6 Current Clinical Approaches to Wound Healing;181
9.7;5.7 Development of Novel Approaches to Skin Regeneration;184
9.7.1;5.7.1 Surgical Use of Cultured Keratinocytes in Burns Patients;184
9.7.2;5.7.2 Commercially Available Skin Substitutes;189
9.7.3;5.7.3 Clinical Application of Skin Substitutes;190
9.8;Questions/Exercises;200
9.9;References;201
10;Angiogenesis in Development, Disease, and Regeneration;203
10.1;6.1 Introduction;204
10.2;6.2 Developmental Angiogenesis;204
10.3;6.3 Angiogenesis in Adult Life;205
10.4;6.4 Endothelial Cell Specialization;207
10.5;6.5 Molecular Regulators of Angiogenesis;209
10.5.1;6.5.1 Vascular Endothelial Growth Factor;211
10.5.2;6.5.2 Hypoxia-Inducible Factor 1;212
10.5.3;6.5.3 Angiopoietins and Tie Receptors;213
10.5.4;6.5.4 Platelet Derived Growth Factor (PDGF) Family;214
10.6;6.6 Structure of the Blood Vessel;215
10.7;6.7 Angiogenesis and Tissue Development;216
10.7.1;6.7.1 Pancreas;216
10.7.2;6.7.2 Liver;216
10.7.3;6.7.3 Nervous System;217
10.7.4;6.7.4 Adipose Tissue;218
10.8;6.8 Angiogenesis in Pathological Conditions;220
10.8.1;6.8.1 Angiogenesis in Tumors;221
10.8.2;6.8.2 Psoriasis;227
10.8.3;6.8.3 Ocular Neovascularization;227
10.8.4;6.8.4 Atherosclerosis;227
10.9;6.9 Tools to Study Angiogenesis;228
10.9.1;6.9.1 Matrigel Tube Formation Assay;229
10.9.2;6.9.2 Cornea Pocket Assay;229
10.9.3;6.9.3 Chamber Models;229
10.10;6.10 Angiogenesis in Regeneration;230
10.10.1;6.10.1 Growth Factors Based Pro-angiogenic Therapy;233
10.10.2;6.10.2 Cell-based Pro-angiogenic Therapy;234
10.11;6.11 Concluding Remarks;236
10.12;Questions/Exercises;236
10.13;References;237
11;Tissue Engineering of Small- and Large- Diameter Blood Vessels;244
11.1;7.1 Introduction;244
11.2;7.2 Historical Overview - Development of Artificial Vascular Grafts;245
11.3;7.3 State of the Art - Currently Used Synthetic Vascular Grafts;246
11.3.1;7.3.1 Dacron (PET);246
11.3.2;7.3.2 Expanded Polytetrafluorethylene (ePTFE);246
11.3.3;7.3.3 Polyurethanes (PU);247
11.3.4;7.3.4 Limitations of the Currently Used Vascular Grafts;247
11.3.4.1;7.3.4.1 Patency Rates;248
11.3.4.2;7.3.4.2 Potential for Regeneration, Remodeling, and Growth;249
11.4;7.4 Requirements for the ‘‘Ideal’’ Vascular Replacement;249
11.5;7.5 Tissue Engineering - A Promising Concept for ‘‘Ideal’’ Vascular Replacements;251
11.5.1;7.5.1 The Golden Standard - Architecture and Characteristics of Native Blood Vessels;251
11.5.1.1;7.5.1.1 General structure;251
11.5.1.2;7.5.1.2 Arteries;253
11.5.1.3;7.5.1.3 Veins;253
11.5.2;7.5.2 Tissue Engineering of Vascular Grafts - Strategies and Approaches;253
11.5.2.1;7.5.2.1 Scaffolds for the Engineering of Vascular Grafts;254
11.5.2.1.1;Natural scaffolds;254
11.5.2.1.2;Permanent Synthetic Scaffolds;255
11.5.2.1.3;Biodegradable Synthetic Scaffolds;255
11.5.2.2;7.5.2.2 Cells;257
11.5.2.2.1;Vascular-Derived Cells;257
11.5.2.2.2;Bone Marrow-Derived Cells;257
11.5.2.2.3;Blood-Derived Cells;258
11.5.2.2.4;Umbilical Cord-Derived Cells;258
11.5.3;7.5.3 How to Match the Mechanical Requirements of Native Tissue ;259
11.5.4;7.5.4 Tissue Engineering of Small-Diameter Vessels - In Vitro and In Vivo Studies;260
11.5.5;7.5.5 Tissue Engineering of Large-diameter Vessels - In Vitro and In Vivo Studies;263
11.5.6;7.5.6 First Clinical Experiences;264
11.6;7.6 Limitations and Future Perspectives;265
11.7;7.7 Summary;266
11.8;Questions/Exercises;267
11.9;References;267
12;Pancreas Biology, Pathology, and Tissue Engineering;274
12.1;8.1 Introduction;274
12.2;8.2 Pancreas Biology;276
12.2.1;8.2.1 Islets of Langerhans;276
12.3;8.3 Pathology;277
12.3.1;8.3.1 Pathogenesis and beta-cell Dysfunction in Diabetes;277
12.3.2;8.3.2 Pathogenesis of Diabetes and Mechanisms of beta-Cell Death;278
12.3.2.1;8.3.2.1 Type 1 diabetes;278
12.3.2.2;8.3.2.2 Type 2 diabetes;280
12.3.2.3;8.3.2.3 Thiazolidinediones (TZDs);280
12.3.2.4;8.3.2.4 GLP-1 and Dipeptidyl Peptidase IV (DPP-IV) Inhibitors;281
12.4;8.4 Tissue Engineering: Generating Replacement beta-cells;282
12.4.1;8.4.1 Islet Transplantation;282
12.4.2;8.4.2 Engineering Replacement beta-cells;283
12.4.3;8.4.3 Adult Stem Cells: Pancreas;284
12.4.4;8.4.4 Liver Cells;286
12.4.5;8.4.5 Bone Marrow;287
12.4.6;8.4.6 Embryonic Stem Cells;288
12.5;8.5 Summary;290
12.6;Questions/Exercises;290
12.7;References;291
13;The Holy Grail of Hepatocyte Culturing and Therapeutic Use;295
13.1;9.1 Introduction;296
13.2;9.2 Legal Aspects of Cell Therapy in Future;296
13.3;9.3 Hepatocyte Isolation and Culture;297
13.4;9.4 Clinical Hepatocyte Transplantation;301
13.5;9.5 Hepatocytes Used in Drug Development - Metabolism and Toxicology;303
13.6;9.6 Hepatocytes Generated by Stem Cell Technology;304
13.6.1;9.6.1 Can Human Hepatocytes Be Produced by Stem Cell Technology? An Overview;304
13.6.2;9.6.2 Transdifferentiation of Extrahepatic Cells to Hepatocytes? First Evidence Pointing towards Bone Marrow Cells;306
13.6.3;9.6.3 Cell Fusion or Transdifferentiation? A Question of Potential Clinical Relevance;307
13.6.4;9.6.4 The Discovery of ‘‘Fusogenic Cells’’ in Mouse Bone Marrow;308
13.6.5;9.6.5 Elegant Reporter Studies Differentiate Between Cell Fusion and Real Differentiation;309
13.6.6;9.6.6 Fate of Human Stem and Precursor Cells in Livers of Mice;312
13.6.7;9.6.7 Transdifferentiation of Extrahepatic Human Stem Cells to Hepatocytes In Vitro?;314
13.6.8;9.6.8 Quantitative Analyses Comparing Stem Cell Derived Cells with Primary Hepatocytes;318
13.6.9;9.6.9 5-Years Perspective;320
13.7;Questions/Exercises;324
13.8;Ten Key Publications;325
13.9;References;326
14;Peripheral Nerve Injury, Repair, and Regeneration;333
14.1;10.1 Introduction;333
14.2;10.2 Current Clinical Methods of Nerve Repair and Reconstruction;335
14.2.1;10.2.1 Direct Co-aption (Neurorrhaphy);336
14.2.1.1;10.2.1.1 Epineurial Repair;336
14.2.1.2;10.2.1.2 Grouped Fascicular Repair;336
14.2.1.3;10.2.1.3 Fascicular Repair;337
14.2.2;10.2.2 Nerve Autografts;337
14.2.3;10.2.3 Nerve Transfers;338
14.2.4;10.2.4 Nerve Guidance Tubes;338
14.2.4.1;10.2.4.1 Silicone Tubes and the Development of Clinically Approved Nerve Guidance Tubes;338
14.2.4.2;10.2.4.2 Future Biotechnological Applications of Nerve Guidance Tubes: Administration of Neurotrophic Factors;339
14.3;10.3 Emerging Technologies for Nerve Repair;340
14.3.1;10.3.1 Electric Fields to Aid and Guide Nerve Growth;340
14.3.2;10.3.2 Potential Cellular Machinery Affected by Electric Field Effects;341
14.3.3;10.3.3 Wound Potentials and Spinal Cord Repair;342
14.4;10.4 Use of Stem Cells to Aid Regeneration;343
14.4.1;10.4.1 Mechanical Guidance of Regeneration;344
14.4.2;10.4.2 Microchip Technologies Under Development;344
14.4.3;10.4.3 Technologies for Aiding Repair;344
14.4.3.1;10.4.3.1 Controlled Delivery of Trophic Factors;344
14.4.3.2;10.4.3.2 Microscopic Guidance Techniques;345
14.4.4;10.4.4 Non-Repair Technologies: Prosthetics;346
14.4.4.1;10.4.4.1 Capacitive Interfacing with Transistors and Nanowires;346
14.4.4.2;10.4.4.2 Current Based Interfacing;346
14.4.4.3;10.4.4.3 Partial Regeneration Through Sieve Electrodes;347
14.5;10.5 Summary;347
14.6;Questions/Exercises;347
14.7;References;348
15;Therapeutic Strategies in Ocular Tissue Regeneration: The Role of Stem Cells;353
15.1;11.1 Introduction;354
15.2;11.2 Historical Perspective;355
15.2.1;11.2.1 Healing, Repair, Regeneration, and Reconstitution;355
15.2.2;11.2.2 Evolution-Two Levels of Regeneration;355
15.2.3;11.2.3 ‘‘Three Type of Cells’’ - The Old Theory;356
15.3;11.3 Regenerative Medicine of the Eye;356
15.4;11.4 Stem Cells;357
15.4.1;11.4.1 Stem Cell Hierarchy;357
15.4.2;11.4.2 Embryonic Stem Cells;357
15.4.3;11.4.3 Sources of Embryonic Stem Cells;358
15.4.3.1;11.4.3.1 Blastocyst;358
15.4.3.2;11.4.3.2 Somatic Cell Nuclear Transfer Techniques (SCNT);358
15.4.3.3;11.4.3.3 Pre-Implantation Diagnostic Screening;359
15.4.4;11.4.4 Adult Stem Cells;359
15.4.5;11.4.5 Stem Cells from Umbilical Cord Blood;359
15.4.6;11.4.6 What Determines the Fate of Stem Cells?;359
15.4.7;11.4.7 Stem Cell Niche;360
15.4.8;11.4.8 How to Identify Stem Cells? Stem Cell Markers;361
15.4.9;11.4.9 How Safe are Stem Cells for Cell Therapy?;361
15.5;11.5 Genetic Regulations of Stem Cells;361
15.5.1;11.5.1 Genes Controlling Embryonic Stem Cells;362
15.5.2;11.5.2 Regulation of Ocular Stem Cells - Pax6;362
15.5.3;11.5.3 Transdifferentiation, Metaplasia, and Re-Programming of Cell Fate;363
15.6;11.6 Ocular Stem Cells;364
15.6.1;11.6.1 Corneal Epithelial Stem Cells;364
15.6.2;11.6.2 Endothelial Stem Cells;365
15.6.3;11.6.3 Retinal Stem Cells;365
15.6.4;11.6.4 Stem Cells in New Blood Vessels;365
15.7;11.7 Disorders of Stem Cells in the Eye;366
15.8;11.8 Strategies of Ocular Regeneration;366
15.8.1;11.8.1 Limitation of Tissue Damage;366
15.8.1.1;11.8.1.1 Inflammation and Tissue Damage;366
15.8.1.2;11.8.1.2 Treatments to Limit Tissue Damage;368
15.8.1.3;11.8.1.3 Modulation by NF-kappaB;368
15.8.2;11.8.2 Ocular Regeneration with Stem Cells;369
15.8.2.1;11.8.2.1 Keratolimbal Transplantation;370
15.8.2.2;11.8.2.2 Ex vivo Limbal Stem Cell expansion;371
15.8.2.3;11.8.2.3 Regeneration of the Retina;371
15.9;11.9 Gene Therapy;372
15.10;11.10 The Future;373
15.11;Questions/Exercises;373
15.12;References;374
16;Cartilage Development, Physiology, Pathologies, and Regeneration;378
16.1;12.1 Introduction;378
16.2;12.2 Articular Cartilage Development, Composition, and Structure;379
16.2.1;12.2.1 Development;379
16.2.2;12.2.2 Composition;380
16.2.3;12.2.3 Structure;382
16.3;12.3 Pathology, Pathophysiology, Pharmacological Therapies of Osteoarthritis;383
16.3.1;12.3.1 Arthritis;383
16.3.2;12.3.2 Osteoarthritis Pathology;383
16.3.3;12.3.3 Risk Factors for Osteoarthritis;384
16.3.4;12.3.4 Pathophysiology of Osteoarthritis;385
16.3.5;12.3.5 Pharmacological Therapies for Osteoarthritis;386
16.4;12.4 Cartilage Repair and Regeneration;386
16.4.1;12.4.1 Articular Cartilage Defects and Spontaneous Repair;386
16.4.2;12.4.2 Current Operative Strategies for Articular Cartilage Repair;388
16.4.3;12.4.3 Mesenchymal Stem Cells (MSCs);390
16.4.4;12.4.4 Chondrogenic Differentiation of MSCs;390
16.4.5;12.4.5 Tissue Engineering;392
16.4.6;12.4.6 Experimental Approaches for Articular Cartilage Tissue Engineering;393
16.5;12.5 Conclusions;397
16.6;Questions/Exercises;397
16.7;References;398
17;Basic Science and Clinical Strategies for Articular Cartilage Regeneration/Repair;405
17.1;13.1 Introduction;405
17.2;13.2 Articular Cartilage and its Repair;406
17.2.1;13.2.1 Normal Articular Cartilage: Basic Science of Structure, Biology, and Function;407
17.2.2;13.2.2 The Vital Role of Growth Factors in Normal Articular Cartilage Matrix Biosynthesis;408
17.2.3;13.2.3 Optimal Chondrocyte Density in Cartilage;410
17.2.4;13.2.4 Clinical Findings of Cartilage Structure Functionality;412
17.3;13.3 Hyaline Articular Cartilage Response to Injury;413
17.4;13.4 Treatment Options for Cartilage Injuries;415
17.5;13.5 Autologous Chondrocyte Implantation;418
17.5.1;13.5.1 ACI Surgical Procedure and Technique;419
17.6;13.6 Key Questions About ACI;422
17.7;13.7 Conclusions: The Clinicians’ View on Treatments for Articular Cartilage Repair;434
17.8;References;436
18;Bone Biology: Development and Regeneration Mechanisms in Physiological and Pathological Conditions;441
18.1;14.1 Introduction;441
18.2;14.2 Macroscopic and Microscopic Structure of Bone;442
18.3;14.3 Differentiation and Functional Activities of Osteoblastic Cells;443
18.4;14.4 Bone Remodeling;444
18.5;14.5 Bone Development and Growth;445
18.6;14.6 Bone Repair and Regeneration;446
18.7;14.7 Bone Morphogenetic Proteins and Transforming Growth Factor-betas;448
18.8;14.8 Bone Tissue Engineering by BMP;451
18.9;14.9 Angiogenesis and Bone Regeneration;453
18.10;14.10 Bone Formation in Pathologic Conditions;453
18.10.1;14.10.1 Bone Tumors;453
18.10.2;14.10.2 Myositis Ossificans and Fibrodysplasia Ossificans Progressiva (FOP);454
18.10.3;14.10.3 Ossification of the Spinal Ligaments;455
18.11;14.11 Conclusions;455
18.12;Questions;456
18.13;References;456
19;Clinical Applications of Bone Tissue Engineering;459
19.1;15.1 Introduction;459
19.2;15.2 The Clinical Problem;462
19.3;15.3 Stem Cells in Orthopedic Therapy;463
19.4;15.4 Biomaterials as Biomimetic Scaffolds;466
19.5;15.5 Clinical Applications in Orthopedics;469
19.6;15.6 Conclusions;470
19.7;Questions/Exercises;472
19.8;References;472
20;Conclusions: Towards High-Performance and Industrially Sustainable Tissue Engineering Products;477
20.1;16.1 Introduction;477
20.2;16.2 From Interfacial to Complete Tissue Regeneration;478
20.2.1;16.2.1 Development of Non-Invasive Implantation Procedures;480
20.2.1.1;16.2.1.1 Injectable Biomaterials;481
20.2.1.2;16.2.1.2 Self-Assembling Biomolecules;482
20.2.1.3;16.2.1.3 Nanostructured Biomaterials;482
20.2.2;16.2.2 Controlling and Exploiting the Inflammatory Response;483
20.2.2.1;16.2.2.1 Control of Macrophage Activation;484
20.2.2.2;16.2.2.2 Exploitation of the Host Response;485
20.2.3;16.2.3 Biochemical Cues Analogues;486
20.2.3.1;16.2.3.1 Bioligands Analogues;486
20.2.3.2;16.2.3.2 Growth Factors Analogues;487
20.2.3.3;16.2.3.3 Drugs and Bioactive Natural Molecules;488
20.2.4;16.2.4 Biostructural Cues Analogues;491
20.3;16.3 Complete Tissue and Organ Regeneration;494
20.3.1;16.3.1 Technical Issues in Tissue and Organ Regeneration;495
20.3.1.1;16.3.1.1 Biomaterials and Bioreactors;495
20.3.1.1.1;Technical Issues Associated to the Use of Biomimetic and Bioresponsive Biomaterials;495
20.3.1.1.2;Technical Issues Associated to the Use of Bioreactors;496
20.3.1.1.3;Technical Issues Associated to the Use of Cells;496
20.4;16.4 Regulatory Issues;497
20.4.1;16.4.1 The American Federal Law;497
20.4.2;16.4.2 The EC Consultation Process and Regulation;498
20.5;16.5 Towards the Exploitation of Tissue Engineering Products;498
20.5.1;16.5.1 Bioactive Biomaterials Market;499
20.5.2;16.5.2 Stem Cells Market;499
20.6;16.6 Overall Conclusions;500
20.7;References;500
21;Index;504