Principles of Tissue Engineering (eBook)

Front cover 1
PRINCIPLES OF TISSUE ENGINEERING 4
Copyright page 5
CONTENTS IN BRIEF 6
Table of contents 8
CONTRIBUTORS 20
FOREWORD 30
PREFACE 32
PREFACE TO THE SECOND EDITION 34
PREFACE TO THE FIRST EDITION 36
Introduction to Tissue Engineering 38
Chapter One: The History and Scope of Tissue Engineering 40
I. INTRODUCTION 40
II. SCIENTIFIC CHALLENGES 41
III. CELLS 41
IV. MATERIALS 42
V. GENERAL SCIENTIFIC ISSUES 42
VI. SOCIAL CHALLENGES 43
VII. REFERENCES 43
Chapter Two: The Challenge of Imitating Nature 44
I. INTRODUCTION 44
II. CELL TECHNOLOGY 45
III. CONSTRUCT TECHNOLOGY 47
IV. INTEGRATION INTO THE LIVING SYSTEM 48
V. CONCLUDING DISCUSSION 49
VI. ACKNOWLEDGMENTS 50
VII. REFERENCES 50
Chapter Three: Moving into the Clinic 52
I. INTRODUCTION 52
II. HISTORY OF CLINICAL TISSUE ENGINEERING 53
III. STRATEGIES TO ADVANCE TOWARD THE CLINIC 57
IV. BRINGING TECHNOLOGY PLATFORMS TO THE CLINICAL SETTING 63
V. TRANSITION TO CLINICAL TESTING 65
VI. ESTABLISHING A REGULATORY PATHWAY 67
VII. CONCLUSIONS 67
VIII. ACKNOWLEDGMENTS 67
IX. REFERENCES 68
Chapter Four: Future Perspectives 70
I. CLINICAL NEED 70
II. CURRENT STATE OF THE FIELD 70
III. CURRENT CHALLENGES 71
IV. FUTURE DIRECTIONS 71
V. FUTURE CHALLENGES 79
VI. REFERENCES 79
Part One: The Basis of Growth and Differentiation 88
Chapter Five: Molecular Biology of the Cell 90
I. INTRODUCTION 90
II. THE CELL NUCLEUS 91
III. THE CYTOPLASM 93
IV. GROWTH AND DEATH 95
V. CYTOSKELETON 97
VI. CELL ADHESION MOLECULES 98
VII. EXTRACELLULAR MATRIX 99
VIII. CULTURE MEDIA 100
IX. CELLS IN TISSUES 101
X. FURTHER READING 102
Chapter Six: Organization of Cells into Higher-Ordered Structures 104
I. INTRODUCTION 104
II. MOLECULAR MECHANISMS OF THE EMT 105
III. THE EMT TRANSCRIPTIONAL PROGRAM 107
IV. MOLECULAR CONTROL OF THE EMT 109
V. CONCLUSION 113
VI. REFERENCES 113
Chapter Seven: The Dynamics of Cell–ECM Interactions 118
I. INTRODUCTION 118
II. CELL–ECM INTERACTIONS 121
III. SIGNAL TRANSDUCTION EVENTS DURING CELL–ECM INTERACTIONS 127
IV. RELEVANCE FOR TISSUE ENGINEERING 130
V. REFERENCES 132
Chapter Eight: Matrix Molecules and Their Ligands 138
I. INTRODUCTION 138
II. COLLAGENS — MAJOR CONSTITUENTS OF ECM 139
III. ELASTIC FIBERS AND MICROFIBRILS 144
IV. OTHER MULTIFUNCTIONAL PROTEINS IN ECM 144
V. PROTEOGLYCANS — MULTIFUNCTIONAL MOLECULES IN THE EXTRACELLULAR MATRIX AND ON CELL SURFACES 148
VI. CONCLUSION 149
VII. REFERENCES 149
Chapter Nine: Morphogenesis and Tissue Engineering 154
I. INTRODUCTION 154
II. BONE MORPHOGENETIC PROTEINS (BMPs) 155
III. CARTILAGE-DERIVED MORPHOGENETIC PROTEINS (CDMPs) 158
IV. PLEIOTROPY AND THRESHOLDS 158
V. BMPs BIND TO EXTRACELLULAR MATRIX 159
VI. BMP RECEPTORS 159
VII. RESPONDING STEM CELLS 160
VIII. MORPHOGENS AND GENE THERAPY 160
IX. BIOMIMETIC BIOMATERIALS 161
X. TISSUE ENGINEERING OF BONES AND JOINTS 161
XI. FUTURE CHALLENGES 162
XII. ACKNOWLEDGMENTS 163
XIII. REFERENCES 163
Chapter Ten: Gene Expression, Cell Determination, and Differentiation 166
I. INTRODUCTION 166
II. DETERMINATION AND DIFFERENTIATION 166
III. MyoD AND THE bHLH FAMILY OF DEVELOPMENTAL REGULATORY FACTORS 168
IV. MEFs — COREGULATORS OF DEVELOPMENT 169
V. PAX IN DEVELOPMENT 169
VI. CONCLUSIONS 169
VII. REFERENCES 170
Part Two: In Vitro Control of Tissue Development 172
Chapter Eleven: Engineering Functional Tissues 174
I. INTRODUCTION 174
II. KEY CONCEPTS 175
III. IN VITRO STUDIES AIMED AT CLINICAL TRANSLATION 176
IV. REPRESENTATIVE IN VITRO CULTURE ENVIRONMENTS 176
V. CONVECTIVE MIXING, FLOW, AND MASS TRANSFER 179
VI. CULTURE DURATION AND MECHANICAL CONDITIONING 182
VII. CONCLUSIONS 186
VIII. ACKNOWLEDGMENTS 187
IX. REFERENCES 187
Chapter Twelve: Principles of Tissue Culture and Bioreactor Design 192
I. INTRODUCTION 192
II. BASIC PRINCIPLES OF CELL AND TISSUE CULTURE 192
III. PRINCIPLES OF BIOREACTOR DESIGN 201
IV. SUMMARY 217
V. ACKNOWLEDGMENTS 217
VI. REFERENCES 217
Chapter Thirteen: Regulation of Cell Behavior by Extracellular Proteins 222
I. INTRODUCTION 222
II. THROMBOSPONDIN-1 222
III. THROMBOSPONDIN-2 224
IV. TENASCIN-C 224
V. OSTEOPONTIN 225
VI. SPARC 226
VII. CONCLUSIONS 227
VIII. REFERENCES 228
Chapter Fourteen: Growth Factors 230
I. INTRODUCTION 230
II. WOUND HEALING 231
III. GROWTH FACTORS AND CYTOKINES ACTIVE AS EARLY MEDIATORS OF THE INFLAMMATORY PROCESS 232
IV. INFLAMMATORY RESPONSE MEDIATORS ACTIVATE TRANSCRIPTION OF QUIESCENT GENES 233
V. BIOLOGIC PROPERTIES OF SIG (CHEMOKINE) FAMILY MEMBERS 234
VI. REGULATION OF JE GENE EXPRESSION BY GLUCOCORTICOIDS 234
VII. GROWTH FACTORS AND ACCELERATED HEALING 234
VIII. ROLE OF BASIC FIBROBLAST GROWTH FACTOR AND ANGIOGENESIS 236
IX. PLEIOTROPHIN REMODELS TUMOR MICROENVIRONMENT AND STIMULATES ANGIOGENESIS 237
X. OTHER ROLES OF GROWTH FACTORS AND CYTOKINES 238
XI. CONCLUSIONS 238
XII. REFERENCES 238
Chapter Fifteen: Mechanochemical Control of Cell Fate Switching 244
I. INTRODUCTION 244
II. EXTRACELLULAR MATRIX STRUCTURE AND FUNCTION 244
III. PATTERN FORMATION THROUGH ECM REMODELING 246
IV. MECHANOCHEMICAL SWITCHING BETWEEN CELL FATES 247
V. SUMMARY 250
VI. THE FUTURE 250
VII. ACKNOWLEDGMENTS 251
VIII. REFERENCES 251
Part Three: In Vivo Synthesis of Tissues and Organs 254
Chapter Sixteen: In Vivo Synthesis of Tissues and Organs 256
I. INTRODUCTION 256
II. MAMMALIAN RESPONSE TO INJURY 257
III. METHODS TO TREAT LOSS OF ORGAN FUNCTION 258
IV. ACTIVE EXTRACELLULAR MATRIX ANALOGS 260
V. BASIC PARAMETERS FOR IN VIVO REGENERATION STUDIES: REPRODUCIBLE, NONREGENERATIVE WOUNDS 264
VI. EXAMPLES OF IN VIVO ORGAN REGENERATION 265
VII. CONCLUSIONS 272
VIII. ACKNOWLEDGMENTS 273
IX. REFERENCES 273
Part Four: Models for Tissue Engineering 276
Chapter Seventeen: Models as Precursors for Prosthetic Devices 278
I. INTRODUCTION 278
II. PIGMENTATION OF THE LIVING-SKIN EQUIVALENT (LSE) IN VITRO 281
III. THE LIVING-SKIN EQUIVALENT AS AN IMMUNOLOGICAL MODEL 281
IV. THE LIVING-SKIN EQUIVALENT AS A DISEASE MODEL 281
V. WOUND-HEALING MODEL 283
VI. VASCULAR MODELS WITHOUT CELLS 284
VII. VASCULAR MODELS WITH CELLS ADDED 284
VIII. CONCLUSIONS 285
IX. REFERENCES 286
Chapter Eighteen: Quantitative Aspects 288
I. INTRODUCTION 288
II. MOLECULAR INTERACTIONS WITH CELLS 288
III. MOLECULAR AND CELL TRANSPORT THROUGH TISSUE 290
IV. CELL AND TISSUE MECHANICS 293
V. REFERENCES 297
Part Five: Biomaterials in Tissue Engineering 300
Chapter Nineteen: Micro-Scale Patterning of Cells and Their Environment 302
I. INTRODUCTION 302
II. SOFT LITHOGRAPHY 303
III. SELF-ASSEMBLED MONOLAYERS (SAMs) 303
IV. MICROCONTACT PRINTING AND MICROFEATURES USED IN CELL BIOLOGY 304
V. MICROFLUIDIC PATTERNING 309
VI. LAMINAR FLOW PATTERNING 309
VII. CONCLUSION AND FUTURE PROSPECTS 311
VIII. ACKNOWLEDGMENTS 312
IX. REFERENCES 312
Chapter Twenty: Cell Interactions with Polymers 316
I. INTRODUCTION 316
II. METHODS FOR CHARACTERIZING CELL INTERACTIONS WITH POLYMERS 316
III. CELL INTERACTIONS WITH POLYMERS 320
IV. CELL INTERACTIONS WITH POLYMERS IN SUSPENSION 326
V. CELL INTERACTIONS WITH THREE-DIMENSIONAL POLYMER SCAFFOLDS AND GELS 328
VI. CELL INTERACTIONS UNIQUE TO THE IN VIVO SETTING 329
VII. REFERENCES 330
Chapter Twenty-One: Matrix Effects 334
I. INTRODUCTION 334
II. EXTRACELLULAR MATRIX PROTEINS AND THEIR RECEPTORS 334
III. MODEL SYSTEMS FOR STUDY OF MATRIX INTERACTIONS 338
IV. CELL PATTERN FORMATION BY SUBSTRATE PATTERNING 341
V. CONCLUSIONS 341
VI. REFERENCES 342
Chapter Twenty-Two: Polymer Scaffold Fabrication 346
I. INTRODUCTION 346
II. FIBER BONDING 347
III. ELECTROSPINNING 348
IV. SOLVENT CASTING AND PARTICULATE LEACHING 348
V. MELT MOLDING 349
VI. MEMBRANE LAMINATION 349
VII. EXTRUSION 349
VIII. FREEZE-DRYING 350
IX. PHASE SEPARATION 350
X. HIGH-INTERNAL-PHASE EMULSION 350
XI. GAS FOAMING 350
XII. POLYMER/CERAMIC COMPOSITE FABRICATION 351
XIII. RAPID PROTOTYPING OF SOLID FREE FORMS 352
XIV. PEPTIDE SELF-ASSEMBLY 353
XV. IN SITU POLYMERIZATION 353
XVI. CONCLUSIONS 354
XVII. ACKNOWLEDGMENTS 354
XVIII. REFERENCES 357
Chapter Twenty-Three: Biodegradable Polymers 360
I. INTRODUCTION 360
II. BIODEGRADABLE POLYMER SELECTION CRITERIA 360
III. BIOLOGICALLY DERIVED BIORESORBABLES 361
IV. SYNTHETIC POLYMERS 364
V. CREATING MATERIALS FOR TISSUE-ENGINEERED PRODUCTS 369
VI. CONCLUSION 370
VII. REFERENCES 370
Chapter Twenty-Four: Micro- and Nanofabricated Scaffolds 378
I. INTRODUCTION 378
II. ADAPTATION OF TRADITIONAL MICRO-SCALE TECHNIQUES FOR SCAFFOLD FABRICATION 379
III. THREE-DIMENSIONAL SCAFFOLDS WITH MICRO-SCALE ARCHITECTURE 383
IV. THREE-DIMENSIONAL SCAFFOLD ASSEMBLY 385
V. MICROFABRICATION OF CELL-SEEDED SCAFFOLDS 389
VI. SUMMARY AND FUTURE DIRECTION 393
VII. REFERENCES 394
Chapter Twenty-Five: Three-Dimensional Scaffolds 396
I. INTRODUCTION 396
II. THREE-DIMENSIONAL SCAFFOLD DESIGN AND ENGINEERING 397
III. CONCLUSIONS 407
IV. REFERENCES 408
Part Six: Transplantation of Engineered Cells and Tissues 412
Chapter Twenty-Six: Tissue Engineering and Transplantation in the Fetus 414
I. INTRODUCTION 414
II. GENERAL CHARACTERISTICS OF FETAL CELLS 415
III. FETAL TISSUE ENGINEERING 416
IV. ETHICAL CONSIDERATIONS 421
V. THE FETUS AS A TRANSPLANTATION HOST 421
VI. CONCLUSIONS 422
VII. REFERENCES 423
Chapter Twenty-Seven: Immunomodulation 426
I. INTRODUCTION 426
II. ORIGIN OF THE DESIGNER TISSUE CONCEPT 427
III. FIRST DEMONSTRATION OF THE CONCEPT 427
IV. EXPANSION OF RESEARCH ON DESIGNER TISSUES 428
V. ANTIBODY MASKING 428
VI. GENE ABLATION 429
VII. RNA ABLATION 430
VIII. ENZYME ABLATION 430
IX. MECHANISMS OF GRAFT SURVIVAL AFTER CLASS I DONOR ABLATION OR ANTIBODY MASKING 431
X. ROLE OF CLASS I MODIFICATIONS IN RESISTANCE TO RECURRENT AUTOIMMUNITY 432
XI. LAUNCHING OF XENOGENEIC HUMAN CLINICAL TRIALS IN THE UNITED STATES USING IMMUNOMODULATION 433
XII. COMMENT 433
XIII. REFERENCES 434
Chapter Twenty-Eight: Immunoisolation 436
I. INTRODUCTION 436
II. THEORY AND CAPSULE FORMAT 436
III. CELL SOURCING 438
IV. HOST IMMUNE RESPONSES TO ENCAPSULATED CELLS 438
V. CONCLUSION 439
VI. REFERENCES 440
Chapter Twenty-Nine: Engineering Challenges in Immunobarrier Device Development 442
I. INTRODUCTION 442
II. ENGINEERING CHALLENGES 443
III. STRATEGIES FOR IMPROVING IMMUNOBARRIER DEVICES 447
IV. THEORETICAL ANALYSIS OF PFC-CONTAINING MICROCAPSULES 448
V. FUTURE DIRECTIONS 453
VI. REFERENCES 453
Part Seven: Stem Cells 456
Chapter Thirty: Embryonic Stem Cells 458
I. INTRODUCTION 458
II. DERIVATION OF HUMAN EMBRYONIC STEM CELLS (hESC) 459
III. SELECTING EMBRYOS FOR PRODUCING EMBRYONIC STEM CELLS 459
IV. MAINTAINING EMBRYONIC STEM CELLS 460
V. PLURIPOTENTIAL MARKERS OF EMBRYONIC STEM CELLS 460
VI. GENETIC MANIPULATION OF EMBRYONIC STEM CELLS 461
VII. DIFFERENTIATION OF EMBRYONIC STEM CELLS 461
VIII. DIRECTING DIFFERENTIATION OF EMBRYONIC STEM CELLS 462
IX. COCULTURE SYSTEMS FOR DIRECTED DIFFERENTIATION OF EMBRYONIC STEM CELLS 462
X. CONCLUDING COMMENTS 463
XI. REFERENCES 463
Chapter Thirty-One: Adult Epithelial Tissue Stem Cells 468
I. INTRODUCTION 468
II. A DEFINITION OF STEM CELLS 469
III. HIERARCHICALLY ORGANIZED STEM CELL POPULATIONS 470
IV. SKIN STEM CELLS 472
V. INTESTINAL STEM CELL SYSTEM 474
VI. STEM CELL ORGANIZATION IN FILIFORM PAPILLAE ON THE DORSAL SURFACE OF THE TONGUE 478
VII. GENERALIZED SCHEME 478
VIII. ADULT STEM CELL PLASTICITY 479
IX. REFERENCES 480
Chapter Thirty-Two: Embryonic Stem Cells as a Cell Source for Tissue Engineering 482
I. INTRODUCTION 482
II. MAINTENANCE OF ESCS 483
III. DIRECTED DIFFERENTIATION 485
IV. ISOLATION OF SPECIFIC PROGENITOR CELLS FROM ESCs 488
V. TRANSPLANTATION 489
VI. FUTURE PROSPECTS 491
VII. CONCLUSIONS 491
VIII. ACKNOWLEDGMENTS 492
IX. REFERENCES 492
Chapter Thirty-Three: Postnatal Stem Cells 496
I. INTRODUCTION 496
II. RESERVOIRS OF POSTNATAL STEM CELLS 496
III. CURRENT APPROACHES TO TISSUE ENGINEERING 497
IV. CONCLUSIONS 502
V. ACKNOWLEDGMENTS 503
VI. REFERENCES 503
Part Eight: Gene Therapy 506
Chapter Thirty-Four: Gene Therapy 508
I. INTRODUCTION 508
II. STRATEGIES OF GENE THERAPY 509
III. EX VIVO VS. IN VIVO GENE THERAPY 509
IV. CHROMOSOMAL VS. EXTRACHROMOSOMAL PLACEMENT OF THE TRANSFERRED GENE 510
V. GENE TRANSFER VECTORS 511
VI. CELL-SPECIFIC TARGETING STRATEGIES 517
VII. REGULATED EXPRESSION OF THE TRANSFERRED GENE 520
VIII. COMBINING GENE TRANSFER WITH STEM CELL STRATEGIES 522
IX. CHALLENGES TO GENE THERAPY FOR TISSUE ENGINEERING 524
X. ACKNOWLEDGMENTS 524
XI. REFERENCES 524
Chapter Thirty-Five: Gene Delivery into Cells and Tissues 530
I. INTRODUCTION 530
II. GENE DELIVERY SYSTEMS 530
III. EXPLORING THE ROLE OF RECEPTOR LIGAND SIGNALING AND RECEPTOR CLUSTERING IN AGENT DELIVERY 532
IV. OVERVIEW OF NANOVEHICLE UPTAKE AND TRAFFICKING 534
V. STABILITY OF NANOVECTORS IN BUFFERS AND BIOLOGICAL FLUIDS: STERIC VS. ELECTROSTATIC STABILIZATION 537
VI. LOCALIZATION AND TARGETING 538
VII. DRUG LOADING 540
VIII. GENE DELIVERY SYSTEMS (GDS) 541
IX. SPECIAL CONSIDERATIONS FOR GENE DELIVERY SYSTEMS 544
X. OUTLOOK 546
XI. ACKNOWLEDGMENT 547
XII. REFERENCES 547
Part Nine: Breast 554
Chapter Thirty-Six: Breast Reconstruction 556
I. INTRODUCTION 556
II. CELL TYPES FOR SOFT-TISSUE ENGINEERING 558
III. MATERIALS 559
IV. ANIMAL MODELS 563
V. STRATEGIES TO ENHANCE THE VASCULARIZATION OF ENGINEERED TISSUE 565
VI. SPECIAL CONSIDERATIONS 567
VII. CONCLUDING REMARKS 567
VIII. REFERENCES 568
Part Ten: Cardiovascular System 572
Chapter Thirty-Seven: Progenitor Cells and Cardiac Homeostasis 574
I. INTRODUCTION 574
II. ORGAN HOMEOSTASIS 574
III. CARDIAC HOMEOSTASIS 576
IV. PROPERTIES OF EXOGENOUS AND ENDOGENOUS CELLS FOR CARDIAC REPAIR 578
V. THE EMBRYO AS A MODEL OF PROGENITOR CELL ENGRAFTMENT AND PLASTICITY 582
VI. CONCLUSIONS 584
VII. REFERENCES 584
Chapter Thirty-Eight: Cardiac-Tissue Engineering 588
I. INTRODUCTION 588
II. CLINICAL PROBLEM 588
III. PROBLEM DEFINITION 589
IV. PREVIOUS WORK 591
V. BIOMIMETIC APPROACH TO CARDIAC-TISSUE ENGINEERING 591
VI. ENGINEERED HEART TISSUE BY MECHANICAL STIMULATION OF CELLS IN COLLAGEN GELS 597
VII. CELL-SHEET TISSUE ENGINEERING 600
VIII. SUMMARY AND CURRENT RESEARCH NEEDS 600
IX. ACKNOWLEDGMENTS 602
X. REFERENCES 603
Chapter Thirty-Nine: Blood Vessels 606
I. INTRODUCTION 606
II. CURRENT STATUS OF VASCULAR CONDUITS 607
III. PHYSICAL OR CHEMICAL MODIFICATION OF CURRENT GRAFTS TO IMPROVE DURABILITY 609
IV. THERAPEUTIC ANGIOGENESIS AND ARTERIOGENESIS 613
V. TISSUE-ENGINEERED VASCULAR GRAFTS 614
VI. ENDOVASCULAR STENTS AND STENT GRAFTS 618
VII. CONCLUSION 619
VIII. REFERENCES 619
Chapter Forty: Heart Valves 622
I. INTRODUCTION 622
II. HEART VALVE FUNCTION AND STRUCTURE 622
III. CELLULAR BIOLOGY OF THE HEART VALVE 623
IV. HEART VALVE DYSFUNCTION AND VALVULAR REPAIR AND REMODELING 625
V. APPLICATION OF TISSUE ENGINEERING TOWARD THE CONSTRUCTION OF A REPLACEMENT HEART VALVE 627
VI. CONCLUSION 634
VII. REFERENCES 634
Part Eleven: Endocrinology and Metabolism 640
Chapter Forty-One: Generation of Islets from Stem Cells 642
I. INTRODUCTION 642
II. ISLET TRANSPLANTATION 643
III. ALTERNATIVE SOURCES OF ISLET CELLS 645
IV. BIOMATERIALS 648
V. ACKNOWLEDGMENTS 652
VI. REFERENCES 653
Chapter Forty-Two: Bioartificial Pancreas 656
I. INTRODUCTION 656
II. CELL TYPES FOR PANCREATIC SUBSTITUTES 657
III. CONSTRUCT TECHNOLOGY 660
IV. IN VIVO IMPLANTATION 663
V. CONCLUDING REMARKS 666
VI. ACKNOWLEDGMENTS 667
VII. REFERENCES 667
Chapter Forty-Three: Engineering Pancreatic Beta-Cells 672
I. INTRODUCTION 672
II. ENGINEERING TO GENERATE INSULIN-PRODUCING CELLS 673
III. ENGINEERING TO IMPROVE ISLET SURVIVAL 677
IV. VECTORS FOR ENGINEERING ISLETS AND BETA-CELLS 678
V. CONCLUSION 680
VI. REFERENCES 680
Chapter Forty-Four: Thymus and Parathyroid Organogenesis 684
I. INTRODUTION 684
II. STRUCTURE AND MORPHOLOGY OF THE THYMUS 684
III. IN VITRO T-CELL DIFFERENTIATION 686
IV. THYMUS ORGANOGENESIS 687
V. SUMMARY 695
VI. ACKNOWLEDGMENTS 695
VII. REFERENCES 695
Part Twelve: Gastrointestinal System 700
Chapter Forty-Five: Adult Stem Cells in Normal Gastrointestinal Function and Inflammatory Disease 702
I. INTRODUCTION 702
II. DEFINING PROPERTIES OF ADULT STEM CELLS 703
III. CELLS OF THE INTESTINE 703
IV. IDENTIFICATION OF INTESTINAL STEM CELLS 706
V. PATHWAYS OF CELLULAR DIFFERENTIATION IN THE INTESTINE 707
VI. ADULT STEM CELL PLASTICITY 709
VII. BONE MARROW CONTRIBUTION TO THE CELLS IN THE ADULT INTESTINE 709
VIII. ORIGIN OF THE ISEMFS 710
IX. BONE MARROW–DERIVED VASCULAR LINEAGES CONTRIBUTE TO TISSUE REGENERATION IN IBD 711
X. STEM CELL PLASTICITY: DE NOVO CELL GENERATION OR HETEROKARYON FORMATION 712
XI. BONE MARROW TRANSPLANTATION AS A POTENTIAL THERAPY FOR CROHN’S DISEASE 713
XII. REFERENCES 713
Chapter Forty-Six: Alimentary Tract 718
I. INTRODUCTION 718
II. TISSUE-ENGINEERED SMALL INTESTINE 718
III. TISSUE-ENGINEERED ESOPHAGUS 723
IV. TISSUE-ENGINEERED STOMACH 726
V. TISSUE-ENGINEERED LARGE INTESTINE 728
VI. CONCLUSIONS 729
VII. REFERENCES 729
Chapter Forty-Seven: Liver Stem Cells 732
I. INTRODUCTION 732
II. DEFINITION OF A TISSUE-DERIVED STEM CELL 732
III. CELLULAR ORGANIZATION OF THE ADULT LIVER 733
IV. HEPATOCYTES: THE FUNCTIONAL UNIT OF THE LIVER WITH STEM CELL PROPERTIES 733
V. LIVER STEM CELLS 736
VI. LIVER STEM CELLS AND THERAPEUTIC APPROACHES 740
VII. CONCLUSION 741
VIII. REFERENCES 741
Chapter Forty-Eight: Liver 744
I. INTRODUCTION 744
II. LIVER FAILURE AND CURRENT TREATMENTS 744
III. CELL SOURCES FOR LIVER CELL–BASED THERAPIES 746
IV. IN VITRO HEPATIC CULTURE MODELS 748
V. EXTRACORPOREAL BIOARTIFICIAL LIVER DEVICES 754
VI. CELL TRANSPLANTATION 758
VII. THREE-DIMENSIONAL HEPATOCELLULAR SYSTEMS: DEVELOPMENT OF IMPLANTABLE THERAPEUTIC CONSTRUCTS 759
VIII. ANIMAL MODELS 763
IX. CONCLUSION 763
X. REFERENCES 763
Part Thirteen: Hematopoietic System 770
Chapter Forty-Nine: Hematopoietic Stem Cells 772
I. INTRODUCTION 772
II. HISTORICAL BACKGROUND 772
III. PROPERTIES OF HEMATOPOIETIC STEM CELLS (HSC) 773
IV. ONTOGENY OF HSC 774
V. MIGRATION, MOBILIZATION, AND HOMING OF HSC 775
VI. HSC PROLIFERATION AND EXPANSION IN VITRO 776
VII. NEGATIVE REGULATION OF HSC 781
VIII. HEMATOPOIETIC STEM CELL NICHES 781
IX. CONCLUSION 782
X. REFERENCES 783
Chapter Fifty: Red Blood Cell Substitutes 786
I. INTRODUCTION 786
II. MODIFIED HEMOGLOBIN 787
III. FIRST-GENERATION MODIFIED HEMOGLOBIN 788
IV. NEW GENERATIONS OF MODIFIED HEMOGLOBIN 790
V. A CHEMICAL APPROACH BASED ON PERFLUOROCHEMICALS 792
VI. CONCLUSIONS 792
VII. LINK TO WEBSITES 793
VIII. ACKNOWLEDGMENTS 793
IX. REFERENCES 793
Chapter Fifty-One: Lymphoid Cells 796
I. INTRODUCTION 796
II. PROPERTIES OF LYMPHOCYTES 797
III. LYMPHOCYTE ENGINEERING: REALITY AND POTENTIAL 797
IV. INDUCTIVE MODEL OF SEQUENTIAL CELL COMMITMENT OF HEMATOPOIESIS 797
V. DIAGRAMS TO EXPLAIN THIS MODEL 798
VI. SOME COMMENTS ON THIS MODEL 798
VII. CRITERIA FOR ENGINEERING DEVELOPMENTAL STAGES OF LYMPHOPOIESIS 800
VIII. STAGES OF LYMPHOPOIESIS FOR ENGINEERING 800
IX. CONCLUDING REMARKS AND PROSPECTS FOR LYMPHOCYTE ENGINEERING 816
X. ACKNOWLEDGMENTS 817
XI. REFERENCES 817
Part Fourteen: Kidney and Genitourinary System 822
Chapter Fifty-Two: Stem Cells in Kidney Development and Regeneration 824
I. INTRODUCTION 824
II. KIDNEY DEVELOPMENT 824
III. GENES THAT SPECIFY EARLY KIDNEY CELL LINEAGES 826
IV. ESTABLISHMENT OF ADDITIONAL CELL LINEAGES 829
V. REGENERATION AND RENAL STEM CELLS 831
VI. ACKNOWLEDGMENTS 834
VII. REFERENCES 834
Chapter Fifty-Three: Renal Replacement Devices 838
I. INTRODUCTION 838
II. BASICS OF KIDNEY FUNCTION 838
III. TISSUE-ENGINEERING APPROACH TO RENAL FUNCTION REPLACEMENT 839
IV. REFERENCES 846
Chapter Fifty-Four: Genitourinary System 848
I. INTRODUCTION 848
II. RECONSTITUTION STRATEGIES 848
III. ROLE OF BIOMATERIALS 849
IV. VASCULARIZATION 849
V. PROGRESS IN TISSUE ENGINEERING OF UROLOGIC STRUCTURES 849
VI. ADDITIONAL APPLICATIONS 853
VII. CONCLUSION 855
VIII. REFERENCES 855
Part Fifteen: Musculoskeletal System 858
Chapter Fifty-Five: Mesenchymal Stem Cells 860
I. INTRODUCTION 860
II. MSC BIOLOGY RELEVANT TO MUSCULOSKELETAL-TISSUE ENGINEERING 860
III. MSCs IN MUSCULOSKELETAL TISSUE ENGINEERING 866
IV. CONCLUSIONS AND FUTURE PERSPECTIVES 875
V. ACKNOWLEDGMENT 875
VI. REFERENCES 875
Chapter Fifty-Six: Bone Regeneration 882
I. INTRODUCTION 882
II. CELL-BASED APPROACH TO BONE-TISSUE ENGINEERING 883
III. GROWTH FACTOR–BASED THERAPIES 890
IV. CONCLUSION AND FUTURE TRENDS 894
V. REFERENCES 894
Chapter Fifty-Seven: Bone and Cartilage Reconstruction 898
I. INTRODUCTION 898
II. BONE RECONSTRUCTION 898
III. CLINICAL APPLICATION OF ENGINEERED BONE 904
IV. CARTILAGE RECONSTRUCTION 905
V. CONCLUSION 910
VI. ACKNOWLEDGEMENTS 911
VII. REFERENCES 911
Chapter Fifty-Eight: Regeneration and Replacement of the Intervertebral Disc 914
I. INTRODUCTION 914
II. IVD STRUCTURE AND FUNCTION 915
III. BIOMATERIALS FOR NUCLEUS PULPOSUS REPLACEMENT 917
IV. CELL-BIOMATERIAL CONSTRUCTS FOR IVD REGENERATION 919
V. CELLULAR ENGINEERING FOR INTERVERTEBRAL DISC REGENERATION 923
VI. GROWTH FACTORS AND BIOLOGICS FOR INTERVERTEBRAL DISC REGENERATION 926
VII. GENE THERAPY FOR INTERVERTEBRAL DISC REGENERATION 926
VIII. CONCLUDING REMARKS 928
IX. ACKNOWLEDGMENTS 928
X. REFERENCES 928
Chapter Fifty-Nine: Articular Cartilage Injury 934
I. INTRODUCTION 934
II. ARTICULAR-CARTILAGE INJURY AND JOINT DEGENERATION 935
III. MECHANISMS OF ARTICULAR-CARTILAGE INJURIES 935
IV. RESPONSE OF ARTICULAR CARTILAGE TO INJURY 937
V. PREVENTING JOINT DEGENERATION FOLLOWING INJURY 939
VI. PROMOTING ARTICULAR SURFACE REPAIR 939
VII. CONCLUSION 941
VIII. REFERENCES 941
Chapter Sixty: Tendons and Ligaments 946
I. INTRODUCTION 946
II. NEED FOR BIOENGINEERED TENDON AND LIGAMENT SUBSTITUTES 947
III. HISTOLOGICAL DESCRIPTION OF TENDONS AND LIGAMENTS 947
IV. TISSUE-ENGINEERED ACL SUBSTITUTES 948
V. CONCLUSION 952
VI. ACKNOWLEDGMENTS 953
VII. REFERENCES 953
Chapter Sixty-One: Mechanosensory Mechanisms in Bone 956
I. INTRODUCTION 956
II. THE CONNECTED CELLULAR NETWORK (CCN) 957
III. MECHANOSENSATION ON THE CCN 958
IV. MESENCHYMAL STEM CELLS 964
V. ACKNOWLEDGMENTS 965
VI. REFERENCES 965
Chapter Sixty-Two: Skeletal-Tissue Engineering 972
I. INTRODUCTION 972
II. DISTRACTION OSTEOGENESIS 973
III. CRITICAL-SIZED DEFECTS 974
IV. CELLULAR THERAPY 974
V. CYTOKINES 975
VI. SCAFFOLDS 977
VII. ANGIOGENESIS 977
VIII. TISSUE ENGINEERING IN PRACTICE 978
IX. CONCLUSION 979
X. REFERENCES 979
Part Sixteen: Nervous System 982
Chapter Sixty-Three: Neural Stem Cells 984
I. INTRODUCTION 984
II. NEURAL DEVELOPMENT 984
III. NEURAL STEM CELLS 985
IV. EMBRYONIC STEM CELL–DERIVED NEURAL STEM CELLS AND NEURAL PROGENY 988
V. APPLICATIONS IN BIOLOGY AND DISEASE 992
VI. CONCLUSION 995
VII. REFERENCES 995
Chapter Sixty-Four: Brain Implants 1004
I. INTRODUCTION 1004
II. CELL REPLACEMENT IMPLANTS 1005
III. CELL PROTECTION AND REGENERATION IMPLANTS 1007
IV. COMBINED REPLACEMENT AND REGENERATION IMPLANTS 1010
V. DISEASE TARGETS FOR BRAIN IMPLANTS 1011
VI. SURGICAL CONSIDERATIONS 1012
VII. CONCLUSIONS 1012
VIII. REFERENCES 1012
Chapter Sixty-Five: Spinal Cord 1014
I. INTRODUCTION 1014
II. THE PROBLEM 1014
III. SPINAL CORD ORGANIZATION 1015
IV. INJURY 1015
V. SPONTANEOUS REGENERATION 1016
VI. CURRENT LIMITATIONS AND APPROACHES TO REPAIR AND REDEFINING GOALS 1016
VII. SPINAL CORD DEVELOPMENT 1017
VIII. EMBRYONIC STEM CELLS 1018
IX. NOVEL APPROACHES TO CNS REPAIR 1023
X. TOWARD HUMAN TRIALS 1026
XI. CONCLUSIONS 1027
XII. ACKNOWLEDGMENTS 1028
XIII. REFERENCES 1028
Chapter Sixty-Six: Protection and Repair of Audition 1032
I. INTRODUCTION 1032
II. INTERVENTIONS TO PREVENT HEARING LOSS/COCHLEAR DAMAGE 1033
III. HAIR CELL REGENERATION 1035
IV. AUDITORY NERVE SURVIVAL FOLLOWING DEAFNESS 1036
V. GENETIC DEAFNESS 1037
VI. METHODS OF THERAPEUTIC INTERVENTION 1037
VII. CONCLUSIONS 1039
VIII. REFERENCES 1040
Part Seventeen: Ophthalmic Applications 1046
Chapter Sixty-Seven: Stem Cells in the Eye 1048
I. INTRODUCTION 1048
II. CORNEAL EPITHELIAL STEM CELLS 1048
III. RETINAL PROGENITOR CELLS 1054
IV. BONE MARROW STEM CELLS 1054
V. POTENTIAL FOR STEM CELLS IN OCULAR REPAIR AND TISSUE ENGINEERING 1055
VI. REFERENCES 1055
Chapter Sixty-Eight: Corneal-Tissue Replacement 1062
I. INTRODUCTION 1062
II. SYNTHETIC CORNEAL REPLACEMENTS 1066
III. CORNEAL-TISSUE ENGINEERING 1068
IV. CURRENT STATE OF CORNEAL-TISSUE ENGINEERING AND FUTURE DIRECTIONS 1080
V. REFERENCES 1080
Chapter Sixty-Nine: Vision Enhancement Systems 1086
I. INTRODUCTION 1086
II. VISUAL SYSTEM, ARCHITECTURE, AND (DYS)FUNCTION 1086
III. CURRENT AND NEAR-TERM APPROACHES TO VISION RESTORATION 1089
IV. EMERGING APPLICATION AREAS FOR ENGINEERED CELLS AND TISSUES 1095
V. CONCLUSION: TOWARD 20/20 VISION 1098
VI. ACKNOWLEDGMENTS 1098
VII. REFERENCES 1098
Part Eighteen: Oral/Dental Applications 1102
Chapter Seventy: Biological Tooth Replacement and Repair 1104
I. INTRODUCTION 1104
II. TOOTH DEVELOPMENT 1104
III. WHOLE TOOTH-TISSUE ENGINEERING 1105
IV. DENTAL-TISSUE REGENERATION 1108
V. CONCLUSIONS 1112
VI. REFERENCES 1112
Chapter Seventy-One: Oral and Maxillofacial Surgery 1116
I. INTRODUCTION 1116
II. SPECIAL CHALLENGES IN ORAL AND MAXILLOFACIAL RECONSTRUCTION 1116
III. CURRENT METHODS OF ORAL AND MAXILLOFACIAL RECONSTRUCTION 1119
IV. RELEVANT STRATEGIES IN ORAL- AND MAXILLOFACIAL-TISSUE ENGINEERING 1122
V. FUTURE OF ORAL- AND MAXILLOFACIAL-TISSUE ENGINEERING 1128
VI. REFERENCES 1128
Chapter Seventy-Two: Periodontal-Tissue Engineering 1132
I. INTRODUCTION 1132
II. FACTORS FOR PERIODONTAL TISSUE ENGINEERING AND REGENERATIVE MEDICINE 1134
III. CURRENT APPROACHES IN PERIODONTAL TISSUE ENGINEERING 1136
IV. FUTURE DIRECTIONS 1141
V. ACKNOWLEDGMENTS 1142
VI. REFERENCES 1142
Part Nineteen: Respiratory System 1148
Chapter Seventy-Three: Progenitor Cells in the Respiratory System 1150
I. INTRODUCTION: LUNG BIOLOGY AND OPPORTUNITIES FOR REGENERATION OF THE LUNG 1150
II. COMPLEXITY OF LUNG STRUCTURE PRESENTS A CHALLENGE FOR TISSUE ENGINEERING 1150
III. LUNG MORPHOGENESIS 1151
IV. ENDOGENOUS PROGENITOR CELLS PLAY CRITICAL ROLES IN REPAIR OF THE RESPIRATORY EPITHELIUM AFTER BIRTH 1155
V. EVIDENCE FOR NONPULMONARY STEM CELLS IN THE LUNG 1157
VI. MODELS FOR STUDY OF LUNG REGENERATION IN VITRO 1158
VII. SUMMARY AND CONCLUSIONS 1158
VIII. REFERENCES 1159
Chapter Seventy-Four: Lungs 1162
I. INTRODUCTION 1162
II. LUNG STRUCTURE 1163
III. CELL SOURCES FOR LUNG REPAIR AND LUNG-TISSUE ENGINEERING 1163
IV. LUNG-TISSUE CONSTRUCTS 1166
V. CONCLUSIONS 1167
VI. REFERENCES 1168
Part Twenty: Skin 1172
Chapter Seventy-Five: Cutaneous Stem Cells 1174
I. INTRODUCTION 1174
II. WHAT ARE EPITHELIAL STEM CELLS? 1175
III. LOCALIZATION OF EPITHELIAL STEM CELLS 1175
IV. IN VITRO ASSESSMENT OF PROLIFERATIVE POTENTIAL 1177
V. MULTIPOTENT BULGE CELLS? 1179
VI. PLASTICITY OF BULGE CELLS? 1180
VII. BULGE CELLS: THE ULTIMATE CUTANEOUS EPITHELIAL STEM CELLS? 1180
VIII. ROLE OF BULGE CELLS IN WOUND HEALING 1180
IX. ROLE OF BULGE CELLS IN TUMORIGENESIS 1181
X. STEM CELLS AND ALOPECIA 1181
XI. BULGE CELLS FOR TISSUE ENGINEERING 1181
XII. MOLECULAR PROFILE — STEM CELL PHENOTYPE 1182
XIII. THE BULGE AS STEM CELL NICHE 1182
XIV. CONCLUSION 1182
XV. ACKNOWLEDGMENTS 1183
XVI. REFERENCES 1183
Chapter Seventy-Six: Wound Repair 1186
I. INTRODUCTION 1186
II. BASIC BIOLOGY OF WOUND REPAIR 1187
III. CHRONIC WOUNDS 1194
IV. TISSUE-ENGINEERED THERAPY: ESTABLISHED PRACTICE 1194
V. TISSUE-ENGINEERED THERAPY: NEW APPROACHES 1196
VI. REFERENCES 1198
Chapter Seventy-Seven: Bioengineered Skin Constructs 1204
I. INTRODUCTION 1204
II. SKIN STRUCTURE AND FUNCTION 1205
III. ENGINEERING SKIN TISSUE 1209
IV. EPIDERMAL REGENERATION 1211
V. DERMAL REPLACEMENT 1211
VI. COMPOSITE SKIN GRAFTS 1212
VII. BIOENGINEERED SKIN: FDA-APPROVED INDICATIONS 1213
VIII. MECHANISMS OF ACTION OF BIOENGINEERED SKIN 1216
IX. CONCLUSION 1219
X. REFERENCES 1219
Part Twenty-One: Clinical Experience 1224
Chapter Seventy-Eight: Current State of Clinical Application 1226
I. INTRODUCTION 1226
II. CURRENT CHALLENGES 1226
III. CLINICAL APPLICATIONS 1227
IV. CONCLUSION 1235
V. REFERENCES 1236
Chapter Seventy-Nine: Tissue-Engineered Skin Products 1238
I. INTRODUCTION 1238
II. TYPES OF THERAPEUTIC TISSUE-ENGINEERED SKIN PRODUCTS 1239
III. COMPONENTS OF TISSUE-ENGINEERED SKIN GRAFTS AS RELATED TO FUNCTION 1240
IV. COMMERCIAL PRODUCTION OF TISSUE-ENGINEERED SKIN PRODUCTS 1241
V. MANUFACTURE OF DERMAGRAFT AND TRANSCYTE 1243
VI. DERMAGRAFT AND TRANSCYTE PRODUCTION PROCESSES 1244
VII. CLINICAL TRIALS 1246
VIII. IMMUNOLOGICAL PROPERTIES OF TISSUE-ENGINEERED SKIN 1247
IX. COMMERCIALIZATION 1247
X. FUTURE DEVELOPMENTS 1248
XI. CONCLUSION 1249
XII. REFERENCES 1249
Chapter Eighty: Tissue-Engineered Cartilage Products 1252
I. INTRODUCTION 1252
II. CLINICAL EXPERIENCE WITH FIRST-GENERATION ACI 1254
III. CLINICAL EXPERIENCE WITH SECOND-GENERATION ACI 1258
IV. CONCLUSIONS 1259
V. REFERENCES 1259
Chapter Eighty-One: Tissue-Engineered Bone Products 1262
I. INTRODUCTION 1262
II. BONE HEALING 1263
III. OSTEOGENIC GRAFTING MATERIALS 1263
IV. OSTEOCONDUCTIVE BONE GRAFT MATERIALS 1265
V. OSTEOINDUCTIVE BONE GRAFT MATERIALS 1266
VI. COMPOSITE BONE GRAFTING 1269
VII. REGULATORY ISSUES 1269
VIII. EXAMPLES OF TISSUE ENGINEERING IN CONTEMPORARY CLINICAL ORTHOPEDICS 1270
IX. THE FUTURE 1270
X. CONCLUSIONS 1272
XI. ACKNOWLEDGMENTS 1272
XII. REFERENCES 1272
Chapter Eighty-Two: Tissue-Engineered Cardiovascular Products 1274
I. INTRODUCTION 1274
II. CLINICAL NEED FOR TISSUE-ENGINEERED CARDIOVASCULAR PRODUCTS? 1275
III. REQUIREMENTS FOR CLINICAL APPLICATION 1276
IV. CURRENT CONCEPTS AND ACHIEVEMENTS IN ENGINEERING CARDIOVASCULAR PRODUCTS 1278
V. STATE OF MYOCARDIAL-TISSUE ENGINEERING 1280
VI. BOTTLENECKS 1283
VII. SUMMARY 1284
VIII. REFERENCES 1285
Chapter Eighty-Three: Tissue-Engineered Organs 1290
I. INTRODUCTION 1290
II. TISSUE ENGINEERING: STRATEGIES FOR TISSUE RECONSTITUTION 1290
III. CELL SOURCES 1291
IV. ALTERNATE CELL SOURCES 1291
V. THERAPEUTIC CLONING 1292
VI. BIOMATERIALS 1293
VII. GROWTH FACTORS 1294
VIII. VASCULARIZATION 1294
IX. CLINICAL APPLICATIONS 1294
X. CONCLUSION 1296
XI. REFERENCES 1296
Part Twenty-Two: Regulation and Ethics 1300
Chapter Eighty-Four: The Tissue-Engineering Industry 1302
I. INTRODUCTION 1302
II. THE AGE OF INNOCENCE 1303
III. THE PERFECT STORM 1304
IV. THE PRESENT ERA 1305
V. CONCLUDING PERSPECTIVES 1307
VI. REFERENCES 1307
Chapter Eighty-Five: The Regulatory Path From Concept to Market 1308
I. INTRODUCTION 1308
II. LEGISLATIVE AUTHORITY 1309
III. PRODUCT REGULATORY PROCESS 1309
IV. PRODUCT PREMARKET SUBMISSIONS 1310
V. REVIEW OF PRODUCT PREMARKET SUBMISSIONS 1312
VI. HUMAN CELLS, TISSUES, AND CELLULAR- AND TISSUE-BASED PRODUCTS 1312
VII. SCIENCE AND PRODUCT DEVELOPMENT 1314
VIII. CONCLUSION AND FUTURE PERSPECTIVES 1315
IX. ACKNOWLEDGMENTS 1316
X. REFERENCES 1316
Chapter Eighty-Six: Ethical Issues 1318
I. INTRODUCTION 1318
II. ARE THERE REASONS, IN PRINCIPLE, WHY PERFORMING THE BASIC RESEARCH SHOULD BE IMPERMISSIBLE? 1319
III. WHAT CONTEXTUAL FACTORS SHOULD BE TAKEN INTO ACCOUNT, AND DO ANY OF THESE PREVENT THE DEVELOPMENT AND USE OF THE TECHNOLOGY? 1321
IV. WHAT PURPOSES, TECHNIQUES, OR APPLICATIONS WOULD BE PERMISSIBLE AND UNDER WHAT CIRCUMSTANCES? 1322
V. ON WHAT PROCEDURES AND STRUCTURES, INVOLVING WHAT POLICIES, SHOULD DECISIONS ON APPROPRIATE TECHNIQUES AND USES BE BASED? 1322
VI. CONCLUSION 1323
VII. REFERENCES 1323
Epilogue 1326
INDEX 1328