Principles of Regenerative Medicine

Front Cover
......Page 1
PRINCIPLES OF REGENERATIVE MEDICINE......Page 2
PRINCIPLES OF REGENERATIVE MEDICINE......Page 4
Copyright......Page 5
Dedication......Page 6
Contents......Page 8
Contributors......Page 20
Preface......Page 26
MOLECULES THAT ORGANIZE CELLS......Page 28
Changes in Cell–Cell Adhesion......Page 29
Invasion of the Basal Lamina......Page 30
Transcription Factors That Regulate Epithelial–Mesenchymal Transition......Page 31
MOLECULAR CONTROL OF THE EPITHELIAL–MESENCHYMAL TRANSITION......Page 32
Wnt Pathway......Page 33
Additional Signaling Pathways......Page 34
CONCLUSION......Page 35
References......Page 36
COMPOSITION AND DIVERSITY OF THE EXTRACELLULAR MATRIX......Page 42
RECEPTORS FOR EXTRACELLULAR MATRIX MOLECULES......Page 43
SIGNAL TRANSDUCTION EVENTS DURING CELL–EXTRACELLULAR MATRIX INTERACTIONS......Page 45
Adhesion and Migration......Page 46
Proliferation and Survival......Page 49
Differentiation......Page 50
Apoptosis......Page 51
Adhesion and Migration......Page 52
Differentiation......Page 54
CELL–EXTRACELLULAR MATRIX INTERACTIONS DURING REGENERATIVE FETAL WOUND HEALING......Page 55
Proliferation......Page 56
IMPLICATIONS FOR REGENERATIVE MEDICINE......Page 57
References......Page 58
BLASTEMA FORMATION......Page 64
Hemostasis and Reepithelialization......Page 65
Mechanisms of Dedifferentiation......Page 66
Cell Cycling During Blastema Formation......Page 67
Blastema Cell Migration and Accumulation......Page 68
The Apical Epidermal Cap–Nerve Interaction......Page 69
Interaction of Cells From Opposite Sides of the Limb Circumference......Page 71
References......Page 72
GROUND STATE AND PRIMED EMBRYONIC STEM CELLS HAVE UNIQUE SIGNALING NETWORKS UNDERLYING PLURIPOTENCY......Page 76
LEUKEMIA INHIBITORY FACTOR AND BONE MORPHOGENIC PROTEIN SIGNALING PATHWAYS REGULATE MOUSE EMBRYONIC STEM CELL SELF-RENEWAL......Page 77
WNT SIGNALING CONTRIBUTES TO MAINTENANCE OF PLURIPOTENCY IN MOUSE EMBRYONIC STEM CELLS AND TO THE NAIVE HUMAN EMBRYONIC STE .........Page 79
THREE TRANSCRIPTION FACTORS, OCTAMER BINDING PROTEIN 4, SRY-BOX 2, AND NANOG, FORM THE CORE PLURIPOTENCY TRANSCRIPTIONAL NE .........Page 80
MYC LINKS CELL SIGNALING TO PLURIPOTENCY GENE REGULATION......Page 81
A SPECIFIC EPIGENETIC PROGRAM HELPS MAINTAIN PLURIPOTENCY......Page 82
MICRORNAS INTEGRATE WITH CELL SIGNALING AND TRANSCRIPTION FACTORS TO REGULATE STEM CELL PROLIFERATION AND DIFFERENTIATION......Page 84
CONCLUSIONS......Page 85
References......Page 86
INTRODUCTION......Page 92
Adult Wound Healing and Scar Formation......Page 93
Fibroproliferative Scarring......Page 95
Hypertrophic Scars......Page 97
Fetal Scarless Wound Repair......Page 99
Targeting the Inflammatory Response......Page 100
Connective Tissue Growth Factor......Page 102
Wingless Type Signaling......Page 103
5-Fluorouracil......Page 104
Bleomycin......Page 105
Cryotherapy......Page 106
Growth Factors and Cell Signaling Molecules......Page 107
Embryonic Stem Cells......Page 108
Mesenchymal Stem Cells......Page 109
Epidermal Stem Cells......Page 110
Induced Pluripotent Stem Cells......Page 111
PERSPECTIVE......Page 112
References......Page 113
INTRODUCTION......Page 120
SINGLE-CELL ISOLATION......Page 122
ACQUIRING SINGLE-CELL DATA......Page 123
Single-Cell Transcriptomics......Page 124
Single-Cell Proteomics......Page 126
Reducing Noise in Single-Cell Data......Page 127
Mathematical Identification of Cellular Subpopulations......Page 128
DETERMINING SUBPOPULATIONS......Page 130
Development of Cell-Based Therapies......Page 131
CLINICAL IMPLICATIONS OF CELLULAR HETEROGENEITY IN TISSUE REPAIR AND DISEASE......Page 132
Cellular Heterogeneity in Wound Healing......Page 133
Cellular Heterogeneity in Aging......Page 134
CONCLUSIONS......Page 135
References......Page 136
Mouse Embryonic Stem Cells......Page 140
Blastocyst......Page 141
Parthenogenesis......Page 142
Microenvironment......Page 143
Maintenance......Page 144
Evolution of Human Embryonic Stem Cell Derivation and Culture Methods......Page 145
HUMAN EMBRYONIC STEM CELL DIFFERENTIATION AND MANUFACTURING FOR CLINICAL APPLICATION......Page 146
References......Page 147
Further Reading......Page 150
INTRODUCTION......Page 152
Single Blastomere Biopsy......Page 153
Irreversibility as a Criterion for Diagnosing Embryonic Death......Page 154
Morphological Criteria for Predicting the Capacity of Irreversibly Arrested, Nonviable Human Embryos to Develop Into a Huma .........Page 155
References......Page 157
PLACENTA: FUNCTION, ORIGIN, AND COMPOSITION......Page 160
AMNIOTIC EPITHELIAL CELLS......Page 161
AMNIOTIC MESENCHYMAL STEM CELLS......Page 162
Preclinical Studies......Page 163
Characterization......Page 165
Preclinical Studies......Page 167
Heart......Page 168
Kidney......Page 169
Intestine......Page 170
References......Page 171
A BRIEF HISTORY......Page 176
PUBLIC VERSUS FAMILY (OR PRIVATE) BANKS......Page 177
Donor Recruitment and Consent......Page 178
Volume and Cell Count Considerations......Page 179
Processing and Cryopreservation......Page 180
Cord Blood Unit Characterization......Page 181
Cord Blood Transplantation for Nonmalignant Hematological Diseases......Page 183
Cord Blood Transplantation for Inherited Metabolic Disorders......Page 184
Cerebral Palsy......Page 186
Stroke......Page 187
Autism Spectrum Disorder......Page 188
References......Page 189
MECHANISMS OF REPROGRAMMING......Page 196
REPROGRAMMING TECHNIQUES......Page 197
INDUCED TRANSDIFFERENTIATION......Page 198
DISEASE MODELING......Page 199
PERSONALIZED MEDICINE......Page 201
CELL THERAPY......Page 202
CONCLUSIONS AND FUTURE DIRECTIONS......Page 203
References......Page 204
ADULT STEM CELLS......Page 208
ISOLATION OF RODENT MULTIPOTENT ADULT PROGENITOR CELL......Page 209
Hematopoietic Reconstitution With Multipotent Adult Progenitor Cells......Page 210
Effect of Multipotent Adult Progenitor Cells on Graft Versus Host Disease......Page 211
Multipotent Adult Progenitor Cell Immunodulatory and/or Trophic Effects in Ischemic Disease......Page 212
Possible Mechanisms of Trophic Effects: Secreted Proteome of Multipotent Adult Progenitor Cells......Page 213
References......Page 214
HEMATOPOIETIC STEM CELL PROPERTIES......Page 218
Fetal Liver Hematopoiesis......Page 219
In Vitro Hematopoiesis......Page 220
Phenotypic Properties of Hematopoietic Stem Cells......Page 221
Bone Marrow Transplantation......Page 222
Autologous Peripheral Blood Stem Cell Transplantation......Page 223
Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency......Page 224
Hematopoietic Stem Cell Transplantation for Tolerance Induction......Page 225
List of Acronyms and Abbreviations......Page 226
References......Page 227
INTRODUCTORY OVERVIEW......Page 232
THE STEM CELL NATURE OF MESENCHYMAL STEM CELLS......Page 233
WHICH TISSUES CONTAIN MESENCHYMAL STEM CELLS?......Page 234
MESENCHYMAL STEM CELL EXOSOMES......Page 235
IMMUNOMODULATORY EFFECTS OF MESENCHYMAL STEM CELLS......Page 238
INDUCED PLURIPOTENT STEM CELL–DERIVED MESENCHYMAL STEM CELLS......Page 239
Acknowledgments......Page 240
References......Page 241
INTRODUCTION AND HISTORY......Page 246
NEW INSIGHT......Page 247
Clinically Relevant Therapies Using Mesenchymal Stem Cells......Page 249
Diabetes......Page 250
THE NEW MESENCHYMAL STEM CELLS......Page 251
References......Page 252
INTRODUCTION......Page 256
Integration of Hepatocytes After Transplantation......Page 258
CLINICAL HEPATOCYTE TRANSPLANTATION......Page 259
Hepatocyte Transplantation in Acute Liver Failure......Page 260
Hepatocyte Transplantation for Metabolic Liver Disease......Page 261
Hepatocyte Transplants for Non–Organ Transplant Candidates......Page 264
Methods to Improve Engraftment and Repopulation......Page 265
Stem Cells and Alternative Cell Sources for Liver Therapy......Page 266
SUMMARY......Page 268
References......Page 269
DEVELOPMENT OF THE HEART FROM CARDIAC STEM/PROGENITOR CELLS......Page 274
c-Kit+ Cardiac Progenitor/Stem Cells......Page 275
Cardiac Neural Crest–Derived Progenitors......Page 277
Epicardial Progenitor Cells......Page 278
CELL-BASED THERAPEUTICS FOR HEART DISEASE......Page 279
MECHANISMS OF ACTION......Page 281
Pluripotent Stem Cells......Page 282
Adult Stem Cells......Page 283
Endothelial Progenitor Cells......Page 284
Mesenchymal Stem Cells......Page 285
Cardiac Stem Cells......Page 288
Other Cardiac Stem Cells......Page 290
COMBINED STEM CELL THERAPEUTICS......Page 292
References......Page 294
INTRODUCTION......Page 300
THE MOLECULAR CHARACTERISTICS OF MUSCLE STEM CELLS DURING MYOGENESIS IN REGENERATION......Page 301
FUNCTIONAL CHARACTERISTICS OF MUSCLE STEM CELLS......Page 303
ISOLATION OF MUSCLE STEM CELLS......Page 304
TRACKING MUSCLE STEM CELL BEHAVIOR THROUGH LIVE IMAGING (BIOLUMINESCENCE IMAGING AND INTRAVITAL IMAGING)......Page 305
Extracellular Matrix Components......Page 306
Biophysical Cues......Page 307
SATELLITE CELL SELF-RENEWAL MECHANISMS......Page 308
MUSCLE STEM CELL–INTRINSIC DEFECTS IN AGING AND DISEASE......Page 310
CHALLENGES IN THE USE OF SATELLITE CELLS IN REGENERATIVE MEDICINE......Page 311
OTHER STEM CELL TYPES WITHIN MUSCLE......Page 312
Induced Pluripotent Stem–Derived Muscle Stem Cells......Page 313
References......Page 314
CELLULAR FRACTIONS......Page 322
Adipose-Derived Stromal Cell......Page 323
CLINICAL DELIVERY OF ADIPOSE-DERIVED CELLS......Page 324
ENGINEERED NEO-TISSUE......Page 327
Carcinogenesis and Tumorigenesis......Page 328
References......Page 329
TYPES AND SOURCE OF STEM CELLS IN THE PERIPHERAL BLOOD......Page 334
Mobilization of Bone Marrow Cells......Page 335
Identification and Isolation of Endothelial Progenitor Cells......Page 338
In Vitro Expansion of Endothelial Progenitor Cells......Page 339
The Role of Endothelial Progenitor Cells in Physiological and Pathological Neovascularization......Page 340
Identification, Isolation, Characterization, and In Vitro Expansion......Page 342
Tissue Regeneration......Page 344
Tissue Engineering......Page 346
Mesenchymal Stem Cells......Page 347
The Use of Mesenchymal Stem/Marrow Stroma Cells for Gene Therapy......Page 349
CONCLUSIONS AND FUTURE DIRECTIONS......Page 352
References......Page 353
FROM ADULT PANCREATIC ISLETS TO STEM CELLS......Page 362
β CELLS FROM PLURIPOTENT STEM CELLS (EMBRYONIC STEM CELLS AND INDUCED PLURIPOTENT STEM CELLS)......Page 363
β CELLS FROM ADULT STEM/PROGENITOR CELLS OF THE BILIARY TREE AND PANCREAS......Page 368
MESENCHYMAL STEM CELLS TO MODULATE IMMUNITY AND PROMOTE TISSUE REPAIR IN DIABETES......Page 371
CONCLUSION......Page 372
References......Page 373
INTRODUCTION......Page 378
The Retina......Page 379
Retinitis Pigmentosa......Page 381
Human Embryonic Stem Cell–Derived Retinal Pigment Epithelium......Page 382
Induced Pluripotent Stem Cell–Derived Retinal Pigment Epithelium......Page 383
Scaffolds for Retinal Pigment Epithelium Transplantation......Page 386
Photoreceptor Transplantation......Page 387
CELL-BASED NEUROPROTECTION......Page 388
DISEASE-IN-A-DISH MODELING FOR RETINAL DISORDERS......Page 389
Three-Dimensional Retinal Organoids......Page 390
CONCLUSION......Page 391
References......Page 392
Epidemiology......Page 396
Primary Versus Secondary Brain Injury......Page 397
Neuroinflammation......Page 398
Blood–Brain Barrier Permeability......Page 400
Cerebral Edema......Page 402
Mechanisms of Action......Page 403
Timing of Infusion......Page 404
Conventional Cell Delivery Routes, Continued......Page 405
Novel Cell Delivery Routes......Page 407
Reduction in Therapeutic Intensity: Pediatric Intensity Level of Therapy Scores......Page 408
Imaging Data......Page 409
Results......Page 410
Phase 1/2 Adipose-Derived Stem/Stromal Cells......Page 411
CONCLUSION......Page 412
Acknowledgments......Page 413
References......Page 414
INTRODUCTION......Page 418
Extracellular Matrix......Page 419
Ion Channels and Mechanoreceptors......Page 420
Cytoskeleton......Page 421
NUCLEUS AS THE CENTRAL ORGANELLE IN REGULATING MECHANOTRANSDUCTION......Page 423
CELLULAR MECHANOTRANSDUCTION MECHANISMS......Page 424
Mechanotransduction Through Cell–Cell Adhesions......Page 425
From Cells to Organs: How Mechanobiology Affects Tissue Development and Function......Page 426
CONCLUSIONS......Page 427
References......Page 428
INTRODUCTION......Page 432
BONE MORPHOGENETIC PROTEINS......Page 433
SCAFFOLDS OF EXTRACELLULAR MATRIX AND BIOMIMETIC BIOMATERIALS......Page 436
REGENERATIVE MEDICINE AND SURGERY OF ARTICULAR CARTILAGE......Page 439
REGENERATION OF ARTICULAR CARTILAGE SURFACE AND LUBRICATION......Page 440
References......Page 441
INTRODUCTION......Page 444
Strain......Page 445
Constitutive Relations......Page 448
Tissue Remodeling......Page 450
Mechanotransduction......Page 451
Mechanical Stimulation In Vivo......Page 454
Bone Bioreactors......Page 456
Blood Vessel Bioreactors......Page 458
CONCLUSIONS......Page 459
References......Page 460
CELL–EXTRACELLULAR MATRIX INTERACTIONS......Page 464
Effect of Physical Properties......Page 465
Stiffness and Compliance......Page 466
Surface Charge......Page 467
Methods of Altering Surface Chemistry......Page 468
Development of Bioactive Surfaces......Page 469
Cell Adhesion......Page 470
Cell Motility......Page 471
Cell Proliferation, Self-renewal, and Differentiation......Page 472
Fabrication Techniques......Page 473
Cellular Responses to Topographical Cues......Page 474
Electrically Conductive Substrate......Page 477
EFFECT OF DIMENSIONALITY......Page 478
Hydrogel Scaffolds......Page 479
Decellularized Tissue......Page 480
New Technology Development......Page 481
Cellular Responses to Three-Dimensional Substrates......Page 482
Cell Migration......Page 483
Effect of Externally Applied Mechanical Stimuli......Page 484
Mechanotransduction......Page 485
Cellular Responses in Modifying Extracellular Matrix......Page 486
CONCLUSION......Page 487
References......Page 488
Thermoresponsive Polymer for Biomedical Applications......Page 496
Controlled Grafting of Thermoresponsive Polymer on Culture Substrates......Page 497
Variety of Fabrication Techniques of Thermoresponsive Cell Culture Substrate......Page 498
Cornea Reconstruction......Page 499
Myocardium Regeneration......Page 500
Cell Sheet Layering Technique......Page 501
Vascularization in Cell Sheets for Large-scale Tissue Construction......Page 502
COMBINATION OF CELL SHEET ENGINEERING AND SCAFFOLD-BASED ENGINEERING......Page 504
Copatterning to Create a Cellular Microenvironment......Page 505
Intelligent Surfaces for Regulating Cell Orientation......Page 506
Skeletal Muscle Tissue Engineering......Page 507
CONCLUSIONS......Page 508
References......Page 509
INTRODUCTION......Page 512
Physical Properties......Page 513
Size......Page 514
Shape......Page 515
Surface Topography......Page 516
Optical Properties......Page 517
NANOBIOMATERIALS......Page 518
Bone Tissue......Page 520
Muscle Tissue......Page 521
Vascular Tissue......Page 522
Other Tissue......Page 523
Stem Cell Transfection......Page 524
Stem Cell Expansion......Page 525
References......Page 526
Mechanical Support......Page 532
Degradation Mechanisms......Page 534
Factors That Affect Degradation Rates......Page 535
Surface Modification for Degradation Control......Page 536
On-Demand Release......Page 537
Anisotropic and Gradient Scaffolds......Page 538
Surface Feature Manipulation......Page 539
SAFETY AND BIOCOMPATIBILITY REQUIREMENTS FOR BIOMATERIAL SCAFFOLDS......Page 540
Infection and Sterilization......Page 541
Hemocompatibility......Page 542
Foreign Body Response......Page 543
SUMMARY......Page 544
References......Page 545
WHY THE NEED FOR PRECISION CONTROL OF PROTEINS AT INTERFACES IN TISSUE ENGINEERING AND REGENERATIVE MEDICINE?......Page 550
SURFACE ANALYSIS AND ITS ROLE IN THE PRECISION DELIVERY OF BIOLOGICAL SIGNALS......Page 551
Sum Frequency Generation......Page 552
Quartz Crystal Microbalance With Dissipation Monitoring......Page 553
TECHNIQUES AND TECHNOLOGIES FOR PRECISION IMMOBILIZATION AT SURFACES......Page 554
Ionic Charge and Charge Control of Orientation......Page 555
Collagen to Control Protein Orientation......Page 556
Streptavidin for Biomolecular Orientation Control......Page 557
CONCLUSIONS......Page 558
References......Page 559
INTRODUCTION......Page 562
Processing Methods......Page 565
COLLAGEN......Page 567
Processing Methods......Page 568
Collagen in Bone Tissue Engineering Applications......Page 569
Processing Methods......Page 570
Gellan Gum in Bone Tissue Engineering Applications......Page 571
Processing Methods......Page 572
Polyhydroxyalkanoates in Bone Tissue Engineering Applications......Page 573
Silk Fibroin in Bone Tissue Engineering Applications......Page 574
STARCH......Page 575
Processing Methods......Page 576
NATURAL-BASED BIOCERAMICS......Page 577
CALCIUM PHOSPHATES......Page 578
Calcium Phosphate in Bone Tissue Engineering Applications......Page 579
Silicate in Bone Tissue Engineering Applications......Page 580
CONCLUSIONS......Page 581
References......Page 582
INTRODUCTION......Page 586
POLYMER SYNTHESIS......Page 587
Poly(ethylene), Poly(propylene), and Poly(styrene)......Page 588
Poly(meth)acrylates and Polyacrylamides......Page 589
Poly(N-isopropylacrylamide)......Page 590
Polyethers......Page 591
Polysiloxanes......Page 592
Hydrolytically Stable Polyurethanes......Page 593
Polyesters......Page 594
Polyesters of α-Hydroxy Acids......Page 595
Polyesters of Lactones......Page 597
Polyorthoesters......Page 598
Polyurethanes......Page 599
Amino Acid–Derived Polymers, Poly(amino Acids), and Peptides......Page 600
Polyanhydrides......Page 601
Biodegradable Cross-linked Polymer Networks......Page 602
Cross-linked Polyesters......Page 603
CONCLUSION/SUMMARY......Page 607
References......Page 608
Calcium Phosphate Bioceramics......Page 618
Basic Properties......Page 620
Apatite Cements......Page 621
Setting/Hardening Mechanism......Page 622
Hydrolysis Interaction......Page 623
Setting Times......Page 624
Strategies to Improve Setting Times......Page 625
Strategies to Improve Injectability......Page 626
Liquid-to-Powder Ratio......Page 627
STRATEGIES TO IMPROVE THE MECHANICAL PROPERTIES......Page 628
Porosity......Page 629
Dual Setting System......Page 631
Mechanics of Fiber-Reinforced Calcium Phosphate Cements......Page 632
Oral, Maxillofacial, and Craniofacial Applications......Page 633
CONCLUSION......Page 634
References......Page 635
EXTRACELLULAR MATRIX: FUNCTION AND COMPONENTS......Page 640
Collagen......Page 642
Fibronectin......Page 643
Glycosaminoglycans/Proteoglycans......Page 644
Matrix-Bound Nanovesicles......Page 645
Decellularization......Page 646
Hydrogels......Page 647
Whole-Organ Scaffolds......Page 648
List of Acronyms and Abbreviations......Page 649
References......Page 650
INTRODUCTION......Page 654
BIOMATERIALS TEMPLATES......Page 655
STRUCTURE–PROPERTY RELATIONSHIPS IN HYDROGELS......Page 658
Bioactive Forms of Poly(ethylene Glycol) as Exemplars of Increasing Sophistication......Page 659
Spatial Heterogeneity......Page 660
Matrix Mechanics......Page 662
Hydrogel Degradation......Page 663
Polymerization Mechanisms......Page 664
Injectable Systems......Page 665
Hyaluronic Acid......Page 666
Alginate......Page 667
Cellulose......Page 668
Collagen and Its Derivatives......Page 669
Elastin Derivatives......Page 670
Fibrin Derivatives......Page 671
Self-assembled Peptides......Page 672
SYNTHETIC HYDROGELS FOR TISSUE ENGINEERING TEMPLATES......Page 673
CONCLUSIONS......Page 675
References......Page 676
Overview of Surface Modification Strategies......Page 678
Topographical Modifications......Page 680
Noncovalent Coatings......Page 682
BIOLOGICAL MODIFICATION OF SURFACES......Page 683
References......Page 686
TISSUE COMPONENTS......Page 688
REGENERATION OF DISEASED TISSUES......Page 689
Cell Sources......Page 690
Porosity......Page 691
Degradation......Page 693
Importance of Microvasculature......Page 694
Hydrogels......Page 696
CONCLUSIONS......Page 697
References......Page 698
INTRODUCTION......Page 702
Blood–Material Interactions and Initiation of the Inflammatory Response......Page 703
Provisional Matrix Formation......Page 704
Temporal Sequence of Inflammation and Wound Healing......Page 705
Chronic Inflammation......Page 706
Macrophage Interactions......Page 707
Foreign Body Giant Cell Formation and Interactions......Page 709
FIBROSIS AND FIBROUS ENCAPSULATION......Page 710
IMMUNOTOXICITY (ACQUIRED IMMUNITY)......Page 711
References......Page 718
Further Reading......Page 721
INTRODUCTION......Page 722
FUNCTIONS OF SCAFFOLDING AND EXTRACELLULAR MATRIX......Page 723
SCAFFOLDING APPROACHES IN BONE TISSUE ENGINEERING......Page 724
Hydrogels......Page 725
Silk......Page 726
Collagen......Page 727
Hyaluronic Acid......Page 728
Alginate......Page 729
Peptide Hydrogels......Page 730
Copolymers......Page 731
Ceramic Scaffolds......Page 732
Bioglass......Page 733
Metallic Scaffolds......Page 734
Polymer–Ceramics Blends......Page 735
Metal–Ceramic Blends......Page 736
References......Page 737
INTRODUCTION AND OVERVIEW OF CANCER IMMUNOTHERAPY......Page 742
ADVANTAGES AND DISADVANTAGES OF CANCER IMMUNOTHERAPY......Page 744
Introduction of Nanomedicine in Cancer......Page 745
Effects of Nanoparticle Surface Functionalization......Page 747
Nanoparticle Targeting of the Tumor Microenvironment......Page 748
Nanoparticle Targeting of Antigen Presenting Cells......Page 749
Implantable Biomaterial Scaffolds as Cancer Vaccines......Page 754
Injectable Biomaterial Systems as Cancer Vaccines......Page 756
Implantable Biomaterial Scaffolds to Enhance Autologous T Cell Therapy......Page 758
CONCLUSION......Page 760
Glossary......Page 761
References......Page 763
Clustered Regularly Interspaced Short Palindromic Repeats......Page 768
Knockouts via Double-Strand Breaks......Page 769
Nickases......Page 770
Homology-Directed Repair......Page 771
SpCas 9 Variants and Orthologues......Page 772
Transcription Activator-like Effector Nucleases......Page 773
Recombinase......Page 774
Proteins......Page 775
DELIVERY METHODS......Page 776
Liver......Page 777
Muscle: Muscular Dystrophy......Page 778
Duchenne Muscular Dystrophy......Page 779
Blood......Page 780
Retina......Page 781
References......Page 782
BIOMINERALIZATION AND BONE REGENERATION......Page 788
Mesenchymal Stem Cells......Page 789
Biochemical Signaling: Growth Factors and Cell Signals......Page 790
In Vivo Preclinical Models......Page 791
Selection Considerations Based on Animal Species......Page 792
References......Page 793
INTRODUCTION......Page 796
ADVANCE OF IN VITRO ORGANOID DEVELOPMENT: PROGRESSION FROM TWO-DIMENSIONAL TO THREE-DIMENSIONAL MODELS......Page 797
Microengineering and Biofabrication......Page 799
Vessel-on-a-Chip......Page 800
Cancer-on-a-Chip......Page 801
BODY-ON-A-CHIP: MULTIORGAN SYSTEMS AND FUTURE APPLICATIONS......Page 802
Cancer......Page 803
Drug Testing and Toxicology......Page 804
Additional Disease Modeling......Page 805
The Ex Vivo Console of Human Organoids Platform......Page 806
Other Body-on-a-Chip Programs......Page 807
Organ-on-a-Chip Systems for Personalized Precision Medicine......Page 809
References......Page 810
DESIGN CONSIDERATIONS FOR CREATING BIOREACTORS......Page 814
Bioengineering Functional Lungs......Page 815
Bioreactors for Regeneration of Small Animal Lungs......Page 816
In Vivo Bioreactors for Lung Regeneration......Page 817
Bioreactors for Study of Lung Biology......Page 819
Evaluation of Bioengineered Lungs......Page 820
Perfusion Bioreactors for Bone Regeneration......Page 822
In Vivo Bone Bioreactors for Solving the Vascularization Problem......Page 824
Bioreactors for Studying Bone Development and Disease......Page 825
Monitoring the Environment and Tissue Development Within Bioreactors......Page 826
References......Page 828
FUNDAMENTALS OF THREE-DIMENSIONAL PRINTING......Page 832
Extrusion-Based Printing......Page 833
Inkjet Bioprinting......Page 834
BIOINKS......Page 835
Matrix or Matrix-Mimicking Bioinks......Page 837
Synthetic Materials......Page 838
Natural Materials......Page 840
Co-printing and Hybrid Bioinks......Page 843
Cell-Laden Bioinks......Page 846
Sacrificial Bioinks......Page 848
Supporting Bioinks and Supporting Baths......Page 850
In Vitro Applications......Page 852
CONCLUSION AND FUTURE DIRECTIONS......Page 853
References......Page 854
BIOPRINTING STRATEGY: FROM MEDICAL IMAGE TO PRINTED TISSUE......Page 858
Jetting-Based Printing......Page 859
Hybrid and Other Mechanisms......Page 861
Synthetic Hydrogels......Page 862
Naturally Derived Hydrogels......Page 863
Biodegradable Synthetic Polymers for Structural Integrity......Page 864
Three-Dimensional Bioprinted Vascular Structures......Page 865
Tumor Models......Page 866
Bone......Page 868
Cartilage......Page 869
Skeletal Muscle and Tendon......Page 872
Skin......Page 873
CONCLUSIONS AND FUTURE PERSPECTIVES......Page 874
Glossary......Page 875
References......Page 876
Fracture Healing......Page 880
Adipose-Derived Stem Cells......Page 881
Induced Pluripotent Stem Cells......Page 882
Porous and Highly Interconnected Scaffolds......Page 883
Nanofibrous Scaffolds for Bone Tissue Engineering......Page 884
Hydrogels......Page 885
Bone Morphogenetic Proteins......Page 886
Nucleotide Delivery and Gene Therapy......Page 887
IMMUNOMODULATION IN BONE REGENERATION......Page 888
T Cells......Page 889
References......Page 890
STRUCTURE OF THE INNER EAR......Page 894
HAIR CELL LOSS......Page 895
HISTORY OF HAIR CELL REGENERATION......Page 896
SPONTANEOUS HAIR CELL REGENERATION IN MAMMALIAN VESTIBULAR ORGANS......Page 897
INSIGHTS FROM DEVELOPMENTAL BIOLOGY......Page 898
INDUCTION OF HAIR CELL REGENERATION USING TRANSGENIC MICE......Page 902
STUDIES OF HAIR CELL REGENERATION USING THE LATERAL LINE......Page 903
FORMATION OF NEW NEUROMASTS FROM MULTIPOTENT PROGENITORS......Page 904
HAIR CELL REGENERATION IN THE LATERAL LINE......Page 905
PATHWAYS COORDINATING HAIR CELL REGENERATION IN THE LATERAL LINE......Page 906
OPEN QUESTIONS ABOUT LATERAL LINE REGENERATION......Page 907
References......Page 908
UNDERSTANDING THE CRANIOFACIAL REGENERATIVE ENVIRONMENT......Page 914
CURRENT METHODS OF MAXILLOFACIAL RECONSTRUCTION......Page 917
Ceramics......Page 918
Bioactive Molecules......Page 919
Platelet-Derived Growth Factor......Page 920
Bone Marrow Aspirate Concentrate Technique......Page 921
Bioreactors......Page 924
Antibiotics......Page 925
CONCLUSION......Page 926
List of Abbreviations......Page 928
References......Page 929
INTRODUCTION......Page 934
TOOTH DEVELOPMENT......Page 935
DENTAL STEM CELLS......Page 936
DENTAL TISSUE ENGINEERING......Page 937
Whole Tooth Engineering......Page 939
Dental Pulp and Dentin Regeneration......Page 940
Periodontal Regeneration......Page 941
Alveolar Bone Regeneration......Page 943
List of Abbreviations......Page 944
References......Page 945
INTRODUCTION......Page 950
Red Blood Cells Generated From Adult Stem Cells In Vitro......Page 951
Red Blood Cells Generated From Human Embryonic Stem Cells......Page 952
Red Blood Cells Generated From Human Induced Pluripotent Stem Cells......Page 954
Where Do We Go From Here?......Page 955
Generation of Megakaryocytes and Platelets From Adult Stem Cells and Somatic Cells......Page 956
Improving the Efficiency for In Vitro Platelet Production......Page 957
HEMATOPOIETIC STEM CELLS......Page 958
References......Page 960
Further Reading......Page 963
CARTILAGE AND CARTILAGE REPAIR......Page 964
Cartilage Surface Modification......Page 965
Bioscaffolds in Cartilage Repair......Page 966
Chitosan......Page 967
Synthetic Scaffolds......Page 968
Biological Factors......Page 969
Bioreactors......Page 970
Clinical Translation......Page 972
CURRENT AND FUTURE TRENDS IN CARTILAGE ENGINEERING......Page 973
References......Page 974
Regulatory and Financial Challenges to Stem Cell Therapies......Page 980
STEM CELL THERAPIES FOR MUSCULOSKELETAL DISEASES......Page 981
Bone......Page 982
Articular Cartilage......Page 983
Osteochondral Tissue......Page 985
Tendon and Ligament......Page 986
Tendon–Bone Interface: Enthesis......Page 987
Meniscus......Page 988
Intervertebral Disc......Page 989
Skeletal Muscle......Page 990
CHALLENGES AND PROSPECTS......Page 991
References......Page 993
SATELLITE CELL–DERIVED MYOBLASTS MEET THE PROPERTIES NEEDED FOR TRANSPLANTATION IN SKELETAL MUSCLES......Page 998
Gene Complementation......Page 999
Formation of New Myofibers......Page 1000
Formation of Graft-Derived Satellite Cells......Page 1002
Technical Approaches for Intramuscular Transplantation......Page 1003
Potential Risks of the Cell Injection Procedure......Page 1004
Improving the Efficiency of Cell Injections......Page 1006
Initial Survival......Page 1007
Long-term Survival......Page 1008
CONCLUSIONS......Page 1009
References......Page 1010
Background......Page 1014
History of Islet Transplantation......Page 1015
The Edmonton Protocol......Page 1016
Patient Assessment and Selection......Page 1017
Islet Transplantation Procedure......Page 1018
Immunosuppressive Therapy and Complications......Page 1019
Living Donor Islet Transplantation......Page 1020
Stem Cell Transplantation......Page 1022
Optimal Transplantation Site......Page 1024
Improving Engraftment Posttransplant......Page 1025
Improved Immunomodulation: Toward Donor-Specific Tolerance......Page 1026
References......Page 1028
FETAL DEVELOPMENT AND REGENERATIVE MEDICINE......Page 1036
PRECLINICAL ANIMAL STUDIES OF IN UTERO STEM CELL TRANSPLANTATION......Page 1038
Barriers to In Utero Stem Cell Transplantation Success......Page 1040
The Need for Better Hemophilia A Treatments......Page 1042
Feasibility and Justification for Treating Hemophilia A Before Birth......Page 1043
Genomic Integration-Associated Insertional Mutagenesis......Page 1045
Genome Editing......Page 1046
CLINICAL EXPERIENCE WITH IN UTERO STEM CELL TRANSPLANTATION......Page 1047
References......Page 1048
INTRODUCTION......Page 1056
Xenogenic Matrices......Page 1057
Tissue Engineering by Self-assembly......Page 1059
Extracellular Matrices Formed by Cell Culture and Synthetic Polymers......Page 1060
Nature-Derived Polymers and Synthetic Polymers......Page 1061
Synthetic Polymers With Seeded Cells......Page 1062
CONCLUSION......Page 1065
References......Page 1066
Young Populations......Page 1068
TISSUE ENGINEERED HEART VALVES......Page 1069
Considerations for Cell Source......Page 1070
Implant Function......Page 1071
Testing Tissue Engineered Heart Valve Function......Page 1072
Decellularized Bioscaffolds......Page 1073
Fibrin......Page 1074
Gelatin......Page 1075
Polyvinyl Alcohol......Page 1076
Hydrolytically Degradable Polymers......Page 1077
Tissue Engineered Heart Valve Fabrication Techniques......Page 1078
Future Direction in Tissue Engineered Heart Valves......Page 1079
CONCLUSIONS......Page 1080
References......Page 1081
LUNG DEVELOPMENT: A ROAD MAP TO REGENERATION......Page 1086
REPAIR AND REGENERATION IN THE NATIVE LUNG......Page 1087
NOVEL CELL POPULATIONS FOR LUNG REPAIR......Page 1088
BIOLOGICAL SCAFFOLDS TO SUPPORT REGENERATION......Page 1090
ADVANCES IN REBUILDING FUNCTIONAL LUNG TISSUE......Page 1092
List of Acronyms and Abbreviations......Page 1095
References......Page 1096
INTRODUCTION: FROM TISSUES TO ORGANS: KEY GOALS AND ISSUES......Page 1100
ENGINEERING OF CARDIAC PATCHES USING CELLS, SCAFFOLDS, AND BIOREACTORS......Page 1101
BIOPRINTING......Page 1105
CARDIAC ORGANOIDS AND ORGAN-ON-A-CHIP ENGINEERING......Page 1107
Oxygen Supply......Page 1110
Mechanical Stimulation......Page 1111
Electrical Stimulation......Page 1112
Tissue Architecture and Electrical Conduction......Page 1113
Vascularization......Page 1114
Host Response and Biocompatibility......Page 1115
In Situ Cardiac Tissue Engineering via Injection of Cells in Hydrogels......Page 1117
Implantation of Cardiac Patches......Page 1118
References......Page 1121
Further Reading......Page 1126
INTRODUCTION......Page 1128
Collagens......Page 1130
Decellularized Extracellular Matrix......Page 1131
Cancer Research......Page 1133
Bioartificial Liver and Transplantation Research......Page 1134
Limitations of Current In Vitro Liver Models to Test Drugs......Page 1135
Organoids in Drug Development......Page 1136
CONCLUSIONS AND FINAL PERSPECTIVES......Page 1137
References......Page 1138
Treatment Options, State of the Art, and Need for Corneal Regenerative Medicine......Page 1142
REGENERATIVE MEDICINE APPLIED TO KERATOPROSTHESIS DEVELOPMENT......Page 1143
Corneal Endothelium......Page 1145
FULLY CELL-BASED, SELF-ASSEMBLED CORNEAL CONSTRUCTS......Page 1146
Decellularized Extracellular Matrix as Implants......Page 1149
Peptide Analogs of Extracellular Matrix......Page 1150
CHALLENGES......Page 1152
References......Page 1153
ESOPHAGUS......Page 1158
STOMACH......Page 1161
SMALL INTESTINE......Page 1162
ANAL CANAL......Page 1168
IN VITRO MODELS......Page 1169
References......Page 1170
REQUIREMENTS OF A RENAL REPLACEMENT DEVICE......Page 1176
DEVICES USED IN CONVENTIONAL RENAL REPLACEMENT THERAPY......Page 1177
ADVANCEMENTS IN CONVENTIONAL RENAL REPLACEMENT THERAPY DEVICES......Page 1178
RENAL ASSIST DEVICE: A MORE COMPLETE RENAL REPLACEMENT THERAPY......Page 1179
RENAL ASSIST DEVICE THERAPY OF ACUTE KIDNEY INJURY CAUSED BY SEPSIS......Page 1180
IMMUNOMODULATORY EFFECT OF THE RENAL ASSIST DEVICE......Page 1181
SELECTIVE CYTOPHERETIC DEVICE......Page 1182
CHALLENGE: COST-EFFECTIVE STORAGE AND DISTRIBUTION FOR CELL DEVICES, BIOARTIFICIAL RENAL EPITHELIAL CELL SYSTEM DESIGN......Page 1183
BIOARTIFICIAL RENAL EPITHELIAL CELL SYSTEM AS AN EXTRACORPOREAL THERAPY TO TREAT ACUTE KIDNEY INJURY......Page 1184
WEARABLE BIOARTIFICIAL KIDNEY IN PRECLINICAL END-STAGE RENAL DISEASE MODEL......Page 1185
FUTURE ADVANCEMENTS FOR WEARABLE AND AMBULATORY RENAL REPLACEMENT THERAPIES......Page 1186
List of Acronyms and Abbreviations......Page 1187
References......Page 1188
INTRODUCTION......Page 1192
Cell Sources: Kidney Tissue–Derived Stem and Primary Cells......Page 1193
Other Cell Sources: Pluripotent, Fetal, or Adult Stem Cells......Page 1195
Engineering of Cell-Based Renal Constructs......Page 1196
CELL-FREE APPROACH: IN SITU RENAL REGENERATION......Page 1199
References......Page 1200
INTRODUCTION......Page 1206
Biomechanics......Page 1207
Uniaxial Tensile Testing......Page 1208
Contribution to Joint Function......Page 1209
HEALING OF LIGAMENTS AND TENDONS......Page 1210
Anterior Cruciate Ligament of the Knee......Page 1211
In Vitro Studies......Page 1212
Gene Therapy......Page 1213
Cell Therapy......Page 1214
Medial Collateral Ligament and Patellar Tendon Healing With Extracellular Matrix (Small Intestinal Submucosa)......Page 1215
Anterior Cruciate Ligament Healing......Page 1216
Mechanical Augmentation......Page 1217
Combined Biological and Mechanical Augmentation......Page 1218
SUMMARY AND FUTURE DIRECTIONS......Page 1219
References......Page 1220
INTRODUCTION......Page 1226
Endogenous Stem Cells......Page 1227
Biomolecule Delivery......Page 1228
Cell Therapy......Page 1229
Factors for Endogenous Stem Cell Stimulation......Page 1230
Cell Transplantation......Page 1232
Biomolecule Delivery......Page 1233
Guiding Axon Regrowth......Page 1234
Retinal Degeneration......Page 1235
Biomolecule Delivery......Page 1237
Cell Transplantation......Page 1238
List of Acronyms and Abbreviations......Page 1240
References......Page 1241
HISTORICAL BACKGROUND......Page 1250
Natural Scaffolds......Page 1251
Synthetic Scaffolds for Nerve Repair......Page 1252
Extracellular Matrix Molecules for Nerve Regeneration......Page 1253
Neurotrophic Factors and Cytokine Delivery for Nerve Regeneration......Page 1254
Seeding Neuronal Support Cells for Nerve Regeneration......Page 1255
ANISOTROPIC SCAFFOLDS FOR NERVE REGENERATION......Page 1256
Neurotrophic Factors......Page 1257
NATURAL NERVE GRAFTS......Page 1258
CONCLUSION......Page 1259
References......Page 1260
PRINCIPLES OF TISSUE ENGINEERING......Page 1264
THE VAGINA......Page 1265
Engineering of Functional Vaginal Tissue......Page 1266
Uterine Tissue Regeneration......Page 1267
THE OVARIES......Page 1269
Tissue Engineered Ovarian Follicles......Page 1270
Regenerating Ovarian Tissue From Stem Cells......Page 1271
Pelvic Organ Prolapse......Page 1272
References......Page 1273
TESTES......Page 1278
Spermatogonial Stem Cell Technology......Page 1279
Androgen Replacement Therapy......Page 1281
Spinal Ejaculation Generator......Page 1282
Penile Transplantation......Page 1284
References......Page 1285
INTRODUCTION......Page 1290
Stem Cell Sources......Page 1291
Multipotentiality......Page 1293
Paracrine Effects and Immunomodulatory Properties......Page 1294
Synthetic Scaffolds......Page 1295
Biodegradable Properties......Page 1296
Collagen......Page 1297
Fibrotic Bladder Model......Page 1298
Clinical Translation......Page 1300
Clinical Studies......Page 1301
References......Page 1302
INTRODUCTION......Page 1308
DEVELOPMENT, ANATOMY, AND FUNCTION OF SKIN......Page 1310
POTENTIAL PREREQUISITE REQUIREMENTS FOR TISSUE ENGINEERED SKIN SOLUTIONS......Page 1312
CURRENT TISSUE ENGINEERING SKIN TECHNOLOGIES......Page 1314
TISSUE ENGINEERING SKIN SOLUTIONS IN CLINICAL PRACTICE......Page 1316
THE FUTURE......Page 1317
References......Page 1319
INTRODUCTION......Page 1324
USE OF AUTOLOGOUS GROWTH FACTORS IN HAIR FOLLICLE REGENERATION......Page 1325
USE OF ADIPOSE-DERIVED STEM CELLS AND THEIR CONDITIONED MEDIUM FOR HAIR GROWTH......Page 1326
SIMULATING THE EMBRYONIC ENVIRONMENT......Page 1327
BIOENGINEERING A HUMAN HAIR FOLLICLE......Page 1331
References......Page 1333
Further Reading......Page 1335
Fetal Cells......Page 1336
Embryos......Page 1337
History of US Stem Cell Law and Policy......Page 1338
State Policy and Private Funding......Page 1340
The National Academies of Science......Page 1343
INTERNATIONAL COMPARISONS......Page 1345
SELECTED ETHICAL, LEGAL, SOCIAL, AND POLICY QUESTIONS OF STEM CELL RESEARCH......Page 1348
Compensating Egg Donors......Page 1350
Commercialization and Access to Treatments......Page 1351
Animal–Human Chimeras......Page 1352
List of Acronyms and Abbreviations......Page 1353
References......Page 1354
IS IT NECESSARY TO USE HUMAN EMBRYOS?......Page 1358
IS IT MORALLY PERMISSIBLE TO DESTROY A HUMAN EMBRYO?......Page 1359
MAY ONE BENEFIT FROM OTHERS' DESTRUCTION OF EMBRYOS?......Page 1360
MAY WE CLONE HUMAN EMBRYOS?......Page 1361
MAY WE USE HUMAN STEM CELLS TO CREATE CHIMERAS?......Page 1362
MAY WE GENETICALLY MODIFY HUMAN EMBRYOS?......Page 1363
Donor and Procurement Issues......Page 1364
Clinical Translation......Page 1365
References......Page 1367
BRIEF LEGISLATIVE HISTORY OF UNITED STATES FOOD AND DRUG ADMINISTRATION......Page 1372
LAWS, REGULATIONS, AND GUIDANCE......Page 1373
FOOD AND DRUG ADMINISTRATION ORGANIZATION AND JURISDICTIONAL ISSUES......Page 1374
APPROVAL MECHANISMS AND CLINICAL STUDIES......Page 1375
Regulation of Human Cells and Tissues Intended for Transplantation......Page 1377
Human Cellular Therapies......Page 1378
Xenotransplantation......Page 1380
Gene Therapy......Page 1381
Cell–Scaffold Combination Products......Page 1382
CLINICAL DEVELOPMENT PLAN......Page 1383
Food and Drug Administration's Standards Development Program......Page 1384
ADVISORY COMMITTEE MEETINGS......Page 1385
FOOD AND DRUG ADMINISTRATION RESEARCH AND CRITICAL PATH SCIENCE......Page 1386
OTHER COORDINATION EFFORTS......Page 1388
References......Page 1389
Primary Challenges for Widespread Adoption......Page 1394
Logistics......Page 1395
Scale-Up and Automation......Page 1396
ENVISIONED REGENERATIVE MEDICINE MANUFACTURING SYSTEMS OF THE FUTURE......Page 1397
Technical Societies......Page 1400
International Efforts......Page 1401
References......Page 1402
A......Page 1404
B......Page 1407
C......Page 1410
D......Page 1416
E......Page 1418
F......Page 1420
G......Page 1422
H......Page 1423
I......Page 1427
L......Page 1430
M......Page 1431
N......Page 1435
P......Page 1438
R......Page 1443
S......Page 1445
T......Page 1450
U......Page 1453
X......Page 1454
Z......Page 1455
Back Cover......Page 1456