Principles of Tissue Engineering

Cover......Page 1
Principles of Tissue Engineering......Page 3
Copyright......Page 4
Part One The basis of growth and differentiation63......Page 5
Part Two In vitro control of tissue development155......Page 7
Part Four Biomaterials in tissue engineering273......Page 8
Part Five Transplantation of engineered cells and tissues361......Page 9
Part Six Stem cells419......Page 10
Part Seven Gene therapy491......Page 11
Part Nine Cardiovascular system577......Page 12
Part Ten Endocrinology and metabolism655......Page 13
Part Eleven Gastrointestinal system707......Page 14
Part Twelve Hematopoietic system755......Page 15
Part Thirteen Kidney and genitourinary system803......Page 16
Part fourteen Musculoskeletal system881......Page 17
Part Fifteen Nervous system1023......Page 18
Part Sixteen Ophthalmic1113......Page 19
Part Seventeen Oral/Dental applications1185......Page 20
Part Eighteen Respiratory system1251......Page 21
Part Nineteen Skin1287......Page 22
Part Twentyone Emerging technologies1389......Page 23
Part Twentytwo Clinical experience1481......Page 24
Part Twenty three Regulation, commercialization and ethics1551......Page 26
List of contributors......Page 28
Preface......Page 39
Current state of the field......Page 40
Smart biomaterials......Page 41
Cell sources......Page 43
Induced pluripotent stem cells......Page 45
Adult stem cells......Page 46
Whole organ engineering......Page 47
Electrospinning......Page 48
Extrusion three-dimensional bioprinting......Page 51
Spheroids and organoids......Page 52
Bioreactors......Page 55
Organ-on-a-chip and body-on-a-chip......Page 56
Integration of nanotechnology......Page 57
Current challenges......Page 58
Smart biomaterials......Page 60
Embryonic stem cells......Page 61
Adult stem cells......Page 62
Biofabrication technologies......Page 63
Integration of nanotechnology......Page 64
References......Page 65
Further reading......Page 74
Modeling stem cell dynamics......Page 75
Positive feedback–based molecular switches......Page 76
Variability in stem cell populations......Page 78
Modeling tissue growth and development......Page 79
Tissue growth on complex surfaces in vitro......Page 80
Three-dimensional tissue growth in vitro......Page 81
Pattern formation......Page 82
Machine learning in tissue engineering......Page 83
Unsupervised methods......Page 84
From mathematical models to clinical reality......Page 85
References......Page 86
Current state of tissue engineering......Page 90
Pathway for clinical translation......Page 91
Regulatory considerations for tissue engineering......Page 95
Further reading......Page 97
Part One: The basis of growth and differentiation
......Page 99
The cell nucleus......Page 100
Control of gene expression......Page 101
Other controls of gene activity......Page 102
The cytoplasm......Page 103
Microfilaments......Page 104
Small GTPases......Page 105
Cell adhesion molecules......Page 106
Extracellular matrix......Page 107
Signal transduction......Page 108
Growth and death......Page 109
Culture media......Page 110
Cell types......Page 111
Organs......Page 112
Cytoskeleton, adhesion molecules and extracellular matrix......Page 113
Molecules that organize cells......Page 114
Changes in celleextracellular matrix adhesion......Page 115
Invasion of the basal lamina......Page 116
Regulation at the promoter level......Page 117
Growth factor-β pathway......Page 118
Signaling by receptor tyrosine kinase ligands......Page 119
A model for epithelial–mesenchymal transition induction......Page 120
Glossary......Page 121
References......Page 122
Extracellular matrix composition......Page 127
Receptors for extracellular matrix molecules......Page 128
Adhesion and migration......Page 130
Proliferation......Page 132
Differentiation......Page 133
Adhesion and migration......Page 134
Proliferation......Page 136
Differentiation......Page 137
Signal transduction events during cell–extracellular matrix interactions......Page 138
Creating the proper substrate for cell survival and differentiation......Page 145
Providing the appropriate environmental conditions for tissue maintenance......Page 146
References......Page 147
Introduction......Page 152
Collagens......Page 153
Fibrillar collagens......Page 154
Fibril-associated collagens with interrupted triple helices (FACIT)......Page 155
Fibronectin......Page 156
Laminin......Page 158
Tenascins......Page 159
Hyaluronan and lecticans......Page 160
References......Page 161
Biology of tissue morphogenesis......Page 166
Morphogens as bioactive signaling molecules during morphogenesis......Page 167
The extracellular matrix as a key regulator of tissue morphogenesis......Page 168
Tissues as integrated systems in the body......Page 169
Cells as building units in tissue engineering......Page 171
Biomaterial scaffolds as artificial extracellular matrices......Page 172
Tissue remodeling in healthy and diseased environments......Page 173
References......Page 174
Determination and differentiation......Page 178
MyoD and the myogenic regulatory factors......Page 180
MicroRNAs—regulators of differentiation......Page 181
Satellite cells in skeletal muscle differentiation and repair......Page 182
Tissue engineering—repairing muscle and fostering regeneration by controlling determination and differentiation......Page 183
References......Page 185
Part Two: In vitro control of tissue development
......Page 188
Introduction......Page 189
Fundamental parameters for engineering functional tissues......Page 190
In vitro studies relevant to tissue engineering and regenerative medicine......Page 191
In vitro platforms relevant for high throughput screening of drugs and other agents......Page 192
Cartilage tissue engineering......Page 193
Fiber-reinforced constructs for cartilage repair......Page 194
Stratified and osteochondral constructs for cartilage repair......Page 195
Bioinductive and bioactive scaffolds......Page 196
Cardiac tissue–engineering biomaterials......Page 197
Cell seeding......Page 198
Cartilage tissue-engineering bioreactors......Page 199
Cardiac tissue-engineering bioreactors......Page 200
Effects of hydrodynamic forces......Page 201
Mechanical effects on engineered cartilage tissue......Page 202
Conclusion......Page 203
References......Page 204
Further reading......Page 209
Introduction......Page 210
Macrobioreactors......Page 211
Mass transport......Page 212
Physiological biomimicry cues......Page 215
Cell environment......Page 217
Sustainable bioreactors......Page 219
Microgravity bioreactor......Page 220
Real-time assessment in the bioreactor......Page 221
Flow rheology......Page 222
Integration of multiple compartments......Page 224
Components and integration into microreactors......Page 225
Drug testing and screening......Page 226
Prognostic/diagnostic tools......Page 227
References......Page 228
Thrombospondin-1......Page 235
Thrombospondin-2......Page 237
Tenascin-C......Page 238
Osteopontin......Page 239
Secreted protein acidic and rich in cysteine......Page 240
References......Page 242
The basis of branching morphogenesis......Page 246
Branching morphogenesis in the lung......Page 247
Branching morphogenesis in the salivary gland......Page 249
Branching morphogenesis in the kidney......Page 251
Contributions of other cell types......Page 253
MicroRNAs in branching morphogenesis......Page 254
Collagen......Page 255
Heparan sulfate proteoglycan......Page 256
Basement membrane microperforations......Page 257
Signaling mechanisms......Page 259
Conclusion......Page 260
References......Page 261
Tension......Page 265
Cellular mechanosensing......Page 266
Stretch-activated ion channels......Page 267
Cell–substrate adhesions......Page 268
The extracellular matrix......Page 269
Cell–cell interactions in collectives......Page 271
Proliferation and differentiation......Page 272
Wound healing......Page 273
Tissue morphogenesis......Page 275
Bone-implant design......Page 276
Organs-on-a-chip......Page 278
References......Page 280
Part Three: In Vivo Synthesis of Tissues and Organs
......Page 285
Historical context......Page 286
Nature’s approach to cellular differentiation and organization......Page 287
In vivo bone engineering—the bone bioreactor......Page 288
In vivo cartilage engineering......Page 291
Induction of angiogenesis using biophysical cues—organotypic vasculature engineering......Page 292
De novo liver engineering......Page 294
Conclusions and outlook......Page 296
References......Page 297
Part Four: Biomaterials in tissue engineering
......Page 300
Adhesion and spreading......Page 301
Migration......Page 303
In vivo methods......Page 304
Synthetic polymers......Page 306
Surface modification......Page 307
Synthetic polymers with adsorbed proteins......Page 308
Hybrid polymers with immobilized functional groups......Page 309
Influence of surface morphology on cell behavior......Page 310
Use of patterned surfaces to control cell behavior......Page 311
Cell interactions with polymers in suspension......Page 312
Inflammation......Page 313
Fibrosis and angiogenesis......Page 314
References......Page 315
Introduction......Page 320
Materials and inks......Page 322
Processing and cell viability......Page 324
Cell types and biological interactions......Page 325
Assessment of cell viability and activity......Page 326
3D printing systems and printer types......Page 327
Inkjet printing......Page 328
Extrusion printing......Page 329
Stereolithography......Page 330
Open source and commercial 3D printing systems......Page 331
Print outputs: patterning, resolution, and porous architecture......Page 332
Print resolution......Page 333
Assessment of scaffold fidelity......Page 334
Conclusion......Page 335
References......Page 336
Biodegradable polymer selection criteria......Page 341
Peptides and proteins......Page 342
Collagen......Page 343
Elastin......Page 344
Silk......Page 345
Polysaccharides......Page 346
Starch......Page 347
Glycosaminoglycans......Page 348
Polyhydroxyalkanoates......Page 349
Aliphatic polyesters......Page 350
Polyglycolide, polylactide, and their copolymers......Page 351
Poly(ortho esters)......Page 353
Biodegradable polyurethanes......Page 354
Polyphosphazenes......Page 355
Poly(amino acids) and pseudo-poly(amino acids)......Page 356
Using polymers to create tissue-engineered products......Page 357
Matrices......Page 358
References......Page 359
Three-dimensional scaffold design and engineering......Page 367
Mass transport and pore architectures......Page 368
Mechanics......Page 370
Electrical conductivity......Page 372
Surface chemistry......Page 373
Surface topography......Page 375
Scaffold degradation......Page 376
Delivery of soluble bioactive factors......Page 377
Spatial control......Page 378
References......Page 379
Part Five: Transplantation of engineered cells and tissues
......Page 385
Immune cells and their roles in building tissues after injury......Page 386
Dendritic cells......Page 387
Tissue engineering/regenerative medicine strategies as immunotherapy......Page 388
References......Page 389
Further reading......Page 391
Introduction......Page 392
Rationale for in utero therapies......Page 393
In utero transplantation......Page 394
In utero transplantation experiments in large preclinical animal models......Page 395
Barriers to in utero transplantation success......Page 396
Rationale for in utero gene therapy......Page 399
Hemophilia A as a model genetic disease for correction by in utero gene therapy......Page 400
Preclinical animal models for hemophilia A and recent clinical successes......Page 401
Sheep as a preclinical model of hemophilia A......Page 402
Feasibility and justification for treating hemophilia A prior to birth......Page 403
Mesenchymal stromal cells as hemophilia A therapeutics......Page 406
Preclinical success with mesenchymal stromal cell–based hemophilia A treatment......Page 407
Genomic integration–associated insertional mutagenesis......Page 408
Potential risk to fetal germline......Page 409
Conclusion and future directions......Page 410
References......Page 411
Rejection and protection of transplanted cells and materials......Page 426
Cellular nutrition......Page 427
Primary cells......Page 428
Immortalized cell lines......Page 429
Device architecture and mass transport......Page 430
Transplantation site......Page 431
Improving oxygenation of immunoprotected cells......Page 432
Controlling immune responses to implanted materials......Page 433
The role of geometry in the foreign body reaction......Page 434
References......Page 435
Part Six: Stem cells
......Page 442
Approaches to human embryonic stem cell derivation......Page 443
Subculture of human embryonic stem cell......Page 447
Directed differentiation......Page 448
Safety concerns......Page 452
References......Page 453
Disease modeling......Page 457
Drug discovery......Page 458
Stem cell–based therapeutic development......Page 460
References......Page 462
Reprogramming of somatic cells into induced pluripotent stem cells......Page 466
Reprogramming techniques......Page 467
Disease modeling......Page 469
Challenges and future possibilities in disease modeling......Page 471
Disease-modifying potential of induced pluripotent stem cells......Page 472
Conclusion......Page 473
References......Page 474
Embryonic stem cells......Page 477
Amniotic fluid stem cells......Page 478
Natural materials......Page 479
Physiology......Page 480
Esophageal atresia......Page 481
Congenital airway anomalies......Page 482
References......Page 483
Introduction......Page 487
Maintenance of embryonic stem cells......Page 488
Genetic reprogramming......Page 491
Microenvironmental cues......Page 492
High-throughput assays for directing stem cell differentiation......Page 495
Physical signals......Page 497
Isolation of specific progenitor cells from embryonic stem cells......Page 499
Transplantation......Page 500
Transplantation and immune response......Page 501
Future prospects......Page 502
References......Page 503
Further reading......Page 510
Part Seven: Gene therapy
......Page 511
Strategies of gene therapy......Page 512
Ex vivo......Page 513
Gene transfer vectors......Page 514
Adenovirus......Page 516
Adeno-associated virus......Page 518
Retrovirus......Page 519
Lentivirus......Page 520
Targeting of Ad vectors......Page 521
Regulated expression of the transferred gene......Page 524
Using gene transfer vectors for gene editing......Page 526
Gene transfer to instruct stem-cell differentiation......Page 527
Challenges to gene therapy for tissue engineering......Page 528
References......Page 529
Fundamentals of gene delivery......Page 538
Tissue biodistribution/targeting......Page 540
Cellular uptake and intracellular trafficking......Page 542
Introduction to viral gene therapy......Page 545
Types of viral vectors......Page 546
Engineering viral vectors......Page 547
Introduction to nonviral nucleic acid delivery......Page 549
Synthetic polymers......Page 550
Polymers derived from natural sources or monomers......Page 553
Lipid-based delivery systems......Page 555
High-throughput screening......Page 556
Viral delivery to engineer tissues......Page 557
Nonviral delivery from scaffolds......Page 559
Future challenges......Page 560
Outlook......Page 561
References......Page 562
Part Eight: Breast
......Page 574
Breast anatomy and development......Page 575
Breast reconstruction......Page 576
Cell transplants......Page 577
Cell types and related challenges......Page 578
Synthetic materials......Page 579
Naturally derived materials......Page 580
Injectable scaffolds......Page 581
Strategies to enhance the vascularization of engineered tissue......Page 582
Animal models......Page 583
Breast tissue test systems......Page 584
In silico breast cancer models......Page 588
References......Page 589
Part Nine: Cardiovascular system
......Page 594
Origin of cardiac stem/progenitor cells......Page 595
Modeling cardiac development with pluripotent stem cells......Page 597
Neonatal cardiac repair......Page 598
Cardiac resident mesenchymal stem cells......Page 600
Cell-based therapy......Page 601
Pluripotent stem cells......Page 602
References......Page 604
Clinical problem......Page 608
Cell source......Page 609
Scaffold......Page 613
Derivation of cardiomyocytes from human pluripotent stem cells......Page 614
Decellularization approach......Page 616
Artificial scaffolds......Page 617
Mechanical stimulation......Page 619
Engineered heart issue......Page 621
Electrical coupling of cardiomyocytes on the heart......Page 623
Cardiac fibrosis......Page 624
Tissue engineering as a platform for pharmacologic studies......Page 626
References......Page 627
Normal and pathologic composition of the vessel wall......Page 632
Conduit patency and failure......Page 633
Hemodialysis vascular access......Page 634
Inflammation and the host response to interventions and grafts......Page 635
Host environment and the critical role of the endothelium......Page 636
Expanded polytetrafluoroethylene......Page 637
Endothelial cell seeding......Page 638
In vitro approaches to tissue-engineered vascular grafts......Page 639
Bioresorbable grafts......Page 640
Surface modifications......Page 641
Porosity......Page 642
Biological modification through exogenous sources......Page 643
Gene therapy......Page 644
References......Page 645
Heart valve function and structure......Page 650
Valvular interstitial cells......Page 651
Heart valve dysfunction......Page 652
Heart valve replacement......Page 653
Biomaterials and scaffolds......Page 655
The search for appropriate cell sources......Page 658
Cell seeding techniques......Page 659
Neotissue development in tissue engineered heart valves......Page 660
Clinical applications of the tissue engineered heart valve......Page 662
Conclusion and future directions......Page 663
References......Page 664
Part Ten: Endocrinology and metabolism
......Page 669
State-of-the-art......Page 670
Recent achievements (first generation of pancreatic progenitors used in the clinic)......Page 671
Strategies to maintain cell viability......Page 672
The concept of cellular medicament......Page 674
References......Page 675
Introduction......Page 678
Replenishable cell sources and encapsulation......Page 679
Macro- or microedevices......Page 680
Factors contributing to biocompatibility of encapsulation systems......Page 682
Multilayer capsule approaches......Page 683
Formation of polymer brushes......Page 684
Intracapsular environment and longevity of the encapsulated islet graft......Page 685
Concluding remarks and future considerations......Page 686
References......Page 687
Structure and morphology of the thymus......Page 693
Complexity of the thymic epithelium compartment......Page 694
In vitro T cell differentiation......Page 695
Cellular regulation of early thymus organogenesis......Page 697
Thymic epithelial progenitor cells......Page 698
Cervical thymus in mouse and human......Page 700
Molecular control of early organogenesis......Page 701
Transcription factors and regulation of third pharyngeal pouch outgrowth......Page 703
Specification of the thymus and parathyroid......Page 704
Foxn1 and regulation of thymic epithelial cell differentiation......Page 707
Maintenance and regeneration of thymic epithelial cells: Progenitor/stem cells in the adult thymus......Page 708
Strategies for thymus reconstitution......Page 709
Summary......Page 710
References......Page 711
Part Eleven: Gastrointestinal system
......Page 719
Cell types of the epithelial layer......Page 720
Stem and progenitor cell types......Page 721
The Wnt pathway......Page 723
Epidermal growth factor receptor/ErbB signaling......Page 724
Organ-specific stem cell progenitors versus pluripotent stem cells......Page 725
Synthetic and biological scaffolds......Page 726
Primary intestinal-derived organoid units......Page 727
Pluripotent stem cell approaches—human intestinal organoids......Page 728
References......Page 729
Liver development......Page 733
Molecular signaling and processes involved in liver regeneration......Page 734
Cholangiocytes and liver stem cells in liver regeneration......Page 735
Pluripotent stem cell–derived hepatoblasts and hepatocytes......Page 736
3D liver organoids and expansion......Page 737
Hepatocyte-derived organoids......Page 738
Novel scaffolds for liver organoids......Page 739
Reprogramming of human hepatocytes to liver progenitors using different culture conditions......Page 740
References......Page 741
Further reading......Page 746
Liver disease burden......Page 747
Liver transplantation......Page 748
In vitro models......Page 750
Three-dimensional liver constructs......Page 751
Controlling three-dimensional architecture and cellular organization......Page 752
Cell number requirements......Page 753
Extracellular matrix for cell therapies......Page 754
Modifications in scaffold chemistry......Page 755
Vascular engineering......Page 756
Conclusion and outlook......Page 757
References......Page 758
Part Twelve: Hematopoietic system
......Page 764
Hematopoietic stem cells and hematopoietic stem cells niche......Page 765
Effects of biomaterials on hematopoietic stem cells......Page 766
Engineering hematopoietic stem cells niche for in vitro expansion......Page 767
Manipulation of the multilineage differentiation of hematopoietic stem cells......Page 768
References......Page 769
Red blood cells......Page 773
Megakaryocytes/platelets......Page 777
Lymphocytes—T cells......Page 778
Lymphocytes—NK cells......Page 781
Lymphocytes—NKT cells......Page 783
Monocyte-derived dendritic cells......Page 784
Monocyte-derived macrophages......Page 785
Granulocytes—neutrophils......Page 786
References......Page 787
Hemoglobin-based oxygen carriers......Page 793
Hemoglobin toxicity......Page 795
Viscosity and colloid osmotic pressure......Page 797
Surface conjugated hemoglobin......Page 798
Sources of hemoglobin......Page 799
Erythrocruorins......Page 800
Perfluorocarbons......Page 801
Organ transplant preservation......Page 802
References......Page 803
Part Thirteen: Kidney and genitourinary system
......Page 810
Kidney development......Page 811
Early embryonic origins of nephrogenic tissues......Page 812
Development of the nephric duct and ureteric bud......Page 814
Maintenance and differentiation of the nephron progenitor cell......Page 815
Role of stromal lineages in kidney organogenesis......Page 817
Nephron endowment......Page 818
Stem cells in kidney repair......Page 819
Sources of nephrogenic cells......Page 820
Differentiation of renal tissue from pluripotent stem cells (organoids)......Page 821
Conclusion......Page 823
References......Page 824
Introduction......Page 830
Primary renal cells......Page 831
Renal stem cells in tubules......Page 833
Embryonic stem cells......Page 834
Engineering three-dimensional kidney constructs using natural and synthetic polymers......Page 835
Decellularization/recellularization strategy......Page 837
Granulocyte-colony stimulating factor......Page 840
Conclusion and future perspectives......Page 842
References......Page 843
Introduction......Page 849
Stem cell sources......Page 850
Multipotentiality......Page 852
Paracrine effects and immunomodulatory properties......Page 853
Biodegradable properties......Page 854
Natural collagen matrix......Page 855
Matrix binding with growth factors......Page 856
Fibrotic bladder model......Page 858
Clinical translation......Page 860
Clinical studies......Page 861
References......Page 862
Uterus......Page 867
Cell-seeded scaffolds for partial uterine repair......Page 868
Ovary......Page 869
Tissue engineering approaches for neovagina reconstruction......Page 870
References......Page 871
Spermatogonial stem cell technology......Page 875
Androgen-replacement therapy......Page 877
Engineering vas deferens......Page 878
Penile reconstruction......Page 879
Stem cell therapy for erectile dysfunction......Page 880
References......Page 881
Part Fourteen: Musculoskeletal system
......Page 885
Mesenchymal stem cell identification......Page 886
Tissue sources of mesenchymal stem cells......Page 888
Mesenchymal stem cell isolation and in vitro culture......Page 889
Mesenchymal stem cell self-renewal and proliferation capacity......Page 890
Plasticity of mesenchymal stem cells......Page 891
Mesenchymal stem cell effect on host immunobiology......Page 892
Cartilage tissue engineering......Page 894
Cells for cartilage tissue engineering......Page 895
Mesenchymal stem cell chondrogenic potential......Page 896
Signaling in mesenchymal stem cell chondrogenesis......Page 897
Scaffolds for cartilage tissue engineering......Page 898
Factors influencing outcomes of tissue-engineered cartilage......Page 899
Bone tissue engineering......Page 900
Osteochondral tissue engineering......Page 901
Tendon/ligament......Page 902
Meniscus......Page 903
Conclusion and future perspectives......Page 904
References......Page 905
Skeletal stem cells......Page 919
Fracture repair—the (limited) self-reparative capacity of bone......Page 921
A framework for bone repair: biomaterial-driven strategies for bone regeneration......Page 924
Growth factors: biomimetic-driven strategies for bone regeneration......Page 925
Bone biofabrication......Page 926
Development of vascular bone......Page 927
Preclinical development—ex vivo/in vivo small and large animal preclinical models......Page 928
Clinical translation......Page 931
References......Page 933
Introduction......Page 938
Intervertebral disk structure and function......Page 939
Nucleus pulposus cell-biomaterial implants......Page 941
Annulus fibrosus repair and regeneration......Page 943
Composite cell-biomaterial intervertebral disk implants......Page 945
Cellular engineering for intervertebral disk regeneration......Page 946
Cell therapy preclinical studies......Page 947
Cell therapy clinical studies......Page 948
In vitro studies......Page 949
In vivo studies: growth factors......Page 953
Gene therapy for intervertebral disk regeneration......Page 954
Gene transfer studies: nonviral......Page 955
In vivo preclinical models for intervertebral disk regeneration and replacement......Page 956
References......Page 958
Introduction......Page 967
Mechanisms of articular cartilage injuries......Page 968
Matrix and cell injuries......Page 970
Osteochondral injuries......Page 971
Penetration of subchondral bone......Page 972
Growth factors......Page 973
References......Page 974
Further reading......Page 977
Biomaterials for cartilage tissue engineering......Page 978
Cell sources for cartilage tissue engineering......Page 979
Scaffolds for cartilage tissue engineering......Page 980
Bioinks for cartilage tissue printing......Page 981
References......Page 984
Introduction......Page 987
Function......Page 988
Requirements for a tissue-engineered tendon/ligament......Page 989
Scaffold......Page 990
Cell......Page 992
Bioactive factors......Page 993
Three-dimensional bioprinting and bioink......Page 994
Bioink inspired from ligament and tendon structures......Page 995
Tissue engineering tendon and ligament in clinical application......Page 996
Summary......Page 997
References......Page 998
Introduction......Page 1004
Distraction osteogenesis......Page 1005
Cellular therapy......Page 1007
Cytokines......Page 1010
Scaffolds......Page 1011
Tissue engineering in practice......Page 1013
References......Page 1014
Part Fifteen: Nervous system
......Page 1019
Primary tissue implants......Page 1020
Cell line implants......Page 1022
Cell implants secreting endogenous factors......Page 1023
Encapsulated cell brain implants......Page 1024
Combined replacement and regeneration implants......Page 1025
Disease targets for brain implants......Page 1026
References......Page 1027
Brain–machine interface signals......Page 1031
Voluntary activity versus evoked potentials......Page 1032
Context-aware brain–machine interface......Page 1034
Future directions......Page 1035
References......Page 1036
Spinal cord organization......Page 1040
Spinal cord injury......Page 1041
The continuum of physical, cellular, and molecular barriers to spinal cord regeneration......Page 1042
The role of tissue engineering in spinal cord injury repair......Page 1044
Animal models of spinal cord injury......Page 1045
Principles of biomaterial fabrication for spinal cord injury repair......Page 1047
Extracellular matrix polymers......Page 1051
Polymers from marine or insect life......Page 1058
Polymers derived from the blood......Page 1064
Biomaterials for spinal cord tissue engineering: synthetic polymers......Page 1065
Poly α-hydroxy acid polymers......Page 1066
Nonbiodegradable hydrogels......Page 1070
References......Page 1073
Protection from “acquired” sensory hair cell loss......Page 1085
Prevention of ototoxicity......Page 1086
Prevention of acoustic trauma......Page 1088
Heat shock proteins......Page 1089
Protection from excitotoxicity: “acquired” loss of auditory nerve connections to hair cells......Page 1090
Interventions for hair cell repair: gene therapy for transdifferentiation......Page 1091
Fully implantable cochlear prostheses......Page 1093
Interventions for repair/replacement: central auditory prostheses......Page 1094
Acknowledgments......Page 1095
References......Page 1096
Further reading......Page 1104
Part Sixteen: Ophthalmic
......Page 1105
Epithelial stem cells......Page 1106
Regulation of limbal epithelial stem cells and transient amplifying cells......Page 1107
The pursuit of corneal epithelial stem cell markers......Page 1108
The potential for tissue engineering of limbal epithelial stem cells in ocular surface disease......Page 1109
Endothelial stem cells......Page 1110
Retinal progenitor cells......Page 1111
Generating retinal pigment epithelial from embryonic stem cells/iPSCs......Page 1112
Generating photoreceptors from embryonic stem cells/iPSCs......Page 1113
Generating hematopoietic/vascular progenitors (CD34/endothelial colony-forming cells) from iPSC......Page 1114
Hematopoietic stem cells/CD34+ and retinal disease......Page 1115
Endothelial colony-forming cells......Page 1116
References......Page 1117
Corneal anatomy and structure......Page 1126
Epithelium......Page 1127
Stroma......Page 1129
Endothelium......Page 1130
Conclusion......Page 1131
References......Page 1132
Structure/function of the retina and cell types affected in retinal degenerative diseases......Page 1135
History of retinal pigment epithelium as a cellular therapy for age-related macular degeneration......Page 1137
Retinal pigment epithelium from pluripotent stem cells......Page 1139
Retinitis pigmentosa......Page 1140
Photoreceptors from pluripotent stem cells......Page 1141
Glaucoma......Page 1143
Stem cell–based therapies to treat glaucoma......Page 1144
Stem cell–based therapies to treat diabetic retinopathy......Page 1145
Future directions and competing therapies......Page 1146
References......Page 1147
Visual system, architecture, and (dys)function......Page 1153
Enhancing the stimulus through optoelectronic and optical means......Page 1156
Visual prostheses based on electrical tissue stimulation......Page 1157
Retinal cell transplantation......Page 1160
Optic nerve protection and regeneration......Page 1161
Genetic interventions......Page 1162
Emerging application areas for engineered cells and tissues......Page 1163
Optogenetics......Page 1164
Cell matrices supporting axonal regrowth......Page 1167
Assessing the functional outcomes of novel retinal therapies......Page 1168
References......Page 1169
Further reading......Page 1173
Part Seventeen: Oral/Dental applications
......Page 1174
Tooth development......Page 1175
Bioteeth from cell-seeded scaffolds......Page 1177
Root formation......Page 1178
Natural tissue regeneration......Page 1179
Importance of the injury-regeneration balance......Page 1180
Control of specificity of dental-tissue regeneration......Page 1181
Dental postnatal stem cells......Page 1182
Signaling-based strategies......Page 1183
Cell- and gene-based strategies......Page 1184
References......Page 1185
Special challenges in oral and maxillofacial reconstruction......Page 1188
Current methods of oral and maxillofacial reconstruction......Page 1191
Mandibular defects......Page 1192
Maxillary defects......Page 1194
Bone applications......Page 1195
Cartilage applications......Page 1199
Oral mucosa applications......Page 1201
Animal models......Page 1202
References......Page 1203
Introduction......Page 1208
Intraoral mysenchymal stem cells......Page 1209
Periodontal tissue–derived stem cells......Page 1210
Dental follicle stem cells......Page 1211
Bone marrow–derived mysenchymal stem cells......Page 1212
Selection of cell types......Page 1213
Signaling molecules......Page 1214
Fibroblast growth factor-2......Page 1215
Enamel matrix derivative......Page 1216
Crucial delivery barriers to progress......Page 1217
Gene delivery as an alternative to growth factor delivery......Page 1218
Requirements of cell scaffolds......Page 1219
Naturally derived polymers......Page 1220
Synthetic polymers......Page 1221
Biomaterial redesign for periodontal application......Page 1222
Periodontal bioengineering strategies......Page 1223
Cell-free approaches......Page 1224
Scaffold-free cell delivery......Page 1226
Scaffold-based cell delivery......Page 1228
Challenges and future directions......Page 1229
References......Page 1230
Part Eighteen: Respiratory system
......Page 1237
Introduction: challenges facing cell and tissue-based therapy for the treatment of lung disease......Page 1238
Lung morphogenesis informs the process of regeneration......Page 1239
The mature lung consists of diverse epithelial and mesenchymal cell types......Page 1241
Structure and function of pulmonary vasculature......Page 1242
Embryonic development of alveolar capillaries......Page 1243
Evidence supporting lung regeneration......Page 1244
A diversity of lung epithelial progenitor/stem cells is active during regeneration......Page 1245
Endothelial progenitor cells in lung repair......Page 1247
Induced pluripotent stem cells for study of treatment of pulmonary disease......Page 1248
Differentiation of induced pluripotent stem and embryonic stem cells to pulmonary epithelial cell lineages......Page 1249
Important role of the extracellular matrix in lung structure and repair......Page 1250
References......Page 1251
Design criteria for pulmonary engineering......Page 1258
Decellularized scaffolds and biofabrication approaches......Page 1259
Distal airway engineering......Page 1261
Pulmonary endothelial engineering......Page 1262
Endothelial seeding into lung scaffolds......Page 1263
Organomimetic endothelial culture......Page 1264
Bioreactor technologies for pulmonary engineering......Page 1265
References......Page 1266
Part Nineteen: Skin
......Page 1271
Interfollicular epidermal stem cells......Page 1272
Models for skin renewal: epidermal proliferative unit versus committed progenitor......Page 1273
The bulge as stem cell source......Page 1274
Quiescence......Page 1275
Molecular signature......Page 1276
Bulge......Page 1277
Sebaceous glands......Page 1278
Nails......Page 1279
Wound healing......Page 1280
Epithelial stem cells in aging......Page 1281
Role of stem cells in alopecia......Page 1282
Cross talk between hair follicles and the immune system......Page 1283
Tissue engineering with epidermal stem cells......Page 1284
References......Page 1285
Introduction......Page 1291
Reepithelialization......Page 1292
Granulation tissue......Page 1294
Fibroplasia......Page 1295
Neovascularization......Page 1297
Wound contraction and extracellular matrix organization......Page 1298
Chronic wounds......Page 1299
Pathological scars......Page 1300
Scarless healing......Page 1301
Engineered epidermal constructs......Page 1302
Engineered skin substitutes......Page 1303
Tissue-engineered therapy with stem cells, bioactives, and biomaterials......Page 1304
References......Page 1306
The epidermis......Page 1312
The dermis......Page 1313
Bacterial colonization......Page 1314
Ischemia......Page 1315
Design considerations......Page 1316
Commercial considerations......Page 1317
Regulatory considerations......Page 1318
Epidermal regeneration......Page 1319
Bioengineered living skin equivalents......Page 1320
Cutaneous indications......Page 1321
Apligraf and Dermagraft: off-label uses......Page 1322
The importance of wound bed preparation......Page 1325
Proposed mechanisms of action of bioengineered skin......Page 1326
Construct priming and a new didactic paradigm for constructs......Page 1328
Conclusion......Page 1329
References......Page 1330
Further reading......Page 1333
Why tissue engineering of food?......Page 1334
Function......Page 1335
Cells......Page 1336
Gel and seeding......Page 1337
Cells......Page 1338
Scaffold and cell seeding......Page 1339
Scale......Page 1340
Taste, texture, juiciness......Page 1341
Other foods......Page 1342
Consumer acceptance......Page 1343
References......Page 1344
Introduction......Page 1348
Need and advantages of cultured meat......Page 1349
Scaffolding techniques......Page 1351
Self-organizing tissue culture......Page 1352
Challenges and requirements for industrial production......Page 1354
Generation of suitable stem cell lines from farm-animal species......Page 1355
Safe differentiation media to produce muscle cells......Page 1356
Scaffolds......Page 1357
Industrial bioreactors......Page 1358
Atrophy and exercise......Page 1359
Regulatory issues......Page 1360
Market for cultured meat......Page 1361
Conclusion......Page 1362
References......Page 1363
Part Twenty one: Emerging technologies
......Page 1368
3D Bioprinting strategy: from medical image to printed bioengineered tissue......Page 1369
Jetting-based bioprinting......Page 1370
Laser-assisted bioprinting......Page 1372
Digital light processing......Page 1373
The required properties of hydrogel-based bioinks......Page 1374
Synthetic hydrogels......Page 1375
Naturally derived hydrogels......Page 1376
Scaffold-free cell printing......Page 1377
In vitro tissue models......Page 1378
Tumor models......Page 1379
Bone......Page 1381
Cartilage......Page 1384
Skeletal muscle and tendon......Page 1385
Skin......Page 1386
Conclusion and future perspectives......Page 1387
Glossary......Page 1388
References......Page 1389
Introduction......Page 1394
Inkjet printing......Page 1395
Extrusion printing......Page 1397
Biomaterials for three-dimensional fabrication......Page 1398
Synthetically derived biomaterials......Page 1399
Cell selection......Page 1401
Brain and nerve tissue models......Page 1402
WARNING!!! DUMMY ENTRY......Page 0
Cancer models......Page 1404
Heart tissue models......Page 1405
Liver tissue models......Page 1407
Vascular tissue models......Page 1409
References......Page 1412
Introduction......Page 1419
Advanced in vitro modeling systems—progression from two-dimensional to three-dimensional models......Page 1420
Organ-on-a-chip technologies and their applications......Page 1421
Microengineering and biofabrication......Page 1422
Vessel-on-a-chip......Page 1423
Cancer-on-a-chip......Page 1424
The importance of multiorganoid integration......Page 1425
Drug testing/toxicology......Page 1426
The Ex vivo Console of Human Organoids platform......Page 1428
Organ-on-a-chip systems for personalized precision medicine......Page 1430
Conclusion and perspectives......Page 1431
References......Page 1432
Introduction......Page 1435
General environmental monitoring and real-time control......Page 1436
Mechanical properties......Page 1438
Cartilage monitoring and real-time control......Page 1439
Concluding remarks......Page 1440
References......Page 1441
Current landscape of biomanufacturing......Page 1444
Current challenges in biomanufacturing for regenerative medicine......Page 1445
Current platform technologies enabling biomanufacturing......Page 1447
Regulatory challenges for biomanufacturing......Page 1448
Food and Drug Administration guidance documents......Page 1449
Creating standards......Page 1450
Closed-modular biomanufacturing systems......Page 1451
Medical applications for biomanufacturing in regenerative medicine......Page 1452
Space exploration......Page 1453
References......Page 1454
Part Twenty two: Clinical experience
......Page 1456
Introduction......Page 1457
Scaffold......Page 1458
Subcutaneous fat......Page 1459
Melanocytes......Page 1460
Overall concept......Page 1461
Shelf life......Page 1462
Medium......Page 1463
The Dermagraft and TransCyte production processes......Page 1464
Distribution and cryopreservation......Page 1465
Clinical trials......Page 1466
Immunological properties of tissue-engineered skin......Page 1467
Mechanism of action......Page 1468
Future developments......Page 1469
References......Page 1470
Cartilage defects pathophysiology......Page 1472
Cells for tissue-engineered cartilage repair......Page 1473
Collagen scaffolds......Page 1474
Bioreactors for tissue-engineered cartilage repair......Page 1475
MACI (Vericel, Cambridge, MA, United States)......Page 1476
Novocart Inject (Tetec, Reutlingen, Germany)......Page 1477
Contraindications......Page 1478
Overview......Page 1479
Data from prospective randomized clinical trials......Page 1480
Clinical factors affecting the clinical outcomes of autologous chondrocyte implantation......Page 1481
References......Page 1482
Conventional bone tissue engineering strategies: cells, scaffolds, and biofactors......Page 1483
Delivery of molecules and/or scaffolds to augment endogenous bone regeneration......Page 1484
Clinical successes and opportunities in regenerative repair of diaphyseal defects......Page 1485
Clinical successes and opportunities in regenerative repair of craniofacial defects......Page 1488
References......Page 1489
Cell sources......Page 1492
Extracellular matrix as scaffold......Page 1495
Vascular grafts......Page 1496
Current valve prostheses......Page 1497
Noncontractile cardiac patches......Page 1498
Achieving electromechanical integration......Page 1499
Building the next level of complexity: whole heart......Page 1500
Pathway to approval and commercialization......Page 1501
References......Page 1503
Cell sources......Page 1508
Types of organoid models......Page 1509
Cardiac organoid......Page 1510
Brain organoid......Page 1511
Gastrointestinal tract organoid......Page 1512
Tumor and disease models......Page 1513
Drug analysis......Page 1514
Developmental biology......Page 1515
References......Page 1516
Part Twenty three: Regulation, commercialization and ethics
......Page 1521
Regulatory background......Page 1522
Early-stage development......Page 1523
Pharmacology and toxicology......Page 1524
Clinical......Page 1525
Required US Food and Drug Administration forms......Page 1526
Pharmacology and toxicology data/electronic common technical document Module 4: nonclinical......Page 1527
Product readiness for Phase 3......Page 1528
Phase 3 clinical development......Page 1529
Combination products......Page 1530
Tissue-engineered and regenerative medicine products......Page 1531
Breakthrough device program......Page 1532
Expedited review programs......Page 1533
Minimal manipulation......Page 1534
Responsibilities of sponsors and investigators......Page 1535
Sponsor–investigator responsibilities......Page 1536
Acknowledgments......Page 1537
Appendix II The list of acronyms......Page 1538
References......Page 1539
The aging population......Page 1542
Rise of regenerative medicine......Page 1544
Product development......Page 1546
Embryonic stem cells......Page 1547
Induced pluripotent stem cells......Page 1548
Reimbursement......Page 1549
References......Page 1551
Introduction......Page 1553
To make is to know: notes on an old problem about knowledge......Page 1555
What contextual factors should be taken into account, and do any of these prevent the development and use of the technology?......Page 1556
What purposes, techniques, or applications would be permissible and under what circumstances?......Page 1557
References......Page 1558
Index......Page 1560