Principles of Tissue Engineering

Now in its fifth edition, Principles of Tissue Engineering has been the definite resource in the field of tissue engineering for more than a decade. The fifth edition provides an update on this rapidly progressing field, combining the prerequisites for a general understanding of tissue growth and development, the tools and theoretical information needed to design tissues and organs, as well as a presentation by the world's experts of what is currently known about each specific organ system. As in previous editions, this book creates a comprehensive work that strikes a balance among the diversity of subjects that are related to tissue engineering, including biology, chemistry, material science, and engineering, among others, while also emphasizing those research areas that are likely to be of clinical value in the future. This edition includes greatly expanded focus on stem cells, including induced pluripotent stem (iPS) cells, stem cell niches, and blood components from stem cells. This research has already produced applications in disease modeling, toxicity testing, drug development, and clinical therapies. This up-to-date coverage of stem cell biology and the application of tissue-engineering techniques for food production – is complemented by a series of new and updated chapters on recent clinical experience in applying tissue engineering, as well as a new section on the emerging technologies in the field. Organized into twenty-three parts, covering the basics of tissue growth and development, approaches to tissue and organ design, and a summary of current knowledge by organ system Introduces a new section and chapters on emerging technologies in the field Full-color presentation throughout 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 Endothelia