لایب سان

ISBN

978-0-12-818422-6

Language

English

Published

2020

Copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Imprint

Academic Press

DOI

https://doi.org/10.1016/C2018-0-03818-9

Cell adhesion molecules 71 Extracellular matrix 72 Signal transduction 73 Growth and death 74 Culture media 75 Cells in tissues and organs 76 Cell types 76 Tissues 77 Organs 77 Reference 78 Further reading 78 5. Molecular organization of cells 79 Jon D. Ahlstrom Introduction 79 Molecules that organize cells 79 Changes in cell
cell adhesion 80 Changes in celleextracellular matrix adhesion 80 Changes in cell polarity and stimulation of cell motility 81 Invasion of the basal lamina 81 The epithelial
mesenchymal transition transcriptional program 82 Transcription factors that regulate epithelial
mesenchymal transition 82 Regulation at the promoter level 82 Posttranscriptional regulation of epithelial
mesenchymal transition transcription factors 83 Molecular control of the epithelial
mesenchymal transition 83 Ligand-receptor signaling 83 Additional signaling pathways 85 A model for epithelial
mesenchymal transition induction 85 Conclusion 86 List of acronyms and abbreviations 86 Glossary 86 References 87 6. The dynamics of cell
extracellular matrix interactions, with implications for tissue engineering 93 M. Petreaca and M. Martins-Green Introduction 93 Historical background 93 Extracellular matrix composition 93 Receptors for extracellular matrix molecules 94 Cell
extracellular matrix interactions 96 Development 96 Wound healing 100 Signal transduction events during cell
extracellular matrix interactions 104 Relevance for tissue engineering 111 Avoiding a strong immune response that can cause chronic inflammation and/or rejection 111 Creating the proper substrate for cell survival and differentiation 111 Providing the appropriate environmental conditions for tissue maintenance 112 References 113 7. Matrix molecules and their ligands 119 Allison P. Drain and Valerie M. Weaver Introduction 119 Collagens 120 Fibrillar collagens 121 Fibril-associated collagens with interrupted triple helices (FACIT) 122 Basement membrane
associated collagens 123 Other collagens 123 Major adhesive glycoproteins 123 Fibronectin 123 Laminin 125 Elastic fibers and microfibrils 126 Other adhesive glycoproteins and multifunctional matricellular proteins 126 Vitronectin 126 Thrombospondins 126 Tenascins 126 Proteoglycans 127 Hyaluronan and lecticans 127 Perlecan 128 Small leucine-rich repeat proteoglycans and syndecans 128 Conclusion 128 References 128 8. Morphogenesis and tissue engineering 133 Priscilla S. Briquez and Jeffrey A. Hubbell Introduction to tissue morphogenesis 133 Biology of tissue morphogenesis 133 Morphogens as bioactive signaling molecules during morphogenesis 134 The extracellular matrix as a key regulator of tissue morphogenesis 135 Cell
cell interactions during tissue morphogenesis 136 Tissues as integrated systems in the body 136 Engineering tissue morphogenesis 138 Cells as building units in tissue engineering 138 Biomaterial scaffolds as artificial extracellular matrices 139 Morphogens as signaling cues in tissue engineering 140 Tissue remodeling in healthy and diseased environments 140 Current focuses and future challenges 141 References 141 9. Gene expression, cell determination, differentiation, and regeneration 145 Frank E. Stockdale Introduction 145 Determination and differentiation 145 MyoD and the myogenic regulatory factors 147 Negative regulators of development 148 MicroRNAs—regulators of differentiation 148 Pax in development 149 Satellite cells in skeletal muscle differentiation and repair 149 Tissue engineering—repairing muscle and fostering regeneration by controlling determination and differentiation 150 Conclusion 152 References 152 Part Two In vitro control of tissue development 155 10. Engineering functional tissues: in vitro culture parameters 157 Jennifer J. Bara and Farshid Guilak Introduction 157 Key concepts for engineering functional tissues 158 Fundamental parameters for engineering functional tissues 158 Fundamental criteria for engineering functional tissues 159 Importance of in vitro studies for engineering functional tissues 159 In vitro studies relevant to tissue engineering and regenerative medicine 159 In vitro platforms relevant for high throughput screening of drugs and other agents 160 Influence of selected in vitro culture parameters on the development and performance of engineered tissues 161 Culture duration 161 Biomaterials 162 Bioreactors and growth factors 166 Bioreactors and mechanical forces 169 Conclusion 171 Acknowledgments 172 References 172 Further reading 177 11. Principles of bioreactor design for tissue engineering 179 Hanry Yu, Seow Khoon Chong, Ammar Mansoor Hassanbhai, Yao Teng, Gowri Balachander, Padmalosini Muthukumaran, Feng Wen and Swee Hin Teoh Introduction 179 Macrobioreactors 180 Design principles 181 Sustainable bioreactors 188 Cell manufacturing quality attributes and process analytics technology 189 Future outlook 189 Microbioreactors 191 Design principles 191 Types of microreactors 194 Components and integration into microreactors 194 Applications 195 Summary 197 Acknowledgments 197 References 197 12. Regulation of cell behavior by extracellular proteins 205 Amy D. Bradshaw Introduction 205 Thrombospondin-1 205 Thrombospondin-2 207 Tenascin-C 208 Osteopontin 209 Secreted protein acidic and rich in cysteine 210 Conclusion 212 References 212 13. Cell and matrix dynamics in branching morphogenesis 217 Shaimar R. Gonza´lez Morales and Kenneth M. Yamada Introduction 217 The basis of branching morphogenesis 217 Branching morphogenesis in the lung 218 Branching morphogenesis in the salivary gland 220 Branching morphogenesis in the kidney 222 Contributions of other cell types 224 MicroRNAs in branching morphogenesis 225 Extracellular matrix components in branching morphogenesis 226 Laminin 226 Collagen 226 Heparan sulfate proteoglycan 227 Fibronectin and integrins 228 Basement membrane microperforations 228 Mathematical and computational models 230 Geometry 230 Mechanical forces 230 Signaling mechanisms 230 Conclusion 231 Acknowledgments 232 References 232 14. Mechanobiology, tissue development, and tissue engineering 237 David Li and Yu-li Wang Introduction 237 Mechanical forces in biological systems 237 Tension 237 Compression 238 Fluid shear 238 Cellular mechanosensing 238 The cytoskeleton 239 Stretch-activated ion channels 239 Cell
cell adhesions 240 Cell
substrate adhesions 240 The extracellular matrix 241 Cellular effects of mechanotransduction 243 Substrate adhesion, spreading, and migration 243 Cell
cell interactions in collectives 243 Proliferation and differentiation 244 Mechanotransduction in biological phenomena 245 Wound healing 245 Tissue morphogenesis 247 Cancer metastasis 248 Mechanobiology in tissue engineering 248 Bone-implant design 248 Organs-on-a-chip 250 References 252 Part Three In Vivo Synthesis of Tissues and Organs 257 15. In vivo engineering of organs 259 V. Prasad Shastri Introduction 259 Historical context 259 Nature’s approach to cellular differentiation and organization 260 Conceptual framework of the in vivo bioreactor 261 In vivo bone engineering—the bone bioreactor 261 In vivo cartilage engineering 264 Induction of angiogenesis using biophysical cues—organotypic vasculature engineering 265 De novo liver engineering 267 Repairing brain tissue through controlled induction of reactive astrocytes 269 Conclusions and outlook 269 References 270 Part Four Biomaterials in tissue engineering 273 16. Cell interactions with polymers 275 W. Mark Saltzman and Themis R. Kyriakides Methods for characterizing cell interactions with polymers 275 In vitro cell culture methods 275 In vivo methods 278 Cell interactions with polymers 280 Protein adsorption to polymers 280 Effect of polymer chemistry on cell behavior 280 Electrically charged or electrically conducting polymers 284 Influence of surface morphology on cell behavior 284 Use of patterned surfaces to control cell behavior 285 Cell interactions with polymers in suspension 286 Cell interactions with three-dimensional polymer scaffolds and gels 287 Cell interactions unique to the in vivo setting 287 Inflammation 287 Fibrosis and angiogenesis 288 References 289 17. Polymer scaffold fabrication 295 Matthew L. Bedell, Jason L. Guo, Virginia Y. Xie, Adam M. Navara and Antonios G. Mikos Introduction 295 Design inputs: materials, processing, and cell types 297 Materials and inks 297 Processing and cell viability 299 Cell types and biological interactions 300 Assessment of cell viability and activity 301 3D printing systems and printer types 302 Inkjet printing 303 Extrusion printing 304 Laser-assisted bioprinting 305 Stereolithography 305 Open source and commercial 3D printing systems 306 Print outputs: patterning, resolution, and porous architecture 307 Printing/patterning of multiple inks 308 Print resolution 308 Porous architecture 309 Assessment of scaffold fidelity 309 Printing applications: vascularized and complex, heterogeneous tissues 310 Conclusion 310 Acknowledgments 311 Abbreviations 311 References 311 18. Biodegradable polymers 317 Julian Chesterman, Zheng Zhang, Ophir Ortiz, Ritu Goyal and Joachim Kohn Introduction 317 Biodegradable polymer selection criteria 317 Biologically derived polymers 318 Peptides and proteins 318 Biomimetic materials 322 Polysaccharides 322 Polyhydroxyalkanoates 325 Polynucleotides 326 Synthetic polymers 326 Aliphatic polyesters 326 Aliphatic polycarbonates 330 Biodegradable polyurethanes 330 Polyanhydrides 331 Polyphosphazenes 331 Poly(amino acids) and pseudo-poly (amino acids) 332 Combinations (hybrids) of synthetic and biologically derived polymers 333 Using polymers to create tissue-engineered products 333 Barriers: membranes and tubes 334 Gels 334 Matrices 334 Conclusion 335 References 335 19. Three-dimensional scaffolds 343 Ying Luo Introduction 343 Three-dimensional scaffold design and engineering 343 Mass transport and pore architectures 344 Mechanics 346 Electrical conductivity 348 Surface properties 349 Temporal control 352 Spatial control 354 Conclusion 355 References 355 Part Five Transplantation of engineered cells and tissues 361 20. Targeting the host immune response for tissue engineering and regenerative medicine applications 363 Jenna L. Dziki and Stephen F Badylak Introduction 363 Immune cells and their roles in building tissues after injury 363 Neutrophils 364 Eosinophils 364 Macrophages 364 Dendritic cells 364 T and B cells 365 Specialized immune cell functions beyond host defense 365 Tissue engineering/regenerative medicine strategies as immunotherapy 365 Future considerations for immune cell targeting tissue engineering/regenerative medicine therapies 366 References 366 Further reading 368 21. Tissue engineering and transplantation in the fetus 369 Christopher D. Porada, Anthony Atala and Grac¸ a Almeida-Porada Introduction 369 Rationale for in utero therapies 370 In utero transplantation 371 Early murine experiments with in utero transplantation 372 In utero transplantation experiments in large preclinical animal models 372 Barriers to in utero transplantation success 373 Clinical experience with in utero transplantation 376 Rationale for in utero gene therapy 376 Hemophilia A as a model genetic disease for correction by in utero gene therapy 377 The need for better hemophilia A treatments 378 Preclinical animal models for hemophilia A and recent clinical successes 378 Sheep as a preclinical model of hemophilia A 379 Feasibility and justification for treating hemophilia A prior to birth 380 Mesenchymal stromal cells as hemophilia A therapeutics 383 Preclinical success with mesenchymal stromal cell
based hemophilia A treatment 384 Risks of in utero gene therapy 385 Genomic integration
associated insertional mutagenesis 385 Potential risk to fetal germline 386 Conclusion and future directions 387 References 388 22. Challenges in the development of immunoisolation devices 403 Matthew A. Bochenek, Derfogail Delcassian and Daniel G. Anderson Introduction 403 Rejection and protection of transplanted cells and materials 403 Rejection pathways 404 Cellular nutrition 404 Therapeutic cells 405 Primary cells 405 Immortalized cell lines 406 Stem cells 407 Device architecture and mass transport 407 Transplantation site 408 Improving oxygenation of immunoprotected cells 409 Controlling immune responses to implanted materials 410 Steps in the foreign body reaction 411 The role of geometry in the foreign body reaction 411 Tuning chemical composition to prevent attachment 412 Directing immune cell behavior in the transplant niche 412 References 412 Part Six Stem cells 419 23. Embryonic stem cells 421 Irina Klimanskaya, Erin A. Kimbrel and Robert Lanza Introduction 421 Approaches to human embryonic stem cell derivation 421 Maintenance of human embryonic stem cell 425 Subculture of human embryonic stem cell 425 Nuances of human embryonic stem cell culture 426 Directed differentiation 426 Safety concerns 430 Conclusion 431 Acknowledgment 431 References 431 24. Induced pluripotent stem cell technology: venturing into the second decade 435 Yanhong Shi, Haruhisa Inoue, Jun Takahashi and Shinya Yamanaka Disease modeling 435 Drug discovery 436 Stem cell
based therapeutic development 438 Concluding remarks 440 Acknowledgements 440 References 440 25. Applications for stem cells 445 Andres M. Bratt-Leal, Ai Zhang, Yanling Wang and Jeanne F. Loring Introduction 445 Reprogramming of somatic cells into induced pluripotent stem cells 445 Epigenetic remodeling 446 Reprogramming techniques 446 Induced transdifferentiation 448 Genomic stability 448 Applications of induced pluripotent stem cells 448 Disease modeling 448 Challenges and future possibilities in disease modeling 450 Disease-modifying potential of induced pluripotent stem cells 451 Other applications for induced pluripotent stem cells 452 Conclusion 452 List of acronyms and abbreviations 453 References 453 26. Neonatal stem cells in tissue engineering 457 Joseph Davidson and Paolo De Coppi Introduction 457 Stem cells 457 Embryonic stem cells 457 Induced pluripotent stem cells 458 Perinatal stem cells 458 Scaffolding specifics in fetal and neonatal tissue engineering 459 Synthetic materials 459 Natural materials 459 Relevance to prenatal therapy 460 Immunology 460 Physiology 460 Conditions of interest 461 Spina bifida 461 Gastroschisis 461 Congenital diaphragmatic hernia 461 Esophageal atresia 461 Congenital heart disease 462 Congenital airway anomalies 462 Bladder 463 Bone and bone marrow 463 Conclusion 463 References 463 27. Embryonic stem cells as a cell source for tissue engineering 467 Ali Khademhosseini, Nureddin Ashammakhi, Jeffrey M. Karp, Sharon Gerecht, Lino Ferreira, Nasim Annabi, Mohammad Ali Darabi, Dario Sirabella, Gordana Vunjak-Novakovic and Robert Langer Introduction 467 Maintenance of embryonic stem cells 468 Directed differentiation 471 Genetic reprogramming 471 Microenvironmental cues 472 Three-dimensional versus two-dimensional cell culture systems 475 High-throughput assays for directing stem cell differentiation 475 Physical signals 477 Isolation of specific progenitor cells from embryonic stem cells 479 Transplantation 480 Transplantation and immune response 481 Future prospects 482 Conclusion 483 Acknowledgments 483 Conflicts of interest 483 References 483 Further reading 490 Part Seven Gene therapy 491 28. Gene therapy 493 Stefan Worgall and Ronald G. Crystal Strategies of gene therapy 493 Ex vivo versus in vivo gene therapy 494 Ex vivo 494 In vivo 495 Chromosomal versus extrachromosomal placement of the transferred gene 495 Gene transfer vectors 495 Nonviral vectors 497 Adenovirus 497 Adeno-associated virus 499 Retrovirus 500 Lentivirus 501 Cell-specific targeting strategies 502 Targeting of Ad vectors 502 Targeting of adeno-associated virus vectors 505 Targeting of retroviral and lentiviral vectors 505 Regulated expression of the transferred gene 505 Using gene transfer vectors for gene editing 507 Combining gene transfer with stem-cell strategies 508 Gene transfer to stem cells 508 Gene transfer to control uncontrolled stem-cell growth 508 Gene transfer to instruct stem-cell differentiation 508 Gene transfer to regulate gene expression 509 Challenges to gene therapy for tissue engineering 509 Acknowledgments 510 References 510 29. Gene delivery into cells and tissues 519 Christopher E. Nelson, Craig L. Duvall, Aleˇs Prokop, Charles A. Gersbach and Jeffrey M. Davidson Introduction 519 Fundamentals of gene delivery 519 Biodistribution, targeting, uptake, and trafficking 521 Tissue biodistribution/targeting 521 Cellular uptake and intracellular trafficking 523 Viral nucleic acid delivery 526 Introduction to viral gene therapy 526 Types of viral vectors 527 Engineering viral vectors 528 Nonviral nucleic acid delivery 530 Introduction to nonviral nucleic acid delivery 530 Oligonucleotide modifications 531 Conjugates 531 Synthetic polymers 531 Polymers derived from natural sources or monomers 534 Lipid-based delivery systems 536 Inorganic nanoparticles 537 High-throughput screening 537 Engineering tissues with gene delivery 538 Introduction to engineering tissue with gene delivery 538 Viral delivery to engineer tissues 538 Nonviral delivery from scaffolds 540 Nucleic acid delivery for tissue engineering advances into the clinic 541 Future challenges 541 Outlook 542 Acknowledgments 543 References 543 Part Eight Breast 555 30. Breast tissue engineering: implantation and three-dimensional tissue test system applications 557 Karen J.L. Burg and Timothy C. Burg Introduction 557 Breast anatomy and development 557 Breast cancer diagnosis and treatments 558 Breast reconstruction 558 Synthetic implants 559 Tissue flaps 559 Cell transplants 559 Cellular scaffolds 560 Special considerations 565 Breast cancer modeling 565 Animal models 565 Breast tissue test systems 566 In silico breast cancer models 570 Concluding remarks 571 Acknowledgement 571 References 571 Part Nine Cardiovascular system 577 31. Cardiac progenitor cells, tissue homeostasis, and regeneration 579 Wayne Balkan, Simran Gidwani, Konstantinos Hatzistergos and Joshua M. Hare Origin of cardiac stem/progenitor cells 579 Modeling cardiac development with pluripotent stem cells 581 In vivo fate mapping of cardiac progenitors 582 Neonatal cardiac repair 582 Reprogramming cardiac fibroblasts 584 Cardiac resident mesenchymal stem cells 584 Cardiomyocytes and cardiac repair/ regeneration 585 Cell-based therapy 585 Cardiac progenitor/stem cell therapy 586 Combination stem cell therapy 586 Pluripotent stem cells 586 Future directions 588 References 588 32. Cardiac tissue engineering 593 Yimu Zhao, George Eng, Benjamin W. Lee, Milica Radisic and Gordana Vunjak-Novakovic Introduction 593 Clinical problem 593 Engineering cardiac tissue: design principles and key components 594 Cell source 594 Scaffold 598 Biophysical stimulation 599 Directed cardiac differentiation of human stem cells 599 Derivation of cardiomyocytes from human pluripotent stem cells 599 Purification and scalable production of stem cell
derived cardiomyocytes 601 Scaffolds 601 Decellularization approach 601 Artificial scaffolds 602 Biophysical cues 604 Electrical stimulation 604 Mechanical stimulation 604 Perfusion 606 In vivo applications of cardiac tissue engineering 606 Engineered heart issue 606 Vascularized cardiac patches 608 Electrical coupling of cardiomyocytes on the heart 608 Modeling of disease 609 Generation of patient-specific cardiomyocytes 609 Engineered heart tissue models 609 Cardiac fibrosis 609 Titin mutation
related dilated cardiomyopathy 611 Diabetes-related cardiomyopathy 611 Chronic hypertension induced left ventricle hypertrophy 611 Barth syndrome 611 Tissue engineering as a platform for pharmacologic studies 611 Summary and challenges 612 Acknowledgments 612 References 612 33. Blood vessels 617 Luke Brewster, Eric M. Brey and Howard P. Greisler Introduction 617 Normal and pathologic composition of the vessel wall 617 Developmental biology cues important in vascular tissue engineering 618 Conduits 618 Arteries 618 Veins 618 Current status of grafts in patients 618 Conduit patency and failure 618 Venous reconstruction 619 Hemodialysis vascular access 619 Inflammation and the host response to interventions and grafts 620 Host environment and the critical role of the endothelium 621 Prevalent grafts in clinical use 622 Vascular tissue engineering 623 Early efforts—in vitro tissue-engineered vascular grafts 623 Endothelial cell seeding 623 In vitro approaches to tissue-engineered vascular grafts 624 In vivo tissue-engineered vascular grafts 625 Bioresorbable grafts 625 The living bioreactor 626 Cellular and molecular mediators of graft outcome 626 Conclusion and predictions for the future 630 References 630 34. Heart valve tissue engineering 635 Kevin M. Blum, Jason Zakko, Peter Fong, Mark W. Maxfield, Muriel A. Cleary and Christopher K. Breuer Introduction 635 Heart valve function and structure 635 Cellular biology of the heart valve 636 Heart valve dysfunction and valvular repair and remodeling 637 Heart valve replacement 638 The application of tissue engineering toward the construction of a replacement heart valve 640 Tissue engineering theory 640 Biomaterials and scaffolds 640 The search for appropriate cell sources 643 Cell seeding techniques 644 Bioreactors 645 Neotissue development in tissue engineered heart valves 645 Clinical applications of the tissue engineered heart valve 647 Conclusion and future directions 648 References 649 Part Ten Endocrinology and metabolism 655 35. Generation of pancreatic islets from stem cells 657 Ba´rbara Soria-Juan, Javier Lo´ pez-Beas, Bernat Soria and Abdelkrim Hmadcha Introduction 657 State-of-the-art 657 The challenge of making a β-cell 658 Recent achievements (first generation of pancreatic progenitors used in the clinic) 658 Need of late maturation: cabimer protocol 659 Strategies to maintain cell viability 659 Encapsulation and tolerogenic strategies 661 The concept of cellular medicament 661 Conclusion 662 Acknowledgments 662 References 662 Biophysical curves 6042 36. Bioartificial pancreas: challenges and progress 665 Paul de Vos Introduction 665 History of the bioartificial pancreas 666 Replenishable cell sources and encapsulation 666 Macro- or microedevices 667 Factors contributing to biocompatibility of encapsulation systems 669 Avoiding pathogen-associated molecular patterns in polymers 670 Natural and synthetic polymers 670 Multilayer capsule approaches 670 Antibiofouling approaches 671 Formation of polymer brushes 671 Immunomodulatory materials 672 Intracapsular environment and longevity of the encapsulated islet graft 672 Concluding remarks and future considerations 673 Acknowledgments 674 References 674 37. Thymus and parathyroid organogenesis 681 Craig Scott Nowell, Kathy E. O’Neill, Paul Rouse, Timothy Henderson, Ellen Rothman Richie, Nancy Ruth Manley and Catherine Clare Blackburn Structure and morphology of the thymus 681 Thymic epithelial cells 682 Complexity of the thymic epithelium compartment 682 Functional diversity 683 In vitro T cell differentiation 683 Thymus organogenesis 685 Cellular regulation of early thymus organogenesis 685 Origin of thymic epithelial cells 686 Thymic epithelial progenitor cells 686 Human thymus development 688 Cervical thymus in mouse and human 688 Molecular regulation of thymus and parathyroid organogenesis 689 Molecular control of early organogenesis 689 Transcription factors and regulation of third pharyngeal pouch outgrowth 691 Specification of the thymus and parathyroid 692 Foxn1 and regulation of thymic epithelial cell differentiation 695 Medullary development and expansion 696 Maintenance and regeneration of thymic epithelial cells: Progenitor/stem cells in the adult thymus 696 Strategies for thymus reconstitution 697 Summary 698 Acknowledgments 699 References 699 Part Eleven Gastrointestinal system 707 38. Stem and progenitor cells of the gastrointestinal tract: applications for tissue engineering the intestine 709 Kathryn M. Maselli, Christopher R. Schlieve, Mark R. Frey and Tracy C. Grikscheit Introduction 709 Stem cells of the intestine 709 Cell types of the epithelial layer 709 Stem and progenitor cell types 710 Signaling pathways in the intestinal epithelium 712 The Wnt pathway 712 The Notch pathway 713 Epidermal growth factor receptor/ErbB signaling 713 The Hedgehog pathway 714 The BMP pathway 714 Tissue engineering the intestine with stem/ progenitor cells 714 Organ-specific stem cell progenitors versus pluripotent stem cells 714 Synthetic and biological scaffolds 715 Primary intestinal-derived organoid units 716 Pluripotent stem cell approaches—human intestinal organoids 717 Remaining barriers to the generation of tissue-engineered intestine 718 Conclusion 718 Acknowledgment 718 References 718 39. Liver stem cells 723 Dagmara Szkolnicka and David C. Hay Introduction 723 Liver architecture and function 723 Liver development 723 Fetal liver stem cells 724 Hepatocytes and liver progenitors in organ regeneration 724 Molecular signaling and processes involved in liver regeneration 724 Hepatocytes’ role in liver regeneration 725 Cholangiocytes and liver stem cells in liver regeneration 725 Pluripotent stem cell
derived hepatoblasts and hepatocytes 726 3D liver organoids and expansion 727 Pluripotent stem cell
derived liver organoids 728 Bile duct
derived organoids 728 Hepatocyte-derived organoids 728 Novel scaffolds for liver organoids 729 Organoids as a model to study liver cancer disease 730 Reprogramming of human hepatocytes to liver progenitors using different culture conditions 730 Conclusion 731 References 731 Further reading 736 40. Hepatic tissue engineering 737 Amanda X. Chen, Arnav Chhabra, Heather E. Fleming and Sangeeta N. Bhatia Liver disease burden 737 Current state of liver therapies 738 Extracorporeal liver support devices 738 Biopharmaceuticals 738 Liver transplantation 738 Hepatocyte transplantation 740 Current clinical trials 740 In vitro models 740 Two-dimensional liver culture 741 Three-dimensional liver constructs 741 Physiological microfluidic models of liver 742 Controlling three-dimensional architecture and cellular organization 742 In vivo models 743 Cell sourcing 743 Cell number requirements 743 Immortalized cell lines 744 Primary cells 744 Fetal and adult progenitors 744 Reprogrammed hepatocytes 744 Extracellular matrix for cell therapies 744 Natural scaffold chemistry and modifications 745 Synthetic scaffold chemistry 745 Modifications in scaffold chemistry 745 Porosity 746 Vascular and biliary tissue engineering 746 Vascular engineering 746 Host integration 747 Biliary network engineering 747 Conclusion and outlook 747 References 748 Part Twelve Hematopoietic system 755 41. Hematopoietic stem cells 757 Qiwei Wang, Yingli Han, Linheng Li and Pengxu Qian Introduction 757 Hematopoietic stem cells and hematopoietic stem cells niche 757 Effects of biomaterials on hematopoietic stem cells 758 Applications 759 Engineering hematopoietic stem cells niche for in vitro expansion 759 Manipulation of the multilineage differentiation of hematopoietic stem cells 760 In vivo tracking hematopoietic stem cells 761 Future perspectives 761 Acknowledgments 761 References 761 42. Blood components from pluripotent stem cells 765 Erin A. Kimbrel and Robert Lanza Introduction and history of modern hematology 765 Red blood cells 765 Megakaryocytes/platelets 769 White blood cells 770 Lymphocytes—T cells 770 Lymphocytes—NK cells 773 Lymphocytes—NKT cells 775 Monocyte-derived dendritic cells 776 Monocyte-derived macrophages 777 Granulocytes—neutrophils 778 Perspectives 779 References 779 43. Red blood cell substitutes 785 Andre Francis Palmer and Donald Andrew Belcher Introduction 785 Replicating red blood cell functions 785 Hemoglobin-based oxygen carriers 785 Hemoglobin toxicity 787 Oxygen delivery 789 Contents xv Viscosity and colloid osmotic pressure 789 Cross-linked and polymeric hemoglobin 790 Surface conjugated hemoglobin 790 Encapsulated hemoglobin 791 Sources of hemoglobin 791 Recombinant hemoglobin 792 Erythrocruorins 792 Perfluorocarbons 793 Perspectives 794 Organ transplant preservation 794 Cancer treatment 795 Tissue-engineered construct oxygenation 795 References 795 Part Thirteen Kidney and genitourinary system 803 44. Stem cells in kidney development and regeneration 805 Kyle W. McCracken and Joseph V. Bonventre Kidney development 805 Early embryonic origins of nephrogenic tissues 806 Development of the nephric duct and ureteric bud 808 Maintenance and differentiation of the nephron progenitor cell 809 Role of stromal lineages in kidney organogenesis 811 Nephron endowment 812 Kidney repair and regeneration 813 Stem cells in kidney repair 813 Sources of nephrogenic cells 814 Differentiation of renal tissue from pluripotent stem cells (organoids) 815 Conclusion 817 Disclosures 818 Acknowledgements 818 References 818 45. Tissue engineering of the kidney 825 Ji Hyun Kim, Anthony Atala and James J. Yoo Introduction 825 Cell-based tissue engineering of the kidney 826 Cell sources 826 Tissue-engineered cellular three-dimensional renal constructs 830 Cell-free tissue engineering of the kidney 835 In situ kidney regeneration 835 Granulocyte-colony stimulating factor 835 Stromal cell
derived factor-1 837 Conclusion and future perspectives 837 Acknowledgment 838 References 838 46. Tissue engineering: bladder and urethra 845 Yuanyuan Zhang, James J. Yoo and Anthony Atala Introduction 845 Cell sources 846 Bladder and ureter cells 846 Stem cell sources 846 Mechanism of cell therapy 848 Biodegradable biomaterials 850 Synthetic scaffolds 850 Natural collagen matrix 851 Preclinical models 854 Tissue regeneration models 854 Fibrotic bladder model 854 Clinical trials 856 Clinical translation 856 Clinical studies 857 Conclusion 858 References 858 47. Tissue engineering for female reproductive organs 863 Renata S. Magalhaes, James K. Williams and Anthony Atala Introduction 863 Uterus 863 Acellular tissue engineering approaches for uterine tissue repair 864 Cell-seeded scaffolds for partial uterine repair 864 Scaffold-free approaches for partial uterine repair 865 Uterine cervix tissue engineering 865 Ovary 865 Tissue engineering ovarian follicles 866 Vagina 866 Tissue engineering approaches for neovagina reconstruction 866 Conclusion and future perspectives 867 References 867 48. Male reproductive organs 871 Hooman Sadri-Ardekani, John Jackson and Anthony Atala Introduction 871 Testes 871 xvi Contents Spermatogonial stem cell technology 871 Androgen-replacement therapy 873 Ejaculatory system 874 Engineering vas deferens 874 Spinal ejaculation generator 875 Penis 875 Penile reconstruction 875 Penile transplantation 876 Stem cell therapy for erectile dysfunction 876 Conclusion 877 References 877 Part fourteen Musculoskeletal system 881 49. Mesenchymal stem cells in musculoskeletal tissue engineering 883 Yangzi Jiang, Dan Wang, Anna Blocki and Rocky S. Tuan Introduction 883 Mesenchymal stem cell biology relevant to musculoskeletal tissue engineering 883 Mesenchymal stem cell identification 883 Tissue sources of mesenchymal stem cells 885 Mesenchymal stem cell isolation and in vitro culture 886 Mesenchymal stem cell self-renewal and proliferation capacity 887 Skeletogenic differentiation of mesenchymal stem cells 888 Plasticity of mesenchymal stem cells 888 Mesenchymal stem cell heterogeneity 889 Mesenchymal stem cell effect on host immunobiology 889 Safety of using mesenchymal stem cells for transplantation 891 Mesenchymal stem cells in musculoskeletal tissue engineering 891 Cartilage tissue engineering 891 General properties of articular cartilage 892 Cells for cartilage tissue engineering 892 Bone tissue engineering 897 Osteochondral tissue engineering 898 Engineering other skeletal tissues with mesenchymal stem cells 899 Tendon/ligament 899 Meniscus 900 Gene therapy in musculoskeletal tissue engineering 901 Conclusion and future perspectives 901 Acknowledgments 902 References 902 50. Bone tissue engineering and bone regeneration 917 J.M. Kanczler, J.A. Wells, D.M.R. Gibbs, K.M. Marshall, D.K.O. Tang and Richard O.C. Oreffo Introduction 917 Skeletal stem cells 917 Fracture repair—the (limited) self-reparative capacity of bone 919 A framework for bone repair: biomaterial-driven strategies for bone regeneration 922 Growth factors: biomimetic-driven strategies for bone regeneration 923 Bone biofabrication 924 Development of vascular bone 925 Preclinical development—ex vivo/in vivo small and large animal preclinical models 926 Clinical translation 929 Summary and future perspectives 931 Acknowledgments 931 References 931 51. Tissue engineering for regeneration and replacement of the intervertebral disk 937 Stephen R. Sloan Jr., Niloofar Farhang, Josh Stover, Jake Weston, Robby D. Bowles and Lawrence J. Bonassar Introduction 937 Intervertebral disk structure and function 938 Cell-biomaterial constructs for intervertebral disk regeneration 940 Nucleus pulposus cell-biomaterial implants 940 Annulus fibrosus repair and regeneration 942 Composite cell-biomaterial intervertebral disk implants 944 Cellular engineering for intervertebral disk regeneration 945 Cell therapy preclinical studies 946 Cell therapy clinical studies 947 Growth factors and other biologics for intervertebral disk regeneration 948 In vitro studies 948 In vivo studies: growth factors 952 In vivo studies: other biologics 953 Gene therapy for intervertebral disk regeneration 953 Gene transfer studies: viral 954 Gene transfer studies: nonviral 954 Endogenous gene regulation 955 Gene therapy in summary 955 Contents xvii In vivo preclinical models for intervertebral disk regeneration and replacement 955 Concluding remarks 957 Acknowledgment 957 References 957 52. Articular cartilage injury 967 J.A. Martin, M. Coleman and J.A. Buckwalter Introduction 967 Articular cartilage injury and joint degeneration 968 Mechanisms of articular cartilage injuries 968 Response of articular cartilage to injury 970 Matrix and cell injuries 970 Chondral injuries 971 Osteochondral injuries 971 Preventing joint degeneration following injury 972 Promoting articular surface repair 972 Penetration of subchondral bone 972 Periosteal and perichondrial grafts 973 Cell transplantation 973 Artificial matrices 973 Growth factors 973 Antiinflammatories 974 Conclusion 974 Acknowledgments 974 References 974 Further reading 977 53. Engineering cartilage and other structural tissues: principals of bone and cartilage reconstruction 979 Batzaya Byambaa and Joseph P. Vacanti Introduction 979 Biomaterials for cartilage tissue engineering 979 Cell sources for cartilage tissue engineering 980 Biofabrication of cartilage tissue 981 Magnetic resonance imaging and computerized tomography scans 981 Scaffolds for cartilage tissue engineering 981 Bioprinting techniques for fabrication of cartilage constructs 982 Bioinks for cartilage tissue printing 982 Osteochondral tissue engineering 985 References 985 54. Tendon and ligament tissue engineering 989 Spencer P. Lake, Qian Liu, Malcolm Xing, Leanne E. Iannucci, Zhanwen Wang and Chunfeng Zhao Introduction 989 Tendon and ligament composition, structure, and function 990 Composition 990 Structure 990 Function 990 Requirements for a tissue-engineered tendon/ligament 991 Scaffold 992 Cell 994 Bioactive factors 995 Three-dimensional bioprinting and bioink 996 Bioink inspired from ligament and tendon structures 997 Tissue engineering tendon and ligament in clinical application 998 Summary 999 References 1000 55. Skeletal tissue engineering 1007 Matthew P. Murphy, Mimi R. Borrelli, Daniel T. Montoro, Michael T. Longaker and Derrick C. Wan Introduction 1007 Distraction osteogenesis 1008 Critical-sized defects 1010 Cellular therapy 1010 Cytokines 1013 Scaffolds 1014 Tissue engineering in practice 1016 Conclusion 1017 References 1017 Part Fifteen Nervous system 1023 56. Brain implants 1025 Lars U. Wahlberg Introduction 1025 Cell replacement implants 1025 Primary tissue implants 1025 Cell line implants 1027 Cell protection and regeneration implants 1028 Cell implants secreting endogenous factors 1028 Cell implants secreting engineered factors (ex vivo gene therapy) 1029 Encapsulated cell brain implants 1029 Controlled-release implants 1030 Combined replacement and regeneration implants 1030 Disease targets for brain implants 1031 xviii Contents Surgical considerations 1032 Conclusion 1032 References 1032 57. Brain
machine interfaces 1037 Jose´ del R. Milla´n and Serafeim Perdikis Introduction 1037 Brain
machine interface signals 1037 Voluntary activity versus evoked potentials 1038 Mutual learning 1040 Context-aware brain
machine interface 1040 Future directions 1041 References 1042 58. Spinal cord injury 1047 Nicolas N. Madigan and Anthony J. Windebank Introduction 1047 Epidemiology 1047 Spinal cord organization 1047 Spinal cord injury 1048 Available clinical interventions 1049 The continuum of physical, cellular, and molecular barriers to spinal cord regeneration 1049 The role of tissue engineering in spinal cord injury repair 1051 Bioengineering for integrated spinal cord biocompatibility 1052 Animal models of spinal cord injury 1052 Principles of biomaterial fabrication for spinal cord injury repair 1054 Biomaterials for spinal cord tissue engineering: natural polymers 1058 Extracellular matrix polymers 1058 Polymers from marine or insect life 1065 Polymers derived from the blood 1071 Biomaterials for spinal cord tissue engineering: synthetic polymers 1072 Poly α-hydroxy acid polymers 1073 Nonbiodegradable hydrogels 1077 Conclusion and future directions: the promise of clinical translation 1080 References 1080 59. Protection and repair of hearing 1093 Su-Hua Sha, Karl Grosh and Richard A. Altschuler Introduction 1093 Protection from “acquired” sensory hair cell loss 1093 Oxidative stress and stress-related mitochondrial pathways 1094 Calcium influx 1094 Endoplasmic reticulum stress 1094 Prevention of ototoxicity 1094 Prevention of acoustic trauma 1096 Antiinflammatory agents 1097 Heat shock proteins 1097 Neurotrophic factors 1098 Protection from excitotoxicity: “acquired” loss of auditory nerve connections to hair cells 1098 Gene transfer for the prevention and treatment of genetic deafness 1099 Interventions for hair cell repair: gene therapy for transdifferentiation 1099 Interventions for repair: hair cell and auditory nerve replacement—exogenous stem cells 1101 Interventions for repair/replacement: cochlear prostheses 1101 Fully implantable cochlear prostheses 1101 Interventions for repair/replacement: central auditory prostheses 1102 Local delivery to cochlear fluids 1103 Conclusion 1103 Acknowledgments 1103 References 1104 Further reading 1112 Part Sixteen Ophthalmic 1113 60. Stem cells in the eye 1115 Chao Huang, Julie Albon, Alexander Ljubimov and Maria B. Grant Introduction 1115 Endogenous ocular stem cells 1115 Corneal stem cells 1115 Stromal stem cells 1119 Endothelial stem cells 1119 Conjunctival epithelial stem cells 1120 The bioengineered cornea 1120 Retinal progenitor cells 1120 Mu¨ ller stem cells 1121 Retinal pigment epithelium stem cells 1121 Nonocular stem cells 1121 Induced pluripotent stem cells (iPSCs) 1121 Embryonic stem cells/iPSCs in retinal regeneration 1121 Bone marrow stem cells 1124 References 1126 Contents xix 61. Corneal replacement tissue 1135 Maria Mirotsou, Masashi Abe and Robert Lanza Introduction 1135 Corneal anatomy and structure 1135 Epithelium 1136 Stroma 1138 Endothelium 1139 Conclusion 1140 References 1141 62. Retinal degeneration 1145 Erin A. Kimbrel and Robert Lanza Epidemiology of visual impairment and blindness 1145 Structure/function of the retina and cell types affected in retinal degenerative diseases 1145 Age-related macular degeneration 1147 History of retinal pigment epithelium as a cellular therapy for age-related macular degeneration 1147 Retinal pigment epithelium from pluripotent stem cells 1149 Retinitis pigmentosa 1150 Photoreceptors from pluripotent stem cells 1151 Glaucoma 1153 Stem cell
based therapies to treat glaucoma 1154 Diabetic retinopathy 1155 Stem cell
based therapies to treat diabetic retinopathy 1155 Future directions and competing therapies 1156 References 1157 63. Vision enhancement systems 1163 Gislin Dagnelie, H. Christiaan Stronks and Michael P. Barry Introduction 1163 Visual system, architecture, and (dys)function 1163 Current- and near-term approaches to vision restoration 1166 Enhancing the stimulus through optoelectronic and optical means 1166 Visual prostheses based on electrical tissue stimulation 1167 Retinal cell transplantation 1170 Optic nerve protection and regeneration 1171 Drug delivery 1172 Genetic interventions 1172 Emerging application areas for engineered cells and tissues 1173 Photosensitive structures 1174 Optogenetics 1174 Outer retinal cell transplantation 1177 Cell matrices supporting axonal regrowth 1177 Repopulating ischemic or diabetic retina 1178 Assessing the functional outcomes of novel retinal therapies 1178 Conclusion: toward 2020 vision 1179 Acknowledgment 1179 References 1179 Further reading 1183 Part Seventeen Oral/Dental applications 1185 64. Biological tooth replacement and repair 1187 Anthony J. (Tony) Smith and Paul T. Sharpe Introduction 1187 Tooth development 1187 Whole tooth-tissue engineering 1189 Stem cell-based tissue engineering of teeth 1189 Bioteeth from cell-seeded scaffolds 1189 Root formation 1190 Cell sources 1191 Dental-tissue regeneration 1191 Natural tissue regeneration 1191 Importance of the injury-regeneration balance 1192 Signaling events in dental regeneration 1193 Control of specificity of dental-tissue regeneration 1193 Dental postnatal stem cells 1194 Directed tissue regeneration 1195 Signaling-based strategies 1195 Cell- and gene-based strategies 1196 Conclusion 1197 References 1197 65. Tissue engineering in oral and maxillofacial surgery 1201 Simon Young, F. Kurtis Kasper, James Melville, Ryan Donahue, Kyriacos A. Athanasiou, Antonios G. Mikos and Mark Eu-Kien Wong Introduction 1201 Special challenges in oral and maxillofacial reconstruction 1201 Current methods of oral and maxillofacial reconstruction 1204 Mandibular defects 1205 Maxillary defects 1207 xx Contents Relevant strategies in oral and maxillofacial tissue engineering 1208 Bone applications 1208 Cartilage applications 1212 Oral mucosa applications 1214 Composite tissue applications 1215 Animal models 1215 The future of oral and maxillofacial tissue engineering 1216 References 1216 66. Periodontal tissue engineering and regeneration 1221 Xiao-Tao He, Rui-Xin Wu and Fa-Ming Chen Introduction 1221 Stem cells for periodontal bioengineering 1222 Intraoral mysenchymal stem cells 1222 Periodontal tissue
derived stem cells 1223 Stem cells from apical papilla 1224 Dental follicle stem cells 1224 Hertwig’s epithelial root sheath 1225 Stem cells from dental pulp or exfoliated deciduous teeth 1225 Extraoral mysenchymal stem cells 1225 Bone marrow
derived mysenchymal stem cells 1225 Adipose-derived stem cells 1226 Selection of cell types 1226 Signaling molecules 1227 Types of signals 1228 Crucial delivery barriers to progress 1230 Gene delivery as an alternative to growth factor delivery 1231 Scaffolding and biomaterials science 1232 Requirements of cell scaffolds 1232 Biomaterial-based immune modulation 1233 Classes of biomaterials 1233 Biomaterial redesign for periodontal application 1235 Periodontal bioengineering strategies 1236 Cell-free approaches 1237 Cell-based approaches 1239 Challenges and future directions 1242 Closing remarks 1243 Acknowledgments 1243 References 1243 Part Eighteen Respiratory system 1251 67. Cell- and tissue-based therapies for lung disease 1253 Jeffrey A. Whitsett, William Zacharias, Daniel Swarr and Vladimir V. Kalinichenko Introduction: challenges facing cell and tissue-based therapy for the treatment of lung disease 1253 Lung morphogenesis informs the process of regeneration 1254 Integration and refinement of signaling and transcriptional pathways during lung formation 1256 The mature lung consists of diverse epithelial and mesenchymal cell types 1256 Structure and function of pulmonary vasculature 1257 Embryonic development of alveolar capillaries 1258 Evidence supporting lung regeneration 1259 A diversity of lung epithelial progenitor/stem cells is active during regeneration 1260 Role of lung microvasculature in lung repair 1262 Endothelial progenitor cells in lung repair 1262 Pulmonary cell-replacement strategies for lung regeneration 1263 Induced pluripotent stem cells for study of treatment of pulmonary disease 1263 Differentiation of induced pluripotent stem and embryonic stem cells to pulmonary epithelial cell lineages 1264 Bioengineering of lung tissues 1265 Mesenchymal stromal cells and mesenchymal stromal cell products for the treatment of lung disease 1265 Important role of the extracellular matrix in lung structure and repair 1265 Tissue engineering for conducting airways 1266 Pulmonary macrophage transplantation for the treatment of interstitial lung disease 1266 Conclusion 1266 Acknowledgments 1266 References 1266 68. Lung tissue engineering 1273 Micha Sam Brickman Raredon, Yifan Yuan and Laura E. Niklason Introduction 1273 Design criteria for pulmonary engineering 1273 Decellularized scaffolds and biofabrication approaches 1274 Pulmonary epithelial engineering 1276 Proximal airway engineering 1276 Distal airway engineering 1276 Mesenchymal support of pulmonary epithelium 1277 Pulmonary endothelial engineering 1277 Endothelial cell sources for lung tissue engineering 1278 Endothelial seeding into lung scaffolds 1278 Organomimetic endothelial culture 1279 Contents xxi Mesenchymal support of pulmonary microvasculature 1280 Bioreactor technologies for pulmonary engineering 1280 Conclusion 1281 References 1281 Part Nineteen Skin 1287 69. Cutaneous epithelial stem cells 1289 Denise Gay, Maksim V. Plikus, Iris Lee, Elsa Treffeisen, Anne Wang and George Cotsarelis Introduction 1289 Interfollicular epidermal stem cells 1289 Models for skin renewal: epidermal proliferative unit versus committed progenitor 1290 Hair follicle stem cells 1291 The bulge as stem cell source 1291 Defining characteristics of the bulge as a stem cell source 1292 Multiple hair follicle stem cell subpopulations by marker expression 1294 Stem cells of other ectodermal appendages 1295 Sebaceous glands 1295 Sweat glands 1296 Nails 1296 Hair follicle stem cells in skin homeostasis, wound healing, and hair regeneration 1297 Homeostasis 1297 Wound healing 1297 Wound-induced hair follicle neogenesis and regeneration 1298 Epithelial stem cells in aging 1298 Role of stem cells in alopecia 1299 Skin as an active immune organ 1300 Cross talk between hair follicles and the immune system 1300 The inflammatory memory of skin cells 1301 Tissue engineering with epidermal stem cells 1301 Epidermal stem cells as a therapy: the future 1302 Conclusion 1302 References 1302 70. Wound repair: basic biology to tissue engineering 1309 Richard A.F. Clark, Michael Musillo and Thomas Stransky Introduction 1309 Basic biology of wound repair 1310 Inflammation 1310 Transition from inflammation to repair 1310 Reepithelialization 1310 Granulation tissue 1312 Wound contraction and extracellular matrix organization 1316 Chronic wounds 1317 Scarring 1318 Pathological scars 1318 Scarless healing 1319 Tissue engineered therapy with skin cells 1320 Engineered epidermal constructs 1320 Engineered dermal constructs 1321 Engineered skin substitutes 1321 Skin autograft harvesting without scarring 1322 Tissue-engineered therapy with stem cells, bioactives, and biomaterials 1322 References 1324 71. Bioengineered skin constructs 1331 Vincent Falanga Introduction 1331 Skin structure and function 1331 The epidermis 1331 The dermis 1332 The process of wound healing 1333 Impaired healing and its mechanisms 1333 Acute versus chronic wound healing 1333 Bacterial colonization 1333 Growth factor imbalances 1334 Matrix metalloproteinase activity 1334 Moist wound healing in chronic wounds 1334 Ischemia 1334 Abnormalities at the cellular level 1335 Engineering skin tissue 1335 Design considerations 1335 Commercial considerations 1336 Process considerations 1337 Regulatory considerations 1337 Immunological considerations 1338 Summary: engineering skin tissue 1338 Epidermal regeneration 1338 Dermal replacement 1339 Bioengineered living skin equivalents 1339 Bioengineered skin: FDA-approved indications 1340 Cutaneous indications 1340 Oral indications 1341 Apligraf and Dermagraft: off-label uses 1341 The importance of wound bed preparation 1344 Proposed mechanisms of action of bioengineered skin 1345 xxii Contents Construct priming and a new didactic paradigm for constructs 1347 Other considerations 1348 Conclusion 1348 References 1349 Further reading 1352 Part Twenty Tissue-engineered food 1353 72. Principles of tissue engineering for food 1355 Mark Post and Cor van der Weele Introduction 1355 Why tissue engineering of food? 1355 Specifics of tissue engineering for medical application 1356 Uniqueness 1356 Function 1356 Skeletal muscle and fat tissue engineering 1357 Tissue engineering of skeletal muscle 1357 Tissue engineering of fat 1359 Specifics of food tissue engineering 1361 Scale 1361 Efficiency 1362 Taste, texture, juiciness 1362 Enhanced meat 1363 Other foods 1363 Consumer acceptance 1364 Regulatory pathway 1365 Conclusion 1365 References 1365 73. Cultured meat—a humane meat production system 1369 Zuhaib F. Bhat, Hina Bhat and Sunil Kumar Introduction 1369 Need and advantages of cultured meat 1370 Cultured meat 1372 Scaffolding techniques 1372 Self-organizing tissue culture 1373 Organ printing 1375 Biophotonics 1375 Nanotechnology 1375 Challenges and requirements for industrial production 1375 Generation of suitable stem cell lines from farm-animal species 1376 Safe media for culturing of stem cells 1377 Safe differentiation media to produce muscle cells 1377 Tissue engineering of muscle fibers 1378 Scaffolds 1378 Industrial bioreactors 1379 Fields 1380 Atrophy and exercise 1380 Senescence 1381 Meat processing technology 1381 Associated dangers and risks 1381 Regulatory issues 1381 Consumer acceptance and perception 1382 Role of media in publicity of cultured meat 1382 Market for cultured meat 1382 Conclusion 1383 References 1384 Part Twentyone Emerging technologies 1389 74. Three-dimensional bioprinting for tissue engineering 1391 Jun Tae Huh, James J. Yoo, Anthony Atala and Sang Jin Lee Introduction 1391 3D Bioprinting strategy: from medical image to printed bioengineered tissue 1391 Three-dimensional bioprinting techniques 1392 Jetting-based bioprinting 1392 Extrusion-based bioprinting 1394 Laser-assisted bioprinting 1394 Laser-based stereolithography 1395 Digital light processing 1395 Hybrid and other techniques 1396 Biomaterials as bioinks for three-dimensional bioprinting 1396 Hydrogel-based bioinks for cell-based three-dimensional bioprinting 1396 Biodegradable synthetic polymers for structure-based three-dimensional bioprinting 1399 Scaffold-free cell printing 1399 Three-dimensional bioprinting in tissue engineering applications 1400 Three-dimensional bioprinted vascular structures 1400 In vitro tissue models 1400 Three-dimensional bioprinted implantable tissue constructs 1403 Conclusion and future perspectives 1409 Abbreviations 1410 Glossary 1410 References 1411 Contents xxiii 75. Biofabricated three-dimensional tissue models 1417 David B. Berry, Claire Yu and Shaochen Chen Introduction 1417 Current methods of three-dimensional biofabrication 1418 Biomaterials for three-dimensional fabrication 1421 Three-dimensional tissue models for drug screening, disease modeling, therapeutics, and toxicology 1425 Conclusion and future directions 1435 Acknowledgments 1435 References 1435 76. Body-on-a-chip: three-dimensional engineered tissue models 1443 Thomas Shupe, Aleksander Skardal and Anthony Atala Introduction 1443 Advanced in vitro modeling systems—progression from two-dimensional to three-dimensional models 1444 Organ-on-a-chip technologies and their applications 1445 Microengineering and biofabrication 1446 Liver-on-a-chip 1447 Vessel-on-a-chip 1447 Lung-on-a-chip 1448 Heart-on-a-chip 1448 Cancer-on-a-chip 1448 Body-on-a-chip: integrated multiorgan systems and future applications 1449 The importance of multiorganoid integration 1449 Cutting edge body-on-a-chip: the first highly functional multiorganoid systems 1452 Conclusion and perspectives 1455 References 1456 77. Monitoring and real-time control of tissue engineering systems 1459 Jean F. Welter and Harihara Baskaran Introduction 1459 Current state-of-the-art 1460 General environmental monitoring and real-time control 1460 Tissue-level monitoring 1462 Mechanical properties 1462 Cell-level monitoring 1463 Reporter-based gene expression imaging 1463 Tissue-specific 1463 Cartilage monitoring and real-time control 1463 Skin 1464 Concluding remarks 1464 Acknowledgments 1465 References 1465 78. Biomanufacturing for regenerative medicine 1469 Joshua G. Hunsberger and Darren H.M. Hickerson Current landscape of biomanufacturing 1469 Highlighting current workflows for biomanufacturing 1470 Current challenges in biomanufacturing for regenerative medicine 1470 Current platform technologies enabling biomanufacturing 1472 Regulatory challenges for biomanufacturing 1473 Food and Drug Administration guidance documents 1474 Creating standards 1475 The future: envisioned advanced biomanufacturing 1476 Closed-modular biomanufacturing systems 1476 Off-the-shelf products 1477 Preservation advances 1477 Synthetic biology advances 1477 Cell banking advances 1477 Medical applications for biomanufacturing in regenerative medicine 1477 Space exploration 1478 References 1479 Part Twentytwo Clinical experience 1481 79. Tissue-engineered skin products 1483 Jonathan Mansbridge Introduction 1483 Types of therapeutic tissue-engineered skin products 1484 Components of tissue-engineered skin grafts as related to function 1484 Scaffold 1484 Keratinocytes 1485 Fibroblasts 1485 Extracellular matrix 1485 Subcutaneous fat 1485 Components of the immune system 1486 Melanocytes 1486 Adnexal structures 1487 xxiv Contents Commercial production of tissue-engineered skin products 1487 Regulation 1487 Product development 1487 Overall concept 1487 Allogeneic cell source 1488 Viability of product and avoidance of a final sterile fill 1488 Shelf life 1488 Size, user convenience 1489 The manufacture of Dermagraft and TransCyte 1489 Cells 1489 Medium 1489 Bioreactor design 1490 The Dermagraft and TransCyte production processes 1490 Release specifications 1491 Distribution and cryopreservation 1491 Problems with commercial culture for tissue engineering 1492 Clinical trials 1492 Immunological properties of tissue-engineered skin 1493 Commercial success 1494 Mechanism of action 1494 Future developments 1495 Conclusion 1496 References 1496 80. Tissue-engineered cartilage products 1499 Henning Madry Introduction 1499 Cartilage defects, osteoarthritis, and reconstructive surgical options 1499 Cartilage defects pathophysiology 1499 Surgical treatment options for articular cartilage defects 1500 Tissue-engineered cartilage products for orthopedic reconstruction 1500 Cells for tissue-engineered cartilage repair 1500 Scaffolds for clinical tissue-engineered cartilage repair 1501 Collagen scaffolds 1501 Hyaluronan 1502 Synthetic polymers 1502 Agarose and alginate 1502 Scaffold-free three-dimensional systems 1502 Bioreactors for tissue-engineered cartilage repair 1502 Clinical nomenclature of scaffold-based techniques 1503 Clinical generations of autologous chondrocyte implantation 1503 Acellular, scaffold-based products 1503 Particulated autologous or allogenic articular cartilage 1503 Commercial autologous chondrocyte implantation products 1503 MACI (Vericel, Cambridge, MA, United States) 1503 ChondroCelect (TiGenix, Leuven, Belgium) 1504 Spherox (Co.don, Berlin, Germany) 1504 Novocart 3D (Tetec, Reutlingen, Germany) 1504 BioSeed C (Biotissue, Geneva, Switzerland) 1504 Novocart Inject (Tetec, Reutlingen, Germany) 1504 Chondron (Sewon Cellontech, Seoul, Korea) 1505 Cartipatch (Tissue Bank of France, Ge´nie Tissulaire, Lyon, France) 1505 CARTISTEM (Medipost, Seongnam, Korea) 1505 Clinical application of autologous chondrocyte implantation in reconstructive articular cartilage surgery 1505 Indications for autologous chondrocyte implantation 1505 Contraindications 1505 Surgical steps 1506 Clinical results of autologous chondrocyte implantation 1506 Overview 1506 Data from prospective randomized clinical trials 1507 Long-term results of autologous chondrocyte implantation 1508 Clinical factors affecting the clinical outcomes of autologous chondrocyte implantation 1508 Conflict of interest 1509 References 1509 81. Bone tissue engineering 1511 Hani A. Awad, Regis J. O’Keefe and Jeremy J. Mao Introduction 1511 Conventional bone tissue engineering strategies: cells, scaffolds, and biofactors 1511 Delivery of molecules and/or scaffolds to augment endogenous bone regeneration 1512 Biomaterials development and three-dimensional printing 1513 Clinical successes and opportunities in regenerative repair of craniofacial defects 1516 Conclusion 1517 Acknowledgments 1517 References 1517 Contents xxv 82. Tissue-engineered cardiovascular products 1521 Doris A. Taylor, Camila Hochman-Mendez, Joern Huelsmann, Abdelmotagaly Elgalad and Luiz C. Sampaio Clinical situation/reality 1521 Considerations for tissue-engineered cardiovascular constructs 1521 Components for tissue-engineered cardiovascular constructs 1521 Cell sources 1521 Scaffolds 1524 Tissue-engineered cardiovascular constructs 1525 Vascular grafts 1525 Valves 1526 Cardiac patches 1527 Building the next level of complexity: whole heart 1529 Pathway to approval and commercialization 1530 Future perspectives 1532 References 1532 83. Tissue organoid models and applications 1537 Timothy S. Leach, Anthony Dominijanni, Sean V. Murphy and Anthony Atala Introduction 1537 Cell sources 1537 Types of organoid models 1538 Cardiac organoid 1539 Liver organoid 1540 Brain organoid 1540 Lung organoid 1541 Gastrointestinal tract organoid 1541 Other organoid models 1542 Applications 1542 Tumor and disease models 1542 Drug analysis 1543 Organ-on-a-chip 1544 Developmental biology 1544 Conclusion 1545 References 1545 Part Twenty three Regulation, commercialization and ethics 1551 84. The regulatory process from concept to market 1553 Kyung Eun Sung, Judith Arcidiacono, Donald W. Fink Jr., Andrea Gray, Johnny Lam, Winson Tang, Iwen Wu and Raj K. Puri Introduction 1553 Regulatory background 1553 Overview of development and approval process 1554 Early-stage development 1554 Chemistry, manufacturing, and controls 1555 Pharmacology and toxicology 1555 Clinical 1556 US Food and Drug Administration/sponsor meetings 1557 Submitting an investigational new drug application 1557 Required US Food and Drug Administration forms 1557 Investigational new drug application contents 1558 US Food and Drug Administration review of an original investigational new drug application submission 1559 Later-stage development topics 1559 Compliance with current good manufacturing practice 1559 Product readiness for Phase 3 1559 Potency assay 1560 Pharmacology and toxicology 1560 Phase 3 clinical development 1560 Combination products 1561 Tissue-engineered and regenerative medicine products 1562 3D bio-printed tissue-engineered/ regenerative-medicine products 1563 Medical devices 1563 Least burdensome principles 1563 Breakthrough device program 1563 Evaluation of devices used with regenerative medicine advanced therapy 1564 Expedited review programs 1564 Other regulatory topics 1565 Minimal manipulation and homologous use of human cells, tissues, and cellular and tissue-based products 1565 Clinical research involving children 1566 Expanded access to investigational drugs for treatment use 1566 Charging for investigational drugs under an investigational new drug application 1566 Responsibilities of sponsors and investigators 1566 Clinical research conducted outside of the United States 1568 Use of standards 1568 US Food and Drug Administration international regulatory activities 1568 The role of cell-based products in medical product testing 1568 Conclusion 1568 Acknowledgments 1568 xxvi Contents Appendix I: Code of Federal Regulations citations relevant to cellular product development 1569 Appendix II: The list of acronyms 1569 References 1570 85. Business issues 1573 Matthew Vincent Introduction 1573 The aging population 1573 Rise of regenerative medicine 1575 Product development 1577 Embryonic stem cells 1578 Induced pluripotent stem cells 1579 Direct reprogramming of differentiated cells 1580 Small molecule-induced differentiation 1580 Reimbursement 1580 Conclusion 1582 References 1582 86. Ethical issues 1585 Laurie Zoloth Introduction 1585 Duty and healing: natural makers in a broken world 1587 To make is to know: notes on an old problem about knowledge 1587 What is a thing? The perils of deconstruction 1588 What contextual factors should be taken into account, and do any of these prevent the development and use of the technology? 1588 What purposes, techniques, or applications would be permissible and under what circumstances? 1589 On what procedures and structures, involving what policies, should decisions on appropriate techniques and uses be based? 1590 Conclusion 1590 References 1590 Index

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