BIOREGENERATIVEENGINEERING:PRINCIPLES ANDAPPLICATIONS
SHU Q. LIU
Universfcjis- und Landes-biblioinsk Darmstadt jBiblicthek Biolooio 1
WILEY-INTERSCIENCE
A JOHN WILEY & SONS, INC., PUBLICATION
CHAPTER SUMMARIES
CHAPTER SUMMARIES
PART I. FOUNDATIONS OF BIOREGENERATIVE ENGINEERING 1
Section 1. Molecular Basis for Bioregenerative Engineering 3
Chapter 1. Structure and Function of Macromolecules 4Introduction to the composition, structure, synthesis, assembly, organiza-tion, function, and metabolism of DNA, RNA, proteins, and lipids with afocus on the contributions of these molecules to the constitution and func-tion of cells and tissues.
Chapter 2. Regulation of Gene Expression 36Structural basis for gene expression; regulation of gene expression at thetranscriptional and posttranscriptional levels; and significance of regulatedgene expression in the control of cell functions and adaptation to environ-mental alterations.
Chapter 3. Structure and Function of Cellular Components 52Structure, organization, function, and interaction of cellular components,including the cell membrane, cytoskeleton, endoplasmic reticulum, Golgiapparatus, endosomes, mitochondria, and nucleus.
Chapter 4. Extracellular Matrix 102Composition, structure, function, synthesis, and degradation of extracellularmatrix components, including the collagen matrix, elastic fibers and laminae,and proteoglycans; and roles of extracellular matrix in the formation oftissues and organs as well as in the regulation of cell organization andfunctions.
Section 2. Regulatory Mechanisms of Regeneration 146
Chapter 5. Cell Signaling Pathways and Mechanisms 147Types, mechanisms, and significance of cell signaling; factors serving assignals; and descriptions of common cell signaling pathways, including theprotein tyrosine kinase-mediated signaling pathways, nonreceptor tyrosine
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kinase-mediated signaling pathways, serine/threonine kinase-mediated sig-naling pathways, protein phosphatase-mediated signaling pathways, cyto-kine-JAK-STAT-mediated signaling pathways, G-protein receptor-mediatedsignaling pathways, NFKB-mediated signaling pathways, ubiquitin and pro-teasome-mediated signaling pathways, nuclear receptor-mediated signalingpathways, and p53-mediated signaling pathways.
Chapter 6. Fundamental Cellular Functions 256Structural basis, processes, regulation, and significance of cellular func-tions, including cell division (mitosis and meiosis), migration, adhesion, andapoptosis; and contributions of these cellular functions to the morphogene-sis and pathogenesis of tissues and organs.
Section 3. Developmental Aspects of Bioregenerative Engineering 328
Chapter 7. Fertilization and Early Embryonic Development 329Structure and function of sex cells, including the sperm and egg; and pro-cesses, regulation, and mechanisms of fertilization, cleavage, blastocystformation, and gastrulation.
Chapter 8. Embryonic Organ Development 346Processes, regulation, and mechanisms of embryonic development and mor-phogenesis of ectodermal organs (nervous system and epidermis), mesoder-mal organs (skeleton, skeletal muscle system, heart, blood, blood vessels,and kidneys), and endodermal organs (digestive tract, liver, pancreas, andlungs).
Chapter 9. Regeneration of Adult Cells, Tissues, and Organs 380Types, structure, and functional characteristics of stem cells; application ofstem cells to regenerative engineering and medicine; and processes andmechanisms of the regeneration of salamander limbs and mammalian liver.
PART II. PRINCIPLES AND APPLICATIONS OF BIOREGENERATIVEENGINEERING TO ORGAN SYSTEMS 417
Section 4. Principles of Bioregenerative Engineering 419
Chapter 10. Molecular Aspects of Bioregenerative Engineering 420Types and mechanisms of gene mutation; disorders due to gene mutation;genetic basis and principles of molecular regenerative engineering or genemanipulation; and application of molecular regenerative engineering to thetreatment of gene mutation-induced disorders.
Chapter 11. Cell and Tissue Regenerative Engineering 456Principles of cell and tissue regenerative engineering; cell identification andpreparation for regenerative engineering; preparation of tissue scaffolds forregenerative engineering; cell and tissue transplantation; and functionaltests for regenerative engineering.
CHAPTER SUMMARIES vii
Chapter 12. Biomaterial Aspects of Bioregenerative Engineering 468Identification, construction, and characterization of biomaterials, includingsynthetic polymers, extracellular matrix, metals, and ceramics; and applica-tion of biomaterials to regenerative engineering.
Section 5. Application of Bioregenerative Engineering to Organ Systems 499
Chapter 13. Nerve Regenerative Engineering 500Structure and function of the central and peripheral nervous systems; patho-genesis, pathology, clinical features, and conventional treatment of nervedisorders, including nerve injury, Alzheimer's disease, Parkinson's disease,Huntington's disease, and multiple sclerosis; and application of regenerativeengineering approaches to the treatment of nerve disorders.
Chapter 14. Cardiac Regenerative Engineering 584Structure and function of the heart; pathogenesis, pathology, clinical fea-tures, and conventional treatment of cardiac disorders, including heartfailure, cardiomyopathy, ischemic heart disease, and valvular diseases; andapplication of regenerative engineering approaches to the treatment ofcardiac disorders.
Chapter 15. Vascular Regenerative Engineering 659Structure and function of the vascular system; structure and function ofvascular endothelial cells, smooth muscle cells, and fibroblasts; pathogene-sis, pathology, clinical features, and conventional treatment of vasculardisorders, including atherosclerosis and hypertension; and applicationof regenerative engineering approaches to the treatment of vasculardisorders.
Chapter 16. Pulmonary Regenerative Engineering 736Structure and function of the pulmonary system; pathogenesis, pathology,clinical features, and conventional treatment of pulmonary disorders, includ-ing asthma, cystic fibrosis, and pulmonary hypertension; and applicationof regenerative engineering approaches • to the treatment of pulmonarydisorders.
Chapter 17. Liver Regenerative Engineering 768Structure and functionof the liver; regenerative characteristics of liver cells,including hepatocytes, epithelial cells, endothelial cells, Ito cells, andKiipffer cells; pathogenesis, pathology, clinical features, and conventionaltreatment of liver disorders, including acute and chronic hepatitis, cirrhosis,liver failure, and cancers; and application of regenerative engineeringapproaches to the treatment of liver disorders.
Chapter 18. Gastrointestinal Regenerative Engineering 798Structure and function of the gastrointestinal system; pathogenesis, pathol-ogy, clinical features, and conventional treatment of gastrointestinal disor-ders, including peptic ulcer, gastrointestinal cancers, inflammatory bowel
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disease, intestinal ischemia and infarction, and short bowel syndrome; andapplication of regenerative engineering approaches to the treatment ofgastrointestinal disorders.
Chapter 19. Pancreatic Regenerative Engineering 819Structure and function of the pancreas; pathogenesis, pathology, clinicalfeatures, and conventional treatment of pancreatic disorders, including dia-betes and pancreatic cancers; and application of regenerative engineeringapproaches to the treatment of pancreatic disorders.
Chapter 20. Urinary Regenerative Engineering 845Structure and function of the kidney and urinary tract; pathogenesis, pathol-ogy, clinical features, and conventional treatment of renal and urinary tractdisorders, including acute and chronic glomerulonephritis, acute and chronicrenal failure, and urinary tract obstruction; and application of regenerativeengineering approaches to the treatment of urinary disorders.
Chapter 21. Skeletal Muscle Regenerative Engineering 873Structure and function of the skeletal muscle system; pathogenesis, pathol-ogy, clinical features, and conventional treatment of muscular dystrophies;and application of regenerative engineering approaches to the treatment ofmuscular dystrophies.
Chapter 22. Bone and Cartilage Regenerative Engineering 906Structure and function of the bones and cartilage; pathogenesis, pathology,clinical features, and conventional treatment of skeletal disorders, includingosteoporosis, Paget's disease, bone tumors, and rheumatoid arthritis; andapplication of regenerative engineering approaches to the treatment ofskeletal disorders.
Chapter 23. Ocular Regenerative Engineering 964Structure and function of the eye; pathogenesis, pathology, clinical features,and conventional treatment of ocular disorders, including corneal injury,glaucoma, cataracts, and retinopathy; and application of regenerativeengineering approaches to the treatment of ocular disorders.
Chapter 24. Skin Regenerative Engineering 1007Structure and function of the skin; pathogenesis, pathology, clinical fea-tures, and conventional treatment of skin disorders, including skin injuryand cancers; and application of regenerative engineering approaches to thetreatment of skin disorders.
Chapter 25. Regenerative Engineering for Cancer 1026Classification, pathogenesis,. pathology, clinical features, and conventionaltreatment of cancers; and application of regenerative engineering approachesto the treatment of cancers.
CONTENTS
PREFACE xxviii
INTRODUCTION TO BIOREGENERATIVE ENGINEERING xxx
PART I FOUNDATIONS OF BIOREGENERATIVE ENGINEERING 1
Section 1. Molecular Basis for Bioregenerative Engineering 3
Chapter 1. Structure and Function of Macromolecules 4
Deoxyribonucleic Acids (DNA) 5Composition and Structure of DNA 5Organization of Chromosomes 9Functional Units of DNA 10DNA Replication 12
Initiation 12DNA Extension 13Proofreading • 14DNA Replication in Prokaryotic and Eukaryotic Cells 14
Ribonucleic Acid (RNA) 14RNA Composition and Structure • 14RNA Transcription . • 15
Initiation 16Elongation 16Termination - 16
' RNA Transcription and Processing in Eukaryotes 16Proteins 17
Protein Composition and Structure 17Protein Translation 20
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CONTENTS
InitiationElongationTermination
Protein Folding and ArchitectureChanges in Protein Conformation
LipidsPhospholipids
Phosphoglycerides/ Shingolipids
GlycolipidsSteroids
Chapter 2. Regulation of Gene Expression
Basic DNA Elements for Regulating Gene ExpressionTrans-Acting Regulatory FactorsRegulation of Gene Transcription
Control of the Activity of Trans-Acting FactorsChromatin ModificationDNA Modification
Regulation of Pre-mRNA Conversion to Mature mRNA5'-Terminal Capping and Decapping of Pre-mRNAPolyadenylationPre-mRNA SplicingmRNA Transport
Regulation of Protein Translation
Chapter 3. Structure and Function of Cellular Components
Cell MembraneCytoskeleton
Actin FilamentsStructure and Organization of Actin FilamentsActin-Binding Proteins
Actin Monomer-Binding ProteinsActin Filament-Capping ProteinsActin Filament-Severing ProteinsActin Filament Crosslinking Proteins
Regulation of Actin Assembly and DisassemblyFunction of Actin Filaments
MicrotubulesStructure and Organization of MicrotubulesMicrotubule Assembly and DisassemblyRegulation of Microtubule DynamicsFunction of Microtubules
Intermediate Filaments ~Structure and Organization of Intermediate FilamentsFunction of Intermediate Filaments
Endoplasmic ReticulumGolgi Apparatus
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Endosomes and Lysosomes 89Mitochondria 90
Structure and Organization 90ATP Generation 90
Cell Nuclei 91
Chapter 4. Extracellular Matrix 102
Collagen Matrix 103Composition and Formation of Collagen Matrix 103Function of Collagen Matrix 107
Elastic Fibers and Laminae 109Composition and Structure of Elastic Laminae 109Function of Elastic Fibers and Laminae 112
Proteoglycans 113Composition and Structure of Proteoglycans 113Function of Proteoglycans 116
Matrix Metalloproteinases 119Structural Features of MMPs 120Activation of MMPs 121
Section 2. Regulatory Mechanisms of Regeneration 146
Chapter 5. Cell Signaling Pathways and Mechanisms 147
Principles of Cell Signaling 148Factors Serving as Signals 148Types of Cell Signaling 149General Mechanisms of Cell Signaling 150
Protein Tyrosine Kinase-Mediated Cell Signaling 151Structure and Function 152Signaling Mechanisms 154
Nonreceptor Tyrosine Kinase-Mediated Cell Signaling 180Structure and Function 180Signaling Mechanisms 180
Serine/Threonine Kinase-Mediated Cell Signaling 183Serine/Threonine Kinase Receptors 184Protein Kinase A 185Protein Kinase C 185
Protein Phosphatase-Mediated Cell Signaling 199Protein Serine/Threonine Phosphatase-Mediated CellSignaling 199
Structure and Function 199Signaling Mechanisms 201
Protein Tyrosine Phosphatase-Mediated Cell Signaling 201Structure and Function - 201Signaling Mechanisms 205
Cytokine-JAK-STAT-Mediated Cell Signaling 207Structure and Function 207Signaling Mechanisms 207
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G-Protein Receptor-Mediated Cell Signaling 217Structure and Function 217Signaling Mechanisms 221
NFKB-Mediated Cell Signaling 222Structure and Function 222Signaling Mechanisms 226
Ubiquitin and Proteasome-Mediated Cell Signaling 226Structure and Function 226Signaling Mechanisms 229
Stimulation of Ubiquitination by SubstratePhosphorylation 229Inhibition of Ubiquitination by Substrate Phosphorylation 229Stimulation of Ubiquitination by Substrate Hydroxylation 229
Nuclear Receptor-Mediated Cell Signaling 231Structure and Function 231Signaling Mechanisms 232
p53-Mediated Cell Signaling 236Structure and Function 236Signaling Mechanisms 237
Chapter 6. Fundamental Cellular Functions 256
Cell DivisionMitosisCycle of Mitotic Cell Division
Gl Phase :S PhaseG2 PhaseM Phase
CytokinesisControl of Cell Division
Constitutive Control of Cell DivisionExtracellular Control of Cell DivisionSignaling Events of Cell Cycle ControlInhibition of Cell Division Cycle
MeiosisExperimental Assessment of Cell Division
Cell MigrationMechanics of Cell Migration
Protrusion of Cell MembraneAttachment of Cell Membrane to Substrate Matrixat the Leading EdgeCell Traction and MovementRetraction of Cell membrane at the Trailing edgeReplenishment of Integrins
Regulation of Cell MigrationRole of the Rho family of GTPasesRole of MAPKs
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Cell Adhesion 274Immunoglobulin-Like Domain-Containing CellAdhesion molecules 275
Classification and Structure 275Functions 277
Role in Mediating Cell-Cell Adhesion 277Role in Mediating Cell-Matrix Adhesion 277Role in Cell Signaling 277
Selectins 289Classification and Structure 289Function 289
Cadherins 292Classification and Structure 292Function 296
Cell Surface Heparin Sulfate Proteoglycans 296Classification and Structure 296Function 298
Integrins 298Classification and Structure 298Function 302Mechanisms of Integrin-Related Activities 303
Apoptosis 304Morphological Characteristics of Apoptosis 304Apoptosis-Inducing Factors 304Regulation of Apoptosis 304Assessment of Cell Apoptosis 307
Assessing Changes in Cell Membrane Structure 307Assessing Changes in Cell Morphology 307Assessing DNA Fragmentation 310Assessing the Translocation of Cytochrome c 310Assessing the Activity of Caspases 310
Section 3. Developmental Aspects of Bioregenerative Engineering 328
Chapter 7. Fertilization and Early Embryonic Development 329
The Sperm 330The Egg 333Fertilization 334
Attraction of Sperm Cells to the Oocyte 334Sperm-Oocyte Interaction 335Sperm-Oocyte Fusion 336Activation of Embryonic Development 339Integration of Gamete Genomes 339
Cleavage 340Formation of the Blastocyst 340Gastrulation 341
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Chapter 8. Embryonic Organ Development
Development of Ectoderm-Derived OrgansEpidermal DevelopmentDevelopment of Neural Crest-Derived Systems
The Neural CrestNeurulation and Formation of Neural Crest CellsMigration of Neural Crest CellsDifferentiation of Neural Crest Cells
Development of Neural Tube-Derived SystemsFate of the Neural TubeFormation of Neurons and Glial Cells
Development of Mesoderm-Derived OrgansThe NotochordThe Paraxial Mesoderm
Formation of the SomitesFormation of the Skeletal Muscle SystemFormation of the Skeleton
The Intermediate Mesoderm: Formation of theKidneyThe Lateral Plate Mesoderm
Formation of the HeartFormation of the Vascular SystemFormation of Blood Cells
Development of Endoderm-Derived OrgansFormation of the Digestive TractFormation of the LiverFormation of the PancreasFormation of the Lung
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Chapter 9. Regeneration of Adult Cells, Tissues, and Organs
The Stem Cell ConceptEmbryonic Stem CellsFetal Stem and Progenitor CellsAdult Stem Cells
Bone Marrow-Derived Stem CellsNeural Stem CellsOther Adult Stem Cells
Regeneration of Adult Tissues and OrgansRegeneration of Salamander LimbsRegeneration of the Mammalian Liver
Biological Processes of Liver RegenerationFeatures of Liver RegenerationExperimental Models of Liver RegenerationRegulation of Liver Regeneration
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CONTENTS xv
PART II PRINCIPLES AND APPLICATIONS OF BIOREGENERATIVEENGINEERING TO ORGAN SYSTEMS 417
Section 4. Principles of Bioregenerative Engineering 419
Chapter 10. Molecular Aspects of Bioregenerative Engineering 420
DNA Engineering 421Gene Mutation 421Disorders Due to Gene Mutation 423Principles of DNA Engineering 425
Identification of Cell Types Involved in a Disorder 425Identification of Mutant Genes 425
Assessing mRNA Transcription 426Extracting and Digesting DNA 428Constructing Recombinant DNA 429Establishing a DNA Library 430Selecting a Gene of Interest from a DNA Library 431Amplification of the Selected Gene 432DNA Sequencing and Analysis 433Testing the Function of the Selected Gene, 434
Constructing a Recombinant Therapeutic Gene 436Transfection of Target Cells with a Therapeutic Gene 436
Virus-Mediated Gene Transfer 438Receptor-Mediated Gene Transfer 442Liposome-Mediated Gene Transfer 443Calcium Phosphate-Mediated Gene Transfer 443Electroporation-Mediated Gene Transfer • 444Gene Gun-Mediated Gene Transfer 444
Assessing the Expression of the Transferred Gene 445Assessing the Effectiveness of Gene Transfer 447Potential Negative Effects of Gene Transfer 447
Homologous Recombination 447Antisense Oligonucleotide-Based Therapy 448Small Interfering RNA-Based Therapy 449
Chapter 11. Cell and Tissue Regenerative Engineering 456
Cell Regenerative Engineering 457Candidate Cell Types for Cell Regenerative Engineering 458Cell Expansion 459Genetic Modulation of Cells 459Cell Transplantation 460Identification of Transplanted Cells 460Functional Tests 461
Tissue Regenerative Engineering 461Tissue Construction • 462Functional Tests of Tissue Replacement 462Tissue Implantation 463
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Morphological Tests of Implanted Tissue Constructs 463Test of Cell Viability and Growth 464Functional Tests for Implanted Tissue Constructs 464
Chapter 12. Biomaterial Aspects of Bioregenerative Engineering 468
Synthetic Polymers as Biomaterials 469Classification 469General Properties 470Nonbiodegradable Polymers 471
Polytetrafluoroethylene 471Poly(ethylene terephthalate) 471Polyethylene 472
Biodegradable Polymers 472Linear Aliphatic Polyesters 473
Polyglycolides and Polylactides 473Polycaprolactones 474Poly(p-hydroxybutyrate) 474
Polycarbonates 475Polyamides 475Polyphosphazenes 476Polyanhydrides 478
Biological Materials 479Collagen Matrix 479Elastic Fibers and Laminae 480Polysaccharides 481
Cellulose 481Alginates 482Chitosan 483Starch - 485Glycosaminoglycans 486
Metallic Materials as Biomaterials 487Stainless Steels as Biomaterials 487Co-Cr Alloys as Biomaterials 487Titanium and Titanium Alloys as Biomaterials 488Potential Problems with Metallic Materials 488
Ceramics as Biomaterials 489Bioactive Ceramics 489Bioinert Ceramics 490Biodegradable Ceramics 490
Section 5. Application of Bioregenerative Engineering to Organ Systems 499
Chapter 13. Nervous Regenerative Engineering 500
Anatomy and Physiology of the .Central and PeripheralNervous Systems 501
Neural Cells 501Neurons 501Glial Cells 503
CONTENTS
Organization of the Nervous SystemBrain
CerebrumDiencephalonCerebellumBrainstemCranial NervesCerebral CirculationMeninges and Cerebral Ventricles
Spinal CordThe Peripheral Nervous System
Functional Integration of the Nervous SystemSensory InputMotor ControlAutonomic Control of Vital Activities
Sympathetic Nervous SystemParasympathetic Nervous SystemAutonomic Regulation of CardiovascularFunctions
Nervous DisordersNerve Injury
Etiology, Pathology, and Clinical FeaturesBrain InjuryCranial Nerve InjurySpinal Cord InjuryPeripheral Nerve Injury
Conventional Treatment of Nerve InjuryMolecular Nerve Regenerative Engineering
Strategies of Molecular Nerve RegenerativeEngineeringEnhancement of Neuron SurvivalPrevention of Cell DeathPrevention of Secondary Nerve InjuryStimulation of Stem Cell DifferentiationEnhancement of Axonal Extension, Adhesion,and ReconnectionPrevention of Fibrous Scar FormationEnhancement of Synaptic Formation
Nerve Cell Regenerative EngineeringEmbryonic and Fetal Stem CellsAdult Neural Stem CellsBone Marrow CellsNeuronal Supporting CellsTransgenic Cell Lines ,.
Tissue Regenerative Engineering for Nerve InjuryStimulation of Neuronal Regeneration and Guidanceof Axonal Outgrowth by Graft-BasedAssistance
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Degenerative Neural Diseases 554Alzheimer's Disease 554
Etiology, Pathology, and Clinical Manifestations 554Conventional Treatment of Alzheimer's Disease 559Molecular Regenerative Engineering for Alzheimer'sDisease 560Cell Regenerative Engineering for Alzheimer's Disease 561
Huntington's Disease 562Etiology, Pathology, and Clinical Features 562Conventional Treatment of Huntington's Disease 563Molecular Regenerative Engineering for Huntington'sDisease 564
Parkinson's Disease 565Etiology, Pathology, and Clinical Manifestation 565Conventional Treatment 567Molecular Regenerative Engineering for Parkinson'sDisease 567Cell Regenerative Engineering for Parkinson's Disease 570
Multiple Sclerosis 572Etiology, Pathogenesis, and Clinical Manifestations 572Conventional Treatment 573Molecular Regenerative Engineering for Multiple Sclerosis 573Cell Regenerative Engineering 574
Chapter 14. Cardiac Regenerative Engineering 584
Anatomy and Physiology of the Heart 585Cardiac Structure 585Cardiac Cells • 586Cardiac Performance and Cycle 587Regulation of Cardiac Performance 589
Cardiac Disorders 589Heart Failure and Cardiomyopathy 589
Pathogenesis, Pathology, and Clinical Features ofHeart Failure 589Experimental Models of Heart Failure 593Pathogenesis, Pathology, and Clinical Features ofCardiomyopathy 594Experimental Model of Cardiomyopathy 595Conventional Treatment of Cardiac Failure andCardiomyopathy 595Molecular Therapy for Cardiac Failure andCardiomyopathy 595Tissue Regenerative. Engineering for Cardiac Failureand Cardiomyopathy . 596
Ischemic Heart Disease 598Pathogenesis, Pathology, and Clinical Features 598Conventional Treatment of Ischemic Heart Disease 599
CONTENTS xix
Molecular Regenerative Engineering for IschemicHeart Disease 600
Growth Factors as Therapeutic Agents for CardiacRegenerative Engineering 600Prevention of Cardiac Injury 624Antioxidant Molecules as Therapeutic Agents 625Enhancement of Angiogenesis 630
Cell Regenerative Engineering for Ischemic Heart Disease 630Replacement of Malfunctioned Cardiomyocytes 635Enhancement of Angiogenesis 636
Tissue Regenerative Engineering for Ischemic HeartDisease 636
Valvular Diseases 637Pathogenesis, Pathological Changes, and Clinical Features 637Treatment 639
Artificial Cardiac Valves 639Tissue-Engineered Cardiac Valves 640
Chapter 15. Vascular Regenerative Engineering 659
Anatomy and Physiology of the Vascular System 660Structure and Organization of Blood Vessels 660Types and Functions of Vascular Cells 660
Endothelial Cells 661Endothelial Barrier Function 661Regulation of Anti- and Procoagulation Activities 663Regulation of Vascular Contractility 663Regulation of Leukocyte and Platelet Adhesion 663Regulation of Cell Proliferation and Migration 667Production of Extracellular Matrix 668
Smooth Muscle Cells 668Contractility 668Regulation of Cell Proliferation and Migration 670Regulation of Extracellular Matrix Production 670
Fibroblasts 670Extracellular Matrix of Blood Vessels 670Regulation of Blood flow 671Regulation of Blood Pressure 672
Regulation by Baroreceptors 672Regulation by Chemoreceptors . 672Regulation by Central Nerve Control Centers 673Regulation by the Renin-Angiotensin-Aldosterone System 673Regulation by the Vasopressin System 673
Vascular Disorders 674Atherosclerosis 674
Pathogenesis, Pathology, and Clinical Features 674Animal Models of Atherosclerosis 682Prevention of Atherosclerosis 683
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Conventional Treatment of Atherosclerosis 684Antihyperlipidemia Agents 684Antiproliferative Agents 684Treatment of Angina Due to Ischemia 685Reduction in Cardiac Workload 685Treatment of Malfunctioned Arteries .with Angioplasty 685Treatment of Malfunctioned Arteries with Stents 685Arterial Reconstruction 686
Molecular Treatment of Atherosclerosis 687Antisense Oligonucleotides for Mitogenic Factors 687Cell Cycle Inhibiting Genes 688Nitric Oxide Synthase Gene 688Herpes Virus Thymidine Kinase Gene : 690Dominant Negative Mutant Mitogenic Genes 690
Vascular Tissue Regenerative Engineering 693Construction of Polymeric Arterial Substitutes withEndothelial Cell Seeding 693Construction of Cell-Integrated Arterial Substituteswith Biodegradable Polymers 693Construction of Arterial Substitutes with DecellularizedCollagen Matrix • . . . 693Construction of Arterial Substitutes in vivo 694Construction of Arterial Substitutes with VascularCells and Matrix Components in vitro 696Modulation of the Structure and Function of ArterialSubstitutes 696
Hypertension 699Pathogenesis, Pathology, and Clinical Features 699
Essential Hypertension 700Renovascular Hypertension 700Endocrine Hypertension 701
Animal Models of Renovascular Hypertension 703Conventional Treatment of Hypertension 706Molecular Engineering 706
Nitric Oxide Synthase Gene : . 707Atrial Natriuretic Peptide Gene 707Kallikrein Genes . 707Antisense Oligonucleotides for Angiotensinogen mRNA 710Antisense Oligonucleotides for Angiotensin II .Type 1 (ATI) Receptor mRNA 710Antisense Oligonucleotides for Adrenergic Receptor mRNA 710
Chapter 16. Pulmonary Regenerative Engineering 736
Anatomy and Physiology of the Respiratory System 737Pulmonary Structure . 737
The Airway and Alveolar Systems 737The Vascular System 738The Lymphatic System 738
CONTENTS xxi
Pulmonary Function 739Gas Ventilation and Exchange 739Ratio of Air Ventilation to Blood Perfusion 739Control of Gas Ventilation 740
Pulmonary Disorders 741Asthma 741
Pathogenesis, Pathology, and Clinical Features 741Experimental Models of Asthma 744Conventional Treatment of Asthma 745Molecular Therapies for Asthma 745
Suppression of Asthmatic Changes by Administrationof Antiinflammatory Cytokine Genes, Antibodies,and Inhibitors 745Suppression of Inflammatory Reactions by Transferringthe Glucocorticoid Receptor Gene 748Inducing Bronchodilation by TransferringBronchodilator Genes and Proteins 748
Cystic Fibrosis 750Pathogenesis, Pathology, and Clinical Features 750Experimental Models of Cystic Fibrosis 750Conventional Treatment of Cystic Fibrosis 752Molecular Engineering 753
Pulmonary Hypertension . 753Pathogenesis, Pathology, and Clinical Features 753
Primary Pulmonary Hypertension 753Hypoxic Pulmonary Hypertension . 754
Conventional Treatment of Pulmonary Hypertension 755Molecular Therapies for Pulmonary Hypertension 755
Nitric Oxide Synthase Gene 757Prostaglandin 12 Synthase Gene 758Preprocalcitonin-Related Peptide Gene 758
Chapter 17. Liver Regenerative Engineering 768
Anatomy and Physiology of the Liver 769Structure 769Functions 769
Metabolism 769Detoxification 770Blood Filtration and Storage < 770Bile Excretion 771
Liver Regeneration 771Hepatic Disorders 771
Acute Viral Hepatitis and Liver Failure 771Pathogenesis, Pathology, and Clinical Features 771Conventional Treatment 772Molecular Regenerative Therapies 773
Suppression of Viral Activities 773Enhancement of Hepatocyte Proliferation 773
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Suppression of Inflammatory Reactions 777Inhibition of Fibrosis 777Enhancing the Activity of Telomerase 777
Cell and Tissue Regenerative Engineering 778Selection, Culture, and Manipulation of Liver Cells 779Fabrication of Liver Scaffolds and Maintenance ofCell Viability and Function 780Implantation of Liver Constructs 784Testing Liver Function 784
Chronic Hepatitis and Cirrhosis 785Pathogenesis, Pathology, and Clinical Features 785Treatment of Chronic Hepatitis and Cirrhosis 787
Liver Cancers 788Pathogenesis, Pathology, and Clinical Features 788Treatment of Liver Cancers 788
Chapter 18. Gastrointestinal Regenerative Engineering 798
Anatomy and Physiology of the Gastrointestinal System 799Structure 799Nutrient Digestion and Absorption 800
Gastrointestinal Disorders 801Peptic Ulcer 801
Pathogenesis, Pathology, and Clinical Features 801Experimental Models of Gastrointestinal Ulcers 802Conventional Treatment 802Molecular Regenerative Engineering 802
Serum Response Factor (SRF) . 804Platelet-Derived Growth Factor (PDGF) 804Vascular Endothelial Growth Factor (VEGF) 805Angiopoietin-1 805
Gastrointestinal Cancers 805Pathogenesis, Pathology, and Clinical Features 805Conventional Treatment 805Molecular Therapy 805Tissue Regenerative Engineering 806
Gastrointestinal Transplantation 806Gastrointestinal Reconstruction Based onAutogenous Pedicles 807Expansion of Intestines 807Regeneration with Peritoneum 807Gastrointestinal Reconstruction Based on PolymericMaterials , 807Extracellular Matrix-Based GastrointestinalReconstruction ^ 808
Experimental Models of Gastrointestinal Reconstruction 809Inflammatory Bowel Disease 809
Pathogenesis, Pathology, and Clinical Features 809Conventional Treatment 810
CONTENTS xxiii
Molecular Therapy 810Interleukin-10 810Interleukin-18 810
Tissue Regenerative Engineering 810Intestinal Ischemia and Infarction [19.20] 811
Pathogenesis, Pathology, and Clinical Features 811Treatment of Intestinal Ischemia and Infarction 812
Short Bowel Syndrome 812Pathogenesis, Pathology, and Clinical Features 812Treatment of Short Bowel Syndrome 812
Chapter 19. Pancreatic Regenerative Engineering 819
Anatomy and Physiology of the Pancreas 820Structure 820Functions of the Pancreatic Endocrine System 820Functions of the Pancreatic Exocrine System 821
Pancreatic Disorders 822Diabetes Mellitus 822
Pathogenesis, Pathology, and Clinical Features 822Experimental Models of Diabetes Mellitus 825Conventional Treatment of Diabetes 825Molecular Regenerative Engineering 825
Enhancement of Glucose Uptake and Storage andInhibition of Glucose Production 826Facilitation of Insulin Synthesis and Activation 826Promotion of the Survival and Prevention of P-CellApoptosis 827Suppression of Autoimmune Processes 830
Cell and Tissue Regenerative Engineering 832Candidate Cell Types 833Prevention of Immune Reactions and p-Cell Injury 835Transplantation of P-Cell-Protecting Devices 835
Pancreatic Cancer 836Pathogenesis, Pathology, and Clinical Features 836Treatment of Pancreatic Cancer 836
Chapter 20. Urinary Regenerative Engineering 845
Anatomy and Physiology of the Urinary System 846Structure and Function of the Kidneys 846Structure and Function of the Urinary Tract 848
Disorders of the Urinary System ,. 848Acute Renal Failure 848
Pathogenesis, Pathology, and Clinical Features 848Experimental Models of Acute Renal Failure 849Conventional Treatment 850
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Molecular Regenerative Engineering 850Growth Factor Genes 851Genes Encoding Mitogenic Signaling Proteins 851Genes Encoding Cell Death Inhibitors 851
Cell and Tissue Regenerative Engineering 851Stem Cell-Based Kidney Regeneration 851Embryonic Tissue-Based Kidney Regeneration 853Nuclear Transfer-Based Kidney Regeneration 855Adult Tubular Cell-Based Kidney Regeneration 855
Chronic Renal Failure . 855Pathogenesis, Pathology, and Clinical Features 855Treatment of Chronic Renal Failure 859
Acute Glomerulonephritis 859Pathogenesis, Pathology, and Clinical Features 859Treatment of Acute Glomerulonephritis 860
Chronic Glomerulonephritis 860Pathogenesis, Pathology, and Clinical Features 860Treatment of Chronic Glomerulonephritis 861
Urinary Tract Obstruction 861Pathogenesis, Pathology, and Clinical Features 861Conventional Treatment of Urinary Tract Obstruction 861Cellular and Tissue Engineering 861
Polymeric Biomaterials for Urinary Tract Reconstruction 862Metallic Materials for Urinary Tract Reconstruction 862Biological Materials for Urinary Tract Reconstruction 862
Chapter 21. Skeletal Muscle Regenerative Engineering 873
Anatomy and Physiology of the Skeletal Muscle System 874Structure 874Mechanisms of Muscle Contraction 876
Disorders of the Skeletal Muscle System 878Muscular Dystrophies 878
Pathogenesis, Pathology, and Clinical Features 878Transgenic Models of Dystrophin Deficiency 881Molecular Treatment of Muscular Dystrophy 882
Transfer of Wildtype Dystrophin Gene 882Delivery of Truncated Dystrophin Genes orMicrodystrophin Gene Constructs 883Mutant Gene Correction by Small FragmentHomologous Replacement (SFHR) 883Correction of Mutant Genes by Chimeraplasty 884Removal of Mutant Gene Fragments by Exon Skipping 885Compensation for Lost Function of Dystrophin 885Transfer of Dystrophin "Booster" Genes 885
Cellular Regenerative Engineering for Muscular Dystrophy 891Muscular Progenitor Cells 891Stem Cells 891Potential Limitations 892
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Chapter 22. Bone and Cartilage Regenerative Engineering 906
Anatomy and Physiology of the BoneStructureFunctions of the Bone
Structural and Mechanical SupportGeneration of Stem CellsBone Formation and ResorptionBone MetabolismRegulation of Bone Metabolism
Role of Parathyroid HormoneRole of Vitamin D
Anatomy and Physiology of the CartilageBone and Cartilage Disorders
OsteoporosisPathogenesis, Pathology, and Clinical FeaturesConventional TreatmentMolecular Engineering Therapy
Vitamin D Receptor (VDR)Type I Collagen GeneEstrogen ReceptorCalcitoninOsteoprotegerin (OPG) and OsteoprotegerinLigand (OPL)Integrin-Binding ProteinsGrowth Factors
Cell Therapy for Bone RegenerationPaget's Disease
Pathogenesis, Pathology, and Clinical FeaturesConventional TherapyMolecular and Cellular Therapies
Bone TumorsPathogenesis, Pathology, and Clinical FeaturesTherapies for Bone Tumors
Rheumatoid ArthritisPathogenesis, Pathology, and Clinical FeaturesConventional TherapyMolecular Therapy
Interleukin-1Tumor Necrosis Factors (TNFs)Antiinflammatory CytokinesDominant-Negative Mutant Ras GeneOsteoprotegerinViral Thymidine Kinase
Bone and Cartilage InjuryPathogenesis, Pathology, and Clinical Features
Inflammatory ResponsesReparative Reactions
907907908908908909911913913915917918918918919919919920921921
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xxvi CONTENTS
Modeling Process 940Complications of Bone Injury 940
Conventional Therapy 940Molecular Regenerative Engineering 940Cell Regenerative Engineering 942Tissue Regenerative Engineering 942
Chapter 23. Ocular Regenerative Engineering 964
Anatomy and Physiology of the Ocular System 965Ocular Disorders 967
Corneal Injury 967Pathogenesis, Pathology, and Clinical Features 967Conventional Treatment of Cornea Injury 968Molecular Regenerative Engineering 968
Molecular Therapies for Corneal Immune Rejection 969Molecular Therapies for Corneal Inflammation andFibrosis 969Molecular Therapies for Corneal Complications Dueto Mucopolysaccharidosis Type VII (MPSVII) 971
Cellular and Tissue Engineering 971Corneal Surface Reconstruction 973Corneal Reconstruction 977
Glaucoma 979Pathogenesis, Pathology, and Clinical Features 979Conventional Treatment of Glaucoma 980Molecular Regenerative Engineering 980
Facilitation of Aqueous Humor Outflow Through theTrabecular Meshwork > 980Prevention of the Occlusion of Surgically CreatedAqueous Humor Fistula 981Protection of Retinal Neurons from Glaucoma-InducedInjury and Death 982
Cataract 983Pathogenesis, Pathology, and Clinical Features 983Conventional Treatment of Cataract 983Molecular Regenerative Engineering 983
Retinopathy 985Pathogenesis, Pathology, and Clinical Features 985Conventional Treatment of Retinopathy 986Molecular Regenerative Engineering 986
Molecular Therapy for Diabetic Retinopathy 986Molecular Therapy for Retinal Degeneration 986
Chapter 24. Skin Regenerative Engineering 1007
Anatomy and Physiology of the Skin 1008Skin Disorders 1009
Skin Injury . 1009Pathogenesis, Pathology, and Clinical Features 1009Conventional Treatment of Skin Injury 1010
CONTENTS xxvii
Skin Regenerative Engineering 1010Cell Types for Constructing Skin Substitutes 1011Matrix Scaffolds for Constructing Skin Substitutes 1014Growth Factors for Stimulating the Growth ofEpidermal Cells 1014Construction of Skin Substitutes 1017
Skin Cancer 1017Pathogenesis, Pathology, and Clinical Features 1017Treatment of Skin Cancers 1019
Chapter 25. Regenerative Engineering for Cancer 1026
Classification of Cancers 1027Pathogenesis of Cancers 1027Pathological Characteristics of Cancers 1028Treatment of Cancers 1029
Conventional Treatment 1029Molecular Engineering Therapies 1029
Overexpression of Tumor Suppressor Genes andCorrection of Mutant Tumor Suppressor Genes 1029Enhancement of Anticancer Immune Responses 1030Activation of Tumorsuppressing Prodrugs 1032Application of Oncolytic Viruses 1033Application of Antisense Oligonucleotides and siRNA 1033Application of Combined Therapeutic Approaches 1034
INDEX 1040
