Tissue Engineering

Preface xvii Introduction 1(19) Cells as Therapeutic Agents 2(2) Illustrative Examples 4(7) Cartilage and chondrocytes 5(1) Liver 5(2) Pancreas β-islet cells 7(1) Skin 8(1) Bone-marrow transplantation (BMT) 8(3) Tissue engineer faces diverse challenges 11(1) Cell Numbers and Growth Rates 11(4) Cell numbers in vivo: orders of magnitude 12(1) What are clinically meaningful numbers of cells? 12(1) What are the fundamental limitations to the production of primary cells? 12(2) How rapidly do primary cells grow in culture? 14(1) How are these cells currently produced? 15(1) How are these cells preserved and harvested? 15(1) How are cells best delivered? 15(1) Outline of Book 15(2) Summary 17(1) Further Reading 17(3) Part I Quantitative Cell and Tissue Biology Tissue Organization 20(14) Tissue Components 20(7) Extracellular matrix 20(5) Cells 25(2) Tissue Types 27(2) Epithelial tissues 27(1) Connective tissue 28(1) Other tissue types 28(1) Functional Subunits 29(1) Problem Decomposition 30(3) Summary 33(1) Further Reading 33(1) Tissue Dynamics 34(12) Dynamic States of Tissues 35(1) Homeostasis in Highly Prolific Tissues 35(3) Bone marrow 35(1) Villi in the small intestine 36(1) Skin 37(1) Tissue Repair 38(5) Sequence of events that underlie wound healing 38(2) Engineering wound healing 40(2) Fetal wound healing 42(1) Tissue Dynamics as Interacting Cellular-Fate Processes 43(1) Summary 44(1) Further Reading 45(1) Morphogenesis 46(15) Morphogenic Processes 46(4) Induction 46(2) Important mesenchymal-epithelial interaction 48(1) Adult transdifferentiation 48(1) Gastrulation 48(2) Morphogenic Dynamics 50(7) Initiation of morphogenesis 51(1) Spatio-temporal process 51(1) Final state 52(1) Some cellular processes involved in morphogenesis 52(5) Constraints on Morphogenesis 57(2) Summary 59(1) Further Reading 60(1) Stem Cells 61(13) Basic Concepts 61(4) Stem-cell properties 61(2) Telomeres and self-renewal 63(1) Stem cells and tissue engineering 64(1) Examples of Stem-Cell Systems 65(4) Mesenchymal stem cells (MSC) 65(1) Liver stem cells 66(1) Neuronal stem cells 67(1) Embryonic stem cell: the mother of all cells 67(2) Dynamic Function of Stem-Cell Systems 69(4) Conceptual models of stem-cell proliferative behavior 69(1) Dynamic models of stem cell proliferative behavior 70(3) Summary 73(1) Further Reading 73(1) Cellular-Fate Processes 74(31) Cell Differentiation 74(7) Differentiation as measured by changes in gene expression 74(2) Differentiation as measured by changes in cell function 76(3) Describing cell differentiation mathematically 79(2) Cell Migration 81(6) Underlying biochemical process 81(2) Describing cell migration mathematically 83(4) Cell Division 87(6) Mitotic cell cycle 87(2) Describing the cell cycle mathematically 89(4) Cell Death 93(3) Biological description of apoptosis 93(2) Describing apoptosis mathematically 95(1) Dynamics of Interacting Cellular-Fate Processes 96(7) Effects of cell division on the differentiation process 96(3) Dynamic interplay among differentiation, division, and apoptosis 99(4) Summary 103(1) Further Reading 104(1) Coordination of Cellular-Fate Processes 105(27) Soluble Signals 105(12) Types of growth factors and chemokines 106(1) Sending a paracrine signal 106(3) Receiving a signal 109(2) Processing a signal 111(1) Integrated responses 112(1) Soluble growth-factor receptors 113(3) Malfunctions in soluble signaling 116(1) Cell--Extracellular Matrix Interactions 117(7) Binding to the ECM 118(2) Modifying the ECM 120(1) Analyzing the rate of ECM modification 120(2) Malfunctions in ECM signaling 122(2) Direct Cell--Cell Contact 124(3) Cell junctions in tissues 124(2) Malfunctions in direct cell-cell contact signaling 126(1) Response to Mechanical Stimuli 127(1) Interaction between Signaling Mechanisms 128(2) Multiple-input/single-output model in fibroblast growth-factor-2 signaling 128(2) Summary 130(1) Further Reading 130(2) Part II Cell and Tissue Characterization High-Throughput Biological Data 132(22) Basics of Molecular Biology 133(2) DNA molecule 133(1) Some historical milestones 134(1) Genomics 135(5) Chain termination 135(1) Automated sequencing 136(2) Informatics challenge 138(1) Sequence variation and individuality 139(1) Sequence annotation 139(1) Transcriptomics 140(6) Measuring how genomes are used 140(2) Microarray data analysis 142(3) Using gene-expression profiling 145(1) Proteomics 146(2) Metabolomics 148(2) Phenomics 150(1) Era of Systems Biology 151(1) Summary 152(1) Further Reading 153(1) Cell and Tissue Properties 154(18) Basic Tools 154(5) Microscopy 154(1) Detection of biochemical components 155(1) In vivo imaging 156(3) Measurement of Cell Characteristics 159(9) Cell morphology 159(1) Cell number and viability 160(2) Cell-fate processes 162(1) Measuring cell motility 162(2) Cell function 164(1) Mechanical 165(3) Measurement of Tissue Characteristics 168(2) General appearance 168(1) Cellular component 168(1) Extracellular matrix component 168(1) Function 168(1) Mechanical measurements 169(1) Physical properties 170(1) Summary 170(1) Further Reading 171(1) Cell and Tissue Culture 172(17) Definition and History 172(1) Types of Tissue Culture 173(3) Types of primary culture 173(1) Cell lines 174(1) Immortalized cell lines 175(1) Variation in cell lines 176(1) Media 176(5) Dissolved gases 176(3) Advantages and disadvantages of serum 179(2) Culture Environment and Maintenance of Cells In Vitro 181(3) Tissue-culture environment 181(2) Kinetics of growth 183(1) Characterization of Cell Function in Tissue Culture 184(1) Cryopreservation 184(3) Contaminants 187(1) Summary 187(1) Further Reading 188(1) Gene Transfer 189(19) Gene Transfer for Gene Therapy 189(2) Gene-Transfer Methods 191(7) Retrovirally mediated gene transfer 191(2) Adenovirus-mediated gene transfer 193(3) Nonviral methods 196(2) Retrovirally Mediated Gene-Delivery Process 198(6) Finding the target cell 198(3) Nonspecific virus binding to the target cell 201(2) Specific virus binding to the target cell 203(1) Viral entry 203(1) Gene Transfer for Modifying Cellular Functions 204(2) Summary 206(1) Further Reading 206(2) Part III Engineering Methods and Design Time Constants 208(15) Definition of Time Constants 208(3) General definitions 208(1) Linear systems 209(2) Important Time Constants 211(6) Diffusion 211(3) Chemical reactions 214(1) Fluid flow 215(1) Biological time constants 216(1) Simplifying Dynamic Descriptions 217(4) Basic concept 217(1) Simultaneous diffusion and chemical reaction 218(3) Summary 221(1) Further Reading 222(1) Scaling up for Ex Vivo Cultivation 223(21) Using in vivo Conditions as a Guide 223(3) Respiratory functions of blood 223(2) Perfusion rates in human bone-marrow cultures 225(1) Nutrient transport in liver reactions 226(1) Key Design Challenges 226(6) Delivering oxygen 226(3) Delivering and removing growth factors 229(2) Delivering nutrients and removing waste products 231(1) Fluid Flow 232(3) Uniformity 232(2) Residence-time distributions 234(1) Cellularity 235(3) Geometry of the Microenvironment 238(1) Multivariable Optimization 239(2) Controllable cell-culture variables 239(2) Biological differences among individuals 241(1) Summary 241(2) Further Reading 243(1) Cell Separation 244(8) Basis for Cell Separation 244(1) Physical properties 244(1) Biochemical properties 245(1) Characterizing Cell Separation 245(1) Practiced Cell-Separation Methods 246(4) Treating populations of cells 246(3) Treating cells individually 249(1) Summary 250(1) Further Reading 251(1) Biomaterial Scaffolds 252(18) Biomaterial Properties 252(9) Surface properties 252(4) Bulk properties 256(1) Mechanical properties 256(2) Biological properties 258(3) Types of Biomaterials 261(8) Biologic materials 261(1) Synthetic materials 262(7) Summary 269(1) Further Reading 269(1) Tailoring Biomaterials 270(20) Tailoring Surface Chemistry and Topography 270(2) Subcellular Length Scale ( < 10 μm) 272(5) Surface chemistry 272(2) Bulk chemistry 274(1) Surface topography 275(2) Cellular Scale (10--100 μm) 277(8) Surface chemistry 278(2) Topography 280(5) Supracellular Scale (100 μm-1 cm) 285(1) Influence of chemistry 285(1) Influence of architecture 285(1) Supracellular scale processing 285(1) Functions of Tailored Biomaterials 286(1) Summary 286(1) Further Reading 287(3) Part IV Clinical Implementation Conventional Clinical Approaches to Tissue Dysfunction 290(13) Medical Therapies for Tissue Dysfunction 290(1) Surgical Therapies for Tissue Dysfunction 291(6) Repair 291(1) Replacement 292(3) Reconstruction from an alternative tissue type 295(1) Removal 296(1) Temporary Support Using Extracorporeal Devices 297(1) Tissue-Engineered Therapies 297(5) Mesodermal tissue case study: articular cartilage 297(2) Ectodermal tissue case study: skin 299(2) Endodermal tissue case study: liver 301(1) Summary 302(1) Further Reading 302(1) Host Integration: Interacting Cell-Fate Processes 303(17) Wound-Healing Response 303(2) Hemostasis (seconds to minutes) 304(1) Inflammation (minutes to days) 304(1) Proliferative phase (days to weeks) 304(1) Remodeling phase (weeks to year) 305(1) Angiogenesis 305(3) Basic process 306(1) Modifying angiogenesis 307(1) Immune Response 308(9) Basics 308(2) Characteristic numbers 310(2) Mechanisms of graft rejection 312(2) Immune response in tissue engineering 314(1) Strategies for modifying the immune response 315(2) Summary 317(2) Further Reading 319(1) Producing Tissue-Engineered Therapies 320(15) Product Characterization 320(5) Components 320(1) Safety 321(3) Efficacy 324(1) Preservation 325(5) Freezing 325(3) Drying 328(2) Patent Protection 330(1) Regulation of Tissue-Engineered Products 331(2) Ethical Issues 333(1) Summary 334(1) Further Reading 334(1) A Tissue-Engineering Study Problems 335(40) Part I: Quantitative Cell and Tissue Biology 335(23) Part II: Cell and Tissue Characterization 358(4) Part III: Engineering Methods and Design 362(9) Part IV: Clinical Implementation 371(4) References 375(22) Index 397