ISBN-10:
1420073494
ISBN-13:
9781420073492
Pub. Date:
06/23/2010
Publisher:
Taylor & Francis
3D Cell-Based Biosensors in Drug Discovery Programs: Microtissue Engineering for High Throughput Screening / Edition 1

3D Cell-Based Biosensors in Drug Discovery Programs: Microtissue Engineering for High Throughput Screening / Edition 1

by William S. Kisaalita

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Product Details

ISBN-13: 9781420073492
Publisher: Taylor & Francis
Publication date: 06/23/2010
Pages: 404
Product dimensions: 6.40(w) x 9.30(h) x 1.00(d)

About the Author

William S. Kisaalita, PhD is professor and former coordinator of graduate engineering programs at the University of Georgia, where he also directs the Cellular Bioengineering Laboratory. The main research focus of his laboratory is cell-surface interactions with applications in cell-based biosensing in drug discovery. He has published more than 80 peer reviewed and trade press papers and made more than 100 poster and podium presentations. He has received numerous instructional awards including membership in the University of Georgia Teaching Academy. He is a member of ACS, AAAS, ASEE, and SBS. Dr. Kisaalita serves on the editorial boards of The Open Biotechnology Journal and The Journal of Community Engagement and Scholarship.

Table of Contents

Preface xv

Author xvii

Part I Introduction

Chapter 1 Biosensors and Bioassays 3

1.1 Conventional Biosensors 3

1.2 Conventional Biosensor Applications 8

1.2.1 Bioprocess Monitoring and Control 9

1.2.2 Food Quality Control 9

1.2.3 Environmental Monitoring 9

1.2.4 Military Biodefense Applications 12

1.2.5 Clinical Diagnostics 13

1.3 Cell-Based Biosensors versus Cell-Based Assays (Bioassays) 13

1.4 3D Cultures 15

1.4.1 Two-Dimensional (2D) Culture Systems 15

1.4.2 3D Culture Systems 18

1.4.3 Tissue Engineering versus Microtissue Engineering 18

1.5 Concluding Remarks 19

References 19

Chapter 2 Target-Driven Drug Discovery 23

2.1 Drug Discovery and Development 23

2.1.1 Target 23

2.1.2 Hit 23

2.1.3 Lead 24

2.1.4 Candidate 24

2.1.5 Investigational New Drug (IND) Application 24

2.1.6 Drug or Product 24

2.2 The Taxol (Paclitaxel) Discovery Case 25

2.3 The Gleevec (Imatinib Mesylate) Discovery Case 35

2.4 Target-Driven Drug Discovery Paradigm 43

2.4.1 Genomics and Proteomics 44

2.4.2 Combinatorial Chemistry 46

2.4.3 HTS/uHTS 47

2.5 The New Discovery Paradigm Promise 47

2.6 Concluding Remarks 49

References 51

Part II 3D versus 2D Cultures

Chapter 3 Comparative Transcriptional Profiling and Proteomics 57

3.1 Transcriptional Profiling Studies 57

3.2 Comparative GO Annotation Analysis 60

3.3 Proteomics Studies 65

3.4 Concluding Remarks 67

References 74

Chapter 4 Comparative Structure and Function 77

4.1 Complex Physiological Relevance 77

4.2 Cardiomyocyte Contractility 78

4.2.1 Cells and Scaffold 78

4.2.2 Comparative Structure 78

4.2.3 Comparative Function 79

4.2.4 HTS Application Feasibility 80

4.3 Liver Cell Bile Canaliculi In Vitro 82

4.3.1 Cells and Scaffold 82

4.3.2 Comparative Structure and Function 83

4.3.3 HTS Application Feasibility 84

4.4 Nerve Cell Voltage-Gated Calcium Signaling 84

4.4.1 Cells and Scaffold 84

4.4.2 Comparative Structure 86

4.4.3 Comparative Function 87

4.4.4 HTS Application Feasibility 89

4.5 Concluding Remarks 89

References 90

Part III Emerging Design Principles

Chapter 5 Chemical Microenvironmental Factors 97

5.1 Cell Adhesion Molecules 97

5.1.1 Cadherins 97

5.1.2 Selectins 99

5.1.3 The Integrin Superfamily 101

5.1.4 The Ig-Domain-Containing Superfamily of CAMs 103

5.2 Short-Range Chemistry 103

5.2.1 ECM Composition 104

5.2.2 Substrate Surface Chemistry 108

5.3 Long-Range Chemistry 110

5.3.1 Cytokines, Chemokines, Hormones, and Growth Factors 111

5.3.2 Matrix Metalloproteinases (MMPs) 112

5.4 Concluding Remarks 112

References 115

Chapter 6 Spatial and Temporal Microenvironmental Factors 121

6.1 Nano- and Microstructured Surfaces 122

6.2 Scaffolds 122

6.3 Nano and Scaffold-Combined Structures 148

6.4 Temporal Factor 148

6.5 Concluding Remarks 153

References 160

Chapter 7 Material Physical Property and Force Microenvironmental Factors 169

7.1 Basics 169

7.1.1 Young's Modulus, Stiffness, and Rigidity 169

7.1.2 Shear Modulus or Modulus of Rigidity 170

7.1.3 Material Physical Properties Characterization 171

7.1.4 Contractile Force Generation in Cells 177

7.1.5 Force and Geometry Sensing 179

7.2 Stiffness-Dependent Responses 180

7.2.1 Biological and Nonbiological Materials' Stiffness 180

7.2.2 Stiffness-Dependent Morphology and Adhesion 182

7.2.3 Stiffness-Dependent Migration 183

7.2.4 Stiffness-Dependent Growth and Differentiation 185

7.2.5 Substrate Stiffness-Dependent Cell's Internal Stiffness 187

7.3 Force-Dependent Responses 189

7.4 Concluding Remarks 193

References 198

Chapter 8 Proteomics as a Promising Tool in the Search for 3D Biomarkers 207

8.1 Why Search for Three-Dimensionality Biomarkers? 207

8.2 Cellular Adhesions 209

8.3 Signaling Pathways 212

8.4 Overview of Proteomics Techniques 213

8.4.1 Protein Separation by Two-Dimensional Polyacrylamide Gel Electrophoresis (2DE) 213

8.4.2 Peptide Detection 214

8.4.3 Protein Identification 214

8.5 Study Design and Methods 215

8.5.1 Addressing Low-Abundance and Poor Solubility Proteins 215

8.5.2 Biomarker Validation 216

8.6 Concluding Remarks 217

References 217

Chapter 9 Readout Present and Near Future 221

9.1 Readout Present and Near Future 221

9.2 Fluorescence-Based Readouts 224

9.2.1 Jablonski Diagram and Fluorescence Basics 224

9.2.2 Fluorescence Readout Configurations 225

9.3 Bioluminescence-Based Readouts 230

9.4 Label-Free Biosensor Readouts 235

9.4.1 Impedance 235

9.4.2 Surface Plasmon Resonance 242

9.5 Concluding Remarks 245

References 246

Chapter 10 Ready-to-Use Commercial 3D Plates 253

10.1 Introduction 253

10.2 Algimatrix™ 254

10.2.1 Fabrication 254

10.2.2 Complex Physiological Relevance 255

10.2.3 Unique Features 256

10.3 Extracel™ 257

10.3.1 Synthesis 257

10.3.2 Complex Physiological Relevance 257

10.3.3 Unique Features 257

10.4 Ultra-Web™ 259

10.4.1 Fabrication 260

10.4.2 Complex Physiological Relevance 260

10.4.3 Unique Features 261

10.5 Market Opportunities 262

10.5.1 The Opportunity 262

10.5.2 Potential Customers 262

10.5.3 Market Size 263

10.5.4 Market Size Estimation 263

10.6 Concluding Remarks 264

References 265

Part IV Technology Deployment Challenges and Opportunities

Chapter 11 Challenges to Adopting 3D Cultures in HTS Programs 269

11.1 Typical HTS Laboratory and Assay Configurations 269

11.2 Just-in-Time Reagents Provision Model 274

11.3 Limited Value-Addition from 3D Culture Physiological Relevance: Transepithelium Drug Transport and Induction of Drug Metabolizing Enzyme Cases 276

11.3.1 Transepithelium Drug Transport: Caco-2 Assay 276

11.3.2 Induction of Drug Metabolizing Enzymes: Hepatocyte Assays 283

11.4 Paucity of Conclusive Support of 3D Culture Superiority 283

References 285

Chapter 12 Cases for 3D Cultures in Drug Discovery 289

12.1 Three Cases 289

12.2 The β1-Integrin Monoclonal Antibody Case 289

12.2.1 Integrins 289

12.2.2 Monoclonal Antibodies 290

12.2.3 Experimental System: Breast Cancer Cells in Matrigel 293

12.2.4 Treatment with β1-Integrin Inhibitory Antibody Reduced Malignancy in In Vitro-3D and In Vivo, but Not in In Vitro-2D Systems 293

12.3 The Matrix Metalloproteinase Inhibitors Case 294

12.3.1 Extracellular Matrix Metalloproteinases (MMPs) 294

12.3.2 MMP Inhibitors (MMPIs) 295

12.3.3 Experimental System: Fibrosarcoma Cells in Collagen Gels 295

12.3.4 Treatment with Pericellular Proteolysis Inhibitors in 3D Cultures and In Vivo Did Not Prevent Cell Migration or Metastasis 296

12.4 Resistance to the Chemotherapeutic Agents Case 297

12.4.1 Experimental System: Multicellular Tumor Spheroid (MCTS) 297

12.4.2 MCTS More Accurately Approximate In Vivo Resistance to Chemotherapeutic Agents 298

12.5 Concluding Remarks 300

References 301

Chapter 13 Ideal Case Study Design 307

13.1 Rationale for the Case Study 307

13.2 Why Hepatotoxicity? 308

13.2.1 Morphology of the Liver 308

13.2.2 What Is Hepatotoxicity? 308

13.3 Hepatotoxicity and hESC-Derived Hepatocyte-Like Cells 310

13.3.1 Two Reasons Why IADRs Have Attracted Proposed Studies 310

13.3.2 IADRs and Mitochondrial Inner Transmembrane Potential (ΔΨm) 314

13.4 Study Design and Methods 317

13.4.1 Experimental Design and Rationale 317

13.4.2 Cell Culture and Drug Exposure 318

13.4.3 Expression of Drug-Metabolizing Enzymes 318

13.4.4 Alanine Aminotransferase (ATL) Activity Assay 318

13.4.5 Mitochondrial Membrane Potential (ΔΨm) Measurement 318

13.5 Analysis and Expected Results 319

13.5.1 Quality Assessment of HTS Assays 319

13.5.2 Expected Results 319

13.5.3 Potential Pitfalls 320

References 320

Appendix A Patents for 3D Scaffolds 323

References 328

Appendix B Current Drug Targets 331

Appendix C Popular Cell Lines in Drug Discovery 357

C1 HEK 293 357

C1.1 Background 357

C1.2 Morphology and Ploidy 358

C2 CHO 358

C2.1 Background 358

C2.2 Morphology and Ploidy 358

C3 HeLa 358

C3.1 Background 358

C3.2 Morphology and Ploidy 359

C4 HepG2 359

C4.1 Background 359

C4.2 Morphology and Ploidy 360

C5 U2OS 360

C5.1 Background 360

C5.2 Morphology and Ploidy 360

C6 COS-7/CV-1 360

C6.1 Background 360

C6.2 Morphology and Ploidy 361

References 361

Appendix D Stem Cells in Drug Discovery 363

References 368

Index 373

Company Index 385

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