Advances in genomics and combinatorial chemistry during the past two decades inspired innovative technologies and changes in the discovery and pre-clinical development paradigm with the goal of accelerating the process of bringing therapeutic drugs to market. Written by William Kisaalita, one of the foremost experts in this field, 3D Cell-Based Biosensors in Drug Discovery Programs: Microtissue Engineering for High Throughput Screening provides the latest information - from theory to practice - on challenges and opportunities for incorporating 3D cell-based biosensors or assays in drug discovery programs.
The book supplies a historical perspective and defines the problem 3D cultures can solve. It also discusses how genomics and combinatorial chemistry have changed the way drug are discovered and presents data from the literature to underscore the less-than-desirable pharmaceutical industry performance under the new paradigm. The author uses results from his lab and those of other investigators to show how 3D micro environments create cell culture models that more closely reflect normal in vivo-like cell morphology and function. He makes a case for validated biomarkers for three-dimensionality in vitro and discusses the advantages and disadvantages of promising tools in the search of these biomarkers. The book concludes with case studies of drugs that were abandoned late in the discovery process, which would have been discarded early if tested with 3D cultures.
Dr. Kisaalita presents evidence in support of embracing 3D cell-based systems for widespread use in drug discovery programs. He goes to the root of the issue, establishing the 3D cell-based biosensor physiological relevance by comparing 2D and 3D culture from genomic to functional levels. He then assembles the bioengineering principles behind successful 3D cell-based biosensor systems. Kisaalita also addresses the challenges and opportunities for incorporating 3D cell-based biosensors or cultures in current discovery and pre-clinical development programs. This book makes the case for widespread adoption of 3D cell-based systems, rendering their 2D counterparts, in the words of Dr. Kisaalita quaint, if not archaic in the near future.
William S. Kisaalita (University of Georgia Athens USA)
Country of Publication:
13 June 2017
Professional and scholarly
Introduction Biosensors and Bioassays Conventional Biosensors Conventional Biosensor Applications Cell-Based Biosensors versus Cell-Based Assays (Bioassays) 3D Cultures Concluding Remarks Target-Driven Drug Discovery Drug Discovery and Development The Taxol (Paclitaxel) Discovery Case The Gleevec (Imatinib Mesylate) Dicovery Case Target-Driven Drug Discovery Paradigm The New Discovery Paradigm Promise Concluding Remarks 3D versus 2D Cultures Comparative Genomics and Proteomics Transcriptional Profi ling Studies Comparative GO Annotation Analysis Proteomics Studies Concluding Remarks Comparative Structure and Function Complex Physiological Relevance Cardiomyocyte Contractility Liver Cell Bile Canaliculi In Vitro Nerve Cell Voltage-Gated Calcium Signaling Concluding Remarks Emerging Design Principles Chemical Microenvironmental Factors Cell Adhesion Molecules Short-Range Chemistry Long-Range Chemistry Concluding Remarks Spatial and Temporal Microenvironmental Factors Nano- and Microstructured Surfaces Scaffolds Nano and Scaffold-Combined Structures Temporal Factor Concluding Remarks Material Physical Property and Force Microenvironmental Factors Basics Stiffness-Dependent Responses Force-Dependent Responses Concluding Remarks Proteomics as a Promising Tool in the Search for 3D Biomarkers Why Search for Three-Dimensionality Biomarkers? Cellular Adhesions Signaling Pathways Overview of Proteomics Techniques Study Design and Methods Concluding Remarks Readout Present and Near Future Readout Present and Near Future Fluorescence-Based Readouts Bioluminescence-Based Readouts Label-Free Biosensor Readouts Concluding Remarks Ready-to-Use Commercial 3D Plates Introduction Algimatrix (TM) Extracel (TM) Ultra-Web (TM) Market Opportunities Concluding Remarks Technology Deployment Challenges and Opportunities Challenges to Adopting 3D Cultures in HTS Programs Typical HTS Laboratory and Assay Configurations Just-in-Time Reagents Provision Model Limited Value-Addition from 3D Culture Physiological Relevance: Transepithelium Drug Transport and Induction of Drug Metabolizing Enzyme Cases Paucity of Conclusive Support of 3D Culture Superiority Cases for 3D Cultures in Drug Discovery Three Cases The ss1-Integrin Monoclonal Antibody Case The Matrix Metalloproteinase Inhibitors Case Resistance to the Chemotherapeutic Agents Case Concluding Remarks Ideal Case Study Design Rationale for The Case Study Why Hepatotoxicity? Hepatotoxicity and hESC-Derived Hepatocyte-Like Cells Study Design and Methods Analysis and Expected Results Appendix A: Patents for 3D Scaffolds Appendix B: Current Drug Targets Appendix C: Popular Cell Lines in Drug Discovery Appendix D: Stem Cells in Drug Discovery Index
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.