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

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

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ISBN 9781420073492
Published June 22, 2010 by CRC Press
404 Pages 109 B/W Illustrations

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Book Description

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.

Table of Contents

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
Nano and Scaffold-Combined Structures
Temporal Factor
Concluding Remarks

Material Physical Property and Force Microenvironmental Factors
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
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 β1-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

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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.