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

3D Cell-Based Biosensors in Drug Discovery Programs

Microtissue Engineering for High Throughput Screening, 1st Edition

By William S. Kisaalita

CRC Press

404 pages | 109 B/W Illus.

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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

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™

Extracel™

Ultra-Web™

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

Index

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.

Subject Categories

BISAC Subject Codes/Headings:
MED009000
MEDICAL / Biotechnology
MED071000
MEDICAL / Pharmacology
SCI010000
SCIENCE / Biotechnology