title: Bi-content micro-collagen chip provides contractility-based biomechanical readout for phenotypic drug screening with expanded and profiled targets.
abstract: Phenotypic screening has regained momentum in the pharmaceutical industry owing to its success over target-based screening. Most phenotypic screening relies on nonspecific biochemical readouts regarding cellular viability, which hampers the discovery of novel drug mechanisms of action (MOAs). Here we present a Contractility-based bi-Content micro-Collagen Chip (3CChip), which establishes cellular contractility as a biomechanics-related phenotype for drug screening. Bi-content analysis of cell contractility (imaged by iPhone) and viability suggests that the label-free contractility-based analysis exhibits superior sensitivity to compounds targeting contractile elements (e.g. focal adhesion, cytoskeleton), resulting in a enlarged target pool for drug assessment. Six typical readout patterns of drug response are summarized according to the relative positions of the contraction/viability curves, and drug targets are profiled into three categories (biomechanical, biochemical and housekeeping) by 3CChip, which will benefit subsequent target identification. The simple-to-use and effective 3CChip offers a robust platform for micro-tissue-based functional screening and may lead to a new era of mechanism-informed phenotypic drug discovery.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, 10084, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Lyu
authors.initials: L
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.forename: Yanan
authors.initials: Y
authors.lastname: Du
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry*; D003599:Cytoskeleton / Q000187:drug effects*; D055808:Drug Discovery / Q000295:instrumentation*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation* / Q000379:methods*; D004867:Equipment Design; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology; D006801:Humans; D046208:Microchip Analytical Procedures; D051381:Rats; D046888:Tissue Array Analysis
chemical_list: D003094:Collagen