Smart, integrated well-plates for ultra-high-throughput screening of excitation-contraction coupling in tissues

Project Summary Heart disease remains the leading cause of mortality in the world and, drug-induced cardiotoxicity is a major cause of drug failure and withdrawal from the clinic or the market, contributing to the poor overall success rate of drug development programs. In vitro models of cardiac contractility have the potential to generate predictive data earlier in the pipeline to reduce later-stage failure due to cardiotoxicity, and enable discovery and development of effective therapeutics more likely to successfully translate in the clinic. Such cardiac contractility models could serve as valuable high-throughput phenotypic screening tools for target-guided (antagonistic) or target-agnostic discovery of contraction-modulating agents (e.g. small molecules, biologics, RNAi) that enhance or rescue the healthy phenotype. Similarly, a high-throughput cardiac contractility assay system could be used to test possible treatments in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) to identify patient specific “precision medicine” treatments. Unfortunately, no single solution address all of the key needs of the end-user and in existing technologies reporting mechanical endpoints, electrical pacing capabilities have come at the expense of throughput. This STTR proposal will deliver an integrated product addressing these needs by combining an optimized version of Forcyte’s FLECS contractility assay with a proposed novel “Pace-Cap” electrical pacing system designed for the standard well-plate format that will be embedded directly on the microplate lid. In aim, a 24-well prototype of the in-lid electrical pacing mechanism will be developed and validated using calcium flux as a preliminary readout. In aim 2, Forcyte’s contractility platform will be developed into a cardiac micro-tissue evaluation platform and the resulting assay will be used to mechano- functionally validate the Pace-Cap. If successful, this would represent the first all-in-one cardiac contractility assay kit that is both high-throughput and has internal pacing capabilities. Phase 2 work will focus on extending the prototype throughput to 96-wells and developing rapid production strategies.NARRATIVE Heart disease is the world’s leading killer and drug side-effects on the heart are a big reason why drugs fail. The main function of the heart is to pump oxygenated blood through the body by beating in response to an electrical signal, so there is a big need to model this heart function outside of the human body to help discover new treatments and test existing ones. A major problem with existing heart-on-a-chip technologies that measure beating in heart cells outside of the body is that systems that can pace heart cells electrically are very slow and complex. This project aims to build a simpler product that has both a micro well-plate format and an electrical pacing system built into the lid of the microplate. If successful, the product will be simple enough for any researcher to use.