Multiplexed quantitative measurements of field potential and contractility on biomimetically-matured hPSC-CMs

Curi Bio Inc, Seattle WA

Investigators

Abstract

PROJECT SUMMARY The development of new drugs is a costly and time-consuming process (~$2.5 billion over 5-10 years) with a very low success rate where only 1 out of 10,000 candidates will ever reaches the market. One of the leading causes for this issue is the cardiotoxicity of drug candidates, wherein a drug has an off-target effect of causing cardiac arrhythmias. As a result, significant effort and resources have been allocated to create more predictive preclinical and in vitro drug screening platforms. Human derived induced pluripotent cardiac myocyte stem cells (hPSC-CMs) are a promising tool to address this problem, but their relative lack of phenotypic maturity remains a barrier to their wide adoption. Some platforms focus on mimicking the structural (e.g. biomimetic cultureware), mechanical (e.g. cell and tissue stretching devices), and electrochemical (e.g. microelectrode array platforms) cues of the extracellular matrix of the tissue to improve hPSC-CM maturity. While these cues are vital to the tissue development, they are oftentimes incompatible with the high-throughput assays that are required by drug developers. Further, measuring maturity within an assay is a challenge. Contractility is considered to be a highly- accurate method of measuring maturity, state of differentiation, and general health of cardiomyocytes. The currently available measurement tools cardiomyocytes (CMs) contractility can be generally grouped as either impedance-based or microscopy-based (such as traction force microscopy; TFM). Impedance-based measurements are often fast and accurate but lacking in terms of capturing quantitative information, as impedance measures only cell shape changes and uses that as proxy of the cell contraction. In contrast, TFM techniques are capable of quantifying CM contraction, but it is laborious and incompatible with high-throughput platforms. Indeed, a critical need of the research community is a multiplexed platform that measures contractility in a high-throughput and quantitative fashion in an environment that applies extracellular cues to drive the development and maturity of CMs. NanoSurface Biomedical?s mission is to develop a first-of-its kind microelectrode array device that provides a biomimetic culture environment and is multiplexed with quantitative contractility measurement. We term this device the ?MP-ForceMEA?. The MP-ForceMEA will use an innovative strain-gauge sensor with an MEA platform and will represent a novel instrument capable of simultaneous detection of electrophysiology and contractility in a highly parallel, high-throughput, and scalable manner. Phase 1 activities will result in the development of a single-well novel platform compatible with standard end-point assays, and this work will then serve as the basis for progression into Phase 2, where the device will be scaled up to high-throughput assay formats. The resulting work will greatly improve the cost, efficiency, and safety of drug development and speed to market new lifesaving drugs.