Enhancing Drug Screening with Automated Single-Cell Electrophysiology and Contractility Measurements in iPSC-CMs

About This Grant

Cardiomyocytes (CM) derived from human induced pluripotent stem cells (iPSC-CMs) hold tremendous potential for cell therapy, drug assessment, and understanding the pathophysiology and genetic foundations of cardiac diseases. Despite this promise, new drug failures are predominantly due to safety issues. iPSC-CMs are promising platforms for predicting cardiotoxicity due to their ability to model human cardiac function. Key indicators of cardiac health, such as action potential and contraction force, are essential for distinguishing between healthy and diseased states and are also predictors of cell maturation. However, current techniques, including the gold standard of patch clamping, have significant limitations in this context. We propose an innovative, automated system that integrates proven micro-electromechanical systems (MEMS) sensor pipettes, automation, and machine vision to simultaneously and directly measure electrophysiological properties (e.g., action potentials) and contractile forces in single iPSC-CMs. This system will provide high-content analysis (HCA) at the single-cell level, enabling the evaluation of iPSC-CM and drug-induced cardiotoxicity with unprecedented efficiency. Compared to conventional patch clamping, which requires 2-4 hours per measurement, our system will significantly reduce the measurement time to less than 2 minutes, greatly enhancing performance and usability. The proposed system will democratize these complex measurements, allowing any laboratory technician to conduct them with minimal training, unlike the conventional patch clamping that demands a Ph.D.-level scientist due to its steep learning curve. To validate our hypothesis and advance this technology, we have outlined three specific aims: (1) design and fabrication of the micro-pipette, (2) integration of automation, machine vision, and sophisticated detection mechanisms, and (3) validation and application of the system in iPSC-CM characterization and drug evaluation. This tool will revolutionize the current gold standard, enabling robust electrophysiological and contractility measurements, streamlining data acquisition, and ensuring high performance. Its applications span iPSC-CM research, drug discovery, and personalized medicine, where it can analyze iPSC-CMs generated from a patient's tissue sample to predict individual drug reactions, providing statistically meaningful insights for personalized treatment plans.