Drug- and cell-based strategies for treating heart disease, including myocardial infarction, face significant roadblocks on the path to the clinic, a primary obstacle being the lack of information-rich in vitro human model systems. Conventional model systems are hampered by at least one of three fundamental limitations which include a) the lack of an in vivo-like microenvironment specifically engineered for the input cell population, b) a relatively low-throughput assays, and c) the low-content nature of output parameters. We describe an integrated computational, design, and experimental strategy for the rational design of a microfabricated high-content screening platform which we term the Cardiac MicroWire (CMW) system. Within this system, we recapitulate the basic microenvironment found in the heart, one which integrates cardiomyocytes, non-myocytes, the extracellular matrix, and dynamic electromechanical forces. Our results highlight the CMW system’s potential as a powerful discovery tool for screening small molecules and transplantable cells toward heart regeneration therapies.

Drug- and cell-based strategies for treating heart disease, including myocardial infarction, face significant roadblocks on the path to the clinic, a primary obstacle being the lack of information-rich in vitro human model systems. Conventional model systems are hampered by at least one of three fundamental limitations which include a) the lack of an in vivo-like microenvironment specifically engineered for the input cell population, b) a relatively low-throughput assays, and c) the low-content nature of output parameters. We describe an integrated computational, design, and experimental strategy for the rational design of a microfabricated high-content screening platform which we term the Cardiac MicroWire (CMW) system. Within this system, we recapitulate the basic microenvironment found in the heart, one which integrates cardiomyocytes, non-myocytes, the extracellular matrix, and dynamic electromechanical forces. Our results highlight the CMW system’s potential as a powerful discovery tool for screening small molecules and transplantable cells toward heart regeneration therapies.