Abstract P1104: Mantarray 3D Engineered Muscle Tissue Platform Demonstrates Clinically-relevant Disease Stratification Of An In Vitro Human Duchenne Muscular Dystrophy Model

Abstract

Accurately modeling disease in vitro is vital for the development of new treatment strategies and therapeutics. For cardiac diseases, direct assessment of contractile output is the “ultimate phenotype” and a reliable metric to study overall tissue function, as other ‘proxy’ measurements or biomarkers are not good predictors of muscle strength. Human 3D engineered heart tissues (EHTs) from induced pluripotent stem cells hold great potential for modeling contractile function. However, the bioengineering strategies required to generate these predictive models present limitations for many investigators. Here, we have developed an instrument platform that utilizes 3D EHTs in conjunction with a label-free, magnetic sensing array (Mantarray). The platform enables facile and reproducible fabrication of 3D EHTs using virtually any cell source and is coupled with parallel direct measurement of contractility. This approach enables clinically relevant functional measurements of muscle, stratification of healthy vs. diseased muscle phenotypes, and facilitates therapeutic modality-agnostic compound safety and efficacy screening. We present a 3D model of Duchenne muscular dystrophy (DMD) that utilizes EHTs formed from an isogenic pair of healthy and diseased cells. DMD tissues display functional deficits across numerous metrics of contractility, including force and relaxation kinetics, though beat rate remains unchanged. EHTs remain functional over months in culture and provide a large experimental window to not only study therapeutic effect, but also disease phenotypes that may present at later stages of development and maturity. We show both acute and chronic effects of compounds in EHTs, including a drug (BMS-986094) that failed clinical trials due to unanticipated cardiotoxicity. These data demonstrate a first-and-only commercial platform that integrates individual, well-based control of electrical stimulation across a 24-well plate of tissues to pace muscle constructs, model force-frequency, and enable exercise regimens or damage protocols. Stimulation is coupled with automated assessment of muscle contraction, providing an inclusive, medium-throughput platform for disease modeling and therapeutic discovery.