Engineering Microphysiological Models of Human Cardiac and Skeletal Muscle Disease
Authors: McCain Megan Laura 
Published: November 2023

Cardiovascular diseases are the leading cause of death in the United States. Furthermore, unforeseen cardiotoxicity is a prevalent reason for market withdrawal of pharmaceuticals. These two statistics highlight our limited mechanistic understanding of heart disease and our inadequate ability to predict the function of the human heart. One reason for these shortcomings is that researchers in academia and industry have been forced to rely on experimental models, such as rodents or basic cell culture systems, that lack relevance to native human heart tissue. In this talk, I will describe our efforts in engineering microphysiological models of human cardiac tissue as next‐generation platforms for cardiac disease modeling and drug screening. To build these platforms, our research group is focused on maturing and integrating three core technologies: (1) Enhancing the differentiation of human induced pluripotent stem cells (hiPSCs) into cardiac myocytes. Because mammalian cardiac myocytes are post‐mitotic, hiPSC‐derived cardiac myocytes are the only renewable source of human cardiac myocytes that are patient‐specific, which is especially important for modeling inherited cardiomyopathies. However, current cardiac differentiation protocols rely primarily on soluble factors and have limited efficiency and consistency. Thus, we are microfabricating cellular microenvironments designed to enhance the differentiation efficiency of cardiac myocytes from hiPSCs to expand the utility of these cells. (2) Engineering cellular microenvironments that mimic key features of native cardiac tissue. Native cardiac tissue is uniaxially aligned and surrounded by a compliant extracellular matrix. We are utilizing photolithography and tunable hydrogels to mimic key physical features of native cardiac tissue and determine their independent and synergistic effects on cardiac tissue structure and function. (3) Developing quantitative assays for characterizing essential functional outputs, such as contractility. The primary function of cardiac tissue is to contract to pump blood. Cardiac myocytes contract due to the release of calcium from the sarcoplasmic reticulum, which is triggered by depolarization of the plasma membrane. We have developed quantitative assays to measure both contractility and action potential propagation to determine how these parameters are affected by different pathological stimuli. In addition to cardiac tissue, I will also describe our recent efforts in extending our technologies to skeletal muscle tissue as new platforms for modeling human skeletal myopathies. Together, these microphysiological models of human striated muscle tissue have many applications in establishing human disease mechanisms and screening the functional effects of drugs with disease and patient specificity.Support or Funding InformationThis work is funded by the American Heart Association Scientist Development Grant 16SDG29950005, the Eli and Edythe Broad Foundation Innovation Award, the USC Viterbi School of Engineering, and the USC Women in Science and Engineering.