Development of a Multi-Organ Microphysiological (MPS) Model to Study Age-Related Comorbidities.

Comorbidities, the concurrent presence of two or more medical conditions, present significant challenges for diagnosis and treatment. Skeletal muscle sarcopenia and hypertrophic cardiomyopathy (HCM) are two distinct yet interrelated conditions, often co-existing in elderly individuals and exacerbating disease progression. Mechanistic understanding of sarcopenia-HCM comorbidity is limited, largely based on clinical correlation analyses and a few available mouse models. To facilitate pathophysiological research and accelerate therapeutic development, a more efficient human-relevant in vitro model is needed. This study presents a human-based sarcopenia-HCM comorbidity model in a multi-organ microphysiological system (MPS) that incorporates primary human hepatocytes, human induced pluripotent stem cells (hiPSC)-derived skeletal muscle and cardiomyocytes. The phenotypes for sarcopenia and HCM were first induced and characterized in single-organ systems, then assembled and analyzed in a multi-organ MPS, maintained in circulated serum-free medium. The functional phenotypes of skeletal muscle, cardiomyocytes, and hepatocytes, as well as inter-organ interactions in this organ-chip system align with clinical reports. This MPS comorbidity platform will enable pathophysiological investigation of sarcopenia, HCM, their comorbidity, and testing of therapeutic efficacy, toxicity, and pharmacokinetics. This study highlights how multi-organ MPS can revolutionize preclinical research as a human-relevant, cost-effective, and ethical alternative for studying comorbidities.