Patient-Derived 3D Heart-On-a-Chip Model of Dilated Cardiomyopathy With Embedded Bead-Based Mapping of Tissue Contractility.

Abstract

Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation, with a 50% risk of progression to heart failure within 5 years. Conventional disease modeling approaches fail to recapitulate the sophisticated function of the human heart. Alternatively, heart-on-a-chip (HOC) platforms enable real-time monitoring of disease progression and drug responses using miniaturized engineered heart tissues. Here, we developed a functional HOC model using patient-specific human induced pluripotent stem cells (hiPSCs), reprogrammed from the patients' blood samples. The chip contains two cell-seeding chambers with flexible silicone pillars to support tissue formation. Healthy and DCM hiPSCs were differentiated into cardiomyocytes, combined with an optimized ratio of human cardiac fibroblasts, encapsulated in a fibrin/Geltrex hydrogel (containing fluorescent beads), and seeded in the device chambers. The tissue gradually compacted and started beating spontaneously. Immunofluorescence assay revealed structural abnormalities in DCM tissues, including reduced cell alignment and elongation. The tissue functional responses (e.g., calcium transients and beating) were investigated after 2 weeks of culture, revealing arrhythmia-like behavior in DCM tissue and highlighting functional hallmarks of the disease. Finally, the platform was validated using norepinephrine to assess the functional responsiveness of the tissues. These results demonstrate the potential of this system for disease modeling and future patient-specific investigations.