Patient-Specific 3D Heart-On-a-Chip Model of Dilated Cardiomyopathy with Embedded Bead-Based Mapping of Tissue Contractility
Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation, with a 50% risk of progression to heart failure within five 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 ventricular tachycardia in DCM tissue and highlighting functional hallmarks of the disease. Finally, the model was validated using a drug with known inotropic and chronotropic effects (i.e., norepinephrine). Our platform demonstrated great potential in drug screening, disease modeling, and personalized medicine.