Heart-On-a-Chip for Drug Screening and Disease Modeling

Heart-on-a-chip (HOC) technology has emerged as a powerful approach to replicate the structural, mechanical, and functional properties of the native heart in vitro, enabling physiologically relevant platforms for drug screening and disease modeling. This thesis presents a series of studies focused on the design, fabrication, and validation of HOC systems using biomaterials, bioprinting, and patient-derived stem cells to address key limitations in conventional cardiac models (e.g., animal models). In the first study, composite bioinks were developed by incorporating gelatin methacryloyl, alginate methacrylate, and reduced graphene oxide to create 3D bioprinted cardiac constructs with suitable electromechanical properties. The optimized bioink demonstrated enhanced mechanical strength, printability, and conductivity while supporting high cell viability, alignment, and contractility of multiple cardiac cell types. These ring-shaped constructs were integrated into an automated high-throughput HOC featuring flexible pillar pairs, validating their utility for scalable applications in cardiac research. In the second study, an innovative approach was established for simultaneous and continuous measurement of contractile stresses at micro- and macro-scales using ultrasoft edge-labeled microspherical stress gauges. Embedded within fibrin/Geltrex-based engineered heart tissues (EHTs), these ultrasoft mechanosensors deformed in response to contractile activity, enabling the visualization and quantification of local stress patterns. The pillar deflection was also used as the tissue-scale contractile measurement method. The platform was further validated with pharmacological agents, revealing distinct effects on contractile function and highlighting the importance of extracellular matrix composition and stiffness in modulating contractility. In the third study, a personalized disease model of dilated cardiomyopathy (DCM) was developed using human induced pluripotent stem cell-derived cardiomyocytes from DCM patients. Co-cultured with human cardiac fibroblasts and integrated with fluorescent beads, the EHTs exhibited disease-specific phenotypes, including disrupted cell organization, impaired calcium handling, reduced contractile strength, and ventricular arrhythmias. Inotropic and chronotropic effects were observed upon norepinephrine treatment, confirming the platform’s responsiveness to therapeutic intervention with known effects and its applicability in precision medicine. Collectively, this thesis advances the field of cardiac tissue engineering by integrating biomaterial innovation, mechanosensing technology, and patient-specific stem cells into functional HOC models. These platforms offer high-fidelity tools for evaluating cardiac physiology, understanding disease mechanisms, and facilitating preclinical drug testing.