Cyclic Mechanical Loading of Cardiomyocytes via Pressure‐Driven Non‐Planar Membrane Deformation in a Bioreactor System

ABSTRACT We introduce a novel bioreactor system that applies cyclic strain through controlled non‐planar membrane deformation. The membrane deformation is driven by tunable pressure profiles spanning clinically reported end‐diastolic pressure ranges observed in physiological and disease‐associated conditions. Applied pressure was quantitatively related to spatial membrane strain through three‐dimensional membrane reconstruction, enabling characterization of the mechanical environment at the cell–substrate interface. Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) are cyclically loaded for three days and analyzed for structural, functional, and transcriptomic responses. The bioreactor system preserves cellular viability under pressures ranging from 0–15 mmHg. Cells exposed to physiological preloads (5 and 10 mmHg) exhibit functional and transcriptional changes associated with cardiomyocyte maturation, including cell elongation and altered contractile waveform kinetics, while those under pathological preloading conditions (15 mmHg) show activation of stress‐related and catabolic signaling pathways commonly reported in mechanical overload and heart failure models. This platform enables precise modeling of myocardial biomechanics and offers a robust tool for investigating cardiomyocyte response across health and disease states.