Heart–Lung-on-a-Chip Featuring Dynamic Flow-Resistance Capture for Drug-Associated Cardiac Dysfunction Assessment under Tumor–Immune-Conditioned Drug Exposure

Abstract

A dual-layer heart–lung-on-a-chip integrating flow-resistance capture was developed to enable the assessment of cardiac responses to lung cancer therapeutics under tumor–immune-conditioned exposure. The compartment incorporates an A549–Jurkat tumor–immune co-culture and exposure to chemotherapy and immune checkpoint inhibitors.. The lower heart compartment incorporates a dynamic flow-resistance capture structure that selectively traps heart organoids with diameters of 150–200 μm, ensuring stable positioning and uniform perfusion. A 4 μm porous membrane separates the compartments, enabling membrane-mediated molecular exchange and providing a simplified inter-compartment exposure model. Three agents—doxorubicin hydrochloride, pembrolizumab, and atezolizumab—were evaluated in monoculture and immune co-culture settings. Cardiac contractile activity was monitored using a custom MATLAB-based image analysis pipeline to quantify the beat rate, inter-beat interval, and heart rate variability. Immune co-culture enhanced drug-induced functional impairment, with the magnitude of immune-co-culture-associated enhancement of drug-induced cardiac functional impairment following the order: doxorubicin > pembrolizumab > atezolizumab. The lung cancer–immune co-culture setting enhanced drug-induced cardiac functional impairment compared with monoculture conditions, revealing differential cardiac functional responses that were not readily apparent in monoculture. This integrated microfluidic system combines multi-organ interactions, precise organoid capture, and automated functional readouts. This offers a reproducible and physiologically relevant approach for preclinical drug safety profiling and has potential applications in precision oncology and personalized medicine.