Doxorubicin-induced cardiomyopathy is a clinically prevalent pathology, occurring as a sequelae following chemotherapy for cancer patients. In particular, the "first dose" effect has been particularly challenging, given the heterogeneous and multifactorial nature of this pathophysiology. Here, we describe the development of a physiologically relevant in vitro model for cardiotoxicity testing, using human cells. Primary cardiomyocytes, endothelial, and smooth muscle cells were tri-cultured in 2D, or within nano-fibrous scaffolds in a 3D environment, under dynamic nutrient flow, using the Quasi Vivo® system. State-ofthe-art sensor chips were used to detect troponin I levels, 2 h after acute exposure to doxorubicin. We demonstrate a significant improvement in cardiomyocyte viability when grown in a 3D tri-culture environment over a 5-day period and a 10-fold reduction in doxorubicin-induced toxicity. Our tri-culture model can be used as a valuable tool for physiologically relevant assessment of drug-induced cardiotoxicity in vitro.

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