Natural Biomimetic Myocardial‐Matched Topography Promotes Engineered Heart Tissue Maturation for Cardiovascular Drug Evaluation and Myocardial Infarction Repair

Engineered heart tissues (EHTs) constructed by human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for disease modeling, drug screening, and regenerative therapy. However, the clinical translation is limited by its structural and functional immaturity. Recapitulating the structural organization of native myocardium is crucial for EHT maturation. Here, we introduce a novel biomimetic substrate derived from natural scales of the American shad. We identified that the parallel micro-scale wrinkles on the scale surface possess a consistent width of ∼25 µm, which closely matches the characteristic feature width of clinical adult human myocardium. When cultured on these scales, hiPSC-CMs self-organized into intact EHTs, exhibiting significant functional maturation, demonstrated by enhanced contractility, accelerated calcium handling kinetics, and a metabolic shift toward increased fatty acid oxidation. Furthermore, the hiPSC-CM/Scale platform reliably replicated adult-like responses to cardiovascular drugs, highlighting its relevance for predictive pharmacology. In a mouse model of myocardial infarction, transplantation of the scale-based EHTs as a cardiac patch improved cardiac function, reduced infarct size, promoted angiogenesis, and facilitated electrical integration within the host myocardium. Collectively, our findings establish shad scales as a unique and effective biomimetic platform for producing mature EHTs for therapeutic and drug screening applications.