Engineering Smart Biomaterial Interfaces for iPSC-CM Maturation: A Biophysical and Metabolic Reprogramming Approach to Regenerative Cardiac Medicine

The maturation of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) remains a major translational bottleneck in regenerative cardiac medicine, as current differentiation platforms yield electrophysiologically and metabolically immature phenotypes. This review explores emerging strategies to engineer "smart" biomaterial interfaces that actively instruct iPSC-CM maturation through synergistic biophysical and metabolic reprogramming. By integrating nanotopographical patterning, mechanoelectric coupling, and tunable substrate stiffness with metabolic interventions such as mitochondrial substrate optimization and fatty acid oxidation induction, the literature reveals consistent links between cell-matrix crosstalk, sarcomeric organization, calcium handling, and oxidative metabolism. Recent advances in bioactive scaffolds and extracellular vesicle (EV)-functionalized hydrogels are highlighted as platforms capable of approximating key features of the myocardium's native electromechanical and bioenergetic environment. Across two- and three-dimensional culture systems, this review identifies recurring maturation patterns, persistent gaps in metric standardization and long-term phenotype stability, and ongoing limitations related to scalability and translational implementation. Collectively, the findings synthesized here indicate that convergence between biomaterial engineering and metabolic programming represents a critical design principle for advancing iPSC-CMs toward functionally mature, clinically relevant phenotypes. This integrated approach enhances the fidelity of iPSC-CMs for disease modeling, drug screening, and regenerative cardiac therapies.