Integrative approaches in cardiac tissue engineering: Bridging cellular complexity to create accurate physiological models

Recent innovations in cardiac tissue engineering (TE) have yet to fully harness integrative genomic mapping of cellular niches to replicate the spatially organized cellular communities and extracellular matrix (ECM) microniches of the heart. Bridging this gap will allow the development of robust platforms for cardiac regeneration and disease modeling. Recapitulating this complexity, including hierarchical vascularization, functional innervation, and immune integration, remains a fundamental challenge in precision cardiac tissue engineering. While iPSC-derived models, engineered biomaterials, and multi-scale 3D bioprinting have advanced creation of cardiac constructs, most of them still lack the optimal maturity and functional multicellular crosstalk. To address these gaps, this review critically evaluates our current understanding of cardiac cellular/ECM heterogeneity and synthesizes progress in recapitulating these features. By aligning challenges with emerging innovations, we provide a roadmap to drive cardiac tissue engineering innovations toward clinically transformative solutions.