Integrative circulatory engineering for regenerative therapy: Dynamic perfusion design and metabolic maturation in...

The adult myocardium couples extreme metabolic demand with a finely tuned coronary microvasculature. Continuous, high-work output is sustained by dense capillary networks, short diffusion distances and dominant reliance on mitochondrial oxidative phosphorylation. By contrast, current cardiac tissue engineering platforms, including scaffold-free myocardial constructs, have achieved robust contraction and basic drug responsiveness but remain constrained by fetal-like cardiomyocyte metabolism and incomplete vascular integration. As pluripotent stem cell-derived cardiomyocytes are driven toward more adult-like phenotypes using metabolic maturation strategies-such as substrate switching from glycolysis to fatty acid oxidation-oxygen consumption rises sharply, exposing the limitations of diffusion-limited culture and underspecified vascular design. This Review proposes integrative circulatory engineering as a framework in which metabolic maturation, vascular architecture and perfusion are co-designed rather than optimized in isolation. Scaffold-free myocardial tissues are highlighted as a particularly suitable platform, enabling close cell-cell contact, self-organized microvascular networks and dynamic remodeling of extracellular matrix. We examine how cell type composition, paracrine crosstalk, matrix mechanics and spatial patterning can be orchestrated to align metabolic demand with vascular supply. Perfusion bioreactors are treated as active components of the engineered circulation, providing controlled oxygen delivery, shear conditioning of endothelial networks, dynamic substrate provision and tunable mechanical loading. The concept is extended to in vitro circulatory units that couple myocardial modules to vascular beds and, in advanced implementations, to other metabolic organs. Finally, translational scenarios, disease modelling opportunities, quality control and computational design are discussed. Together, these elements outline a path toward myocardial tissues that approximate the structural, metabolic and functional complexity required for regenerative therapy and high-fidelity disease modeling.