Biomimetic Mechanical Stimulation Enhances Vascular Network Formation in Engineered Cardiac Scaffold

ABSTRACT Myocardial tissue engineering employs cell‐loaded biomaterial scaffolds to repair heart damage, but poor vascularization limits effectiveness. Meanwhile, post‐infarction cardiac tissue suffers severe vascular deficiency, creating a hypoxic microenvironment that critically impairs the viability of engrafted cells. Current engineered tissues have 7‐fold fewer microvessels than natural heart tissue, highlighting the need for better vascularization methods. Mechanical forces can regulate cellular behaviors like proliferation and morphogenesis, especially promote vascular network formation by enhancing endothelial sprouting. Moreover, unlike other blood vessels, cardiovascular vessels perceive mechanical stimulation derived from both hemodynamic forces and cardiac cyclic strain. Inspired by this, we designed a biomimetic mechanical stimulation system by combining a 3D printed myocardial‐like structure scaffold and a frequency and volume adjustable ventilator. This system replicated native myocardial architecture, including cellular alignment, and delivered biomimetic forces with tunable intensity and frequency. By applying human cardiac microvascular endothelial cells (HCMECs) to this system, we proved that biomimetic mechanical stimulation enhances NO production and tube formation through Piezo2 activation. And the therapeutic efficacy of biomimetic mechanical stimulated HCMECs is validated in the MI mice model. The biomimetic mechanical stimulation system replicates the mechanical microenvironment of the heart and provides a new strategy in vascularization improvement of myocardial tissue engineering.