Biomimetic vascular scaffolds <i>via</i> hybrid 3D printing-phase separation for vascularized cardiac tissue with enhanced perfusion and maturation

Cardiac tissue engineering (CTE) shows great potential for repairing chronic myocardial damage. However, inadequate vascularization in engineered myocardial constructs thicker than 200 μm limits nutrient perfusion and leads to core necrosis, restricting its clinical application. Here, we combine 3D printing with phase separation to fabricate biomimetic vascular scaffolds, polycaprolactone (PCL) tubes, exhibiting enhanced mechanical resilience and biocompatibility. The PCL-tube facilitates the self-assembly of human umbilical vein endothelial cells (HUVECs) into microvascular networks that recapitulate the barrier functions of native vasculature, enabling selective molecular transport while preserving structural integrity. The endothelialized PCL-tube (ECs-PCL-tube) is integrated with cardiomyocyte (CM)-loaded fibrinogen-GelMA (FG) hydrogel through modular assembly to form a multi-scale, vascularized engineered cardiac tissue. The results show that the ECs-PCL-tubes significantly improve cell viability and enhance nutrient perfusion efficiency. Furthermore, the vascularized engineered cardiac tissue exhibited superior CM sarcomere formation, gap junction expression, and contractility, promoting enhanced cell-cell communication. In summary, our study addresses the limitations of lumen collapse and nutrient diffusion in conventional hydrogel systems, offering a scalable and cost-effective solution for constructing functional, vascularized cardiac tissues. This approach holds significant potential for applications in regenerative medicine and drug screening.