Uniting 4D Printing and Melt Electrowriting for the Enhancement of Regenerative Small Diameter Vascular Grafts

Abstract The development of mechanically robust, cell‐instructive, and seweable small‐diameter (≤ Ø 6 mm) tubular scaffolds remain a major challenge in vascular tissue engineering. Here, a hybrid biofabrication strategy is presented that combines 4D printing of alginate‐methylcellulose (AlgMC) hydrogels with melt electrowritten (MEW) poly(ε‐caprolactone) (PCL) reinforcement to produce tubular constructs with programmable shape‐morphing capacity. The MEW fiber meshes significantly improve mechanical integrity, enabling suturing and perfusion, while preserving the anisotropic swelling behavior required for morphogenesis. Scaffold functionalization using human blood‐derived protein coatings — such as fresh frozen plasma, platelet lysate, and fibrinogen — markedly enhances cellular adhesion and fibroblast proliferation without compromising structural transformation. Biological evaluation using mono and co‐cultures of fibroblasts, endothelial cells (HUVEC), and vascular smooth muscle cells (vSMC) reveals the formation of organized bi‐layers and phenotype‐specific cell morphologies on AlgMC/PCL composites. Notably, a confluent endothelial layer promotes contractile marker expression in vSMC, while vSMC support endothelial coverage in the absence of a growth‐arrested fibroblast feeder layer, indicating reciprocal stabilization. While further optimization is needed to meet the demands of small‐diameter vascular grafts fully, the presented system offers a versatile and promising platform for engineering soft tissue constructs that benefit from topographical guidance, spatially controlled adhesion, and adaptive geometry.