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

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.