Biofunctionalized Vascular Access Graft Improves Patency and Endothelialization in a Porcine Arteriovenous Model

Reliable vascular access remains a major clinical challenge for hemodialysis patients, as expanded polytetrafluoroethylene (PTFE) grafts exhibit poor patency and frequent complications driven by thrombosis and neointimal hyperplasia. Tissue-engineered vascular grafts offer a regenerative alternative but often lack the mechanical resilience required for high-flow arteriovenous (AV) environments. Here, we developed a reinforced, biofunctionalized coaxial electrospun graft comprising a poly(ε-caprolactone) mechanical core and a norbornene-functionalized poly(ethylene glycol) sheath incorporating pro-endothelialization cues. Circumferential PTFE rings were added to improve kink resistance. Grafts were implanted in a porcine AV configuration that recapitulates clinical hemodynamic conditions. Mechanical characterization included compliance, burst pressure, and kink resistance; host remodeling was assessed using histology, immunofluorescence, and multiphoton imaging at 4 weeks. Ring-reinforced electrospun grafts demonstrated a kink radius of 0.187 cm, compliance of 1.04 ± 0.29%/100 mmHg, and burst pressure of 1505 ± 565 mmHg, values all comparable to Gore-Tex PTFE and within industrial performance standards. In vivo, the electrospun grafts showed extensive host cell infiltration, collagen deposition, and formation of smooth muscle-like tissue, whereas PTFE controls remained largely acellular. Immunofluorescence confirmed intramural α-SMA⁺ and CD31⁺ cell populations, and multiphoton microscopy revealed significantly greater collagen and elastin content compared with PTFE (<i>p</i> < 0.05). Collectively, these findings demonstrate that the reinforced electrospun graft maintains mechanical integrity under physiological AV loading while supporting in situ endothelialization and extracellular matrix remodeling in a clinically relevant, large animal model. This work provides one of the first demonstrations of functional tissue regeneration within a fully synthetic, acellular scaffold in a porcine hemodialysis model and advances the translational development of durable, regenerative vascular access grafts that couple mechanical resilience with bioactive healing capacity.