Heparinized Elastomeric Nanofibrillar Grafts: Mechanically Tunable, Cell-Supportive, and Thromboresistant Vascular Substitutes.

The clinical success of vascular grafts relies on three main prerequisites: artery-tuned mechanics, a cell-supportive microstructure, and a thromboresistant interface. Most current solutions address only a subset of this triad and equate mechanical matching with compliance alone, which can lead to disturbed hemodynamics, maladaptive mechanobiology, and adverse graft-host biochemical interactions that frequently culminate in clinical complications and graft failure. This study presents polyurethane-based heparin-functionalized elastomeric nanofibrillar grafts (H-ENGs) that integrate all three prerequisites while allowing multi-parameter mechanical mimicry. To address the principal failure mode of early thrombosis, a small fraction of polyethyleneimine (PEI) is added to the ENG electrospinning solution to form P-ENGs, enabling one-step covalent heparin conjugation to form H-ENGs. The decoupled design of the ENG platform preserves the biomimetic microstructure and mechanics following PEI incorporation and heparinization, enabling adaptable, indication-specific optimization. In vitro, H-ENGs demonstrate strong benchtop performance, exhibiting a suture retention strength of 2.91 ± 0.40 N and a burst pressure of 634 ± 66 mmHg, both above physiological requirements. Relative to non-heparinized ENG controls, H-ENGs reduce the water contact angle from 117.3° to 90.6°, platelet adhesion density from 410 ± 61 to 35 ± 9 platelets/mm2, and static blood clot formation from 1.2 ± 0.4 to 0.3 ± 0.8 mg/cm2, consistent with markedly improved hemocompatibility. Pilot porcine abdominal aorta interposition studies (n = 2) confirm surgical feasibility, immediate anastomotic hemostasis, and absence of suture-hole bleeding. At two weeks, H-ENGs remain patent, show no aneurysmal degeneration, and retain artery-like pulsatility (1.99 ± 1.41% vs 1.72 ± 1.82%). Ex vivo mechanical analysis confirms preservation of biomimetic mechanics, while XPS shows persistence of the S 2p signal, indicating heparin stability under high-flow conditions. Collectively, these findings suggest that H-ENGs satisfy the three core requirements for clinically successful vascular grafts and warrant further evaluation in more extensive preclinical studies.