Heparin and adipose stem cell exosome functionalization improves performance of SIS/PLCL small-diameter vascular grafts.

INTRODUCTION: The development of small-diameter vascular grafts remains clinically challenging. Decellularized small intestinal submucosa (SIS) is a promising candidate biomaterial for vascular grafts owing to the satisfactory biocompatibility and low immunogenicity. Nevertheless, its efficacy remains limited, primarily by thrombosis or dilation-induced failure. OBJECTIVES: This study presents a novel SIS / Poly (L-Lactide-co-caprolactone) (PLCL) composite graft co-functionalized with heparin and human adipose-derived stem cell exosomes (HASCs-Exo) , aiming to meet the standards of blood vessel replacement. METHODS: In this study, we fabricated SIS/PLCL hierarchical fibrous grafts via electrospinning, followed by a dual-functionalization strategy to load heparin and HASCs-Exo. The grafts were then evaluated in vitro and in vivo. RESULTS: Comprehensive in vitro characterization revealed that the composite graft possessed optimal surface topography, enhanced tensile strength, sustained in situ release of HASCs-Exo, and favorable hemocompatibility. In a rat subcutaneous implantation model, the HASCs-Exo-modified SIS/PLCL grafts exhibited significantly improved biocompatibility, as evidenced by reduced inflammatory cell infiltration compared to unmodified SIS/PLCL grafts. In rabbit carotid artery replacement experiments, HASCs-Exo-modified SIS/PLCL grafts demonstrated superior performance, evidenced by a higher patency rate on Doppler ultrasound and enhanced endothelialization confirmed by CD31 and eNOS immunofluorescent staining. Mass spectrometry and Western blot showed that ATP2B1 was enriched in HASCs-Exo. Mechanistic studies further demonstrated that HASCs-Exo promoted endothelial cell functionality by upregulating eNOS and VEGF through ATP2B1. CONCLUSION: This study presents a novel strategy that combinines HASCs-Exo with SIS/PLCL grafts to fabricate functional small-diameter vascular grafts, achieving dual optimization of mechanical integrity and endothelialization capacity.