Sulfide-based, pro-regenerative, anti-inflammatory vascular grafts: Impregnation of slow-released sulfide signals into graft implants

Abstract

Hydrogen sulfide exhibits significant potential in vascular therapy due to its anti-inflammatory, antioxidant, and cytoprotective properties. However, clinical translation is hindered by the absence of biomaterial systems capable of sustained, physiologically relevant sulfide release. To address this, we have developed two coaxial electrospun systems as vascular grafts, which are impregnated with diallyl trisulfide, a stable sulfide donor, enabling controlled sulfide release through a core-shell fiber structure that enhances mechanical properties and cellular interactions. Results show that both polysulfide-impregnated graft systems significantly mitigated inflammation while promoting endothelial cell proliferation and migration in vitro. Over seven days, these grafts released over an order of magnitude more sulfide than controls (non-polysulfide grafts), leading to higher endothelial proliferation and reduced TNF-α-induced inflammation. When implanted as abdominal aorta interposition grafts in rats, grafts maintained full patency at both 1 and 12 weeks. In vivo, compared to controls, polysulfide-impregnated grafts exhibited rapid cell penetration and reduced inflammation at one week. Histological and immunofluorescence analyses confirmed robust endothelialization and a predominantly M2-type macrophage response, indicative of a pro-healing environment. By 12 weeks, polysulfide-impregnated grafts demonstrated reduced capsule formation, uniform extracellular matrix remodeling, and superior integration with neighboring arteries. These findings highlight the potential of polysulfide-impregnated coaxial fibers for sustained sulfide delivery, mitigating anti-inflammation, enhancing early vascular cell function, and long-term graft stability. This strategy represents a promising approach to improving small-diameter vascular graft outcomes by leveraging sulfide-based signaling to prevent thrombosis and inflammation, addressing key limitations of current synthetic grafts. STATEMENT OF SIGNIFICANCE: Current small-diameter vascular grafts often suffer from poor integration and chronic inflammation. This study introduces new designs of coaxial electrospun fiber graft systems that release hydrogen sulfide (H₂S), an endogenous gasotransmitter that supports vascular regeneration and modulates inflammation. By incorporating a polysulfide emulsion into the fiber core, we mimic physiological H₂S delivery. Two crosslinked graft systems were developed, featuring either a protein-based sheath for native adhesion or a functional sheath enabling 'click chemistry' for peptide tethering. In vitro, H₂S release enhanced endothelial cell proliferation and migration while suppressing proinflammatory signaling. In vivo implantation in rat abdominal aortas demonstrated improved endothelialization, reduced inflammation with increased M2 macrophage polarization, and balanced vascular remodeling. This platform offers a bioinspired strategy for improving graft integration and long-term patency.

Keywords: Coaxial fiber; Endothelialization; Sulfide signal.