Nitrate-Functionalized poly(ε-Caprolactone) Small-Diameter Vascular Grafts Enhance Vascular Regeneration via Sustained Release of Nitric Oxide

Abstract

Artificial small-diameter vascular grafts (SDVG) fabricated from synthetic biodegradable polymers, such as poly(ε-caprolactone) (PCL), exhibit beneficial mechanical properties but are often faced with issues impacting their long-term graft success. Nitric oxide (NO) is an important physiological gasotransmitter with multiple roles in orchestrating vascular tissue function and regeneration. We fabricated a functional vascular graft by electrospinning of nitrate-functionalized poly(ε-caprolactone) that could release NO in a sustained manner via stepwise biotransformation in vivo. Nitrate-functionalized SDVG (PCL/NO) maintained patency following abdominal arterial replacement in rats. PCL/NO promoted cell infiltration at 3-months post-transplantation. In contrast, unmodified PCL SDVG showed slow cell in-growth and increased incidence of neointima formation. PCL/NO demonstrated improved endothelial cell (EC) alignment and luminal coverage, and more defined vascular smooth muscle cell (VSMC) layer, compared to unmodified PCL SDVG. In addition, release of NO stimulated Sca-1+ vascular progenitor cells (VPCs) to differentiate and contribute to rapid luminal endothelialization. Furthermore, PCL/NO inhibited the differentiation of VPCs into osteopontin-positive cells, thereby preventing vascular calcification. Overall, PCL/NO demonstrated enhanced cell ingrowth, EC monolayer formation and VSMC layer regeneration; whilst inhibiting calcified plaque formation. Our results suggested that PCL/NO could serve as promising candidates for improved and long-term success of SDVG implants.

Preparation and performance of random- and oriented-fiber membranes with core–shell structures via coaxial electrospinning

“…If both random- and oriented-fiber membranes could maintain sufficient mechanical support in the early stage when implanted in vivo , there would be sufficient time to ensure new tissue regeneration. According to the literature ( De Valence et al, 2012 ; Zhou et al, 2014 ; Wang et al, 2017 ; Sevostyanova et al, 2018 ; Yin et al, 2020b ; Wen et al, 2020 ; Yang et al, 2021 ), when a graft was implanted in vivo , the endothelial cells gradually formed an intima, and smooth muscle cells and fibroblasts were also arranged along the axial direction of the graft, thus forming new blood vessel tissue. After 3 months, the vascular development was almost complete.…”

Cellular energy supply for promoting vascular remodeling of small-diameter vascular grafts: a preliminary study of a new strategy for vascular graft development

“…It has been previously reported that quick endothelialization plays an essential role in vascular graft survival, as the endothelial cell layer can inhibit thrombosis and inflammation. 49,50,55 At 12 weeks post-implantation, more endothelial cells grew on the AICAR-modified grafts. Interestingly, there was more matrix deposition but without obvious thrombus-like tissues in the AICAR group.…”

“…In all, AICAR exhibited a promising pharmacological therapy to ensure better regenerative potential in vitro.Importantly, in vivo implantation also showed better remodeling processes in the AICAR-modified vascular grafts. It is previously reported that quick endothelialization plays an essential role in vascular graft survival, as the endothelial cell layer can inhibit thrombosis and inflammation 50,51,56. At 12-week Biomaterials Science Accepted Manuscript Open Access Article.…”

Recent Advances in Hydrogel-Mediated Nitric Oxide Delivery Systems Targeted for Wound Healing Applications

“…NO also accelerates endothelium proliferation, as demonstrated in a study with arterial grafts. Although no significant difference was observed after 3 months, NO-releasing arterial grafts exhibited greater endothelium coverage than the non-NO-releasing graft after the first month [ 66 ]. For further information about NO’s role in cell proliferation, the interested reader is referred to reference [ 67 ].…”