Anti-inflammatory itaconate-loaded, cell-adhesive peptide-conjugated artificial small diameter vascular grafts for blood vessel regeneration.

Abstract

The adverse remodeling is a major cause of the low patency rate of artificial small-diameter vascular grafts (SDVGs), preventing clinical application in vascular disease treatment. To inhibit intimal hyperplasia and achieve rapid endothelialization after implantation, we designed PLCL/OI@REDV grafts composed of poly (l-lactide-co-ε-caprolactone) (PLCL) electrospinning tubes loaded with anti-inflammatory 4-octyl itaconate (OI) and coated with cell-adhesive REDV peptide. PLCL/OI@REDV grafts showed a micro-scale fibrous crosslinked structure and a burst pressure higher than 1600 mmHg. Then, PLCL/OI@REDV membranes were verified to inhibit the smooth muscle cell (SMC) proliferation via the release of OI and to promote the adhesion and proliferation of endothelial cells (ECs) due to REDV modification, contributing to the competitive growth of ECs. Furthermore, it was confirmed that OI showed significant suppression of M1 macrophage polarization, thereby reducing the production of inflammatory factors and reactive oxygen species, which in turn maintained the viability and function of ECs. Subcutaneous implantation in rats demonstrated that PLCL/OI@REDV membranes elicited lower levels of inflammatory and fibrotic reactions than PLCL membranes. In rat abdominal aorta replacement models, compared with PLCL grafts, PLCL/OI@REDV grafts were found to down-regulate the M1 macrophage expression, inhibit excessive SMC proliferation, and promote endothelialization, collectively improving vascular regeneration and patency. In summary, PLCL/OI@REDV represents a promising artificial vascular graft with endogenous regeneration ability. STATEMENT OF SIGNIFICANCE: Small-diameter artificial vascular grafts (SDVGs) hold broad application prospects in clinical hemodialysis, and peripheral or coronary artery bypass grafting. However, they are faced with a high risk of thrombosis and stenosis caused by inflammation, intimal hyperplasia and slow endothelialization. In this study, we prepared a SDVG, PLCL/OI@REDV, composed of poly (l-lactide-co-ε-caprolactone) (PLCL) electrospinning tube loaded with anti-inflammatory and anti-fibrotic 4-octyl itaconate, and coated with cell-adhesive peptide REDV. PLCL/OI@REDV collectively reduced inflammation by suppressing M1 macrophage polarization, inhibited intimal hyperplasia by decreasing the excessive smooth muscle cell proliferation, and facilitated endothelialization via improving endothelial cell adhesion and proliferation, thus increasing patency rate. Therefore, PLCL/OI@REDV is a promising SDVG with endogenous regenerative ability.