Novel non-glutaraldehyde bioprosthetic heart valve construction strategy based on ATRP with enhanced anticoagulant and anti-calcification properties

Abstract

Minimally invasive transcatheter heart valve replacement (THVR) has provided a more convenient and effective means for curing heart valve diseases and defects. Bioprosthetic heart valves (BHVs), with superior hemodynamic performance and no need for long-term anticoagulation, have become the first choice for THVR in recent years. However, almost all the clinically used BHVs are crosslinked by glutaraldehyde, and due to calcification, inflammation, difficulty in endothelialization and other factors, the service cycle of these glutaraldehyde crosslinked BHVs is affected, thus limiting their further application. To avoid defects of these glutaraldehyde crosslinked BHVs, a novel non-glutaraldehyde synergistic crosslinking and modification strategy based on ATRP (atom transfer radical polymerization) has been developed in this study. Firstly, the decellularized porcine pericardium (D-PP) is grafted with an alkyl bromine group (Br-PP) to initiate the ATRP reaction, and then the four-arm double-bond substance is used to achieve crosslinked PP (PT-PP) through the in situ ATRP reaction to endow PT-PP with good mechanical properties. Finally, utilizing the advantage of controllable and active polymerization of ATRP, the surface of PT-PP can be further functionalized with sulfonic acid groups by the secondary polymerization to obtain the functionalized PP (PT-BS-PP). The feasibility of non-glutaraldehyde crosslinked and functionalized PPs has been further systematically evaluated as a potential leaflet material of BHVs. Good biocompatibility, superior anticoagulation properties, minimal immune rejection, enhanced endothelialization potential and excellent anti-calcification effects of the functionalized PT-BS-PP have been proven by in vitro and in vivo investigations, suggesting that PT-BS-PP is a great potential candidate for the further clinical applications of BHVs.