A synergistic strategy of dual-crosslinking and loading intelligent nanogels for enhancing anti-coagulation, pro-endothelialization and anti-calcification properties in bioprosthetic heart valves

Currently, glutaraldehyde (GA)-crosslinked bioprosthetic heart valves (BHVs) still do not guarantee good biocompatibility and long-term effective durability for clinical application due to their subacute thrombus, inflammation, calcification, tearing and limited durability. In this study, double-modified xanthan gum (oxidized/vinylated xanthan gum (O2CXG)) was acquired from xanthan gum for subsequent double crosslinking and modification platform construction. Sulfonic acid groups with anticoagulant properties were also introduced through the free radical polymerization of vinyl sulfonate (VS) and vinyl on O2CXG. Taking advantage of the drug-loading function of xanthan gum, the treated pericardium was further loaded with inflammation-triggered dual drug-loaded nanogel (heparin (Hep) and atorvastatin (Ator)). Mechanical properties of O2CXG-crosslinked porcine pericardium (O2CXG-PP) were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Due to the presence of sulfonic acid groups as well as the dual drug release from nanogels under the stimulation of H2O2, the hemocompatibility, anti-inflammatory, pro-endothelialization and anti-calcification properties of the crosslinked pericardium modified with nanogels loaded with Hep and Ator (O2CXG+VS+(Hep+Ator) nanogel-PP) was significantly better than that of GA-crosslinked PP (GA-PP). The collaborative strategy of double crosslinking and sequential release of anticoagulant/endothelium-promoting drugs triggered by inflammation could effectively meet the requirement of enhanced multiple performance and long-term durability of bioprosthetic heart valves and provide a valuable pattern for multi-functionalization of blood contacting materials. STATEMENT OF SIGNIFICANCE: Currently, glutaraldehyde-crosslinked bioprosthetic heart valves (BHVs) are subject to subacute thrombus, inflammation, calcification and tearing, which would not guarantee good biocompatibility and long-term effective durability. We developed a cooperative strategy of double crosslinking and surface modification in which double-modified xanthan gum plays a cornerstone. The mechanical properties of this BHV were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Inflammation-triggered combination delivery of heparin and atorvastatin has been demonstrated to enhance anticoagulation, anti-inflammatory and pro-endothelialization of BHVs by utilizing local inflammatory response. The collaborative strategy could effectively meet the requirement of enhanced multiple performance and long-term durability of BHVs and provide a valuable pattern for the multi-functionalization of blood-contacting materials.