College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, PR China.
Experimental and Research Animal Institute, Sichuan University, Chengdu 610065, PR China.
Acta Biomater. 2023 Nov;171:466-481. doi: 10.1016/j.actbio.2023.09.045. Epub 2023 Oct 2.
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 (OCXG)) 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 OCXG. 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 OCXG-crosslinked porcine pericardium (OCXG-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 HO, the hemocompatibility, anti-inflammatory, pro-endothelialization and anti-calcification properties of the crosslinked pericardium modified with nanogels loaded with Hep and Ator (OCXG+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.
目前，戊二醛（GA）交联的生物心脏瓣膜（BHV）由于亚急性血栓、炎症、钙化、撕裂和有限的耐久性，仍然不能保证良好的生物相容性和长期有效的耐久性。在这项研究中，从黄原胶中获得了双改性黄原胶（氧化/乙烯基黄原胶（OCXG）），用于随后的双交联和修饰平台构建。通过自由基聚合引入具有抗凝性能的磺酸基，然后在 OCXG 上接枝乙烯基磺酸盐（VS）和乙烯基。利用黄原胶的载药功能，进一步将处理过的心包负载炎症触发的双重载药纳米凝胶（肝素（Hep）和阿托伐他汀（Ator））。OCXG 交联猪心包（OCXG-PP）的机械性能通过席夫碱键形成的第一个网络和第二个 C-C 键网络得到显著改善。由于磺酸基的存在以及纳米凝胶在 HO 刺激下从纳米凝胶中释放出双重药物，载 Hep 和 Ator 的纳米凝胶修饰的交联心包（OCXG+VS+（Hep+Ator）纳米凝胶-PP）的血液相容性、抗炎、促内皮化和抗钙化性能明显优于 GA 交联的 PP（GA-PP）。这种由炎症触发的双交联和顺序释放抗凝/促内皮药物的协同策略可以有效地满足增强生物心脏瓣膜的多种性能和长期耐久性的要求，并为血液接触材料的多功能化提供了一种有价值的模式。
