Inflammation-triggered dual release of nitroxide radical and growth factor from heparin mimicking hydrogel-tissue composite as cardiovascular implants for anti-coagulation, endothelialization, anti-inflammation, and anti-calcification.
Inflammation-triggered dual release of nitroxide radical and growth factor from heparin mimicking hydrogel-tissue composite as cardiovascular implants for anti-coagulation, endothelialization, anti-inflammation, and anti-calcification.
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DOI：
10.1016/j.biomaterials.2022.121761
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发表时间：
2022-08
期刊：
影响因子：
14
通讯作者：
Fan Yang;Gaoyang Guo;Yunbing Wang
中科院分区：
文献类型：
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作者：
Fan Yang;Gaoyang Guo;Yunbing Wang
由异质组织（HT）制成的心血管植入物在临床上经常面临过早失效，如血栓形成、炎症和钙化。在此，我们报告了一种水凝胶-组织复合材料，其表现出多种组分的炎症指导性释放，以防止凝血、促进内皮生长和调节活性氧（ROS）稳态。由MMP响应性片段交联的肝素模拟聚合物组成的水凝胶通过ROS可裂解的硼酸酯键负载有氮氧自由基，并通过静电吸引负载有血管内皮生长因子（VEGF）。据报道，基质金属蛋白酶（MMP）在对外来植入物的炎症反应中表现出升高的表达，其降解水凝胶并导致肝素模拟聚合物和VEGF的释放，增强其抗凝能力并加速其上内皮细胞的生长。该复合物可以感知炎症环境中存在的氧化生物信号，并随后释放ROS清除剂，ROS平衡的调节。小鼠皮下植入表明该复合物可使免疫反应向抗炎状态转变，大鼠皮下植入表明其具有抗钙化作用，通过覆膜支架递送的组织血管内植入进一步证实了其增强的血液相容性和内皮化效果。目前的研究结果表明，将功能性水凝胶结合到组织中，巧妙地利用宿主反应来控制多种活性物质的释放，是增强基于HT的心血管植入物的抗凝、内皮化、抗炎和抗钙化功能的可行方法。
Cardiovascular implants made from heterogeneous tissues (HT) often clinically face premature failures such as thrombosis, inflammation, and calcification. Herein, we report a hydrogel-tissue composite exhibiting inflammation instructive release of multiple components towards preventing coagulation, promoting endothelial growth, and modulating reactive oxygen species (ROS) homeostasis. The hydrogel composed of MMP-responsive segment-crosslinked heparin mimicking polymer was loaded with a nitroxide radical via ROS cleavable boronic ester bonds and vascular endothelial growth factor (VEGF) via electrostatic attraction. Matrix metalloproteinase (MMP), which reportedly showed elevated expression in inflammation response to foreign implant degraded the hydrogel and led to the release of heparin mimicking polymer and VEGF, enhancing its anti-coagulation capacity and accelerating the growth of endothelial cells on it. In addition, the composite could sense oxidation biosignal present in the inflammation environment and subsequently release a ROS scavenger for auto-regulation of ROS balance. Subcutaneous implantation in mice suggested that the composite could steer the immune response toward an anti-inflammation state and subcutaneous implantation in rats suggested an anti-calcification effect of it. The enhanced hemocompatibility and endothelialization effectsin vivowere further confirmed by the endovascular implantation of tissues via membrane-covered stent delivery. The current findings demonstrate that the incorporation of functional hydrogel into the tissue sophistically exploiting host response for controlled release of multiple active cargos is a feasible approach to boost the anticoagulant, endothelialization, anti-inflammatory, and anti-calcification functions of HT-based cardiovascular implants.