环氧合酶抑制性一氧化氮供体(CINOD)复合材料对抑制人工血管搭桥术后吻合口狭窄的作用研究

Anastomotic stenosis (AS) after man-made vascular graft bypass restricts the postoperative patency rate. A major step in the pathogenesis of AS is the proliferation of vascular smooth muscle cells (VSMC), which is related to inflammatory reaction. Nitric Oxide (NO) has dual functions of anti-inflammatory reaction and inhibiting proliferation of VSMC. Cyclooxygenase-inhibiting nitric oxide donator (CINOD) is a new class of drugs that combines the actions of the parent COX inhibitor with nitric oxide, and provides controlled releasing of NO in blood. We have successfully combined aspirin into a polyurethane-silk fibroin (PU-SF) prosthetic membrane, which dramatically improved the tissue compatibility of the material and reduced the local inflammatory reaction around the material. .This research is going to combine CINOD into PU-SF membrane, and detect the concentration and speed of the controlled releasing of NO from the material in vitro, investigate its cyto-compatibility, influence to the proliferation of VSMC, effect of the anti-inflammatory reaction and postoperative patency rate after graft bypass. There is no similar report in the world, and this is also the first time that CINOD is used in the biomaterial field, which may make a great breakthrough in the surgical implant material research work, including man-made ureter, biliary and pancreiatic duct.

人造血管搭桥术后的吻合口狭窄是影响搭桥术后远期通畅率的主要原因。吻合口狭窄的主要病理基础为血管平滑肌细胞（VSMC）的增生，炎性反应是其主要调控因素。一氧化氮（NO）具有抗炎性反应和抑制VSMC增生的双重作用，而环氧合酶抑制性一氧化氮供体（CINOD）是NO与阿斯匹林衍生物结合的化合物，能在血液中缓慢释放NO。我们已成功将阿斯匹林合成到聚氨酯-蚕丝粉体（PU-SF）复合人造血管材料中，发现能明显改善复合材料的组织相容性，减轻局部组织的炎性反应。.本课题拟将CINOD合成到PU-SF复合材料中，通过体外实验检测NO从材料中释放的浓度和速率，细胞毒性反应，对VSMC增生的影响，抗炎性反应的作用及人造血管搭桥术后的远期通畅率。该课题目前在国内外未见任何相关的研究报道，同时也是首次将CINOD运用到生物材料中，有可能在外科植入材料领域带来重大突破，包括人造输尿管、胆管和胰管等方面都可借鉴。

人造血管搭桥术后的吻合口狭窄是影响搭桥术后远期通畅率的主要原因，其主要病理基础为炎性反应调控的血管平滑肌细胞（VSMC）的增生。环氧合酶抑制性一氧化氮供体（CINOD）是NO与阿斯匹林衍生物结合的化合物，能在血液中缓慢释放NO，具有抗炎性反应和抑制VSMC增生的双重作用，从而减小吻合口部位的炎性反应。本课题将CINOD成功合成到PU-SF复合材料中，制备出含NpO、Np的PU-SF复合膜，通过体外实验证实只有NpO-PU-SF复合膜具有一定的缓释NO的作用，并且计算出准确的缓释曲线。通过CCK-8细胞毒性试验证实NpO-PU-SF复合膜较PU-SF复合膜及Np-PU-SF复合膜具有更好的抗炎性反应的作用，并且无明显的细胞毒性。在大鼠PC12和VSMC及小鼠RAW264.7细胞系培养在PU-SF，NpO-PU-SF，Np-PU-SF三组人工血管材料表面，证实NpO-PU-SF复合膜具有更好的抑制VSMC增殖的效果。通过动物活体试验证实用NpO-PU-SF复合膜制备的人造血管搭桥术后吻合口狭窄情况明显改善，而且远期通畅率较对照组能够显著提高。本项目创新性的成功合成并证实NpO-PU-SF复合膜能够缓慢释放NO，而且具有良好的生物相容性；首次证实NpO-PU-SF复合膜能够有效抑制炎性反应，抑制VSMC的增殖，促进内皮细胞生长，抑制吻合口的狭窄，增加人造血管搭桥术后的通畅率，从而让直径小于6mm的人造血管应用于临床成为可能，甚至可以应用到心脏搭桥手术中。另外吻合口狭窄问题还存在于器官移植的血管吻合，胆管吻合，胰管吻合以及输尿管吻合等多方面，本课题的成功将为大大促进相关人工植入性器官的研究和发展提供新方向。本课题在研期间培养硕士研究生2名；撰写论文并在SCI期刊上发表1篇论著，申请发明专利5项。