可降解涂层紫杉醇洗脱支架在猪外周动脉模型中的研究

发布时间：2018-05-25 20:01

本文选题：可降解涂层 + 药物洗脱支架　；参考：《清华大学》2016年博士论文

【摘要】：尽管药物洗脱支架与金属裸支架相比,可以有效抑制新生内膜的增生,降低支架内再狭窄(in-stent restenosis,ISR)的发生率,但药物释放完毕后,永久存留的聚合物涂层可能引起内皮延迟愈合及炎症反应,从而导致晚期支架内血栓形成以及再狭窄的发生。聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid),PLGA)是一种可降解的功能高分子有机化合物,其降解产物为乳酸和羟基乙酸,同时也是人体代谢的正常副产物,将其作为涂层材料,理论上可以解决因聚合物涂层长期存留而引起的问题。本研究包括两个部分的工作,第一部分对以PLGA作为涂层材料的自扩张式可降解涂层紫杉醇洗脱支架28天内的体内药代动力学进行研究。实验采用猪外周动脉模型,运用液相色谱-质谱联用技术(liquid chromatograph-mass spectrometer,LC-MS),从药物洗脱支架残余药量、药物洗脱支架植入段血管药量、药物洗脱支架植入段临近血管药量及血药浓度等方面对自扩张式可降解涂层紫衫醇洗脱支架的药代动力学进行评价。结果显示,自扩张式可降解涂层紫杉醇洗脱支架能够实现药物的准确、稳定以及持续释放。第二部分对自扩张式可降解涂层紫杉醇洗脱支架在28天、90天、180天抑制新生内膜增生的有效性和安全性进行研究。实验采用随机对照双盲设计,运用支架过度扩张建立的猪外周动脉再狭窄模型,以自扩张式金属裸支架作为对照,运用定量血管造影(quality vascular angiography,QVA)、组织病理、扫描电镜等方法,从最小管腔直径、管腔丢失、新生内膜面积、面积狭窄百分率等方面对自扩张式可降解涂层紫杉醇洗脱支架抑制新生内膜增生的有效性进行评价,而从内皮化积分、炎症积分、损伤积分等方面对其安全性进行评价。结果显示,自扩张式可降解涂层紫杉醇洗脱支架能够有效抑制新生内膜的增生,并且具有安全性。本研究通过动物实验验证了国内企业自主研发的自扩张式可降解涂层紫杉醇洗脱支架既能有效控制药物的释放,又具有抑制新生内膜增生的有效性和安全性,为解决外周动脉疾病支架内再狭窄的发生提供了新的手段,为进一步的临床研究提供了参考性资料。
[Abstract]:Although drug-eluting stents can effectively inhibit neointimal proliferation and reduce the incidence of restenosissis-in-stent ISR compared with bare metal stents, after drug release, The permanent retention of polymer coating may lead to delayed healing and inflammation of the endothelium, leading to late thrombosis and restenosis in the stent. Poly (lactic actic-co-glycolic acid) PLGA is a biodegradable functional polymer organic compound. The degradation products of PLGA are lactic acid and glycolic acid, as well as normal by-products of human metabolism, which are used as coating materials. Theoretically, the problems caused by long-term retention of polymer coatings can be solved. In the first part, the pharmacokinetics of a self-expandable biodegradable paclitaxel eluting stent with PLGA as coating material was studied in vivo for 28 days. A porcine peripheral artery model was used. Liquid chromatography-mass spectrometry (LC-MS) technique was used to elucidate the residual drug content of the stents and the vascular volume of the drug-eluting stents. The pharmacokinetics of the drug-eluting stents was evaluated from the aspects of drug volume and blood concentration in the vicinity of the drug-eluting stents. The results showed that the self-expandable biodegradable paclitaxel eluting stent could achieve the accuracy, stability and sustained release of the drug. In the second part, the efficacy and safety of self-expandable biodegradable paclitaxel eluting scaffold in inhibiting neointimal hyperplasia at 28 days and 90 days after 180 days were studied. A double-blind randomized controlled design was used to establish a porcine model of peripheral artery restenosis by excessive dilatation of stents, and self-expanding bare metal stents were used as controls. Quantitative angiography (QA), histopathology, scanning electron microscopy (SEM) and so on were used. The effectiveness of the self-expandable biodegradable paclitaxel eluting stent in inhibiting neointimal hyperplasia was evaluated from the aspects of minimum lumen diameter, lumen loss, neointimal area and area narrowing percentage, while the endothelialization score and inflammation score were used to evaluate the efficacy of the self-expandable biodegradable paclitaxel eluting stent in inhibiting neointimal hyperplasia. Its safety was evaluated in terms of damage score and so on. The results showed that the self-expandable biodegradable paclitaxel eluting scaffold could effectively inhibit neointimal proliferation and was safe. The animal experiments proved that the self-expandable biodegradable paclitaxel eluting scaffold developed by domestic enterprises can effectively control the release of the drug, and has the efficacy and safety of inhibiting neointimal hyperplasia. It provides a new method to solve the restenosis in the stents of peripheral artery disease and provides reference materials for further clinical research.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R543.5;R-332

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