新型可降解聚合物血管支架的体内血栓形成评价
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摘要
新型可降解血管支架可降低异物留存体内的顾虑,因此广受重视且已有产品进入临床。但这些支架的可降解性质可能带来更多与血栓相关安全性的担忧。现有GB/T 16886.4标准明确其必须进行血栓相关评价,但未给出具体的评价方法。本研究以实验猪为模型,通过体内植入方式进行血栓评价,针对支架植入时、短期及长期植入后血栓形成等与已上市金属支架进行了比较性研究。其评价方法包括大体观察、数字血管造影术中分析、光学干涉成像技术分析、扫描电镜等。利用以上各种评价方法的优势,本研究实现了对此类血管内器械在考虑其降解过程中血栓形成的综合评价。结果说明,对可降解血管内植入器械的体内血栓形成评价,需考虑植入手术及术后与其体内变化过程相关的两个阶段,并充分利用各种评价手段的优势,并且适宜的已上市对照样品的选择也甚为重要。本研究力图通过实例提供新型可降解类血管支架可行的体内血栓评价方案,解决其临床前评价过程中的有关方法学问题,并为类似产品的评价方案设计提供参考。
New biodegradable intravascular stent can reduce risk of foreign bodies retained, thus, it is widely concerned and some of the products have been introduced into the clinic. However, the characteristic of biodegradable may lead to more safety concerns associated with thrombosis. To ensure the safety, the thrombus formation experiment in vivo needs to be carefully designed and evaluated based on GB/T 16886.4 standard, but current standard do not provide explicit testing and evaluating methods. Establishing animal model with experimental pigs, the study compares biodegradable coronary stents and metal stents by simulating clinical implantation in vivo on the thrombus formation in the implanting process, and after the short-term and long-term implantation. The evaluation methods include gross observation, digital subtraction angiography intraoperative analysis, optical coherence tomography analysis, scanning electron microscopy and so on. The results show that combining these methods could comprehensively evaluate the whole process of the thrombus formation from the beginning of implantation to the end of preclinical animal experiments, so that, it may better predict the clinical thrombosis risk, and the selection of the control was very important. The study tries to use the comparison examples of thrombosis on the new medical instrument to provide the clue for thrombosis evaluation in vivo on similar instruments and show the methodology on the preclinical evaluation.
New biodegradable intravascular stent can reduce risk of foreign bodies retained, thus, it is widely concerned and some of the products have been introduced into the clinic. However, the characteristic of biodegradable may lead to more safety concerns associated with thrombosis. To ensure the safety, the thrombus formation experiment in vivo needs to be carefully designed and evaluated based on GB/T 16886.4 standard, but current standard do not provide explicit testing and evaluating methods. Establishing animal model with experimental pigs, the study compares biodegradable coronary stents and metal stents by simulating clinical implantation in vivo on the thrombus formation in the implanting process, and after the short-term and long-term implantation. The evaluation methods include gross observation, digital subtraction angiography intraoperative analysis, optical coherence tomography analysis, scanning electron microscopy and so on. The results show that combining these methods could comprehensively evaluate the whole process of the thrombus formation from the beginning of implantation to the end of preclinical animal experiments, so that, it may better predict the clinical thrombosis risk, and the selection of the control was very important. The study tries to use the comparison examples of thrombosis on the new medical instrument to provide the clue for thrombosis evaluation in vivo on similar instruments and show the methodology on the preclinical evaluation.
引文
1Angelousi A, Girerd N, Benetos A, et al. Association between orthostatic hypotension and cardiovascular risk, cerebrovascular risk, cognitive decline and falls as well as overall mortality:a systematic review and meta-analysis. J Hypertens, 2014, 32(8):1562-1571.
2刘明伟,蒋立虹.冠状动脉粥样硬化性心脏病的支架置入治疗现状.中国组织工程研究与临床康复, 2010, 14(4):693-697.
3侯俊华.血管组织工程的研究与进展.中国组织工程研究, 2012,16(37):6979-6986.
4 陈佳龙,李全利,陈俊英,等.心血管植入材料体内内皮化研究进展.生物医学工程学杂志, 2009, 26(6):1380-1383.
5纪兆乐,胡建华,杨亚丽,等.全吸收式血管支架的临床研究进展.心脏杂志, 2016, 28(6):727-730.
6郭清奎,吕志前.可完全生物降解材料聚乳酸-聚羟基乙酸复合壳聚糖在人工心血管支架制备中的应用.北京生物医学工程,2011, 30(6):652-655.
7中华人民共和国国家质量监督检验检疫总局,中国国家标准化管理委员会. GB/T 16886.1-2011医疗器生物学评价第1部分:风险管理过程中的评价与实验. 2011.
8凡六章,马根山.药物洗脱支架血栓形成.现代医学, 2010, 38(6):685-689.
9郭志福,郑兴,秦永文.药物洗脱支架内血栓形成研究进展.介入放射学杂志, 2007, 16(8):568-571.
10陈宝爱,罗七一.可降解支架材料热学、机械性能及与受体的生物相容性.中国组织工程研究与临床康复, 2010, 14(29):5475-5478.
11谭志刚,周倩,蒋宇钢.生物可降解镁合金血管支架:缺点及未来研究趋势.中国组织工程研究, 2015, 19(8):1284-1288.
12马嘉丽,于振华,朱明,等.镍钛合金血管支架性能研究综述.金属功能材料, 2015, 22(2):56-59.
13中华人民共和国国家质量监督检验检疫总局. GB/T 16886.4-2003医疗器械生物学评价第4部分:与血液相互作用试验选择.2003.
14International Organization for Standardization. ISO 10993-4 2017Biological evaluation of medical devices–Part 4:Selection of tests for interactions with blood. 2017.
15方儒修.防止血栓形成和血栓再形成的新进展.心血管病学进展, 1991, 12(3):149, 165.
16Bundhun P K, Soogund M Z, Pursun M, et al. Stent thrombosis and adverse cardiovascular outcomes observed between six months and five years with sirolimus-eluting stents and other drug-eluting stents in patients with Type 2 diabetes mellitus complicated by coronary artery disease:A systematic revi. Medicine(Baltimore),2016, 95(27):e4130.
17Rizik D G, Hermiller J B, Klassen K J, et al. Xience side branch access stent for treatment of bifurcation coronary disease:a review of preclinical data. J Interv Cardiol, 2012, 25(4):337-343.
18McKeage K M, Goa K L. The sirolimus-eluting stent:a review of its use in the treatment of coronary artery disease. Am J Cardiovasc Drugs, 2003, 3(3):211-230.
19Banerjee S. The resolute integrity zotarolimus-eluting stent in coronary artery disease:a review. Cardiol Ther, 2013, 2(1):17-25.
20 Iliadis E A, Duvernoy C S. Stent placement for coronary stenosis in Kawasaki disease:case report and literature review. J Interv Cardiol, 2002, 15(1):29-31.
2刘明伟,蒋立虹.冠状动脉粥样硬化性心脏病的支架置入治疗现状.中国组织工程研究与临床康复, 2010, 14(4):693-697.
3侯俊华.血管组织工程的研究与进展.中国组织工程研究, 2012,16(37):6979-6986.
4 陈佳龙,李全利,陈俊英,等.心血管植入材料体内内皮化研究进展.生物医学工程学杂志, 2009, 26(6):1380-1383.
5纪兆乐,胡建华,杨亚丽,等.全吸收式血管支架的临床研究进展.心脏杂志, 2016, 28(6):727-730.
6郭清奎,吕志前.可完全生物降解材料聚乳酸-聚羟基乙酸复合壳聚糖在人工心血管支架制备中的应用.北京生物医学工程,2011, 30(6):652-655.
7中华人民共和国国家质量监督检验检疫总局,中国国家标准化管理委员会. GB/T 16886.1-2011医疗器生物学评价第1部分:风险管理过程中的评价与实验. 2011.
8凡六章,马根山.药物洗脱支架血栓形成.现代医学, 2010, 38(6):685-689.
9郭志福,郑兴,秦永文.药物洗脱支架内血栓形成研究进展.介入放射学杂志, 2007, 16(8):568-571.
10陈宝爱,罗七一.可降解支架材料热学、机械性能及与受体的生物相容性.中国组织工程研究与临床康复, 2010, 14(29):5475-5478.
11谭志刚,周倩,蒋宇钢.生物可降解镁合金血管支架:缺点及未来研究趋势.中国组织工程研究, 2015, 19(8):1284-1288.
12马嘉丽,于振华,朱明,等.镍钛合金血管支架性能研究综述.金属功能材料, 2015, 22(2):56-59.
13中华人民共和国国家质量监督检验检疫总局. GB/T 16886.4-2003医疗器械生物学评价第4部分:与血液相互作用试验选择.2003.
14International Organization for Standardization. ISO 10993-4 2017Biological evaluation of medical devices–Part 4:Selection of tests for interactions with blood. 2017.
15方儒修.防止血栓形成和血栓再形成的新进展.心血管病学进展, 1991, 12(3):149, 165.
16Bundhun P K, Soogund M Z, Pursun M, et al. Stent thrombosis and adverse cardiovascular outcomes observed between six months and five years with sirolimus-eluting stents and other drug-eluting stents in patients with Type 2 diabetes mellitus complicated by coronary artery disease:A systematic revi. Medicine(Baltimore),2016, 95(27):e4130.
17Rizik D G, Hermiller J B, Klassen K J, et al. Xience side branch access stent for treatment of bifurcation coronary disease:a review of preclinical data. J Interv Cardiol, 2012, 25(4):337-343.
18McKeage K M, Goa K L. The sirolimus-eluting stent:a review of its use in the treatment of coronary artery disease. Am J Cardiovasc Drugs, 2003, 3(3):211-230.
19Banerjee S. The resolute integrity zotarolimus-eluting stent in coronary artery disease:a review. Cardiol Ther, 2013, 2(1):17-25.
20 Iliadis E A, Duvernoy C S. Stent placement for coronary stenosis in Kawasaki disease:case report and literature review. J Interv Cardiol, 2002, 15(1):29-31.