摘要
阻塞性血管疾病包括心脑血管及外周血管疾病严重威胁着人类健康,而且发病率呈逐年上升趋势。血管内支架植入术已经成为冠状动脉和外周血管阻塞性疾病的主要治疗手段。但是支架的长期存留导致的内膜增生严重影响了支架置入术的中远期疗效。药物洗脱支架(Drug-Eluting Stent, DES)由于抗增殖药物的使用减轻了新生内膜的形成,但药物释放完毕后仍以异物永久存在于血管壁中,持续刺激血管壁导致再狭窄(In-Stent Restenosis, ISS)。如何缩短支架在体内的存留时间,减轻机械刺激是血管内支架研究的热点之一。可降解血管内支架几乎和永久性金属血管内支架同时提出。可降解血管内支架(Biodegradable Endovascular Stent,BES)具有暂时存留的特点,在人体内完成使命后降解消失,因此受到医学界关注。早在1988年,Stack等人就利用聚乳酸材料(Poly-Lactic Acid,PLA)研制开发了生物可降解支架。目前研究较多的可降解支架包括生物大分子支架,可降解铁支架及可降解镁合金支架(Biodegradable Magnesium Alloy Stent, BMS)。生物大分子支架机械性能差限制了它在小血管中的应用,可降解铁支架降解速度慢,近年来研究较少。镁合金支架较其他两种可降解支架具有支撑力强、炎症反应小等特点,近年来发展迅速。国外镁合金支架的动物实验及临床试验报道认为镁合金支架安全有效,但存在中度新生内膜增生以及降解速度过快等问题,因此如何延长降解时间、减轻新生内膜增生摆在了广大研究者的面前。中科院金属研究所研制出了一种雷帕霉素涂层AZ31可降解镁合金支架,表面经过(1)电抛光以增加支架表面光滑程度,减少血栓形成；(2)化学钝化处理以延长降解时间。同时在支架的表面涂以雷帕霉素,旨在抑制新生内膜增生,药物载体为聚(乳酸-三亚甲基碳酸酯)(Poly (Lactic Acid-co-Trimethylene Carbonate)，P(LA-TMC))。该支架的机械性能、血液相容性、血小板黏附实验、模拟血浆中的降解性能实验已完成,试验结果理想。本实验的目的在于初步研究该支架在兔腹主动脉中的降解时间及抑制新生内膜的性能。目前国内外尚没有药物涂层可降解镁合金支架的相关实验及临床报道。本研究分为以下两个方面：
第一部分：雷帕霉素涂层AZ31可降解镁合金支架在兔腹主动脉的降解性能研究。目的：初步评价雷帕霉素涂层AZ31可降解镁合金支架在兔腹主动脉的降解性能。方法：将20枚雷帕霉素涂层AZ31可降解镁合金支架置入20只新西兰大白兔肾下腹主动脉中。分别于术后1个月(n=5)、两个月(n=5)、3个月(n=5)及4个月(n=5)处死动物。对支架段血管进行钼靶照相及病理处理。(1)通过钼靶照相评价支架在降解过程中的大体形态改变。(2)对病理图像进行计算机图像分析,计算支架不同时间段剩余支杆的截面积。对截面积进行直线回归分析,得到支架完全降解所需要的时间。结果：20只大白兔在随访期存活良好。钼靶照相显示1个月时支架形态完整,扩张完全；2个月时支架部分支杆降解断裂,失去支撑作用；3个月时大部分支架支杆降解,4个月时所有支架完全降解。计算机病理图像分析示平均每天支架支杆降解面积为0.00192mm2,支架在兔腹主动脉中完全降解所需时间为105.0天。结论：雷帕霉素涂层可降解AZ31镁合金支架在兔主动脉中2个月内失去支撑作用,完全降解所需时间为105.0天。降解时间较已报道的其他镁合金支架有所延长,但仍有待于进一步延长。
第二部分：雷帕霉素涂层AZ31可降解镁合金支架在兔腹主动脉抑制新生内膜性能研究。目的：初步评价雷帕霉素涂层AZ31可降解镁合金支架在兔腹主动脉抑制新生内膜的性能。方法：术前一周常规喂养。AZ31可降解镁合金支架及雷帕霉素涂层AZ31可降解镁合金支架各22枚配对置入22只新西兰大白兔腹主动脉中,前者置于肾下腹主动脉近端,后者置于肾下腹主动脉远端。术后青霉素抗炎,阿司匹林抗凝。分别于术后第3天(n=2),1个月(n=5),2个月(n=5),3个月(n=5),4个月(n=5)处死动物。术后3天随访观察有无急性血栓形成。其余随访期将支架段血管取出后进行病理学及血管数字形态计量分析。结果：22只新西兰大白兔术后存活良好。造影及病理未见血栓形成。随访期间,雷帕霉素涂层AZ31可降解镁合金支架的新生内膜面积明显小于AZ31可降解镁合金支架新生内膜面积。1个月时二者为0.60±0.22mm2 vs.1.44±0.04mm2,P<0.05。第2、3、4个月时,二者比分别为0.63±0.27mm2 vs. 1.41±0.08mm2、0.57±0.14mm2 vs.1.43±0.02mm2、0.58±0.10mm2 vs. 1.47±0.03mm2,P值均小于0.05。药物涂层镁合金支架新生内膜厚度明显小于裸镁合金支架,第1、2、3、4个月时,二者分别110.32±65.31μm vs.250.36±114.39μm、91.28±35.31μm vs.225.12±75.14μm、89.32±38.82μm vs.214.08±75.13μm、116.95±10.44μm vs.239.37±9.49μm,P值均小于0.05。与之对应,随访期内,前者的血管管腔面积明显小于后者,2.44±0.64mm2 vs.1.58±0.43mm2、2.64±0.17mm2 vs.1.93±0.27mm2、2.84±0.54mm2 vs.2.04±0.34mm2、3.00±0.13mm2 vs.2.16±0.08mm2,P值均小于0.05。术后第1个月,雷帕霉素涂层组的内皮化评分低于裸支架,为1.0±0.21 vs.2.45±0.35,P<0.05。术后第2、3、4个月,二者分别为：2.57±0.39vs.2.25±0.36、2.46±0.11 vs.2.56±0.39、2.56±0.28 vs.2.38±0.31,P值均大于0.05。证明雷帕霉素涂层造成血管内皮化延迟。随访期内,两组支架在内弹力膜下面积、炎性评分、损伤评分无明显差别,P值均大于0.05。结论：与AZ31镁合金支架相比,雷帕霉素涂层AZ31可降解镁合金支架能减少新生内膜面积形成,增加管腔面积,但会延缓血管的内皮化。
Cardiovascular disease has became more and more common because of the development of economy and the diet of people, and threatened people's health seriously. According to statistics, some scholars have anticipated that cardiovascular disease will be the most frequent fatality factor in 2020. Clinically, the use of intravascular stents has gained popularity and becomes an eatablished mode of treatment in percutaneous cardiovascular interventions. However, mural thrombus, elastic recoil and neointimal hyperplasia limit the long-term effectiveness of this treatment. While thrombosis has been controlled with antiplatelet therapy, elastic recoil has been solved with the high radial force of permanent stents, and neointimal hyperplasia has been reduced with the use of drug-eluting stents(paclitaxel and rapamycin). But when the drug is eluted, drug-eluting stents pose problems similar to that of bare metal stents, as permanent foreign bodies in vessel wall which have the risk of continuous interaction between the stent and the surrounding tissue, leading to long-term endothelial dysfunction or chronic inflammatory reaction. These interactions are known as the possible factors for in-stent restenosis(ISS). So how to lessen the mechanical stimulation is one of the hotest points in endovascular stent study. Biodegradable Endovascular Stent(BES) may act as a new biomedical tool which are "fulfilling the mission and stepping away" because of its more physiological repair, reconstitution of local vascular compliance, and a temprory, limited, longitudinal, and radial straightening effect, including the possibility of growth. In 1988, Stack developed the original biodegradable endovascular stent made of poly-lactic acid(PLA). At present, there are three types of BES which are studied most frequently: biodegradable polymers stent, biodegradable iron stent and biodegradable magnesium alloy stent(BMS). Stents made of biodegradable polymers have limited success because of their low radial strength and local inflammation, thus leaving corrodible metals as the best alternatives. BMS's strong radial force, less inflammatory reaction makes it become the most promising biodegradable stent. In earlier studies, biodegradable magnesium alloy stents were proved to be safe and efficient. However, preliminary preclinical and clinical trials had demonstrated that these stents resulted in higher restenosis rates than seen in drug-eluting stents for a modest degree of neointima formation, late recoil and faster degradation. So how to prolong the degradation and lessess the intimal hyperplasia faces reserchers. A new style of BMS called rapamycin-eluting AZ31 biodegradable magnesium alloy stent has been developed by the Institute of Metal Research Chinese Academy of Sciences(Shenyang, China). The stent's surface is electropolished so as to prolong cloting time and decrease thrombosis, also inactivated to lengthen corrosion period. The stent was coated by rapamycin whose carrier is poly (lactic acid-co-trimethylene carbonate) (P(LA-TMC)). The mechanical parameter, blood compatibility, plate adhesion experiment and degradation performance have been completed, and the result is ideal. The purpose of present study was to evaluate the degradation time and the character of inhibiting intimal hyperplasia of rapamycin-eluting AZ31 biodegradable magnesium alloy stent. There have been no reports of drug-eluting magnesium alloy stent all over the world. The study included two parts:
Part I:The degradable performance of rapamycin-eluting AZ31 biodegradable magnesium alloy stents in rabit abdominal aorta. Objective:The purpose of this study was to study the degradable performance of rapamycin-eluting AZ31 bioabsorbable magnesium alloy stents in rabbit abdominal aortas. Method:Twenty AZ31 biodegradable magnesium alloystents were deployed in infrarenal abdominal aortas of twelve New Zealand white rabbits. Rabbits were sacrificed in one month (n=5), two months(n=5), three months (n=5) and four months (n=5) after stents implantation. Vessels were harvested, radiographed,and then treated with pathology in order to evaluate degradable performance. Radiography of stented vessel was made to show the whole figure, and the pathology was analyzed by computer in order to anticipate the corrosion time. Results:All animals survived in the scheduled follow-up period. Radiography showed stents were expanded fully in one month, most struts had been already corroded partly in two months and completely in three months, all struts were corroded completely in four months. The corrosion period of AZ31 magnesium alloy stents in rabbit aorta was 105.0 days. Conclusion:Rapamycin-eluting AZ31 bioabsorbable magnesium alloy stents lose radial force in rabbit abdominal aorta in two months, and the corrosion period is 105.0 days.
PartⅡ:The study of inhibiting intimal hyperplasia character of rapamycin-eluting AZ31 biodegradable magnesium alloy stent. Objective:The purpose of this study was to evaluate inhibiting intimal hyperplasia character of rapamycin-eluting AZ31 biodegradable magnesium alloy stent in rabbit aortas. Methods:Rapamycin-eluting AZ31 biodegradable magnesium alloy stent (n=22) and AZ31 magnesium alloy stents (n=22) were deployed in aortas of 22 New Zealand white rabbits (2 stents each rabbit). Rabbits were sacrificed in 3 days (n=2),1 month (n=5),2 months (n=5),3 months (n=5) and 4 months (n=5) after stents implantation. Stented vessels were harvested to be made pathology and then calculated with computer. Results:All rabbits survived during follow-up period. No evidence of thrombosis was found in angiography and pathology. Neointimal area in the segment deployed with rapamycin-eluting AZ31 magnesium alloy stent was smaller than that deployed with magnesium alloy stent during follow-up period(1 month:0.60±0.22mm2 vs.1.44±0.04mm2, P<0.05; 2、3、4 months after operation:0.63±0.27mm2 vs.1.41±0.08mm2、0.57±0.14mm2 vs.1.43±0.02mm2、0.58±0.10mm2 vs.1.47±0.03mm2, all P＜0.05). Neointimal thichness in the segment deployed with rapamycin-eluting AZ31 magnesium alloy stent was shorter than that deployed with magnesium alloy stent during follow-up period. The data of two groups are:110.32±65.31μm vs.250.36±114.39μm、91.28±35.31μm vs. 225.12±75.14μm、89.32±38.82μm vs.214.08±75.13μm、116.95±10.44μm vs. 239.37±9.49μm, all P<0.05 in 1、2、3、4 months. So the lumen area was significantly larger in the rapamycin-eluting AZ31 magnesium alloy stents group when compared with AZ31 magnesium alloy stents group. The data of every follow-up time was baned as following:2.44±0.64mm2 vs.1.58±0.43mm2 (1 month)、2.64±0.17mm2 vs. 1.93±0.27mm2 (2 months)、2.84±0.54mm2 vs.2.04±0.34mm2、(3 months)、3.00±0.13mm2vs.2.16±0.08mm2 (4 months), all P<0.05。
The endothelialization score of two groups was different obviously in 1 month(1.0±0.21 (experiment group) vs.2.45±0.35(contral group), P<0.05),contrasting with the performance in 2、3、4 months(2.57±0.39 vs.2.25±0.36、2.46±0.11 vs. 2.56±0.39、2.56±0.28 vs.2.38±0.31, all P＜0.05.), which suggested that rapamycin-eluting AZ31 magnesium alloy stents group had delayed endothelialization. There was no obvious difference in internal elastic lamina(IEL) area, injury score, inflammation score between two groups during follow-up period. Conclusion: Rapamycin-eluting AZ31 biodegradable magnesium alloy stent obviously reduces the neointimal hyperplasia and improves the lumen area when compared to AZ31 magnesium alloy stent, but it delays vessel's healing and endothelialization.
引文
1 Virmani R, Farb A, Guagliumi G, et al. Drug-eluting stents:Caution and concerns for long-term outcome. Coron Artery Dis.2004; 15(6):313-318.
2 Van der Giessen WJ, Lincoff AM, Schwartz RS, et al. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation.1996; 94:1690-1697.
3 Yamawaki T, Shimokawa H, Kozai T, et al. Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo. J Am Coll Cardiol.1998; 32: 780-786.
4 Tamai H, Igaki K, Kyo E, et al. Initial and 6-month results of biodegradable poly-1-lactic acid coronary stents in humans. Circulation.2000; 102:399-404.
5 Hehrlein C. Promises of biodegradable stents. Catheter Cardiovasc Interv.2007, Apr 1; 69(5):739.
6 Hansi C, Arab A, Rzany A, et al. Differences of platelet adhesion and thrombus activation on amorphous silicon carbide, magnesium alloy, stainless steel, and cobalt chromium stent surfaces. Catheter Cardiovasc Interv.2009 Mar 1; 73(4): 488-496.
7 Waksman R, Erbel R, Di Mario C, et al. Early-and long-term intravascular ultrasound and angiographic findings after bioabsorbable magnesium stent implantation in human coronary arteries. JACC Cardiovasc Interv.2009 Apr; 2(4): 312-320.
8 Ghimire G, Spiro J, Kharbanda R, et al. Initial evidence for the return of coronary vasoreactivity following the absorption of bioabsorbable magnesium alloy coronary stents. Eurointervention.2009 Jan; 4(4):481-484.
9 Waksman R, Pakala R, Okabe T, et al. Efficacy and safety of absorbable metallic stents with adjunct intracoronary beta radiation in porcine coronary arteries. J Interv Cardiol.2007 Oct; 20(5):367-372.
10 Schuhlen H, Kastrati A, Mehilli J, et al. Restenosis detected by routine angiographic follow-up and late mortality after coronary stent placement. Am Heart J.2004; 147:317-322.
11 Farb A, Burke AP, Kolodgie FD, et al. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation.2003; 108:1701-1706.
12 Bax L, Mali WP, Van De Ven PJ, et al. Repeated intervention for in-stent restenosis of the renal arteries. J Vase Interv Radiol.2002; 13:1219-1224.
13 Grenacher L, Saam T, Geier A, et al. PTA vs. Palmaz stent placement in femoropopliteal artery obstruction:results of a multicenter prospective randomized study (REFSA). Fortschr Roentgenstr.2004; 176:1302-1311.
14 Boland JL, Corbeij HA, Van Der Giessen W, et al. Multicenter evaluation of the phosphoryl-choline-coated stent in short de novo coronary lesions:the SOPHOS study. Int J Cardiovasc Intervent.2000; 3:215-225.
15 Zheng H, Barragan P, Corcos T, et al. Clinical Experience with a new biocompatible phosphorylcholine-coated coronary stent. J Invasive Cardiol.1999; 11:608-614.
16 Gibbons GH, Dzau VJ. The emerging concept to vascular remolding. N Eng J Med. 1994; 330(20):1431-1438.
17 Post MJ, de Smet BJGL, van der Helm Y, Borst C, et al. Arterial remodeling after balloon angioplasty or stenting in the Yucatan atherosclerotic micropig model:an angiographic, serial intravascular ultrasound and histology study. Circulation.1997; 96(3):996-1003.
18 Nakatani M, Takeyama Y, Shibata M, et al. Mechanisms of restenosis after coronary intervention:difference between plain old balloon angioplasty and stenting. Cardiovasc Patho.2003; 12:40-48.
19 Tsuruda T, Kato J, Matsui E, et al. Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats. Eur J Pharmaco.2005; 508(1-3):201-204.
20 Tanguay JF, Geoffroy P, Dorval JF, et al. Percutaneous endoluminal arterial cryoenergy improves vascular remodeling after angioplasty. Thromb Haemos.2004; 92:1114-1121.
21 肖敏,黄从新,张群林.血管重塑与判断再狭窄的标准.郧阳医学院学报.2000；19(3)：186-188.
22 Cowan DB, Langille BL. Cellular and molecular biology of vascular remodeling. Curr Opin Lipidol.1996; 7(2):94-100.
23 Labinaz M, Pels K, Hoffert C, et al. Time course and importance of neoadventitial formation in arterial remodeling following ballon angioplasty of porcine coronary arteries. Cardiovasc Res.1999; 41(1):255-266.
24 Pasterkamp G, de Kleijin DPV, Borst C. Arterial remodeling in atherosclerosis,restenosis and after alteration of blood flow:potential mechanisms and clinical implications. Cardiovasc Res.2000; 45(4):843-852.
25 Herity NA, Ward MR, Lo S, Yeung AC. Review:Clinical aspects of vascular remodeling. J Cardiovasc Electrophysiol.1999; 10(7):1016-1024.
26 Hong MK, Mintz GS, Hong MK, et al. Intravascular ultrasound assessment of the presence of vascular remodeling in diseased human saphenous vein bypass grafts. Am J Cardiol.1999; 84(9):992-998.
27 Gibbons GH, Dzau VJ. The emerging concept to vascular remolding. N Eng J Med. 1994; 330(20):1431-1438.
28 Moscucci M, Ricciardi M, Eagle KA, et al. Frequency, predictors, and appropriateness of blood transfusion after percutaneous coronary interventions. Am J Cardiol.1998; 81(6):702-707.
29 Peuster M, Wohlsein P, Brugmann, et al. A novel approach to temporary stenting: Degradable cardiovascular stents produced from corrodible metal-results 6-18 months after implantation into New Zealand white rabbits. Heart.2001; 86(5): 563-569.
30 俞耀庭等.生物医用材料.天津大学出版社,2000.
31 Heublein B, Rohde R, Kaese V, et al. Biocorrosion of magnesium alloys:a new principle in cardiovascular implant technology? Heart.2003; 89 (6):651-656.
32 杨小强,袁明龙,李伟,等.聚乳酸共混三亚甲基碳酸酯生物膜的生物性能表征及动物实验研究。生物医学工程学杂志.2006；23(3)：578-582.
33 Cai Jie, Zhu KJ. Preparation, characterization and biodegradable characteristics of poly(D, L-lactide-co-1,3-trimethylene carbonate). Polymer International.1997; 42:373-379.
34 Konig A, Schiele TM, Rieber J, et al. Influence of stent design and deployment technique on neointima formation and vascular remoldeling. Z Kardiol.2002; 91(Suppl 3):98-102.
35 Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med.2003; 348(16):1537-1545.
36 Colombo A, Karvouni E. Biodegradable stents “fulfilling the mission and stepping away". Circulation.2000; 102:371-373.
37 Wintermantel E, Mayer J, Ruffieux K, et al. Biomaterialien:humane Toleranz und Integration. Chirurg.1999; 70:847-857.
38 Lemos PA, Serruys PW, Van Domburg RT, et al. Unrestrictedutilization of sirolimus-eluting stents compared with conventionalbare-metal stent implantation in the "real world”:the Rapamycin-Eluting Stent Evaluated At Rotterdam CardiologyHospital registry. Circulation.2004; 109(2):190-195.
39 Stack RS, Califf RM, Phillips HR, et al. Interventional cardiac catheterization at Duke Medical Center. Am J Cardiol.1988; 62 (10 Pt 2):3F-24F.
40 Lowe HC, Oesterle SN, Khachigian LM. Coronary instent restenosis：current status and future strategies. J Am Coll Cardiol.2002; 39:183-193.
41 Ruef J, Hofmann M, Haase J. Endovascular interventions in iliac and inf rainguinal occlusive artery disease. J Interv Cardiol.2004; 17(6):427-435.
42 Ron Waksman, Rajbabu Pakala, Pramod K, et al. Safety and Efficacy of Bioabsorbale Magnesium Alloy Stents in Porcine Coronary Arteries. Catheterization and Cardiovascular Interventions.2006; 68:607-617.
43 Ron Waksman, Rajbabu Pakala,Teruo Okabe, et al. Efficacy and Safety of Absorbable Metallic Stents with Adjunct Intracoronary Beta Radiation in Porcine Coronary Arteries. Journal of Interventional Cardiology.2007; 20(5):367-372.
44 Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. NEngl J Med.2005; 353: 653-662.
45 Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J.2002; 346:1773-1780.
46 Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents verses standard stents in patients with stenosis in a native coronary artery. N Engl J.2003; 349: 1315-1323.
47 Suzuki T, Kopia G, Hayashi S, et al. Stent based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation.2001; 104 (10):1188-1193.
48 Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury:Results in a porcine model. J Am Coll Cardiol.1992; 19:267-274.
49 Fattori R, Piva T. Drug-eluting stent invascular intervention. Lancet.2003; 363(9353):247-249.
50 Mauro MA. The battle of intimal hyperplasia in the war against femoropopliteal disease. Radiology.2004; 231(2):299-301.
51 Patel S, Shi Y, Niculesou R, et al. Characteristics of coronary smooth muscle cells and adventitial fibroblasts. Circulation.2000; 101:524-532.
52 Schwartz SM. Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest.1997; 100:587-589.
53 Nakamura Y, Nakamura K, Ohta K, et al. Anti-inflammatory effects of long-lasting locally delivered human recombinant tissue factor pathway inhibitor after balloon angioplasty. Basic Res Cardiol.2002; 97(3):198-205.
54 Durand E, Mallat Z, Addad F, et al. Time courses of apoptosis and cell proliferation and their relationship to arterial remodeling and restenosis after angioplasty in an atherosclerotic rabbit model. Am Coll Cardiol.2002; 39(10) 680-685.
55 Lafont A, Durand E, Samuel JL, et al. Endothelial dysfunction and collagen accumulation:two independent factors for restenosis and constrictive remolding after experimental angioplasty. Circulation.1999; 100(10):1109-1115.
56 Wilcox JN, Okamato El, Nakahara KI, et al. Perivascular responses after angioplasty which may contribute to postangioplasty restenosis:a role for circulating myofibroblast precursors? Ann N Y Acad.2001; 947:68-92.
57 Ruygrok P, Muller D, Serruys P, et al. Rapamycin in cardiovascular medicine. Intern Med J.2003; 33:103-109.
58 Waksman R, Buch AN, Torguson R. Long-term clinical outcomes and thrombosis rates of sirolimus-eluting versus paclitax-eluting stents in an unselected population with coronary artery disease. Am J Cardiol.2007; 100(1):45-51.
59 Haude M, Konorza TF, Kalnins U, et al. Heparin-coated stent placement for the treatment of stenoses in small coronary arteries of symptomatic patients. Circulation.2003; 107(9):1265-1270.
60 Bauerschmidt P, Schaldach M. The electrochemical aspects of the thrombogenicity of a material. Bioeng.1977; 1:261-278.
61 Komowski R, Hong MK, Tio FO, et al. Instent restenosis contribution of inflammatory response and arterial injury to neointimal hyperplasia. J Am Coll Cardiol.1998; 31(1):224-230.
62 Zhao H, Van Humbeeck J, Sohier J, et al. Electrochemical polishing of 316L stainless steel slotted tube coronary stents. J Mater SciMacer Med.2002; 13(10): 911-916.
63 Sousa JE, Serruys PW, CostaM A. New frontiers in cardiology:drug-eluting stents: Part 2. Circulation.2003; 107(18):2383-2389.
64 Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping Sirolimus-or Pacliyaxel-eluting stents. Circulation.2005; 112:270-278.
65 Shen L, Ge JP. Puzzle or hope? Are endothelial progenitor cell capture stents the next potential treatment for restenosis. Molecular Cardiology of China.2006; 6(3):184-187.
66 Fukuda D, Sata M, Tanaka K, et al. Potent inhibitory effect of sirolimus on circulating vascular progenitor cells. Circulation.2005; 111(7):926-931.
67 Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med.2007; 356(10):1020-1029.
68 Jaffe R, Strauss B H. Late and very late thrombosis of drug-eluting stents evolving concepts and perspectives. J Am Coll Cardio.2007; 50(2):119-127.
69 Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical pratice: data from a large two-institutional cohort study. Lancet.2007; 369(956-964).
70 Kulkarni RK, Pani KC, Neumanc, et al. Polylactic acid for surgical implants. Arch Surg,1996,93(5):839.
71 Tang yan. Preparation and Properties of Drug-loaded Coating on Biodegradable MagnesiumAlloy Coronary Stents. Ph M Dissertation, Institute of Metal Research, Chinese Academy of Sciences, (2009).
72 Nishida T, Ueno H, et al. Adenovirus mediated local expression of human tissue factor pathway inhibitor eliminates shear stress induced recurrent thrombosis in the injured carotid artery of the rabbit. Circ Res.1999; 84(12):1446-1452.
73 张朝颖,傅羽,张改改,等.组织因子途径抑制物基因对支架内再狭窄的抑制作用.中国 动脉硬化杂志.2008；16(5)：357-360.
1 Sahler LG, Morris TW, Owusu KN, et al. Luminal diameter and Vasa vasorum response to stent dilation in the rabbit aorta. Acad Radiol.1996; 3:545-549.
2 Pisco JM, Correia M, Esperanca-Pina JA, et al. Vasa vasorum changes following stent placement in experimental arterial stenosis. J Vasc Interv Radiol.1993; 4:269-273.
3 Pisco JM, Correia M, Esperanca-Pina JA, et al. Changes in the vasa vasorum following precutaneous transluminal angioplasty in a canine model of aortic stenosis. J Vasc Interv Radiol.1994; 45:561-566.
4 Fichman DL, Leon MB, Baim DS. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl Med.1994; 331:496-501.
5 Carrozza JP, Kuntz RE, Levine MJ, et al. Angiographic and clinical outcome of intracoronary stenting:immediate and long-term results from a large single-center experience. J Am Coll Cardiol.1992; 20:328-337.
6 Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med.2002; 346:1773-1780.
7 Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents verses standard stents in patients with stenosis in a native coronary artery. N Engl J Med.2003; 349:1315-1323.
8 Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans, delayed healing and late thrombotic risk. J Am Coll Cardiol.2006; 48:193-202.
9 Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping Sirolimus-or Paclitaxel- eluting stents. Circulation.2005; 112:270-278.
10 Colombo A, Karvouni E. Biodegradable stents "fulfilling the mission and stepping away". Circulation.2000; 102:371-373.
11 Stack RS, Califf RM, Phillips HR, et al. Interventional cardiac catheterization at Duke Medical Center. Am J Cardiol.1988; 62 (10 Pt 2):3F-24F.
12 Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000; 2 (24):2529-2543.
13 徐克,邹英华,欧阳墉.管腔内支架治疗学.北京：科学出版社.2004.4.
14 Yamawakit, Shimokawa H, Kozai T. Intramural delivery of a specific tyrosinekinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo. J Am coll Cardiol.1998; 32(3): 780-786.
15 Tsuji T, Tamai H, Igaki K, et al. Biodegradable Polymeric Stents. Curr Interv Cardiol Rep.2001 Feb; 3(1):10-17.
16 Tamai H, Igaki K, Kyo E, et al. Initial and 6-month results of biodegradable poly-L-lactic acid coronary stents in humans. Circulation.2000; 102:399-404.
17 肖越勇,张金山,崔福斋,等.生物可降解性血管内支架的制备及其性能研究.中华放射学杂志2003年11月第37卷第11期.
18 Schell hammer F, Berlis A, Bloss HG, et al. Poly-lactic-acid for coating of endovascular stents:preliminary results in canine experimental avfistulae. Material wissenschaft undwerkst offtechnik.2001; 32(2):193-199.
19 Grube E, Sonoda S, Ikeno F, Honda Y, et al. Six-and twelve-month results from first human experience using everolimus-eluting stents with bioabsorbable polymer. Circulation.2004; 10(18):2168-2171.
20 Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation.2001; 104(4):473-479.
21 Nguyena KT, Sua DSH, Shenga A, et al. In vitro hemocompatibility studies of drugloaded poly-(lactic acid) fibers. Biomaterials.2003; 24 (28):5191-5201.
22 Wieneke H, Dirsch 0, Saw-itowski T, et al. Synergistic effects of a novel Nanoporous stent coating and tacrolimus on intima proliferation inrabbits. Catheterization and Cardiovascular interventions.2003; 60(3):399-407.
23 Ruef J, Hofmann M, Haase J. Endovascular interventions in iliac and infrainguinal occlusive artery disease. J Interv Cardiol.2004; 17 (6):427-435.
24 Lincoff AM, Fursr J G, Ellis SG, et al. Sustained local delievery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol.1997; 29(4):808-816.
25 Giessen WJ, Lincoff AM, Schwartz RS, et al. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation.1996; 94 (7):1690-1697.
26 Regar E, Sianos G, Serruys PW. Stent development and local drug delivery. Br Med Bull.2001; 59:227-248.
27 Asplund B, Sperens J, Mat hisen T, et al. Effects of hydrolysis on a new biodegradable copolymer. J Biomater Sci Polym Ed.2006; 17(6):615-630.
28 俞耀庭等.生物医用材料.天津大学出版社,2000.
29 Witte F, Kaese V, Haferkamp H. In vivo corrosion of four magnesium alloys and the associated bone response. Biomaterials.2005; 26(17):3557-3563.
30 Witte F, Fischer J, Nellesen J. In vitro and in vivo corrosion measurements of Magnesium alloys. Biomaterials.2006; 27(7):1013-1018.
31 Heublein B, Rohde R, Kaese V, et al. Biocorrosion of magnesium alloys:a new principle in cardiovascular implant technology?. Heart.2003; 89 (6):651-656.
32 Carlo Di Mario, Huw Gf iff iths, Omer Goktekin, et al. Drug-Eluting Bioabsorbable Magnesium Stent. Journal of Interventional Cardiology.2004; 17(6):391-395.
33 Ron Waksman, Rajbabu Pakala, Pramod K, et al. Safety and Efficacy of Bioabsorbale Magnesium Alloy Stents in Porcine Coronary Arteries. Catheterization and Cardiovascular Interventions.2006; 68:607-617.
34 Ron Waksman, Rajbabu Pakala, Teruo Okabe, et al. Efficacy andSafety of Absorbable Metallic Stents with Adjunct Intracoronary Beta Radiation inPorcine Coronary Arteries. Journal of Interventional Cardiology.2007; 20(5):367-372.
35 Zartner P, Cesnjevar R, Singer H, et al. First successful implantation of a biodegradable metal stent into the left pulmonary artery of a preterm baby. Catheter Cardiovasc Interv.2005; 66(4):590-594.
36 Zartner Bosiers M, Deloose K, Verbist J, et al. Percutaneous transluminal angioplasty for treatment of “below-the-knee" critical limb ischemia:early outcomes following the use of sirolimus eluting stents. J cardio vasc Surg(Torino).2006; 47(2):171-176.
37 Erbel R. PROGRESS AMS I Clinical Study. Late Breaking Clinical Trials. Presented at ACC 2006, Atlanta, GA.
38 Mueller PP, May T, Perz A, et al. Control of smooth muscle cell proliferation by ferrous iron. Biomaterials.2006 Apr; 27(10):2193-2200.
39 Peuster M, Wohlsein P, Brugmann M, et al. A novel approach to temporary stenting:Degradable cardiovascular stents produced from corrodible metal results 6-18 months after implantation into New Zealand white rabbits. Heart. 2001; 86(5):563-569.
40 Peuster M, Hesse C, Schloo T, et al. Long-term biocompatibility of a corrodible peripheral iron stent in the porcine descending aorta. Biomaterials.2006 Oct; 27(28):4955-4962.
41 Ramcharitar S, Serruys PW. Fully biodegradable coronary stents:progress to date. Am J Cardiovasc Drugs.2008; 8(5):305-314.
