生物可降解性血管内支架的研究
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摘要
目的
采用生物可降解材料PLLA制备生物可降解性血管内支架(BIS)，对支架的综合性能进行测试使其达到或接近金属血管内支架的性能；研究BIS的生物相容性，评价BIS植入动物血管内不同时期的组织学变化以确定其植入血管的可行性；制备携带抗增生药物紫杉醇的BIS，将紫杉醇BIS和裸BIS植入到实验动物的动脉血管内，探讨紫杉醇BIS防治血管再狭窄的作用。
材料与方法
1．应用分子量100 000单位的PLLA制作直径为0.1-0.6mm的支架基杆，将基杆成形制备出直径为6-15mm的螺旋型和“Z”型支架。对支架的基杆进行造孔和涂膜。测量径向支撑力、表面覆盖率、轴向收缩率和支架扩张率等参数。
2．“Z”型BIS植入到11只实验犬的腹主动脉和髂动脉内，分期处死动物行病理学观察。
3．紫杉醇BIS和裸BIS植入到8只再狭窄实验动物模型犬的腹主动脉内，6周后处死实验动物完整取出支架段血管行病理学观察及免疫组化评价。
结 果
1．制备出螺旋型和“ Z”型两种型号支架，基杆直径为 0．10石nun，支架扩
张后直径在 6上，长度在 3｛。
二．支架植入后 IWk支架杆部有少许纤维组织并有少量血小板沉着，ZWk新
生内膜形成但内膜覆盖不完全，4wb支架杆部基本被新生内膜覆盖，SWk
后新生内膜不再显著增厚，血管壁完整管腔通畅。
3．裸支架组血管平均管腔面积I。于紫杉醇支架组血管平均管腔面积门586
u m‘vs 43 5 u mZ，p＜0．00卜裸支架组血管新生内膜平均增生面积
大于紫杉醇组平均内膜增生面积口4 8们卜m’1）SI二93pm＼p叼刀＊）；
裸支架组PCNA细胞阳性率高于紫杉醇支架组o8％士15％。11％士
0．31％，P功刀1），两组具有显著统计学差异。
结 论
1．生物可降解材料PLLA制作的BIS其机械力学特性可满足支架植入血管内
各项参数的要求。
2．生物可降解性“ Z”型血管内支架易于释放和展开，植入动物血管内无显
著异物和炎性反应，SWk时血管内膜覆盖完全，SWk后内膜生长减弱不引
起显著的内膜增生性改变，具有可靠的机械强度和良好的生物相容性。
3．生物可降解性血管内支架作为载荷和释放药物的有效平台，通过所携带抗
增生药物紫杉醇可以显著地抑制VSMC增殖和血管内膜的增生是防治血
管再狭窄的新策略和理想手段。
Purpose
1 To prepare biodegradable intravascular stents (BIS) with biodegradable materials poly- L -acid (PLLA), the capability of BIS is similar to metallic stents.
2 To investigate BIS's biocompatibility, and evaluate the histopathological findings at a fixed timetable after the BIS implanted so as to determine the possibility of BIS implanted into arteries.
3 To prepare drug eluting BIS with antiproliferation agent-paclitaxel, and both the drug release BIS and bare BIS (without any drug) be implanted into the aorta of canine models of restenosis, to assess the effect of paclitaxel releasing drug BIS at preventing neointimal hyperplasia.
Materials and Methods
1 BIS were prepared with PLLA, porous structures were fabricated and the films were coated at the strut of BIS. The stringent physical and mechanical properties of the BIS were tested.
2 Appropriately sized zigzag BISs were implanted into the aorta and iliac arteries of 11 canines, the animals were euthanized according to a fixed timetable for
histopathological assessment.
3 Both paclitaxel eluting BIS and bare BIS were implanted into the infrarenal aortas of the canine models of restenosis, the animals were euthanized 6 weeks after implantation for histopathological and immunohistochemical assessment.
Results
1 Two types of spiral and zigzag BIS were prepared with PLLA (MW^IOOOOOD), the strut of BIS is from 0.1-0.6, the diameter of BIS from 6-15mm, and the length from 3-8cm.
2 Fibrosis was evidence surrounded the struts of BIS Iwk days after implantation, and scarce blood platelets were deposited on it. At 2wk, endothelialization of the BIS was not completed. At 4wk, the struts were covered completely by neointima. At 8 wk, the neointima seemed not to be thickening, the arteries' wall were smooth and intact.
3 Some significant differences were noted between the paclitaxel BIS group and bare BIS group. The mean lumen area (LA) of bare BIS was smaller than that of the paclitaxel BIS group(77586 n m2 vs 113 435 u m2, pO.OOl). And the mean intimal area (IA) of bare BIS was larger than that of paclitaxel BIS group (24 803 u m2 vs 12 931 u m2 , pO.OOl).
4 The PCNA positive ratio of bare BIS group was higher than that of paclitaxel group (38%?15% vs 11%?.31%, PO.01).
Conclusion
1 The mechanical characteristics of BIS could fulfill the stringent physical, mechanical and chemical properties for the stents implanting to arteries.
2 The type of zigzag BIS is convenient to be deployed with stringent mechanical properties and good biocompatibility. After implanted into arteries, the BIS do not induce severe inflammatory or foreign body reaction. At 4wk, BISs were covered completely by neointima, after 8 wk, the neointima thickening seem reduced.
3 BIS as a vehicle of loading and releasing drugs could be inhibit significantly the VSMC and neointimal hyperplasia with antiproliferation agent- paclitaxel.
4 BIS is promising and a new strategy in preventing restenosis.
采用生物可降解材料PLLA制备生物可降解性血管内支架(BIS)，对支架的综合性能进行测试使其达到或接近金属血管内支架的性能；研究BIS的生物相容性，评价BIS植入动物血管内不同时期的组织学变化以确定其植入血管的可行性；制备携带抗增生药物紫杉醇的BIS，将紫杉醇BIS和裸BIS植入到实验动物的动脉血管内，探讨紫杉醇BIS防治血管再狭窄的作用。
材料与方法
1．应用分子量100 000单位的PLLA制作直径为0.1-0.6mm的支架基杆，将基杆成形制备出直径为6-15mm的螺旋型和“Z”型支架。对支架的基杆进行造孔和涂膜。测量径向支撑力、表面覆盖率、轴向收缩率和支架扩张率等参数。
2．“Z”型BIS植入到11只实验犬的腹主动脉和髂动脉内，分期处死动物行病理学观察。
3．紫杉醇BIS和裸BIS植入到8只再狭窄实验动物模型犬的腹主动脉内，6周后处死实验动物完整取出支架段血管行病理学观察及免疫组化评价。
结 果
1．制备出螺旋型和“ Z”型两种型号支架，基杆直径为 0．10石nun，支架扩
张后直径在 6上，长度在 3｛。
二．支架植入后 IWk支架杆部有少许纤维组织并有少量血小板沉着，ZWk新
生内膜形成但内膜覆盖不完全，4wb支架杆部基本被新生内膜覆盖，SWk
后新生内膜不再显著增厚，血管壁完整管腔通畅。
3．裸支架组血管平均管腔面积I。于紫杉醇支架组血管平均管腔面积门586
u m‘vs 43 5 u mZ，p＜0．00卜裸支架组血管新生内膜平均增生面积
大于紫杉醇组平均内膜增生面积口4 8们卜m’1）SI二93pm＼p叼刀＊）；
裸支架组PCNA细胞阳性率高于紫杉醇支架组o8％士15％。11％士
0．31％，P功刀1），两组具有显著统计学差异。
结 论
1．生物可降解材料PLLA制作的BIS其机械力学特性可满足支架植入血管内
各项参数的要求。
2．生物可降解性“ Z”型血管内支架易于释放和展开，植入动物血管内无显
著异物和炎性反应，SWk时血管内膜覆盖完全，SWk后内膜生长减弱不引
起显著的内膜增生性改变，具有可靠的机械强度和良好的生物相容性。
3．生物可降解性血管内支架作为载荷和释放药物的有效平台，通过所携带抗
增生药物紫杉醇可以显著地抑制VSMC增殖和血管内膜的增生是防治血
管再狭窄的新策略和理想手段。
Purpose
1 To prepare biodegradable intravascular stents (BIS) with biodegradable materials poly- L -acid (PLLA), the capability of BIS is similar to metallic stents.
2 To investigate BIS's biocompatibility, and evaluate the histopathological findings at a fixed timetable after the BIS implanted so as to determine the possibility of BIS implanted into arteries.
3 To prepare drug eluting BIS with antiproliferation agent-paclitaxel, and both the drug release BIS and bare BIS (without any drug) be implanted into the aorta of canine models of restenosis, to assess the effect of paclitaxel releasing drug BIS at preventing neointimal hyperplasia.
Materials and Methods
1 BIS were prepared with PLLA, porous structures were fabricated and the films were coated at the strut of BIS. The stringent physical and mechanical properties of the BIS were tested.
2 Appropriately sized zigzag BISs were implanted into the aorta and iliac arteries of 11 canines, the animals were euthanized according to a fixed timetable for
histopathological assessment.
3 Both paclitaxel eluting BIS and bare BIS were implanted into the infrarenal aortas of the canine models of restenosis, the animals were euthanized 6 weeks after implantation for histopathological and immunohistochemical assessment.
Results
1 Two types of spiral and zigzag BIS were prepared with PLLA (MW^IOOOOOD), the strut of BIS is from 0.1-0.6, the diameter of BIS from 6-15mm, and the length from 3-8cm.
2 Fibrosis was evidence surrounded the struts of BIS Iwk days after implantation, and scarce blood platelets were deposited on it. At 2wk, endothelialization of the BIS was not completed. At 4wk, the struts were covered completely by neointima. At 8 wk, the neointima seemed not to be thickening, the arteries' wall were smooth and intact.
3 Some significant differences were noted between the paclitaxel BIS group and bare BIS group. The mean lumen area (LA) of bare BIS was smaller than that of the paclitaxel BIS group(77586 n m2 vs 113 435 u m2, pO.OOl). And the mean intimal area (IA) of bare BIS was larger than that of paclitaxel BIS group (24 803 u m2 vs 12 931 u m2 , pO.OOl).
4 The PCNA positive ratio of bare BIS group was higher than that of paclitaxel group (38%?15% vs 11%?.31%, PO.01).
Conclusion
1 The mechanical characteristics of BIS could fulfill the stringent physical, mechanical and chemical properties for the stents implanting to arteries.
2 The type of zigzag BIS is convenient to be deployed with stringent mechanical properties and good biocompatibility. After implanted into arteries, the BIS do not induce severe inflammatory or foreign body reaction. At 4wk, BISs were covered completely by neointima, after 8 wk, the neointima thickening seem reduced.
3 BIS as a vehicle of loading and releasing drugs could be inhibit significantly the VSMC and neointimal hyperplasia with antiproliferation agent- paclitaxel.
4 BIS is promising and a new strategy in preventing restenosis.
引文
1 Dotter C. Transluminally placed coil-spring endoarterial tube grafts, long term patency in canine popliteal artery. Inves Radiol. 1969; 4:327-332.
2 Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation. 1991; 84:1426-1436.
3 张金山．当前我国内支架应用中存在的一些问题．中华放射学杂志 1997，31：295．
4 张金山，王艳萍，徐亚峰．血管内支架植入术后再狭窄的机制与治疗．中国医学影像技术．1998；14：677
5 张金山．严格掌握金属内支架置入术的适应证．中华放射学杂志．1998，32：653-654．
6 Colombo A, Karvouni E. Biodegradable stents: "fulfilling the mission and stepping away". Circulation. 2000 Jul 25; 102(4): 399-404.
7 Stack TE, Califf RM, Phillips HR, et al. Interventional cardiac catheterization at Duke Medical Center. Am J Cardiol. 1988; 62(suppl F): 3F-24F.
8 Rajasubramanian G, Meidell RS, Landau C, et al. Fabrication of resorbable microporous intravascular stents for gene therapy applications. ASAIO J 1994; 40:M584-M589.
9 Ye YW, Landau, C, Meidell RS, et al. Improved bioresorbable microporous intravascular stents for gene therapy. ASAIO J. 1996; 42(5): M823-7.
10 Verheyen CCPM, J R de Wijn, CA Van Blitterswijk, et al. Evaluation of Hydroxylapatite/Poly(L-Lactide) Composites: Mechanical Behavior. J Biomed Mater Res. 1992,26:1277-1281.
11 Freed CE, Vunjak-novakovic G, Iron KJ. Biodegradable polymer scaffolds for tissue engineering. Biotechnology N.Y. 1994,12:689-693.
12 陈锐，陈怀卿，韩君，等．聚L乳酸(PLLA)／β—磷酸三钙(β—TCP)多孔复合材料的制备和性能研究．生物医学工程学杂志，2001；18：177-180．
13 刘俊，刘义荣．聚乳酸的合成及应用．生物医学工程学杂志．2001，18：285-287．
14 王身国．可生物降解高分子的类型、合成和应用．化学通报，1997，2：45-47．
15 Serruys PW, Emanuelsson H, Van der Giessen W et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Early outcome of the Benestent-Ⅱ Pilot Study. Circulation 1996; 93:412-422.
16 Ahn YK, Jeong MH, Kim JW et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model. Cathet Cardiovasc Interv 1999; 48:324-330.
17 Van der Giessen WJ, van Beusekom HM, et al. Heparin-coating of coronary stents. Semin Interv Cardiol 1998; 3:525-531.
18 Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation. 2001 May 8; 103:2289-2295.
19 Alt E, Haehnel I, Beilharz C, et al. Inhibition of neointimal formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost. Circulation 2000 Mar 28; 101:1453-1458.
20 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 Sep; 32:780-786.
21 张金山，欧阳墉．管腔内支架的作用机制和性能．现代腹部介入放射学．北京：科学出版社，2000；239-241．
2 Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation. 1991; 84:1426-1436.
3 张金山．当前我国内支架应用中存在的一些问题．中华放射学杂志 1997，31：295．
4 张金山，王艳萍，徐亚峰．血管内支架植入术后再狭窄的机制与治疗．中国医学影像技术．1998；14：677
5 张金山．严格掌握金属内支架置入术的适应证．中华放射学杂志．1998，32：653-654．
6 Colombo A, Karvouni E. Biodegradable stents: "fulfilling the mission and stepping away". Circulation. 2000 Jul 25; 102(4): 399-404.
7 Stack TE, Califf RM, Phillips HR, et al. Interventional cardiac catheterization at Duke Medical Center. Am J Cardiol. 1988; 62(suppl F): 3F-24F.
8 Rajasubramanian G, Meidell RS, Landau C, et al. Fabrication of resorbable microporous intravascular stents for gene therapy applications. ASAIO J 1994; 40:M584-M589.
9 Ye YW, Landau, C, Meidell RS, et al. Improved bioresorbable microporous intravascular stents for gene therapy. ASAIO J. 1996; 42(5): M823-7.
10 Verheyen CCPM, J R de Wijn, CA Van Blitterswijk, et al. Evaluation of Hydroxylapatite/Poly(L-Lactide) Composites: Mechanical Behavior. J Biomed Mater Res. 1992,26:1277-1281.
11 Freed CE, Vunjak-novakovic G, Iron KJ. Biodegradable polymer scaffolds for tissue engineering. Biotechnology N.Y. 1994,12:689-693.
12 陈锐，陈怀卿，韩君，等．聚L乳酸(PLLA)／β—磷酸三钙(β—TCP)多孔复合材料的制备和性能研究．生物医学工程学杂志，2001；18：177-180．
13 刘俊，刘义荣．聚乳酸的合成及应用．生物医学工程学杂志．2001，18：285-287．
14 王身国．可生物降解高分子的类型、合成和应用．化学通报，1997，2：45-47．
15 Serruys PW, Emanuelsson H, Van der Giessen W et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Early outcome of the Benestent-Ⅱ Pilot Study. Circulation 1996; 93:412-422.
16 Ahn YK, Jeong MH, Kim JW et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model. Cathet Cardiovasc Interv 1999; 48:324-330.
17 Van der Giessen WJ, van Beusekom HM, et al. Heparin-coating of coronary stents. Semin Interv Cardiol 1998; 3:525-531.
18 Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation. 2001 May 8; 103:2289-2295.
19 Alt E, Haehnel I, Beilharz C, et al. Inhibition of neointimal formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost. Circulation 2000 Mar 28; 101:1453-1458.
20 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 Sep; 32:780-786.
21 张金山，欧阳墉．管腔内支架的作用机制和性能．现代腹部介入放射学．北京：科学出版社，2000；239-241．