In vivo blood compatibility and histocompatibility of rapamycin-tirofiban eluting stent★

Abstract

AIM：To observe the thrombosis and restenosis, the changes of histopathological and biochemical indexes after rapamycin-tirofiban eluting stent (RTES) transplantation, and evaluate the blood compatibility and histocompatibility of RTES.

METHODS：The experiment was accomplished in the Laboratory of Experimental Surgery, the Fourth Military Medical University of Chinese PLA between March and November in 2005. Grouping: Eight miniature pigs were randomly divided into experimental group (n =4) and control group (n =4). Stents made with rapamycin-tirofiban and polymer were implanted into the coronary arteries of pigs in experimental group, while stents made with rapamycin and polymer were implanted in the control group. Coronary artery restenosis model was established with coronary over-stretch in swine, 2 stents for each swine. Clopidogrel of 75 mg/d was given for antiplatelet therapy, 3 months in control group and 1 month in experimental group. Evaluation:①The behavior states of animal post-operatively.②The whole blood cell counts and biochemical indexes before and 2 days, 7 days, 4 weeks, 12 weeks after stents were implanted.③All the animals were sacrificed, and the implanted vessels were selected to conduct histopathology observation and then calculate the lumen area losing rate. Losing rate of lumen area (%)=(Surrounding area of stents－lumen area)/surrounding area of stents ×100%.④Lungs, livers, kidneys and the ventricular walls, which infused by the stents supported arteries, were also observed histologically.

RESULT:Eight miniature pigs were involved in the result analysis.①Animal ethology: Before, during and 3 months after the implantation, there was no significant difference in heart rate, blood pressure and body weight between two groups. Behavior, diet or urination was not influenced.②Blood cell count and biochemistry: White blood cell number was increased in both groups 2 days post-operatively [(13.1±2.8)×109, (7.2±2.1)×109 L－1; (12.5±3.3)×109, (6.3±2.2)×109 L－1], with the significant difference (t =3.37, 3.08, P < 0.05); There was no obvious change in whole blood cell, white blood cell and blood platelet counts in the two groups (P > 0.05). γ-glutamic-pyruvic transaminase, glutamyl transpeptidase creatinine and urea nitrogen were all identical with those before implantation (P > 0.05).③Histopathology of vessels: No adhesive thrombosis appeared in the two groups. The lumen area and intimal area were both higher in experimental group than in control group [(4.96±0.35), (4.89±0.46) mm2; (1.12±0.10), (1.05±0.09) mm2], but the losing rate of lumen area was lower than that in control group [(19±9)%, (21±7)%].④Morphology and pathology of organs: All the cells were confirmed normal. No definite inflammatory cell, hemolysis or necrosis was found.

CONCLUSION:Both the blood compatibility and histocompatibility of RTES is implanted in coronary arteries of miniature pigs for three months are good. RTES can decrease the systemic administration dose of antiplatelet drugs.

Diao FR, Lü AL, Zhang W, Li JJ, Zhang RQ, Yuan Y, Hu XJ, Hu Y.In vivo blood compatibility and histocompatibility of rapamycin?鄄tirofiban eluting stent.Zhongguo Zuzhi Gongcheng Yanjiu yu Linchuang Kangfu 2007;11(13):2411-2414(China)
[www.zglckf.com/zglckf/ejournal/upfiles/07-13/13k-2411(ps).pdf]

摘要
目的:观察雷帕霉素－替罗非班复合药物涂层支架置入后再狭窄、血栓、生化指标和重要器官组织病理学变化情况，评估其血液及组织相容性。
方法?押 实验于2005－03/11在解放军第四军医大学实验外科实验室完成。以聚合高分子材料为药物载体，采用微喷法制备雷帕霉素支架及雷帕霉素－替罗非班复合药物涂层支架。实验分组：8只小型猪按随机数字表法分为两组，复合药物组和雷帕霉素组，每组4只。复合药物组应用雷帕霉素－替罗非班复合药物涂层支架，雷帕霉素组应用雷帕霉素支架。再狭窄模型采用国际公认的小型猪冠状动脉过度扩张再狭窄模型。每只猪于冠状动脉中成功置入上述支架各2枚。术后两组小型猪服用硫酸氯吡格雷75 mg/d抗血小板治疗，雷帕霉素组服用3个月，复合药物组服用1个月。实验评估：①观察术后动物行为状态。②支架置入术前、术后2，7 d，4，12周分析全血细胞计数、生化指标。③麻醉后处死动物，取出支架置入段血管,行组织病理学观察，计算管腔面积丢失率。管腔面积丢失率（%）=(支架围绕面积－管腔面积)/支架围绕面积×100%。④取肺、肝、肾组织及支架血管段供血的心室壁行组织学观察。
结果?押8只小型猪均进入结果分析。①术后动物行为学观察：两组术前、术中及术后3个月造影时，动物心率、血压、体质量的变化差异无显著性意义，术后也无明显行为异常及饮食、排尿便异常。②血细胞计数和生化检测结果：复合药物组、雷帕霉素组术后2 d白细胞计数均高于术前[分别为（13.1±2.8）×109，（7.2±2.1）×109 L－1；（12.5±3.3）×109，（6.3±2.2）×109 L－1],差异有显著性意义(t =3.37，3.08，P < 0.05)；其余各时段两组外周全血红细胞、白细胞、血小板计数差异无显著性意义(P > 0.05)。γ－血清谷丙转氨酶、谷氨酰转肽酶及肌酐、尿素氮未见明显改变(P > 0.05)。③血管组织病理学检测:两组血管均未见附壁血栓。复合药物组血管腔面积、新生内膜面积高于雷帕霉素组[分别为（4.96±0.35），（4.89±0.46）mm2；（1.12±0.10），（1.05±0.09）mm2]，管腔面积丢失率低于雷帕霉素组[（19±9）%，（21±7）%]，差异均无显著性意义（P > 0.05）。④重要脏器大体形态及病理学检查：证实细胞形态结构正常，无炎性细胞浸泡、出血和坏死。
结论?押 雷帕霉素－替罗非班复合药物涂层支架置入小型猪冠状动脉后3个月的血液相容性及组织相容性良好，并可减少术后抗血小板药物的全身用药量。
关键词：支架；组织相容性；雷帕霉素；替罗非班；生物材料

刁繁荣，吕安林，张薇，李军杰，张荣庆，苑媛，胡小菁，胡艳.雷帕霉素－替罗非班复合药物涂层支架的血液及组织相容性[J].中国组织工程研究与临床康复，2007，11(13):2411-2414 [www.zglckf.com/zglckf/ejournal/upfiles/07-13/13k-2411(ps).pdf]