新型明胶微球栓塞实验动物组织器官的有效性及安全性的初步研究

发表时间:2018/8/24   来源:《健康世界》2018年14期   作者:何凡 王露平 文振超 李启洋 陈旭东
[导读] 初步探讨新型明胶微球颗粒栓塞实验动物组织器官的有效性及安全性,为新型明胶微球的进一步临床应用提供研究数据

深圳市人民医院介入科  518000
        摘要:目的:初步探讨新型明胶微球颗粒栓塞实验动物组织器官的有效性及安全性,为新型明胶微球的进一步临床应用提供研究数据。方法:将6只家犬分为A、B两组,A组3只(对照组),B组3只(实验组),分别行股动脉穿刺插管,采用单管导管及微导管超选择插管至右侧肾动脉近分叉处行DSA造影检查,记录肾动脉分支形态及末梢血运情况。A组采用5ml生理盐水注射治疗,B组采用(直径500~710μm)新型明胶微球颗粒行栓塞治疗,栓塞终点为末梢血运消失,保留分支血管显影。栓塞结束后再次行DSA造影检查,再次记录肾动脉分支形态,评估栓塞疗效。栓塞术后1天、3天及1周抽血检查犬血常规、肝功能及肾功能,术后2周取肾组织送病理检查,观察栓塞范围及组织缺血坏死情况。结果:6只家犬均成功完成股动脉插管、肾动脉造影及栓塞术。术后1天及3天新型明胶微球颗粒栓塞组血常规白细胞值较对照组增高(P<0.05),术后1周两组血常规比较差异无统计学意义。术后1天、3天及1周两组犬肝功能及肾功能对比差异无统计学意义。术后2周肾组织病理示新型明胶微球组栓塞肾脏后肾实质呈均匀缺血坏死表现。结论:新型明胶微球能安全、有效的栓塞实验动物组织器官。
        关键词:DSA;明胶微球;栓塞术
        He fan,Wang Luping,Wen Zhenchao,Li Qiyang,Chen Xudong
        Interventional Department of Shenzhen People's Hospital 518000
        [Abstract] Objective:To investigate the effectiveness and safety of the new gelatin microspheres in the experimental animal tissues and organs,and to provide the research data for the further clinical application of the new gelatin microspheres. Methods:6 dogs were divided into groups of A and B,3 in group A(control group)and 3 in group B(experimental group). The femoral artery puncture intubation was performed respectively. Single tube catheterization and micro catheter were selected to be put into the proximal part of the right renal artery by DSA contrast examination,and the morphology of the renal artery and the peripheral blood transport were recorded. Group A was treated with 5ml saline injection,and group B was treated with a new gelatin microsphere particle(500~710 um diameter). The end point of the embolization was disappearance of peripheral blood,and the branch vessel was retained. After the end of embolization,DSA angiography was performed again,and the morphology of the renal artery branch was re-recorded to evaluate the embolic effect. Blood routine,liver function and renal function were examined at 1 days,3 days and 1 weeks after embolization. The renal tissue was taken for pathological examination at 2 weeks after the operation,and the extent of embolism and tissue ischemia and necrosis were observed. Results:femoral artery catheterization,renal arteriography and embolization were successfully completed in all 6 dogs. The blood routine leucocyte value of the new gelatin microspheres 1 and 3 days after the operation was higher than that of the control group(P<0.05). There was no significant difference between the two groups in 1 weeks after the operation. There was no significant difference in liver function and renal function between the two groups after 1 days,3 days and 1 weeks after operation. At 2 weeks postoperatively,the pathological changes of renal tissue showed that after the embolization of the kidney,a new gelatin microsphere group showed homogeneous ischemic necrosis. Conclusion:the new gelatin microspheres can effectively and effectively embolate the tissues and organs of experimental animals.
        [Key words]DSA;Gelatin microspheres;Embolization


        血管内栓塞材料,尤其是明胶颗粒栓塞材料在介入治疗中起着不可或缺的作用。优良的栓塞材料在介入治疗过程中,以其生物相容性好、可控的体内降解速率、抗原性极其微弱、可选定的栓塞材料颗粒大小等优点,在血管畸形闭塞、体内血管破裂时紧急快速止血、栓塞肿瘤血管、阻断体内异常分流、携带治疗性药物或生物活性分子(如基因材料、干细胞、免疫疫苗、抗癌药品、示踪材料等)等治疗过程中起着重要的作用[1,2]。
        1.材料与方法
        1.1材料
        实验动物:选用杂种健康犬6只(由深圳市雄威犬培育基地提供),雌雄不限,未孕,体重10~25kg。主要器械设备及材料:数字减影血管造影机(美国GE公司),4F动脉鞘(日本TERUMO公司),蓝泥鳅导丝(Cordis公司),4F单弯导管(Cordis公司),直径0.021微导管及配套微导丝(Cook公司),对比剂为碘普罗胺(300mI/ml,拜耳保健广州公司),新型明胶海绵颗粒(深圳依威迪公司)。
        1.2方法
        将6只家犬分为A、B两组,A组3只(对照组),B组3只(实验组)。阿托品
(1ml)臀部肌肉内注射10min后,予戊巴比妥钠(30mg/kg)行静脉内注射维持麻醉状态。右侧腹股沟处备皮,消毒,铺无菌巾,手触股动脉搏动处,作一5mm长切口,使用改良Seldinger穿刺技术将血管鞘插入右侧股动脉,采用单弯导管及微导管超选择插管至右侧肾动脉近分叉处行DSA造影检查,记录肾动脉分支形态及末梢血运情况。A组采用5ml生理盐水注射治疗,B组采用(直径500~710μm)新型明胶微球颗粒行栓塞治疗,栓塞终点为末梢血运消失,保留分支血管显影。栓塞结束后再次行DSA造影检查,再次记录肾动脉分支形态,评估栓塞疗效。栓塞术后1天、3天及1周抽血检查犬血常规、肝功能及肾功能,术后2周取肾组织送病理检查,观察栓塞范围及组织缺血坏死情况。
        2.结果
        6只家犬均成功完成股动脉插管、肾动脉造影及栓塞术。术后1天及3天新型明胶微球颗粒栓塞组血常规示白细胞值较对照组增高(P<0.05),术后1周两组血常规比较差异无统计学意义。术后1天、3天及1周两组犬肝功能及肾功能对比差异无统计学意义。术后2周肾组织病理示新型明胶微球组栓塞肾脏后肾实质呈均匀缺血坏死表现。


               图4,HE染色见栓塞肾组织呈坏死改变

        3.讨论
        血管内栓塞材料沿着追求颗粒均一、颗粒大小稳定、组织分布均衡、可操控性强及毒副作用小等方向发展。血管内介入栓塞治疗的早期,肌肉碎块、丝线条、塑料颗粒、发丝、乳胶等曾用作栓塞材料来使用。早期的栓塞材料没有统一的标准,颗粒大小不均匀,稳定性差,不能达到靶器官末梢栓塞的目的,且栓塞不均衡,可控性差,易发生异位栓塞。理想的血管内栓塞材料应具备以下条件:良好的生物相容性;能有效地栓塞血管病变;无毒、不致癌、不致畸、廉价易获得;良好的悬浮性易通过不同规格的微导管,避免栓塞过程中颗粒堵塞微导管;能产生非损害性炎症[3],诱发血栓形成、具有不透射线的可视性;易消毒,能控制闭塞血管的时间长短、一旦需要可经皮回收或使血管再通等[4]。
        明胶以其良好的生物相容性在医学上长期用来作为人体内置入假体、人工血管、组织缺损实行人工再造的细胞培养构建支架等的重要材料。明胶颗粒栓塞临床效果尤为突出。以往明胶颗粒制作采用毒性戊二醛交联的方法,毒性物质使用操作的过程和毒性戊二醛在栓塞材料中残留一直是限制其使用的问题[5]。本研究使用的是已获得自主知识产权,采用新型独特生产工艺和无毒交联生产的明胶微球颗粒,前期体外实验已证实了该产品具有颗粒分布均一、无毒、颗粒大小稳定等特点。本研究的目的是验证新型栓塞材料的栓塞效果及安全性。通过犬肾动脉栓塞实验术后观察,前3天出现白细胞升高,考虑与栓塞术后炎性反应有关,为组织自身反应。栓塞术后1周血象恢复正常,且肝、肾功能栓塞前后对比无统计学差异,提示栓塞材料安全、无毒性。术后2周观察栓塞效果大体标本示栓塞范围呈均匀缺血坏死表现,组织病理表现已呈均匀完成坏死改变,说明本栓塞材料颗粒大小均匀且稳定,能在血管内稳定其颗粒粒径,较好的适应血管的走行,达到栓塞动脉血管的末梢,实现完全栓塞组织血管的目的,满足临床对栓塞材料的要求。

参考文献:
[1] Khayata MH,Dean BL,Spetzler RF. Materials and embolic agents for endovascular treatment. Neurosurg Clin N Am 1994;5(3):475-484
[2]Matsumaru Y,Hyodo A,Nose T,et al. Embolic materials for endovascular treatment of cerebral lesions. Biomater Sci Polym Ed. 1997;8(7):555-569
[3]Vinters H V et al. Collagen microbeads:Turjman F. Massound T F experimental evaluation of an embolic agent in the rete mirabile of the swine. AJNR Am J Neuroradiol 1995;16(5):1031-1036.
[4]赵成如。介入医学栓塞材料。山东生物医学工程,2002;21(3):54-57.
[5]Senturk C,Cakir V,Yorukoglu K et al. Looking for the ideal particle:an experimental embolization study.Cardiovasc Intervent Radiol. 2010;33(2):336-45.
基金项目:深圳市重点学科建设能力提升项目 201506013


 
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