液体栓塞材料2-聚甲基丙烯酸羟乙酯的实验研究
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摘要
概述
目前脑动静脉畸形(arteriovenous malformation,AVM)的治疗是以手术切除、血管内栓塞及放射治疗为主要治疗手段的综合治疗,血管内栓塞治疗在脑AVM的治疗中占有重要的地位。除脑AVM本身血管构筑特性外,栓塞材料的选用对治疗效果有着直接影响。目前临床上应用的栓塞材料包括:颗粒材料聚乙烯醇(polyvinyl alcohol,PVA)、粘性液体材料α-氰丙烯酸正丁酯(n-butyl cyanoacrylate,NBCA),以及近年来开始使用的非粘附性液体材料乙烯-乙烯醇共聚物(ethylenevinyl alcohol,EVAL)。颗粒在畸形血管团中弥散差,治疗效果不满意。临床上使用时间最长且应用最广的是NBCA,虽具有栓塞牢固,持久等优点,但它不易操作,且有“粘管”缺点。NBCA栓塞后病灶较硬,不易切除。而Onyx(EVAL的商品名)虽有非粘性特性,操控较简单,但它以二甲基亚砜(dimethyl sulfoxide,DMSO)为溶剂,DMSO具有较明显的血管毒性,可能损伤血管周围的脑组织,因此Onyx的安全性受到质疑。因此,寻找既具备较好的栓塞性能,又有良好的生物相容性栓塞材料具有重要意义。我们与武汉工程大学联合开发出一种新型液体栓塞材料2-聚甲基丙烯酸羟乙酯(2-poly-hydroxyethyl-methacrylate,2-P-HEMA),此材料利用乙醇为溶剂,避免了DMSO的毒性。本课题拟通过研究2-P-HEMA的物理性质、生物相容性以及血管内栓塞实验,来评价其栓塞性能,为进一步的临床应用研究提供实验依据。
本课题分四个部分进行研究:首先研究了2-P-HEMA的物理性质,第二部分研究了生物相容性,随后应用2-P-HEMA栓塞兔肾动脉及其它动脉,最后一部分,通过建立不同流量的脑AVM模型,评价2-P-HEMA栓塞AVM有效性。
第一部分液体栓塞材料2-P-HEMA物理性质的实验研究
目的:研究栓塞材料2-P-HEMA的在乙醇及DMSO溶液中的溶解性能、在水中的固化特性以及固化速度,了解是否达到液体栓塞材料的基本条件,为进一步动物实验提供基础。
方法:1、分别测定2-P-HEMA在不同溶度的乙醇溶液、乙醇/碘比醇溶液、DMSO溶液及DMSO/碘比醇溶液中的溶解性;2、分别配制2%、3.5%、5%、6.5%、8%、9.5%等浓度2-P-HEMA的乙醇溶液、乙醇/碘比醇溶液、乙醇/三氧化二铋溶液、及DMSO/碘比醇溶液,并分别标记组别:1A至6A、1B至6B、1C至6C、1D至6D;3、分别测定以上各组材料在静止盐水中的凝固时间;4、分别测定各组材料在流动盐水的凝固时间。
结果:1、2-P-HEMA在纯乙醇中溶解度很低,在80%以下乙醇浓度中溶解度明显增大,但在20%以下浓度的乙醇中的溶解度较低。2-P-HEMA在纯DMSO溶液中溶解度较高,随着DMSO浓度的降低,2-P-HEMA的溶解度降低。加入显影剂(碘比醇、Bi_2O_3等)不影响2-P-HEMA在乙醇及DMSO溶液中的溶解度。2、2-P-HEMA的乙醇或DMSO溶液注入水中呈絮状固化。以乙醇为溶剂的各组中,低浓度(2%)与高浓度(9.5%)材料在静止水中的凝固时间较中间浓度(3.5%～8.0%)长,以DMSO为溶剂的材料在静止水中的凝固时间随浓度增高而延长。加入显影剂(碘比醇、Bi_2O_3等)不影响凝固时间。3、2-P-HEMA的乙醇或DMSO溶液注入流动水中,较快发生固化,凝固时间明显短于在静止水中时。
结论:1、2-P-HEMA能溶于20%～80%浓度乙醇或30%浓度以上的DMSO溶液中。加入碘比醇或Bi_2O_3等显影剂不影响溶解度。2、2-P-HEMA的乙醇或DMSO溶液注入水中能固化,在静止水中的固化速度明显慢于在流动水中,显影剂不影响固化速度。
第二部分:液体栓塞材料2-P-HEMA的生物相容性研究
目的:对2-P-HEMA进行生物相容性研究,为临床应用的安全性提供依据。
方法:分别对2-P-HEMA进行以下各项实验:Ames致突变实验、体外细胞毒性实验、全身急性、亚急性及慢性毒性实验、溶血实验、出血和凝血时间测定、凝血功能实验等。
结果:1、Ames实验:2-P-HEMA材料各浓度浸提液的突变比值(MR)均小于2,阳性对照组MR值均大于2,提示此材料无致突变作用。2、体外细胞毒性实验:材料浸提液各实验组L929细胞生长无明显抑制现象,对细胞毒性为Ⅰ级,表明此材料无细胞毒性。3、全身急性、亚急性及慢性毒性实验:三种实验中实验组动物一般情况好,无腹泻、运动减少、体重下降等异常情况,各标本组织学检查无细胞变性坏死及炎性细胞浸润,结果提示此材料无全身的毒性作用。4、溶血实验:各浓度材料浸提液无未导致溶血,表明材料无溶血毒性。5、出血、凝血时间测定:材料的各浓度浸提液组小鼠出血、凝血功能均在正常范围,表明其对出血及凝血时间无明显影响。6、凝血功能测定:各实验组对血液的凝血功能各项指标均在正常范围,此材料不影响大鼠的凝血功能。
结论:2-P-HEMA具有良好的生物相容性,无细胞毒性,无致突变,不引起动物全身毒性反应,且血液相容性好,达到了体内置入材料的安全要求。
第三部分液体栓塞剂2-P-HEMA血管内栓塞效应的实验研究
目的:通过应用2-P-HEMA栓塞兔肾动脉、颈外动脉及股动脉,评价2-P-HEMA的短期栓塞及长期栓塞效应。
方法:1、短期栓塞:分别对兔肾动脉、颈外动脉及股动脉进行短期栓塞实验。按栓塞材料的浓度,将肾动脉栓塞实验的动物分为三大组(2%、5%及8%浓度组)。动物麻醉后,手术显露并切开股动脉,插管一侧肾动脉,每大组分别栓塞第一部分中配制好的栓塞剂(B、C、D组材料)。栓塞完成后处死动物,取肾脏组织及肾动脉,进行大体和光镜检查。兔颈外动脉栓塞采用解剖颈总动脉,插管至一侧上颌动脉,注射3B材料,兔股动脉栓塞采用顺行穿刺股动脉置管,注射3B材料,分别在透视下观察栓塞程度;2、长期栓塞:按股动脉插管法,注射3B材料栓塞兔一侧肾动脉,分别于术后一周、一个月及三个月行肾动脉彩超检查及造影复查,处死动物,取肾脏及肾动脉进行大体及光镜检查。
结果:1、中低浓度各亚组材料能顺利通过微导管,注射阻力小,无粘管现象。高浓度各亚组注射阻力大,不易通过微导管。各组材料在透视下显影良好。2、中低浓度各亚组均能完全栓塞肾动脉及其分支,部分动脉肾动脉栓塞时出现材料“再塑形”现象。3、长期栓塞动物多普勒彩超检查未能检测到肾脏血流,肾脏体积逐渐缩小,复查造影未见肾动脉再通。4、肾脏标本可见肾脏动脉腔内填充有栓塞材料,自肾动脉至肾小球动脉内均可见到栓塞材料。早期肾间质内轻度炎性反应,血管壁无破坏,后期肾脏体积缩小,肾组织凝固性坏死,周边炎性细胞浸润,血管内膜轻度增厚。
结论:1、合适浓度2-P-HEMA既能有效栓塞兔肾动脉及其它动脉,又能顺利通过微导管,且无“粘管”现象。2、远期栓塞可靠,无血管再通。术后病理反应轻微,无明显毒性反应。
第四部分液体栓塞剂2-P-HEMA栓塞脑AVM动物模型的实验研究
目的:1、建立三种不同流量的脑AVM动物模型。2、使用2-P-HEMA栓塞三种不同流量的脑AVM动物模型,探讨其栓塞不同流量脑AVM的技术可行性、栓塞有效性及安全性。
方法:1、动物模型的建立:6只动物随机分成低流量组、中流量组及高流量组。低流量模型利用猪天然颅底异网(rete mirabile,RMB),2只中流量组动物采用结扎右侧颈总动脉,造成右侧颈外动脉由对侧咽升动脉经双侧RMB供血,增大了双侧RMB的血流。2只高流量组动物行右侧颈总动脉-颈外静脉吻合术,形成以左侧咽升动脉为供血动脉,双侧RMB为畸形团,右颈总动脉-右颈外静脉为引流静脉的脑AVM模型。2、脑AVM栓塞:各组动物采用股动脉插管法,将微导管置于左侧咽升动脉内,注射栓塞材料栓塞RMB。各组分别于术后第一个月及三个月复查造影。动物处死后取双侧RMB行组织学检查。
结果:1、中高流量组动物手术操作顺利,成功建立了中、高流量脑AVM模型。高流量组一只动物出现吻合口狭窄。2、全部6只动物均顺利完成栓塞,复查造影未见RMB显影。栓塞均在未更换导管情况下完成栓塞,未发性堵管及粘管现象。中高流量组动物栓塞后短期内处死,低流量组动物1个月及3个月后复查造影,见栓塞完全,无血管再通。栓塞材料在RMB内弥散铸型好,无严重炎性反应。
结论:1、通过利用猪天然RMB、结扎猪一侧颈总动脉,以及颈部动静脉吻合,能够建立不同流量的脑AVM模型。2、2-P-HEMA能够有效栓塞不同流量的AVM模型,操作方便、安全性高,有望成为一种新型的脑AVM的非粘附性液体栓塞材料。
Introduction
Brain arteriovenous malformations (AVM) are frequent diseases of cerebral vessel, need diagnosing and treating earlier because of leading to cerebral hemorrgage. Surgery, endovascular embolization and radiosurgery are the basic methods for the treatment of AVMs. The endovascular embolization is an important treatment. The embolic material is the most important factor influencing the curative effects besides angioarchitecture of AVM. Embolization materials used to treat AVM ever since include particle polyvinyl alcohol (PVA), liquid n-butyl cyanoacrylate (NBCA), as well as non-adhesive liquid ethylene vinyl alcohol (EVAL). Partical materials are difficult to deliver through microcatheter, and do not penetrate into nidus deeply. Among the liquids, except the persistent embolization effect, NBCA, used widely in clinics, is difficult to handle, sometimes, they cause the catheter to adhere the artery. NBCA precipitates in nidus vessels and form a rigid solid, which impacts upon resection of nidus. Though EVAL, regarded as non-adhesive embolic agent, sometimes make satisfactory embolization, it is based on dimethylsulfoxide (DMSO). DMSO has angionecrotic properties and may cause degeneration of the white matter or damage the tissue surrounding the AVM. Therefore, a search for an embolic material with optimized physical characteristics and better biocompatibility is mandatory. Wuhan institute of technology and us have developed a new liquid embolic material, 2-poly-hydroxyethyl-methacrylate (2-P-HEMA). 2-P-HEMA can be dissolved in ethanol, so can avoid the angiotoxicity as DMSO. The physical property, biocompatibility, and the embolic effects are to be studied, in order to evaluate its embolic property, and to provide evidence for clinical usage.
This paper includes four parts. In first part, the physical character of 2-P-HEMA is studied. Secondly, the biocompatibility of 2-P-HEMA is investigated. Then, its embolic effect is evaluated by embolizing renal and other artery of rabbit. Lastly, the different flow AVM animal models are established to test the safety and effect of this material for embolizing AVMs.
Part 1. Study on Physical Property of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: The dissolving property of 2-P-HEMA, a new non-adhensive liquidembolic agent, in ethanol and DMSO, and the precipitation property in water werestudied in this part to test whether 2-P-HEMA is suitable for endovascularembolization.
Methods: The highest concentration of 2-P-HEMA in ethanol of differentconcentration was tested respectively. The highest concentration of 2-P-HEMA inother solution such as ethanol/iobitridol mixture, DMSO and DMSO/iobitridol ofdifferent concentration also were tested. The different concentration embolic agents(2%, 3.5%, 5%, 6.5%, 8%, 9.5%) were prepared by mixing 2-P-HEMA with differentsolution (ethanol, ethanol/iobitridol, ethanol/Bi_2O_3, and DMSO/iobitridol). Theseembolic agents were marked as 1A to 6A (ethanol solution), 1B to 6B(ethanol/iobitridol solution), 1C to 6C (ethanol/Bi_2O_3 mixture), and 1D to 6D(DMSO/iobitridol solution). The precipitation time of above agents were tested inimmobile normal sodium (NS) and in floating NS respectively.
Results: The solubility of 2-P-HEMA in pure ethanol was low, and solubility became higher in ethanol of 20% to 80% concentration, but also low in less than 20% ethanol. The dissolution degree of 2-P-HEMA in pure DMSO was higher than other concentration, and also higher than all concentration ethanol solution. With the decline of DMSO concentration, the solubility of 2-P-HEMA in DMSO dropped gradually. The solubility of 2-P-HEMA in ethanol or DMSO was not changed when the mixtures were added by opacifiers such as iobitridol, and Bi_2O_3. The mixtures of 2-P-HEMA with ethanol or DMSO were precipitated to formed flocci form solid after injection into water. The precipitation time of embolic mixture as ethanol solvent was longer in low (2%) and high concentration (9.5%) than medial concentration (3.5% to 8.0%), and was longer in high concentration as DMSO solvent than low concentration. The precipitation time was not affected by adding iobitridol or Bi_2O_3 to mixtures with ethanol or DMSO solvent. The mixture of 2-P-HEMA and ethanol or DMSO was precipitated in few seconds time when injected into floating water in tube, and its precipitation time was shorter than in immobile water.
Conclusion: 2-P-HEMA could be dissolved in 20%~80% ethanol and more than 30% DMSO. The mixture of 2-P-HEMA and ethanol or DMSO can be precipitated when injected into water, and its precipitation time in immobile water is much shorter than in floating water. The solubility and precipitation property of mixtures are not affected by adding opacifiers to mixtures. The physical property of 2-P-HEMA may be suitable for endovascular embolization.
Part 2. Study on Biocompatibility of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: the biocompatibility of 2-P-HEMA in this part was to be studied to evaluate its safety for endovascular embolization and to provide evidence for clinical performance.
Methods: In this part, the following items were made to test the biocompatibility of 2-P-HEMA: Ames test, cytotoxicity test in vitro, acute, subacute, andchronic systemic toxicity test, hemolytic test, measurement of bleeding and clotting time, and hemopexis function.
Results: In ames test, the MR values of leaching liquors of 2-P-HEMA in different concentration were all less than 2, whereas the MR values in positive control group were both more than 2, which revealed 2-P-HEMA being non-mutagenic. The result of cytotoxicity test in vitro showed that L929 cells growth well without inhibition in all experimental groups, and the cytotoxicity was grade I, which proved no cytotoxicity of this embolic agent. The animals of experimental groups were no change in the acute, subacute, andchronic systemic toxicity test. All specimens of different organs and tissues were not be disclosed the cell degeneration and necrosis, and infiltration of inflammatory cells. The evidences of these systemic toxicity tests indicated that 2-P-HEMA have no systemic toxicity. The fact that the leaching liquors of 2-P-HEMA in all concentration could not result in hemolysis indicated obviously that 2-P-HEMA was no hemolysis. The bleeding and clotting times of rats were all among normal range, provided that 2-P-HEMA could not affect bleeding and clotting time. The last test showed 2-P-HEMA had little impact upon the blood coagulation function because the blood coagulation function in experimental groups was normal.
Conclusion: 2-P-HEMA has good biocompatibility with no cytotoxicity, no mutagenic, good hemocompatibility, and not leading to systemic toxicity. 2-P-HEMA can be used as implant for clinical appliance.
Part 3. Experimental Study on Endovascular Embolization Effect of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: The arm of this part is to evaluate the embolism property of 2-P-HEMA by occluding the renal artery, external carotid artery and femoral artery in rabbits.
Methods: The short-term and long-term embolism properties of 2-P-HEMA were studied respectively. In short-term study, according to the concentration of 2-P-HEMA, eighteen animals were divided randomly into three groups: low concentration group (2%), medial concentration group (5%), and high concentration group (8%). After general anesthesia achievement, the right femoral artery of rabbit was cannulated surgically by placement of 4F introducer sheath, and the microcatheter was inserted into the renal artery of one side. The embolic agents marked 1B, 1C, 1D, 3B, 3C, 3D, 5B, 5C, 5D were injected into renal arteries of 2 animals in each subgroup respectively. The embolic agent, made radiopacity by Bi_2O_3, was shaked thoroughly before injection to prevent sedimentation of Bi_2O_3. The embolizations of external carotid artery and femoral artery were performed with embolic agent marked 3B. After the complete embolization was achieved in each animal, the animal was executed immediately, and the kidneys of two sides were taken for macroscopic and microscopic exam. In long-term study, the renal arteries of 6 animals were embolized by agent marked 3B. The ultrasonic exam and angiographic follow-up investigation were performed at 7days, 1 month and 3 months respectively after the embolization procedure. The kidneys of animal were inspected macroscopically and microscopically after angiographic follow-up.
Results: The 2-P-HEMA of low and medial concentration was easy to inject through microcatheter, and difficult to inject in high concentration. There not existed adhesion of microcatheter to vessels in all procedures. The embolic agents were radiopaque clearly. The renal arteries of animals were occluded completely by 2-P-HEMA of low and medial concentration, and the phenomenon of "remodeling" was observed in some embolizations of kidneys. The renal arteries of animals were not detected and the size of kidneys became shrinking gradually by Doppler ultrasonic examination after embolization for a long time. The recanalization of occluded renal arteries was not visible by angiographic follow-up. The renal arteries were found filled by embolic agents when kidney was cut open. Mild inflammatory reaction surrounding arteries in early stage, and chronic reaction to "foreign body" in later stage were detected microscopically.
Conclusion: The embolic agent apparently provides complete occlusion of vessels, is easy to deliver through microcatheter, and unlikely to cause catheter to become adhesive to the vessel. Radiopacity is sufficient, and toxic histopathologic response to the material is mild. The recanalization of occluded vessels is rare and long-term occlusion is achieved. 2-P-HEMA has great potential as an endovascular embolic agent.
Part 4. Embolization of Experimental Brain Arteriovenous Malformation with Liquid 2-Poly-Hydroxyethyl Methacrylate in Swine
Objective: Three blood flows of brain AVM animal models were to be established. The technique feasibility, embolism effects and safety of 2-P-HEMA as embolic agents were to be explored in this part by occluding these AVM models.
Methods: six pigs were randomly divided into three groups: low flow group, medial flow group and high flow group. The normal RMB of pig was used as low flow model. The medial flow model is established by ligation of right common carotid artery, increasing the blood flow through bilateral RMB. The high flow model was built on by surgical anastomosis between right common carotid artery and external jugular vein, which increases greatly the blood flow of RMB because the direct arteriovenous shunt. In medial and high flow models, left and right ascending pharyngeal artery (PA) acted as afferent artery and draining vein respectively, and the bilateral RMB as AVM nidus. All animal models were embolized with 2-P-HEMA by deploying of microcatheter in left PA via transfemoral cannulation. The angiographic follow-up was performed at 1 month and 3 month after embolization procdure in each group. Histopathologic studies of bilateral RMBs were taken to prove occlusion and assess pathologic responses.
Results: All procedures were performed successfully, and three flows of AVM models were constructed as expected. The arteriovenous fistula of one animal became narrow detected by Doppler ultrasonic and angiographic exam in high flow group. Each AVM model was embolized repeatedly with only one microcatheter until RMBs became opaque with fluoroscopy. 2-P-HEMA was easily injected through microcatheters without catheter occlusion and adhesion to vessel. The animals in medial and high flow groups were executed shortly after embolization because animals did not eat food. The angiographic follow-up revealed the complete occlusion without recanalization at 1 month and 3 month after embolization. Deep nidus penetration of materials and no marked inflammatory reaction in the vessel wall or perivascular tissue was observed in the embolized RMB.
Conclusion: Ligation of common carotid artery of one side can construct medial flow of AVM model, and carotid jugular anastomosis can construct high flow of AVM model. The different flow AVM models embolized with 2-P-HEMA are technically feasible, performed easily and safely in swine. Because of its properties, 2-P-HEMA has great potential as a therapeutic embolic agent.
目前脑动静脉畸形(arteriovenous malformation,AVM)的治疗是以手术切除、血管内栓塞及放射治疗为主要治疗手段的综合治疗,血管内栓塞治疗在脑AVM的治疗中占有重要的地位。除脑AVM本身血管构筑特性外,栓塞材料的选用对治疗效果有着直接影响。目前临床上应用的栓塞材料包括:颗粒材料聚乙烯醇(polyvinyl alcohol,PVA)、粘性液体材料α-氰丙烯酸正丁酯(n-butyl cyanoacrylate,NBCA),以及近年来开始使用的非粘附性液体材料乙烯-乙烯醇共聚物(ethylenevinyl alcohol,EVAL)。颗粒在畸形血管团中弥散差,治疗效果不满意。临床上使用时间最长且应用最广的是NBCA,虽具有栓塞牢固,持久等优点,但它不易操作,且有“粘管”缺点。NBCA栓塞后病灶较硬,不易切除。而Onyx(EVAL的商品名)虽有非粘性特性,操控较简单,但它以二甲基亚砜(dimethyl sulfoxide,DMSO)为溶剂,DMSO具有较明显的血管毒性,可能损伤血管周围的脑组织,因此Onyx的安全性受到质疑。因此,寻找既具备较好的栓塞性能,又有良好的生物相容性栓塞材料具有重要意义。我们与武汉工程大学联合开发出一种新型液体栓塞材料2-聚甲基丙烯酸羟乙酯(2-poly-hydroxyethyl-methacrylate,2-P-HEMA),此材料利用乙醇为溶剂,避免了DMSO的毒性。本课题拟通过研究2-P-HEMA的物理性质、生物相容性以及血管内栓塞实验,来评价其栓塞性能,为进一步的临床应用研究提供实验依据。
本课题分四个部分进行研究:首先研究了2-P-HEMA的物理性质,第二部分研究了生物相容性,随后应用2-P-HEMA栓塞兔肾动脉及其它动脉,最后一部分,通过建立不同流量的脑AVM模型,评价2-P-HEMA栓塞AVM有效性。
第一部分液体栓塞材料2-P-HEMA物理性质的实验研究
目的:研究栓塞材料2-P-HEMA的在乙醇及DMSO溶液中的溶解性能、在水中的固化特性以及固化速度,了解是否达到液体栓塞材料的基本条件,为进一步动物实验提供基础。
方法:1、分别测定2-P-HEMA在不同溶度的乙醇溶液、乙醇/碘比醇溶液、DMSO溶液及DMSO/碘比醇溶液中的溶解性;2、分别配制2%、3.5%、5%、6.5%、8%、9.5%等浓度2-P-HEMA的乙醇溶液、乙醇/碘比醇溶液、乙醇/三氧化二铋溶液、及DMSO/碘比醇溶液,并分别标记组别:1A至6A、1B至6B、1C至6C、1D至6D;3、分别测定以上各组材料在静止盐水中的凝固时间;4、分别测定各组材料在流动盐水的凝固时间。
结果:1、2-P-HEMA在纯乙醇中溶解度很低,在80%以下乙醇浓度中溶解度明显增大,但在20%以下浓度的乙醇中的溶解度较低。2-P-HEMA在纯DMSO溶液中溶解度较高,随着DMSO浓度的降低,2-P-HEMA的溶解度降低。加入显影剂(碘比醇、Bi_2O_3等)不影响2-P-HEMA在乙醇及DMSO溶液中的溶解度。2、2-P-HEMA的乙醇或DMSO溶液注入水中呈絮状固化。以乙醇为溶剂的各组中,低浓度(2%)与高浓度(9.5%)材料在静止水中的凝固时间较中间浓度(3.5%～8.0%)长,以DMSO为溶剂的材料在静止水中的凝固时间随浓度增高而延长。加入显影剂(碘比醇、Bi_2O_3等)不影响凝固时间。3、2-P-HEMA的乙醇或DMSO溶液注入流动水中,较快发生固化,凝固时间明显短于在静止水中时。
结论:1、2-P-HEMA能溶于20%～80%浓度乙醇或30%浓度以上的DMSO溶液中。加入碘比醇或Bi_2O_3等显影剂不影响溶解度。2、2-P-HEMA的乙醇或DMSO溶液注入水中能固化,在静止水中的固化速度明显慢于在流动水中,显影剂不影响固化速度。
第二部分:液体栓塞材料2-P-HEMA的生物相容性研究
目的:对2-P-HEMA进行生物相容性研究,为临床应用的安全性提供依据。
方法:分别对2-P-HEMA进行以下各项实验:Ames致突变实验、体外细胞毒性实验、全身急性、亚急性及慢性毒性实验、溶血实验、出血和凝血时间测定、凝血功能实验等。
结果:1、Ames实验:2-P-HEMA材料各浓度浸提液的突变比值(MR)均小于2,阳性对照组MR值均大于2,提示此材料无致突变作用。2、体外细胞毒性实验:材料浸提液各实验组L929细胞生长无明显抑制现象,对细胞毒性为Ⅰ级,表明此材料无细胞毒性。3、全身急性、亚急性及慢性毒性实验:三种实验中实验组动物一般情况好,无腹泻、运动减少、体重下降等异常情况,各标本组织学检查无细胞变性坏死及炎性细胞浸润,结果提示此材料无全身的毒性作用。4、溶血实验:各浓度材料浸提液无未导致溶血,表明材料无溶血毒性。5、出血、凝血时间测定:材料的各浓度浸提液组小鼠出血、凝血功能均在正常范围,表明其对出血及凝血时间无明显影响。6、凝血功能测定:各实验组对血液的凝血功能各项指标均在正常范围,此材料不影响大鼠的凝血功能。
结论:2-P-HEMA具有良好的生物相容性,无细胞毒性,无致突变,不引起动物全身毒性反应,且血液相容性好,达到了体内置入材料的安全要求。
第三部分液体栓塞剂2-P-HEMA血管内栓塞效应的实验研究
目的:通过应用2-P-HEMA栓塞兔肾动脉、颈外动脉及股动脉,评价2-P-HEMA的短期栓塞及长期栓塞效应。
方法:1、短期栓塞:分别对兔肾动脉、颈外动脉及股动脉进行短期栓塞实验。按栓塞材料的浓度,将肾动脉栓塞实验的动物分为三大组(2%、5%及8%浓度组)。动物麻醉后,手术显露并切开股动脉,插管一侧肾动脉,每大组分别栓塞第一部分中配制好的栓塞剂(B、C、D组材料)。栓塞完成后处死动物,取肾脏组织及肾动脉,进行大体和光镜检查。兔颈外动脉栓塞采用解剖颈总动脉,插管至一侧上颌动脉,注射3B材料,兔股动脉栓塞采用顺行穿刺股动脉置管,注射3B材料,分别在透视下观察栓塞程度;2、长期栓塞:按股动脉插管法,注射3B材料栓塞兔一侧肾动脉,分别于术后一周、一个月及三个月行肾动脉彩超检查及造影复查,处死动物,取肾脏及肾动脉进行大体及光镜检查。
结果:1、中低浓度各亚组材料能顺利通过微导管,注射阻力小,无粘管现象。高浓度各亚组注射阻力大,不易通过微导管。各组材料在透视下显影良好。2、中低浓度各亚组均能完全栓塞肾动脉及其分支,部分动脉肾动脉栓塞时出现材料“再塑形”现象。3、长期栓塞动物多普勒彩超检查未能检测到肾脏血流,肾脏体积逐渐缩小,复查造影未见肾动脉再通。4、肾脏标本可见肾脏动脉腔内填充有栓塞材料,自肾动脉至肾小球动脉内均可见到栓塞材料。早期肾间质内轻度炎性反应,血管壁无破坏,后期肾脏体积缩小,肾组织凝固性坏死,周边炎性细胞浸润,血管内膜轻度增厚。
结论:1、合适浓度2-P-HEMA既能有效栓塞兔肾动脉及其它动脉,又能顺利通过微导管,且无“粘管”现象。2、远期栓塞可靠,无血管再通。术后病理反应轻微,无明显毒性反应。
第四部分液体栓塞剂2-P-HEMA栓塞脑AVM动物模型的实验研究
目的:1、建立三种不同流量的脑AVM动物模型。2、使用2-P-HEMA栓塞三种不同流量的脑AVM动物模型,探讨其栓塞不同流量脑AVM的技术可行性、栓塞有效性及安全性。
方法:1、动物模型的建立:6只动物随机分成低流量组、中流量组及高流量组。低流量模型利用猪天然颅底异网(rete mirabile,RMB),2只中流量组动物采用结扎右侧颈总动脉,造成右侧颈外动脉由对侧咽升动脉经双侧RMB供血,增大了双侧RMB的血流。2只高流量组动物行右侧颈总动脉-颈外静脉吻合术,形成以左侧咽升动脉为供血动脉,双侧RMB为畸形团,右颈总动脉-右颈外静脉为引流静脉的脑AVM模型。2、脑AVM栓塞:各组动物采用股动脉插管法,将微导管置于左侧咽升动脉内,注射栓塞材料栓塞RMB。各组分别于术后第一个月及三个月复查造影。动物处死后取双侧RMB行组织学检查。
结果:1、中高流量组动物手术操作顺利,成功建立了中、高流量脑AVM模型。高流量组一只动物出现吻合口狭窄。2、全部6只动物均顺利完成栓塞,复查造影未见RMB显影。栓塞均在未更换导管情况下完成栓塞,未发性堵管及粘管现象。中高流量组动物栓塞后短期内处死,低流量组动物1个月及3个月后复查造影,见栓塞完全,无血管再通。栓塞材料在RMB内弥散铸型好,无严重炎性反应。
结论:1、通过利用猪天然RMB、结扎猪一侧颈总动脉,以及颈部动静脉吻合,能够建立不同流量的脑AVM模型。2、2-P-HEMA能够有效栓塞不同流量的AVM模型,操作方便、安全性高,有望成为一种新型的脑AVM的非粘附性液体栓塞材料。
Introduction
Brain arteriovenous malformations (AVM) are frequent diseases of cerebral vessel, need diagnosing and treating earlier because of leading to cerebral hemorrgage. Surgery, endovascular embolization and radiosurgery are the basic methods for the treatment of AVMs. The endovascular embolization is an important treatment. The embolic material is the most important factor influencing the curative effects besides angioarchitecture of AVM. Embolization materials used to treat AVM ever since include particle polyvinyl alcohol (PVA), liquid n-butyl cyanoacrylate (NBCA), as well as non-adhesive liquid ethylene vinyl alcohol (EVAL). Partical materials are difficult to deliver through microcatheter, and do not penetrate into nidus deeply. Among the liquids, except the persistent embolization effect, NBCA, used widely in clinics, is difficult to handle, sometimes, they cause the catheter to adhere the artery. NBCA precipitates in nidus vessels and form a rigid solid, which impacts upon resection of nidus. Though EVAL, regarded as non-adhesive embolic agent, sometimes make satisfactory embolization, it is based on dimethylsulfoxide (DMSO). DMSO has angionecrotic properties and may cause degeneration of the white matter or damage the tissue surrounding the AVM. Therefore, a search for an embolic material with optimized physical characteristics and better biocompatibility is mandatory. Wuhan institute of technology and us have developed a new liquid embolic material, 2-poly-hydroxyethyl-methacrylate (2-P-HEMA). 2-P-HEMA can be dissolved in ethanol, so can avoid the angiotoxicity as DMSO. The physical property, biocompatibility, and the embolic effects are to be studied, in order to evaluate its embolic property, and to provide evidence for clinical usage.
This paper includes four parts. In first part, the physical character of 2-P-HEMA is studied. Secondly, the biocompatibility of 2-P-HEMA is investigated. Then, its embolic effect is evaluated by embolizing renal and other artery of rabbit. Lastly, the different flow AVM animal models are established to test the safety and effect of this material for embolizing AVMs.
Part 1. Study on Physical Property of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: The dissolving property of 2-P-HEMA, a new non-adhensive liquidembolic agent, in ethanol and DMSO, and the precipitation property in water werestudied in this part to test whether 2-P-HEMA is suitable for endovascularembolization.
Methods: The highest concentration of 2-P-HEMA in ethanol of differentconcentration was tested respectively. The highest concentration of 2-P-HEMA inother solution such as ethanol/iobitridol mixture, DMSO and DMSO/iobitridol ofdifferent concentration also were tested. The different concentration embolic agents(2%, 3.5%, 5%, 6.5%, 8%, 9.5%) were prepared by mixing 2-P-HEMA with differentsolution (ethanol, ethanol/iobitridol, ethanol/Bi_2O_3, and DMSO/iobitridol). Theseembolic agents were marked as 1A to 6A (ethanol solution), 1B to 6B(ethanol/iobitridol solution), 1C to 6C (ethanol/Bi_2O_3 mixture), and 1D to 6D(DMSO/iobitridol solution). The precipitation time of above agents were tested inimmobile normal sodium (NS) and in floating NS respectively.
Results: The solubility of 2-P-HEMA in pure ethanol was low, and solubility became higher in ethanol of 20% to 80% concentration, but also low in less than 20% ethanol. The dissolution degree of 2-P-HEMA in pure DMSO was higher than other concentration, and also higher than all concentration ethanol solution. With the decline of DMSO concentration, the solubility of 2-P-HEMA in DMSO dropped gradually. The solubility of 2-P-HEMA in ethanol or DMSO was not changed when the mixtures were added by opacifiers such as iobitridol, and Bi_2O_3. The mixtures of 2-P-HEMA with ethanol or DMSO were precipitated to formed flocci form solid after injection into water. The precipitation time of embolic mixture as ethanol solvent was longer in low (2%) and high concentration (9.5%) than medial concentration (3.5% to 8.0%), and was longer in high concentration as DMSO solvent than low concentration. The precipitation time was not affected by adding iobitridol or Bi_2O_3 to mixtures with ethanol or DMSO solvent. The mixture of 2-P-HEMA and ethanol or DMSO was precipitated in few seconds time when injected into floating water in tube, and its precipitation time was shorter than in immobile water.
Conclusion: 2-P-HEMA could be dissolved in 20%~80% ethanol and more than 30% DMSO. The mixture of 2-P-HEMA and ethanol or DMSO can be precipitated when injected into water, and its precipitation time in immobile water is much shorter than in floating water. The solubility and precipitation property of mixtures are not affected by adding opacifiers to mixtures. The physical property of 2-P-HEMA may be suitable for endovascular embolization.
Part 2. Study on Biocompatibility of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: the biocompatibility of 2-P-HEMA in this part was to be studied to evaluate its safety for endovascular embolization and to provide evidence for clinical performance.
Methods: In this part, the following items were made to test the biocompatibility of 2-P-HEMA: Ames test, cytotoxicity test in vitro, acute, subacute, andchronic systemic toxicity test, hemolytic test, measurement of bleeding and clotting time, and hemopexis function.
Results: In ames test, the MR values of leaching liquors of 2-P-HEMA in different concentration were all less than 2, whereas the MR values in positive control group were both more than 2, which revealed 2-P-HEMA being non-mutagenic. The result of cytotoxicity test in vitro showed that L929 cells growth well without inhibition in all experimental groups, and the cytotoxicity was grade I, which proved no cytotoxicity of this embolic agent. The animals of experimental groups were no change in the acute, subacute, andchronic systemic toxicity test. All specimens of different organs and tissues were not be disclosed the cell degeneration and necrosis, and infiltration of inflammatory cells. The evidences of these systemic toxicity tests indicated that 2-P-HEMA have no systemic toxicity. The fact that the leaching liquors of 2-P-HEMA in all concentration could not result in hemolysis indicated obviously that 2-P-HEMA was no hemolysis. The bleeding and clotting times of rats were all among normal range, provided that 2-P-HEMA could not affect bleeding and clotting time. The last test showed 2-P-HEMA had little impact upon the blood coagulation function because the blood coagulation function in experimental groups was normal.
Conclusion: 2-P-HEMA has good biocompatibility with no cytotoxicity, no mutagenic, good hemocompatibility, and not leading to systemic toxicity. 2-P-HEMA can be used as implant for clinical appliance.
Part 3. Experimental Study on Endovascular Embolization Effect of Liquid 2-Poly-Hydroxyethyl Methacrylate
Objective: The arm of this part is to evaluate the embolism property of 2-P-HEMA by occluding the renal artery, external carotid artery and femoral artery in rabbits.
Methods: The short-term and long-term embolism properties of 2-P-HEMA were studied respectively. In short-term study, according to the concentration of 2-P-HEMA, eighteen animals were divided randomly into three groups: low concentration group (2%), medial concentration group (5%), and high concentration group (8%). After general anesthesia achievement, the right femoral artery of rabbit was cannulated surgically by placement of 4F introducer sheath, and the microcatheter was inserted into the renal artery of one side. The embolic agents marked 1B, 1C, 1D, 3B, 3C, 3D, 5B, 5C, 5D were injected into renal arteries of 2 animals in each subgroup respectively. The embolic agent, made radiopacity by Bi_2O_3, was shaked thoroughly before injection to prevent sedimentation of Bi_2O_3. The embolizations of external carotid artery and femoral artery were performed with embolic agent marked 3B. After the complete embolization was achieved in each animal, the animal was executed immediately, and the kidneys of two sides were taken for macroscopic and microscopic exam. In long-term study, the renal arteries of 6 animals were embolized by agent marked 3B. The ultrasonic exam and angiographic follow-up investigation were performed at 7days, 1 month and 3 months respectively after the embolization procedure. The kidneys of animal were inspected macroscopically and microscopically after angiographic follow-up.
Results: The 2-P-HEMA of low and medial concentration was easy to inject through microcatheter, and difficult to inject in high concentration. There not existed adhesion of microcatheter to vessels in all procedures. The embolic agents were radiopaque clearly. The renal arteries of animals were occluded completely by 2-P-HEMA of low and medial concentration, and the phenomenon of "remodeling" was observed in some embolizations of kidneys. The renal arteries of animals were not detected and the size of kidneys became shrinking gradually by Doppler ultrasonic examination after embolization for a long time. The recanalization of occluded renal arteries was not visible by angiographic follow-up. The renal arteries were found filled by embolic agents when kidney was cut open. Mild inflammatory reaction surrounding arteries in early stage, and chronic reaction to "foreign body" in later stage were detected microscopically.
Conclusion: The embolic agent apparently provides complete occlusion of vessels, is easy to deliver through microcatheter, and unlikely to cause catheter to become adhesive to the vessel. Radiopacity is sufficient, and toxic histopathologic response to the material is mild. The recanalization of occluded vessels is rare and long-term occlusion is achieved. 2-P-HEMA has great potential as an endovascular embolic agent.
Part 4. Embolization of Experimental Brain Arteriovenous Malformation with Liquid 2-Poly-Hydroxyethyl Methacrylate in Swine
Objective: Three blood flows of brain AVM animal models were to be established. The technique feasibility, embolism effects and safety of 2-P-HEMA as embolic agents were to be explored in this part by occluding these AVM models.
Methods: six pigs were randomly divided into three groups: low flow group, medial flow group and high flow group. The normal RMB of pig was used as low flow model. The medial flow model is established by ligation of right common carotid artery, increasing the blood flow through bilateral RMB. The high flow model was built on by surgical anastomosis between right common carotid artery and external jugular vein, which increases greatly the blood flow of RMB because the direct arteriovenous shunt. In medial and high flow models, left and right ascending pharyngeal artery (PA) acted as afferent artery and draining vein respectively, and the bilateral RMB as AVM nidus. All animal models were embolized with 2-P-HEMA by deploying of microcatheter in left PA via transfemoral cannulation. The angiographic follow-up was performed at 1 month and 3 month after embolization procdure in each group. Histopathologic studies of bilateral RMBs were taken to prove occlusion and assess pathologic responses.
Results: All procedures were performed successfully, and three flows of AVM models were constructed as expected. The arteriovenous fistula of one animal became narrow detected by Doppler ultrasonic and angiographic exam in high flow group. Each AVM model was embolized repeatedly with only one microcatheter until RMBs became opaque with fluoroscopy. 2-P-HEMA was easily injected through microcatheters without catheter occlusion and adhesion to vessel. The animals in medial and high flow groups were executed shortly after embolization because animals did not eat food. The angiographic follow-up revealed the complete occlusion without recanalization at 1 month and 3 month after embolization. Deep nidus penetration of materials and no marked inflammatory reaction in the vessel wall or perivascular tissue was observed in the embolized RMB.
Conclusion: Ligation of common carotid artery of one side can construct medial flow of AVM model, and carotid jugular anastomosis can construct high flow of AVM model. The different flow AVM models embolized with 2-P-HEMA are technically feasible, performed easily and safely in swine. Because of its properties, 2-P-HEMA has great potential as a therapeutic embolic agent.
引文
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