颅内动脉机械取栓装置的研制及实验研究
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摘要
概述
脑卒中是全球第二死亡原因,其中约80%是由动脉阻塞引起的局灶性缺血性脑卒中引起,是引起病人致死致残的主要原因。在缺血性脑卒中患者中,主要由较大血管(直径>2mm)栓塞所致,这种较大血管闭塞形成的脑梗死称为栓塞性脑梗死,其致死率在53%-92%。据统计我国每年有325万人新发生脑血栓。因此寻求一种新的、安全有效的治疗方式,提高此类疾病的治愈率将尤为重要。
对于颅内动脉栓塞性脑梗死的治疗目前经静脉和(或)动脉内重组人组织型纤溶酶原激活剂(Rt-PA)药物溶栓已经显示出能够改善神经系统预后的效果,但由于动静脉溶栓时间窗短,血管再通的时间长,溶栓症状性脑出血率高,以及一些患者不适合溶栓治疗,因此仅有4.5%-6.3%的患者能够接受溶栓治疗,基于这种情况如何以更短的时间、最小的风险使血管再通是治疗血栓栓塞性脑梗死的关键。目前机械装置取栓为栓塞性脑梗死的患者提供了一种新的治疗手段,因其具有血管再通率高、治疗时间窗长,相关并发症发生率低以及血管再通所需时间短等优势受到了越来越多的关注,成为近年血管内治疗领域研究的热点。
这些颅内血管取栓装置的研制及治疗技术多处于研究阶段,一些已经处于Ⅰ、Ⅱ期临床试验阶段。目前国内外用于治疗急性栓塞性脑梗死的取栓装置仅有美国FDA认证的MERCI取栓器和去年刚刚应用于临床的Permumbra负压吸引取栓系统,应用临床病例有限,价格昂贵,更为关键的问题是,这些机械取栓系统均无远端保护装置,有的还需阻断血流,使得脑出血,远端血管再次梗塞的发生机率较高,因此研制出更为安全有效的机械取栓装置尤为必要,将使栓塞性脑梗死血管内治疗发生质的飞跃。基于此我们与湖南埃普特医疗器械有限公司合作研制出结构完善、价格合理具有血栓取出和远端保护一体化的新型颅内动脉取栓装置并进行相关实验研究,以验证取栓装置的安全性、有效性,探讨机械性取栓的时间窗及优势,为颅内动脉取栓装置应用于临床提供理论依据和安全保证,加快国产颅内动脉取栓装置的临床应用步伐,推动急性栓塞性脑梗死机械取栓技术的开展,提高此类疾病的治愈率和改善预后。
本课题研究分两大部分,第一部分为颅内动脉机械取栓装置的研制和动物模型的建立,实验分两步进行：实验研究一颅内动脉机械取栓装置的研制及体外实验研究；实验研究二适合机械性取栓的急性栓塞性脑梗死动物模型的建立与评价。第二部分为颅内动脉机械取栓装置取栓的动物实验研究,实验分两步进行：实验研究一急性血栓栓塞性脑梗死机械性取栓疗效评价的对比实验研究；实验研究二急性栓塞性脑梗死不同时间窗取栓后磁共振弥散成像及脑组织中BDNF蛋白表达变化的动物实验研究。
第一部分颅内动脉机械取栓装置的研制和动物模型的建立
实验研究一颅内动脉机械取栓装置的研制及体外实验研究
目的：开发研制出一种具有取栓和远端保护一体化的颅内动脉取栓装置。
方法：与湖南埃普特医疗器械有限公司合作,以镍钛合金丝和铂铱合金为材料,克服目前美国Merci取栓器械的不足,更新设计理念,应用精密编织机和激光焊接机械编织成一种可调控直径大小具有斜面结构的取栓网篮,并利用高密度聚乙烯(HDPE High-density polyethylene)、聚四氟乙烯(PTFE polytetrafluoroethylene)、丙烯腈-丁二烯-苯乙烯塑料(ABS Acrylonitrile Butadiene Styrene plastic)、聚碳酸脂(PC Polycarbonate)、铂钨合金(PtW)等材料生产出与之匹配的导引管、收集管、导引导丝、装载器及控制手柄等输送取栓控制系统。并进行取栓装置的体外模拟实验。按照医疗器械国家推荐标准YY0450.1项目中力学检测要求进行取栓装置外观、X射线探测性、网篮密度和断裂力、弯曲、破裂、连接强度等物理性能检测试验；按照中国医药行业标准GB/T16886.1.2.4.11项目中医疗器械生物学评价要求进行溶血、毒性、致敏、热源反应等生物学检测。
结果：通过体外模拟实验证实可控的取栓网篮可以有效的取出血管内血栓,并具有远端保护功能,避免血栓碎片栓塞远端血管,增加了取栓的安全性,取栓输送控制系统顺畅。取栓装置力学检测结果显示外观无扭结、腐蚀、折痕等非自然弯曲,各部件示标在X线下具有可视性。取栓网篮断裂力>5N,网篮网孔最大直径小于0.4mm。破裂试验无破裂痕迹,弯曲试验无缺陷及损坏痕迹,连接强度达到行业标准；生物学检测未发现明显过敏、溶血、发热及毒性反应,具有良好的生物相容性。
结论：颅内动脉取栓装置设计理念先进,结构合理,生产技术和工艺达到国内外同类产品领先水平。本装置具有取栓和远端保护一体化的优势,未见相关报道,有自主知识产权,体外实验安全有效,为其进行相关的动物和临床试验提供了可靠保证。
实验研究二适合机械取栓的急性栓塞性脑梗死动物模型的建立与评价
目的建立适合动脉内机械取栓的近似于人急性栓塞性脑梗死的动物模型,并对模型及取栓效果进行评价。
方法30只新西兰大白兔行一侧颈总动脉结扎,一侧颈总动脉血流临时阻断凝血酶注入法制作急性栓塞性脑梗死模型。应用数字减影血管造影(DSA)、脑磁共振弥散成像(DWI)、经颅多普勒(TCD)及病理检查来评价模型建立的效果。取制膜成功的新西兰兔20只,按随机数字表法分为非治疗组和取栓治疗组,每组10只,非治疗组不作任何治疗,取栓组于栓塞后6h应用颅内动脉取栓装置取栓。分别于栓塞前、栓塞后1h、栓塞后6h行TCD检查记录右侧大脑中动脉平均流速；于栓塞后6h、24h行磁共振弥散成像记录ADC值。非治疗组栓塞24h后处死动物并取脑5只行TTC染色、5只行HE染色及组织切片应用光学、电子显微镜观察病理变化。取栓组取栓后行DSA检查了解血管再通情况,比较两组不同时段磁共振表观弥散系数(ADC)、大脑中动脉流速(Vmca)的变化情况。
结果：30只新西兰大白兔造膜后行DSA显示栓塞侧颈总动脉的闭塞率为83%。栓塞6h DWI显示梗塞灶,24h病理检查TTC染色可见梗死区,光镜下梗死区可见脑组织水肿,神经细胞发生凝固性坏死,核固缩、消失,神经细胞和胶质细胞明显减少甚至消失。电镜神下可见神经元形态、结构破坏,细胞器肿胀明显,部分线粒体空泡化,星形细胞足板空泡化,内皮细胞核变性坏死。取栓后栓塞血管再通率80%,栓塞前后、取栓前后Vmca的比较有统计学意义(栓塞前后：P=0.000;取栓前后：P=0.000),栓塞后6h取栓组Vmca为42.28±1.92cm/s,非治疗组Vmca为29.02±1.72cm/s,两组间Vmca比较有统计学意义(F=47.490P=0.000)；取栓组取栓后ADC值呈上升趋势,非治疗组ADC值下降,栓塞后24h取栓组ADC值为0.81±0.08,非治疗组ADC值为0.56±0.10,两组ADC值比较有统计学意义(P=0.000)。
结论：应用血流临时阻断凝血酶注入法制作适合机械取栓的急性动脉栓塞动物模型的成功率高,模型稳定,重复性好,适用于颅内动脉取栓装置的实验研究和疗效评价。
第二部分颅内动脉机械取栓装置取栓的动物实验研究
实验研究一急性血栓栓塞性脑梗死机械取栓疗效评价的对比实验研究
目的通过实验研究论证国产颅内动脉取栓装置取栓的有效性及安全性,与动脉内溶栓比较探讨机械取栓的优势,为颅内动脉取栓装置应用于临床提供理论依据。
方法采用血流临时阻断凝血酶注入法制备适合机械取栓的兔急性栓塞性脑梗死模型30只,按随机数字表法分为非治疗组、溶栓组、机械取栓组,治疗组于栓塞后3h分别应用颅内动脉取栓装置行机械取栓和应用重组人组织型纤溶酶原激活剂(Rt-PA)动脉内溶栓,取、溶栓前后行数字减影血管造影(DSA)了解血管再通情况,行经颅多普勒(TCD)记录大脑中动脉流速(VMCA)变化情况。各组分别于栓塞后3h、6h、8h、12h、24h行磁共振弥散成像(MR-DWI)比较各组间表观弥散系数(ADC)的差异；治疗组于24h行头颅CT平扫检查了解治疗后颅内并发症发生情况。治疗结束24h时行神经功能评分,磁共振及CT检查结束后处死动物取栓塞取栓部位血管行病理光镜、电镜观察,断头取脑行脑组织切片的光镜电镜病理学观察。
结果取栓、溶栓组的血管再通率分别是80%,20%,再通率的差异有统计学意义(P=0.025),两组治疗后VMCA的比较有统计学意义(P=0.000)；取栓部位血管病理光镜及电镜观察提示血管内皮细胞排列整齐,无血管内皮损伤表现；头颅CT检查提示取栓组未见颅内出血情况,溶栓组颅内出血的发生率为10%；取栓组与溶栓组、非治疗组12h、24h时磁共振ADC值的比较差异均有统计学意义(P均<0.05),其它各时间点两组ADC值的比较差异均无统计学意义(P均>0.05)；取栓组取栓后ADC值呈上升趋势,溶栓组、非治疗组ADC值呈下降趋势；取栓组神经功能缺陷评分明显高于溶栓组和非治疗组,与溶栓组和非治疗组比较差异具有统计学意义(溶栓组：P=0.003；非治疗组：P=0.001)；光镜和电镜检查发现取栓组脑组织神经元形态未见明显异常,星形细胞足板轻度空泡化,神经元损伤较轻微；溶栓组细胞器度中-重度肿胀,血管腔受压,星形细胞足板空泡化,星形胶质细胞水肿,神经元损伤明显；非治疗组脑神经元形态、结构破坏,染色质边集,核固缩、碎裂,核膜溶解、消失,星形细胞足板明显空泡化,血管腔受压变窄,内皮细胞核变性。
结论实验证实颅内动脉取栓装置取栓能够迅速恢复闭塞动脉血流,有效提高了闭塞动脉的再通率,早期取栓后可挽救缺血性损伤的脑组织,是急性血栓栓塞性脑梗死安全、有效的治疗方式,治疗效果优于目前应用的血管内治疗方法,具有很好的临床应用前景。
实验研究二急性栓塞性脑梗死不同时间窗取栓后磁共振弥散成像及脑组织中BDNF蛋白表达变化的动物实验研究
目的：应用国产颅内动脉取栓装置对兔急性栓塞性脑梗死行机械取栓,研究分析不同时间窗取栓后磁共振弥散加权成像ADC值、梗死体积及脑组织中脑源性神经营养因子表达的变化,探讨颅内动脉取栓装置机械取栓的效果和治疗的时间窗。
方法：采用血流临时阻断凝血酶注入法制备适合机械取栓的兔急性血栓栓塞性脑梗死模型25只,按随机数字表法分为非治疗组(不作任何治疗)、3h机械取栓组、6h机械取栓组、8h机械取栓组、12h机械取栓组(分别于制模成功后3h、6h、8h、12h在DSA引导下经股动脉插管应用颅内动脉取栓装置行机械取栓),每组5只,各组分别在3h、6h、8h、12h、24h行磁共振弥散加权成像,计算各时段表观弥散系数(ADC)和梗死体积。检查结束后处死动物,断头取脑免疫组化法观察脑组织中BDNF蛋白表达变化并行脑组织切片的光镜电镜病理学观察。
结果：非治疗组、12h取栓组在急性期内ADC值逐渐降低,梗死体积逐渐扩大,而3h、6h、8h取栓组在急性期取栓后ADC值逐渐上升,梗死体积缩小；3h、6h、8h取栓组梗塞体积在12h、24h较非治疗组同时段分别缩小10.4%、9.8%、5.1%和18.7%、15.9%、10.6%。梗死后24h,与非治疗组和12h取栓组比较,3h、6h和8h取栓组ADC值较高,梗死体积较低,差异均有统计学意义(P值均<0.05)；与8h取栓组比较,3h、6h取栓组ADC值较高,梗死体积较低,ADC值的差异均有统计学意义(3h：P=0.000；6h：P=0.000),梗死体积的差异无统计学意义(3h：P=0.699；6h：P=1.000)；与6h取栓组比较,3h取栓组ADC值较高,梗死体积较低,ADC值差异无统计学意义(P=0.235),梗死体积的差异无统计学意义(P=1.000)。24h BDNF蛋白表达结果显示：3h、6h和8h取栓组BDNF表达明显高于12h取栓组和非治疗组,差异均有统计学意义(P值均<0.05)；3h取栓组BDNF蛋白表达高于6h、8h取栓组,3h取栓组与6h、8h取栓组BDNF蛋白阳性细胞表达数的比较有统计学意义(P值分别为：0.002；0.000),6h与8h取栓组间的比较无统计学意义(P=0.580)。光镜和电镜检查发现3h取栓组脑组织神经元形态未见明显异常,神经元损伤较轻微呈轻度改变；6h和8h取栓组神经元有明显损伤,部分神经元变性,呈中度改变；非治疗组神经元形态、结构破坏,神经元细胞广泛坏死呈重度改变。
结论：栓塞性脑梗死早期应用颅内动脉取栓装置取栓可减轻脑缺血性损伤的程度,机械取栓是急性栓塞性脑梗死有效的治疗方式。机械取栓因其有快速恢复血流的特点适当地延长了治疗的时间窗,超早期治疗是机械取栓的最佳治疗时机,8小时内的取栓均有治疗意义；DWI是动态观察评价急性脑梗死治疗效果的敏感影像学手段。
Introduction
Stroke is the second leading cause of death worldwide, of which80percent is caused by focal ischemic stroke resulting from artery embolism.And in ischemic stroke patients, when the diameter of blood vessels greater than2millimeters became blocked, embolic encephalon infarction of which fatality rate is53%-92%formed. According to the statistics,3.25million cerebral thrombosis patients occur in our country every year, so it is important to look for a safe, effective, and feasible method in the treatment of patients with cerebral thrombosis in order to improve the cure rate of this disease.
At present, thrombolysis with intravenous or arterial rt-PA for treatment of cerebral infarction is effective because it can improve prognosis of the nervous system. However, only4.5%-6.3%patients can receive thrombolytic therapy due to some reasons such as short window for thrombolytic therapy,long recanalization time,high incidence of cerebral hemorrhage and so on. Based on above phenomenon.how to gain higher recanalization and minimize risks in shorter time is the key to cure arterothrombtic cerebral infarction(ACI). Mechanical thrombectomy provides a newly valuable technology for treatment of embolic encephalon infarction. Now, it attracts more and more attention and is becoming the hot spot in the field of endovascular therapy for its higher rate of recanalization, lower complication rate and longer time windows.
Most of the mechanical thrombectomy device is still under preclinical study phase,although some in Phase I or II Clinical Trial. At the moment, thrombectomy device for curing acute arterothrombtic cerebral infarction is very few in the world. As far as we know, there are only two systems, one is MERCI thrombectomy device passed authentication via U.S.A. FDA,and the other is penumbra negative pressure thrombectomy device applied to clinical use last year. Due to some shortcomings of present thrombectomy devices such as short application in Clinical Cases, high price, lack of distal protection device and high rate of again infarction,it seems to be particularly necessary to develop a safe and effective thrombectomy device. We have developed a new type of cerebral artery thrombectomy device which has many advantages of perfect structure, reasonable price and distal protection device, cooperated with Medical Apparatus&Instruments Company. Its effectiveness and safety as well as time windows were verified through experimental study. The study is to provide the theoretic foundation and security guarantees for cerebral artery thrombectomy device in clinical application, promote the application of homemade device and the development of cerebral artery thrombectomy technique so as to increase the cure rate and improve the prognosis of this disease
The study includs two parts,one is research of mechanical thrombectomy device in cerebral artery and establishment of acute embolic cerebral infarction animal model, the other is experimental study on the mechanical thrombectomy in the treatment of cerebral artery embolism. The first part is divided into two experiments.The first experiment is about research on the mechanical thrombectomy in the treatment of cerebral artery embolism and vitro experiment. The second experiment is about establishment and evaluation of acute embolic cerebral infarction animal model which is suit to mechanical thrombectomy. The third experiment comprise two parts.The first part is about Comparative efficacy evaluation experimental study of acute thromboembolic cerebral infarction using mechanical thrombectomy,the second is about Animal experiment study of magnetic resonance diffusion imaging and brain BDNF protein expression changes after acute embolic cerebral infarction embolectomy at different time windows
Part I Development of mechanical thrombectomy device and establishment of animal model for intracranial arterial mechanical thrombectomy
Experiment1Development and experiment in vitro of mechanical thrombectomy device for intracranial arterial thrombus
Objective:Design&Manufacture a device which not only removes thrombus but also protects distalend.
Methods:We renewed design idea and overcame shortcomings of commercially produced import thrombectomy device at present, cooperating with Hunan putnam's medical instrument Co. LTD. niti wire and platinoiridium was applied as materials and a thrombectomy bascket which can control the diameter size and has a cant was produced, by using precision braiding machine and laser welding machines basket. Meanwhile, matching fairlead、collecting pipe、wire-guide、Loader、controlling handle and other control system were manufactured by using HDPE、PTFE、ABS、 PC、PtW and other material. Do vitro tests. According to YY0450.1of national criteria, the appearance of mechanical thrombectomy、X-ray detectability, basket's density、disruptive force、bend、fracture. Joint strength and other inspection of playsical properties were proceed; According to GB/T16886.1.2.4.11of Chinese medicine industry standards, hemolysis、toxicity、sensitization、fever reaction and other biological tests were performed.
Results:It was confirmed by vitro tests that thrombectomy bascket can effectively remove intravascular thrombi, protect remote blood vessels from thrombosis fragments blocking and increase the safety of thrombectomy. The result of device mechanical property examination didn't show twist、corrode、Creases and other unnatural bent. All Components can be detected in the X-ray. The disruptive force>5N, the diameter of wire-mesh basket less than0.4mm。 Bursting test hasn't break trace, bend test is zero defect, Joint strength meet the industry standard; Biological tests showed that there were no hemolysis, toxicity,sensitization, fever reaction, and indicated it has good biocompatibility.
Conclusion:The design idea of mechanical thrombectomy is advanced, rational construction. Technology have reached the technical level of the similar products at home and abroad. The device has advantages of incorporated thrombectomy, distal protection,safety, and provide reliability for its animal experiment and clinical test.
Experiment2Establishment and evaluation of acute embolic infarction animal model for mechanical thrombectomy
Objective:To Establish Animal models of acute arterial embolism which is suit to mechanical thrombectomy, similar to human acute embolic cerebral infarction, and evaluate the effectiveness of embolectomy to the model.
Methods:Acute embolic cerebral infarction model was established by methods of carotid artery ligated on one side, temporary carotid artery occlusion and Injection of thrombin on the other side in New Zealand rabbits (n=30). evaluated the effectiveness of the model by Using DSA、DWI、TCD and pathological examination.20New Zealand rabbits which were successfully modeled were randomly assigned by random number table into non-treatment group and thrombectomy treatment group(10rabbits for each group), the non-treatment group did not get any treatment, thrombectomy treatment group received the intracranial arterial embolectomy by device6h later after embolism onset. Used the TCD examination respectively and record the average velocity of the right middle cerebral artery before the embolism and after embolism1h and6h; used DWI to record ADC value after embolism6h and24h. the non-treatment group were sacrificed after embolism24h,5brains were dyed with TTC stain, the rest of5brain with HE stain were observed the pathological changes light microscope, electron microscope and immunohistochemistry. the Vascular recanalization were detected under DSA after embolectomy of the treatment group. Comparing the ADC and Vmca changes between the two group in different time.
Results:The DSA showed that the occlusion rate of the embolization side of the carotid artery is83%after the30New Zealand rabbits model establishment. The DWI showed infarcts after embolization6h,24h pathological checking (dyed with TTC stain) showed infarcted zone, Brain edema, nerve cell coagulation necrosis, Karyopyknosis and disappearance, nerve cell and glial cell obvious decrease or disappearance. It showed that the ultra-structure of the nerve cell was damaged, the organelle was obviously swelling, part of the mitochondria vacuolized, the foot board of the astrocytes vacuolized, endothelial nuclei degenerated.the blood vessel recanalization rates was80%after embolectomy, it is statistical significance (before and after embolization:P=0.000; before and after embolectomy: P=0.000)compared the Vmca before and after embolization,before and after the embolectomy. The Vmca of the thrombolysis after embolized6h group was42.28±1.92cm/s, the Vmca of the non-treatment group was29.02±1.72cm/s, comparison between the two groups was statistical significance(F=47.490P=0.000); the ADC of the embolectomy group after embolectomy was on the rise, the ADC of the non-treatment group was on the decline, the ADC of the thrombolysis after embolized24h group was0.81±0.08, the ADC of the non-treatment group was0.56±0.10, compared the ADC of the two group was statistical significance(P=0.000).
Conclusion:The success rate is high,the stability of the model is satisfactory and it has a good repeatability to use the method of temporary carotid artery occlusion and Injection of thrombin to make animal models of acute arterial embolism which is suit to mechanical thrombectomy, this method is suit to experimental study and effect evaluation for intracranial arteries thrombectomy device.
Part Ⅱ Animal experiment study of intracranial arterial mechanical embolectomy device
Experiment1Comparative experimental study of efficacy evaluation of acute thromboembolic cerebral infarction mechanical thromboectomy
Objective:To demonstrate the efficacy and safety of domestic intracranial arterial embolectomy device through the experimental study, to explore the advantages between mechanical thrombectomy and mtra-arterial thrombolysis. Providing a basic theory for intracranial arterial embolectomy using into clinically.
Methods:The acute arterial thromboembolism animal model was established by injection thrombin into rabbit artery with blood flow temporary block, which is suitable to mechanical embolectomy in30rabbit. According to the random number table, the30rabbit are divided into non-treatment group, the thrombolysis group, mechanical thrombectomy group. After3hours of embolization, the thrombolysis group received intra-arterial recombinant human tissue-type plasminogen activator (Rt-PA) thrombolysis, mechanical thrombectomy of intracranial arterial embolectomy device was applied to mechanical thrombectomy group, the situation of vessel recanalization was observed under digital subtraction angiography (DSA), as well middle cerebral artery flow velocity (VMCA) changes were record through the transcranial Doppler (TCD), before and after treatment. Each group, after embolization,3h,6h,8h,12h,24h respectively received magnetic resonance diffusion imaging (MR-DWI). differences in apparent diffusion coefficient (ADC) were compared; brain CT scan was performed to check the intracranial complications after treatment in treatment group at24hours, the neurological deficits were scored24h later, pathological changes of vessel and brain tissue were observed by a light microscope and transmission electron microscope after examination of24h magnetic resonance and CT.
Results:Embolectomy, thrombolysis group recanalization rate was80%,20%respectively, re-pass rate difference was statistically significant (P=0.025), the VMCA of the two groups after treatment was statistically significant (P=0.000).; the vascular pathology of embolectomy parts observed by light microscopy and electron microscopy demonstrated endothelial cells arranged in neat rows, without performance of the vascular endothelial damage; head CT examinations showed the thrombectomy group had no intracranial bleeding, the intracranial hemorrhage rate of the thrombolytic group was10%; The differences of ADC value after12h and24h MRI between the thrombectomy group and the thrombolysis group were statistically significant (P<0.05), the ADC value differences in other each time were not statistically significant (P>0.05);; thrombectomy group ADC values showed an upward trend after the embolectomy. In thrombolysis group, non-treatment group, ADC values showed a downward trend; neurological deficit score of thrombectomy group was significantly higher than the thrombolysis group and the non-treatment group, had statistically significant difference compared with the thrombolysis group and non-treatment group (thrombolysis group:P=0.003non-treatment group: P=0.001); light and electron microscope examination revealed that the brain neuronal morphology of the thrombectomy group did not significantly abnormal, astrocytic foot plate mild vacuolization, neuronal damage is minor; thrombolysis group organelles degree in-re-swelling, compression of the vessel lumen, astrocytic foot plate vacuolization, edema of the astrocytes, and neuronal damage obvious; neurons form of non-treatment group, structural damage, chromatin margination, nuclear solid shrinkage, fragmentation, nuclear membrane dissolved and disappeared, was vacuolization of the astrocytic foot plate, compression narrowing of the vessel lumen, endothelial cell nucleus degeneration.
Conclusion:The experiment confirmed that embolectomy of intracranial arterial embolectomy device can quickly restore the occluded artery blood flow to improve the occlusive vascular recanalization rate, early embolectomy can save ischemic brain, it is an effective and safe treatment for the acute thromboembolic cerebral infarction.It is better than the current application of endovascular treatment, has good prospect for clinical application.
Experiment2Animal experiment study of magnetic resonance diffusion imaging and brain BDNF protein expression changes after acute embolic cerebral infarction embolectomy at different time windows
Objective:Mechanical embolectomy with the domestic intracranial arterial embolectomy device was performed in rabbit model of acute embolic cerebral infarction. To research and analyze the changes of magnetic resonance diffusion-weighted imaging, ADC value, infarct volume and brain-derived neurotrophic factor expression at different time windows after embolectomy, and to explore the effects and time window using mechanical thrombectomy treatment by intracranial arterial embolectomy device
Methods:The acute arterial thromboembolism animal model was established by injection thrombin into rabbit artery with blood flow temporary block, which is suitable mechanical embolectomy in25rabbit. According to the random number table,25rabbits were divided into non-treatment group,3hours mechanical thrombectomy group,6hours mechanical thrombectomy group,8hours mechanical thrombectomy group,12hours mechanical thrombectomy group (n=5each group).(mechanical embolectomy was performed at3h,6h,8h,12h through the femoral artery undering DSA guide), magnetic resonance diffusion-weighted imaging, the calculation of each period of apparent diffusion coefficient (ADC) and infarct volume were observed at3h,6h,8h,12h,24h. The animals were sacrificed after MRI, brains were removed and observed BDNF protein expression changes with immunohistochemical method, as well pathology examination by light and electron microscopy,(the experiment of3hours thrombectomy group used the experimental data of second part of the experiment one, the total using experimental animals are20).
Results:In the acute phase, ADC values of the non-treatment group and12h thrombectomy group gradually decreased, and infarct volume gradually expanded. In acute phase after embolectomy, ADC values of3h,6h,8h thrombectomy groups gradually increased, and infarct volume gradually reduced. From6h to24h, infarct volume gradually expanded in non-treatment group and12h thrombectomy group. Compared with non-treatment group, infarct volume of3h,6h,8h thrombectomy groups were reduced by10.4%,9.8%,5.1%and24.7%,23.9%,10.6%at the same time segment of12h and24h.24hours after infarction, compared with non-treatment group and12h thrombectomy group,3h,6h and8h thrombectomy groups were with higher ADC values and lower infarct volumes, the differences were statistically significant (P<0.05). Compared with8h thrombectomy group,3h,6h thrombectomy groups were with higher ADC values and lower infarct volumes. Differences of the ADC values were statistically significant (3h:P=0.000;6h:P=0.000); infarct volumes had no significant difference (3h:P=0.699;6h:P=1.000). Compared with6h thrombectomy group,3h thrombectomy group were with higher ADC values and lower infarct volumes, the difference between them wase not statistically significant (ADC values:P=0.235infarct volumes:P=1.000).24h BDNF protein expression results presented that BDNF expression of3h,6h and8h thrombectomy groups were significantly higher than12h thrombectomy group and non-treatment group, where differences were statistically significant (P<0.05). BDNF protein expression in3h thrombectomy group was higher than in6h,8h thrombectomy groups, Compared with6h and8h thrombectomy group, Differences of the BDNF protein expression were statistically significant (6h:P=0.00208h:P=0.000); Compared with8h thrombectomy group,6h thrombectomy group were with higher BDNF protein expression, the difference between them wase not statistically significant (P=0.580). Light and electron microscope examination revealed that there were no obvious morphological abnormalities of brain tissue neurons in3h thrombectomy group. Neuronal damage was minor with slight changes. There were obvious damage of neurons in6h and8h thrombectomy groups, with part of the neuronal degeneration and moderate changes. Morphous and structure of neurons were damaged in non-treatment group, there were extensive necrosis of neuronal cells with severe changes.
Conclusion:Application of intracranial arterial embolectomy device to thrombectomy in the early stage of thromboembolic cerebral infarction can reduce cerebral ischemic injury. It's an effective for acute embolic cerebral infarction.The characteristic that mechanical embolectomy could rapidly recovered the blood flow make it more appropriate to extend the therapeutic time window. The ultra-early treatment is the best occasion for mechanical embolectomy. Thrombectomy within eight hours has therapeutic significance; DWI is a sensitive imaging method for dynamic observing and evaluating the therapeutic effect of acute cerebral infarction.
脑卒中是全球第二死亡原因,其中约80%是由动脉阻塞引起的局灶性缺血性脑卒中引起,是引起病人致死致残的主要原因。在缺血性脑卒中患者中,主要由较大血管(直径>2mm)栓塞所致,这种较大血管闭塞形成的脑梗死称为栓塞性脑梗死,其致死率在53%-92%。据统计我国每年有325万人新发生脑血栓。因此寻求一种新的、安全有效的治疗方式,提高此类疾病的治愈率将尤为重要。
对于颅内动脉栓塞性脑梗死的治疗目前经静脉和(或)动脉内重组人组织型纤溶酶原激活剂(Rt-PA)药物溶栓已经显示出能够改善神经系统预后的效果,但由于动静脉溶栓时间窗短,血管再通的时间长,溶栓症状性脑出血率高,以及一些患者不适合溶栓治疗,因此仅有4.5%-6.3%的患者能够接受溶栓治疗,基于这种情况如何以更短的时间、最小的风险使血管再通是治疗血栓栓塞性脑梗死的关键。目前机械装置取栓为栓塞性脑梗死的患者提供了一种新的治疗手段,因其具有血管再通率高、治疗时间窗长,相关并发症发生率低以及血管再通所需时间短等优势受到了越来越多的关注,成为近年血管内治疗领域研究的热点。
这些颅内血管取栓装置的研制及治疗技术多处于研究阶段,一些已经处于Ⅰ、Ⅱ期临床试验阶段。目前国内外用于治疗急性栓塞性脑梗死的取栓装置仅有美国FDA认证的MERCI取栓器和去年刚刚应用于临床的Permumbra负压吸引取栓系统,应用临床病例有限,价格昂贵,更为关键的问题是,这些机械取栓系统均无远端保护装置,有的还需阻断血流,使得脑出血,远端血管再次梗塞的发生机率较高,因此研制出更为安全有效的机械取栓装置尤为必要,将使栓塞性脑梗死血管内治疗发生质的飞跃。基于此我们与湖南埃普特医疗器械有限公司合作研制出结构完善、价格合理具有血栓取出和远端保护一体化的新型颅内动脉取栓装置并进行相关实验研究,以验证取栓装置的安全性、有效性,探讨机械性取栓的时间窗及优势,为颅内动脉取栓装置应用于临床提供理论依据和安全保证,加快国产颅内动脉取栓装置的临床应用步伐,推动急性栓塞性脑梗死机械取栓技术的开展,提高此类疾病的治愈率和改善预后。
本课题研究分两大部分,第一部分为颅内动脉机械取栓装置的研制和动物模型的建立,实验分两步进行：实验研究一颅内动脉机械取栓装置的研制及体外实验研究；实验研究二适合机械性取栓的急性栓塞性脑梗死动物模型的建立与评价。第二部分为颅内动脉机械取栓装置取栓的动物实验研究,实验分两步进行：实验研究一急性血栓栓塞性脑梗死机械性取栓疗效评价的对比实验研究；实验研究二急性栓塞性脑梗死不同时间窗取栓后磁共振弥散成像及脑组织中BDNF蛋白表达变化的动物实验研究。
第一部分颅内动脉机械取栓装置的研制和动物模型的建立
实验研究一颅内动脉机械取栓装置的研制及体外实验研究
目的：开发研制出一种具有取栓和远端保护一体化的颅内动脉取栓装置。
方法：与湖南埃普特医疗器械有限公司合作,以镍钛合金丝和铂铱合金为材料,克服目前美国Merci取栓器械的不足,更新设计理念,应用精密编织机和激光焊接机械编织成一种可调控直径大小具有斜面结构的取栓网篮,并利用高密度聚乙烯(HDPE High-density polyethylene)、聚四氟乙烯(PTFE polytetrafluoroethylene)、丙烯腈-丁二烯-苯乙烯塑料(ABS Acrylonitrile Butadiene Styrene plastic)、聚碳酸脂(PC Polycarbonate)、铂钨合金(PtW)等材料生产出与之匹配的导引管、收集管、导引导丝、装载器及控制手柄等输送取栓控制系统。并进行取栓装置的体外模拟实验。按照医疗器械国家推荐标准YY0450.1项目中力学检测要求进行取栓装置外观、X射线探测性、网篮密度和断裂力、弯曲、破裂、连接强度等物理性能检测试验；按照中国医药行业标准GB/T16886.1.2.4.11项目中医疗器械生物学评价要求进行溶血、毒性、致敏、热源反应等生物学检测。
结果：通过体外模拟实验证实可控的取栓网篮可以有效的取出血管内血栓,并具有远端保护功能,避免血栓碎片栓塞远端血管,增加了取栓的安全性,取栓输送控制系统顺畅。取栓装置力学检测结果显示外观无扭结、腐蚀、折痕等非自然弯曲,各部件示标在X线下具有可视性。取栓网篮断裂力>5N,网篮网孔最大直径小于0.4mm。破裂试验无破裂痕迹,弯曲试验无缺陷及损坏痕迹,连接强度达到行业标准；生物学检测未发现明显过敏、溶血、发热及毒性反应,具有良好的生物相容性。
结论：颅内动脉取栓装置设计理念先进,结构合理,生产技术和工艺达到国内外同类产品领先水平。本装置具有取栓和远端保护一体化的优势,未见相关报道,有自主知识产权,体外实验安全有效,为其进行相关的动物和临床试验提供了可靠保证。
实验研究二适合机械取栓的急性栓塞性脑梗死动物模型的建立与评价
目的建立适合动脉内机械取栓的近似于人急性栓塞性脑梗死的动物模型,并对模型及取栓效果进行评价。
方法30只新西兰大白兔行一侧颈总动脉结扎,一侧颈总动脉血流临时阻断凝血酶注入法制作急性栓塞性脑梗死模型。应用数字减影血管造影(DSA)、脑磁共振弥散成像(DWI)、经颅多普勒(TCD)及病理检查来评价模型建立的效果。取制膜成功的新西兰兔20只,按随机数字表法分为非治疗组和取栓治疗组,每组10只,非治疗组不作任何治疗,取栓组于栓塞后6h应用颅内动脉取栓装置取栓。分别于栓塞前、栓塞后1h、栓塞后6h行TCD检查记录右侧大脑中动脉平均流速；于栓塞后6h、24h行磁共振弥散成像记录ADC值。非治疗组栓塞24h后处死动物并取脑5只行TTC染色、5只行HE染色及组织切片应用光学、电子显微镜观察病理变化。取栓组取栓后行DSA检查了解血管再通情况,比较两组不同时段磁共振表观弥散系数(ADC)、大脑中动脉流速(Vmca)的变化情况。
结果：30只新西兰大白兔造膜后行DSA显示栓塞侧颈总动脉的闭塞率为83%。栓塞6h DWI显示梗塞灶,24h病理检查TTC染色可见梗死区,光镜下梗死区可见脑组织水肿,神经细胞发生凝固性坏死,核固缩、消失,神经细胞和胶质细胞明显减少甚至消失。电镜神下可见神经元形态、结构破坏,细胞器肿胀明显,部分线粒体空泡化,星形细胞足板空泡化,内皮细胞核变性坏死。取栓后栓塞血管再通率80%,栓塞前后、取栓前后Vmca的比较有统计学意义(栓塞前后：P=0.000;取栓前后：P=0.000),栓塞后6h取栓组Vmca为42.28±1.92cm/s,非治疗组Vmca为29.02±1.72cm/s,两组间Vmca比较有统计学意义(F=47.490P=0.000)；取栓组取栓后ADC值呈上升趋势,非治疗组ADC值下降,栓塞后24h取栓组ADC值为0.81±0.08,非治疗组ADC值为0.56±0.10,两组ADC值比较有统计学意义(P=0.000)。
结论：应用血流临时阻断凝血酶注入法制作适合机械取栓的急性动脉栓塞动物模型的成功率高,模型稳定,重复性好,适用于颅内动脉取栓装置的实验研究和疗效评价。
第二部分颅内动脉机械取栓装置取栓的动物实验研究
实验研究一急性血栓栓塞性脑梗死机械取栓疗效评价的对比实验研究
目的通过实验研究论证国产颅内动脉取栓装置取栓的有效性及安全性,与动脉内溶栓比较探讨机械取栓的优势,为颅内动脉取栓装置应用于临床提供理论依据。
方法采用血流临时阻断凝血酶注入法制备适合机械取栓的兔急性栓塞性脑梗死模型30只,按随机数字表法分为非治疗组、溶栓组、机械取栓组,治疗组于栓塞后3h分别应用颅内动脉取栓装置行机械取栓和应用重组人组织型纤溶酶原激活剂(Rt-PA)动脉内溶栓,取、溶栓前后行数字减影血管造影(DSA)了解血管再通情况,行经颅多普勒(TCD)记录大脑中动脉流速(VMCA)变化情况。各组分别于栓塞后3h、6h、8h、12h、24h行磁共振弥散成像(MR-DWI)比较各组间表观弥散系数(ADC)的差异；治疗组于24h行头颅CT平扫检查了解治疗后颅内并发症发生情况。治疗结束24h时行神经功能评分,磁共振及CT检查结束后处死动物取栓塞取栓部位血管行病理光镜、电镜观察,断头取脑行脑组织切片的光镜电镜病理学观察。
结果取栓、溶栓组的血管再通率分别是80%,20%,再通率的差异有统计学意义(P=0.025),两组治疗后VMCA的比较有统计学意义(P=0.000)；取栓部位血管病理光镜及电镜观察提示血管内皮细胞排列整齐,无血管内皮损伤表现；头颅CT检查提示取栓组未见颅内出血情况,溶栓组颅内出血的发生率为10%；取栓组与溶栓组、非治疗组12h、24h时磁共振ADC值的比较差异均有统计学意义(P均<0.05),其它各时间点两组ADC值的比较差异均无统计学意义(P均>0.05)；取栓组取栓后ADC值呈上升趋势,溶栓组、非治疗组ADC值呈下降趋势；取栓组神经功能缺陷评分明显高于溶栓组和非治疗组,与溶栓组和非治疗组比较差异具有统计学意义(溶栓组：P=0.003；非治疗组：P=0.001)；光镜和电镜检查发现取栓组脑组织神经元形态未见明显异常,星形细胞足板轻度空泡化,神经元损伤较轻微；溶栓组细胞器度中-重度肿胀,血管腔受压,星形细胞足板空泡化,星形胶质细胞水肿,神经元损伤明显；非治疗组脑神经元形态、结构破坏,染色质边集,核固缩、碎裂,核膜溶解、消失,星形细胞足板明显空泡化,血管腔受压变窄,内皮细胞核变性。
结论实验证实颅内动脉取栓装置取栓能够迅速恢复闭塞动脉血流,有效提高了闭塞动脉的再通率,早期取栓后可挽救缺血性损伤的脑组织,是急性血栓栓塞性脑梗死安全、有效的治疗方式,治疗效果优于目前应用的血管内治疗方法,具有很好的临床应用前景。
实验研究二急性栓塞性脑梗死不同时间窗取栓后磁共振弥散成像及脑组织中BDNF蛋白表达变化的动物实验研究
目的：应用国产颅内动脉取栓装置对兔急性栓塞性脑梗死行机械取栓,研究分析不同时间窗取栓后磁共振弥散加权成像ADC值、梗死体积及脑组织中脑源性神经营养因子表达的变化,探讨颅内动脉取栓装置机械取栓的效果和治疗的时间窗。
方法：采用血流临时阻断凝血酶注入法制备适合机械取栓的兔急性血栓栓塞性脑梗死模型25只,按随机数字表法分为非治疗组(不作任何治疗)、3h机械取栓组、6h机械取栓组、8h机械取栓组、12h机械取栓组(分别于制模成功后3h、6h、8h、12h在DSA引导下经股动脉插管应用颅内动脉取栓装置行机械取栓),每组5只,各组分别在3h、6h、8h、12h、24h行磁共振弥散加权成像,计算各时段表观弥散系数(ADC)和梗死体积。检查结束后处死动物,断头取脑免疫组化法观察脑组织中BDNF蛋白表达变化并行脑组织切片的光镜电镜病理学观察。
结果：非治疗组、12h取栓组在急性期内ADC值逐渐降低,梗死体积逐渐扩大,而3h、6h、8h取栓组在急性期取栓后ADC值逐渐上升,梗死体积缩小；3h、6h、8h取栓组梗塞体积在12h、24h较非治疗组同时段分别缩小10.4%、9.8%、5.1%和18.7%、15.9%、10.6%。梗死后24h,与非治疗组和12h取栓组比较,3h、6h和8h取栓组ADC值较高,梗死体积较低,差异均有统计学意义(P值均<0.05)；与8h取栓组比较,3h、6h取栓组ADC值较高,梗死体积较低,ADC值的差异均有统计学意义(3h：P=0.000；6h：P=0.000),梗死体积的差异无统计学意义(3h：P=0.699；6h：P=1.000)；与6h取栓组比较,3h取栓组ADC值较高,梗死体积较低,ADC值差异无统计学意义(P=0.235),梗死体积的差异无统计学意义(P=1.000)。24h BDNF蛋白表达结果显示：3h、6h和8h取栓组BDNF表达明显高于12h取栓组和非治疗组,差异均有统计学意义(P值均<0.05)；3h取栓组BDNF蛋白表达高于6h、8h取栓组,3h取栓组与6h、8h取栓组BDNF蛋白阳性细胞表达数的比较有统计学意义(P值分别为：0.002；0.000),6h与8h取栓组间的比较无统计学意义(P=0.580)。光镜和电镜检查发现3h取栓组脑组织神经元形态未见明显异常,神经元损伤较轻微呈轻度改变；6h和8h取栓组神经元有明显损伤,部分神经元变性,呈中度改变；非治疗组神经元形态、结构破坏,神经元细胞广泛坏死呈重度改变。
结论：栓塞性脑梗死早期应用颅内动脉取栓装置取栓可减轻脑缺血性损伤的程度,机械取栓是急性栓塞性脑梗死有效的治疗方式。机械取栓因其有快速恢复血流的特点适当地延长了治疗的时间窗,超早期治疗是机械取栓的最佳治疗时机,8小时内的取栓均有治疗意义；DWI是动态观察评价急性脑梗死治疗效果的敏感影像学手段。
Introduction
Stroke is the second leading cause of death worldwide, of which80percent is caused by focal ischemic stroke resulting from artery embolism.And in ischemic stroke patients, when the diameter of blood vessels greater than2millimeters became blocked, embolic encephalon infarction of which fatality rate is53%-92%formed. According to the statistics,3.25million cerebral thrombosis patients occur in our country every year, so it is important to look for a safe, effective, and feasible method in the treatment of patients with cerebral thrombosis in order to improve the cure rate of this disease.
At present, thrombolysis with intravenous or arterial rt-PA for treatment of cerebral infarction is effective because it can improve prognosis of the nervous system. However, only4.5%-6.3%patients can receive thrombolytic therapy due to some reasons such as short window for thrombolytic therapy,long recanalization time,high incidence of cerebral hemorrhage and so on. Based on above phenomenon.how to gain higher recanalization and minimize risks in shorter time is the key to cure arterothrombtic cerebral infarction(ACI). Mechanical thrombectomy provides a newly valuable technology for treatment of embolic encephalon infarction. Now, it attracts more and more attention and is becoming the hot spot in the field of endovascular therapy for its higher rate of recanalization, lower complication rate and longer time windows.
Most of the mechanical thrombectomy device is still under preclinical study phase,although some in Phase I or II Clinical Trial. At the moment, thrombectomy device for curing acute arterothrombtic cerebral infarction is very few in the world. As far as we know, there are only two systems, one is MERCI thrombectomy device passed authentication via U.S.A. FDA,and the other is penumbra negative pressure thrombectomy device applied to clinical use last year. Due to some shortcomings of present thrombectomy devices such as short application in Clinical Cases, high price, lack of distal protection device and high rate of again infarction,it seems to be particularly necessary to develop a safe and effective thrombectomy device. We have developed a new type of cerebral artery thrombectomy device which has many advantages of perfect structure, reasonable price and distal protection device, cooperated with Medical Apparatus&Instruments Company. Its effectiveness and safety as well as time windows were verified through experimental study. The study is to provide the theoretic foundation and security guarantees for cerebral artery thrombectomy device in clinical application, promote the application of homemade device and the development of cerebral artery thrombectomy technique so as to increase the cure rate and improve the prognosis of this disease
The study includs two parts,one is research of mechanical thrombectomy device in cerebral artery and establishment of acute embolic cerebral infarction animal model, the other is experimental study on the mechanical thrombectomy in the treatment of cerebral artery embolism. The first part is divided into two experiments.The first experiment is about research on the mechanical thrombectomy in the treatment of cerebral artery embolism and vitro experiment. The second experiment is about establishment and evaluation of acute embolic cerebral infarction animal model which is suit to mechanical thrombectomy. The third experiment comprise two parts.The first part is about Comparative efficacy evaluation experimental study of acute thromboembolic cerebral infarction using mechanical thrombectomy,the second is about Animal experiment study of magnetic resonance diffusion imaging and brain BDNF protein expression changes after acute embolic cerebral infarction embolectomy at different time windows
Part I Development of mechanical thrombectomy device and establishment of animal model for intracranial arterial mechanical thrombectomy
Experiment1Development and experiment in vitro of mechanical thrombectomy device for intracranial arterial thrombus
Objective:Design&Manufacture a device which not only removes thrombus but also protects distalend.
Methods:We renewed design idea and overcame shortcomings of commercially produced import thrombectomy device at present, cooperating with Hunan putnam's medical instrument Co. LTD. niti wire and platinoiridium was applied as materials and a thrombectomy bascket which can control the diameter size and has a cant was produced, by using precision braiding machine and laser welding machines basket. Meanwhile, matching fairlead、collecting pipe、wire-guide、Loader、controlling handle and other control system were manufactured by using HDPE、PTFE、ABS、 PC、PtW and other material. Do vitro tests. According to YY0450.1of national criteria, the appearance of mechanical thrombectomy、X-ray detectability, basket's density、disruptive force、bend、fracture. Joint strength and other inspection of playsical properties were proceed; According to GB/T16886.1.2.4.11of Chinese medicine industry standards, hemolysis、toxicity、sensitization、fever reaction and other biological tests were performed.
Results:It was confirmed by vitro tests that thrombectomy bascket can effectively remove intravascular thrombi, protect remote blood vessels from thrombosis fragments blocking and increase the safety of thrombectomy. The result of device mechanical property examination didn't show twist、corrode、Creases and other unnatural bent. All Components can be detected in the X-ray. The disruptive force>5N, the diameter of wire-mesh basket less than0.4mm。 Bursting test hasn't break trace, bend test is zero defect, Joint strength meet the industry standard; Biological tests showed that there were no hemolysis, toxicity,sensitization, fever reaction, and indicated it has good biocompatibility.
Conclusion:The design idea of mechanical thrombectomy is advanced, rational construction. Technology have reached the technical level of the similar products at home and abroad. The device has advantages of incorporated thrombectomy, distal protection,safety, and provide reliability for its animal experiment and clinical test.
Experiment2Establishment and evaluation of acute embolic infarction animal model for mechanical thrombectomy
Objective:To Establish Animal models of acute arterial embolism which is suit to mechanical thrombectomy, similar to human acute embolic cerebral infarction, and evaluate the effectiveness of embolectomy to the model.
Methods:Acute embolic cerebral infarction model was established by methods of carotid artery ligated on one side, temporary carotid artery occlusion and Injection of thrombin on the other side in New Zealand rabbits (n=30). evaluated the effectiveness of the model by Using DSA、DWI、TCD and pathological examination.20New Zealand rabbits which were successfully modeled were randomly assigned by random number table into non-treatment group and thrombectomy treatment group(10rabbits for each group), the non-treatment group did not get any treatment, thrombectomy treatment group received the intracranial arterial embolectomy by device6h later after embolism onset. Used the TCD examination respectively and record the average velocity of the right middle cerebral artery before the embolism and after embolism1h and6h; used DWI to record ADC value after embolism6h and24h. the non-treatment group were sacrificed after embolism24h,5brains were dyed with TTC stain, the rest of5brain with HE stain were observed the pathological changes light microscope, electron microscope and immunohistochemistry. the Vascular recanalization were detected under DSA after embolectomy of the treatment group. Comparing the ADC and Vmca changes between the two group in different time.
Results:The DSA showed that the occlusion rate of the embolization side of the carotid artery is83%after the30New Zealand rabbits model establishment. The DWI showed infarcts after embolization6h,24h pathological checking (dyed with TTC stain) showed infarcted zone, Brain edema, nerve cell coagulation necrosis, Karyopyknosis and disappearance, nerve cell and glial cell obvious decrease or disappearance. It showed that the ultra-structure of the nerve cell was damaged, the organelle was obviously swelling, part of the mitochondria vacuolized, the foot board of the astrocytes vacuolized, endothelial nuclei degenerated.the blood vessel recanalization rates was80%after embolectomy, it is statistical significance (before and after embolization:P=0.000; before and after embolectomy: P=0.000)compared the Vmca before and after embolization,before and after the embolectomy. The Vmca of the thrombolysis after embolized6h group was42.28±1.92cm/s, the Vmca of the non-treatment group was29.02±1.72cm/s, comparison between the two groups was statistical significance(F=47.490P=0.000); the ADC of the embolectomy group after embolectomy was on the rise, the ADC of the non-treatment group was on the decline, the ADC of the thrombolysis after embolized24h group was0.81±0.08, the ADC of the non-treatment group was0.56±0.10, compared the ADC of the two group was statistical significance(P=0.000).
Conclusion:The success rate is high,the stability of the model is satisfactory and it has a good repeatability to use the method of temporary carotid artery occlusion and Injection of thrombin to make animal models of acute arterial embolism which is suit to mechanical thrombectomy, this method is suit to experimental study and effect evaluation for intracranial arteries thrombectomy device.
Part Ⅱ Animal experiment study of intracranial arterial mechanical embolectomy device
Experiment1Comparative experimental study of efficacy evaluation of acute thromboembolic cerebral infarction mechanical thromboectomy
Objective:To demonstrate the efficacy and safety of domestic intracranial arterial embolectomy device through the experimental study, to explore the advantages between mechanical thrombectomy and mtra-arterial thrombolysis. Providing a basic theory for intracranial arterial embolectomy using into clinically.
Methods:The acute arterial thromboembolism animal model was established by injection thrombin into rabbit artery with blood flow temporary block, which is suitable to mechanical embolectomy in30rabbit. According to the random number table, the30rabbit are divided into non-treatment group, the thrombolysis group, mechanical thrombectomy group. After3hours of embolization, the thrombolysis group received intra-arterial recombinant human tissue-type plasminogen activator (Rt-PA) thrombolysis, mechanical thrombectomy of intracranial arterial embolectomy device was applied to mechanical thrombectomy group, the situation of vessel recanalization was observed under digital subtraction angiography (DSA), as well middle cerebral artery flow velocity (VMCA) changes were record through the transcranial Doppler (TCD), before and after treatment. Each group, after embolization,3h,6h,8h,12h,24h respectively received magnetic resonance diffusion imaging (MR-DWI). differences in apparent diffusion coefficient (ADC) were compared; brain CT scan was performed to check the intracranial complications after treatment in treatment group at24hours, the neurological deficits were scored24h later, pathological changes of vessel and brain tissue were observed by a light microscope and transmission electron microscope after examination of24h magnetic resonance and CT.
Results:Embolectomy, thrombolysis group recanalization rate was80%,20%respectively, re-pass rate difference was statistically significant (P=0.025), the VMCA of the two groups after treatment was statistically significant (P=0.000).; the vascular pathology of embolectomy parts observed by light microscopy and electron microscopy demonstrated endothelial cells arranged in neat rows, without performance of the vascular endothelial damage; head CT examinations showed the thrombectomy group had no intracranial bleeding, the intracranial hemorrhage rate of the thrombolytic group was10%; The differences of ADC value after12h and24h MRI between the thrombectomy group and the thrombolysis group were statistically significant (P<0.05), the ADC value differences in other each time were not statistically significant (P>0.05);; thrombectomy group ADC values showed an upward trend after the embolectomy. In thrombolysis group, non-treatment group, ADC values showed a downward trend; neurological deficit score of thrombectomy group was significantly higher than the thrombolysis group and the non-treatment group, had statistically significant difference compared with the thrombolysis group and non-treatment group (thrombolysis group:P=0.003non-treatment group: P=0.001); light and electron microscope examination revealed that the brain neuronal morphology of the thrombectomy group did not significantly abnormal, astrocytic foot plate mild vacuolization, neuronal damage is minor; thrombolysis group organelles degree in-re-swelling, compression of the vessel lumen, astrocytic foot plate vacuolization, edema of the astrocytes, and neuronal damage obvious; neurons form of non-treatment group, structural damage, chromatin margination, nuclear solid shrinkage, fragmentation, nuclear membrane dissolved and disappeared, was vacuolization of the astrocytic foot plate, compression narrowing of the vessel lumen, endothelial cell nucleus degeneration.
Conclusion:The experiment confirmed that embolectomy of intracranial arterial embolectomy device can quickly restore the occluded artery blood flow to improve the occlusive vascular recanalization rate, early embolectomy can save ischemic brain, it is an effective and safe treatment for the acute thromboembolic cerebral infarction.It is better than the current application of endovascular treatment, has good prospect for clinical application.
Experiment2Animal experiment study of magnetic resonance diffusion imaging and brain BDNF protein expression changes after acute embolic cerebral infarction embolectomy at different time windows
Objective:Mechanical embolectomy with the domestic intracranial arterial embolectomy device was performed in rabbit model of acute embolic cerebral infarction. To research and analyze the changes of magnetic resonance diffusion-weighted imaging, ADC value, infarct volume and brain-derived neurotrophic factor expression at different time windows after embolectomy, and to explore the effects and time window using mechanical thrombectomy treatment by intracranial arterial embolectomy device
Methods:The acute arterial thromboembolism animal model was established by injection thrombin into rabbit artery with blood flow temporary block, which is suitable mechanical embolectomy in25rabbit. According to the random number table,25rabbits were divided into non-treatment group,3hours mechanical thrombectomy group,6hours mechanical thrombectomy group,8hours mechanical thrombectomy group,12hours mechanical thrombectomy group (n=5each group).(mechanical embolectomy was performed at3h,6h,8h,12h through the femoral artery undering DSA guide), magnetic resonance diffusion-weighted imaging, the calculation of each period of apparent diffusion coefficient (ADC) and infarct volume were observed at3h,6h,8h,12h,24h. The animals were sacrificed after MRI, brains were removed and observed BDNF protein expression changes with immunohistochemical method, as well pathology examination by light and electron microscopy,(the experiment of3hours thrombectomy group used the experimental data of second part of the experiment one, the total using experimental animals are20).
Results:In the acute phase, ADC values of the non-treatment group and12h thrombectomy group gradually decreased, and infarct volume gradually expanded. In acute phase after embolectomy, ADC values of3h,6h,8h thrombectomy groups gradually increased, and infarct volume gradually reduced. From6h to24h, infarct volume gradually expanded in non-treatment group and12h thrombectomy group. Compared with non-treatment group, infarct volume of3h,6h,8h thrombectomy groups were reduced by10.4%,9.8%,5.1%and24.7%,23.9%,10.6%at the same time segment of12h and24h.24hours after infarction, compared with non-treatment group and12h thrombectomy group,3h,6h and8h thrombectomy groups were with higher ADC values and lower infarct volumes, the differences were statistically significant (P<0.05). Compared with8h thrombectomy group,3h,6h thrombectomy groups were with higher ADC values and lower infarct volumes. Differences of the ADC values were statistically significant (3h:P=0.000;6h:P=0.000); infarct volumes had no significant difference (3h:P=0.699;6h:P=1.000). Compared with6h thrombectomy group,3h thrombectomy group were with higher ADC values and lower infarct volumes, the difference between them wase not statistically significant (ADC values:P=0.235infarct volumes:P=1.000).24h BDNF protein expression results presented that BDNF expression of3h,6h and8h thrombectomy groups were significantly higher than12h thrombectomy group and non-treatment group, where differences were statistically significant (P<0.05). BDNF protein expression in3h thrombectomy group was higher than in6h,8h thrombectomy groups, Compared with6h and8h thrombectomy group, Differences of the BDNF protein expression were statistically significant (6h:P=0.00208h:P=0.000); Compared with8h thrombectomy group,6h thrombectomy group were with higher BDNF protein expression, the difference between them wase not statistically significant (P=0.580). Light and electron microscope examination revealed that there were no obvious morphological abnormalities of brain tissue neurons in3h thrombectomy group. Neuronal damage was minor with slight changes. There were obvious damage of neurons in6h and8h thrombectomy groups, with part of the neuronal degeneration and moderate changes. Morphous and structure of neurons were damaged in non-treatment group, there were extensive necrosis of neuronal cells with severe changes.
Conclusion:Application of intracranial arterial embolectomy device to thrombectomy in the early stage of thromboembolic cerebral infarction can reduce cerebral ischemic injury. It's an effective for acute embolic cerebral infarction.The characteristic that mechanical embolectomy could rapidly recovered the blood flow make it more appropriate to extend the therapeutic time window. The ultra-early treatment is the best occasion for mechanical embolectomy. Thrombectomy within eight hours has therapeutic significance; DWI is a sensitive imaging method for dynamic observing and evaluating the therapeutic effect of acute cerebral infarction.
引文
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