血栓内微泡联合超声增强导管介入溶栓

发布时间：2018-05-05 05:38

本文选题：超声 + 微泡　；参考：《第三军医大学》2017年博士论文

【摘要】：研究背景:血栓形成及栓塞是大量心脑血管疾病的病理基础。目前,经静脉给予tPA等药物溶栓是这类疾病主流的治疗方法。经静脉溶栓有严格的时间窗,安全性和有效性也还有较大的提高空间。经导管介入治疗是当前临床血栓性疾病的另一类治疗方法。最近几年,随着更有效的新型介入取栓导管的使用,研究表明,机械取栓联合全身或局部注射溶栓药可以提高梗阻血管的早期再通率、改善预后,因此,经导管介入治疗逐渐获得了临床越来越多的认可。超声溶栓技术是溶栓治疗的一个重要发展方向。尽管超声溶栓的机制目前仍未得到彻底阐明,但一般认为其中一个重要的机制是超声激励体内生成的微气泡或者经静脉注射的微泡产生的空化效应。微泡的参与在超声增强溶栓的过程中起了十分重要的作用,但是由于生物体自身一般缺乏超声空化需要的空化核微泡,因此,在超声溶栓过程中引入外源性微泡是非常必要和有利的选择。经体表超声辅助溶栓研究和应用存在的一个重要的问题是临床上大多数血栓都是梗阻性的,经外周静脉注射的微泡无法输送到血栓局部,造成血栓的“空化靶向性”较差。课题组前期研究发现,采用直接血栓内注射微泡联合体外超声辐照增强尿激酶溶栓方法产生的溶栓效果,显著优于常规经外周循环液注射微泡增强的超声溶栓方法,也优于单纯血栓内注射尿激酶的溶栓效果。血栓内注射微泡则可以通过血管内导管介入方法实现。经体表超声溶栓存在的另一个问题是大量需要溶栓治疗的血栓缺乏合适的体外超声辐照声窗。采用血管腔内超声导管溶栓的方法是目前已开始在临床应用的溶栓方法。在欧美,EKOS公司的EkoSonic?血管内超声溶栓导管已获批准用于临床急性肺动脉栓塞和下肢深静脉血栓等的溶栓治疗。但这种超声溶栓导管由于超声能量较高,仍可能产生血管壁损伤的副作用,因此需要实时测温和水冷循环系统降温,这就导致导管设计工艺复杂,价格昂贵。本课题拟在动物实验验证血栓内输注微泡增强超声溶栓有效性及可行性基础上,设计制作一种基于微泡空化的血管腔内超声溶栓导管,综合血栓内微泡超声溶栓和血管内超声导管声窗理想的优点,有望产生更为有效、迅速的溶栓效果。研究目的:1.证实超声联合血栓内持续输注微泡溶液,可以显著提高经导管介入药物溶栓效果;2.设计制作基于微泡空化的新型血管内超声溶栓导管,并证实其可以在持续输注微泡溶液的配合下,在体外梗阻性血栓模型中有效增强rt-PA介入溶栓效果。材料与方法:1.主要实验仪器:⑴改进的彩色多普勒超声诊断仪——VINNO 70(飞依诺科技有限公司,苏州,中国),配备X4-12L线阵探头。为溶栓实验增加的Vflash治疗脉冲发射程序,主要的改进为在其常规的极低机械指数(MI=0.04)造影成像软件的基础上叠加一个可调节治疗窗,治疗窗内治疗脉冲受控间断发射。本研究中设定,在每一个治疗帧频时间内,中心频率为2.5 MHz、脉冲宽度为5μsec的治疗脉冲逐线发射;治疗窗中发射的治疗脉冲线密度约为32/cm,调整治疗窗大小,以完整覆盖整个血栓栓塞血管节段。设定治疗脉冲发射重复频率为50 Hz,脉冲作用时间及间歇时间分别设定为0.5 sec和2.0 sec,MI约为0.50。在水槽微泡空化预实验中证实,以上设置可以有效击破治疗窗中的大部分微泡,而治疗窗两侧的微泡基本无明显破坏。⑵微量匀速注射泵:Longerpump?TJP-3A,保定兰格恒流泵有限公司生产。⑶多功能酶标仪:型号Varioskan Flash 3001-1723,由美国Thermo Fisher科技公司生产。⑷超声换能器阻抗分析系统:Agilent E4991A,美国Agilent科技有限公司生产。⑸任意信号发生器:Hantek HDG 2022B,青岛汉泰电子有限公司生产。⑹针式水听器:ONDA HNC-0100,美国ONDA公司生产,传感器直径为0.1 mm。⑺3D声场扫描系统:英国Precision Acoustics有限公司生产。⑻声场仿真软件:COMSOL Multiphysics 4.3a多物理场仿真系统,瑞典COMSOL公司开发。⑼激光共聚焦显微镜:莱卡TCS SP5,德国Leica显微系统有限公司生产。2.主要实验试剂:⑴微泡:本实验室自制的包裹全氟丙烷核心气体的脂膜微泡“脂氟显”,微泡平均粒径约为1.95±0.52μm,浓度约为2.0-9.0×109/ml,根据实验需要稀释使用。⑵溶栓药物:注射用重组组织型纤维蛋白溶酶原激活剂(rt-PA),德国Boehringer Ingelheim药业有限公司生产。⑶兔D二聚体酶联免疫检测试剂盒:美国休斯敦Cloud-Clone公司生产。⑷抗凝牛全血:郑州市九龙生物制品有限公司生产,由健康牛全血添加血液保存液抗凝处理制成,4℃保存。⑸抗凝牛新鲜冰冻血浆:郑州市九龙生物制品有限公司生产,由新鲜抗凝牛全血在取血后6 h内经4℃低速离心取得的血浆,于-30℃以下迅速冰冻制得。试剂存储于-20℃冰箱,使用前于37℃水浴中快速复温。⑹兔抗牛纤维蛋白原抗体:购自北京博奥森生物技术有限公司。⑺羊抗兔Ig G:购自北京中杉金桥生物技术有限公司。抗体使用前先用异硫氰酸荧光素(FITC)进行标记。3.实验动物:健康新西兰大白兔40只,均为雄性,体质量为2.5-3.0 kg,由第三军医大学实验动物中心提供并完成检疫。4.实验方法:⑴改进的诊断超声联合血栓内输注微泡提高经导管介入药物溶栓动物实验:(1)建立实验兔急性梗阻性下腔静脉血栓模型:模拟“Virchow三部曲”的过程,主要步骤包括血管内皮损伤(目标血管局部止血钳钳夹损伤)、血流状态改变(目标血管节段近端使用血管夹夹闭)和血液凝固状态改变(目标血管局部管腔内注入凝血酶)。(2)随机对照实验:40只实验兔按随机分组顺序,分别接受以下四组治疗,每组10只:超声Vflash联合微泡增强经导管rt-PA溶栓(CDT+UT)组、超声Vflash联合微泡溶栓(UT)组、单纯经导管rt-PA溶栓(CDT)组、生理盐水对照(Control)组。(3)有效性评价指标:基于二维超声及超声造影所见的梗阻性血栓溶栓效果评分(治疗开始30 min及60 min);ELISA法检测各组实验兔溶栓前后血浆D二聚体水平;实验段下腔静脉血栓病理检查。(4)安全性观察:兔近心段下腔静脉、右心系统、肺动脉及分支血栓形成及继发性栓塞发生情况。⑵新型血管内超声溶栓导管探头的设计及声学检测:(1)选取微型超声换能器并通过阻抗测试筛选合适的激发频率。(2)制备单换能器超声探头,并对其进行适宜频率激发下的声场扫描、电-声转换测试。(3)利用COMSOL Multiphysics仿真系统对溶栓导管单换能器、换能器组、多组换能器组合声场进行仿真,并优化其组合方案。(4)采用被动空化检测方法检测超声溶栓导管探头微泡空化能力,并通过对散射信号半定量分析方法确定使介质中微泡发生稳态空化及瞬态空化的适合激励电压,为下一步实验筛选合适参数。⑶基于微泡空化的血管内超声增强tPA体外溶栓实验:(1)制备牛全血血栓:洁净2.0 ml EP管中加入5%氯化钙溶液33μL(相当于氯化钙1.11 mg),加入1.0 ml牛全血样品,混匀后静置于37℃恒温水箱中水浴3小时,制备牛全血血栓。(2)构建梗阻性血栓体外溶栓实验系统。(3)随机对照实验:实验共设以下5组(n=10),分别为血栓内超声联合微泡增强t PA溶栓组(US+MB+TPA)、血栓内超声增强tPA溶栓组(US+NS+TPA)、血栓内超声联合微泡溶栓组(US+MB)、单纯血栓内注射tPA溶栓组(TPA alone)及血栓内注射生理盐水对照组(Control)。(4)有效性评价指标:各组溶栓率。(5)溶栓机制探讨:残余血栓石蜡包埋切片HE染色光镜观察;纤维蛋白免疫荧光染色激光共聚焦显微镜观察。结果:1.改进的诊断超声联合血栓内输注微泡提高经导管介入药物溶栓动物实验:⑴所有实验兔均建模成功并完成整个溶栓实验。实验结束后对摘取的实验兔近心段下腔静脉、心脏及肺动脉进行检查,均未发现有局部血栓形成及继发血栓栓塞;⑵治疗开始30 min时,CDT+UT组溶栓效果评分显著高于其他各组(P0.05),单纯CDT组、单纯UT组及对照组溶栓效果评分差异无统计学意义(P0.05);治疗开始60 min时,CDT+UT组及单纯CDT组溶栓效果评分均显著高于UT组及对照组(P0.05);⑶CDT+UT组治疗后兔血浆D二聚体浓度显著升高(P0.05),而其他各组实验兔血浆D二聚体水平变化均无统计学意义;⑷病理检查见CDT+UT组实验段下腔静脉血栓几乎全部或大部分溶解,仅残存小片状血栓附着于受损伤较明显的IVC血管壁上;单纯UT组及单纯CDT组实验段下腔静脉血栓中部可见不同程度部分溶解,因固定、制片过程中血栓退缩,血栓边缘部分与血管壁脱离,形成不规则腔隙;对照组血栓中部见小片状溶解,血栓边缘与血管壁之间亦可见因血栓退缩形成小片不规则腔隙。2.新型血管内超声溶栓导管探头的设计及声学检测:⑴阻抗测试显示1.5 MHz为选取的微型超声换能器的次最佳谐振频率。单个微型换能器声场分布可以表征为点声源,其声压随与换能器表面距离增大迅速降低。在测量范围内峰值声压与换能器外加交变电压(15-52.5 V)呈良好的线性相关,具有良好的电—声转换效率。⑵声场仿真结果显示,双换能器背靠背组合成换能器组,可形成绕换能器组一周的较均匀声场;两组、多组换能器组沿导管方向并联组合后,沿导管长轴方向可形成叠加声场;当换能器组间距为5.0 mm及以下时,沿导管长轴方向可形成较均匀的声场。⑶被动空化检测及散射信号半定量分析显示,当换能器声压为0.25 MPa时,仅检测到较小幅值的微泡谐振信号;换能器声压为0.50 MPa时,超谐波信号幅度超过噪声至少3d B,为稳态空化为主;换能器声压为0.75 MPa及以上时,特定噪声分量幅值上升达二次谐波信号10dB以内,提示为瞬态空化为主。3.基于微泡空化的血管内超声增强tPA体外溶栓实验:⑴血栓内超声联合微泡增强t PA溶栓组(US+MB+TPA)溶栓率显著高于其他各组(P0.05);US+NS+TPA组、TPA alone组溶栓率也显著高于血栓内注射生理盐水(Control)对照组(P0.05);但US+MB组与血栓内注射生理盐水对照组溶栓率差异无统计学意义(P=0.142)。⑵残余血栓HE染色显示,除血栓内注射生理盐水对照组外,其余各组均可见血栓残体内部范围、程度不一的疏松改变,以US+MB+TPA组为著;纤维蛋白免疫荧光染色显示对照组血栓内密集交联的纤维蛋白网以及网罗于血栓纤维蛋白网中间的细胞成分,血栓中部导管插入部位附近由于血块收缩,纤维蛋白条索较血栓内部增粗、密集;使用tPA的各组血栓纤维蛋白网结构均可见不同程度松解、断裂,以接近血栓中部导管插入部位为著。结论:1.诊断超声仪发射的经过适当改进的中等MI、较长脉冲超声联合血栓内微泡,可以显著提高经导管介入的药物溶栓效果。这种综合溶栓治疗方法有望加速血栓清除、进一步降低溶栓药使用总量,从而降低溶栓相关并发症发生的风险。2.基于微泡空化的新型血管内超声溶栓导管,综合利用了血栓内微泡增强的超声溶栓作用和血管内超声直接接触作用于血栓的优点,可以有效增强rt-PA的溶栓作用。3.超声联合血栓内微泡增强药物溶栓的机制为空化效应促进溶栓药物对血栓的渗透、加速其纤溶进程,并促进纤维蛋白降解产物向周围的弥散。
[Abstract]:Background: thrombosis and embolism are the pathological basis of a large number of cardiovascular and cerebrovascular diseases. At present, intravenous thrombolytic therapy, such as tPA, is the mainstream treatment for these diseases. There is a strict time window for thrombolytic therapy through venous thrombolysis. The safety and effectiveness of thrombolytic therapy are also greatly improved. Transcatheter interventional therapy is a current clinical thrombotic disease. Another kind of treatment. In recent years, with the use of more effective new interventional embolectomy catheter, it has been shown that the combination of mechanical thrombolysis combined with systemic or local injection of thrombolytic drugs can improve the early repassage rate and improve the prognosis of the obstructed vessels. Therefore, interventional therapy has gradually gained more and more recognition. Although the mechanism of ultrasonic thrombolysis has not been thoroughly clarified, one of the most important mechanisms is that the microbubbles generated by ultrasonic stimulation or the cavitation effect produced by the microbubbles injected through the vein are important. However, the introduction of exogenous microbubbles in the process of ultrasonic thrombolysis is a necessary and beneficial choice because the organism itself generally lacks the need for ultrasonic cavitation. Therefore, an important problem in the study and application of thrombolytic assisted thrombolysis is that most of the thrombus on the bed is obstructive and transstatic through peripheral static. The microbubbles injected into the vein can not be transported to the part of the thrombus, and the "cavitation targeting" of the thrombus is poor. In the previous study, we found that the thrombolytic effect produced by the direct thrombus injection combined with in vitro ultrasound irradiation enhanced the thrombolytic method of urokinase was significantly better than that of the conventional percutaneous injection of microbubble enhanced ultrasound thrombolysis. It is also better than the thrombolytic effect of intravascular injection of urokinase. The intravascular catheter intervention can be achieved by intravascular injection of microbubbles in thrombus. Another problem of thrombolytic thrombolytic therapy is that a large number of thrombolytic thrombolytic patients lack appropriate external ultrasound irradiation windows. The method of thrombolytic therapy by intravascular ultrasound catheter is the goal of the thrombolytic therapy. EKOS's EkoSonic? Intravascular ultrasound thrombolytic catheter has been approved for thrombolytic therapy for acute pulmonary embolism and deep vein thrombosis in the lower extremities in Europe and America. However, the ultrasonic thrombolytic catheter can still produce the side effects of vascular wall injury due to high ultrasonic energy. On the basis of the effectiveness and feasibility of the intravascular infusion of microbubble enhanced ultrasound thrombolytic thrombolysis, a kind of intravascular supersonic thrombolytic catheter based on microbubble cavitation is designed and fabricated on the basis of the effectiveness and feasibility of the intravascular infusion microbubble enhanced ultrasound thrombolytic thrombolysis. The ideal advantage of the intravascular ultrasound catheter is expected to produce more effective and rapid thrombolytic effects. 1. it is proved that continuous infusion of microbubbles in ultrasound combined with thrombus can significantly improve the thrombolytic effect of transcatheter interventional drugs; (2.) a new intravascular ultrasound thrombolytic catheter based on microbubble cavitation is designed and proved to be possible Under the combination of continuous infusion microbubble solution, the effect of rt-PA interventional thrombolysis was effectively enhanced in the external obstructive thrombus model in vitro. Materials and methods: 1. main experimental instruments: (1) the improved color Doppler ultrasonic diagnostic instrument - VINNO 70 (fleno Technology Co., Suzhou, China), equipped with X4-12L linear array probe. The increase of Vflash for thrombolytic experiments The main improvement is to superimpose an adjustable therapeutic window on the basis of its conventional extremely low mechanical index (MI=0.04) imaging software, and to treat pulse controlled intermittent launch in the treatment window. In this study, a therapeutic pulse with a center frequency of 2.5 MHz and a pulse width of 5 sec within each frame frequency time is set in this study. The pulse line emission of the treatment window was about 32/cm, the treatment window was adjusted to adjust the size of the treatment window to complete the whole thromboembolic vascular segment. The repetition frequency of the pulse emission was set to 50 Hz, the pulse time and the interval time were set to 0.5 sec and 2 sec respectively, and MI was about 0.50. in the trough microbubble cavitation test. In fact, the above setting can effectively break down most of the microbubbles in the treatment window, and the microbubbles on both sides of the treatment window have no obvious damage. 2. Micro speed injection pump: Longerpump? TJP-3A, Baoding Lange constant flow pump Co., Ltd. (3) multi function enzyme scale instrument: model Varioskan Flash 3001-1723, produced by Thermo Fisher technology company in the United States. Acoustic transducer impedance analysis system: Agilent E4991A, American Agilent Technology Co., Ltd. production. Arbitrary signal generator: Hantek HDG 2022B, Qingdao Han Tai Electronics Co., Ltd. production. The needle type hydrophone: ONDA HNC-0100, American ONDA company production, sensor diameter is 0.1 mm. 3D sound field scanning system: UK Precision Limited COMSOL Multiphysics 4.3a multi physical field simulation system, Sweden COMSOL Co., Ltd. development. Laser confocal microscope: Leica TCS SP5, German Leica microsystem Co., Ltd. to produce.2. main experimental reagent: (1) microbubble: lipid membrane microbubble "lipid membrane" made in our laboratory for parcel perfluoropropane core gas The average particle size of the microbubble is about 1.95 + 0.52 m, and the concentration is about 2.0-9.0 x 109/ml, which is diluted in accordance with the needs of the experiment. (2) thrombolytic drugs: recombinant tissue type fibrinolytic enzyme activator (rt-PA) and German Boehringer Ingelheim Pharmaceutical Co., Ltd. (3). (3) the enzyme linked immunoassay kit for rabbit D two polymer: Cloud-C of Houston, USA Lone production. 4. Whole blood of anticoagulant cattle: produced by Zhengzhou Kowloon Biological Products Co., Ltd., made of healthy cattle whole blood with Anticoagulation Solution anticoagulant treatment, preserved at 4 C. Fresh frozen plasma of anticoagulant cattle: Zhengzhou Jiulong Biological Products Co., Ltd., obtained by fresh anticoagulant bovine whole blood in 6 h after taking blood at 4 degrees centigrade after taking blood Plasma, quickly frozen below -30 C. The reagent is stored at -20 centigrade refrigerator and quickly reheated at 37 centigrade water bath before use. The Rabbit anti bovine fibrinogen antibody: purchased from Beijing Boosen Biotechnology Co., Ltd. and purchased from rabbit Ig G: from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.. Before the use of antibody, isothiocyanate (FI TC test animals: 40 healthy New Zealand white rabbits, all of which were male and body mass of 2.5-3.0 kg, were provided by the laboratory animal center of Third Military Medical University and completed the quarantine.4. experimental method: (1) improved diagnostic ultrasound combined with thrombus infusion microbubbles to improve the experimental thrombolytic experiment of percutaneous thrombolytic therapy: (1) the establishment of experimental rabbit acute stem A model of hindrance inferior vena cava thrombosis: the process of simulating the "Virchow Trilogy", the main steps include vascular endothelial injury (the local hemostasis clamp injury of the target vessel), the change of blood flow state (the use of blood vessel clamp in the near end of the target vascular segment) and the change of blood coagulation state (thrombin injected into the local lumen of the target vessel). (2) random control Experiment: 40 rabbits were treated in the following four groups according to random grouping, 10 in each group: ultrasound Vflash combined with microbubble enhanced transcatheter rt-PA thrombolysis (CDT+UT), ultrasound Vflash combined with microbubble thrombolysis (UT), simple transcatheter rt-PA thrombolysis (CDT), and saline control (Control). (3) based on two-dimensional ultrasound and The thrombolytic effect score of obstructive thrombus (30 min and 60 min) was observed by contrast echocardiography; ELISA method was used to detect the level of plasma D two polymer before and after thrombolysis in the experimental rabbits; the pathological examination of the inferior vena cava thrombus in the experimental segment. (4) safety observation: the inferior vena cava, the right heart system, the pulmonary artery and branch thrombosis and secondary embolism in the rabbit The design and acoustic detection of the new intravascular ultrasound thrombolytic catheter probe: (1) select the micro ultrasonic transducer and select the appropriate excitation frequency through the impedance test. (2) the single transducer ultrasonic probe is prepared, and the sound field scanning under the appropriate frequency excitation, the electrical acoustic conversion test. (3) using the COMSOL Multiphysics simulation system The single transducer, transducer group, multi group transducer combination sound field is simulated and its combination scheme is optimized. (4) the passive cavitation detection method is used to detect the microbubble cavitation ability of ultrasonic thrombolytic probe, and a suitable method for determining the steady cavitation and transient cavitation of microbubbles in the medium is determined by the method of semi quantitative analysis of the scattered signal. Stimulating voltage, selecting suitable parameters for the next experiment. (3) intravascular ultrasound enhanced tPA thrombolytic experiment based on microbubble cavitation: (1) preparation of bovine whole blood thrombus: 5% calcium chloride solution 33 mu L (equivalent to calcium chloride 1.11 mg) in a clean 2 ml EP tube, and 1 ml bovine whole blood samples, and after mixing at 37 centigrade constant temperature water tank for 3 hours, To prepare whole blood thrombus of cattle. (2) construct an in vitro thrombolytic experimental system for obstructive thrombus. (3) randomized controlled experiment: the following 5 groups (n=10) were set up, including thrombus ultrasound combined with microbubble enhanced T PA thrombolysis group (US+MB+TPA), thrombolytic thrombolytic thrombolysis group (US+NS+ TPA), thrombolytic ultrasound combined with microbubble thrombolysis group (US+MB), and simple intravascular injection TPA thrombolytic group (TPA alone) and thrombolytic injection of physiological saline control group (Control). (4) evaluation index of effectiveness: thrombolytic rate in each group. (5) thrombolytic mechanism: residual thrombus embedded section HE staining light microscopy; fibrin immunofluorescence staining laser confocal microscope observation. Results: 1. improved diagnostic ultrasound combined thrombus infusion The microbubbles improved the thrombolytic experiment of transcatheter interventional drugs: (1) all experimental rabbits were successfully modeled and completed the whole thrombolytic experiment. After the experiment, the inferior vena cava, heart and pulmonary arteries of the rabbits were examined. No local thrombus formation and secondary blood Se were found. (2) group CDT+UT thrombolysis at the beginning of 30 min treatment The score of effect was significantly higher than that of other groups (P0.05). There was no significant difference in thrombolytic effect between simple CDT group, simple UT group and control group (P0.05). The thrombolytic effect score of group CDT+UT and pure CDT group was significantly higher than that of group UT and control group (P0.05) at the beginning of 60 min treatment. (3) the concentration of D two polymer in rabbit plasma after treatment was significantly higher (P0.05). There was no significant difference in the level of D two polymer in the plasma of the rabbits in other groups. (4) pathological examination showed that the inferior vena cava thrombus was almost all or most dissolved in the experimental segment of group CDT+UT, only the remnants of small fragment thrombosis were attached to the more obvious IVC vascular wall of the injured group, and the central part of the inferior vena cava thrombus in the pure UT group and the single pure CDT group was seen in the middle of the vena cava thrombus. With the same degree of dissolution, the thrombus was reduced and the thrombus was separated from the vessel wall in the process of production. The central part of the thrombus in the control group was small dissolving, and the design and sound of the new intravascular ultrasound thrombolytic probe probe between the thrombus edge and the blood vessel wall was also seen between the thrombus and the blood vessel wall formed in the irregular lacunae of.2.. Test: (1) the impedance test shows that 1.5 MHz is the second best resonant frequency of the selected micro ultrasonic transducer. The sound field distribution of a single micro transducer can be characterized as a point sound source, and the sound pressure decreases rapidly with the surface distance of the transducer. The peak sound pressure in the measurement range is in good linearity with the applied alternating voltage (15-52.5 V) of the transducer. The results of sound field simulation show that the double transducer is combined into a transducer group with back to back, which can form a more uniform sound field around the transducer group for a week. The two groups of transducer groups can form superposition sound field along the direction of the catheter along the direction of the catheter in parallel, and the interval between the transducers is 5 mm and the two groups are in the direction of the transducer. At the next time, a more uniform sound field can be formed along the long axis of the duct. (3) the semi quantitative analysis of passive cavitation detection and scattering signal shows that when the transducer's sound pressure is 0.25 MPa, only a small amplitude microbubble resonant signal is detected. When the transducer's sound pressure is 0.50 MPa, the amplitude of the super harmonic signal exceeds the noise at least 3D B, which is the main steady cavitation; the transducer is the main transducer. When the sound pressure is above 0.75 MPa and above, the amplitude of the specific noise component rises to two times the harmonic signal within 10dB, suggesting that the transient cavitation is the main.3.

【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R454.3

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