MSNC-PFP增效连续波HIFU表面消融的实验研究

发布时间：2018-02-04 19:03

  本文关键词： 高强度聚焦超声 纳米增效剂 表面消融 离体牛肝　出处：《重庆医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：高强度聚焦超声(High Intensity Focused Ultrasound,HIFU)消融已成为临床治疗良恶性实体肿瘤的有效方法。其消融效率与肿瘤的位置和大小息息相关,长时间的HIFU辐照和治疗给患者和医生带来巨大的挑战。目前采用的完全覆盖性消融,在消融区投放的辐照剂量较大、治疗时间长,产生如皮肤灼伤及邻近脏器损伤等并发症或毒副反应增加,严重影响着HIFU消融大体积肿瘤的安全性、高效性。恶性肿瘤边缘呈浸润性生长、微毛细血管增生如同“生发层”给其增殖、转移带来活力;但内部区域组织,在低灌流情况下缺血缺氧,存在程度不一的坏死。针对恶性肿瘤的这种特性,以闭环式凝固性坏死侵润生长带、阻断血流,有望达到治疗的目的。以恶性肿瘤为感兴趣区(Region Of Intrest,ROI),利用HIFU使组织发生凝固性坏死,在ROI周边形成完整的凝固性坏死带,减少内部区域的能量投放,有望提高HIFU对大体积肿瘤的消融效率,减少因长时间辐照而带来的并发症。而限于组织的生物学性质,HIFU消融带来的组织变性坏死、温升、产生空化和汽化影响后续的焦斑(lesion)的产生;血流及呼吸运动的存在,建立的表面消融模式坏死带壳层“封闭性”不完整。大量研究证实纳米微泡可增强HIFU焦域的能量沉积,有望用于增效HIFU消融,提高消融效率。因此,在前期的基础上,本课题使用无机核壳纳米介孔二氧化硅微球装载全氟戊烷(Perfluoropentane Drops-Encapsulated Mesoporous Silica Nanocapsules,MSNC-PFP)作为HIFU增效剂,以期达到较小能量投放能形成完整的、足够厚度的凝固性坏死壳层的目的,为进一步完善“高强度聚焦超声表面消融模式”提供实验基础。本课题的研究主要包括以下两部分:第一部分MSNC-PFP注射区域对HIFU表面消融的影响目的:在HIFU消融离体牛肝实验中探讨MSNC-PFP注射区域对线性扫描消融的影响,对比观察增效剂完全分布于感兴趣区与逐步分布于消融区对消融结果的影响,为后续试验奠定基础。方法:选取新鲜离体脱气后复温备用,使用连续波HIFU线性扫描方式,扫描线长40mm,使用不同功率依次从深度40mm处往浅部层面各层面消融,以监控声像图出现条状强回声为有效消融,测量线性凝固性坏死的宽度及高度,筛选不同深度处的HIFU声输出参数;在线性扫描路径设计5个位点,位点间距10mm,分别在各位点注射MSNC-PFP(浓度1mg/ml)后立即进行HIFU辐照,观察线性消融结果;表面消融组分为空白对照组,一次性注射增效剂组、分次注射增效剂组,完成注射后立即进行HIFU辐照。表面消融模式由六个凝固性坏死面组合成完整的坏死带壳层,内部区域不直接进性消融。消融结束后,分别沿声束长轴或短轴切开肝脏,测量消融范围,计算坏死凝固性坏死体积并进行统计学分析。分别取未消融区、凝固性坏死带交界区组织进行HE染色,观察坏死形态。结果:在离体牛肝深度分别为14mm、22mm、29mm、35mm、40mm处,HIFU声功率处在140W~240W、线扫描速度5mm/s时能产生条状凝固性坏死带;首尾点注射MSNC-PFP后,消融线为渐进性增大,中间位点注射MSNC-PFP增效的凝固性坏死束表现为局部膨大,5个位点同时注射MSNC-PFP后可增效整条线的消融体积;进行表面消融后,一次性注射增效剂组、分次注射组能更易且更完整的形成凝固性坏死带,且分次注射组形成的凝固性坏死带厚度大于一次性注射组(P0.05),对照组凝固性坏死带不完整。一次性注射组及对照组内部未消融区大面积热损伤坏死,而分次注射增效剂组未见。结论:使用HIFU连续波线性扫描的方式,以在离体肝脏内形成的凝固性坏死带为核心,组合线-线成面到体、内部区域未直接消融的方式,形成坏死带不连续、融合欠佳;沿消融线注射MSNC-PFP,协同HIFU消融能形成完整封闭的凝固性坏死带壳层,且一次性注射增效剂组能增强HIFU对内部未消融区组织热损伤。第二部分MSNC-PFP浓度对HIFU表面消融的影响目的:纳米增效剂的注射量及浓度差异会带来增效HIFU消融不同的结果,前部分已经探索出增效剂分布于消融区带来的HIFU消融效果,本部分旨在探讨纳米增效剂的浓度差异对HIFU表面消融离体牛肝的影响。方法:50块新鲜离体牛肝,根据注射增效剂的浓度随机分为A组(0.25mg/ml)、B组(0.5 mg/ml)、C组(1 mg/ml)、D组(2 mg/ml)、及空白对照组E组。在机载超声图像的监控下,沿消融区计划的注射点推注增效剂,注射结束后立即用进行HIFU表面辐照,并观察消融中声像图的改变。结束后沿声束长轴切开牛肝,观察凝固性坏死带范围,测量并计算凝固性坏死体积、能效因子,比对各组与计划消融范围的差异。结果:声像图上未见对照组、0.25mg/ml组及0.5mg/ml组出现增效剂的强回声表现;1mg/ml组、2mg/ml组出现稍强回声,即刻后消退。各组HIFU辐照区均出现强回声带,随着增效剂浓度的提高,条状强回声带出现几率升高及灰度值改变越大。除对照组的消融区坏死带不完整外,实验组各组均能形成完整的凝固性坏死带。随着增效剂浓度的增加,所致凝固性坏死带厚度增宽,消融体积增大,所需能效因子减小;消融中所产生的热向未消融区扩散,扩大坏死体积,产生比计划消融范围更广的凝固性坏死带。结论:高浓度纳米增效剂可产生声像图强回声且可提高HIFU消融过程中灰度值改变。注射增效剂浓度越高,HIFU连续波表面消融离体牛肝组织产生的凝固性坏死体积越大,坏死向未消融区内部及外周的扩展。
[Abstract]:High intensity focused ultrasound (High Intensity, Focused Ultrasound, HIFU) ablation has been an effective method for treating malignant solid tumors. The location and size of the ablation efficiency and tumor is closely related to HIFU irradiation and treatment long time for patients and doctors to bring great challenges. The complete coverage of ablation, larger in irradiation dose delivery of ablation zone, treatment for a long time, such as skin burns and adjacent organ damage and other complications or adverse reactions increase, seriously affect the safety of HIFU large volume tumor ablation efficiency. Malignant tumor edge infiltrative growth, micro capillary hyperplasia as "germinal layer" for its proliferation, metastasis bring vitality; but the internal regional organizations, in low perfusion under hypoxia ischemia, necrosis exist different levels. Based on this characteristic of malignant tumor, with closed coagulation necrosis Runsheng invasion Long belt, blocking blood flow, is expected to achieve the purpose of treatment to malignant tumor region of interest (Region Of, Intrest, ROI), using HIFU to make tissue necrosis, the formation of coagulation necrosis with complete in around ROI, reduce the internal energy of the area running, is expected to improve the efficiency of HIFU ablation for large volume tumor due to long time, reduce radiation complications. Due to the limitation of biological properties of tissue, HIFU ablation caused tissue degeneration and necrosis, temperature rise, produce subsequent cavitation and vaporization of the focal spot effect (lesion) generation; blood flow and respiratory movement, the surface ablation model with shell necrosis "closed" not complete. A large number of studies confirmed that nano microbubbles can enhance the energy deposition of HIFU focal region, is expected for the synergism of HIFU ablation, improve the ablation efficiency. Therefore, in the early stage on the basis of the use of inorganic core-shell nano mesoporous silica Microspheres loaded perfluoropentane (Perfluoropentane Drops-Encapsulated Mesoporous Silica Nanocapsules, MSNC-PFP HIFU) as a synergist, in order to achieve smaller energy can be formed on the complete and sufficient thickness of the coagulated necrosis of the shell, in order to further improve the high intensity focused ultrasound ablation mode "to provide the experimental basis. This thesis mainly includes the following two part: the first part of the MSNC-PFP area of injection effect on HIFU surface ablation in vitro Objective: HIFU ablation of bovine liver experiment of MSNC-PFP injection region affected the linear scanning ablation, comparative observation of synergist completely distributed in the region of interest and gradually distributed in the area of ablation effect on ablation results, lays the foundation for the follow-up test. Selected fresh in vitro after degassing rewarming standby, using continuous wave HIFU linear scanning, scanning length 40mm, the different functions. The rate of turn from the depth of 40mm to the shallow level at all levels to monitor the sonographic appearance of ablation, strip strong echo for effective ablation, the width and height of the linear measurement of coagulation necrosis, HIFU screening of acoustic output parameters at different depths; the design of 5 loci in the linear scanning path, site spacing 10mm, respectively in each point injection MSNC-PFP (concentration of 1mg/ml) immediately after HIFU irradiation, the observation results of linear ablation; ablation group was divided into blank control group, injected synergist group, injected synergist group, HIFU irradiation completed immediately after injection. The surface ablation mode by six bad coagulation combined into a complete necrosis with unleavened dough shell not, directly into the inner region of the ablation. After ablation, respectively along the long axis of the sound beam or short axis cut liver, measuring the ablation range, calculate the necrosis volume of coagulative necrosis were collected and analyzed statistically. Unablated Zone of coagulative necrosis with junctional tissue HE staining to observe necrotic morphology. Results: in vitro bovine liver depth were 14mm, 22mm, 29mm, 35mm, 40mm, HIFU in 140W~240W sound power, line scanning speed 5mm/s can produce a strip of coagulative necrosis zone; end point injection after MSNC-PFP. The ablation line of gradual increase of coagulation necrosis of the beam sites injected with MSNC-PFP showed synergistic local swelling, the ablation volume of 5 sites at the same time after injection of MSNC-PFP will increase the whole line; surface ablation, one-time injection synergist group, the injected group can form coagulation necrosis with more and more complete the coagulation necrosis and fractional injection group formed with a thickness greater than single injection group (P0.05), the control group with incomplete coagulation necrosis. The one-time injection group and the control group without internal ablation area large area thermal damage and necrosis, injection efficiency No agent group. Conclusion: using HIFU continuous wave linear scanning mode in coagulation necrosis of isolated liver formed within the band as the core, combination of lines into the surface to the body, the internal region without direct ablation mode, the formation of necrosis with continuous, poor fusion; along the ablation line injection MSNC-PFP, collaborative HIFU ablation can form coagulation necrosis with complete closed shell, and one-time injection synergist group can enhance HIFU of internal unablated thermal damage zone. The second part effects of MSNC-PFP concentration on the HIFU surface ablation Objective: injection amount of nano synergistic agent and concentration difference will bring different results of HIFU ablation efficiency, the front part has to explore a synergist distribution in the ablation zone brings HIFU ablation effect, this part aims to explore the differences of concentration on the surface of HIFU nano synergist ablation in vitro bovine liver. Methods: 50 pieces of fresh bovine liver in vitro, according to injection 澧炴晥鍓傜殑娴撳害闅忔満鍒嗕负A缁，

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