發(fā)布時間：2018-02-04 19:03

  本文關(guān)鍵詞： 高強度聚焦超聲 納米增效劑 表面消融 離體牛肝　出處：《重慶醫(yī)科大學》2017年碩士論文　論文類型：學位論文

【摘要】：高強度聚焦超聲(High Intensity Focused Ultrasound,HIFU)消融已成為臨床治療良惡性實體腫瘤的有效方法。其消融效率與腫瘤的位置和大小息息相關(guān),長時間的HIFU輻照和治療給患者和醫(yī)生帶來巨大的挑戰(zhàn)。目前采用的完全覆蓋性消融,在消融區(qū)投放的輻照劑量較大、治療時間長,產(chǎn)生如皮膚灼傷及鄰近臟器損傷等并發(fā)癥或毒副反應(yīng)增加,嚴重影響著HIFU消融大體積腫瘤的安全性、高效性。惡性腫瘤邊緣呈浸潤性生長、微毛細血管增生如同“生發(fā)層”給其增殖、轉(zhuǎn)移帶來活力;但內(nèi)部區(qū)域組織,在低灌流情況下缺血缺氧,存在程度不一的壞死。針對惡性腫瘤的這種特性,以閉環(huán)式凝固性壞死侵潤生長帶、阻斷血流,有望達到治療的目的。以惡性腫瘤為感興趣區(qū)(Region Of Intrest,ROI),利用HIFU使組織發(fā)生凝固性壞死,在ROI周邊形成完整的凝固性壞死帶,減少內(nèi)部區(qū)域的能量投放,有望提高HIFU對大體積腫瘤的消融效率,減少因長時間輻照而帶來的并發(fā)癥。而限于組織的生物學性質(zhì),HIFU消融帶來的組織變性壞死、溫升、產(chǎn)生空化和汽化影響后續(xù)的焦斑(lesion)的產(chǎn)生;血流及呼吸運動的存在,建立的表面消融模式壞死帶殼層“封閉性”不完整。大量研究證實納米微泡可增強HIFU焦域的能量沉積,有望用于增效HIFU消融,提高消融效率。因此,在前期的基礎(chǔ)上,本課題使用無機核殼納米介孔二氧化硅微球裝載全氟戊烷(Perfluoropentane Drops-Encapsulated Mesoporous Silica Nanocapsules,MSNC-PFP)作為HIFU增效劑,以期達到較小能量投放能形成完整的、足夠厚度的凝固性壞死殼層的目的,為進一步完善“高強度聚焦超聲表面消融模式”提供實驗基礎(chǔ)。本課題的研究主要包括以下兩部分:第一部分MSNC-PFP注射區(qū)域?qū)IFU表面消融的影響目的:在HIFU消融離體牛肝實驗中探討MSNC-PFP注射區(qū)域?qū)�性掃描消融的影響,對比觀察增效劑完全分布于感興趣區(qū)與逐步分布于消融區(qū)對消融結(jié)果的影響,為后續(xù)試驗奠定基礎(chǔ)。方法:選取新鮮離體脫氣后復溫備用,使用連續(xù)波HIFU線性掃描方式,掃描線長40mm,使用不同功率依次從深度40mm處往淺部層面各層面消融,以監(jiān)控聲像圖出現(xiàn)條狀強回聲為有效消融,測量線性凝固性壞死的寬度及高度,篩選不同深度處的HIFU聲輸出參數(shù);在線性掃描路徑設(shè)計5個位點,位點間距10mm,分別在各位點注射MSNC-PFP(濃度1mg/ml)后立即進行HIFU輻照,觀察線性消融結(jié)果;表面消融組分為空白對照組,一次性注射增效劑組、分次注射增效劑組,完成注射后立即進行HIFU輻照。表面消融模式由六個凝固性壞死面組合成完整的壞死帶殼層,內(nèi)部區(qū)域不直接進性消融。消融結(jié)束后,分別沿聲束長軸或短軸切開肝臟,測量消融范圍,計算壞死凝固性壞死體積并進行統(tǒng)計學分析。分別取未消融區(qū)、凝固性壞死帶交界區(qū)組織進行HE染色,觀察壞死形態(tài)。結(jié)果:在離體牛肝深度分別為14mm、22mm、29mm、35mm、40mm處,HIFU聲功率處在140W~240W、線掃描速度5mm/s時能產(chǎn)生條狀凝固性壞死帶;首尾點注射MSNC-PFP后,消融線為漸進性增大,中間位點注射MSNC-PFP增效的凝固性壞死束表現(xiàn)為局部膨大,5個位點同時注射MSNC-PFP后可增效整條線的消融體積;進行表面消融后,一次性注射增效劑組、分次注射組能更易且更完整的形成凝固性壞死帶,且分次注射組形成的凝固性壞死帶厚度大于一次性注射組(P0.05),對照組凝固性壞死帶不完整。一次性注射組及對照組內(nèi)部未消融區(qū)大面積熱損傷壞死,而分次注射增效劑組未見。結(jié)論:使用HIFU連續(xù)波線性掃描的方式,以在離體肝臟內(nèi)形成的凝固性壞死帶為核心,組合線-線成面到體、內(nèi)部區(qū)域未直接消融的方式,形成壞死帶不連續(xù)、融合欠佳;沿消融線注射MSNC-PFP,協(xié)同HIFU消融能形成完整封閉的凝固性壞死帶殼層,且一次性注射增效劑組能增強HIFU對內(nèi)部未消融區(qū)組織熱損傷。第二部分MSNC-PFP濃度對HIFU表面消融的影響目的:納米增效劑的注射量及濃度差異會帶來增效HIFU消融不同的結(jié)果,前部分已經(jīng)探索出增效劑分布于消融區(qū)帶來的HIFU消融效果,本部分旨在探討納米增效劑的濃度差異對HIFU表面消融離體牛肝的影響。方法:50塊新鮮離體牛肝,根據(jù)注射增效劑的濃度隨機分為A組(0.25mg/ml)、B組(0.5 mg/ml)、C組(1 mg/ml)、D組(2 mg/ml)、及空白對照組E組。在機載超聲圖像的監(jiān)控下,沿消融區(qū)計劃的注射點推注增效劑,注射結(jié)束后立即用進行HIFU表面輻照,并觀察消融中聲像圖的改變。結(jié)束后沿聲束長軸切開牛肝,觀察凝固性壞死帶范圍,測量并計算凝固性壞死體積、能效因子,比對各組與計劃消融范圍的差異。結(jié)果:聲像圖上未見對照組、0.25mg/ml組及0.5mg/ml組出現(xiàn)增效劑的強回聲表現(xiàn);1mg/ml組、2mg/ml組出現(xiàn)稍強回聲,即刻后消退。各組HIFU輻照區(qū)均出現(xiàn)強回聲帶,隨著增效劑濃度的提高,條狀強回聲帶出現(xiàn)幾率升高及灰度值改變越大。除對照組的消融區(qū)壞死帶不完整外,實驗組各組均能形成完整的凝固性壞死帶。隨著增效劑濃度的增加,所致凝固性壞死帶厚度增寬,消融體積增大,所需能效因子減小;消融中所產(chǎn)生的熱向未消融區(qū)擴散,擴大壞死體積,產(chǎn)生比計劃消融范圍更廣的凝固性壞死帶。結(jié)論:高濃度納米增效劑可產(chǎn)生聲像圖強回聲且可提高HIFU消融過程中灰度值改變。注射增效劑濃度越高,HIFU連續(xù)波表面消融離體牛肝組織產(chǎn)生的凝固性壞死體積越大,壞死向未消融區(qū)內(nèi)部及外周的擴展。
[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 澧炴晥鍓傜殑嫻撳害闅忔満鍒嗕負A緇，

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