脉冲高强度聚焦超声联合微泡非热损伤组织的实验研究
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摘要
背景和目的高强度聚焦超声(high intensity focused ultrasound,HIFU)是一种新兴的非侵入性局部治疗技术。HIFU治疗肿瘤的机制除了热机制外,还有机械机制和空化机制。非热机制(机械机制和空化机制)在HIFU治疗中的作用一方面认为应尽量对空化现象进行抑制,另一方面认为空化有助于热损伤和监控。目前对HIFU形成损伤的机制中仍很难确切描述热机制、空化机制和机械机制在组织损伤中相对独立作用。单纯的非热损伤(机械机制和空化机制)在HIFU治疗中的研究和应用较少。
实验首先进行脉冲高强度聚焦超声(pulsed high intensity focused ultrasound,PHIFU)辐照离体牛肝组织,探讨形成非热损伤的辐照参数。然后在此辐照参数下进一步研究PHIFU联合超声微泡造影剂(ultrasound contrast agent ,UCA)非热损伤活体肿瘤组织的可行性及非热损伤的生物学行为,为HIFU治疗肿瘤提供新方法和基础理论支持,进一步推进HIFU技术在肿瘤治疗中的应用。
材料和方法参数设置时维持总能量恒定,按不同工作周期1%、5%、15%、25%、50%、75%和100%分成7组,在B超图像监控下将热电偶测温探针插入牛肝,并使针尖位于PHIFU焦点,然后进行定点辐照。观察各辐照参数下焦域温度、灰度和组织学改变。
采用肿瘤组织块开腹包埋接种方法,建立兔肝VX2移植瘤动物模型。将36只荷瘤兔随机分为假照组、PHIFU组和PHIFU+UCA组。用第一部分实验筛选出的辐照参数(超声频率0.87 MHz、焦距150 mm、声功率150 W、脉冲重复频率100 Hz、工作周期15%)对兔肝VX2移植瘤进行PHIFU辐照。治疗后1天取材观察肿瘤组织学改变、超微结构改变,应用末端脱氧核苷酸转移酶(TdT)介导脱氧核苷酸(dUTP)缺口末端标记技术(in situ deoxynucleotityl transferase-mediated dUTP nick end labeling,TUNEL)检测细胞凋亡和用免疫组化法检测细胞增殖核抗原(proliferating cell nuclear antigen,PCNA),并用凋亡指数(apoptosis index, PI)和增殖指数(proliferating index, AI)比较细胞凋亡和增殖情况。
结果PHIFU辐照离体牛肝时,工作周期25%、50%、75%和100%组平均温升分别为63.4±9.2℃、65.0±11.5℃、66.6±9.9℃、79.6±10.6℃,最高温度大于85℃且有明显的凝固性坏死。1%、5%和15%组平均温升分别29.2±1.9℃、30.0±2.8℃、31.0±2.4℃,最高温度不高于56℃且无肉眼可见的凝固性坏死形成。在25%、50%、75%、100%组,PHIFU损伤后形成的凝固性坏死区光镜下主要表现为胞浆颜色变淡,部分核仁消失、细胞核固缩、染色质边集且随工作周期延长而增加。15%组光镜下细胞间裂隙增宽,肝细胞胞浆内见大量大小不等空泡,而1%组、5%组无明显改变,核仁清晰。
PHIFU辐照兔肝VX2移植瘤后,假照组、PHIFU组和PHIFU+UCA组经2,3,5-氯化三苯基四氮唑(2,3,5-triphenyl tetrazolium chloride ,TTC)染色后,肉眼可见肿瘤组织被均匀红染,表明各组均无肉眼可见的凝固性坏死形成。光镜下PHIFU组见肿瘤细胞胞浆嗜伊红染色浅,细胞肿胀,胞浆疏松,胞浆内大量空泡,少量细胞核固缩、染色质边集;PHIFU+UCA组见胞浆内大量大小不等空泡,可见染色质边集和细胞核固缩。电镜下见PHIFU组瘤细胞胞浆内大量线粒体肿胀和内质网扩张,PHIFU+UCA组部分细胞核固缩和染色质边集,两组肿瘤组织内均见凋亡小体及细胞胞浆内大小不等空泡。TUNEL法检测发现,假照组发现少量阳性染色的肿瘤细胞,PHIFU组和PHIFU+UCA组见较多细胞核棕褐色染色的阳性细胞。PCNA检测结果表明,假照组靶区组织见大量着色部位在肿瘤细胞核的阳性细胞,而PHIFU组和PHIFU+UCA组阳性染色细胞少。PHIFU组和PHIFU+UCA组肿瘤组织的AI比假照组高,而PI阳性表达率比假照组低。PHIFU+UCA组AI比PHIFU组高,但PHIFU+UCA组PI比PHIFU组低。
结论1.脉冲工作周期长在PHIFU辐照时可形成热凝固性坏死,而脉冲工作周期短可通过非热效应损伤组织。2.一定工作周期的PHIFU(超声频率0.87 MHz、焦距150 mm、声功率150 W、脉冲重复频率100 Hz、工作周期15%)可通过非热效应损伤肿瘤,表现为胞浆内大小不等空泡和促进肿瘤细胞凋亡及抑制其增殖。3.微泡造影剂可增强超声对组织的非热效应损伤。4.可通过控制PHIFU的工作周期实现非热损伤,为HIFU治疗肿瘤提供了一种新的治疗思路。
Background and objective
High Intensity Focused Ultrasound (HIFU) is a promising new technique that provides the possibility of producing tissue destruction selectively and noninvasively. Biological effects of HIFU include thermal effect, mechanical effect and cavitational effect. Non-thermal effects (mechanical effect and cavitational effect) play roles that some people believe we should restraint cavitational effects as possiblely, the others think cavitation can assist thermal damage and monitoring. It’s true that we are able to produce predictable tissue lesion, however, individual contribution of each effect is poorly defined. Non-thermal effects (mechanical effect and cavitational effect) were rarely studied and applied.
In the first stage of this study, we exposed ox liver to Pulsed High Intensity Focused Ultrasound (PHIFU) in vitro so as to screen out parameter set that produce non-thermal effects. In the second stage PHIFU with the screened non-thermal parameter sets was then combined with Ultrasound Contrast Agent (UCA)to investigate the possibility and the biological effects of tumor tissue in vivo by non-thermal effects. The study aims to give theory support and a new method of enhancing HIFU efficiency clinically.
Methods
First stage (non-thermal parameter set screening stage): There were 7 parameter sets which were grouped based on different duty cycles: 1%, 5%,15%, 25%, 50%,75% and 100% .Total energy was held constant for each parameter set, a thermal needle (temperature sensor) was inserted into the liver tissue under guidance of B-mode ultrasound, and move HIFU focal point to the hyperechoic region, and then temperature、gray scale and histological changes of the irradiated point were observed.
Second stage: A VX2 liver tumor model was established in 36 rabbits. The rabbits were divided randomly and averagely into three groups: sham PHIFU group, PHIFU group and PHIFU+UCA group. Both PHIFU group and PHIFU+UCA group were given PHIFU exposure of non-thermal parameters screened out in the first stage of our study (ultrasound frequency 0.87 MHz, total acustic power 150 W, focal length 150 mm, pulse repetition frequency 100 Hz, and duty cycle 15%). One day after PHIFU exposure, the liver tumors were sectioned and observed. histo-pathological and ultra-structural changes were examined. Proliferating cell nuclear antigen (PCNA) expression was detected by immunohistochemical staining, and apoptosis was observed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL). Observed with light microscope, apoptosis index (AI) and proliferating index (PI) were recorded and calculated.
Results
First stage: The mean values of temperature difference after PHIFU irradiation were 63.4±9.2℃, 65.0±11.5℃, 66.6±9.9℃and 79.6±10.6℃for group 25%, 50%, 75% and 100%, respectively. In these four groups, the highest temperature was over 85℃and obvious coagulated necrosis was found. In contrast, for group 1%, 5% and 15%, the mean values were 29.2±1.9℃, 30.0±2.8℃, and 31.0±2.4℃, respectively, and the highest temperature was 56℃or even lower. In addition, no necrosis could be seen with naked eye. In group25%、50%、75%、and 100%, we observed blanched cytoplasm, nucleole disappearance、karyopyknosis and chromatin margination and increased with duty cycle prolongation.In group 15% light microscopic observation found that intercellular space was widened and many vacuoles of different sizes were found in the cytoplasm. But no significant changes were found in group 1% and 5%.
Second stage: After PHIFU exposure, we found grossly that liver tumors of all the three groups were uniformly stained red by Triphenyl tetrazolium chloride (TTC) staining, suggesting that none of the animals had coagulated necrotic changes. In group PHIFU, histopathological examination demonstrated that eosinophilic staining is weak in the cytoplasm of tumour cells; we observed cellular swelling, cytoplasm looseness, cytoplasm vacuoles, and in a few tumor cells we found karyopyknosis and chromatin margination. In group PHIFU+UCA, light microscope displayed presence of abundant vacuoles of different sizes in the cytoplasm; we also found chromatin margination and karyopyknosis. Under transmission electron microscope (TEM), we discovered mitochondrion swelling and endocytoplasmic reticulum expanding in PHIFU group; while in PHIFU+UCA group, we observed condensation of the nuclear chromatin with margination. Both PHIFU group and PHIFU+UCA group had apoptotic body and cytoplasm vacuoles. TUNEL method detect few positive staining tumor cells in the sham PHIFU group, but in the PHIFU group and PHIFU+UCA group we found a lot of brow-colored positive apoptotic cells. PCNA detection showed more brow-colored positive cells in the sham PHIFU group than in the PHIFU group and PHIFU+UCA group. AI of the tumor cells in the PHIFU group and PHIFU+UCA group was higher than that of the tumor cells in the sham-HIFU group, while PI expression of the tumor cells in the PHIFU group and PHIFU+UCA group was lower than that of the tumor cells in the sham-HIFU group (P<0.05). AI of the tumor cells in the PHIFU+UCA group was higher than that of the tumor cells in the PHIFU group, while PI expression of the tumor cells in the PHIFU+UCA group was lower than that of the tumor cells in the PHIFU group(P<0.05).
Conclusions: 1. Long duty cycle PHIFU induces tissue necrosis mainly by thermal effects, while short duty cycle may damage tissues by nonthermal effect. 2. Tumor tissue in vivo was destroyed mainly by nonthermal effects under the following HIFU parameters (ultrasonic frequency 0.87 MHz, focal length 150 mm, acustic power 150 W, pulse repetition frequency 100 Hz, duty cycle 15%). 3. UCA may enhance nonthermal damage of PHIFU. 4. We regulated duty cycle of PHIFU to nonthermal damage and provided a new method to therapy.
实验首先进行脉冲高强度聚焦超声(pulsed high intensity focused ultrasound,PHIFU)辐照离体牛肝组织,探讨形成非热损伤的辐照参数。然后在此辐照参数下进一步研究PHIFU联合超声微泡造影剂(ultrasound contrast agent ,UCA)非热损伤活体肿瘤组织的可行性及非热损伤的生物学行为,为HIFU治疗肿瘤提供新方法和基础理论支持,进一步推进HIFU技术在肿瘤治疗中的应用。
材料和方法参数设置时维持总能量恒定,按不同工作周期1%、5%、15%、25%、50%、75%和100%分成7组,在B超图像监控下将热电偶测温探针插入牛肝,并使针尖位于PHIFU焦点,然后进行定点辐照。观察各辐照参数下焦域温度、灰度和组织学改变。
采用肿瘤组织块开腹包埋接种方法,建立兔肝VX2移植瘤动物模型。将36只荷瘤兔随机分为假照组、PHIFU组和PHIFU+UCA组。用第一部分实验筛选出的辐照参数(超声频率0.87 MHz、焦距150 mm、声功率150 W、脉冲重复频率100 Hz、工作周期15%)对兔肝VX2移植瘤进行PHIFU辐照。治疗后1天取材观察肿瘤组织学改变、超微结构改变,应用末端脱氧核苷酸转移酶(TdT)介导脱氧核苷酸(dUTP)缺口末端标记技术(in situ deoxynucleotityl transferase-mediated dUTP nick end labeling,TUNEL)检测细胞凋亡和用免疫组化法检测细胞增殖核抗原(proliferating cell nuclear antigen,PCNA),并用凋亡指数(apoptosis index, PI)和增殖指数(proliferating index, AI)比较细胞凋亡和增殖情况。
结果PHIFU辐照离体牛肝时,工作周期25%、50%、75%和100%组平均温升分别为63.4±9.2℃、65.0±11.5℃、66.6±9.9℃、79.6±10.6℃,最高温度大于85℃且有明显的凝固性坏死。1%、5%和15%组平均温升分别29.2±1.9℃、30.0±2.8℃、31.0±2.4℃,最高温度不高于56℃且无肉眼可见的凝固性坏死形成。在25%、50%、75%、100%组,PHIFU损伤后形成的凝固性坏死区光镜下主要表现为胞浆颜色变淡,部分核仁消失、细胞核固缩、染色质边集且随工作周期延长而增加。15%组光镜下细胞间裂隙增宽,肝细胞胞浆内见大量大小不等空泡,而1%组、5%组无明显改变,核仁清晰。
PHIFU辐照兔肝VX2移植瘤后,假照组、PHIFU组和PHIFU+UCA组经2,3,5-氯化三苯基四氮唑(2,3,5-triphenyl tetrazolium chloride ,TTC)染色后,肉眼可见肿瘤组织被均匀红染,表明各组均无肉眼可见的凝固性坏死形成。光镜下PHIFU组见肿瘤细胞胞浆嗜伊红染色浅,细胞肿胀,胞浆疏松,胞浆内大量空泡,少量细胞核固缩、染色质边集;PHIFU+UCA组见胞浆内大量大小不等空泡,可见染色质边集和细胞核固缩。电镜下见PHIFU组瘤细胞胞浆内大量线粒体肿胀和内质网扩张,PHIFU+UCA组部分细胞核固缩和染色质边集,两组肿瘤组织内均见凋亡小体及细胞胞浆内大小不等空泡。TUNEL法检测发现,假照组发现少量阳性染色的肿瘤细胞,PHIFU组和PHIFU+UCA组见较多细胞核棕褐色染色的阳性细胞。PCNA检测结果表明,假照组靶区组织见大量着色部位在肿瘤细胞核的阳性细胞,而PHIFU组和PHIFU+UCA组阳性染色细胞少。PHIFU组和PHIFU+UCA组肿瘤组织的AI比假照组高,而PI阳性表达率比假照组低。PHIFU+UCA组AI比PHIFU组高,但PHIFU+UCA组PI比PHIFU组低。
结论1.脉冲工作周期长在PHIFU辐照时可形成热凝固性坏死,而脉冲工作周期短可通过非热效应损伤组织。2.一定工作周期的PHIFU(超声频率0.87 MHz、焦距150 mm、声功率150 W、脉冲重复频率100 Hz、工作周期15%)可通过非热效应损伤肿瘤,表现为胞浆内大小不等空泡和促进肿瘤细胞凋亡及抑制其增殖。3.微泡造影剂可增强超声对组织的非热效应损伤。4.可通过控制PHIFU的工作周期实现非热损伤,为HIFU治疗肿瘤提供了一种新的治疗思路。
Background and objective
High Intensity Focused Ultrasound (HIFU) is a promising new technique that provides the possibility of producing tissue destruction selectively and noninvasively. Biological effects of HIFU include thermal effect, mechanical effect and cavitational effect. Non-thermal effects (mechanical effect and cavitational effect) play roles that some people believe we should restraint cavitational effects as possiblely, the others think cavitation can assist thermal damage and monitoring. It’s true that we are able to produce predictable tissue lesion, however, individual contribution of each effect is poorly defined. Non-thermal effects (mechanical effect and cavitational effect) were rarely studied and applied.
In the first stage of this study, we exposed ox liver to Pulsed High Intensity Focused Ultrasound (PHIFU) in vitro so as to screen out parameter set that produce non-thermal effects. In the second stage PHIFU with the screened non-thermal parameter sets was then combined with Ultrasound Contrast Agent (UCA)to investigate the possibility and the biological effects of tumor tissue in vivo by non-thermal effects. The study aims to give theory support and a new method of enhancing HIFU efficiency clinically.
Methods
First stage (non-thermal parameter set screening stage): There were 7 parameter sets which were grouped based on different duty cycles: 1%, 5%,15%, 25%, 50%,75% and 100% .Total energy was held constant for each parameter set, a thermal needle (temperature sensor) was inserted into the liver tissue under guidance of B-mode ultrasound, and move HIFU focal point to the hyperechoic region, and then temperature、gray scale and histological changes of the irradiated point were observed.
Second stage: A VX2 liver tumor model was established in 36 rabbits. The rabbits were divided randomly and averagely into three groups: sham PHIFU group, PHIFU group and PHIFU+UCA group. Both PHIFU group and PHIFU+UCA group were given PHIFU exposure of non-thermal parameters screened out in the first stage of our study (ultrasound frequency 0.87 MHz, total acustic power 150 W, focal length 150 mm, pulse repetition frequency 100 Hz, and duty cycle 15%). One day after PHIFU exposure, the liver tumors were sectioned and observed. histo-pathological and ultra-structural changes were examined. Proliferating cell nuclear antigen (PCNA) expression was detected by immunohistochemical staining, and apoptosis was observed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL). Observed with light microscope, apoptosis index (AI) and proliferating index (PI) were recorded and calculated.
Results
First stage: The mean values of temperature difference after PHIFU irradiation were 63.4±9.2℃, 65.0±11.5℃, 66.6±9.9℃and 79.6±10.6℃for group 25%, 50%, 75% and 100%, respectively. In these four groups, the highest temperature was over 85℃and obvious coagulated necrosis was found. In contrast, for group 1%, 5% and 15%, the mean values were 29.2±1.9℃, 30.0±2.8℃, and 31.0±2.4℃, respectively, and the highest temperature was 56℃or even lower. In addition, no necrosis could be seen with naked eye. In group25%、50%、75%、and 100%, we observed blanched cytoplasm, nucleole disappearance、karyopyknosis and chromatin margination and increased with duty cycle prolongation.In group 15% light microscopic observation found that intercellular space was widened and many vacuoles of different sizes were found in the cytoplasm. But no significant changes were found in group 1% and 5%.
Second stage: After PHIFU exposure, we found grossly that liver tumors of all the three groups were uniformly stained red by Triphenyl tetrazolium chloride (TTC) staining, suggesting that none of the animals had coagulated necrotic changes. In group PHIFU, histopathological examination demonstrated that eosinophilic staining is weak in the cytoplasm of tumour cells; we observed cellular swelling, cytoplasm looseness, cytoplasm vacuoles, and in a few tumor cells we found karyopyknosis and chromatin margination. In group PHIFU+UCA, light microscope displayed presence of abundant vacuoles of different sizes in the cytoplasm; we also found chromatin margination and karyopyknosis. Under transmission electron microscope (TEM), we discovered mitochondrion swelling and endocytoplasmic reticulum expanding in PHIFU group; while in PHIFU+UCA group, we observed condensation of the nuclear chromatin with margination. Both PHIFU group and PHIFU+UCA group had apoptotic body and cytoplasm vacuoles. TUNEL method detect few positive staining tumor cells in the sham PHIFU group, but in the PHIFU group and PHIFU+UCA group we found a lot of brow-colored positive apoptotic cells. PCNA detection showed more brow-colored positive cells in the sham PHIFU group than in the PHIFU group and PHIFU+UCA group. AI of the tumor cells in the PHIFU group and PHIFU+UCA group was higher than that of the tumor cells in the sham-HIFU group, while PI expression of the tumor cells in the PHIFU group and PHIFU+UCA group was lower than that of the tumor cells in the sham-HIFU group (P<0.05). AI of the tumor cells in the PHIFU+UCA group was higher than that of the tumor cells in the PHIFU group, while PI expression of the tumor cells in the PHIFU+UCA group was lower than that of the tumor cells in the PHIFU group(P<0.05).
Conclusions: 1. Long duty cycle PHIFU induces tissue necrosis mainly by thermal effects, while short duty cycle may damage tissues by nonthermal effect. 2. Tumor tissue in vivo was destroyed mainly by nonthermal effects under the following HIFU parameters (ultrasonic frequency 0.87 MHz, focal length 150 mm, acustic power 150 W, pulse repetition frequency 100 Hz, duty cycle 15%). 3. UCA may enhance nonthermal damage of PHIFU. 4. We regulated duty cycle of PHIFU to nonthermal damage and provided a new method to therapy.
引文
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