Development of Noninvasive Therapeutic Devices and Clinical Techniques for Treating Uterine Fibroid by Occluding Feeding Vessels Through Exposure to High Intensity Focused Ultrasound

本研究的最终目的是开发一种无创治疗妇科肿瘤，特别是子宫肌瘤的方法，即利用高强度聚焦超声（HIFU）闭塞供血血管。下面的基础研究是我们实现这一目标的第一步。首先，我们构建了一个谐振频率为3.2 MHz的HIFU换能器原型，并结合了一个提供彩色多普勒成像和多普勒测速的成像探头。通过皮肤对Sprague-Dawley大鼠左大腿股深动脉进行HIFU；血流的彩色图像被用来瞄准HIFU光束。峰值强度分别为530、1080、2750和4300 W/cm2。每次HIFU照射时间为5秒。在4300 W/cm2强度下，HIFU可以阻断血流，但在较低强度下血流仍在继续。多普勒测速仪测量的血流峰值收缩速度（psv）在应用HIFU的动脉中增加…更多的是在1080和2750 W/cm2。增高与HIFU强度相应。暴露在530 W/cm2的HIFU下没有改变血流速度。组织学研究表明，暴露于2750和4300 W/cm2的HIFU会导致空泡变性和动脉中膜弹性纤维的破坏。暴露在1080 W/cm2下导致PSV增加，但没有引起血管壁的组织学改变。这些结果表明，动脉对HIFU的反应随强度而变化。低强度血管收缩，无组织变性；随着强度的增加，组织学上可检测到的组织变性降低了血管直径，最后，在高强度下，血流被阻塞。在第二项研究中，我们假设在血流中注射超声造影剂可能会降低阻塞的最低HIFU强度。本研究旨在探讨造影剂对HIFU暴露后动脉血流和形态变化的影响。5只大鼠注射Levovist 60mg， 5只大鼠注射生理盐水0.5ml作为对照。在530、870、1550和2750 W/cm2的HIFU照射强度下，给药Levovist的大鼠血流阻断率分别为0%（0/5）、60%（3/5）、100%（5/5）和100%（5/5）。在对照大鼠中，每个HIFU强度的血流阻断成功率分别为0%（0/5）、0%（0/5）、0%（0/5）和80%（4/5）。H-E染色显示大鼠中膜明显空泡变性，内皮细胞从血管壁脱落。这些结果表明，在HIFU照射下，造影剂的空化对血管内皮有显著影响，因此，注射造影剂提示了降低HIFU强度以实现靶动脉闭塞的可能性。总之，在临床适用的强度下，HIFU可能在无创治疗肿瘤时闭塞供血动脉是有用的。少

The ultimate purpose of this study is to develop a noninvasive therapy for gynecologic tumors, particularly uterine fibroid, using high intensity focused ultrasound (HIFU) to occlude the feeding vessels. The following basic studies comprise our first step toward that goal. First, we constructed a prototype HIFU transducer which has a resonant frequency of 3.2 MHz, in combination with an imaging probe that provides color Doppler imaging and Doppler velocimetry. HIFU was applied through the skin to deep femoral arteries in left thighs of Sprague-Dawley rats ; color images of the blood flow were used to aim the HIFU beam. Peak intensities used were 530, 1080, 2750 and 4300 W/cm2. The duration of each HIFU exposure was 5 seconds. Blood flow occlusion was accomplished by HIFU at an intensity of 4300 W/cm2, but the flow continued with the lower intensities. Peak systolic velocities (PSVs) of blood flow as measured by Doppler velocimetry increased in the arteries to which HIFU had been applie … More d at 1080 and 2750 W/cm2. The increase corresponded with HIFU intensity. Exposure to HIFU at 530 W/cm2 did not change the blood flow velocity. Histologic studies have demonstrated that exposure to HIFU at 2750 and 4300 W/cm2 leads to vacuolar degeneration and destruction of elastic fibers of the tunica media of the artery. Exposure at 1080 W/cm2 led to increased PSV, but did not induce histologic changes in the vessel wall. These results suggest that the response of the artery to HIFU varied with intensity. Vascular contraction without tissue degeneration occurred at low intensity; with increasing intensity, the tissue degeneration detectable in histology reduced the vascular diameter and, finally, at high intensity, the blood flow was occluded. In the second study, we hypothesized that the injection of ultrasound contrast agents into blood flow might decrease the minimal HIFU intensity for the occlusion. The study was conducted to investigate the effect of contrast agents on changes in blood flow and morphology of arteries by HIFU exposure. Five rats had injection of 60mg of Levovist, and other 5 had 0.5ml of saline as control. Blood flow occlusion was achieved in 0%(0/5), 60%(3/5), 100%(5/5) and 100%(5/5) of rats with administration of Levovist by HIFU exposure at the intensity of 530, 870, 1550 and 2750 W/cm2, respectively. In control rats, the rate of successful blood flow occlusion were 0%(0/5), 0%(0/5), 0%(0/5), and 80%(4/5), for each HIFU intensity. The H-E stain revealed a strong vacuolar degeneration in the tunica media and endothelium cells fall off the vessel wall in rats with Levovist. These results imply that the cavitation of contrast agents under HIFU exposure exerts significant effects on the endothelium of vessels, therefore, the, injection of contrast agents suggests the possibility for reduction of the intensity of HIFU to achieve the occlusion of targeting arteries. In conclusion, HIFU at clinically applicable intensity might prove useful in occluding feeding arteries for treating tumors non-invasively. Less