超音波顯影劑強化高強度聚焦超音波加熱效應之研究

Abstract

近年來，無論是針對惡性或良性腫瘤，高強度聚焦式超音波（HIFU）已被證實可以有效的殺死癌細胞，儘管HIFU具有非侵入式且無輻射累積之優點，但每次燒灼所治療之區域很小，因此造成整體治療時間過長，故需一有效的方法來提昇治療區域，降低治療時間。 本研究主在探討藉由超音波顯影劑（UCA）強化超音波之加熱效應，進一步增大焦斑體積。將超音波顯影劑均勻地摻入仿體中，濃度從0%（對照組）、0.001%至0.1%（v/v），仿體大小為2 cm*2 cm*4 cm，換能器之驅動頻率為1.85MHz，燒灼時間皆為30秒，無超音波顯影劑下，電功率50W和70W下之焦斑為「紡錘狀」及「蝌蚪狀」。在此定義體積提升率（Volume Enlargement Ratio, VER）為同電功率下，有超音波顯影劑之焦斑體積除以無超音波顯影劑之焦斑體積，來評估超音波顯影劑對超音波熱效應之強化效果。當超音波顯影劑濃度為0.001%, 0.005%, 0.01% 和 0.015%時，電功率50W下之VER值為10.58, 39.11, 55.08以及 64.65，電功率70W下之VER值為2.27, 5.29, 12.09以及10.61，超音波顯影劑對焦斑體積之提升居然可達65倍！ 超音波顯影劑也可降低治療時換能器的驅動能量，舉例來說 超音波顯影劑濃度0.001%，電功率50W下之焦斑體積相當於無超音波顯影劑下，電功率70W之焦斑體積，降低了約3成之電功率，可有效降低前場過熱之問題。本研究也探討了超音波顯影劑對焦斑的位置的影響，將不同濃度、不同電功率下，焦斑最大寬度與焦點之間的距離做一統計分析，超音波顯影劑濃度為0%, 0.001%, 0.005%, 0.01% 及0.015%,，電功率為50W下之統計量為0.1, 0.65, 0.99, 1.32以及1.51公分；電功率為70W下之統計量為0.65, 0.80, 1.38, 2.01, 2.16公分，若超音波顯影劑濃度大於0.1%，則氣泡會大量反射超音波能量導致焦斑會完全形成於仿體表面。 為了探討在高強度（電功率大於70W）以及有超音波顯影劑下，蝌蚪狀焦斑之成因，本研究先從電功率70W下，有無超音波顯影劑之焦斑生成過程來分析；再量測有無超音波顯影劑，不同電功率下，深1.25及2.5公分之溫度來判斷對照組之蝌蚪狀焦斑是因為汽化效應。最後比較電功率70W，有無超音波顯影劑下，焦斑軸向剖面圖來看是否有因汽化現象造成之凹洞。無超音波顯影劑，燒灼時間30秒下，電功率超過70W時會產生蝌蚪狀焦斑是因能量累積所造成之汽化現象而導致；有超音波顯影劑時，第一秒即產生空化作用，使蛋白變性，產生焦斑，之後不斷產生慣性空化，產生更多氣泡，進而導致能量大幅散射，並產生更多的諧波，使得焦斑體積大幅增加，也使溫度上升更廣更均勻。本研究也對不同聚焦深度（1.25 & 2.5 cm）做一探討，在超音波顯影劑濃度同為0.005%，電功率70W，燒灼時間30秒下，深4.5 cm之焦斑體積比深2.5 cm要來得小，但焦斑最大寬度與焦點之距離則未有顯著差異。 總而言之，超音波顯影劑會增加超音波的散射，因而強化熱效應，進而提升焦斑體積，且焦斑體積隨著濃度之上升而增加。然而，焦斑也會隨著濃度上升而向換能器方向移動，若超音波顯影劑濃度過高，則無法順利於仿體內部形成焦斑。大體上，低濃度（0.001%）以及較低電功率（50W）已足夠產生39倍大之焦斑，而且焦斑最大寬度之位移量為最小（0.65公分）。

In recent years, high intensity focused ultrasound (HIFU) was shown to have promising effect on ablating both malignant and benign tumors. Despite its unique advantages such as minimal invasiveness and radiation free, the size of the ablation lesion is small and thus the duration for complete tumor ablation is usually too long. In this study, the effect of using ultrasound contrast agent (UCA) to enhance the ultrasound thermal effect, and thus enlarge the lesion size, was studied. Different concentration of UCA ranging from 0% (control), 0.001% to 0.1% (v/v) was mixed evenly with polyacrylamide gel phantoms containing egg white as a temperature indicator. A 1.85-MHz HIFU transducer was used to form thermal lesions inside the 2 cm*2 cm*4 cm phantoms. For the electric power of 50W and 70W, 'cigar' and 'tadpole’ shaped lesions were formed inside the control phantoms, respectively. The volume enlargement ratio (VER), defined as the ratio of volume formed in phantoms with UCA to the volume without UCA at the same power level, was used to evaluate the effect of UCA on thermal ablation. When the concentrations of UCA were 0.001%, 0.005%, 0.01% and 0.015%, the VER were 10.58, 39.11, 55.08, 64.65 at 50W, and 2.27, 5.29, 12.09, 10.61 at 70W, respectively. The administration of UCA significantly increased the lesion size up to 65 times! UCA also reduced the necessary power to form a lesion of a certain size. For example, 0.001% of UCA at 50W produced a lesion close to controls at 70W in size. Same concentration of UCA at 70W formed lesions equivalent in size for phantoms without UCA at 100W. 30% reduction of the power level was achieved. Complications of overheating could certainly be reduced when the output power decreased. The forward shift of a lesion, defined as the distance of the most heating position to the HIFU focus, was also investigated. When the UCA concentration was 0%, 0.001%, 0.005%, 0.01% and 0.015%, the lesion shifts at 50W and 70W were 0.1, 0.65, 0.99, 1.32, 1.51 cm and 0.65, 0.80, 1.38, 2.01, 2.16 cm, respectively. If the concentration of the UCA was greater than 0.1%, the lesion was basically formed at the surface of the phantom since most of the incident ultrasound waves were reflected. In order to understand the mechanism of lesion shape transformation at higher intensity (electric power > 70W) and/or introducing UCA, the lesion growing process & the internal temperature change with or without UCA under 70W 30s were continuously monitored. At higher intensity without UCA, the tadpole-shaped lesion was due to boiling effect. The lesion enhanced by UCA was because inertial cavitation, which produced more bubble inside the phantom, and made ultrasound be scattered, finally resulted in larger lesion and wider increase of temperature. In conclusion, UCA could increase the size of lesion by enhancing scattering, and the lesion size increased with the increase of the UCA concentration. However, lesions moved toward the transducer when concentration increased. It would be unable to produce the lesion inside the phantom if the concentration of UCA was too high. Overall, low concentration (0.001%) of concentration agent and low power (50 W) were enough to produce a lesion 39 times larger, and produced minimal lesion movement (0.65 cm).