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研究生： 林奕辰
論文名稱： 超音波激發相變液滴汽化用於組織侵蝕術之研究
指導教授： 葉秩光
口試委員: 劉浩澧
廖愛禾
陳文翔
學位類別： 碩士
Master
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2013
畢業學年度： 101
語文別： 中文
論文頁數： 87
中文關鍵詞： 相變液滴 、組織侵蝕術 、聲學激發相變液滴汽化
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    • 組織摧毀術是一項利用超音波對生理組織造成機械性傷害的技術，其低侵入性以及能用超音波影像導引的特性使組織摧毀術有應用於腫瘤治療方面的潛力。先前研究提出在組織摧毀術中加入微氣泡能夠提升治療效率，更能提高超音波影像的對比度有利於定位治療的區域。然而微氣泡於體內循環時穩定存在時間過短，限制此技術在臨床應用的可能性。和微氣泡相比，相變液滴能夠在體內穩定存在，而且受到超音波作用後會被激發汽化形成微氣泡，稱為聲學激發相變液滴汽化。本研究的目的是探討相變液滴汽化是否會造成組織傷害，以取代微氣泡進行組織侵蝕；並透過調控實驗參數以控制侵蝕區域的型態，最佳化使用的參數。最後是利用汽化過程產生的特殊訊號建立偵測組織侵蝕產生的工具。
    在觀察侵蝕行為的實驗中，使用中心頻率為2 MHz的聚焦式超音波作用於仿體通道內的相變液滴使其汽化。透過改變超音波的聲學參數如負壓峰值、脈衝重複頻率、脈衝長度，以及相變液滴的濃度，觀察不同參數下相變液滴汽化對仿體侵蝕效率的影響。
    為了解造成侵蝕的機制，本研究也在相變液滴汽化瞬間偵測所產生的散射訊號進行分析。首先是偵測由穴蝕效應產生的寬頻特徵訊號和相變液滴膨脹產生的特殊低頻訊號，藉以探討穴蝕效應於侵蝕機制扮演的角色；另外，透過分析穿透相變液滴汽化通道後的訊號強度探討所產生的氣泡對侵蝕效率的影響。
    　　本研究的結果證實，透過聲學激發相變液滴汽化確實能對和生理組織硬度相同的仿體造成局部性侵蝕傷害。同時，聲場中的氣泡能夠屏蔽遠端的侵蝕的發生，增強近端的侵蝕效果使侵蝕為反向進行。而提高負壓峰值、脈衝重複頻率、脈衝長度，及相變液滴的濃度都能提升侵蝕的速率。
    　　訊號分析的結果中顯示，慣性穴蝕效應的產生為起始侵蝕現象的必要條件，而且所使用的負壓峰值必須超過一特定閥值才會起始侵蝕現象；而比較穴蝕效應的寬頻訊號及代表相變液滴膨脹的低頻訊號對偵測相變液滴汽化的能力，則發現使用代表相變液滴膨脹的訊號其靈敏度較高。
    　　本研究的結果說明利用相變液滴汽化能侵蝕組織的特性具有應用於腫瘤治療的潛力，而其侵蝕的主要機制是由慣性穴蝕效應所起始。為使此技術在臨床上更能有效應用，未來工作則著重於利用相變液滴膨脹產生的特殊低頻訊號建立能偵測侵蝕產生的影像工具以追蹤治療區域。

    　　Histotripsy is a technique using ultrasound pulses to liquefy bio-tissues, which is less invasive comparing with other tumor therapy. As the cavitation nuclei, microbubbles (MBs) had been reported can improve the treatment efficiency and also enhance the ultrasound image contrast during the treatment for guiding the treatment location. However, the short lifetime of MBs in the circulation limits the clinical application of this method. Comparing to MBs, phase-change droplets (PCDs) are stable in the circulation. PCDs will triggered vaporize into bubbles under ultrasound sonication, and this transient process is called acoustic droplet vaporization (ADV). Previous studies showed that surrounding structure could be damaged during ADV and the possibly mechanism of the erosion behavior is inertial cavitation, which makes PCDs have potential to be used in histotripsy.
    　　The aim of this study is to find out the mechanism of tissue damage during ADV occurred by using PCDs vaporing in tissue-mimicking phantoms. Moreover, by varying the acoustic parameters of ultrasound pulses, the shape and size of eroded region can be control and then optimizing the dose of ultrasound exposure to increase the safety and possibility of the therapy at clinical use.
    In this research, the erosion behavior of ADV was observed using an acousto-optics system during PCDs vaporizing within the vessel of tissue-mimicking phantoms. The erosion rates were also quantified under different experiment coditions. The backscatter signals of the ADV were then collected and quantified to verify the effects of bubbles created by ADV to the erosion behavior. By processing the characterization wideband signal of inertial cavitation, the intensity and the time of inertial cavitation appeared were determined to find out the role of inertial cavitation in the erosion process.
    It is found that the intensity in the near field will increased while bubble density in the focused region increased, which makes the direction of erosion opposite to the ultrasound transmission direction. Meanwhile, the ultrasound intensity will be attenuated thus prevent distal side of phantom from damage. Besides, the inertial cavitation only happened at the first few cycle of vaporization pulses. This result showed that short pulses are much effective comparing to long pulses in tissue erosion. Nevertheless, the thermal effect caused by short pulses is relative lower, and the resolution of ultrasound image is better using short pulses rather than long pulses. In the case of irradiating continuously and other parameters fixed, the level of erosion rate increase was the most significant while pulse duration increase.

    章節目錄 第一章 緒論 1 　1.1. 惡性腫瘤 1 　　1.1.1 腫瘤治療方法與限制 2 　1.2 超音波和生物組織的交互作用 3 　　1.2.1 機械效應 3 　　1.2.2 熱效應 4 　　1.2.3 穴蝕效應 5 　1.3 超音波對比劑 7 　　1.3.1 傳統超音波對比劑-微氣泡 7 　　1.3.2 新式超音波對比劑-相變液滴 8 　　　1.3.2.1 相變液滴的物理性質 9 　　　1.3.2.2 聲學激發相變液滴汽化 10 　1.4. 超音波用於腫瘤治療 13 　　1.4.1 熱燒灼治療 14 　　1.4.2 組織摧毀術 14 　　　1.4.2.1 傳統組織摧毀術 15 　　　1.4.2.2 超音波對比劑於超音波組織摧毀術的應用 16 　　　1.4.2.3 聲學參數和組織摧毀術 18 　1.5 研究目的及論文架構 19 第二章 實驗材料與方法 21 　2.1. 概論 21 　2.2. 相變液滴之製備 21 　　2.2.1. 相變液滴之物理性質量測 24 　　　2.2.1.1. 光學定性分析 24 　　　2.2.1.2. 濃度與粒徑分布量測 25 　2.3. 組織模擬仿體製備 25 　　2.3.1. 流動式血管模擬仿體製備 26 　　2.3.2. 流動式訊號偵測仿體製備 26 　　2.3.3. 組織模擬仿體之楊氏係數測定 28 　2.4. 相變液滴汽化侵蝕觀測 29 　　2.4.1. 實驗硬體系統架構 29 　　2.4.2. 高能聚焦式超音波探頭之輸出聲壓校正 31 　　2.4.3. 針筒式注射幫浦之流速校正及流速換算 32 　　2.4.4. 實驗步驟 33 　2.5. 汽化侵蝕速率定量 34 　　2.5.1. 實驗硬體系統架構 34 　　2.5.2. 實驗步驟 34 　　2.5.3. 影像分析 35 　2.6. 穿透衰減測試實驗 36 　　2.6.1. 實驗硬體系統架構 37 　　2.6.2. 實驗步驟 39 　　2.6.3. 訊號分析 39 　2.7. 被動式穴蝕效應偵測 40 　　2.7.1. 實驗硬體系統架構 41 　　2.7.2. 實驗步驟 41 　　2.7.3. 訊號分析 43 　2.8. 統計分析 44 第三章 結果與討論 45 　3.1. 相變液滴的物理性質 45 　　3.1.1. 相變液滴的光學定性影像 45 　　3.1.2. 相變液滴的粒徑分布與濃度 45 　3.2. 組織模擬仿體物理性質 48 　　3.2.1. 仿體楊氏係數測定 48 　　3.2.2. 仿體光學穿透性 51 　3.3相變液滴汽化侵蝕觀測結果 52 　　3.3.1. 相變液滴濃度對侵蝕方向的影響 54 　　3.3.2. 脈衝重複頻率對侵蝕方向的影響 55 　3.4. 穿透衰減測試 59 　　3.4.1. 改變相變液滴濃度 59 　　3.4.2. 改變脈衝重複頻率 60 　3.5. 汽化侵蝕速率定量 62 　　3.5.1. 侵蝕持續效應 65 　3.6. 被動式穴蝕效應偵測 66 　　3.6.1. 時頻分析 66 　　3.6.2. 頻譜分析 69 　　3.6.3. 慣性穴蝕效應強度 71 3.7. 特殊低頻訊號 72 　　3.7.1. 時頻分析 73 　　3.7.2. 頻譜分析 74 　　3.7.3. 低頻訊號機制探討 75 第四章 結論與未來工作 77 　4.1. 結論 77 　4.2. 未來工作 78 參考文獻 81 圖目錄 圖1-1 美國2011年主要死亡原因比例圖 1 圖1-2 氣泡穴蝕效應示意圖 5 圖1-3 氣泡穴蝕效應造成震波之影像 6 圖1-4 相變液滴汽化瞬間光學影像 11 圖1-5 相變液滴汽化粒徑隨時間變化圖 11 圖1-6 慣性穴蝕效應特徵寬頻訊號之頻譜 13 圖1-7 相變液滴汽化粒徑隨時間變化圖 15 圖1-8 相變液滴汽化用於組織摧毀術示意圖 20 圖2-1 相變液滴製備流程圖 23 圖2-2 相變液滴組成結構示意圖 24 圖2-3 流動式血管模擬仿體尺寸及外觀 27 圖2-4 流動式組織模擬仿體尺寸及外觀 27 圖2-5 材料試驗機操作示意圖 28 圖2-6 相變液滴汽化侵蝕觀測實驗架構示意圖 30 圖2-7 相變液滴汽化侵蝕觀測實驗實際架構圖 30 圖2-8 高能聚焦式超音波探頭聲壓校正實驗架構示意圖 31 圖2-9 施加電壓與探頭對應輸出聲壓校正曲線 32 圖2-10 以光學影像定量侵蝕深度示意圖 36 圖2-11 衰減偵測實驗架構示意圖 38 圖2-12 衰減偵測實驗實際架構圖 38 圖2-13 被動式穴蝕效應偵測實驗架構示意圖 42 圖2-14 被動式穴蝕效應偵測實驗實際架構圖 42 圖3-1 自製相變液滴光學影像 45 圖3-2 自製相變液滴以庫爾特計數器測量之粒徑分布圖 47 圖3-3 自製相變液滴以DLS測量之粒徑分布圖 47 圖3-4 各種瓊脂比例的仿體其應力-應變曲線圖 49 圖3-5 各種瓊脂比例的組織模擬仿體其楊氏係數 50 圖3-6 組織模擬仿體之光學影像 51 圖3-7 仿體近端侵蝕區域之時序影像 52 圖3-8 相變液滴對仿體侵蝕效果之影響 53 圖3-9 微氣泡於不同超音波頻率下造成的侵蝕區域比較 53 圖3-10 不同相變液滴稀釋倍率對侵蝕區域之比較 54 圖3-11 層流的流體模型 56 圖3-12 實驗用仿體通道實際流速分布圖 56 圖3-13 脈衝重複頻率對侵蝕效果的影響 57 圖3-14 相變液滴濃度對DOA的影響 60 圖3-15 聚焦式超音波脈衝重複頻率對DOA的影響 61 圖3-16 不同侵蝕深度於光學影像比較示意圖 62 圖3-17 聲學參數及相變液滴濃度對侵蝕速率的影響 63 圖3-18 仿體近端在受超音波脈衝前後之比較 66 圖3-19 使用3 cycles，不同聲壓的超音波脈衝侵蝕之訊號時頻分析 67 圖3-20 使用10 cycles，不同聲壓的超音波脈衝侵蝕之訊號時頻分析 67 圖3-21 使用20 cycles，不同聲壓的超音波脈衝侵蝕之訊號時頻分析 68 圖3-22 使用3 cycles，不同聲壓的超音波脈衝侵蝕之訊號頻譜分析 69 圖3-23 使用10 cycles，不同聲壓的超音波脈衝侵蝕之訊號頻譜分析 70 圖3-24 使用20 cycles，不同聲壓的超音波脈衝侵蝕之訊號頻譜分析 70 圖3-25 聲學參數對ICD的影響 72 圖3-26 使用20 cycles、10 MPa的超音波脈衝產生之低頻訊號時頻分析 73 圖3-27 使用3–20 cycles、4–10 MPa的超音波產生之低頻訊號頻譜分析 74 圖4-1 組織摧毀術於小鼠體內治療前後之影像 79 表目錄 表1-1 各式商用微氣泡對比劑 8 表1-2 超音波對比劑用於組織摧毀術之參數比較 17 表2-1 超音波探頭規格列表 32 表2-2 汽化侵蝕速率定量實驗參數表 34 表3-1 各種生理組織楊氏係數表 51

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