臺灣博碩士論文加值系統

本研究之目的在題出以超音波影像導引聚焦式超音波應用於血腦屏障開啟之系統設計。設計頻率為270kHz, 80通道之半球頭罩式超音波系統，結合功率放大器、特製大鼠固定器與影像超音波進行實驗，動物實驗進行前，藉由高精準度水聽筒與超音波影像座標關係進行治療位置影像導引，實驗中，對大鼠靜脈注射超音波對比劑(UCA)，並對治療區域施予叢集脈衝模式之聚焦超音波使血腦屏障開啟。實驗過程中保留大鼠頭骨，藉由不同功率與治療時間等參數進行測試。藉由Evans Blue標示出血腦屏障開啟的區域，最後再以H＆E染色法分析周圍組織細胞的傷害程度。實驗結果顯示以超音波影像導引聚焦式超音波應用於血腦屏障開啟之系統設計，可以達到透骨式之血腦屏障開啟之效果，臨界值功率範圍介於5W至7.5W並且配合治療時間長短為30s到180s，此系統設計可以準確的達到在腦中以非侵入性的方式局部釋放藥物之目的。

The purpose of this study is to propose the ultrasonic-imaging guided focused ultrasound induced blood-brain barrier (BBB) disruption system design. This system comprises of a 270-kHz, 80-channel hemispherical ultrasound phased array, RF power amplifier, animal holder, and a clinical used ultrasound imager. Before animal treatment, we propose to use high-precision hydrophone and ultrasound imager coordinate transformation to achieve the alignment, focused ultrasound guidance, and treatment position targeting. During the treatment, Forty Sprague-Dawley rats were sonicated, and burst-mode ultrasonic energy was delivered in the presence of microbubble injected IV to disrupt the BBB. All Rats were skull-intact during the sonication, and different power output and duration durations were tested. Evans Blue dye was serves as an indicator to verify the BBB disruption in gross animal sectioning, and Hematoxylin and Eosin staining was conducted for brain tissue damage analysis. Results showed that the designed hemispherical multiple channel phased array system under the ultrasonic imaging guidance can successfully disrupt BBB through intact skull at the targeting position. Safety parameter was characterized which ranges from 5 – 7.5 w of electrical power with the sonication duration of 30 – 180s. The design provides the possibility toward using ultrasonic imaging to guide the focused ultrasound induced BBB disruption process for targeting drug delivery

目錄
誌 謝…………………………………………………………………………………i
中文摘要……………………………………………………………………………ii
Abstract…………………………………………………………………………iii
目錄…………………………………………………………………………………iv
圖目錄………………………………………………………………………………vi
表目錄……………………………………………………………………………viii
第一章 緒 論………………………………………………………………………1
1-1超音波概述……………………………………………………………………1
1-2診斷用超音波與治療用超音波之發展………………………………………1
1-3聚焦式超音波…………………………………………………………………1
1-4超音波與生物物質作用之相互效應…………………………………………2
1-4-1超音波導入效應(機械效應)………………………………………………3
1-4-2熱治療效應(熱燒灼)………………………………………………………3
1-4-3超音波生物效應(空蝕效應)………………………………………………3
1-5超音波對比劑……………………………………………………………………4
1-6血腦屏障(Blood-Brain Barrier, BBB)…………………………………5
1-7 研究動機………………………………………………………………………6
第二章 實驗材料與方法……………………………………………………………7
2-1研究設備…………………………………………………………………………8
2-2系統架構…………………………………………………………………………9
2-3多通道探頭設計………………………………………………………………10
2-4實驗動物………………………………………………………………………12
2-5影像定位步驟…………………………………………………………………13
2-6 超音波輸出訊號……………………………………………………………17
2-7取腦、組織切片與染色………………………………………………………18
2-7-1 Hematoxylin & Eosin (H&E)染色法………………………………20
第三章 系統測試結果……………………………………………………………23
3-1 聚焦探頭壓力場實際量測…………………………………………………23
3-1-1 聚焦探頭動物實驗量測結果……………………………………………24
3-2 超音波影像收取與位置驗證………………………………………………24
3-2-1 固定器外標記影像測試…………………………………………………24
3-2-2 超音波影像對位驗證……………………………………………………26
第四章 動物實驗結果……………………………………………………………31
4-1不同電功率對血腦屏障開啟之影響…………………………………………31
4-2不同治療時間對血腦屏障開啟之影響………………………………………34
4-3細胞損傷程度比較……………………………………………………………34
4-4影像導引治療區域結果………………………………………………………35
第五章 結論與未來規劃………………………………………………………37
5-1 結論…………………………………………………………………………37
5-2 未來研究方向………………………………………………………………38
參考文獻……………………………………………………………………………39


圖目錄
圖1-1 超音波對比劑外觀………………………………………………………5
圖1-2 血腦屏障主要的結構……………………………………………………5
圖2-1 系統架構…………………………………………………………………9
圖2-2 系統架構實體圖…………………………………………………………10
圖2-3 直徑6公分聚焦型壓電陶瓷外觀………………………………………11
圖2-4 直徑6公分聚焦型壓電陶瓷模擬結果…………………………………11
圖2-5 壓電陶瓷外觀……………………………………………………………11
圖2-6 壓電陶瓷模擬位置圖……………………………………………………12
圖2-7 焦點強度模擬……………………………………………………………12
圖2-8 動物實驗前準備…………………………………………………………13
圖2-9 特製固定器………………………………………………………………13
圖2-10 熱電偶感測器……………………………………………………………13
圖2-11 固定器外標記……………………………………………………………14
圖2-12 三維定位平台控制介面…………………………………………………14
圖2-13 定位流程圖………………………………………………………………14
圖2-14 系統配置圖………………………………………………………………15
圖2-15 影像超音波標記位置圖…………………………………………………16
圖2-16 影像超音波決定治療位置………………………………………………16
圖2-17 聚焦於水面之焦點………………………………………………………16
圖2-18 焦點位置峰對峰值(功率2W連續輸出峰對峰值)………………………16
圖2-19 大鼠顱內A、B、C、D點不同解剖位置…………………………………18
圖2-20 叢集波訊號………………………………………………………………18
圖2-21 腦組織外觀與實驗設計位置圖…………………………………………19
圖2-22 腦組織外觀與冷凍切片肉眼觀察………………………………………20
圖2-23 H&E染色細胞傷害分級…………………………………………………21
圖3-1 實際測得2W電功率下本實驗探頭聚焦效果……………………………23
圖3-2 實際測得2W電功率下直徑6公分聚焦型探頭聚焦效果………………23
圖3-3 不同功率大小血腦屏障開啟範圍與聲壓梯度之比對…………………24
圖3-4 外標記超音波影像(每張間格0.1227cm)……………………………25
圖3-5 大鼠全腦超音波影像(每張間格0.1227cm)…………………………25
圖3-6 治療前後實驗影像………………………………………………………26
圖3-7 治療前後減贅影像………………………………………………………30
圖4-1 不同功率條件下血腦屏障開啟效果……………………………………32
圖4-2 90W 3min功率條件下腦組織出血情形………………………………32
圖4-3 3min條件下低功率引發血腦屏障開啟結果……………………………33
圖4-4 5W血腦屏障開啟結果..…………………………………………………33
圖4-5 7.5W功率條件下不同時間引發血腦屏障開啟結果……………………34
圖4-6 治療時間3min且不同功率條件下傷害統計……………………………35
圖4-7 5W 1min 2×2血腦屏障開啟結果………………………………………36
圖4-8 5W 1min 3×3血腦屏障開啟結果………………………………………36
圖5-1 研究初期精密平台與對位程序圖………………………………………36
圖5-2 400KHz 48通道系統設計與測試圖……………………………………37


表目錄
表4-1 實驗次數統計表…………………………………………………………31

參考文獻
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