臺灣博碩士論文加值系統

穿顱脈衝超音波與微氣泡作用已經證實能夠暫時性的打開血腦屏障，並促進治療劑滲入中樞神經系統以獲得治療的功效。最近的研究指出，當聚焦式超音波裝置整合被動式空穴效應檢測(PCD)設備時， 使用PCD具有即時監控血腦屏障開啟的可行性。平面式超音波具有獨特的優勢，包括單次發射所造成大範圍血腦屏障開啟的能力、操作簡單且成像引導的可靠性低。然而，目前的平面式超音波發射裝置普遍缺乏PCD接收設計，也沒有即時PCD監控或者進一步執行即時血腦屏障開啟控制的發展可能性。在本篇論文中，我們提出了一種可以提供PCD和即時分析的新型平面超音波系統設計，以及其對進行即時平面超音波血腦屏障開啟的監控與控制之可行性探討。研究結果顯示，體外實驗證明了ESD與微氣泡濃度的比例關係，使用105 - 108 微氣泡/毫升，本系統可以檢測出 35 - 120 dB的能量變化，在體內實驗中，實驗組在發射期間內檢測出明顯的ESD上升變化，而控制組檢測出相對較低的ESD變化，ESD閥值於5-dB良好的區分了兩組間能量的差異。本研究驗證了平面式超音波系統開啟血腦屏障的能力，為開啟血腦屏障與釋放腦部藥物的設計提供了有價值的訊息。

Transcranial pulsed ultrasound with the presence of microbubbles has been shown to be able to temporally open the blood-brain barrier (BBB) to facilitate the therapeutic agent penetrating into CNS to gain therapeutic efficacy. Recent studies show the feasibility to employ passive cavitation detection (PCD) attempting to monitor or real-time control BBB opening when integrating PCD apparatus with the focused type ultrasound device. Planar ultrasound has unique advantage includes the capability to create larger BBB-opened dimension in single exposure, simplicity in operation, and less reliability in imaging guidance. Unfortunately, current planar ultrasound exposure apparatus all lacks of passive cavitation emission receiving design, nor to extend its possibility to perform real-time PCD monitoring or further perform the real-time BBB opening control. In this study, we proposed a novel planar ultrasound apparatus design that can provide PCD and real-time analysis, with the intention to perform real-time planar ultrasound BBB opening monitoring and control. Our results demonstrated that in-vitro experiments confirmed the dependence of the ESD change level with the infused microbubbles concentration. With 105 - 108 microbubble/mL, the system can detect sufficient high ESD change ranging from 35 - 120 dB compared to baseline. In in-vivo experiments, BBB-opened animal groups detected a significantly higher ESD change during exposure duration, whereas the BBB-intact animal groups detected a relatively low ESD change. The 5-dB ESD change level provides good discrimination between these two animal groups. This study demonstrates the capability in using planar ultrasound system to open the BBB, and provide valuable information toward designing a planar ultrasound treatment apparatus for the purpose of BBB opening and brain drug delivery.

目錄
指導教授推薦書
口試委員會審定書
誌謝 iii
摘要 iv
Abstract v
目錄 vii
圖目錄 x
表目錄 xii
第一章 緒論 - 1 -
1-1 超音波概述 - 1 -
1-2 空穴效應 - 1 -
1-3 血腦屏障 - 2 -
1-3.1 微米氣泡對比劑(Microbubble) - 3 -
1-3.2 超音波開啟血腦屏障之原理 - 3 -
1-4 論文回顧 - 4 -
1-5 研究動機與目的 - 5 -
第二章 實驗材料與方法 - 7 -
2-1 系統架構 - 7 -
2-1.1 體外實驗 - 10 -
2-1.2 體內實驗 - 10 -
2-2 訊號分析 - 11 -
2-3 實驗動物 - 13 -
2-4 實驗方法 - 14 -
2-5 分析與判斷 - 15 -
第三章 平面式超音波體外實驗之訊號分析 - 17 -
3-1 與浸水式探頭接收效果比較 - 17 -
3-2 聲壓與訊號之關係 - 19 -
3-3 Microbubble濃度與訊號比較 - 20 -
第四章 平面式超音波開啟血腦屏障之訊號分析 - 23 -
4-1 訊號判斷之可行性分析 - 23 -
4-2 實驗結果分析 - 24 -
4-2.1 能量強度與血腦屏障開啟狀況之分析 - 25 -
4-2.2 各諧波對訊號判斷之影響 - 29 -
4-2.3 EB 定量與訊號之關係 - 31 -
第五章 結論與未來展望 - 33 -
5-1 結論 - 33 -
5-2 未來展望 - 33 -
參考文獻 - 35 -

 
圖目錄
圖 1-1、血腦屏障示意圖(CUHK Shun Hing Institute of Advanced Engineering, 2014-2016) - 3 -
圖 1-2、超音波開啟血腦皮障示意圖(©Focused Ultrasound Foundation, Blood-Brain Barrier State of the Field Report - November 2015) - 4 -
圖 2-1、系統架構圖 - 8 -
圖 2-2、平面超音波發射探頭 - 8 -
圖 2-3、壓電環 - 9 -
圖 2-4、系統介面 - 9 -
圖 2-5、體外實驗環境 - 10 -
圖 2-6、體內實驗環境 - 11 -
圖 2-7、時域訊號(綠色為注入前，黑色為注入後) - 12 -
圖 2-8、頻域訊號(綠色為注入前，黑色為注入後) - 12 -
圖 2-9、老鼠前置作業 (a)標記實驗位置 (b)尾靜脈置針 - 13 -
圖 2-10、訊號產生器輸出訊號 - 14 -
圖 2-11、實驗步驟時間軸 - 15 -
圖 2-12、犧牲取腦 (a)血腦屏障開啟 (b)血腦屏障未開啟 - 16 -
圖 2-13、能量與時間關係圖 - 16 -
圖 3-1、壓電環與浸水式探頭之時域訊號 - 17 -
圖 3-2、壓電環與浸水式探頭之頻域訊號 - 18 -
圖 3-3、壓電環與浸水式探頭之各頻段能量比較圖 - 18 -
圖 3-4、聲壓與微氣泡濃度關係圖 - 19 -
圖 3-5、能量與微氣泡濃度關係圖_0.5倍頻 - 21 -
圖 3-6、能量與微氣泡濃度關係圖_主頻 - 21 -
圖 3-7、能量與微氣泡濃度關係圖_1.5倍頻 - 22 -
圖 3-8、能量與微氣泡濃度關係圖_2倍頻 - 22 -
圖 4-1、未經處理響應訊號(a)控制組 (b)實驗組 - 23 -
圖 4-2、經處理之時間響應圖(a), (e)為平均 4 次 (b), (f)為平均 8 次(c), (g)為平均 16 次 (d), (h)為平均 128 次 - 24 -
圖 4-3、各聲壓之能量訊號(a)0.5 倍頻 (b)主頻 (c)1.5 倍頻 (d)2 倍 - 26 -
圖 4-4、血腦屏障開啟狀況 (a) 0.105 MPa (b) 0.332 MPa (c) 0.463 MPa - 27 -
圖 4-5、HE染色 (a) 0.105 MPa (b) 0.332 MPa (c) 0.463 MPa - 28 -
圖 4-6、各頻段能量分布圖 - 30 -
圖 4-7、靈敏度與專一性趨勢比較 - 31 -
圖 4-8、EB與 ESD能量關係圖 - 32 -


表目錄
表 4-1、實際血腦屏障開啟與未開啟狀況與能量關係 - 29 -

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