本研究結合超音波與雷射的非侵入式光聲技術，應用於雷射光熱治療時的溫度量測，並進行複合式超音波與光聲的疊合造影，同時發展定量式熱影像之成像技巧。光聲信號可用來研究金奈米粒子受連續波雷射照射後，因表面電漿共振效應所產生的加熱反應。此種結合超音波與光聲效應的方法，在治療前與治療中可分析腫瘤的解剖學構造，並於治療期間監測雷射電漿光熱治療時的組織溫度，有助於維持光熱治療的安全性與有效性。許多形式的能量皆可產生光聲信號，本研究選擇脈衝式雷射為光聲信號來源，同時搭配高頻超音波探頭，以利於產生高解析度的光聲影像。
光聲信號可用於非侵入式組織造影，影響聲波振幅壓力P(z) 的關係式為 ，在能量穩定的雷射系統中，振幅P(z)除了受Grüneisen參數Γ影響之外，尚與吸收係數μa有關。溫度變化不會影響吸收係數，而水的Γ參數對溫度呈線性關係，軟組織具有大於70%的水份，故可借用水的Γ參數，由光聲效應的壓力信號，測量熱治療過程中，富含水份的組織溫度。
溫度除了影響光聲振幅外，尚會造成光聲射頻超音波信號的位置偏移，若以聲速公式校正，並扣除熱膨脹的效應，可將這些超音波信號調整至相同的位置。熱膨脹與聲速雖對超音波信號時間偏移量產生影響，但不影響光聲信號振幅，故適宜採用光聲信號來測量較大範圍的溫度變化。
光聲影像系統品質與本系統之空間解析度有關，超音波探頭中心頻率愈高，空間解析度將會愈高。本研究採用的20MHz高頻超音波探頭，可達200-300 μm的空間解析度。提高脈衝式雷射系統的能量輸出穩定度，可減少脈衝能量的標準差，進而提高溫度準確度。本系統可快速對熱流反應，並可長時間工作，對於連續波雷射的開閉與輸出功率的波動，立即產生振幅的改變，此特性可提昇熱治療過程的安全性與有效性。
金奈米粒子的存在、連續波雷射的照射，皆可增加光聲信號的振幅。與組織原本就存在的載色體相較，金奈米粒子在吸收脈衝式雷射能量後，可激發更高的光聲信號振幅，所以適合擔任光聲造影的「對比劑」。在雷射光熱治療前後，本系統可疊合超音波與光聲影像，準確定位腫瘤與奈米粒子所在位置，有利於擬定治療計劃與提昇治療品質。
以光聲效應為主的溫度量測方法，具有應用於熱治療監測的潛力，且使用金奈米粒子輔助的雷射電漿光熱治療模式，特別適用於配合雷射的光聲效應測溫法，同時也可利用定量式熱影像的熱測繪技術，進行雷射光熱治療過程的即時監控。

This study applied the ultrasound (US) and laser for the non-invasive photoacoustic (PA) technology to monitor the temperature during laser-induced photothermotherapy. The US and PA images were also combined for imaging purpose, and technology for quantitative thermal imaging was developed. PA signal can be used to research the thermal reaction of the surface plasmon resonance of the gold nanoparticles irradiated with the continuous wave mode laser. The safety and efficacy of the laser-assisted plasmonic photothermal therapy were kept by combining the US and PA signals to elucidate the anatomical structure of the tumor, and to monitor the tissue temperature during therapy. Many kinds of energy may trigger PA signal. We selected the pulsed laser to produce the PA signal and used the high-frequency ultrasonic transducer to obtain PA images with high resolution.
PA signal may be used for non-invasive tissue imaging. The amplitude of the PA pressure P(z) is governed by the equation . Under the stable laser system, the amplitude is affected by the Grüneisen parameter Γ and the absorption coefficient μa. However, the absorption coefficient is independent to temperature change, and the Grüneisen parameter Γ for water is a linear relationship to the temperature. The soft tissue is composed of more than 70% of water, and thus we can use the Grüneisen parameter Γ of water to measure the temperature of the water-contained tissue during the thermotherapy.
Temperature may not only have influence on the amplitude of PA signal, but also cause the echo-shift of the ultrasound signal. With the correction of the speed of sound and thermal expansion according to the temperature change, the ultrasound radiofrequency signals can be adjusted to the same position. Though thermal expansion and speed of sound affect the ultrasound echo time shift, they are independent to the amplitude of PA signal. We may use the PA signal to measure the temperature change for a large range.
The quality of PA imaging system is related to our spatial resolution. By increasing the central frequency of the ultrasound transducer, the spatial resolution is able to be improved. We used the 20MHz high frequency transducer to approach the spatial resolution of 200-300 μm.
We can increase the accuracy of temperature measurement by improving the stability of output energy of the pulsed laser. This system can respond to the heat flux quickly and produce change of the amplitude of PA signal immediately according to the output power of the CW laser. It may secure the safety and efficacy of the thermotherapy.
The gold nanoparticles and irradiation of CW laser can increase the amplitude of the PA signal. Compared to the intrinsic chromophores of soft tissue, the gold nanoparticles may trigger higher PA amplitude after absorption the energy of the pulsed laser and thus are suitable for contrast agent during PA imaging. Before and after the laser-induced thermotherapy, this system can combine the UA and PA images to locate the position of the tumor and the nanoparticles to facilitate better treatment plan and therapeutic quality.
Photoacoustic technology for temperature measurement has the potential to monitor the thermotherapy and is suitable for gold nanoparticle-assisted laser-induced plasmonic photothermal therapy. We can also use the technique of quantitative thermal imaging for real-time monitoring during the laser-induced thermotherapy.

目 錄
口試委員會審定書
誌謝
中文摘要
英文摘要
第一章 緒論……………………………………………………………………….......1
1.1 熱治療簡介……………………………………………………………….…1
1.1.1 射頻腫瘤消融術…………………………………………………….1
1.1.2 微波消融術………………………………………………………….3
1.1.3 高強度聚焦超音波………………………………………………….5
1.1.4 雷射誘導熱治療…………………………………………………….7
1.2 雷射與溫度對生物組織的作用…………………………………………….8
1.2.1 雷射對生物組織的作用…………………………………………….9
1.2.1.1 光化學反應………………………………………………...9
1.2.1.2 熱交互作用……………………………………………….11
1.2.1.3 光剝離作用……………………………………………….13
1.2.1.4 電漿誘發剝離作用…………………………………….…13
1.2.1.5 光分裂效應…………………………………………….…14
1.2.2 溫度對生物組織的作用…………………………………………...15
1.3 使用金奈米粒子進行雷射誘導熱治療…………………………………...18
1.3.1 金奈米粒子的表面電漿共振……………………………………...18
1.3.2 馬克斯威爾方程式………………………………………………...20
1.3.3 表面電漿共振……………………………………………………...22
1.3.4 利用表面電漿共振之雷射誘導熱治療…………………………...25
1.4 各種監測熱治療溫度的方法……………………………………………...26
1.4.1 非侵入式監測溫度法………………………………………….……26
1.4.2 超音波測溫法……………………………………………………….29
1.4.2.1 聲速法…………………………………………………….31
1.4.2.2 衰減係數法……………………………………………….32
1.4.2.3 反散射能量變化法……………………………………….34
1.4.2.4 回音偏移法……………………………………………….37
1.5 光聲效應…………………………………………………………………...40
1.6 利用超音波與光聲效應對軟組織造影…………………………………...41
1.7 光聲效應測溫法與研究動機……………………………………………...43
第二章 光聲效應測溫法之理論基礎……………………………………………….44
2.1 光聲信號之產生…………………………………………………………...44
2.2 由熱力學推導光聲信號之振幅…………………………………………...45
2.3 光聲信號與溫度之關係…………………………………………………...50
2.4 影響解析度的因素………………………………………………………...54
2.4.1 解析度……………………………………………………………….54
2.4.2 空間解析度………………………………………………………….54
2.4.3 溫度解析度………………………………………………………….55
第三章 實驗方法…………………………………………………………………….56
3.1 實驗所用之高頻光聲探頭與雷射系統…………………………………...56
3.2 仿體實驗架構……………………………………………………………...59
3.3 活體實驗架構……………………………………………………………...63
第四章 實驗結果與討論…………………………………………………………….67
4.1 光聲信號產生的位置與振幅……………………………………..……….67
4.2 溫度對吸收係數之影響…………………………………………………...71
4.3 溫度對光聲信號位置之影響……………………………………………...73
4.4 熱效應對光聲信號振幅之影響…………………………………………...88
4.4.1 以脈衝式雷射加熱仿體…………………………………………….88
4.4.2 以熱水浴槽加熱仿體…………………………………………………...95
4.4.3 不同物質對於光聲信號振幅與溫度線性關係之影響…………...100
4.5 系統之解析度與誤差來源……………………………………………….105
4.6 光聲信號對溫度變化之靈敏度與穩定性……………………………….110
4.7 以光聲-超音波雙重造影辨識腫瘤……………………………………...112
4.8 連續波雷射與金奈米粒子對於腫瘤的熱效應………………………….115
4.9 以連續波雷射為熱源進行熱治療的光聲信號強度…………………….119
4.10 定量式熱影像技術……………………………….. ……………………..124
4.11 標靶式雷射光熱治療之定量式熱影像………………………………….131
第五章 結論……………………………….. ………………………………………140
5.1 溫度與光聲造影的關係…………………………….. …………………..140
5.2 定量式熱影像技術…………………………….. ………………………..142
5.2 未來展望……………………………….. ………………………………..143
第六章 參考文獻……………………………….. …………………………………144
第七章 聲明……………………………….. ………………………………………153

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