直接在大氣壓力下分析樣品可以免除繁瑣的前處理步驟，可以提升分析速度因應大量的樣品分析需求，因此大氣壓力游離法成為目前質譜游離法發展的趨勢。從2003年開始陸續有多種(DART - Direct Analysis in Real Time, DESI - Desorption Electrospray Ionization, ELDI - Electrospray Assisted Laser Desorption Ionization, ASAP - Atmospheric Solids Analysis Probe)可以在大氣壓力游離 ”固態樣品” 的游離法被發展出來，然而有更多樣品並非以固態而是以液態存在。因此若能開發一套可以直接在大氣壓力下不經前處理直接分析液體樣品的技術，將可以涵蓋目前絕大多數的快速分析需求。

本研究的目的即是開發出能在大氣壓力下直接分析液體樣品的技術，研究中在分析溶液中添加石墨粉末(carbon graphite powder)，再以UV雷射(337 nm)轟擊液滴表面。此時碳粉會吸收大部分的雷射能量而將樣品由表面脫附出來，在液滴的上方以電噴灑輔助分析物游離，成功的得到各式蛋白質標準品帶多價電荷的質譜圖。而實驗中也得到蛋白質標準品(Lysozyme, Cytochrome C, Myoglobin)以低價數存在的質譜圖，證實經過此方法脫附出來的蛋白質可以維持其三級結構。

而研究中也以此技術分析常見的生物體液(包含血液、血清、眼淚)，成功的得到其主要成份的訊號(Hemoglobin, Albumin, Lysozyme)，證實的確可以利用此技術直接在大氣壓力之下游離液體樣品。並將此技術應用在快速分析糖尿病患者血液中糖化血色素比例，充分發揮大氣壓力液相質譜法不需樣品前處理、可以反映溶液中成分的比例的優點。

因為大部分的反應都是在液相中進行，因此也將大氣壓力液相質譜法應用於反應的即時監測。研究中監測了一個有機化學反應的進行，以及一個生化反應的進行。證實大氣壓力液相質譜法可以監測在液相中反應的進行。

由於使用UV雷射進行脫附，因此必須在溶液中添加碳粉以吸收雷射能量並傳遞給周圍的分子使其脫附。但水溶液在紅外線光譜有很強的吸收，所以使用IR雷射應該可以不用添加碳粉來吸收雷射能量，即可直接由液體中將分析物脫附。本研究中也進行了一系列的實驗，證實使用IR雷射不需要添加碳粉即可進行大氣壓力液相質譜法分析。

整體而言大氣壓力液相質譜法是一種在一大氣壓下直接將樣品自液體中脫附並游離的一種質譜分析法。可以使用大氣壓力液相質譜法分析的液體樣品非常廣泛，自水溶液如生物體液或是蛋白質標準品到各種極性的有機溶劑如甲醇、二氯甲烷、甲苯與正己烷，甚至強酸強鹼環境如14M的氫氧化鈉以及12N的鹽酸水溶液。因此大氣壓力液相質譜法不但具有分析速度快、可以去除樣品中的鹽類干擾以及反映液體樣品中分析物組成的比例等優點，其應用範圍幾乎沒有任何限制。

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目 錄
論文摘要.…....…....…...…....….......…....…..…..…....…....….. i
目錄.…....…....…...…....….......…....…..…..…....…....…..….... iv
圖目錄....…....…...…....….......…....…..…..…....…....…..…..... viii
表目錄....…....…...…....….......…....…..…..…....…....…..…..... xv
壹、緒論.…....…....…...…....….......…....…..…..…....…....….. 1
一、傳統的大氣壓力質譜法…....…..…..…....…....….. 2
1. 大氣壓力化學游離法…..…..…....…....….. 4
2. 電噴灑游離法...…....…..…..…....…....….. 7
3. 大氣壓力基質輔助雷射脫附游離法...….. 12
二、近代大氣壓力游離法...…....…..…..…....…....….. 16
"1. 即時直接分析 (Direct Analysis in Real Time, DART)" ….......…....…..…..…....…....…. 16
2. 大氣壓力固態分析探針…..…..…......….... 20
三、近代大分子大氣壓力游離法..…..…..…....…....… 23
1. 脫附電噴灑游離法…....…..…..…....…....… 23
2. 電噴灑輔助雷射脫附游離法…..…....….... 27
四、兩階段式游離法之沿革..…....…..…..…....…....… 31
五、研究目的…....….......…....…..…..…....…....…..…. 33
貳、實驗.…....…....…...…....….......…....…..…..…....…....…. 36
一、四極-時間飛行質譜儀…....…..…..…....…....…. 36
二、傅利葉轉換離子迴旋共振質譜儀..…....…....…. 37
三、氮氣雷射系統....….......…....…..…..…....…....…. 39
四、Nd:YAG雷射系統.......…....…..…..…....…....…. 40
五、光學平台.…....….......…....…..…..…....…......… 42
六、大氣壓力液相質譜法儀器裝置..…..…....…......… 44
七、化學藥品與其製備..…....…..…..…....…......….… 45
1. MALDI基質溶液製備方式…....…......….… 45
2. 肌紅蛋白/水溶性碳六十衍生物…......….… 45
3. 肌紅蛋白/奈米金粒子樣品溶液製備.….… 45
4. 以大氣壓力液相質譜法分析眼淚、牛奶與血清實驗條件.......…....…..…..…....…......… 46
5. 以大氣壓力液相質譜法分析細菌萃取液的條件....…...…....….......…....…..…..…....….... 46
6. 以大氣壓力液相質譜法分析蛋白質標準品混合物.…...…....….......…....…..…..…....….... 47
7. 以大氣壓力液相質譜法偵測各式有機溶劑中的有機小分子….......…....…..…..…....….... 48
8. 以大氣壓力液相質譜法偵測無機化合物... 48
9. 以大氣壓力液相質譜法監測化學反應的進行.…...…....….......…....…..…..…....…....….... 49
10. 以大氣壓力液相質譜法監測生化反應….. 52
參、大氣壓力液相質譜法之研發...…....…..…..…....…....…... 53
一、概念成形...…....….......…....…..…..…....…....…... 53
二、大氣壓力液相質譜法的初步結果..…....…....…... 55
三、碳粉使用量....….......…....…..…..…....…....….... 67
四、不同顆粒在大氣壓力液相質譜法的應用…....…... 78
五、大氣壓力液相質譜法之負離子圖譜...…....….... 88
六、探討進樣方式.….......…....…..…..…....…....….... 90
七、大氣壓力液相質譜法偵測極限…..…....…....….... 94
八、大氣壓力液相質譜法概述即可能的游離機制…... 96
肆、大氣壓力液相質譜法應用於監測蛋白質結構改變....….. 103
一、以質譜法進行蛋白質結構的研究.…....…....….... 103
二、改變電噴灑以及樣品溶液組成觀察蛋白質結構的變化....…....…...…....….......…....…..…..…....…....…. 104
三、以ALMS監測液滴中溶液隨時間逐漸揮發蛋白質結構的變化…...…....….......…....…..…..…....…....…. 111
四、以大氣壓力質譜法觀察溶液的黏滯度對蛋白質結構的影響…...…....….......…....…..…..…....…....…..….. 119
五、以大氣壓力液相質譜法監測蛋白質變化之概述… 123
伍、大氣壓力液相質譜法應用於直接偵測生物體液…..….. 125
一、以大氣壓力液相質譜法直接分析眼淚..…....….. 125
二、以大氣壓力液相質譜法直接分析牛奶..…....….. 129
三、以大氣壓力液相質譜法直接分析血清..…....….. 131
四、以大氣壓力液相質譜法直接分析細菌萃取液…. 134
五、以大氣壓力液相質譜法分析蛋白質標準品混合物 136
六、以大氣壓力液相質譜法進行血液中糖化血色素含量的快速分析....…...…....….......…....…..…..…....….... 140
1. 血色素與糖化血色素…....…..…..…....….... 141
2. 確認方法可行.….......…....…..…..…....….... 142
3. 以大氣壓力液相質譜法分析病人的血液進行定量分析…....….......…....…..…..…....….... 145
七、以大氣壓力液相質譜法分析生物體液之概述….. 148
陸、大氣壓力液相質譜法應用於反應的線上直接偵測....…... 150
一、以大氣壓力液相質譜法偵測各式有機溶劑中的有機小分子…...…....….......…....…..…..…....…....…..….. 151
二、以大氣壓力液相質譜法偵測無機化合物...…..….. 155
三、以大氣壓力液相質譜法監測化學反應的進行.….. 157
四、以大氣壓力液相質譜法監測生化反應…....…..… 162
五、大氣壓力液相質譜法應用於反應的線上直接偵測概述…...…....….......…....…..…..…....…....…..…..… 164
柒、以紅外線雷射進行大氣壓力液相質譜法分析.…..…..… 166
一、以IR-ALMS分析蛋白質標準品與血液樣品..… 166
二、IR-ALMS改變進樣方式的研究..…....…..…..… 169
三、IR-ALMS挑戰嚴苛環境中的分析..…....…..….. 172
四、IR-ALMS概述.…....…..…..…....…....…..…..… 176
捌、結論.…....…....…...…....….......…....…..…..…....…....…. 177
玖、參考文獻..…....…...…....….......…....…..…..…....…....…. 179
拾、附錄.…....…....…...…....….......…....…..…..…....…....…. 192
一、局部放大攝影裝置.....…....…..…..…....…....…. 192
二、批次匯出平均質譜圖軟體....…..…..…....…....…. 194

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