成人的皮膚面積約為1.5到2平方公尺，為身體和外界環境的介面，作用是保護人類不受外界的各種刺激所傷，且皮膚表面的化學組成在部分程度上仍是未被定義的。傳統檢測皮膚表面組成的方法是以氣相層析質譜法（Gas Chromatography Mass Spectrometry, GC/MS）或是液相層析質譜法（Liquid Chromatography Mass Spectrometry, LC/MS）來進行，因需要進行樣品前處理，因此往往需耗費很多時間及人力。近年來發展的大氣質譜法（Ambient Mass Spectrometry, AMS），其特點是不需事先對樣品進行前處理，且這類型的技術也已經可以對植物的葉子、各種器官的組織切片和微生物培養基進行分析和成像。熱脫附電噴灑游離質譜法（Thermal Desorption-Electrospray Ionization/Mass Spectrometry, TD-ESI/MS）為其一種新穎的AMS，此技術具有樣品置換快速、高通量分析且非侵入性取樣等優勢，在本研究中係以TD-ESI/MS為分析工具，探索人體皮膚表面上所存在的分子。我們成功地先以探針輕刮取皮膚的方式，得到皮膚上各分子的輪廓（profile），包括咖啡因及其代謝物、尼古丁與角鯊烯等等，接著進行皮膚取樣位置的畫分（約300等分），再予以探針採樣後將其放入熱的烘箱中以加熱脫附探針上的分析物，接著藉由載流氮氣將分析物送至電噴灑游離（Electrospray Ionization, ESI）區域進行游離後，離子進入質譜內便可得到訊號圖譜，最後從質譜數據中抓取特定的分子離子峰進行成像。由分子影像的結果而知，上述分子在皮膚表面上的分佈不盡相同，可能根據該區皮膚下的腺體數量或構造不同而有所差異。藉由以TD-ESI/MS建立的分子影像模型，有助於人體皮膚表面上分子分佈的相對關係，具未來個人化醫療應用的潛力。

The adult skin provides the interface between the body and its outside world with a surface area of about 1.5 to 2 square meters. The role of the skin is to protect the human body from the outside world of various dangers. The chemical composition of the skin surface is still not well-defined. The traditional methods of detecting the surface composition of the skin is by gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), which need for sample pretreatment and take a lot of time and manpower. In recent years, the development of atmospheric mass spectrometry (AMS) significantly reduces analytical times because it avoids complex sample pretreatment. This technique is also capble of analyzing the leaves of plants, tissue sections of various organs and microbial culture and could go even further in constructing relevant images. A new AMS technique, which is known as thermal desorption-electrospray ionization/mass spectrometry (TD-ESI/MS), has the advantages of rapid, high-throughput analysis and non-invasive sampling. In this study, TD-ESI/MS was used as an analytical tool to find out the molecules present on the surface of human skin. We succeeded in scraping the skin with a probe to get the profile of the molecules on the skin, including caffeine and its metabolites, cholesterol, squalene and nicotine. Followed by a partition of the skin sampling position about 300 equally, and a sampling probe to obtain analyte from skin was putting into a heated oven for thermally desorbing analyte. Then, the analyte was sent to the Electrospray Ionization (ESI) region for post-ionizing and obtain the mass spectra. Finally, a specific molecular ion peak was captured from the mass spectrometry data for imaging. From the result of molecular imaging, the distribution of these molecules on the surface of the skin was found to be different, which in turn depended on the number or structure of glands under the skin. The molecular imaging by TD-ESI/MS will contributes to the identification and mapping of molecular distribution of various compounds on the surface of human skin, with promising potential applications in personal medicine in the coming future.

論文審定書 i
論文公開授權書 ii
誌謝 iii
中文摘要 v
英文摘要 vi
圖目錄 x
表目錄 xii
壹、緒論 1
一、前言 1
二、醫學影像（nuclear medicine imaging） 3
1、X光電腦斷層掃描（x-ray computed tomography, X-ray CT） 3
2、磁振造影（magnetic resonance imaging, MRI） 5
3、超音波顯影（ultrasonic imaging） 7
4、核子醫學影像（nuclear medical imaging） 8
5、醫學影像技術優缺點比較 11
6、皮膚影像 12
三、質譜影像 13
1、二次離子質譜法（secondary ion mass spectrometry, SIMS） 14
2、基質輔助雷射脫附游離質譜法（matrix assisted laser desorption ionization imaging mass spectrometry, MALDI/MS） 15
3、大氣質譜法（ambient mass spectrometry, AMS） 17
4、液相層析質譜法（liquid chromatography mass spectrometry, LC/MS） 24
四、皮膚 25
1、皮脂腺與皮脂 27
2、汗腺與汗液 27
五、論文目標 28
貳、實驗 29
一、實驗試劑與藥品 29
1、實驗試劑 29
2、實驗藥品 29
3、試劑配製 29
4、檢測之化合物 30
二、儀器設備與軟體 32
1、熱脫附電噴灑游離源 32
2、質譜儀 34
3、參數設定 35
4、影像處理軟體 36
三、受試者 38
四、實驗方法 39
1、大規模皮膚取樣事前準備工作 39
2、熱脫附電噴灑游離影像質譜法（thermal desorption-electrospray ionization imaging mass spectrometry, TD-ESI IMS）與皮膚取樣的操作流程 40
3、快速取樣裝置設計 43
參、結果與討論 44
一、使用TD-ESI/MS檢測皮膚表面上的角鯊烯於全身的分布影像 44
1、角鯊烯的介紹 44
2、TD-ESI/MS針對皮膚表面樣品的分析 46
3、使用TD-ESI/MS檢測皮膚表面的角鯊烯於全身的分佈 50
4、角鯊烯於全身皮膚表面的分佈影像 53
二、使用TD-ESI/MS檢測皮膚表面上的咖啡因於全身的分布影像 58
1、咖啡因的介紹 58
2、TD-ESI/MS針對皮膚表面咖啡因的分析 59
3、咖啡因於全身皮膚表面的分佈影像 66
4、咖啡因於局部皮膚表面的分佈影像 69
三、使用TD-ESI/MS檢測皮膚表面上的尼古丁於全身的分布影像 75
1、尼古丁的介紹 75
2、TD-ESI/MS針對皮膚表面尼古丁的分析 76
3、尼古丁於上半身皮膚表面的分佈影像 80
肆、結論 82
伍、參考文獻 83

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