臺灣博碩士論文加值系統

為因應人類基因研究的需要，先進的微蝕刻MEMS技術與傳統生化分析技術的結合，而造就了微全分析系統(µ-Total Analysis System, µ-TAS)，至今已有10年的發展，並逐漸在臨床檢驗、新藥開發、基因研究等生技產業領域佔有一席之地。然一個完整的分析系統中須包含採樣、樣品前處理、分析及數據處理等部份，這些煩雜的步驟相當繁瑣、耗費時間，甚至需佔用實驗室龐大的空間，儀器微小化的任務不可小視，必須收納採樣、前處理分析等繁瑣的步驟。上述的微型分析系統不但價廉、靈敏、快速、耗量小，在結合高選擇性與高靈敏度的電化學檢測器後，整合性更高。本文所敘述的微電泳電化學檢測器晶片，將逐章討論其緣起及特性。前兩章主要是討論製程參數，如晶片及電極基材的選擇、光罩設計、光阻材質、曝光光源、顯影、蝕刻、放電加工等。其次討論電極晶片製作參數，最後探討熱貼合方法的接合技術及電極佈置的最佳化以求取最大電流訊號、靈敏度與解析度。
第三章主要探討晶片蝕刻的最佳化，如配方和蝕刻時間長短的關係，流道深寬比及電泳層析峰的對稱性、電流訊號和理論板數等參數。
第四章研究主題是利用前管柱酵素反應以應用於臨床生化分析，如對肌酸酐(creatinine)、葡萄糖(glucose)、抗壞血酸(ascorbic acid)和尿酸(uric acid)等物質的臨床分析。其中不具電活性的肌酸酐和葡萄糖，可修改流道以前管柱酵素反應的方式使其具電活性。其中以分離條件與酵素含量等參數的探討為主，並應用於真實樣品尿液和血清分析。最佳條件為20 mM pH = 7.5的磷酸緩衝溶液在1.5 kV下、進樣5秒，隨後同樣以1.5 kV施加於5公分流道兩端以分離肌酸酐、葡萄糖、尿酸和抗壞血酸。檢量線線性範圍為10-800 μM，所有樣品的迴歸係數都落在0.995-0.998，而偵測極限以抗壞血酸0.71 μM最低，電流訊號的再現性(n = 7)介於1.5-2.2%之間，而遷移時間的變化也在0.5% (n = 7)以內。
第五章研究討論外接銅電極在醣類，含蔗糖(sucrose)、葡萄糖(glucose)、棉子糖(raffinose)、纖維二糖(cellobiose)、半乳糖(galactose)、木糖(xylose)、果糖(fructose)和乳糖(lactose)分析上之應用，其中討論分離條件最佳化，及實際樣品分析如可口可樂。以80 mM pH = 12.5的氫氧化鈉溶液在2 kV下進樣3秒，隨之施加2 kV在10公分流道的兩端，可分離醣類物質。檢量線線性範圍落在於10-1000 μM，而迴歸係數皆於0.997-0.999，並可偵測至2.3 μM(葡萄糖)。電流訊號的再現性(n = 7)皆在1.24%的相對標準偏差以內，而遷移時間的變化也在0.6% (n = 7)以內。
第六章討論外接銅電極偵測胺基酸、胜肽與醣類，其中討論分離條件最佳化，及實際樣品分析如蜂膠和樟芝。以80 mM pH = 12.5的氫氧化鈉溶液在1 kV下進樣3秒，隨之施加1 kV在5公分流道的兩端，可分離胺基酸和胜肽。檢量線線性範圍落在於80-800 μM，而迴歸係數皆於0.995以上，並可偵測至25.7 µM組胺酸(S/N = 3)，而遷移時間的變化皆在2%的相對標準偏差以內。
第七章為總結，說明微電泳晶片結合電化學檢測器的優點，未來可應用於基因表現分析、臨床診斷、藥物篩選、基因定序、蛋白質分析等相關領域等等。利用MEMS所製作的微全分析系統之微電泳晶片，將因為系統的縮製及整合，而使生化檢驗時間快速效率提高、樣品及藥品用量大幅降低，終將：在生物醫學上將造成革命性的影響。目前微全分析系統已成為全球各大學與研究機構競相投入的熱門研究領域，相關的生物微機電產業終將蛻化成未來明星產業。

As we are still lost in a reverie about the digital wonders that Semicon has brought us, the notion of miniaturization has in fact been around for several decades. But, its role in instrument miniaturization was obscure─most likely to thrive as its sibling yet lying dormant soon after its debut. Today, after a decade’s efforts, the microfluidic systems capable of performing chemical reactions, separation and detection on a single chip are not uncommon.
Chapter 1 and 2 detail the construction for microchip capillary electrophoresis (μCE) using the standard photolithography, followed by chip evaluation.
Chapter 3 depicts the dimension effect on performance. Dimension either width or depth alone fails to relate the chip performance: it’s the aspect ratio, w/d, which guides the performance. But it only works in hindsight; tailored-made chips are not yet possible. Large aspect ratio benefits separation efficiency, peak symmetry, and detection current up to a certain point where hydrodynamics start to intervene. In a study employing electrodes arrayed down the stream to locate the optimal electrode position, the detection current sinks 1.7 nA across the electrode─averaging 0.1 nA or 7% drop for every decade of micrometer off the exit. The separation efficiency also suffers a 2,000 N/m drop in the same span.
Chapter 4 demonstrates a new multiple-enzymatic assay; the chip is capable of precise intake of sample or reagent in nanoliter. In these instances, simultaneous analysis of creatinine and uric acid is shown to be easy. The sensitivities also escalate to 1 µM. The migration time repeats from injection to injection within 0.5% R.S.D. (n = 7), but the peak current within 2.2% R.S.D. The detection limits (S/N = 3) range from 0.71 μM for ascorbic acid to 10 μM for glucose. The calibration curves are linear from 10 to 800 μM (R2 > 0.995). Serum or urine samples containing glucose, creatinine, uric acid and ascorbic acid were analyzed to verify its feasibility.
Chapter 5 exemplifies a variation of detector for the otherwise insensitive carbohydrates. The ability of the 50-μm Cu wire electrode to maximize current collection, while suppressing the overwhelming noise, is largely due to its strategic spot at the exit. High alkalinity that transforms carbohydrates into alcolate anions makes an excellent complement to Cu electrode in carbohydrate detection. All carbohydrates including sucrose, cellobiose, glucose and fructose have migrated in 400 seconds. The linear range covers 10 to 1000 µM with R2 > 0.996. Variation in current for glucose is within 1.24% (n = 7) and migration time 0.6%. The detection limit is a low 2.3 µM for glucose (S/N = 3), or 27.6 attomole in mass detection.
Chapter 6 details the development of a selective analytical method for amino acid and peptide at Cu electrode. The 5-cm chip, though lengthy for a regular chip, is advantageous of higher N, supposedly adequate for separating arginine, sucrose, glucose, fructose and tryptophan. All of the calibration plots are linear from 80 to 800 µM with R2 > 0.995. The reproducibility in migration times varies within 2% for the substances analyzed. The detection limit is a low 27.5 µM for histidine (S/N = 3).
The last chapter prospects the development of μCE-EC, as a proven feasible analytical tool. Though somewhat limited by its own selectivity, the incorporation of electrode is a viable plan in its own right: it is simple, rugged, versatile and sensitive. Its scope of application should at least cover clinical diagnosis, pathogen detection, forensic science, drug screening, genomics and proteomics.

中文摘要 i
Abstract iii
目錄 v
圖目錄 x
表目錄 xv
第一章 緒論 1
1-1 研究背景與目的 1
1-2 毛細管電泳與微電泳晶片概論 4
1-2-1 毛細管電泳與微電泳晶片發展史 4
1-2-2 電泳原理 5
1-2-3 微電泳晶片偵測方法 8
1-3 參考文獻 14
第二章 微電泳晶片製程之研究 17
2-1 導論 17
2-1-1 電泳晶片蝕刻方法介紹 19
2-1-2 電泳晶片偵測方法介紹 22
2-2 微電泳晶片製程研究 27
2-2-1 製程設備 27
2-2-2 試劑與材料 28
2-2-3 微電泳晶片設計與製作流程 28
2-2-3-1 電泳晶片光罩圖設計 28
2-2-3-2 流道基板製作 29
2-2-3-3 感應電極基板製作 35
2-2-3-4 高溫熔融接合 38
2-2-3-5 微電泳晶片系統組裝 38
2-3 微電泳晶片實驗方法 38
2-3-1 藥品 38
2-3-2 儀器 39
2-3-3 微電泳晶片清洗方法 39
2-3-4 微電泳晶片電化學檢測系統的建立 40
2-3-5 微電泳晶片之進樣與分離模式 40
2-3-6 微電泳晶片效能評估 41
2-4 結果與討論 43
2-4-1 基材選擇之研究 43
2-4-2 薄膜沈積之研究 43
2-4-3 流道基板蒸鍍阻障層金屬之研究 44
2-4-4 感應電極基板製作之研究 50
2-4-5 微影製程之研究 54
2-4-5-1 光阻塗佈參數的探討 54
2-4-5-2 曝光參數的探討 55
2-4-5-3 顯影參數的探討 55
2-4-6 蝕刻製程之研究 58
2-4-7 微放電加工之研究 60
2-4-8 高溫熔融接合之研究 61
2-4-9 微電泳晶片與微電極佈放位置之研究 69
2-4-9-1 單電極微電泳晶片系統 71
2-4-9-2 四電極微電泳晶片系統 80
2-4-9-3 四流道微電泳晶片系統 80
2-4-10 微電泳晶片微電極清洗與維護之研究 85
2-4-10-1 微電極清洗與維護的探討 85
2-4-10-2 微電極再生的探討 85
2-5 結論 88
2-6 參考文獻 94
第三章 微電泳晶片流道參數最佳化的研究 98
3-1 導論 98
3-2 實驗 100
3-2-1 藥品 100
3-2-2 儀器 101
3-2-3 實驗步驟 103
3-2-3-1 蝕刻溶液配製 103
3-2-3-2 晶片效能測試 103
3-3 結果與討論 103
3-3-1 蝕刻時間與蝕刻溶液配方參數的探討 104
3-3-2 不對稱因子與深寬比的探討 104
3-3-3 深寬比與電流訊號及理論板數的探討 107
3-3-4 串聯式四電極系統的探討 107
3-3-5 分析與應用 108
3-4 結論 116
3-5 參考文獻 117
第四章 微電泳晶片結合前管柱酵素反應-分析肌酸酐、葡萄糖、尿酸和抗壞血酸 118
4-1 導論 118
4-2 實驗 122
4-2-1 藥品 122
4-2-2 儀器 123
4-2-3 實驗裝置 123
4-2-4 晶片效能測試 127
4-2-5 簡單型微電泳晶片 127
4-2-5-1 進樣模式 127
4-2-6 前管柱型微電泳晶片 127
4-2-6-1 進樣模式 129
4-3 結果與討論 129
4-3-1 晶片效能評估 129
4-3-2 樣品最佳化偵測電位之研究 131
4-3-2-1 樣品流體動力式伏安法的探討 131
4-3-3 不同設計型式的微電泳晶片之研究 131
4-3-3-1 簡單型微電泳晶片 132
4-3-3-2 前管柱型微電泳晶片 135
4-3-4 前管柱型微電泳晶片之研究 135
4-3-4-1 分離流道長度和緩衝溶液的探討 135
4-3-4-2 緩衝溶液pH值對分離效果的探討 136
4-3-4-3 緩衝溶液濃度對分離效果的探討 137
4-3-4-4 樣品進樣與分離電壓對分離效果的探討 137
4-3-4-5 系統的再現性與檢量線的建立 138
4-3-4-6 真實樣品分析 138
4-4 結論 144
4-5 參考文獻 145
第五章 微電泳晶片結合電化學檢測器偵測醣類化合物 146
5-1 導論 146
5-1-1 藥品 149
5-1-2 儀器 150
5-1-3 實驗裝置 150
5-1-4 外接式電極晶片改裝 150
5-1-5 晶片效能測試-5公分與10公分流道 156
5-1-6 進樣模式 156
5-2 結果與討論 156
5-2-1 銅電極在鹼性溶液的電化學性質 156
5-2-2 醣類的分離和偵測之研究 159
5-2-2-1 醣類循環伏安法測試的探討 159
5-2-2-2 醣類流體動力式伏安法測試的探討 159
5-2-2-3 選擇不同長度的分離流道的探討 162
5-2-2-4 電解質溶液pH值對分離效果的探討 162
5-2-2-5 電解質濃度對分離效果的探討 165
5-2-2-6 樣品進樣與分離電壓對分離效果的探討 165
5-2-2-7 系統的再現性與檢量線的建立 166
5-2-2-8 真實樣品分析 166
5-3 結論 174
5-4 參考文獻 176
第六章 微電泳晶片結合電化學檢測器偵測胺基酸與胜肽 178
6-1 導論 178
6-2 實驗 180
6-2-1 藥品 180
6-2-2 儀器 181
6-2-3 實驗裝置圖 181
6-3 結果與討論 184
6-3-1 銅電極在鹼性溶液的電化學性質 184
6-3-2 胺基酸和胜肽的分離和偵測之研究 184
6-3-2-1 循環伏安法測試的探討 184
6-3-2-2 流體動力式伏安法測試的探討 187
6-3-2-3 電解質溶液pH值對分離效果的探討 187
6-3-2-4 電解質濃度對分離效果的探討 187
6-3-2-5 樣品進樣與分離電壓對分離效果的探討 189
6-3-2-6 系統的再現性與檢量線的建立 189
6-3-2-7 真實樣品分析 193
6-4 結論 198
6-5 參考文獻 199
第七章 總結 200
附錄 發表論文 204

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