診斷是醫學治療過程中很重要的一個步驟，幫助人類確實的了解自身的身體狀況，並給予合適的治療處置。體外診斷系統能在不侵入人體情況下，得到身體相關資訊，是生醫產業不可缺少的一環。因此開發新穎式體外診斷裝置能快速檢測、操作簡單、又兼具經濟成本是生醫相關研究者努力的目標。拉曼光譜法(Raman Sepectrometry)是近三十年來發展迅速的光學檢測技術，能偵測分子等級訊號，並且不需複雜的前處理步驟，配合表面增強拉曼散射(Surface enhanced Raman Scattering, SERS)原理能進一步提高靈敏度。建置微流體晶片，配合一個手提箱大小的光譜儀是開發體外診斷裝置的優質選擇。本研究中應用微機電相關技術以及奈米工程開展兩個研究項目，打造適用於拉曼光譜法的體外診斷系統用於癌症早期檢測、細菌檢測。
首先，利用微機電技術打造高增進因數的陣列式表面增強拉曼矽奈米柱基板，來檢測結直腸癌的癌症標誌物，微小RNA-21 (miRNA-21)。藉由奈米級遮罩與非等向性蝕刻法打造穩定性高的矽奈米柱陣列，並且藉由優化柱頭上奈米級結構，增進其表面增強效益。在矽奈米柱上接合設計的奈米探針，專一性地抓取特定序列的微小RNA，並且能在不進行放大核酸的情況下，有聚合酶連鎖反應(PCR)核酸放大後的檢測靈敏度。整體的檢測時間也縮短至一個小時內完成。
第二個研究項目中，我們用微機電技術中的電動力學原理，製作為微流體細菌聚集晶片。晶片中產生的交流電介電泳力(AC-DEP)與交流電滲流(AC-EOF)的交互作用下，能選擇性地聚集血液中的細菌於收集井中，將血球排除在收集井外。在避免血球細胞干擾後，結合銀奈米粒子的表面增強拉曼散射作用，得到細菌特有的拉曼光譜，對照資料庫以分辨其種類，其靈敏度可達7 CFU/mL。接著，在聚集晶片中進行抗生素感受性試驗，測試了臨床上常見的大腸桿菌(E. coli)、金黃色葡萄球菌(S. aureus)以及產吲哚金黃桿菌(C. indologenes)，並且得到與傳統培養法一致的結果。
綜合這兩項基於拉曼光譜法開發的新穎體外診斷系統，跟傳統檢測裝置相比，能達到縮短時間、提高靈敏度的功效。設計檢測晶片僅一個手掌大小，搭配手持式的拉曼光譜儀未來可應用到移地檢測、即時檢測等。

Diagnosis is an ensencial process in medical treatment, helping humans to truly understand their own physical conditions and provide appropriate treatments. Therefore, developing in vitro diagnostic devices with properties of rapid, easy-use, and cost-effective, is always a desired goal. In this aspect, Raman spectroscopy with surface enhanced Raman scattering (SERS), which can directly detect water solution without complex pretreatment and provide molecular-level signals, shows great potentials. In this dissertation, two diagnostic system based on micro/nano-technology and Raman spectroscopy technology have been developed to early cancer detection and disease diagnosis.
In the first part, a silicon nanopillar (SiNP) with high SERS enhancement factors have been introduced to detect colorectal cancer cancer markers, microRNA-21. With nano-shielding mechanism and anisotropic etching, high aspect ratio, stable silicon nano-pillar array was developed, and its SERS effect is improved by optimizing the nanostrutures on the pillar head. SiNP immobilized with nanoprobe demonstrated great ability to detect miR-21-Cy5, which not only specificially recognized 2-mismatch sequences, but also push the detection limit to 0.1 nM, comparable with one wiht polymerase chain reaction (PCR). The overall inspection time has also been shortened to one hour.
In the second part, we demonstrated a novel multi-functional microfluidic system, designated three dimensional Alternative Current Electrokinetic/Surface Enhanced Raman Scattering (3D-ACEK/SERS) platform, which can concentrate bacteria from whole blood, identify bacteria species, and determine antibiotic susceptibilities of the bacteria rapidly. For bacteria, S. aureus, E. coli, and C. indologenes, the combined electrokinetic mechanism integrating AC-electroosmosis (AC-EO) and dielectrophoresis (DEP), allows thousand-fold concentration of bacteria in the center of an electrode with a wide range of working distance, while blood cells are excluded away through negative DEP forces. This microchip performs SERS based assay to determine the identity of the concentrated bacteria in approximately two minutes with a limit of detection of 7 CFU/ml. Finally, label-free antibiotic susceptibility testing has been successfully demonstrated on the platform using both antibiotic-sensitive and multidrug-resistant bacterial strains.
In summary, the above two novel in vitro diagnostic systems have achieved the desired goals, ie., shortening detection time and improving sensitivities, compared with traditional methods. Moreover, the portable Raman spectroscopy and plam-size microchip provided excellent moblitiy. Together, we believe that these innovations can find important applications in clinical diagnosis, mobile examination, as well as in-situ testing.

摘要 I
Abstracts III
致謝 V
目錄 VII
表目錄 IX
圖目錄 X
第 1 章 緒論 1
1.1 微流體 4
1.1.1 微流體在生醫方面應用 5
1.2 體外診斷系統 8
1.2.1 紙基晶片 11
1.2.2 側向流體檢測裝置 11
1.2.3 聚合物類型微流體檢測裝置 12
1.2.4 拉曼型微流體檢測裝置 12
1.3 研究動機 14
1.4 研究目標 15
第 2 章 文獻探討 17
2.1 拉曼光譜學 18
2.1.1 拉曼光學原理 19
2.1.2 表面增強拉曼散射的原理 20
2.1.3 拉曼儀器結構 22
2.1.4 拉曼光譜法於產業應用 24
2.1.5 SERS材料影響因素探討 24
2.2 癌症標誌物檢測 28
2.2.1 核甘酸癌症標誌物 29
2.2.2 傳統miRNA 檢測法 32
2.3 細菌檢測 34
2.3.1 傳統細菌檢測法 35
2.3.2 細菌快速檢測方法 36
2.3.3 細菌感染治療 38
2.3.4 抗生素藥敏試驗 38
第 3 章 奈米陣列檢測直腸癌標誌物 40
3.1 研究方法 43
3.1.1 實驗材料 43
3.1.2 通過奈米遮罩法製造奈米柱結構 43
3.1.3 電子顯微鏡操作參數 45
3.1.4 奈米柱之SERS效能比較 45
3.1.5 核甘酸探針設計 46
3.1.6 核酸探針製備與基板修飾 47
3.1.7 晶片專一性測試 50
3.2 研究結果與討論 51
3.2.1 SERS 效能與矽奈米柱結構探討 53
3.2.2 miR-21檢測探討 56
3.3 小結 60
第 4 章 細菌集中檢測晶片 61
4.1 細菌檢測晶片之研究方法 66
4.1.1 晶片原理與設計 66
4.1.2 微流道晶片製作 68
4.1.3 交流介電泳和電滲流 70
4.1.4 介電泳參數設定 71
4.1.5 合成SERS奈米粒子 73
4.1.6 計算奈米粒子濃度 76
4.2 細菌檢測晶片之研究成果 77
4.2.1 ACEK-SERS聚集晶片之參數優化 77
4.2.2 用晶片聚集細菌及分析 80
4.2.3 晶片式的抗生素感受性測驗 86
4.3 小結 91
第 5 章 結語與未來展望 92
附錄 參考資料 93

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