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研究生: 張瑋哲
Wei-Zhe Zhang
論文名稱: 利用積層製造一耐高壓層析微流道晶片並整合LC-MS/MS系統於新興毒品檢測
Additive Manufacturing A High Pressure Microfluidic Chip Coupled to LC-MS/MS System for Detecting New Psychoactive Substances
指導教授: 陳品銓
Pin-Chuan Chen
口試委員: 陳珮珊
Pai-Shan Chen
葉怡均
Yi-Chun Yeh
劉沂欣
Yi-Hsin Liu
林鼎晸
Lin Ding-Zheng
學位類別: 碩士
Master
系所名稱: 工程學院 - 機械工程系
Department of Mechanical Engineering
論文出版年: 2021
畢業學年度: 109
語文別: 中文
論文頁數: 124
中文關鍵詞: 層析微流晶片液相層析式質譜儀毒品檢測光固化3D列印技術
外文關鍵詞: Integrating microfluidics chip, chromatography, LC-MS, addictive polymeric, one-piece, drugs of abuse
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  • 本研究開發一可整合於液相層析串聯質譜儀系統之3D列印微流道晶片,用來檢測濫用毒品。傳統上在利用液相層析串聯式質譜儀(LC-MS/MS)系統分析待測物時,需使用層析管柱來分離待測物中的不同成分來分辨待測物中的化學物質;透過相關文獻探討後發現越來越多研究團隊投入微流體製程並將其整合於相關物質檢測系統上,開發相關物質檢測技術應用於臨床醫療以及檢測工作,然而有鑑於傳統微流體製程所製作的裝置無法耐受層析過程中所衍生的高壓,因而容易發生洩漏露或是結構破壞的狀況,因此,本研究欲利用微製程技術開發一可耐高壓達1500-2000psi之微型化層析微流晶片,以克服上述應用上的問題,藉由聚合物材質的耐壓性與堅韌性,製作一可連續上機使用3,024分鐘的微流道晶片,且僅需花費較低的成本以解決目前低流速液相層析質譜儀偵測濫用毒品之瓶頸。
    針對層析微流晶片製程,本研究利用光固化3D列印技術製作微流晶片本體,搭配自行開發之兩種層析固定相粒子(PFPP,HILIC)填充與封裝技術,製作檢測更多樣性毒品的層析微流到晶片,並藉由14種毒品檢體上機進行晶片穩定性測試,證明層析晶片上機過程中壓力維持穩定且訊號滯留時間維持毒理標準(AAFS-SOFT 2006)之2%內,證明層析微流道晶片不僅於高壓層析環境有高度程度穩定性且成功地將毒品檢體進行層析分離。


    A microfluidic chip coupled to a liquid chromatography-mass spectrometry (LC-MS) system is used to determine components of interest in drug samples. However, producing a reusable and robust chip for LC-MS systems remains analytically challenging due to the high back pressure. In this study, a one-piece and high-pressure-resistant polymeric microfluidic chip was additive manufactured and coupled to regular LC-MS. Experiments results demonstrated the following conclusions: (1) the customized additive manufactured polymeric microfluidic device can be connected to a regular LC-MS at low flowrate, forming an integrated system, and operating under a high pressure between 1500~2000 psi. (2) Applying constant high pressure, continuously pressure change or high organic composition to the system, the chip remained intact based on scanning electron microscopy findings and can be used for over fifty hours (approximately three-hundred runs) without leakage. (3) The platform performed proper stability and can be reused to analyze 14 abused drugs without contamination, which fits for clinical/forensic toxicology purpose in 2%. The experimental results listed above prove that the customized additive-manufactured polymeric microfluidic chip integrated with LC-MS can be an efficient and precise tool for bioanalysis.

    目錄 摘要 iv Abstract v 誌謝 vi 目錄 vii 圖目錄 x 表目錄 xv 第1章 緒論 1 1.1 研究背景 1 1.1.1微流體生醫晶片 1 1.2 研究動機與目的 3 1.2.2液相層析串聯式質譜儀 5 1.3 研究方法 9 1.4 論文架構 11 第2章 文獻回顧 14 2.1 LC-MS/MS檢測及整合微流體系統相關文獻 14 2.1.1 以光刻法製作微流體晶片製作搭配質譜儀-電噴灑系統進行檢測 15 2.1.2 以軟光刻法製作微流體晶片搭配質譜系統進行檢測作業 18 2.1.3 利用微銑削加工製作微流體晶片進行生醫相關檢測作業 21 2.2 積層製造技術應用於微流體 25 2.2.1 3D列印微流體裝置元件與製程優勢 25 2.2.2 3D列印微流體晶片應用於細胞增值培養領域 27 2.2.3 3D列印微流體晶片應用於癌症與腫瘤病症檢測領域 29 2.2.4 3D列印微流體晶片於其他生醫領域之應用 31 第3章 晶片製程 33 3.1 微流晶片設計 34 3.1.1 PFPP層析晶片 34 3.1.2 HILIC層析晶片 36 3.2 微流晶片製程 40 3.2.1 設計圖檔格式轉換與圖檔切層 43 3.2.2 晶片列印與工件後處理程序 47 3.3 固定相粒子填充封裝製程 49 3.3.1 封裝製程元件製備與操作流程 49 3.3.2 PFPP固定相粒子填充/封裝 52 3.3.3 HILIC固定相粒子封裝 54 第4章 研究設備介紹 56 4.1 製程設備與軟體 56 4.2 量測設備與軟體 60 第5章 實驗方法 62 5.1 PFPP層析晶片耐壓上限與耐用度測試 63 5.1.1 實驗設計與操作 64 5.2 PFPP層析晶片以不同流率上機對質譜訊號的影響 65 5.2.1 實驗設計與操作 66 5.3 PFPP層析晶片以等梯度層析方法上機對質譜訊號的影響 67 5.3.1 實驗設計與操作 67 5.4 PFPP層析晶片以梯度層析方法上機對質譜訊號的影響 68 5.4.1實驗設計與操作 69 5.5 利用流場流速公式推算固定相填充率 70 5.5.1 實驗設計與操作 71 5.6 HILIC層析晶片上機層析結果探討 72 5.6.1 實驗設計與操作 73 5.7 層析晶片穩定性測試 73 5.7.1 實驗設計與操作 74 第6章 實驗結果與討論 75 6.1 PFPP層析晶片耐壓上限與耐用度測試 75 6.2 PFPP層析晶片以不同流率上機對質譜訊號的影響 78 6.3 PFPP層析晶片以等梯度層析方法上機對質譜訊號的影響 80 6.4 PFPP層析晶片以梯度層析方法上機對質譜訊號的影響 85 6.5利用流場流速公式推算固定相填充率 91 6.6 HILIC層析晶片上機層析結果探討 93 6.7 層析晶片穩定性測試 95 第7章 結論與未來展望 98 7.1結論 98 7.2 未來展望 99 參考文獻 101

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