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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 許聿翔(Yu-Hsiang Hsu) | |
| dc.contributor.author | Cheng-Je Lee | en |
| dc.contributor.author | 李承哲 | zh_TW |
| dc.date.accessioned | 2022-11-25T03:06:00Z | - |
| dc.date.available | 2024-02-14 | |
| dc.date.copyright | 2022-02-21 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-02-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81893 | - |
| dc.description.abstract | 聚合酶連鎖反應技術已是目前核酸分子檢測的黃金標準並廣泛應用在臨床醫學、環境科學、以及食安問題。然而現今可攜式的聚合酶連鎖反應裝置，在產業界仍多舊停留在即時定量或恆溫核酸擴增技術開發，且提供一般診所或民眾居家操作的機型的研究方向則停留在一般的定性分析，目前尚未能從結果數據提供更多的資訊做後續的分析與處理。關鍵原因在於現有技術僅能部分實現可攜式裝置研發需求。本研究的目的是開發一個突破性的整合應用技術，以實現具有量化能力的可攜式的快數位聚合酶連鎖反應裝置，本研究之中心理念為針對數位聚合酶連鎖反應的各項技術進行觀念上的改進以有效提升其可攜式及個人化的性能，並實際完成此系統的初步驗證與實現。為達到輕薄的目標，本研究開發薄膜熱壓印技術，發展出全塑膠之薄膜型微流道裝置的製造技術。為達到精準定量的目標，本研究開發被動式微液體珠產生裝置，用以實現數位聚合酶連鎖反應裝置，並驗證可進行微液滴核酸放大技術與進行濃度定量。為達到可攜性及簡易操控能力，本研究結合被動式微流道設計，開發真空袋微流體填充技術，整體裝置重量僅約2公克、厚度小於0.4毫米，達到能在不同流率區段驅動微混合器，可在10秒內完成20μl的溶液混合，以及可連續依序驅動油水試劑，在2分鐘完成175顆體積為31pl的液滴陣列。藉由所開發裝置的薄型優勢，具有低熱質量及熱傳導距離短的特點，本研究開發快速熱循環裝置，僅需以薄膜式加熱片以及冷卻風扇即可達到在5分鐘以內完成35次熱循環的目標。總結，本研究開發一種全新的薄膜型微流體裝置及製造技術，驗證其可實現微流體驅動及操控的目標，以及在快數位聚合酶連鎖反應裝置上的實際應用可能性，此裝置為全塑膠製成，輕薄可拋棄且可大量製造，具備產品化優勢。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T03:06:00Z (GMT). No. of bitstreams: 1 U0001-1002202214152900.pdf: 17777835 bytes, checksum: 60e845549c0af1990c2d82a8ba76a5ae (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | "CONTENTS 口試委員會審定書 # 誌謝 i 中文摘要 ii ABSTRACT iii CONTENTS iv LIST OF FIGURES x LIST OF TABLES xxii Chapter 1 前言 1 1.1 研究背景 1 1.2 研究動機 4 1.3 研究目標 6 Chapter 2 研究領域文獻回顧 9 2.1 微流體系統 9 2.1.1 微流體發展簡史 10 2.1.2 微流道材料與製造 11 2.1.3 微流道系統基礎制動元件簡介 16 2.1.4 微流體混合器 19 2.1.5 微流體液滴產生器 24 2.2 生物分子檢測介紹 28 2.2.1 精準醫學與分子檢測技術 28 2.2.2 聚合酶連鎖反應 31 2.2.3 數位聚合酶連鎖反應與定量 33 2.2.4 可攜式檢測裝置研發要求 36 2.2.5 核酸檢測裝置現況與面臨問題 38 2.3 研究脈絡與章節安排 41 Chapter 3 氣體輔助軟模熱壓印製程開發 46 3.1 本章目標 46 3.2 文獻回顧 47 3.2.1 熱塑性塑膠材料 47 3.2.2 環烯烴聚合物材料 49 3.2.3 微熱壓印製程 51 3.2.4 壓印過程之擠壓流理論模型 53 3.2.5 氣體輔助熱壓印製程工具機 60 3.2.6 聚二甲基矽氧烷模具之軟模熱壓印製程 61 3.3 研究方法 65 3.3.1 氣體輔助軟模熱壓印工具機 65 3.3.2 軟模熱壓印模具製作流程 67 3.3.3 壓印微結構設計與參數條件測試 73 3.3.4 氣體輔助軟模熱壓印操作流程 77 3.3.5 轉印結構量測工具與分析 78 3.4 實驗結果 81 3.4.1 壓印溫度對結構複製保真度試驗 84 3.4.2 成模壓力對結構複製保真度試驗 86 3.4.3 保持時間對結構複製保真度試驗 88 3.4.4 線性結構寬度對結構複製保真度試驗 91 3.4.5 線性結構間距對結構複製保真度試驗 93 3.4.6 圓形結構寬度對結構複製保真度試驗 95 3.4.7 圓形結構間距對結構複製保真度試驗 97 3.4.8 長直流道下方微室位置安排對結構複製保真度試驗 99 3.4.9 脫模溫度對結構複製表面輪廓試驗 102 3.4.10 模具平面尺寸與材料於凹槽結構邊緣累積之現象討論 106 3.5 本章結論 108 Chapter 4 真空袋驅動微流體系統開發 110 4.1 本章目標 110 4.2 文獻回顧 112 4.2.1 被動幫浦微流體系統技術回顧 112 4.2.2 以PDMS抽氣驅動動力源之微流體系統 115 4.2.3 以PDMS抽氣驅動微流體系統之面臨問題 119 4.2.4 真空袋微流體系統設計理念 122 4.2.5 熱塑性塑膠微流道密封技術 124 4.2.6 以哈根-普瓦塞伊二氏定律描述VPM系統方程式 128 4.2.7 蜿蜒混合流道的定性討論 134 4.3 研究方法 137 4.3.1 被動式蜿蜒微流道設計 137 4.3.2 塑膠薄膜晶片密封接合製程 138 4.3.3 真空袋微流體系統-微混合器製程 143 4.3.4 真空袋微流體系統實驗步驟 146 4.3.5 PDMS微流體晶片製程暨實驗操作步驟 148 4.3.6 影像分析方法 150 4.4 實驗結果 153 4.4.1 真空袋微流體系統的三種填充模式 155 4.4.2 討論VPM film-mixer之流道高度對填充流速影響 157 4.4.3 討論VPM film-mixer之黏度對填充流速影響 160 4.4.4 討論VPM film-mixer之保存期限對填充流速影響 162 4.4.5 以有限元素分析法討論之流速對混合效率影響 163 4.4.6 以針筒幫浦-PDMS流道討論之流速對混合效率影響 167 4.4.7 以VPM film-mixer討論可達成之混合效率 169 4.4.8 以VPM film-mixer應用於金屬離子檢測 170 4.5 結論 172 Chapter 5 微液滴產生與數位聚合酶連鎖反應 174 5.1 本章目標 174 5.2 文獻回顧 175 5.2.1 近五年數位聚合酶連鎖反應晶片文獻回顧 175 5.2.2 商用數位聚合酶連鎖反應裝置系統 182 5.2.3 光子聚合酶連鎖反應 187 5.2.4 自吸引數位核酸定量微流體系統 192 5.2.5 微液滴產生方法與設計 195 5.2.6 靜態水滴陣列產生之自分散流道設計 203 5.2.7 核酸擴增溫度控制系統 209 5.2.8 小分子核醣核酸應用於生物檢測 218 5.2.9 慢性肺部阻塞性疾病 221 5.3 研究方法 226 5.3.1 微液滴陣列產生流道設計 226 5.3.2 液滴陣列產生晶片與真空袋流體驅動系統製程 231 5.3.3 有限元素分析法模擬液滴產生 232 5.3.4 熱對流與熱傳導理論 233 5.3.5 核酸擴增熱循環機架構與設計 235 5.3.6 熱循環機加熱載台設計 236 5.3.7 有限元素分析法分析參數影響熱循環機效能 239 5.3.8 小分子核糖核酸反轉錄試劑與操作流程 241 5.3.9 聚合酶連鎖反應試劑與VPM-dPCR操作流程 242 5.3.10 聚合酶連鎖反應試劑與RT-qPCR操作流程 247 5.3.11 數位聚合酶連鎖反應試劑與QuantStudio 3D system操作流程 249 5.4 實驗結果 251 5.4.1 以VPM系統產生微液滴陣列之結果與分析 251 5.4.2 有限元素分析法佐證液滴可產生於微室 254 5.4.3 有限元素分析法探討晶片厚度對熱循環效率影響 255 5.4.4 有限元素分析法探討加熱平面溫度均勻性 258 5.4.5 有限元素分析法與熱循環加熱平台升降溫曲線擬合 261 5.4.6 有限元素分析法探討輸入電壓對熱循環時間影響 263 5.4.7 有限元素分析法探討對流環境溫度與流速對熱循環時間影響 264 5.4.8 熱循環機輸入電壓與熱循環時間影響 267 5.4.9 以VPM系統可執行聚合酶連鎖反應之實證 271 5.4.10 以VPM-dPCR系統執行微液滴聚合酶連鎖反應 273 5.4.11 以VPM-dPCR與即時定量系統進行樣本溶液連續稀釋測試 276 5.4.12 以VPM-dPCR與商用digital PCR平台進行絕對定量核酸分子濃度 280 5.4.13 以VPM-dPCR執行雙目標核酸分子數位聚合酶連鎖反應 284 5.4.14 低溫變性應用於小分子核醣核酸擴增試驗 286 5.4.15 整合式VPM-RT-PCR系統初步驗證 289 5.4.16 以可攜式電源供熱循環裝置運作之驗證 291 5.4.17 快速微液滴數位聚合酶連鎖反應初步驗證 292 5.5 本章結論 295 Chapter 6 結論與未來發展 297 6.1 結論 297 6.2 未來發展 300 REFERENCE 302 LIST OF FIGURES 圖 1- 1失能調整人年(Disability-adjusted Life Years, DALYs)所評估之疾病負擔(disease burden)1990年與2017年 [2-3] 4 圖 2- 1微流體發展時間線 [13] 11 圖 2- 2微流體晶片材料之文獻發表年代統計圖[24] 12 圖 2- 3微流道晶片製程流程圖 [27] 14 圖 2- 4微流體晶片製程量產成本評估 [27] 15 圖 2- 5微流體幫浦分類 [34] 17 圖 2- 6主動式與被動式微液滴產生器 [46] 25 圖 2- 7聚焦流(focusing-flow)之連續相(continuous phase)與分離相(discrete phase)之液滴產生形式毛細管數相位圖[46] 26 圖 2- 8微液滴產生器三種主要流道幾何設計 [45] 27 圖 2- 9靜態微液滴陣列產生流道設計、實驗方法與產生時序圖[47] 27 圖 2- 10聚合酶連鎖反應(a)與即時定量螢光曲線示意圖(b) [58] 32 圖 2- 11三種PCR發展歷史中應用的定量技術[58] 33 圖 2- 12微流體平台於實驗室晶片需求要點之評估與比較[63] 37 圖 2- 13 核酸分子檢測裝置研發受FDA-EUA核可之統計(2020年)[68] 40 圖 2- 14可攜式裝置開發需求準則與本論文研發章節之關聯性 42 圖 2- 15論文各章開發或使用技術以及其對應之原因與目標 44 圖 3- 1聚合物分子結構種類 [71] 47 圖 3- 2兩類熱塑性聚合物其溫度對材料剪力模數影響 [72] 48 圖 3- 3熱壓印與熱成型技術示意圖 [77] 52 圖 3- 4熱壓印製程步驟 [76, 79] 53 圖 3- 5黏彈性材料之牛頓流體的擠壓流動模型(squeezing flow of Newtonian fluid) [80] 54 圖 3- 6具結構平行線性模具尺寸示意圖 [82] 57 圖 3- 7正向壓印壓力與殘餘層厚度關係圖[82] 59 圖 3- 8氣體輔助熱壓印的機具與製程示意圖[83-84] 60 圖 3- 9氣體輔助熱壓印系統示意圖應用於塑膠透鏡陣列製作 [81] 61 圖 3- 10以PDMS為模具熱壓印結構於PMMA材料步驟流程圖 [86] 62 圖 3- 11以長尾夾與烘箱執行簡易熱壓印流道製程 [87] 62 圖 3- 12以環氧樹酯做為熱壓印模具製程流程圖 [94] 63 圖 3- 13熱壓印工具機外觀現況組圖 65 圖 3- 14熱壓印工具機元件組成示意圖 66 圖 3- 15(A)不鏽鋼下方腔體與模具材料實體圖(B)覆蓋耐熱膜隔絕膜並開啟真空幫浦之實體照片 67 圖 3- 16氣體輔助-軟模熱壓印製程模具製造流程圖 67 圖 3- 17黃光微影製程使用之光阻旋轉塗佈機、曝光機與加熱板 68 圖 3- 18 SU-8黃光微影製程流程圖 69 圖 3- 19 以不鏽鋼框限制軟模形變固化(A) 熱壓印前(B)與熱壓印後(C) 72 圖 3- 20實驗結構設計的示意圖 76 圖 3- 21本研究熱壓印製程作業流程圖 77 圖 3- 22熱壓製程溫度與壓力參數曲線示意圖 78 圖 3- 23量測熱壓印複製結構儀器 (A)探針表面輪廓儀(B)雷射共軛焦顯微鏡 79 圖 3- 24結構分析初始四種數據：結構高度、底部寬度、頂部寬度與結構體積 80 圖 3- 25三種雷射共軛焦顯微鏡量測之結構表面輪廓形式 81 圖 3- 26單層結構實驗組材料與模具結構成果評估圖 82 圖 3- 27製程參數實驗組材料與模具結構成果評估圖 82 圖 3- 28 實際量測結果之寬度判定標準示意圖 83 圖 3- 29不同熱壓印溫度設定之圓柱(A)突起與(B)凹槽結構保真度圖 84 圖 3- 30不同熱壓印溫度設定之線性(A)突起與(B)凹槽結構保真度圖 85 圖 3- 31不同熱壓印施加壓力之圓柱(A)突起與(B)凹槽結構保真度圖 86 圖 3- 32不同熱壓印施加壓力之線性(A)突起與(B)凹槽結構保真度圖 87 圖 3- 33不同熱壓印時間之圓柱(A)突起與(B)凹槽結構保真度圖 88 圖 3- 34不同熱壓印時間之線性(A)突起與(B)凹槽結構保真度圖 89 圖 3- 35線性(A)突起與(B)凹槽與結構之寬度對於複製保真度試驗結果圖 91 圖 3- 36雷射共軛焦顯微鏡量測線性模具與材料結構形貌圖 92 圖 3- 37雷射共軛焦顯微鏡量測(A)平行線性結構材料(COP)與(B)模具(PDMS)影像 93 圖 3- 38平行線性(A)突起與(B)凹槽結構間距對於複製保真度試驗結果圖 94 圖 3- 39圓形(A)突起與(B)凹槽結構之直徑對於複製保真度試驗結果圖 95 圖 3- 40雷射共軛焦顯微鏡量測圓柱結構材料(C-D)與模具(A-B) 96 圖 3- 41雷射共軛焦顯微鏡量測凹槽圓形陣列結構COP材料與PDMS模具影像 97 圖 3- 42雷射共軛焦顯微鏡量測圓柱陣列COP結構影像圖 98 圖 3- 43圓柱陣列結構間距對於複製保真度試驗結果圖 98 圖 3- 44雙層微流道之白光光學影像與截面輪廓圖(A) 單排微室間距40μm (B) 單排微室間距80μm (C) 單排微室間距160μm (D) 三排微室相鄰間距40μm 99 圖 3- 45方形流道上圓形凹槽之結構對於複製結構尺寸比較圖與數值 100 圖 3- 46熱壓印於材料上圓形凹槽體積與凹槽密度的關係圖 101 圖 3- 47熱壓印於三列圓形凹槽體積(A)各列體積比較圖(B)取樣位置圖 102 圖 3- 48以探針輪廓儀量測不同脫模溫度複製結構之表面起伏(A) 線性寬度200μm (B) 線性寬度1600μm (C) 圓柱直徑100μm與(D) 圓柱直徑1000μm 103 圖 3- 49熱壓印脫模溫度影響形貌以Pm-10與P1,2-10進行評估(A) 線性寬度200μm (B) 線性寬度1600μm (C) 圓柱直徑100μm與(D) 圓柱直徑1000μm 105 圖 3- 50大跨度凹槽產生之邊緣累積現象討論 106 圖 3- 51探針表面輪廓儀量測大跨度凹槽產生之邊緣累積現象 107 圖 3- 52目前與未來用於產生微液滴陣列的流道設計示意圖 109 圖 4- 1於Google學術搜尋2000-2018年有關被動式微流體技術的分類數量與文獻發表比例 [100] 113 圖 4- 2被動式微流體技術分類 [100] 114 圖 4- 3以PDMS氣體可溶性應用於免幫浦微流體驅動於金奈米粒子捕捉DNA分子研究[103] 116 圖 4- 4以PDMS氣體高通透性應用於免幫浦微流體驅動之定量分析研究[104] 117 圖 4- 5以PDMS高氣體通透性應用於側向微室流體填充[41] 118 圖 4- 6兩種PDMS驅動微流體系統之2D與3D形式示意圖 [101] 119 圖 4- 7兩種在微流體晶片內儲存負壓的方法製程[105,106] 120 圖 4- 8真空驅動PDMS微流體系統操作流程圖[41] 122 圖 4- 9真空袋微流體驅動系統(vacuum pouch microfluidic driven system )操作方法示意圖 123 圖 4- 10以紫外光固化材料黏合的樹酯引導通道設計與製造流程[108] 125 圖 4- 11表面改質形成高強度鍵結於COC與PDMS材料製程[110] 126 圖 4- 12塑膠微流道晶片密封製程之設備成本與量產能力定位圖[27] 127 圖 4- 13 Poiseuille flow通過任意截面之長直微流道示意圖[112] 128 圖 4- 14長方形流道斷面其尺寸定義 [112] 129 圖 4- 15流體系統與電學系統之類似性示意 [22] 132 圖 4- 16染色水以真空袋驅動微流體系統(VPM)示意圖與填充時序圖 133 圖 4- 17 Hossain等人進行蜿蜒流道設計之微混合器研究 [114] 135 圖 4- 18 Muhammad等人進行蜿蜒流道設計之微混合器研究 [115] 135 圖 4- 19不同雷諾數之流線模擬於蜿蜒流道設計比較圖 [114] 136 圖 4- 20微混合器之(A)流道設計與(B)實體照片 [42] 137 圖 4- 21微流道晶片之壓力薄膜密封製程步驟 139 圖 4- 22微流道晶片之熱熔接合前置流程 140 圖 4- 23研究中執行塑膠晶片熱熔接合之護貝機 141 圖 4- 24手動於COP薄膜塑膠晶片填充染色水結果 142 圖 4- 25(A)側向流系統元件示意圖[116]與(B)真空袋驅動系統元件示意圖 143 圖 4- 26微流體晶片更動元件以產生三種壓力差變動幅度的模式 144 圖 4- 27微液滴產生晶片真空袋內部組成 145 圖 4- 28真空袋微流體自驅動裝置抽真空製程步驟 145 圖 4- 29用於真空袋微流體系統驅動之針尖工具 147 圖 4- 30混合指數(Mixing index)計算示意照片 150 圖 4- 31螢光微粒軌跡用於計算流速示意照片 151 圖 4- 32典型的真空袋微流體驅動系統應用於混合流程各階段影像 153 圖 4- 33真空袋驅動微流體系統三種壓降模式概念設計[42] 155 圖 4- 34五種真空袋封裝組成模式於填充定量流體之體積流率與填充時間關係曲線 [42] 156 圖 4- 35真空袋填充系統之流道高度與平均體積流率之關係 159 圖 4- 36以FS-HP模式驅動不同甘油比例水溶液之體積流率與填充時間關係曲線 160 圖 4- 37正規化平均流率與填充流體黏度關係圖 161 圖 4- 38以FS-HP模式驅動不同儲存之體積流率與填充時間關係曲線 162 圖 4- 39分析混合流道單位元內流場與混合現象 [42] 164 圖 4- 40模擬本研究使用之微混合器設計在不同體積流率設定混合結果 165 圖 4- 41利用模擬獲得雷諾數與混合指數關係曲線 166 圖 4- 42以針筒幫浦驅動流體之輸入體積流率與混合結果影像組圖 [42] 167 圖 4- 43以針筒幫浦實驗討論雷諾數與混合指數關係 168 圖 4- 44VPM五種壓降模式體積流率分布對應至對流混合指數比較，左側為10階障礙物右側則是20階障礙物之輪廓虛線 169 圖 4- 45不同模式之真空袋驅動微混合器之影像與混合指數分布 170 圖 4- 46以釘書機機構驅動雙入口微混合器之金屬離子混合試驗 [42] 171 圖 5- 1本節討論之digital PCR晶片技術研發種類 182 圖 5- 2 Applied Biosystems™ QuantStudio™ 3D Digital PCR System設備 183 圖 5- 3 QuantStudio™ 3D Digital PCR 20K Chip v2晶片 183 圖 5- 4 Bio-Rad QX100™ ddPCR™ System設備 184 圖 5- 5 DG8™ Cartridges (含底座固定器與微量吸管尖) 184 圖 5- 6 JN Medsys開發的Clarity™ Digital PCR System設備與晶片 185 圖 5- 7 Bio-Rad QX ONE機台 186 圖 5- 8電漿光熱效應之說明圖與以LED制動熱循環示意圖 [120] 187 圖 5- 9金奈米薄膜應用於PCR熱循環器之定量研究圖 [120] 188 圖 5- 10 digital LAMP SD chip流道設計與裝置架構圖 [121] 189 圖 5- 11 微流體自驅動SIMPLE chip 流道設計圖 [41] 190 圖 5- 12 光子聚合酶鏈鎖反應Luke. P. Lee團隊近年來研究結合細胞裂解步驟與[124] 與奈米柱陣列基底設計加快熱循環設計[125] 191 圖 5- 13 以Self-priming 自驅動系統進行微液滴陣列產生[126] 192 圖 5- 14 自吸引fractal branching 微液滴陣列產生流道設計 [5-15] 193 圖 5- 15結合智慧型手機檢測裝置的self-priming系統平台 [5-12] 194 圖 5- 16自吸引微流體系統應用於多目標數位聚合酶連鎖反應[127] 195 圖 5- 17微流體系統分散PCR反應溶液方法分類 [129] 196 圖 5- 18以主動元件制動常關微閥門之分液技術 [5-37] 197 圖 5- 19 Slipchip設計與操作原理示意圖 [134] 198 圖 5- 20 On-Chip DNA Amplification操作流程 [136] 199 圖 5- 21 Megapixel digital PCR流道設計與液滴訊號強度圖[137] 200 圖 5- 22實驗室碟片與即時定量PCR流道設計 [141] 201 圖 5- 23兩種以離心力產生微液滴之技術 [5-18,5-19] 201 圖 5- 24一百萬微液滴產生裝置應用於數位聚合酶連鎖反應[142] 202 圖 5- 25自數位化流道設計與液滴產生流程圖 [144] 203 圖 5- 26樣本溶液流速對產生水滴尺寸影響 [144] 204 圖 5- 27三種流道接觸角之毛細管數與水滴產生體積關係 [144] 205 圖 5- 28氣泡可能存在的位置、原因與可避免之策略 [145] 206 圖 5- 29產生微液滴之μAPPAD方法示意圖與結果[146] 207 圖 5- 30交錯微室設計用於微液滴完整填充試驗 [147] 208 圖 5- 31執行PCR熱循環方法種類數例 [129] 209 圖 5- 32由Houssin等人開發快速即時定量PCR裝置[164] 210 圖 5- 33由Farrar與Wittwer開發快速即時定量PCR裝置 [165] 211 圖 5- 34連續流聚合酶連鎖反應設計[166,167] 212 圖 5- 35以電熱效應做為PCR熱循環機研究與設計 [88-89] 213 圖 5- 36聲波加熱基材設計用於連續流聚合酶連鎖反應 [171] 214 圖 5- 37以感應電流加熱的熱循環裝置研究[172] 215 圖 5- 38微波加熱技術應用於微流體裝置內聚合酶連鎖反應[174-176] 216 圖 5- 39小分子核糖核酸形成與發展 [150] 218 圖 5- 40存在於血清之小分子核糖核酸對凍融環境、酸鹼環境與富剪切酶環境之耐受性測試 [154] 219 圖 5- 41慢性阻塞性肺部疾病 [155] 221 圖 5- 42臨床診斷COPD的GOLD分期說明圖 [155] 222 圖 5- 43 COPD患者體內miR-15b[158] 與miR-146a [161] 表現量差異 223 圖 5- 44同時以miR-21與miR-181a對COPD進行診斷與ROC曲線 224 圖 5- 45以真空袋微流體系統應用於類水滴產生器結果 226 圖 5- 46微液滴產生流道設計-側向微室陣列設計 227 圖 5- 47微液滴產生流道設計並聯子流道底部微室陣列設計 228 圖 5- 48目前使用於微液滴產生流道設計 229 圖 5- 49以真空袋驅動系統進行大面積微液滴陣列產生(流道寬度:400μm) 230 圖 5- 50本研究製作的PCR熱循環機示意圖 235 圖 5- 51 (A) 熱循環機內部與熱電偶量測點位置 (B)外觀照片 236 圖 5- 52軟式聚酰亞銨薄膜電熱片與分層結構圖[179] 237 圖 5- 53熱顯像儀觀測薄膜電熱片加熱[180]與實驗室過去量測致冷晶片加熱[181]影像 237 圖 5- 54石墨結構示意圖與異向熱傳導係數量測結果[182-183] 238 圖 5- 55觀測石墨片有無對於平面溫度分布影響之斷面選擇 239 圖 5- 56 VPM-dPCR晶片與裝置操作流程 243 圖 5- 57 VPM-dPCR晶片與裝置操作步驟圖 244 圖 5- 58微液滴PCR訊號辨識流程(A)原始照片(B)色彩通道分離(C) 光強閥值設定(D)尺寸與圓度判定 245 圖 5- 59經歷攝氏90度後晶片上螢光微液珠形貌變化 246 圖 5- 60 Bio-Rad CFX384 qPCR 於台大TechComm科技共同空間 247 圖 5- 61 Applied Biosystems™ 的QuantStudio™ 3D Digital PCR System 儀器於林口長庚紀念醫院基因體醫學核心實驗室 249 圖 5- 62以QuantStudio™ 3D Digital PCR System方法與VPM-dPCR系統定量濃度比較流程圖 250 圖 5- 63真空袋微流體驅動系統應用於微液滴陣列產生結果 (scale bar=0.5mm) 251 圖 5- 64微液滴陣列產生時序影像圖 252 圖 5- 65熱循環前後螢光微液珠訊號強度變化分析(A)所有液滴熱循環前後訊號尺寸與強度分布圖(B)尺寸比較(C)強度比較(D)計算預估體積比較 253 圖 5- 66以有限元素分析法佐證兩種油填充設定對水滴產生之差異 254 圖 5- 67有限元素分析法討論晶片厚度對熱循環影響(A-B) 模型樣貌(C-D)循環溫度曲線圖，實線為偵測點虛線為晶片中心點溫度(E-F)偵測點與中心點溫度差值 255 圖 5- 68有限元素分析法討論2mm晶片各層溫度循環曲線 257 圖 5- 69加熱平面溫度變化討論線段示意圖 258 圖 5- 70(A)僅有薄膜電熱片(B)不鏽鋼與薄膜電熱片疊層 (C) 導熱石墨片與不鏽鋼以及薄膜電熱片疊層之溫度分布曲線 259 圖 5- 71(A)模型各層結構組成(B)擷取時間點(C)溫度分布圖 260 圖 5- 72(A)有限元素分析法與(B)熱循環機溫度40次循環曲線 261 圖 5- 73(A)模擬結果與(B)熱循環機升溫、降溫與單次循環所需時間 262 圖 5- 74輸入電壓與循環時間關係 (A)平均循環時間 (B)以6V輸入為基準正規化數值 263 圖 5- 75 散熱風扇提供對流透過狹縫之流速分布示意 264 圖 5- 76對流環境溫度與循環時間關係 (A)平均循環時間 (B)以攝氏20度為基準正規化數值 265 圖 5- 77強制對流風速與循環時間關係 (A)平均循環時間 (B)以風速30 m/s為基準正規化數值 266 圖 5- 78薄片式熱循環機升溫與降溫隨循環次數變化 267 圖 5- 79不同塑膠晶片厚度與電熱片電壓供應下系統溫度梯度圖 268 圖 5- 80改變偵測點位置於塑膠晶片上方之晶片厚度與電熱片電壓供應下系統溫度梯度圖 270 圖 5- 81首次有效執行VPM-dPCR之影像結果 272 圖 5- 82含螢光素鈉之PCR混合液反應前後訊號強度變化圖，miR-146a的設定樣本濃度為108 copies/μl (scale bar=0.2mm) 274 圖 5- 83含螢光素鈉之PCR混合液反應前後訊號強度變化圖，miR-146a的設定樣本濃度為106 copies/μl(scale bar=0.2mm) 275 圖 5- 84 VPM-dPCR正負訊號螢光影像與強度曲線[184] 276 圖 5- 85對miR-15b反轉錄產物連續稀釋之RT-qPCR曲線 277 圖 5- 86對miR-15b反轉錄產物設定濃度與Ct值關係 277 圖 5- 87不同miR-15b濃度在VPM-dPCR執行核酸擴增反應(scale bar=0.5mm 278 圖 5- 88對於miR-15b連續稀釋之Ct值與晶片絕對定量比較 279 圖 5- 89對於miR-146a連續稀釋之Ct值與晶片絕對定量比較 279 圖 5- 90以QuantStudio™ 3D Digital PCR System量測無目標分子模板與模板濃度為103copies/μl之結果 282 圖 5- 91 以QuantStudio 3D Digital PCR System與VPM-dPCR絕對定量濃度曲線 283 圖 5- 92以VPM-dPCR執行雙目標數位聚合酶連鎖反應 284 圖 5- 93於VPM-dPCR系統同時偵測兩種核酸分子之訊號疊加影像圖 285 圖 5- 94 HBV DNA序列之融化曲線與變性溫度對RT-qPCR之曲線圖比較[104] 286 圖 5- 95正常變性溫度與低溫變性溫度於小分子核醣核酸之RT-qPCR曲線 287 圖 5- 96兩種核酸分子濃度範圍與獲得的Ct值在不同變性溫度之比較 288 圖 5- 97用於混合反轉錄試劑與樣本溶液的流道設計(A)與實際照片(B)以及實驗中利用的小型自製溫度控制裝置(C)與紀錄的執行反轉錄溫度曲線 289 圖 5- 98晶片上反轉錄樣本溶液之聚合酶連鎖反應前後樣本微液滴螢光訊號影像 290 圖 5- 99市售行動電源供應器(A-B廠商照片)與以此供能之架構與實體圖(C-D)其中實現為電源供應而虛線則是訊號傳遞 291 圖 5- 100以市售行動電源供應升降溫元件可達到的熱循環溫度曲線 292 圖 5- 101薄膜載台式熱循環裝置照片與結構示意圖 293 圖 5- 102 以VPM-dPCR應用於快速聚合酶連鎖反應初步測試結果(A) 熱循環曲線(B)反應前樣本液滴訊號(C)反應後樣本液滴訊號 (scale bar=400μm) 294 LIST OF TABLES 表 2- 1常見微流體晶片使用塑膠材料特性表 [24] 13 表 2- 2主動式微混合器研究回顧(2012-2017)整理[41] 22 表 2- 3主動式微混合器研究回顧(2012-2017)整理[41] 23 表 2- 4於2012年左右廠商開發的數位聚合酶連鎖反應桌上型機台[62] 34 表 2- 5定點診斷裝置設計的關鍵元件需求要點 [65] 37 表 2- 6核酸分子檢測廠商,2012年 [66] 39 表 2- 7取得FDA臨床實驗室改進修正認證豁免的NAT裝置技術與廠商 [70] 40 表 3- 1常見熱塑性塑膠特性表[24] 48 表 3- 2 ZeonorFilm 材料特性表 [74] 50 表 3- 4製程參數測試實驗組參數表 74 表 3- 4單層結構實驗組結構參數表 74 表 3- 5雙層流道結構實驗組結構參數表 75 表 3- 6代號縮寫對應中文 83 表 4- 1本論文微流晶片兩種製程架構比較 138 表 4- 2空袋填充系統之流道高度與流體填充時間試驗 158 表 4- 3甘油濃度對黏度關係表 [117] 161 表 5- 1dPCR技術種類為自吸引驅動與水滴產生系統之研究 177 表 5- 2dPCR技術種類為自數位流道設計、與乳化池水滴產生於油之研究 178 表 5- 3dPCR技術種類為玻璃錯位、移動水滴熱循環以及固質介面反應之研究 179 表 5- 4dPCR技術種類為其他非幫浦驅動以及連續流產生液滴之研究 180 表 5- 5dPCR技術種類為多步驟產生水滴產生液滴之研究 181 表 5- 6 應用於digital PCR 之分液技術種類 [128] 197 表 5- 7 PCR熱循環技術分類 [129] 213 表 5- 8本研究使用之小分子核醣核酸編號與序列 241 表 5- 9即時定量聚合酶連鎖反應測試參數 248 表 5- 10以RT-qPCR獲得各管稀釋樣本溶液之Ct值數據表 280 表 5- 11推算執行VPM-dPCR時目標分子濃度與設定濃度之關係 283 表 5- 12以VPM-dPCR對兩種目標絕對定量數值統計 284 " | |
| dc.language.iso | zh-TW | |
| dc.subject | 微液滴陣列產生器 | zh_TW |
| dc.subject | 真空袋微流體自驅動裝置 | zh_TW |
| dc.subject | 微混合器 | zh_TW |
| dc.subject | 可攜式定點診斷裝置 | zh_TW |
| dc.subject | 快速數位聚合酶連鎖反應 | zh_TW |
| dc.subject | 薄膜塑膠熱壓印與微流體晶片製程 | zh_TW |
| dc.subject | thin-film hot embossing | en |
| dc.subject | Vacuum pouch microfluidic driven system | en |
| dc.subject | Point-of-care testing | en |
| dc.subject | self-compartmentation microchannel | en |
| dc.subject | Rapid digital PCR | en |
| dc.subject | micromixer | en |
| dc.title | 以真空袋驅動之薄膜式塑膠微流體系統開發 —在可自驅動之快速數位聚合酶連鎖反應裝置之應用與驗證 | zh_TW |
| dc.title | Development of a Vacuum Pouch Driven Thin-Film Microfluidic System —Application and verification of a self-driven dPCR platform | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-3306-8672 | |
| dc.contributor.oralexamcommittee | 王安邦(Shiang-Jiuun Chen),胡文聰(Fu-Chiun Hsu),林致廷,饒達仁,陳建甫 | |
| dc.subject.keyword | 快速數位聚合酶連鎖反應,可攜式定點診斷裝置,真空袋微流體自驅動裝置,薄膜塑膠熱壓印與微流體晶片製程,微混合器,微液滴陣列產生器, | zh_TW |
| dc.subject.keyword | Rapid digital PCR,Point-of-care testing,Vacuum pouch microfluidic driven system,thin-film hot embossing,micromixer,self-compartmentation microchannel, | en |
| dc.relation.page | 318 | |
| dc.identifier.doi | 10.6342/NTU202200526 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-02-12 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 應用力學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-02-14 | - |
| Appears in Collections: | 應用力學研究所 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| U0001-1002202214152900.pdf | 17.36 MB | Adobe PDF | View/Open |
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