臺灣博碩士論文加值系統

腎臟損傷為動物常見的疾病之一，儘管目前的醫療科技發展快速，依然無法有效的檢測，故需找出方便即時檢測之方法用於腎臟疾病嚴重性評估和臨床應用。本研究開發出一種奈/微米複合結構生物感測電極，應用於無標記檢測嗜中性白血球明膠酶相關脂質運載蛋白(Neutrophil gelatinase-associated lipocalin, NGAL)。本研究先以黃光微影技術於矽基板上製作微米半球結構陣列母模，再以電鑄法製作鎳模具，接著利用熱壓印將微米半球結構熱壓印於聚對苯二甲酸乙二酯 (polyethylene terephthalate, PET)上，再於微米半球結構陣列上濺鍍一層金薄膜後，以自組裝的方式將帶有硫基的醇類化合物1,6-hexanedithol與奈米金顆粒依序均勻沉積於PET試片上，形成奈/微米複合結構生物感測電極，接附NGAL抗體後以電化學阻抗分析法（Electrochemical Impedance Spectroscopy, EIS）量測NGAL濃度。實驗結果結果顯示本研究所提出之方法可檢測NGAL濃度之線性範圍為5 ng/mL至100 ng/mL，線性度為0.986，檢測極限為1.286 ng/mL，檢測時間約為2分鐘。相較於傳統的酵素結合免疫吸附分析法(Enzyme-linked immunosorbent assay, ELISA)，本研究之方法具有不需昂貴的專業分析儀器及相關專業技術人員的操作、檢測成本低與檢測時間短等優勢。後續能夠進一步結合智慧手機，進行定點照護檢驗(Point-of-care testing, POCT)，有極大之臨床應用可行性。

Kidney damage is one of the common diseases in animals. Despite the rapid development of current medical technology, it is still not possible to quickly detect kidney damage. Therefore, it is necessary to find a convenient and instant detection method for the severity assessment and clinical application of kidney disease. In this study, a nano/micron composite structure biosensing electrode is developed for label-free detection of neutrophil gelatinase-associated lipocalin (NGAL). We first use semiconductor lithography technology to fabricate micron hemispherical structure array on a silicon wafer. Then electroforming is used to make a nickel mold, followed by transferring the micron hemispherical structure onto a polyethylene terephthalate (PET) film using the hot embossing process. A layer of gold film was sputtered on the micron hemispherical structure array, and then 1,6-hexanedithol and gold nano particles are uniformly deposited on the PET membrane to form a sensing electrode of nano/micro hybrid structure. After attaching the NGAL antibody, the NGAL concentrations are measured by Electrochemical Impedance Spectroscopy (EIS). The experimental results show that the method proposed in this study can detect the concentration of NGAL in a broad linear range from 5 ng/mL to 100 ng/mL with linearity and a detection limit of 0.986 and 1.286 ng/mL, respectively. The detection can be completed in 2 min. Compared with the traditional enzyme-linked immunosorbent assay (ELISA), the method proposed in this research has the advantages of not requiring expensive analytical instruments and related professional technical operators, low detection cost and short detection time. The technology of this study can be further combined with smart phones to conduct Point-of-care testing (POCT), hence has great clinical application feasibility.

摘要 i
Abstract iii
目錄 v
圖目錄 viii
表目錄 x
第一章 緒論 1
1.1 研究動機 1
1.2 研究目的 1
第二章 文獻回顧 3
2.1 腎臟疾病簡介 3
2.1.1 急性腎損傷(Acute Kidney Injury, AKI) 3
2.1.2 慢性腎臟病(Chronic kidney disease, CKD) 4
2.1.3 診斷腎臟疾病之方法 4
2.2 嗜中性白血球明膠酶相關脂質運載蛋白(NGAL) 6
2.3 嗜中性白血球明膠酶相關脂質運載蛋白(NGAL)之檢測方法 7
2.3.1化學發光微粒免疫分析法 (Chemiluminescent microparticle immunoassay, CLIA) 8
2.3.2顆粒增強比濁免疫分析法 (Particle-enhanced turbidimetric immunoassay, PETIA) 8
2.3.3 酵素結合免疫吸附分析法 (Enzyme-linked immunosorbent assay, ELISA) 9
2.3.4免疫墨點分析法 (Western blot analysis) 9
2.3.5電化學免疫分析法 (Electrochemistry Immunoassay) 10
2.4 電化學生物感測器 10
2.4.1 電化學分析法 11
2.4.2 電化學阻抗分析法（Electrochemical Impedance Spectroscopy, EIS） 12
2.4.3 循環伏安法（Cyclic Voltammetry, CV） 15
第三章 實驗材料與方法 17
3.1 實驗藥品表 19
3.2 溶液配製 21
3.3 實驗設備與分析儀器 22
3.4 檢測電極試片製作 24
3.4.1 微米半球陣列結構製備 24
3.5 膠體奈米金顆粒製備與定量 27
3.6 電極表面之奈米金顆粒修飾 29
3.7 抗體-抗原自組裝製備 29
3.8 電化學阻抗譜分析 32
第四章 結果與討論 34
4.1 微米半球陣列結構表面形貌觀察 34
4.2 奈米金顆粒修飾表面形貌觀察 35
4.3感測電極表面修飾MUA 37
4.4電極表面修飾EN (EDC/NHS)結果 38
4.5 Anti-NGAL抗體飽和濃度探討 39
4.6非專一性鍵結阻斷 (Blocking) 41
4.7 NGAL檢測標準曲線 42
4.8 NGAL真實樣本分析與測定 44
第五章 結論與未來展望 48
5.1 結論 48
5.2 未來展望 50
文獻參考 52

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