生物標記亦是一種可對臨床問題提供有意義分析的生理指標，可用作身體發炎指標來預估重症、了解免疫反應程度、辨識感染源以及分析預後等。例如白血球介素-6（IL-6）與前降鈣素（PCT）已被研究證明分別與炎症程度與細菌性感染等高度相關。針對生物標記的即時定點照護檢測（POCT）可使我們對生物標記進行即時、連續的檢測，對於早期發現、診斷疾病與預後追蹤等能提供相當大的幫助。
在此篇研究中，我們開發了一種新型的電化學生物感測器，用於檢測白血球介素-6或前降鈣素，該感測器使用標準CMOS製程的奈米電極矩陣（NEA）。當電極縮小至奈米級並排列為矩陣以形成NEA，有助於產生更高的電場強度，這相比使用微電極更能提高生物感測器的靈敏度。NEA中的每個奈米電極都是圓半徑0.1微米的圓柱結構，頂層為經物理氣相沉積形成的氮化鈦（TiN）。每個感測器被分為四個獨立的電極區塊，每個區塊能夠獨立地輸入和輸出電信號，此設計允許NEA生物感測器通過循環伏安法的輸入進行選擇性修飾。在此，我們展示了單一區塊和全晶片區塊的感測器製作。
我們討論了與CMOS製造相關的材料和污染問題及其作為生物感測器的使用。為了改善這些問題，我們將晶片存放於氮氣櫃中儲存，並對感測器進行預處理清潔。這些步驟顯著地影響了電極表面的清潔度，進而影響後續的修飾與固定效果。NEA表面經由重氮鹽電接枝進行功能化，隨後使用EDC/NHS以固定抗體。在這過程中，我們尤其討論了修飾與抗體固定前後之電子轉移電阻（Rct）變化。
完成的NEA生物感測器展示了足夠的靈敏度，可以快速區分炎症狀況和疾病嚴重程度。在純水系統中，NEA生物感測器對白血球介素-6與前降鈣素的檢測極限分別為19.62 pg/mL與20.19 pg/mL；在血清系統中，NEA生物感測器對前降鈣素的檢測極限為15.62 pg/mL。此篇研究展示了使用CMOS量產的NEA用作POCT設備的潛力。

Biomarkers serve as meaningful physiological indicators for clinical analysis. They can be used as inflammation indicators to predict severe disease, assess immune response levels, identify the source of infection, and analyze prognosis. For example, interleukin-6 (IL-6) and procalcitonin (PCT) have been proven to be highly correlated with the extent of inflammation and bacterial infections, respectively. Point-of-care testing (POCT) for biomarkers allows for real-time, continuous monitoring, which is extremely beneficial for early disease detection, diagnosis, and prognosis tracking.
In this study, we developed a novel electrochemical biosensor for detecting IL-6 or PCT, using a nano-electrode array (NEA) fabricated via standard CMOS processing. Miniaturizing the electrodes to the nanoscale and arranging them in an array to form an NEA facilitated the creation of a higher electric field magnitude compared to that available via the use of microelectrodes, thereby improving biosensor sensitivity. Each nano-electrode in the NEA was cylindrically shaped, with a radius of 0.1 µm, and featured a top layer of titanium nitride (TiN) formed via physical vapor deposition. Each biosensor was divided into four independent banks, capable of independently inputting and outputting electrical signals. This design allowed the NEA biosensor to undergo selective modification by CV input. We demonstrated the biosensor fabrication of single-bank and whole-chip banks.
We addressed material and contamination issues associated with CMOS-produced NEAs and their uses as biosensors. To alleviate these issues, we stored materials and chips in a nitrogen-controlled cabinet and conducted pretreatment cleaning on the electrodes. Both steps had a noticeable impact on the cleanliness of the electrode surfaces, thus affecting subsequent modification and immobilization effectiveness. The NEA surface was functionalized by electrochemically grafting diazonium salts, and subsequently immobilized with antibodies via EDC/NHS chemistry. The changes in electron transfer resistance (Rct) before and after modification and antibody immobilization were particularly discussed.
The resulting NEA biosensor demonstrated sufficient sensitivity to distinguish inflammatory conditions and disease severity rapidly. In ultrapure water systems, the LOD for IL-6 and PCT detection by the NEA biosensor were 19.62 pg/mL and 20.19 pg/mL, respectively. In serum systems, the LOD for PCT detection was 15.62 pg/mL. This showcases the potential for using NEA mass-produced via standard CMOS processing as a biosensor for POCT devices.

中文摘要--------------------i
Abstract--------------------iii
誌謝--------------------v
目錄--------------------vi
圖目錄--------------------ix
表目錄--------------------xiii
英文縮寫表--------------------xiv
第一章 緒論--------------------1
1.1 電化學阻抗感測器--------------------1
1.1.1 電化學生物感測器--------------------1
1.1.2 電化學阻抗圖譜--------------------5
1.2 三維氮化鈦奈米電極矩陣電化學生物感測晶片--------------------11
1.2.1 奈米電極矩陣（NEA）--------------------11
1.2.2 應用CMOS製程之三維 TiN NEA晶片--------------------13
1.2.2 TiN NEA生物感測器製作--------------------17
1.3 生物標記與定點照護檢測--------------------20
1.4 研究動機與目的--------------------24
第二章 實驗材料與方法--------------------25
2.1 實驗材料--------------------25
2.1.1 化學品--------------------25
2.1.2 抗體與純化蛋白--------------------25
2.2 實驗方法--------------------26
2.2.1 電化學阻抗圖譜量測--------------------26
2.2.2 阻抗分析與檢測原理--------------------26
2.2.2 晶片保存與預處理清潔--------------------27
2.2.3 電極表面修飾--------------------28
2.2.4 抗體固定與抗原檢測--------------------28
2.2.7 統計方法--------------------29
第三章 TiN NEA白血球介素-6感測器--------------------30
3.1 晶片儲存環境之於阻抗變化--------------------30
3.2 一代電極排列與奈米電極矩陣結構--------------------32
3.3 預處理清潔效果--------------------35
3.4 表面重氮鹽電接枝修飾--------------------40
3.5 抗體固定與抗原檢測--------------------45
第四章 TiN NEA前降鈣素感測器--------------------48
4.1 二代電極排列與奈米電極矩陣結構--------------------48
4.2 初始阻抗表現與量測條件--------------------51
4.3 清洗與預處理清潔效果--------------------57
4.4 表面修飾與抗體固定--------------------61
4.5 於緩衝液、血清與檢體中的抗原檢測--------------------68
第五章 結論--------------------72
第六章 參考文獻--------------------75

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