臺灣博碩士論文加值系統

膀胱癌在男性癌症的發生率排名全世界第六名，因為膀胱癌是泌尿系統常見的惡性疾病之一，目前主要檢測方式是透過膀胱鏡，但其診療過程為侵入性，會引起患者的不適感之外，術後亦有機會造成尿道感染，使得患者複檢意願降低。除了膀胱鏡外還有利用尿液細胞學的方式去判斷，但此方式靈敏度僅16-30%，因此，如何開發靈敏且特異性高的生物感測器即顯得相當重要。
近年來，有研究指出可以利用膀胱癌患者的尿液檢體，針對美國食品藥物管理局(FDA)認證的膀胱癌標籤分子「Complement Factor H (CFH)」進行辨別，分析檢體中標籤分子的含量來達到膀胱癌之診斷。此診斷方法雖然不能達到如膀胱鏡效果在臨床上的高準確度，但可透過非侵入性診療且操作人員不需進行專業儀器訓練，即可讓患者自行長期追蹤病情外，亦可節省時間與費用。
有鑑於此，本研究使用奈米金屬轉印技術，透過製程相對簡單且低成本的方式去製作雙模態之金奈米井陣列結構，藉此應用於折射率感測與無標籤分子檢測上。由於其製程簡單，感測器均勻度的相對標準偏差(RSD)為0.13%外，結合表面電漿共振與共振腔模態，使頻寬更窄獲得更好的增益效果，進而讓靈敏度達到637.31 nm/RIU，得出品質因數(FOM)為22.44。另外，在膀胱癌標籤分子CFH的檢測中，偵測極限(LoD)可達1.00×10-9 g/ml。綜上所述，此非侵入性生物感測器在偵測膀胱癌分子中極具潛力。

Bladder cancer ranks sixth in the world in the incidence of male cancers, because bladder cancer is one of the common malignant diseases of the urinary system. At present, the main detection method is through cystoscopy, but the diagnosis and treatment process are invasive and can cause discomfort to patients. In addition to feelings of the patients, there is also a chance of urinary infection after surgery, which reduces the willingness of patients to re-examine. Besides cystoscopy, urine cytology is another way to consider, but the sensitivity of this method is only 16-30%. Therefore, how to develop a sensitive and highly specific biosensor is very important.
In recent years, studies have pointed out that urine specimens of patients with bladder cancer can be used to identify the bladder cancer label molecule "Complement Factor H (CFH)" certified by the U.S. Food and Drug Administration (FDA) and analyze the label molecules in the specimens. Content to reach the diagnosis of bladder cancer, although this method cannot achieve clinically high accuracy such as the effect of cystoscopy, it can be non-invasively diagnosed and treated without the need for professional instrument training for the operator to allow patients to track their condition for a long time and save time and cost.
In view of this, this research uses nanotransfer lithography to fabricate a bimodal gold nanowell array structure through a relatively simple and low-cost method for application in refractive index sensing and label-free molecular detection. Due to its simple manufacturing process, the relative standard deviation (RSD) of the sensor uniformity is 0.13%, combined with the surface plasmon resonance and resonant cavity mode, the bandwidth is narrower, and the electric field gain effect is better, and the sensitivity can reach 637.31 nm/RIU, the figure of merit (FOM) is 22.44. In addition, in the detection of bladder cancer label molecule CFH, the detection limit (LoD) can reach 1.00×10-9 g/ml. In summary, this non-invasive biosensor has great potential in detecting bladder cancer molecules.

摘要 i
致謝 ix
目錄 x
圖次 xiii
表次 xviii
第一章 緒論 1
1.1 前言 1
1.2 研究動機 2
1.3 論文架構 4
第二章 理論原理與文獻回顧 5
2.1 表面電漿共振 5
2.1.1 傳播式表面電漿共振原理 5
2.1.2 侷域化表面電漿共振原理 7
2.1.3 傳播式表面電漿與侷域式表面電漿共振之比較 8
2.1.4 Cavity Resonance原理 9
2.2 表面電漿共振生物感測器之發展 9
2.3 膀胱癌之介紹 11
第三章 研究方法 18
3.1 奈米井陣列數值模擬方法 18
3.2 奈米井陣列結構製作 18
3.2.1 母模具製作方法 19
3.2.2 奈米轉印微影術 20
3.3 折射率靈敏度量測架構及方法 22
3.3.1 實驗設備 23
3.3.2 實驗材料 23
3.3.3 反射光譜與靈敏度的量測 23
3.4 無標籤分子鍵結 24
3.4.1 實驗設備 24
3.4.2 實驗材料 25
3.4.3 實驗材料配置 25
3.4.4 CFH分子量測 26
3.4.5 CFH分子量測方法 27
3.5 利用金奈米粒子放大CFH分子之訊號 27
3.5.1 金奈米粒子合成 27
3.5.2 利用金奈米粒子將CFH分子訊號增強 28
3.6 檢視結構之機台 30
第四章 實驗與數值模擬分析結果 36
4.1 奈米井陣列結構之光學特性模擬分析 36
4.1.1 表面電漿共振模態分析 36
4.1.2 奈米井陣列結構參數最佳化 37
4.2 奈米井陣列結構之實驗結果 38
4.2.1 奈米井陣列之靈敏度量測 39
4.2.2 基板表面改質 41
4.3 膀胱癌無標籤分子技術應用 41
4.3.1 CFH分子鍵結參數最佳化 42
4.3.2 CFH分子量測 43
第五章 討論與未來展望 64
5.1 結論 64
5.2 未來展望 64
第六章 參考文獻 66

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