本篇論文不同於以往癌症相關液態活檢將標誌物聚焦於CTCs和ctDNA等已成熟之市場，我們將microRNA (miRNA)作為生物標誌物，並且製作一款生醫晶片，使其對目標miRNA達到低濃度之檢測極限，從而實現癌症早期篩查之最終目的。
現已有多篇生醫相關領域研究不同miRNA與不同癌症之間的相關性，使miRNA對於病理的判讀極具意義。傳統檢測鹼基序列的方式是以螢光標定並追蹤，但由於螢光分子並不存在特異性，若是在複雜之生理環境下同時存在多種miRNA，僅透過螢光標定則無法針對不同內源miRNA作判讀。因此本論文近一步結合具有分子結構訊息特性(Finger Structure)之拉曼頻譜，欲達到利用拉曼頻譜定性、並同時使用螢光技術之高靈敏度定量之實驗目的。
由於拉曼屬於非彈性散射，在特定頻率下產生拉曼散射的機率極低，因此相較於不同光學原理之螢光技術而言，拉曼散射之截面積(Cross-section)低了近10-12個數量級，意即若要使用拉曼頻譜作為鹼基之直接量測，則在靈敏度不及螢光的前提下，檢測之極限值LOD (Limit Of Detection)勢必會大幅增加。在本研究中得出：若要使用拉曼頻譜直接量測miRNA，則需約1.291*1014/# miRNA分子，此數量級遠超過人體中存在之miRNA的表現量，因此在捕獲生物標誌物後，勢必再導入qPCR之概念作序列擴增、才得以進一步進行量測分析。
由於qPCR所使用之螢光染料SYBR Green不具有專一性，因此在本論文中設計出一款增益表面拉曼散射訊號之奈米粒子Nano-Mushrooms (NMs)，使其同時鍵結上miRNA之primer以及所對應之非標定Nano-Barcode序列，藉由Nano-Barcode之拉曼散射頻譜，可形成判讀內源miRNA之依據。
在本論文中，為提升表面增益拉曼散射(Surface Enhanced Raman Spectroscopy, SERS)效益，藉由製造奈米級高深寬比微結構於奈米粒子表面之粗糙化製程、以物理性作用力DEP Force (Dielectrophoresis Force)及EOF (Electroosmotic Flow)聚集奈米粒子等方式增加奈米粒子表面之粗糙程度，以形成更多的Hot-Spots分布。同時在被檢測之序列上設計SH官能基，使其接和至奈米粒子之鍍金屬表面產生自組裝效應SAM等方式，以增加分子吸附率，使序列坐落於Hot-Spots之作用範圍內，才得以使序列訊號具有SERS之最大效益，最後與無粗糙化製程之Bare Silicon 基板相比，可以使SERS效益放大近1160倍。
透過最佳化之SERS增益方式，我們可以達到以非標定的方式直接量測到終濃度為4 μM之鹼基序列，可將此結果應用於Nano-Barcode。定義不同之鹼基組合為不同的Nano-Barcode，就現有技術而言，已可鑑別出至少10種Nano-Barcode訊號，進而將此訊號作為輔助判讀，彌補螢光頻譜無法定性之不足。
最後透過「螢光訊號之高靈敏特性作為定量依據；同時判讀具分子結構之拉曼頻譜作為定性標準」的概念，可以在未知之人體環境中同時判讀多種miRNA的表現量，達到癌症早期篩查的主要目的。

This paper is different from previous cancer-related liquid biopsy markers that focus on mature bio-markets such as CTCs and ctDNA. We used microRNA (miRNA) as a biomarker and make a biomedical chip that achieves the low LOD (Limit Of Detection) value of target miRNA. Ability of detecting lower concentration of biomarker can further achieve the ultimate goal of early cancer screening.
There are many biomedical related researches to study the correlation between different miRNAs amounts and different cancers, making miRNA's interpretation of pathology very meaningful. The traditional method of detecting nucleotides sequences is based on Fluorescence technologies including cursor and tracking. However, since the fluorescent molecules are not specific, if multiple miRNAs exist simultaneously in a complex physiological environment, it is impossible to target different endogenous
miRNAs only through the fluorescent cursor. Therefore, this paper further combines the Raman spectrum features in finger-print which can obtain the molecular scaled information. To achieve the purpose of qualitative through the Raman spectrum and simultaneously use the high sensitivity to quantitate by fluorescence technology.
Since Raman Scattering belongs to inelastic scattering, the probability of Raman scattering at a specific frequency is extremely low, so the cross-section of Raman scattering is nearly 1010-1012 lower than that of fluorescent technology with different optical principles. Meaning that if the Raman spectrum is to be used as a label-free measurement of the nucleotides sequences, the Limit Of detection (LOD) is bound to increase significantly under the premise that the sensitivity is not as good as that of fluorescence. In this paper, it is concluded that if the miRNA is directly measured through label-free way by the Raman spectrum, about 1.291*1014/# miRNA molecules are needed, which is much larger than the amount of miRNA present in the human body. Therefore, it is bound to introduce the concept of Real-time polymerase chain reaction (qPCR) for sequence amplification before further measurement and analysis.
According to the fluorescent dye SYBR Green used in qPCR is not specific, in this paper, a Nano-Mushrooms (NMs) particles with a surface-enhancement Raman scattering signal is designed to simultaneously bind the miRNA primer. And the corresponding Nano-Barcode sequence characterised by label-free, through the Raman scattering spectrum of Nano-Barcode, can form the basis for diagnosis of endogenous miRNA.
In this paper, in order to improve the benefits of Surface-Enhanced Raman spectroscopy (SERS), by making a nano-scaled structure features in high aspect ratio on the surface of the nanoparticle, applying the physical force including Dielectrophoresis Force (DEP Force) and Electroosmotic Flow (EOF) tin order to aggregate nano particles, which can increase the roughness of the nanoparticles’ surface to form more Hot-Spots distribution.
At the same time, the SH functional group is designed on the 5’ terminate of analyte sequence, and it is connected to the metallized surface of the nanoparticle to produce a self-assembly effect (SAM) to increase the molecular adsorption rate onto NPs, so that the analyte sequence is located within the scope of action of Hot-Spots, it will produce greatest benefit of SERS through these ways. Finally, the SERS benefit can be magnified nearly 1160 times compared to the bare silicon substrate without the abovementioned process.
Through the optimized SERS fabrication, we can directly measure the nucleotides sequence characterised by label-free with a final concentration of 4 μM, and this result can be served as Nano-Barcode. Different base of nucleotide combinations are defined as different Nano-Barcodes. In the prior art, at least 10 Nano-Barcode signals can be identified, and this signal is used as an auxiliary interpretation to make up for the insufficiency of the fluorescence spectrum.
Finally, through the concept of "highly sensitive characteristics of fluorescent signals as a quantitative basis; and reading the Raman spectrum with molecular structure as a qualitative standard", it is possible to simultaneously interpret the expression of multiple miRNAs in an unknown human environment to achieve final purpose of early cancer screening.

摘要 i
Abstract iii
誌謝詞 vi
目錄 vii
圖目錄 x
表目錄 xiv
第一章 緒論 1
1.1.前言 1
1.1.1.大腸癌(colorectal cancer, CRC) 1
1.1.2 液態生物檢體 / 液態活檢 (Liquid Biopsy) 2
1.2.液態活檢的發展 3
1.3.研究動機與目的 7
1.4. 研究方向MicroRNAs（miRNAs） 10
1.5. 研究手法(一) 螢光光譜分析 13
1.5.1. 現有研究方法 13
1.5.2. 螢光光譜分析實驗設計 14
1.6. 研究手法(二) 表面增強拉曼效應(Surface-Enhance Raman Scattering, SERS)分析 16
1.6.1. SERS原理 17
1.6.2. 電磁場增強效應(Electromagnetic enhancement) 19
1.6.3. 化學增強效應(Chemical enhancement) 22
1.6.4. 熱點效應(Hot spots) 23
第二章 文獻回顧 24
2.1. miRNA與不同癌症相關性之研究 25
2.2.螢光手法量測鹼基序列之相關研究 27
2.2.1. Molecular beacon 28
2.2.2. TaqMan probe 29
2.3. SERS放大訊號機制測得鹼基序列相關研究。 30
第三章 研究方法與分析 34
3.1.羧化聚苯乙烯奈米微珠(carboxylated polystyrene beads,PSBs-COOH) 34
3.1.1. 羧化聚苯乙烯奈米微珠單層排列機制 35
3.1.2.實驗製備 36
3.1.3.實驗步驟 37
3.2.反應離子蝕刻(Reactive-Ion Etching, RIE) 38
3.2.1.蝕刻氣體之選擇 39
3.2.2.實驗步驟 40
3.3.電子腔真空蒸鍍系統(E-gun system) 40
3.3.1.實驗步驟 42
3.4. Scanning Electron Microscope(SEM)結合Image J影像軟體分析 42
3.4.1. 相鄰微珠之間的電漿子耦合效應 42
3.4.2. 次結構(nano-finger)深寬比之計算 43
3.5. Atomic Force Microscope, AFM原子力顯微鏡分析平均粗糙度 45
第四章 實驗製程及結果討論 46
4.1. 螢光實驗量測分析 46
4.1.1 雙股雜交最佳條件 48
4.2. Au-coated finger structure 52
4.2.1 Au-coated finger structure 製程 52
4.2.2. Au-coated finger structure基板SEM影像形貌、AFM分析以及量測R6G螢光之拉曼頻譜 54
4.2.3. Au-coated finger structure分析及改良 56
4.3. Au-coated Nano-finger structure所製作之AuNMs- Substrate 57
4.3.1. AuNMs- substrate製程 57
4.3.2.AuNMs-substrate SEM影像形貌分析以及量測R6G螢光之拉曼頻譜 59
4.3.2.1 不同氧電漿蝕刻參數基板之R6G拉曼頻譜結果及其SEM影像分析 59
4.3.2.2 E-gun沉積不同金厚度基板之R6G拉曼頻譜結果及其SEM影像分析 60
4.3.3 AuNMs- substrate之增益 64
4.3.4.miRNA序列配於AuNMs- substrate 64
4.3.5. AuNMs- substrate分析及改良:導入Barcode概念 70
4.4. AgNMs- Substrate 73
4.4.1. AgNMs-substrate製程及其拉曼散射訊號增益 74
4.4.2.鹼基序列配於AgNMs-substrate 77
4.4.3.AgNMs-substrate分析及改良 80
4.5. AgNMs-Sonics 81
4.5.1. AgNMs-sonics製程 81
4.5.2.鹼基序列配於AgNMs-sonics 82
4.5.3. AgNMs-sonics分析及改良 85
4.6. AgNMs-Sonics + EOF (Electroosmotic Flow) 87
4.7. 總結 92
第五章 未來工作 93
參考文獻 96

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