臺灣博碩士論文加值系統

感測元件與生物分子的連結應用在未來的疾病診斷是個重要且具發展性的課題。在此篇論文中，我們選擇甲狀腺乳突癌症相關變異基因BRAFV599E 以及癌症指標物甲型胎兒蛋白抗原來當作偵測目標。我們以半導體奈米線為元件基礎的裝置做為新穎的生物感測器，可偵測的生物分子或是化學物種包括有低濃度化學成分離子、小分子、抗原抗體反應、檢測蛋白質、DNA 和病毒。在我的研究裡，使用了互補式金氧半場效電晶體的技術來製作新穎側向閘極場效電晶體生物感測器。利用矽的局部氧化製程來製作內縮線寬的奈米線，而此奈米線可以達到優異的高比表面積比以及獲得側向閘極控制，此兩項主要特色對於目前感測元件整合於微流道組件上有極大優勢及應用面。我們量測甲狀腺乳突癌症相關變異基因BRAFV599E 以及癌症指標物甲型胎兒蛋白抗原對於奈米線元件的電性變化影響，另外還利用了紅外線光譜儀、螢光顯微鏡以及紫外光光譜量測儀確認表面自組裝固定化的技術以及生物分子實驗條件的確立。最後總結出我們利用矽的局部氧化製程製作出的奈米線通道可使其線寬內縮到100 nm 以下的線寬，此條件提供元件電性達到優異的105 倍的開關電流比。利用此靈敏度高的元件我們可以偵測到濃度100 fM 的標的突變DNA 以及3 ng/mL的癌症標誌物抗原分子。結果顯示此新穎的側向閘極奈米線感測元件可以作為未來的免標定、即時偵測、高靈敏度以及優異專一性結合的場效電晶體生物感測器。另外，此元件具有獨立控制側向閘極的能力更提供了未來感測元件與微流道技術整合上的一大優勢。

It is an important and developing capable issue to combine the semiconductor sensor devices with biomolecules for the future application of disease diagnosis. In the present work, the BRAFV599E mutation gene and cancer marker α-fetoprotein, which have been recently reported to restrict to the papillary thyroid carcinomas (PTCs) and liver cancer, respectively, were chosen as the target biomolecules. The devices based on semiconductor nanowires exhibit high sensitive and selective characteristics for the real-time, label-free, and excellent specificity detection of biomolecules and chemical species. A novel side-gate silicon nanowire field effect transistor (SiNW-FET) is fabricated by using the complementary metal oxide
semiconductor (CMOS) FET compatible technology. The shrank nanowires with higher surface-to-volume ratio and individual side-gate for integration are achieved by the LOCOS process. Because of the above advantages, the devices have potential to integrate with microfluidic system for bio-detection application. Therefore, the detection strategy for PTC and liver cancer has been investigated with our SiNW-FET integration with microfluidic system for real-time sensing by measuring thecharacteristics of electrical signals. The FT-IR, fluorescence microscopy and UV spectrophotometer are also examined to check out our efficiency of the SAM and appropriate experimental parameters for bio-sensing. In the conclusion, the width of shrank nanowire by LOCOS process can be thinner than 100 nm. The drain current versus gate voltage (ID-VG) characteristic of the SiNW-FET exhibits about five orders of magnitude of Ion/Ioff ratio, and the threshold voltage shifts positively after hybridization of 100fM concentrations of BRAFV599E mutation gene and 3ng/mL concentrations of the cancer marker, α-fetoprotein,
respectively. The results show that the side-gate nanowire device has the capability of acting as a real-time, label-free, highly sensitive and excellent selectivity SiNW-FET
biosensor for important biomolecules. In addition, our approach offers a highly potential possibility to integrate with microfluidic-channel system for future parallel real-time detection of multiple chemical and biological species with controlling the individual side-gate in a single integrated chip.

Chapter 1: Introduction ..............................................................................................1
1.1 General Introduction .....................................................................................1
1.3 Introduction to Biosensor............................................................................10
1.3.1 Electrochemical biosensors ..............................................................11
1.3.2 Optical biosensors .............................................................................13
1.3.3 Piezoelectric biosensors ....................................................................15
1.4 Introduction to the Importance in Detection of Biomolecules.................17
Chapter 2: Literature Review...................................................................................19
2.1 Silicon Nanowire Field Effect Transisitor (Top–Down SiNW-FET) .......19
2.2 Real-time Nanowire Field-Effect-Transisitor Biosensors.........................28
2.3 Detection of Important Cancer Markers...................................................31
2.3.1 Introduction of Mutation Genes-BRAFV599E ..................................31
2.3.2 Introduction of Cancer Marker Alpha-Fetoprotein ......................33
2.4 Motivation.....................................................................................................35
2.5 Organization of the Thesis ..........................................................................38
Chapter 3: Experiments ............................................................................................39
3.1 General introduction ...................................................................................39
3.2 Experimental Procedure .............................................................................42
3.2.1 Fabrication of Side-gate Silicon Nanowire Field Effect Transistor
(NWFET) ....................................................................................................42
3.2.2 Fabrication of the Microfluidic System and Integration with the
SiNW-FET ..................................................................................................45
3.2.3 Immobilization of the Probe-DNA onto the Nanowire ..................48
3.2.4 Characterization of Detection Probe-DNA, Hybridization with
Target-DNA and Non-complementary DNA ...........................................50
3.2.5 Immobilization of the Anti-alpha-fetoprotein onto the Nanowires
......................................................................................................................52
3.2.6 Characterization of Detection Interaction of
Antigen-Alpha-Fetoprotein to the Antibody onto the Nanowires .........54
Chapter 4: Results and Discussions..........................................................................55
4.1 Physical and Electrical Properties of the Side-Gate SiNW-FET.............55
4.1.2 Determination of the Sub-threshold Swing ....................................59
4.1.3 Determination of On/Off Current Ratio.........................................59
4.1.4 Determination of the Field-effect Mobility .....................................60
4.2 Real-Time Detection of Multi-Steps-APTES Immobilization and
BRAFV599E Mutation Genes for Hybridization and Dehybridization Assay 61
4.2.1 Real-time Detection of the Different pH Value Solutions..............61
4.2.2 The Confirmation of Effect between Debye Length and Detecting
DNA Hybridization Signal ........................................................................65
4.2.3 Real-time Detection for Hybridization and Dehybridization of
Target-DNA on Immobilized Probe-DNA Modified Surface ................66
4.2.4 The Influence of Temperature on Efficiency of Hybridization and
Dehybridization Assay...............................................................................73
4.2.5 Quantification of Detection Target-DNA........................................81
4.3 Detection of Immobilized Anti-Alpha-Fetoprotein and Interacted with
Alpha-Fetoprotein..............................................................................................82
4.3.1 Detection of Anti-α-fetoprotein by FT-IR Assay ............................83
4.3.2 The Real-Time Detection of Antigen-Alpha-Fetoprotein ..............85
4.3.3 Quantification of Detection Antigen-Alpha-Fetoprotein...............89
Chapter 5: Conclusions .............................................................................................91
References...................................................................................................................92
Chapter1 ............................................................................................................92
Chapter2 ............................................................................................................95
Chapter3 ............................................................................................................99
Chapter4 ..........................................................................................................100

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