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論文名稱 Title |
甲型胚胎蛋白之彎曲平板波生物感測器研發 Development of Flexural Plate-wave Based Biosensor for Alpha-fetoprotein Detection |
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系所名稱 Department |
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畢業學年期 Year, semester |
語文別 Language |
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學位類別 Degree |
頁數 Number of pages |
130 |
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研究生 Author |
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指導教授 Advisor |
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召集委員 Convenor |
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口試委員 Advisory Committee |
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口試日期 Date of Exam |
2013-05-18 |
繳交日期 Date of Submission |
2013-06-14 |
關鍵字 Keywords |
甲型胚胎蛋白、溝槽式反射結構、品質因子、插入損耗、彎曲平板波 AFP, quality factor, insertion loss, FPW, reflective grating structure |
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統計 Statistics |
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中文摘要 |
根據行政院衛生署的統計資料顯示,肝癌為台灣癌症死亡率的第二名。過去肝癌常因診斷不易,直到末期才被診斷出,因而錯失治療的黃金時間,以至於存活率相當低;所以若能做到早期發現與早期治療,則可提升治療成效。臨床上,初期肝癌常借助血清甲型胎兒蛋白 (Alpha-fetoprotein, AFP)篩檢,配合進一步的檢查來確定診斷。本論文運用微機電技術與自我組裝單分子層技術,以開發一種可檢測人體血清中微量甲型胚胎蛋白濃度之彎曲平板波(Flexural Plate-wave, FPW)生物感測器,可應用於肝癌之初期檢驗。 傳統之彎曲平板波感測器因為具有高插入損耗(Insertion Loss, LI > - 50 dB)與低品質因子(Quality Factor, Q < 50)的缺點,故很難應用在生物感測之上。除此之外,一般彎曲平板波感測器為了可運用於液態測量,需將矽薄膜蝕刻至約幾微米之厚度以使其聲波之波速低於液體中之聲速,造成製程難度增加且厚度難以控制。針對這些缺點,本論文採用具低波速之二氧化矽取代傳統之矽來作為平板波傳遞之介質,以有效降低彎曲平板波之波速;另外,本研究亦導入溝槽式反射結構設計(Groove-type Reflective Grating Structures)以降低彎曲平板波元件之插入損耗與提升其品質因子。以上之結構設計可利用商用有限元素模擬軟體ANSYS模擬彎曲平板波元件之操作模態、波速與操作頻率隨平板厚度變化之情形,將其模擬所得波速搭配理論公式可計算出溝槽式反射結構之反射係數以作為元件設計之參考。本論文所採用的製程技術為自我組裝單分子層固定化技術與微機電系統技術,所設計之彎曲平板波生物感測器其主要製程包含五道黃光與十一道薄膜沉積,其中最為關鍵的製程技術為甲型胚胎蛋白抗體固定化技術與高優質氧化鋅壓電薄膜沉積技術。 本論文先以商用電子微天秤(QCM)與自我組裝單分子薄膜技術開發甲型胚胎蛋白抗體於金電極上之固定化技術,並將其應用於所開發之彎曲平板波元件之上。另外,為了得到高優質氧化鋅壓電薄膜,本論文針對不同的氬氣/氧氣之比例進行調變,並搭配X光繞射分析系統,找出最佳化之壓電薄膜濺鍍參數。 根據量測結果顯示,在最佳化製程條件下,本研究所開發之彎曲平板波甲型胚胎蛋白生物感測器具有高品質因子(206)、低損耗(-40.854 dB)、低操作頻率(6.388 MHz)、低偵測極限(5 ng/mL)與高線性度(90.17%),未來可望進一步應用於肝癌早期之檢驗。 |
Abstract |
According to the statistics from Department of Health, Executive Yuan, ROC, the hepatocellular carcinoma (HCC) has become the second major cancer killer in Taiwan. In the past, HCC was difficult to be diagnosed until became terminal, and thus missed the treatment time, so that the survival rate was quite low. If the detection and treatment can be done early, the survival rate can be improved. Clinically, the initial stage of HCC is often diagnosed by the concentration of alpha-fetoprotein (AFP) in human serum, and confirmed with further examination. This thesis aims to develop a flexural plate-wave (FPW) based biosensor for early detection of the AFP concentration in human serum by integrating microelectromechanical systems (MEMS) and self-assembly monolayer (SAM) technologies. Conventional FPW transducers have limited applications in biomedical sensing due to their disadvantages such as high insertion loss (> -50 dB) and low quality factor (< 50). Further, the thickness of the substrate is needed to be etched to extreme thin to make sure the phase velocity is lower than the sound velocity in liquid for avoiding the energy dissipation and the extreme thin plate makes the device fragile and hard to fabricate. To overcome these shortcomings, this dissertation proposed a FPW transducer on a low phase velocity insulator membrane with a novel groove-type reflective grating structure (RGS) design. The finite element software ANSYS was used to simulate the propagation wave mode, phase velocity, operating frequency and mass sensitivity of the proposed FPW device. The reflective coefficient can also calculated by the simulated velocity and the theoretical equation derived by Nakagawa. The manufacturing technologies adopted in this dissertation were SAM and MEMS technologies. The main fabrication process included five photolithography and eleven thin films deposition. The key technologies of the fabrication process were AFP antibody immobilization technology and high C-axis ZnO piezoelectric thin film deposition. This dissertation firstly developed the technology to immobilize the AFP antibody on Cr/Au electrode was develop by using commerical quartz crystal microbalance (QCM) and SAM technologies. The developed immobilization technology was then apply to the proposed FPW device. To obtained the high C-axis piezoelectric ZnO thin film, three different Ar/O2 flow were emplyed and were analyzed by X-ray analyzer to find the highest intesity and narrowest half maximum values. According to the experimental results, the proposed FPW based AFP biosensor demonstrated a very high quality factor (206), low insertion loss (-40.854 dB), low operating frequency (6.388 MHz), low detection limit (5ng/mL) and high sensing linearity (90.17%). |
目次 Table of Contents |
論文審定書 i 誌謝…….. iii 中文摘要… iv Abstract…. vi List of Figures xii List of Tables xvii Chapter 1 Introduction 1 1.2 Biosensors 4 1.2.1 Optical Biosensors 7 1.2.2 Gravimetric Biosensors 8 1.2.3 Electrochemical Biosensors 9 1.2.4 Thermal Biosensors 10 1.2.5 Immobilization Technologies 11 1.3 Overview of Dissertation 13 Chapter 2 Acoustic Wave Sensors for Sensing Application 16 2.1 Introduction 16 2.2 QCM Sensors 18 2.3 SAW Sensors 19 2.4 APM Sensors 22 2.5 FPW Sensors 23 Chapter 3 Theory Description 27 3.1 The Rayleigh-Lamb Frequency Equation for the Plate 27 3.2 Piezoelectric Constitutive Equations 34 3.3 Interdigital Transducers (IDTs) 35 3.4 Mass Sensitivity 37 Chapter 4 Simulation and Layout Design of the FPW device 39 4.1 Finite Element Simulations for Propagating Lamb Wave Mode in 4 mm-thick Aluminum Plate 39 4.2 Simulation for Propagation Properties of FPW 47 4.3 Reflective Coefficient of the Proposed Groove-type RGS 52 4.4 Layout Specification of the Proposed FPW Device 53 Chapter 5 Development of AFP Immobilization Method Using QCM and SAM Technologies 55 5.1 Materials and Apparatus 55 5.2 Operating Method of QCM 56 5.3 Fabrication of QCM Based AFP Biosensor 57 5.4 Investigation of the Molar-binding-ratio of the AFP Ag-Ab Pairs under Different Concentration of Glutaraldehyde 61 5.5 Surface Roughness Analysis of the AFP Antibody using AFM System 64 5.6 Effect of Glutaraldehyde Cross-linking Layer on the Sensing Performances of QCM Based AFP Biosensor 68 5.7 Quantification Analysis of the AFP Antibody-antigen Immobilized on 96-well Micro-titer Plate and Si/SiO2/Si3N4/Cr/Au/cystamine/glutaraldehyde Chip 72 5.8 Summary 74 Chapter 6 Development of FPW Based AFP Biosensor 75 6.1 Fabrication of the FPW device 75 6.2 Immobilization of the cystamine SAM/glutaraldehyde layers in the backside cavity of FPW device 79 6.3 Dip Coating of the AFP Antibody/BSA/AFP Antigen in the Backside Cavity 79 6.4 SEM and XRD Analysis of the Piezoelectric ZnO Film 81 6.5 Characterization of the Proposed FPW-AFP Biosensor 83 6.6 Summary 89 Chapter 7 Conclusions and Future Works 91 7.1 Conclusions 91 7.2 Future Works 93 References 95 Personal Publication 109 |
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