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系統識別號 U0026-0812200910380799
論文名稱(中文) 生醫物質微感測技術的研發
論文名稱(英文) Development of Micro-Sensing Techniques for Bio-relative Samples
校院名稱 成功大學
系所名稱(中) 醫學工程研究所碩博士班
系所名稱(英) Institute of Biomedical Engineering
學年度 91
學期 2
出版年 92
研究生(中文) 吳靖宙
研究生(英文) Ching-Chou Wu
電子信箱 chingchouwu@seed.net.tw
學號 p8887102
學位類別 博士
語文別 英文
論文頁數 127頁
口試委員 指導教授-張憲彰
口試委員-湯銘哲
召集委員-朱銘祥
口試委員-鄭 國 順
口試委員-廖峻德
口試委員-楊倍昌
口試委員-徐善慧
口試委員-林世明
口試委員-林奇宏
中文關鍵字 黏彈性  生物力學  膠原蛋白  掃描式探針顯微術  電化學電滲透流控制  毛細管電泳晶片  微機電系統 
英文關鍵字 micro-electromechanical system  capillary electrophoresis microchip  electrochemistry  electroosmotic flow control  scanning probe microscopy  collagen  biomechanics  viscoelasticity 
學科別分類
中文摘要 本研究利用微機電製程技術與掃描式探針顯微術進行生物醫學相關物質之微感測技術的研發。其研究主題包括:(1)整合三極式電化學(electrochemical, EC)電極與白金接地電極於毛細管電泳(capillary electrophoresis, CE)晶片的安培法偵測系統;(2)以自組性薄膜(self-assembled monolayer, SAM)為絕緣層的製作法於電滲透流(electroosmotic flow, EOF)之微流體的控制;(3)利用原子力式顯微術(atomic force microscopy, AFM)對含水的聚鄰二苯胺(poly (o-phenylenediamine), PPD)薄膜厚度的量測;(4)不同年紀的含水膠原蛋白凝膠其微結構和生物機械特性與細胞凋亡關係的探討。
本論文之各部分內容敘述如下:

Part 1:
整合三極式電化學電極與白金接地電極於毛細管電泳晶片的安培法偵測系統
在此部分的研究中利用微機電製程技術製作一結合含有三極式EC電極與白金接地電極的玻璃基板與一經過氧化電漿處理含有分離泳道的聚甲基矽氧烷(poly(dimethylsiloxane), PDMS)薄層的毛細管電泳晶片。此一白金接地電極位於EC電極之前以隔離電泳電場對EC偵測時的干擾,從10 mM 的嗎林乙基磺酸(2-(N-morpholino) ethanesulfonic acid (MES, pH 6.5)) 溶液中所量測的背景電流顯示,經此預接地處理後的EC電流背景值可降至0.05 pA,另外以鍍白金的擬參考電極在安培法的偵測中也可提供一穩定的參考電位。實驗結果顯示在量測多巴胺(dopamine)濃度為0.125 M時其訊號雜訊比(S/N ratio)為4,在多巴胺濃度從0.25 M到50 M線性範圍的相關係數可達0.9974,且其靈敏度為11.76 pA/M。此完全整合的CE-EC 微晶片應具有儀器微小化的要求與商業化的價值。

Part 2:
以自組性薄膜為絕緣層的製作法於電滲透流之微流體的控制
在本實驗中提出一新的製程概念,即利用SAM作為一絕緣層並透過電極的誘發以產生場效應流,以達到控制EOF與微流體的目地。由於以十八烷硫醇(1-octadecanethiol, ODT)為SAM的絕緣層厚度僅約3 nm,所以當誘發的閘極電壓(gate voltage, Vg)施予0.8 V時,其垂直電場可高達2.7 MV/cm。藉由 +0.8 到 -0.8 V的Vg控制,在MES的 pH值為6.0或3.0的溶液中,其EOF遷移率(eof)的範圍可從-3.1× 10-4 cm2/Vs到 3.4 × 10-4 cm2/Vs。此外若利用十一烷羧基硫醇(1-mercaptoundecanoic acid, MUDA)為絕緣層,在pH值6.0的MES溶液中,因SAM的表面會解離呈負電性,所以會加強正eof的強度。因此選用不同官能基的SAM為絕緣層則可加強或限制eof的強度與方向。從原子力顯微術的力距離曲線的結果驗證,在負誘發電位下相較於ODT絕緣層,MUDA絕緣層因具有較強的表面電位,所以可誘發出較大的eof。此一新穎的製程具有良好的eof控制、低消耗功率與容易製作的優點,未來應具有可將微流體晶片微小化與可攜式化的潛力。

Part 3:
利用原子力式顯微術對含水的聚鄰二苯胺薄膜厚度的量測
PPD薄膜常被使用作生醫感測器的辨識層基材,在此部分將提出以利用AFM的力距離曲線(force versus distance curve, force curve)進行含水狀態的PPD薄膜厚度量測的方法。當AFM的掃描器以1~0.25 μm/s的上升速率進行量測,並取50%的信心區間做厚度統計分析時,其厚度為19.3±8.2 nm。另外利用AFM的影像掃瞄功能,比較一使用光蝕刻技術製成階梯狀的金電極在聚合PPD薄膜之前與之後的厚度變化量,其所得PPD薄膜的厚度為19.6±5.2 nm,以當為force curve量測的參考標準值。然而若以電聚合電量來計算PPD薄膜厚度時,其厚度只約為AFM影像法或force curve法的三分之一,此結果顯示PPD薄膜在含水狀態下會呈現膨潤的現象。

Part 4:
不同年紀的含水膠原蛋白凝膠其微結構和生物機械特性與細胞凋亡關係的探討
細胞的生理狀態特別是凋亡的出現都與細胞外基質的微觀結構與其生物機械特性有關,之前的研究指出以膠原蛋白凝膠為細胞培養基材時,其細胞凋亡的比率與所萃取出膠原蛋白的年齡有關。本實驗將針對自一個月、四個月與八個月大的老鼠尾巴中所萃取並製成的膠原蛋白凝膠進行量測,並比較其微結構與機械特性的差異。以流變儀量得的結果發現,膠原蛋白的剪切模量隨著年齡的增加而增加,此結果應是膠原蛋白纖維間產生較多的交聯所造成。其較大的基質彈性,可提供細胞生長所需的張力,因而使細胞凋亡的比率下降,從AFM的影像中也觀察到年齡愈大的凝膠其結構較為緻密。比較以動態量測分析儀與流變儀在潛變模式的量測結果,發現凝膠在水平方向的彈性模量約為垂直結構的1.4~2.7倍,顯示此含水的凝膠在水平方向具有較大的抗負載能力。
英文摘要 This study utilizes the micro electromechanical system and scanning probe microscopy to develop the micro-sensing techniques for bio-relative samples. The topics include: (1) three-electrode electrochemical (EC) detector and platinum film decoupler integrated with a capillary electrophoresis (CE) microchip for amperometric detection; (2) self-assembled monolayer (SAM) as an ultrathin insulator for electroosmotic flow (EOF) control; (3) estimating the thickness of hydrated ultra-thin poly(o-phenylenediamine) (PPD) film by atomic force microscopy (AFM); (4) microstructure and biomechanics of hydrated age-related collagen gels for cell apoptosis. The contents of each chapter are listed below:

Part 1:
Three-electrode electrochemical detector and platinum film decoupler integrated with a capillary electrophoresis microchip for amperometric detection
This article demonstrates that a three-electrode EC detectors and an electric decoupler could be fabricated in the same glass chip and integrated with an O2-plasma-treated poly(dimethylsiloxane) (PDMS) layer using microfabrication techniques to form the CE microchip. The platinized decoupler could mostly decouple the EC detection circuit from the interference of a separation electric field in 10 mM 2-(N-morpholino) ethanesulfonic acid (MES, pH 6.5) solution. The baseline offset of background current recorded from the working electrode with and without application of a separation electric field was maintained at less than 0.05 pA in 10 mM MES. In addition, the platinized pseudoreference electrode was demonstrated to offer a stable potential in electrochemical detection. As a consequence, the limit of detection of dopamine was 0.125 μM at a S/N= 4. The responses for dopamine to different concentrations were found to be linear between 0.25 and 50 μM with a correlation coefficient of 0.9974 and a sensitivity of 11.76 pA/μM. The totally integrated CE-EC microchip should be able to fulfill the ideal of miniaturization and commercialization.


Part 2:
Self-assembled monolayer as an ultrathin insulator for electroosmotic flow control
A novel fabrication process using a SAM as the insulator to generate the field-effect flow is presented. The perpendicular electric field controlling zeta potential can reach 2.7 MV/cm, using only a gate voltage (Vg) of 0.8 V through the SAM insulator of 1-octadecanethiol. Electroosmotic mobility (eof) ranges from -3.1 to 3.4 × 10-4 cm2/V•s by modulating the Vg from +0.8 to -0.8 V, regardless of 2-(N-morpholino)ethanesulfonic acid (MES) buffer pH. Additionally, the insulator of 11-mercaptoundecanoic acid can enhance the strength of positive eof by a negative Vg in MES with pH 6.0 due to the dissociation of carboxylic group. Therefore, the choices of SAM insulators with different functional group can enhance or restrict the strength and direction of EOF. From the force-curve measurement of AFM, the greater eof strength induced by MUDA insulator was attributed to its greater surface potential than the ODT insulator in the same negative Vg. The characteristics of excellent eof control, low power consumption and ease of fabrication of the insulator allow the microfluidic control the potential for miniaturization and portability.

Part 3:
Estimating the thickness of hydrated ultrathin poly(o-phenylene -diamine) film by atomic force microscopy
A novel method to measure ultrathin PPD film electropolymerized on gold electrode in liquid was developed. It is based on the force vs. distance curve (force curve) of AFM. When 1 to 0.25 m/s was chosen as the rising rate of the scanner, and 50% of the confidence interval as the qualifying threshold value, the thickness of the hydrated polymer film could be calculated. This result was compared with one obtained from an AFM image. A step-like electrode fabricated by a photolithographic process was used. The height difference of the electrode before and after the PPD coating was imaged in liquid, and then the real thickness, 19.6  5.2 nm, was obtained. The sample was also measured by estimating the transition range of the force curve of hydrated PPD film, and the thickness of the hydrated PPD film was determined to be 19.3  8.2 nm. However, the results calculated by integrating the electropolymerized charge for the oxidation process of o-PD was only one-third as large as it was when using the two previously described methods. This indicated that the structure of hydrated PPD film might have been swollen.

Part 4:
Microstructure and biomechanics of hydrated age-related collagen gels for cell apoptosis
The microstructure and biomechanical properties of extracellular matrix may affect the cellular physiological status, especially in apoptosis ratio. The apoptosis ratio of cells was essentially related to the age of the collagen gel used as a supporting matrix. In the present study, the differences in mechanical properties and in microstructure among three kinds of age-related hydrated collagen gels were further evaluated. Rheometer and dynamic mechanical analyzer were used to measure shear and compressive properties of hydrated collagen gels extracted from 1-, 4- and 8-month-old rat tail tendon. The results indicated the shear elastic modulus of collagen gels apparently increased with the increasing age, resulting in a reduction of apoptosis ratio of cells. Such a highest shear modulus of the oldest (8-month-old) collagen gels was attributed to more crosslinking among the collagen fibrils. Morphological images of collagen gels obtained by AFM also exhibited an older collagen gel had a denser network structure. The creep behaviors of collagen gels after compression are considerably different from those in shear. The horizontal-structure moduli obtained in shear creep test were 1.4-2.7 times greater than those in the vertical compressive direction. The shear viscosity also indicated a higher value as compared with that of compressive creep.
論文目次 Chapter 1
INTRODUCTION
1.1 Background of Study
1.2 Techniques of Capillary Electrophoresis
1.2.1 History
1.2.2 Principle and Theory
1.2.3 CE Categories and Applications
1.3 Techniques of Scanning Probe Microscopy
1.3.1 History
1.3.2 Principle and Structure of SPM
1.3.3 SPM Categories
1.3.4 Applications of SPM in Biology
1.4 Dissertation Organization
Chapter 2
THREE-ELECTRODE ELECTROCHEMICAL DETECTOR AND PLATINUM FILM DECOUPLER INTEGRATED WITH A CAPILLARY ELECTROPHORESIS MICROCHIP FOR AMPEROMETRIC DETECTION
2.1 Introduction
2.2 Experimental Section
2.2.1 Reagent
2.2.2 Electrode Fabrication and Layout
2.2.3 Channel Fabrication and Chip Bonding
2.3.4 Electrophoresis Procedure
2.3.5 Electrochemical Detection
2.3 Results and Discussion
2.3.1 CE-EC Microchip Fabrication
2.3.2 Evaluation of Decoupler Performance
2.3.3 Stability of the Pt Pseudoreference Electrode
2.3.4 Efficiency and Lifetime of the CE-EC Microchip
2.4 Conclusion
Chapter 3
SELF-ASSEMBLED MONOLAYER AS AN ULTRA-THIN INSULATOR FOR ELECTROOSMOTIC FLOW CONTROL
3.1 Introduction
3.2 Experimental Section
3.2.1 Reagents
3.2.2 Electrode Fabrication and SAM Modification
3.2.3 Channel Fabrication and Chip Bonding
3.2.4 Measurement of EOF Velocity
3.2.5 Measurement of Electric Double Layer
3.3 Results and Discussion
3.3.1 Measurement of EOF Mobility
3.3.2 Control efficiency of EOF
3.3.3 Strength of Electric Double Layer
3.3.4 Durability of SAM Insulators
3.4 Conclusion
Chapter 4
ESTIMATING THE THICKNESS OF HYDRATED ULTRATHIN POLY(O-PHENYLENEDIAMINE) FILM BY ATOMIC FORCE MICROSCOPY
4.1 Introduction
4.2. Experimental Section
4.2.1 Electropolymerization of PPD Film
4.2.2 Fabrication of Step-Like Au Electrode
4.2.3 Thickness Estimation from AFM Image
4.2.4 Data Analysis of Force Curve
4.3 Results and Discussion
4.3.1 Fabrication of PPD Membrane
4.3.2 Height Difference from AFM Image
4.3.3 Film Thickness from Force Curve
4.4 Conclusions
Chapter 5
MICROSTRUCTURE AND BIOMECHANICS OF AGE-RELATED COLLAGEN GELS FOR CELL APOPTOSIS
5.1 Introduction
5.2 Experimental Section
5.2.1 Solution for Gelation
5.2.2 Cell Culture
5.2.3 Morphology Observation of Collagen Gels
5.2.4 Shear Test
5.2.5 Compression Test
5.2.6 Data Analysis
5.3 Results and Discussion
5.3.1 Morphology of Cells and Collagen Gels
5.3.2 Mechanical Properties
5.4 Conclusions
Chapter 6
CONCLUSIONS-OVERVIEW AND FUTURE APPLICATIONS
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