臺灣博碩士論文加值系統

苯妥英為近來使用最廣泛的抗癲癇藥物之一，其可藉由降低大腦電訊號的傳遞，抑制大腦不正常活動，進而達到避免癲癇發作的效果。苯妥英的治療劑量範圍很小而難以控制，若治療劑量過高，可能會導致藥物中毒；若劑量太低，則無法產生藥效。因此，須將藥物控制在適當的濃度方能充分發揮治療效果。治療藥物監測是一個觀察血液中苯妥英濃度的重要方法。隨著微機電系統(Micro-electromechanical System，MEMS）技術的進步，可攜帶、靈敏且可靠的壓阻式微懸臂樑生物感測器已被發展出來，其整合微流道系統後，可作為一免螢光標定之檢測平台。
為了能夠在胎牛血清（Fetal Bovine Serum，FBS）這種複雜的體液環境中測量苯妥英的濃度，需先量測苯妥英抗體和藥物的等電點（Isoelectric point，pI），以確定使用的FBS 其pH值應調整的範圍，而根據測量結果選用pH值8.05的50%及100% FBS來檢測100μg/ml苯妥英。使用壓阻式懸臂樑生物感測器時須先固定自組裝單層膜（Self-assembly Monolayer，SAM）和苯妥英抗體，最後加入藥物進行量測。在本研究中，首先測量在去離子（Deionized Water）水環境中，壓阻式微懸臂樑對10μg/ml苯妥英之反應性，得到解離常數（Dissociation Constant，KD）為58 μg/ml。接著測量100μg/ml苯妥英在pH 8.5的50%和100% FBS之反應，結果分別為0.36和0.24 N/m。此外，壓阻懸臂樑生物感測器的實驗結果，與傳統之螢光偏振免疫法（Fluorescence Polarization Immunoassay，FPIA）具有很高的一致性。

Phenytoin is one of the most widely used antiepileptic drugs recently. Its function is to suppress the abnormal brain activity seen in seizure by diminishing electrical conductance. However, its therapeutic dosage range in a circulatory system is very narrow and hard to be controlled. Otherwise, adverse effects may occur if the treatment dosage is too high, or an ineffective treatment may happen if the dosage is too low. So, only appropriate dosage must be given to reach a sufficient remedy. Therapeutic drug monitoring (TDM) is a crucial method to observe the concentration of phenytoin in blood vessel. With advances in micro-electromechanical system technology, a portable, sensitive and reliable piezoresistive-based microcantilever biosensor is fabricated and integrated with a microfluidic system for a label-free fluorescence detection.
In order to measure phenytoin in fetal bovine serum (FBS) which is complex body fluid environment, the isoelectric points (pI) of phenytoin antibody and drug were measured to determine the window of pH value of FBS. As a result, the pH 8.05 of 50% and 100% FBS were selected to detect 100 μg/ml phenytoin. The piezoresistive microcantilever biosensor was utilized by first immobilizing a self-assembly monolayer (SAM) and followed by phenytoin antibody. Next, the biosensor was approved to detect phenytoin drug with 10 μg/ml limit of detection under deionized water environment. The dissociation constant (KD) was 58 μg/ml and the detection linear range was between 10 – 75 μg/ml. The concentration sensitivity was 2.94 х 10-6 (μg/ml)-1. Then, 100μg/ml phenytoin drug was also detected in the 50% and 100% FBS with adjusted pH8.05. Besides, the piezoresistive microcantilever biosensor showed an outstanding experimental agreement with a fluorescence polarization immunoassay (FPIA).

口試委員會審定書 #
Acknowledgement i
中文摘要 iii
ABSTRACT v
CONTENTS vii
LIST OF FIGURES xi
LIST OF TABLES xviii
Chapter 1 Introduction 1
1.1 Preface 1
1.2 Motivation 2
1.3 Literature Review 3
1.3.1 Epilepsy and Antiepileptic Drugs 3
1.3.2 Biochemical Detection by using Microcantilever Biosensor 8
1.4 Overview of the Thesis 13
Chapter 2 Biosensor Technology 15
2.1 A Response of Biological Immune System 16
2.1.1 Antigen 17
2.1.2 Antibody 18
2.1.3 A Binding affinity of antigen and antibody 19
2.2 A Fundamental Principle of Biosensor 21
2.3 Current Immunoassay Technology 23
2.3.1 Competitive Immunoassays 23
2.3.2 Immunometric Assays 24
2.3.2 Indirect Immunoassays 25
2.3.4 Fluorescence Polarization Immunoassays 25
2.3.5 A Label-free Immunoassay based upon Surface Plasmon Resonance 27
2.4 Microcantilever Biosensors 28
2.4.1 An Optical-based Microcantilever Sensor 29
2.4.2 A Piezoresistive-based Microcantilever Sensor 30
2.4.3 The Association Kinetics at Solid-Liquid Interface of Microcantilever 31
2.5 Isoelectric Point of Antibody and Antigen 35
Chapter 3 A Theoretical Analysis of Piezoresistive Microcantilever 39
3.1 A Property of Piezoresistive Material 39
3.1.1 Piezoresistor and Gauge Factor 40
3.1.2 Piezoresistive Response 42
3.1.3 Piezoresistive Theory 45
3.2 Polycrystalline Silicon 45
3.2.1 Electrical Properties 46
3.2.2 Mechanical Properties 47
3.2.3 Fabrication of Polysilicon 48
3.3 The Characteristics of Microcantilever 53
3.3.1 Spring Constant and Natural Frequency 53
3.3.2 A Stress Analysis of Microcantilever 55
3.4 Design Analysis of Piezoresistive Microcantilever 61
3.5 Noise in Piezoresistors 65
3.5.1 Virational Noise 65
3.5.2 Johnson Noise 65
3.5.3 Flicker Noise 66
3.5.4 Total Noise 67
Chapter 4 Design and Fabrication of Piezoresistive Microcantilever Biosensor 68
4.1 Position of Piezoresistive Layer 68
4.2 Design and Dimension of Piezoresistive Microcantilever 69
4.3 A Fabrication of Piezoresistive Microcantilever on Silicon Wafer 70
4.3.1 Thin-film Deposition of Si3N4 and SiO2 Layer 71
4.3.2 Polycrystalline Silicon Deposition and Patterning 73
4.3.3 Gold connecting Wire Depositon and Patterning 74
4.3.4 A Passivation Layer Depositon 75
4.3.5 Gold Pad Releasing 76
4.3.6 Etching Passivation Layer 77
4.3.7 Defining the Shape and Position of Microcantilever 77
4.3.8 Defining the Position of Backside Etching 78
4.3.9 Gold Sensing Layer Deposition 78
4.3.10 KOH Backside Etching 79
4.3.11 Wafer Dicing 82
4.4 Design and Fabrication of Microchannel Substrate 83
4.5 Design and Fabrication of PDMS Substrate 84
4.6 Design and Fabrication of PC Board 87
4.7 Microcantilever Biosensor Device Assembly 89
4.8 Calculation of Neutral Axis and Gauge Factor 90
4.8.1 Neutral Axis Computation 91
4.8.2 Gauge Factor Calculation 92
Chapter 5 Experimental Results and Discussions 95
5.1 Isoelectric Point of Phenytoin Antibody and Drug 95
5.1.1 Methodology 96
5.1.2 Result 96
5.1.2 Discussion 97
5.2 Phenytoin Detection by Piezoresistive Microcantilever Biosensor 98
5.2.1 Methodology 98
5.2.2 Results and Discussions 103
5.3 Phenytoin Detection by Fluorescence Polariztion Immunoassay (FPIA) 112
5.3.1 Methodology 112
5.3.2 Results and Discussions 113
Chapter 6 Conclusions and Future Work 117
5.1 Conclusions 117
5.2 Future Work 118
REFERENCES 119

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