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研究生:李忠憲
研究生(外文):Chung-Hsien Li
論文名稱:具熱補償設計之標準CMOS製程微懸臂樑於抗癲癇藥物丙戊酸之量測
論文名稱(外文):Detection of Anti-epileptic Drug Valproic Acid By Thermally Self-Compensated CMOS BioMEMS Microcantilever
指導教授:黃榮山
指導教授(外文):Long-Sun Huang
口試委員:沈弘俊陳俊杉
口試委員(外文):Horn-Jiunn SheenChuin-shan Chen
口試日期:2014-07-10
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:應用力學研究所
學門:工程學門
學類:機械工程學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:99
中文關鍵詞:熱效應壓阻式微懸臂樑CMOS BioMEMS丙戊酸
外文關鍵詞:Thermal effectPiezoresistive MicrocantileverCMOS BioMEMSPETINIAValproic acid
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近年來由於國內人口趨於高齡化,在預防勝於治療的觀點下,生醫檢測晶片應用於居家照護自我檢測的需求也就與日俱增。然而,鑒於目前普及的免螢光標定SPR生物感測器不適用於小分子生物量測,且醫院的傳統檢測設備成本昂貴,因此,本研究建立於商業化標準製程TSMC 0.35μm 2P4M CMOS之技術平台下,搭配BioMEMS後製程及MEMS後製程發展一可應用於小分子藥物量測的低成本、可攜式、微型化、高靈敏度、免螢光標記及能快速即時檢測的微懸臂樑感測晶片,並期未來能透過相容性高的標準CMOS製程整合後端電路,於感測晶片上實現多項功能,成為一跨領域的整合系統,以取代傳統高成本的大型檢測設備。
此外,壓阻式微懸臂樑易受溫度效應影響,僅1°C變化便能屏蔽量測到的生物訊號,因此,本論文針對標準CMOS製程製作之微懸臂樑感測晶片的熱效應予以研究,以建立一具熱效應自補償系統的微懸臂樑感測元件,而能應用於生醫檢測,以符合檢驗上之精確量測需求,並提高診斷與治療的便利性。然而,實驗結果顯示,微懸臂樑於室溫下及交變的溫度環境中量測時,可透過熱補償系統將溫度效應自我扣除。
最後,具有熱補償系統的標準CMOS製程之壓阻式微懸臂樑感測器,應用於小分子的抗癲癇藥物丙戊酸之濃度監測中,可成功定量分析出50μg/ml、75μg/ml及100μg/ml的訊號反應,此外,將相同樣本以醫院現行檢測的方式作驗證,得到良好的一致性,說明此晶片於未來取代傳統檢測儀器的前瞻性。


With the growing interest and fast development in bio-nanotechnology, biosensing tools have been moving towards miniaturization, high sensitivity, portability and wireless networking. In this study, piezoresistive microcantilever biosensor is made with the foundry process by TSMC. The sensor manufacturing technology utilizes 0.35 um 2P4M CMOS process with post MEMS processes of silicon dry etching, and with post BioMEMS process of gold metallization. Meanwhile, this biosensing mechanism is based on protein-drug recognition, which results in conformational change and thus induced cantilever deflection.
However, thermal effect is the most important issue when it comes to detection of biomarker by piezoresistive microcantilever. Only 1 celcius degree change may override the real bio signal. As a result, the self-compensation system of thermal effect is developed in this study. In this thermal effect of the cantilever, the temperature coefficient of resistance (TCR) effect was about 7 times larger than the bimorph effect. Finally, thermal effect of a CMOS BioMEMS microcantilever under room temperature and fluctuated temperature environment can be eliminated by the thermal compensation system.
The detection of the anti-epileptic drug valproic acid concentration of 50 μg/ml、75 μg/ml and 100 μg/ml was achieved by a thermally compensated CMOS BioMEMS microcantilever. Meanwhile, the comparison and limitation result to the conventional method PETINIA was conducted. The values give a promising result for microcantilever biosensor to be further developed on the wireless point-of-care system.


誌謝 I
摘要 II
ABSTRACT III
目錄 IV
表目錄 VII
圖目錄 VIII
符號對照表 XII
第一章 緒論 1
1.1前言 1
1.2研究動機及目的 2
1.3文獻回顧 3
1.3.1 微懸臂樑感測器 3
1.3.3應用CMOS製程之微懸臂樑感測器 9
1.3.4 微懸臂樑於熱效應補償之研究 11
1.3.4 癲癇症與抗癲癇藥物 12
1-4 論文大綱 19
第二章 生物感測器 20
2.1生物的免疫反應 20
2.1.1抗體 21
2.1.2抗體-抗原辨識 22
2.2生物感測器之基本原理 25
2.3 辨識分子層的固定化技術 26
2.4表面電漿共振生物感測器(SPR) 28
2.5 粒子增強型比濁抑制免疫分析法 29
2.6 微懸臂樑生物感測器 31
第三章 壓阻式微懸臂樑之特性分析與量測 35
3.1基本微懸臂樑理論 35
3.2壓阻材料特性分析 37
3.2.1壓阻因子 38
3.2.2壓阻效應與應力分析 40
3.3微懸臂樑尺寸分析 47
3.4雜訊分析 50
3.5 CMOS壓阻式微懸臂樑的機電特性量測 51
3.6 CMOS壓阻式微懸臂樑的機械特性量測 55
第四章 CMOS BioMEMS壓阻式微懸臂樑設計製作 57
4.1 CMOS BioMEMS壓阻式微懸臂樑設計 57
4.2 CMOS BioMEMS壓阻式微懸臂樑製作 59
4.3電路板設計與製作 61
4.4微流道系統設計與製作 62
4.4.1微流道基板製作 62
4.4.2微流道上蓋製作 63
4.5 CMOS BioMEMS壓阻式微懸臂樑感測系統之封裝 64
第五章 溫度效應之量測、消除與應用 66
5.1溫度對壓阻的影響探討 66
5.1.1壓阻熱效應 66
5.1.2雙膜效應 67
5.2溫度效應之影響量測 75
5.3熱效應自補償系統 78
5.3.1實驗架構與方法 79
5.3.2實驗結果 82
5.4小分子抗癲癇藥物丙戊酸之量測 84
5.4.1實驗架構與方法 85
5.4.2實驗結果 88
第六章 結論與未來展望 92
6.1結論 92
6.2未來展望 93
參考文獻(References) 94


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