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

Detection of Anti-epileptic Drug Valproic Acid By Thermally Self-Compensated CMOS BioMEMS Microcantilever

李忠憲(Chung-Hsien Li)

指導教授 ： 黃榮山

國立臺灣大學/工學院/應用力學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.00226

摘要

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。

關鍵字

熱效應 ； 壓阻式微懸臂樑 ； CMOS BioMEMS ； 丙戊酸

並列摘要

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.

並列關鍵字

Thermal effect ； Piezoresistive Microcantilever ； CMOS BioMEMS ； PETINIA ； Valproic acid

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