利用封裝改良之壓阻式微懸臂樑生物感測器於腹膜炎治療藥物慶大黴素之偵測

Abstract

在近代社會健康意識抬頭，並且邁向高齡化社會的階段，以病人為中心的醫療環境越來越受重視，故遠距醫療照護也就越趨成熟。對於可攜式生醫檢測的需求也日益增大，也代表藥物療劑監測觀念已經受到重視，對於病患當下的身體狀況而調整藥物劑量，不僅增加治療效果也將副作用降至最低。但是目前醫院檢測的流程繁複、耗時且需高費用。本研究欲以CMOS標準製程製造之微懸臂樑生醫感測器，應用於治療腹膜炎藥物慶大黴素的濃度即時偵測。 以商業化CMOS標準製程整合微奈米機電技術(MEMS)及生醫微機電技術(BioMEMS)製作出壓阻式微懸臂樑感測器，並且針對此感測器設計一套標準封裝流程，降低外部雜訊對於感測晶片的訊號影響，並且提高感測系統的良率，使該感測器成功定量量測到小分子藥物慶大黴素。另外，更應用了電場操控的方式，使此微懸臂樑感測器靈敏度提升，成功量測到極低濃度之慶大黴素。 本研究之待測藥物慶大黴素(Gentamicin)與抗體以專一性鍵結的方式鍵結，該鍵結發生所引發的表面應力變化導致壓阻層訊號改變，因此在小分子量測上具有其優勢。實驗量測電場操控造成靈敏度的改變，以未加電場與60伏特電場操控做比較，60伏特電場操控比未加電場操控之訊號提升了2.36倍。最後，成功以60伏特電場操控定量偵測了濃度50 μg/ml、35 μg/ml、20 μg/ml的慶大黴素，分別得到16.77 ppm、9.91 ppm以及4.09 ppm的訊號變化，並且與現行醫院所用的檢測儀器做比較得到趨勢一致的結果。證明了微懸臂樑生醫感測器未來有機會發展成一可定量偵測小分子藥物之生醫感測器。

Adverse drug reaction has received increasing attention recently. For some specific drugs with narrow therapeutic ranges, use of therapeutic drug monitoring (TDM) may reduce the adverse drug reactions for an individual to avoid drug toxicity. Gentamicin, managed in TDM, is a widely used antibiotic drug for patients with renal failure. This drug, composed of a mixture of related gentamicin components and fractions, is used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. In this study, a label-free drug detection of antibiotic gentamicin is made with the CMOS BioMEMS cantilever sensing transduction in a microfluidic channel. The sensor manufacturing technology utilizes 0.35 um 2P4M CMOS process with post MEMS processes of gold metallization and silicon dry etching. Meanwhile, this biosensing mechanism is based on protein-drug recognition, which results in conformational change and thus induced cantilever deflection. In this subproject, to enhance the sensor sensitivity, the CMOS BioMEMS cantilever sensor is firstly developed for the high capture antibody surface density of immobilization with the introduction of device electric field and simultaneous antibody-immobilized monitoring. The enhanced antibody immobilization is expected to significantly increase antibody-drug binding onto the sensing surface, and the simultaneous monitoring assures the device for biosensing detection and biosensor availability. By comparing the change of the signals in no electric field of antibody immobilization, the results showed that the signal of Gentamicin with 60 volt electric field was improved by around 2 folds. At last, the detection of the Gentamicin with concentration of 50 µg/ml、35 µg/ml and 20 µg/ml was achieved by a packaged piezoresistive microcantilever biosensor with the 60 volts of applied electric fields enhancement. The induced change in resistance was measured 16.77 ppm, 9.91 ppm and 4.09 ppm respectively. The results presented an excellent agreement with those in conventional method PETINIA. Detection of gentamicin by the CMOS-MEMS cantilever biosensor provides a promising potential for a portable, palm-sized device in service of patient-centered health care.