CMOS-BioMEMS壓阻式微懸臂樑生物感測器於 腹膜炎治療藥物慶大黴素檢測之研究

Abstract

研究證實以CMOS MEMS製程之壓阻式微懸臂樑生醫感測器結合電場操控技術，達成低成本、可攜式、微型化、微量檢體且可定量之小分子藥物感測器。根據實驗結果，壓阻式微懸臂樑生物感測器可針對腹膜炎治療藥物慶大黴素進行定量分析，且此定量分析之線性區域包含慶大黴素有效治療濃度範圍，因此壓阻式微懸臂樑生醫感測器是有絕對的潛力供需要執行療劑監測之病人進行即時檢測慶大黴素在血液中的濃度。 近年來，社會的健康意識逐漸抬頭，諸多檢測逐漸被重視，如食安、環境工程、化工藥劑用量等等，因此對於能夠可攜式且即時檢測之感測器的需求越來越多。其中，以病人為中心的醫療環境也逐漸被重視，所以遠距照護也逐年成長，要達成遠距照護的願景，科技的支援是無可避免的。因此對於可攜式且即時檢測之生醫感測器的需求日益大增，醫生對於病人在藥物的使用上非常的關注，故療劑監測為醫生重視之參考依據，對於病患當下的身體狀況調整藥物的劑量，不僅增加療效外更能避免副作用的發生。但現行醫院儀器的檢測流程繁瑣、耗時，因此在非即時檢測的情況下，醫生容易對病人造成誤判。而本研究以CMOS MEMS製程之壓阻式微懸臂樑生醫感測器應用於治療腹膜炎藥物慶大黴素之檢測。 以台積電已商業化CMOS MEMS 0.35標準製程搭配微機電(MEMS)之後製程和生醫微機電技術(BioMEMS)製作出壓阻式微懸臂樑生醫感測器，並且以低成本的方式針對感測器進行封裝。使之成功定量量測小分子藥物慶大黴素，另外為了提升感測器的靈敏度，更應用了電場操控技術，搭配小分子等電位點之調整，成功增加壓阻式微懸臂樑生醫感測器之靈敏度，同時量測到更低濃度之慶大黴素 本研究之待測藥物慶大黴素和抗體以專一性鍵結的方式鍵結，其鍵結後分子構形的變化在微懸臂樑表面產生表面應力，導致壓阻層訊號發生改變，因此在量測小分子上具有其優勢。實驗上得知在60 V的電場操控比無電場操控之訊號提升量為，於濃度為20 μg/mL的慶大黴素為2.195倍，於濃度為35 μg/mL的慶大黴素為1.954倍，於濃度為50 μg/mL的慶大黴素為，因此在60 V的電場操控下相較未加電場操控平均能夠提升1.823倍的訊號量。最後以60 V定量分析，並且得到微懸臂樑生醫感測器之飽和曲線，其檢測濃度分別為10 μg/mL、20 μg/mL、35 μg/mL、50 μg/mL、150 μg/mL、200 μg/mL，對應其變化量分別為5.030 mΩ、20.912 mΩ、40.854 mΩ、62.087 mΩ、125.796 mΩ、123.391 mΩ，故可知濃度在10 ~50 μg/mL做圖可得到一線性區間，此線性區間便可被療劑監測所用。本研究壓阻式微懸臂樑生醫感測晶片之可偵測最小濃度(LOD)為17.57 μg/mL，可定量最小濃度(LOQ)為23.885 μg/mL，可定量濃度區間為23.885 μg/mL ~50 μg/mL，而慶大黴素在血液中的有效濃度範圍有落在壓阻式微懸臂樑感測晶片之可定量濃度區間內，因此證實本研究之壓阻式微懸臂樑生醫感測器在量測小分子藥物上具有一定的潛力且擁有能針對具有有效治療濃度範圍的藥物進行定量分析之能力。

The study prove that piezoresistive microcantilever can accomplish the low cost, portable, minimization sample and quantitative analysis the small molecule drug which is made by CMOS MEMS process and integrate the technique of electric field at the same time. Accroding to the experiment ruslt, the quantitative analysis curve contain the effective treatment range of Gentamicin which is measured by piezoresistive microcantilever. So piezoresistive microcantilever have the great potential to implement the TDM for patient to monitor the concentration of Gentamicin in blood. In rescent year, there is the growing number of the need of the sensor which can portable and timely detection for lots of detection had been emphasized. The surroundings of medical treatment have being taken seriously. So the need of home care growing year by year. The growing number of the need of protable detection sensor is to fulfill the home care. 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. The piezoresistive microcantilever is made by TSMC CMOS MEMS 0.35 process which integrate the MEMS and BioMEMS technique and package by low cost. The piezoresistive microcantilever can detect the small molecule drug and promote the sensitivity by control the electric field to detect more lower concentration By comparing the change of the signals in no electric field of antibody immobilization and 60 volt electric field of antibody immobilization, the result showed that the average singal promote 1.8 times. The quantitative analysis after 60 volt electric field of antibody immobilization show that the different concentration of Gentamicin which contain 10 μg/mL、20 μg/mL、35 μg/mL、50 μg/mL、150 μg/mL、200 μg/mL got the signal indivudlly．5.030 mΩ、20.912 mΩ、40.854 mΩ、62.087 mΩ、125.796 mΩ、123.391 mΩ. according to the result of Gentamicin, it can obtain a quantitative analysis curve of TDM patient.