CMOS標準製程之微懸臂樑於抗癲癇藥物丙戊酸之研究

Abstract

本研究證明了以CMOS MEMS製程之壓阻式微懸臂量晶片，結合電場操控的訊號加強，成就一可攜式、可定量之小分子藥物感測器。 現行對於長期施打需療劑監測(Therapeutic Drug Monitoring)需要患者透過定期回診抽血，而為實現居家照護本研究欲打造出一具可攜式、可定量之潛力的感測晶片，用以改善此狀況。現行諸多可定量之生物感測器，其工作機制不易於量測小分子藥物。惟壓阻式微懸臂樑感測機制係透過蛋白質構型變化，因其不必受制於待測物的質量限制，較利於偵測小分子藥物。透過國家晶片系統設計中心下線的晶片，以台積電MEMS製程製造之含表面金箔之生醫感測器，結合微流道系統封裝，加入導電玻璃作為電場操控之用。該導電玻璃可與經設計後的微懸臂樑金屬層形成電場，該電場對於帶電的蛋白質具有導引作用使其更易佈植於感測表面。 以抗癲癇藥物-丙戊酸(Valproic acid)作為抗原，透過抗體以專一性鍵結的方式捕捉丙戊酸分子，該鍵結發生引發的表面應力變化致使壓阻層訊號改變，在療劑監測範圍中可定量感測，50 μg/mL得6.87 ppm之訊號、75 μg/mL得10.03 ppm之訊號及100 μg/mL得12.68 ppm之訊號，而施加30 Volt的電場操控，感測訊號可提升1.84倍。 本研究不僅驗證了該微懸臂樑可用於量測丙戊酸，另外更驗證了結合電場操控的技術於該微懸臂樑，對其感測訊號有顯著提升，這項結果對於量測更小濃度的藥物具其意義。

This study demonstrates a standard CMOS-MEMS piezoresistive microcantilever biosensor with electric field enhancement of capture antibody immobilization to be a portable, real-time and quantitative biosensor for drug detection. For patients under the therapeutic drug monitoring that manages drug dosage of very narrow concentration in blood, this device shows a potential of fast turn-around-time, low cost and efficient management for point-of-care applications or personal diagnosis. The microcantilever biosensor based on immobilized antibody conformation change for specific recognition is able to yield minute induced surface stresses of cantilever deflection. Especially, this biosensor exhibits unique advantages on small-molecule detection over available label-free biosensors. Meanwhile, the microcantilever sensors were fabricated by tsmc 0.35 μm 2P4M CMOS-MEMS process with an additional gold layer coating on top of the sensing surface. The sensors were packaged into a micro-channel and its associated fluidic system. The ITO (Indium tin oxide) was embedded within the micro-channel system as to apply an electric field in a capture protein immobilized processs. Valproic acid has long been used as an antiepileptic medication, which is administered through therapeutic drug monitoring and has a narrow therapeutic dosage range of 50–100 μg/mL in blood or serum for drug effectiveness. The measurement of the antiepileptic drug Valproic acid used a single free-standing, electrical detection microcantilever biosensor in a thermally controlled system. This study showed the results of response electrical signal and associated surface stresses with respect to the valproic acid drug concentrations of 50 μg/mL, 75 μg/mL, 100 μg/mL. With the 30 volts of applied electric fields, the study achieved the valproic acid drug detection by 1.84 folds of signal response increase over a regular measurement. This study shows the capability of microcantilever biosensors for detection of small-molecule drug Valproic acid. With an introduction of the electric field for enhanced capture protein immobilization, the standard CMOS-MEMS piezoresistive microcantilever biosensor exhibits efficient use of small-molecule drug detection for potential personal diagnostics.