A CMOS MEMS-based Membrane-Bridge Nanomechanical Sensor for Small Molecule Detection

Yi-Kuang Yen,Chao-Yuan Chiu

doi:10.1038/s41598-020-60057-8

Abstract

Small molecule compounds are necessary to detect with high sensitivity since they may cause a strong effect on the human body even in small concentrations. But existing methods used to evaluate small molecules in blood are inconvenient, costly, time-consuming, and do not allow for portable usage. In response to these shortcomings, we introduce a complementary metal-oxide-semiconductor bio-microelectromechanical system (CMOS BioMEMS) based piezoresistive membrane-bridge (MB) sensor for detecting small molecule (phenytoin) concentrations as the demonstration. Phenytoin is one of anticonvulsant drugs licensed for the management of seizures, which has a narrow therapeutic window hence a level of concentration monitoring was needed. The MB sensor was designed to enhance the structural stability and increase the sensitivity, which its signal response increased 2-fold higher than that of the microcantilever-based sensor. The MB sensor was used to detect phenytoin in different concentrations from 5 to 100 μg/mL. The limit of detection of the sensor was 4.06 ± 0.15 μg/mL and the linear detection range was 5–100 μg/mL, which was within the therapeutic range of phenytoin concentration (10–20 μg/mL). Furthermore, the MB sensor was integrated with an on-chip thermal effect eliminating modus and a reaction tank on a compact chip carrier for disposable utilization. The required amount of sample solution was only 10 μL and the response time of the sensor was about 25 minutes. The nano-mechanical MB sensing method with thermal effect compensation is specific, sensitive, robust, affordable and well reproducible; it is, therefore, an appropriate candidate for detecting small molecules.

Highlights

Microcantilever (MCL) -based biosensor is one of the label-free molecular sensing methods which has been developed and applied in many fields, such as clinical diagnostics[1,2], homeland security[3], environmental monitoring[4,5] and small molecule detection for therapeutic drug monitoring (TDM) purpose[6,7,8]
The gauge factor represents the ability of the MB sensor to convert mechanical signals into electronic signals
The gauge factor can be determined to be 21 which was higher than the value of MCL sensor we developed in previous works[17]

Summary

Introduction

Microcantilever (MCL) -based biosensor is one of the label-free molecular sensing methods which has been developed and applied in many fields, such as clinical diagnostics[1,2], homeland security[3], environmental monitoring[4,5] and small molecule detection for therapeutic drug monitoring (TDM) purpose[6,7,8]. The piezoresistive MCL biosensing chips fabricated by using MEMS process was employed for drug concentration monitoring of valproic acid[6] and phenytoin[7] Those works demonstrated enough drug detection ranges for TDM, device sensitivities were limited and additional temperature control systems were needed, which cannot satisfy the demands of personal diagnostic devices. We developed a CMOS MEMS-based membrane-bridge (MB) nanomechanical biosensor for applying to detect small molecule phenytoin as verification of the feasibility and sensitivity of the sensor. The MB nanomechanical biosensor with an on-chip real-time thermal effect eliminating method[16] was operated in static mode This method enhanced the sensitivity of the sensor, and reduced the overall detection system. The MB sensor was demonstrated its capability for phenytoin detection and shows the superior sensitivity than the traditional MEMS based piezoresistive MCL sensor, which may provide a label-free, rapid, sensitive, reliable and miniaturized device for small molecules detection

Methods

Results

Conclusion