Design and Analysis of a Sample-and-Hold CMOS Electrochemical Sensor for Aptamer-based Therapeutic Drug Monitoring

Jun-Chau Chien; Sam W Baker; H Tom Soh; Amin Arbabian

doi:10.1109/jssc.2020.3020789

Design and Analysis of a Sample-and-Hold CMOS Electrochemical Sensor for Aptamer-based Therapeutic Drug Monitoring

IEEE J Solid-State Circuits. 2020 Nov;55(11):2914-2929. doi: 10.1109/jssc.2020.3020789. Epub 2020 Sep 16.

Authors

Jun-Chau Chien¹, Sam W Baker², H Tom Soh³, Amin Arbabian¹

Affiliations

¹ Department of Electrical Engineering, Stanford University, Stanford, CA 94305 USA.
² Department of Comparative Medicine, Stanford University, Stanford, CA 94305 USA.
³ Department of Radiology and the Department of Electrical Engineering, Stanford University, Stanford, CA 94305 USA.

Abstract

In this paper, we present the design and the analysis of an electrochemical circuit for measuring the concentrations of therapeutic drugs using structure-switching aptamers. Aptamers are single-stranded nucleic acids, whose sequence is selected to exhibit high affinity and specificity toward a molecular target, and change its conformation upon binding. This property, when coupled with a redox reporter and electrochemical detection, enables reagent-free biosensing with a sub-minute temporal resolution for in vivo therapeutic drug monitoring. Specifically, we design a chronoamperometry-based electrochemical circuit that measures the direct changes in the electron transfer (ET) kinetics of a methylene blue reporter conjugated at the distal-end of the aptamer. To overcome the high-frequency noise amplification issue when interfacing with a large-size (> 0.25 mm²) implantable electrode, we present a sample-and-hold (S/H) circuit technique in which the desired electrode potentials are held onto noiseless capacitors during the recording of the redox currents. This allows disconnecting the feedback amplifiers to avoid its noise injection while reducing the total power consumption. A prototype circuit implemented in 65-nm CMOS demonstrates a cell-capacitance-insensitive input-referred noise (IRN) current of 15.2 pA_rms at a 2.5-kHz filtering bandwidth. We tested our system in human whole blood samples and measured the changes in the ET kinetics from the redox-labeled aptamers at different kanamycin concentrations. By employing principal component analysis (PCA) to compensate for the sampling errors, we report a molecular noise floor (at SNR = 1) of 3.1 µM with sub 1-sec acquisition time at 0.22-mW power consumption.

Keywords: Aptamer; CMOS; DNA; aminoglycoside; chronoamperometry; electrochemical detection; electron transfer kinetics; implantable; in vivo monitoring; kanamycin; methylene blue; personalized drug dosing; pharmacokinetics; precision medicine; principal component analysis; sample-and-hold circuit; square-wave voltammetry; wearable.

Abstract

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