Citation: Demirhan, A.; Eksin, E.; Kilic, Y.; Erdem, A. Low-Cost High-Resolution Potentiostat for Electrochemical Detection of Nucleic Acids and Biomolecular Interactions. Micromachines 2022, 13, 1610. https://doi.org/10.3390/ mi13101610 Academic Editors: Ran Peng and Shuailong Zhang Received: 14 August 2022 Accepted: 17 September 2022 Published: 27 September 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). micromachines Article Low-Cost High-Resolution Potentiostat for Electrochemical Detection of Nucleic Acids and Biomolecular Interactions Alper Demirhan 1 , Ece Eksin 2 , Yalin Kilic 3,4 and Arzum Erdem 2, * 1 Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir 35100, Turkey 2 Department of Analytical Chemistry, Faculty of Pharmacy, Ege University, Izmir 35100, Turkey 3 Department of Biomedical Engineering, Izmir University of Economics, Izmir 35330, Turkey 4 Solar Biyoteknoloji Ltd. (SolarBiotec), Bayrakli, Izmir 35530, Turkey * Correspondence: arzum.erdem@ege.edu.tr; Tel.: +90-232-311-5131 Abstract: A handheld USB-powered instrument developed for the electrochemical detection of nucleic acids and biomolecular interactions is presented. The proposed instrument is capable of scanning ± 2.25 V while measuring currents up to ±10 mA, with a minimum current resolution of 6.87 pA. Therefore, it is suitable for nucleic acid sensors, which have high background currents. A low-cost microcontroller with an on-chip 16-bit analog-to-digital converter, 12-bit digital-to-analog converter, and a built-in USB controller were used to miniaturize the system. The offset voltages and gain errors of the analog peripherals were calibrated to obtain a superior performance. Thus, a similar performance to those of the market-leader potentiostats was achieved, but at a fraction of their cost and size. The performance of the application of this proposed architecture was tested successfully and was found to be similar to a leading commercial device through a clinical application in the aspects of the detection of nucleic acids, such as calf thymus ssDNA and dsDNA, and their interactions with a protein (BSA) by using single-use graphite electrodes in combination with the differential pulse voltammetry technique. Keywords: potentiostat; differential pulse voltammetry; point-of-care testing 1. Introduction In the last few decades, various electrochemical sensors have been developed and successfully applied in various fields over the extensive surfaces of transducers and fabri- cating elements. There is an increasing demand for electrochemical sensors because they are rapid, sensitive, selective, easily prepared, and low-cost devices [1]. Much effort has been put into the electrochemical detection of nucleic acids for improving the sensitivity, stability, and reproducibility [2–4]. Voltammetric techniques have the benefits of easy, rapid, and sensitive measurement up to the nano level, showing a promising future in the analyses of various analytes. Differ- ential pulse voltammetry (DPV) and square wave voltammetry (SWV) were utilized, which are sensitive and fast techniques in comparison with the other voltammetric techniques, and the extent of the overoxidation can be controlled in a facile manner. The development of new materials as electrode materials is successfully fulfilling the need of modern electro- chemical technology. In this context, instead of common electrodes, such as carbon-paste electrodes, glassy-carbon electrodes, etc., disposable electrodes, including screen-printed electrodes and pencil-graphite electrodes (PGEs), have been used for voltammetric analyses in recent years. PGEs have the advantages of being inexpensive and readily available, and they have the best mechanical resistance [5]. Nowadays, the on-site measurement demand for economic, field-utilizable, easy-to-fabricate voltammetric sensors has been steadily increasing. In this context, pencil-graphite electrodes are more popular due to their good stability, easy disposability, reproducibility, and uniform quality. Therefore, PGEs Micromachines 2022, 13, 1610. https://doi.org/10.3390/mi13101610 https://www.mdpi.com/journal/micromachines