Wide Dynamic Range CMOS Potentiostat for Amperometric Chemical Sensor

Presented is a single-ended potentiostat topology with a new interface connection between sensor electrodes and potentiostat circuit to avoid deviation of cell voltage and linearly convert the cell current into voltage signal. Additionally, due to the increased harmonic distortion quantity when detecting low-level sensor current, the performance of potentiostat linearity which causes the detectable current and dynamic range to be limited is relatively decreased. Thus, to alleviate these irregularities, a fully-differential potentiostat is designed with a wide output voltage swing compared to single-ended potentiostat. Two proposed potentiostats were implemented using TSMC 0.18-μm CMOS process for biomedical application. Measurement results show that the fully differential potentiostat performs relatively better in terms of linearity when measuring current from 500 pA to 10 uA. Besides, the dynamic range value can reach a value of 86 dB

Oxidase-Coupled Amperometric Glucose and Lactate Sensors with Integrated Electrochemical Actuation System

Unpredictable baseline drift and sensitivity degradation during continuous use are two of the most significant problems of biosensors including the amperometric glucose and lactate sensors. Therefore, the capability of on-demand in situ calibration/diagnosis of biochemical sensors is indispensable for reliable long-term monitoring with minimum attendance. Another limitation of oxidase enzyme-based biosensors is the dependence of enzyme activity on the background oxygen concentration in sample solution. In order to address these issues, the electrolytic generation of oxygen and hydrogen bubbles were utilized 1) to overcome the background oxygen dependence of glucose and lactate sensors and 2) to demonstrate the feasibility of in situ self-calibration of the proposed glucose and lactate sensors. Experimental data assure that the proposed techniques effectively establish the zero calibration value and significantly improve the measurement sensitivity and dynamic range in both glucose and lactate sensors

A fully integrated CMOS microelectrode system for electrochemistry

Electroanalysis has proven to be one of the most widely used technologies for point-of-care devices. Owing to the direct recording of the intrinsic properties of biochemical functions, the field has been involved in the study of biology since electrochemistry’s conception in the 1800’s. With the advent of microelectronics, humanity has welcomed self-monitoring portable devices such as the glucose sensor in its everyday routine. The sensitivity of amperometry/ voltammetry has been enhanced by the use of microelectrodes. Their arrangement into microelectrode arrays (MEAs) took a step forward into sensing biomarkers, DNA and pathogens on a multitude of sites. Integrating these devices and their operating circuits on CMOS monolithically miniaturised these systems even more, improved the noise response and achieved parallel data collection. Including microfluidics on this type of devices has led to the birth of the Lab-on-a-Chip technology. Despite the technology’s inclusion in many bioanalytical instruments there is still room for enhancing its capabilities and application possibilities. Even though research has been conducted on the selective preparation of microelectrodes with different materials in a CMOS MEA to sense several biomarkers, limited effort has been demonstrated on improving the parallel electroanalytical capabilities of these devices. Living and chemical materials have a tendency to alter their composition over time. Therefore analysing a biochemical sample using as many electroanalytical methods as possible simultaneously could offer a more complete diagnostic snapshot. This thesis describes the development of a CMOS Lab-on-a-Chip device comprised of many electrochemical cells, capable of performing simultaneous amperometric/voltammetric measurements in the same fluidic chamber. The chip is named an electrochemical cell microarray (ECM) and it contains a MEA controlled by independent integrated potentiostats. The key stages in this work were: to investigate techniques for the electrochemical cell isolation through simulations; to design and implement a CMOS ECM ASIC; to prepare the CMOS chip for use in an electrochemical environment and encapsulate it to work with liquids; to test and characterise the CMOS chip housed in an experimental system; and to make parallel measurements by applying different simultaneous electroanalytical methods. It is envisaged that results from the system could be combined with multivariate analysis to describe a molecular profile rather than only concentration levels. Simulations to determine the microelectrode structure and the potentiostat design, capable of constructing isolated electrochemical cells, were made using the Cadence CAD software package. The electrochemical environment and the microelectrode structure were modelled using a netlist of resistors and capacitors. The netlist was introduced in Cadence and it was simulated with potentiostat designs to produce 3-D potential distribution and electric field intensity maps of the chemical volume. The combination of a coaxial microelectrode structure and a fully differential potentiostat was found to result in independent electrochemical cells isolated from each other. A 4 x 4 integrated ECM controlled by on-chip fully differential potentiostats and made up by a 16 × 16 working electrode MEA (laid out with the coaxial structure) was designed in an unmodified 0.35 μm CMOS process. The working electrodes were connected to a circuit capable of multiplexing them along a voltammetric measurement, maintaining their diffusion layers during stand-by time. Two readout methods were integrated, a simple resistor for an analogue readout and a discrete time digital current-to-frequency charge-sensitive amplifier. Working electrodes were designed with a 20 μm side length while the counter and reference electrodes had an 11 μm width. The microelectrodes were designed using the aluminium top metal layer of the CMOS process. The chips were received from the foundry unmodified and passivated, thus they were post-process fabricated with photolithographic processes. The passivation layer had to be thinned over the MEA and completely removed on top of the microelectrodes. The openings were made 25 % smaller than the top metal layer electrode size to ensure a full coverage of the easily corroded Al metal. Two batches of chips were prepared, one with biocompatible Au on all the microelectrodes and one altered with Pd on the counter and Ag on the reference electrode. The chips were packaged on ceramic pin grid array packages and encapsulated using chemically resistant materials. Electroplating was verified to deposit Au with increased roughness on the microelectrodes and a cleaning step was performed prior to electrochemical experiments. An experimental setup containing a PCB, a PXIe system by National Instruments, and software programs coded for use with the ECM was prepared. The programs were prepared to conduct various voltammetric and amperometric methods as well as to analyse the results. The first batch of post-processed encapsulated chips was used for characterisation and experimental measurements. The on-chip potentiostat was verified to perform alike a commercial potentiostat, tested with microelectrode samples prepared to mimic the coaxial structure of the ECM. The on-chip potentiostat’s fully differential design achieved a high 5.2 V potential window range for a CMOS device. An experiment was also devised and a 12.3 % cell-to-cell electrochemical cross-talk was found. The system was characterised with a 150 kHz bandwidth enabling fast-scan cyclic voltammetry(CV) experiments to be performed. A relatively high 1.39 nA limit-of-detection was recorded compared to other CMOS MEAs, which is however adequate for possible applications of the ECM. Due to lack of a current polarity output the digital current readout was only eligible for amperometric measurements, thus the analogue readout was used for the rest of the measurements. The capability of the ECM system to perform independent parallel electroanalytical measurements was demonstrated with 3 different experimental techniques. The first one was a new voltammetric technique made possible by the ECM’s unique characteristics. The technique was named multiplexed cyclic voltammetry and it increased the acquisition speed of a voltammogram by a parallel potential scan on all the electrochemical cells. The second technique measured a chemical solution with 5 mM of ferrocene with constant potential amperometry, staircase cyclic voltammetry, normal pulse voltammetry, and differential pulse voltammetry simultaneously on different electrochemical cells. Lastly, a chemical solution with 2 analytes (ferrocene and decamethylferrocene) was prepared and they were sensed separately with constant potential amperometry and staircase cyclic voltammetry on different cells. The potential settings of each electrochemical cell were adjusted to detect its respective analyte

Study on Integrated Redox Image Sensor Employing Square Wave Voltammetry

豊橋技術科学大

Development and evaluation of a calibration free exhaustive coulometric detection system for remote sensing.

Most quantitative analytical measurement techniques require calibration to correlate signal with the quantity of analyte. The purpose of this study was to employ exhaustive coulometry, an implementation of coulometric analysis in a stopped-flow, fixed-volume, thin-layer cell, to attain calibration-free measurements that would directly benefit intervention-free analysis systems designed for remote deployment. This technique capitalizes on the short diffusion lengths (\u3c 100 µm) to dramatically reduce the time for analysis (\u3c 30 sec). For this work, a thin-layer fluidic cell was designed in software, fabricated via CNC machining, and evaluated using Ferri/Ferrocyanide {Fe(CN)63-/4-} as a model analyte. The 2 µL fixed volume incorporated an oval, 8mm by 4 mm, thin-film gold electrode sensor with an integrated Ag|AgCl pseudo-reference electrode. The flow cell area matched the shape of the sensor, with a volume set by the thickness of a laser-cut silicone rubber gasket (~80 µm). A semi-permeable membrane isolated the working electrode and counter electrode chambers to prevent analyte diffusion. A miniaturized custom potentiostat was designed and built to measure reaction currents ranging from 10 mA to 0.1 nA. Software was developed to perform step voltammetry as well as cyclic voltammetry analysis for verifying electrode condition and optimal redox potential levels. Experimentally determined oxidation/reduction potentials of -100 mV and 400 mV, respectively, were applied to the working electrode for sample concentrations ranging from 50 µM to 10,000 µM. The current generated during the reactions was recorded and the total charge captured at each concentration was obtained by integrating the amperograms. When compared to the expected charge for a 2 µL sample, the total charge vs. concentration plots displayed a near perfect linearity over the full concentration range, and the expected charge (100 % converted) was reached within 20 seconds. The reaction currents ideally should have decayed to background levels, but exhibited constant offset values slightly larger than the background signal, a phenomenon assumed to be lingering residual flow from sample injection. After adding rigid tubing and external valves, the thin-layer cell was shown to remain within 6% of the theoretical charge after 200 seconds. Continued development of this system will offer the possibility of remote, calibration-free determinations of real-world analytes such mercury and lead

Electrochemical Plug-and-Power e-readers for Point-of-Care Applications

Point-of-Care diagnostic tests enable monitor health conditions and obtain fast results close to the patient, reducing medical costs, and allowing the control of infectious outbreaks. The interest in developing Point-of-Care devices is increasing due to they are suitable for a wide variety of applications. This doctoral thesis focuses on the development of Plug-and-Power electronic readers (e- readers) for electrochemical detections and the demonstration of their possibilities as Point-of-Care diagnostic testing. The solutions proposed in this study make it possible to improve Point-of-Care tests whose premises are laboratory decentralization, personalized medicine, rapid diagnosis, and improvement of patient care. Developed electronic readers can be powered from a conventional system, such as a USB port or a lithium battery, or can be defined as self-powered systems, capable of extracting energy from alternative energy sources, such as fuel cells, defining Plug-and-Power systems. The designed electrochemical detection devices in this thesis are based on low-power consumption electronic instrumentation circuits. These circuits are capable of controlling the sensing element, measuring its response, and representing the result quantitatively. The implemented devices can work with both electrochemical sensors and fuel cells. Furthermore, it is possible to adapt its measurement range, enabling its use in a wide variety of applications. Thanks to their reduced energy consumption, some of these developments can be defined as self-powered platforms able to operate only with the energy extracted from the biological sample, which in turn is monitored. These devices are easy-to-use and plug-and-play, enabling those unskilled individuals to carry out tests after prior training. Moreover, thanks to their user-friendly interface, results are clear and easy to understand. This doctoral dissertation is presented as an article compendium and composed of three publications detailed in chronological order of publication. The first contribution describes an innovative portable Point-of-Care device able to provide a quantitative result of the glucose concentration of a sample. The proposed system combines an e-reader and a disposable device based on two elements: a glucose paper-based power source, and a glucose fuel cell-based sensor. The battery-less e-reader extracts the energy from the disposable unit, acquires the signal, processes it, and shows the glucose concentration on a numerical display. Due to low-power consumption of the e-reader, the whole electronic system can operate only with the energy extracted from the disposable element. Furthermore, the proposed system minimizes the user interaction, which only must deposit the sample on the strip and wait a few seconds to see the test result. The second publication validates the e-reader in other scenarios following two approaches: using fuel cells as a power element, and as a dual powering and sensing element. The device was tested with glucose, urine, methanol, and ethanol fuel cells and electrochemical sensors in order to show the adaptability of this versatile concept to a wide variety of fields beyond clinical diagnostics, such as veterinary or environmental fields. The third study presents a low-cost, miniaturized, and customizable electronic reader for amperometric detections. The USB-powered portable device is composed of a full- custom electronic board for signal acquisition, and software, which controls the systems, represents and saves the results. In this study, the performance of the device was compared against three commercial potentiostats, showing comparable results to those obtained using three commercial systems, which were significantly more expensive. As proof of concept, the system was validated by detecting horseradish peroxidase samples. However, it could be easily extended its scope and measure other types of analytes or biological matrices since it can be easily adapted to detect currents a wide range of currents.Las pruebas de diagnostico Point-of-Care permiten monitorizar las condiciones de salud y obtener resultados rápidos cerca del paciente, reduciendo los costes médicos y permitiendo controlar brotes infecciosos. El interés por desarrollar dispositivos de Point- of-Care está aumentando debido a que son aplicables a una amplia variedad de aplicaciones. Esta tesis doctoral se centra en el desarrollo de lectores electrónicos (e-readers) Plug-and- Power para detecciones electroquímicas y la demostración de sus posibilidades como pruebas de diagnóstico de punto de atención (Point-of-Care). Las soluciones propuestas en este trabajo permiten mejorar las pruebas Point-of-Care, cuyas premisas son la descentralización de laboratorio, la medicina personalizada, el diagnóstico rápido y la mejora de la atención al paciente. Los lectores electrónicos desarrollados pueden ser alimentados desde un sistema convencional, como puede ser un puerto USB o una batería de litio, o definirse como sistemas autoalimentados, capaces de extraen energía de fuentes alternativas de energía, como celdas de combustible (fuel cells), definiendo así sistemas Plug-and-Power. Los dispositivos de detección electroquímica diseñados se basan en circuitos de instrumentación electrónica de bajo consumo. Estos circuitos son capaces controlar el elemento de sensado, medir su respuesta y representar el resultado de forma cuantitativa. Los dispositivos implementados pueden trabajar tanto con sensores electroquímicos como con fuel cells. Además, es posible adaptar su rango de medida, permitiendo su utilización en una amplia variedad de aplicaciones. Gracias a su reducido consumo de energía, algunos de estos desarrollos pueden definirse como plataformas autoalimentadas capaces de operar solo con la energía extraída de la muestra biológica, que a su vez es monitorizada. Estas plataformas electrónicas son fáciles de usar y Plug-and-Play, permitiendo que personas no cualificadas puedan utilizarlas después de un previo entrenamiento. Además, gracias a su interfaz fácil de usar, los resultados son claros y fáciles de interpretar