An integrated circuit to enable electrodeposition and amperometric readout of sensing electrodes

This paper presents the design of an integrated circuit (IC) for (i) electrochemical deposition of sensor layers on the on-chip pad openings to form sensing electrodes, and (ii) amperometric readout of electrochemical sensors. The IC consists of two main circuit blocks: a Beta-multiplier based current reference for galvanostatic electrodeposition, and a switch-capacitor based amperometric readout circuit. The circuits are designed and simulated in a 180-nm CMOS process. The reference circuit generates a stable current of 99 nA with a temperature coefficient of 141 ppm/°C at best and 170 ppm/°C on average (across corners) over a supply voltage range of 1.2-2.4 V, and a line regulation of 0.7 %/V. The readout circuit measures current within pm 2 mu mathrmA with 99.9% linearity and a minimum integrated input-referred noise of 0.88 pA

Real-Time Telemetry System for Amperometric and Potentiometric Electrochemical Sensors

A real-time telemetry system, which consists of readout circuits, an analog-to-digital converter (ADC), a microcontroller unit (MCU), a graphical user interface (GUI), and a radio frequency (RF) transceiver, is proposed for amperometric and potentiometric electrochemical sensors. By integrating the proposed system with the electrochemical sensors, analyte detection can be conveniently performed. The data is displayed in real-time on a GUI and optionally uploaded to a database via the Internet, allowing it to be accessed remotely. An MCU was implemented using a field programmable gate array (FPGA) to filter noise, transmit data, and provide control over peripheral devices to reduce power consumption, which in sleep mode is 70 mW lower than in operating mode. The readout circuits, which were implemented in the TSMC 0.18-μm CMOS process, include a potentiostat and an instrumentation amplifier (IA). The measurement results show that the proposed potentiostat has a detectable current range of 1 nA to 100 μA, and linearity with an R2 value of 0.99998 in each measured current range. The proposed IA has a common-mode rejection ratio (CMRR) greater than 90 dB. The proposed system was integrated with a potentiometric pH sensor and an amperometric nitrite sensor for in vitro experiments. The proposed system has high linearity (an R2 value greater than 0.99 was obtained in each experiment), a small size of 5.6 cm × 8.7 cm, high portability, and high integration

IEEE Trans Biomed Circuits Syst

Airborne pollutants are a leading cause of illness and mortality globally. Electrochemical gas sensors show great promise for personal air quality monitoring to address this worldwide health crisis. However, implementing miniaturized arrays of such sensors demands high performance instrumentation circuits that simultaneously meet challenging power, area, sensitivity, noise and dynamic range goals. This paper presents a new multi-channel CMOS amperometric ADC featuring pixel-level architecture for gas sensor arrays. The circuit combines digital modulation of input currents and an incremental \uce\ua3\ue2\u2c6\u2020 ADC to achieve wide dynamic range and high sensitivity with very high power efficiency and compact size. Fabricated in 0.5 [Formula: see text] CMOS, the circuit was measured to have 164 dB cross-scale dynamic range, 100 fA sensitivity while consuming only 241 [Formula: see text] and 0.157 [Formula: see text] active area per channel. Electrochemical experiments with liquid and gas targets demonstrate the circuit's real-time response to a wide range of analyte concentrations.R01 ES022302/ES/NIEHS NIH HHS/United StatesR01 OH009644/OH/NIOSH CDC HHS/United States2017-08-01T00:00:00Z27352395PMC505675

Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Portable Bio-Devices: Design of Electrochemical Instruments from Miniaturized to Implantable Devices

The integration of biosensors and electronic technologies allows the development of biomedical systems able to diagnose and monitoring pathologies by detecting specific biomarkers. The chapter presents the main modules involved in the development of such devices, generically represented in Fig. 1, and focuses its attention on the essential components of these systems to address questions such as: how is the device powered? How does it communicate the measured data? What kind of sensors could be used?, and What kinds of electronics are used

Integrated circuit & system design for concurrent amperometric and potentiometric wireless electrochemical sensing

Complementary Metal-Oxide-Semiconductor (CMOS) biosensor platforms have steadily grown in healthcare and commerial applications. This technology has shown potential in the field of commercial wearable technology, where CMOS sensors aid the development of miniaturised sensors for an improved cost of production and response time. The possibility of utilising wireless power and data transmission techniques for CMOS also allows for the monolithic integration of the communication, power and sensing onto a single chip, which greatly simplifies the post-processing and improves the efficiency of data collection. The ability to concurrently utilise potentiometry and amperometry as an electrochemical technique is explored in this thesis. Potentiometry and amperometry are two of the most common transduction mechanisms for electrochemistry, with their own advantages and disadvantages. Concurrently applying both techniques will allow for real-time calibration of background pH and for improved accuracy of readings. To date, developing circuits for concurrently sensing potentiometry and amperometry has not been explored in the literature. This thesis investigates the possibility of utilising CMOS sensors for wireless potentiometric and amperometric electrochemical sensing. To start with, a review of potentiometry and amperometry is evaluated to understand the key factors behind their operation. A new configuration is proposed whereby the reference electrode for both electrochemistry techniques are shared. This configuration is then compared to both the original configurations to determine any differences in the sensing accuracy through a novel experiment that utilises hydrogen peroxide as a measurement analyte. The feasibility of the configuration with the shared reference electrode is proven and utilised as the basis of the electrochemical configuration for the front end circuits. A unique front-end circuit named DAPPER is developed for the shared reference electrode topology. A review of existing architectures for potentiometry and amperometry is evaluated, with a specific focus on low power consumption for wireless applications. In addition, both the electrochemical sensing outputs are mixed into a single output data channel for use with a near-field communication (NFC). This mixing technique is also further analysed in this thesis to understand the errors arising due to various factors. The system is fabricated on TSMC 180nm technology and consumes 28µW. It measures a linear input current range from 250pA - 0.1µW, and an input voltage range of 0.4V - 1V. This circuit is tested and verified for both electrical and electrochemical tests to showcase its feasibility for concurrent measurements. This thesis then provides the integration of wireless blocks into the system for wireless powering and data transmission. This is done through the design of a circuit named SPACEMAN that consists of the concurrent sensing front-end, wireless power blocks, data transmission, as well as a state machine that allows for the circuit to switch between modes: potentiometry only, amperometry only, concurrent sensing and none. The states are switched through re-booting the circuit. The core size of the electronics is 0.41mm² without the coil. The circuit’s wireless powering and data transmission is tested and verified through the use of an external transmitter and a connected printed circuit board (PCB) coil. Finally, the future direction for ongoing work to proceed towards a fully monolithic electrochemical technique is discussed through the next development of a fully integrated coil-on-CMOS system, on-chip electrodes with the electroplating and microfludics, the development of an external transmitter for powering the device and a test platform. The contributions of this thesis aim to formulate a use for wireless electrochemical sensors capable of concurrent measurements for use in wearable devices.Open Acces

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

Characterization and development towards electrochemical real-time LAMP detection in an integrated and portable device

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Eletrónica Médica)Nos últimos anos os biossensores eletroquímicos têm sido reportados como uma abordagem promis sora para a deteção de DNA. São atrativos para dispositivos point-of-care pela facilidade de miniaturização, compatibilidade com técnicas de microfabricação e facilidade de instrumentação. Contudo, a integração de uma fase de amplificação com a deteção de sinais continua a ser um desafio. A técnica LAMP (loop mediated isothermal amplification ) surgiu como solução, destacando-se pela sua robustez e sensibilidade. Uma plataforma portátil para deteção eletroquímica de DNA (Mobi-E) foi desenvolvida para incorporar as caraterísticas mencionadas. Neste trabalho foram caraterizados os principais componentes do disposi tivo: potencióstatos ASIC, controlo de temperatura e um chip fluídico que integra elétrodos e estruturas de aquecimento impressas. Seguidamente, efetuou-se uma pesquisa para funcionalização universal desses elétrodos utilizando MD LAMP (mediator displacement LAMP). O desempenho do potencióstato, especificamente a rotina de voltametria de onda quadrada e a leitura quase simultânea dos 6 elétrodos de trabalho de uma câmara, foi provado e comparado com um dispositivo comercial, obtendo-se resultados qualitativamente comparáveis. Foram ainda realizadas otimizações para estabilização do potencial de referência, através da conversão Ag/AgCl por FeCl3, e para precaver dificuldades de medição resultantes da limitada tensão de conformidade do potencióstato (1.8 V). Para tal, aumentou-se a área do elétrodo auxiliar, através da impressão de 8 camadas de Au (4 no elétrodo de trabalho), e efetuou-se, entre medições, o curto-circuito entre o elétrodo auxiliar e o de referência. O sistema de controlo de temperatura provou ser efetivo no aquecimento das câmaras até 65 ºC em 2.5 min e na monitorização assertiva das suas temperaturas. Não foi detetado cross-talk entre câmaras vizinhas, nem a formação severa de bolhas de ar. Como prova de conceito, foram testadas quatro abordagens para MD LAMP e foi identificada uma alternativa promissora (Stem-Loop ) ao standard, com a respetiva mudança relativa de sinal: 0.3 e 177.6. Esta dissertação culmina com a otimização da reação LAMP para uma libertação eficiente do medi ador. Duas promissoras combinações de concentrações de mediador, primer modificado e loop primer foram identificadas: 200 nM, 400 nM, 400 nM e 100 nM, 200 nM, 600 nM, respetivamente, obtendo-se uma relação sinal/ruído de 3.7 e 2.9. Os conhecimentos adquiridos viabilizam o avanço da investigação no sentido da obtenção de um dispositivo capaz de realizar LAMP eletroquímico em tempo real.Electrochemical biosensors have been reported in recent years as a promising approach for DNA detection. The ease of miniaturization, compatibility with microfabrication techniques and simple instru mentation make these sensors attractive for point-of-care (POC) devices. However, integrating an ampli fication stage with signal detection remains a challenge. Loop-mediated isothermal amplification (LAMP) has emerged as a robust and highly sensitive isothermal strategy. A novel portable platform for rapid electrochemical DNA detection (Mobi-E device) was developed to incorporate the aforementioned features. Within this work, an extensive characterization of the main components of the Mobi-E device, which comprises ASIC potentiostats, temperature control, and a fluidic chip with integrated inkjet-printed electrodes and heating structures, was performed, followed by a research towards target-independent electrode functionalization employing mediator displacement (MD) LAMP. The operation of the general functionalities of the ASIC potentiostat, specifically the square wave voltammetry (SWV) routine and the quasi-simultaneous read-out of all 6 working electrodes (WEs) of a chamber, was proven and its performance was benchmarked against a commercial device, achieving qualitatively comparable results. Inherent optimizations of the device were performed to stabilize the reference electrode (RE) potential, through Ag/AgCl conversion by FeCl3, and to address the criticality that the 1.8 V compliance voltage of the potentiostat brought to the measurements. For this issue, it is suggested to increase the counter electrode (CE) area by printing 8 Au layers (WE with 4 layers) and to short-circuit the CE and RE between measurements. The temperature control system proved to be effective in heating the chambers to 65 ºC in about 2.5 min and assertively monitoring their temperature. Furthermore, no cross-talk between neighbouring chambers and no severe bubble formation was detected. Four concepts for target-independent MD LAMP were tested as proof-of-concept and a promising alternative (”Stem-Loop universal reporter (UR)”) to the standard approach was identified. The following relative signal change was achieved: 0.3 and 177.6, respectively. This thesis culminates with the optimization of fluorescent LAMP reaction parameters towards an efficient mediator release. Two promising concentration combinations of mediator, modified primer (LB_Medc) and loop primer (LB) were identified: 200 nM, 400 nM, 400 nM and 100 nM, 200 nM, 600 nM, respectively. For these, the signal-to-noise ratio was 3.7 and 2.9. The knowledge acquired in this thesis allows moving forward towards a device able to perform electrochemical real-time LAMP readout

BPOD: A WIRELESS INTEGRATED SENSOR PLATFORM FOR CONTINUOUS LOCALIZED BIOPROCESS MONITORING

Process parameter spatial inhomogeneities inside cell culture bioreactors has attracted considerable attention, however, few technologies allow investigation of the impact of these variations on process yield. Commercially available sensing probes sit at fixed locations, failing to capture the spatial distribution of process metrics. The bio-Processing online device (bPod) addresses this problem by performing real-time in situ monitoring of dissolved oxygen (DO) within bioreactor cell cultures. The bPod is an integrated system comprised of a potentiostat analog-front-end, a Bluetooth Low Energy microcontroller, and a Clark-type electrochemical DO sensor. The Clark-type sensor uses chronoamperometry to determine the DO percent saturation within a range relevant for mammalian cell culture. The free-floating capsule is packaged inside a 3D-printed biocompatible shell and wirelessly transmits data to a smartphone while submerged in the reactor. Furthermore, the bPod demonstrated a sensitivity of 37.5 nA/DO%, and can be adapted to multiple sensor types, enabling numerous bioprocess monitoring applications