Biosensors and CMOS Interface Circuits

abstract: Analysing and measuring of biological or biochemical processes are of utmost importance for medical, biological and biotechnological applications. Point of care diagnostic system, composing of biosensors, have promising applications for providing cheap, accurate and portable diagnosis. Owing to these expanding medical applications and advances made by semiconductor industry biosensors have seen a tremendous growth in the past few decades. Also emergence of microfluidics and non-invasive biosensing applications are other marker propellers. Analyzing biological signals using transducers is difficult due to the challenges in interfacing an electronic system to the biological environment. Detection limit, detection time, dynamic range, specificity to the analyte, sensitivity and reliability of these devices are some of the challenges in developing and integrating these devices. Significant amount of research in the field of biosensors has been focused on improving the design, fabrication process and their integration with microfluidics to address these challenges. This work presents new techniques, design and systems to improve the interface between the electronic system and the biological environment. This dissertation uses CMOS circuit design to improve the reliability of these devices. Also this work addresses the challenges in designing the electronic system used for processing the output of the transducer, which converts biological signal into electronic signal.Dissertation/ThesisM.S. Electrical Engineering 201

Sub-mW Reconfigurable Interface IC for Electrochemical Sensing

The IronIC project has the aim of developing a fully implantable and remotely powered platform for the real- time monitoring of human metabolites. In this paper we present a mixed-signal interface IC for the electrochemical sensing data acquisition chain. The IC controls and reads out up to five biomolecular sensors, by receiving commands from a standard interface to conduct chronoamperometry (CA) and cyclic voltammetry (CV). Different voltage profiles are generated by using a single fully on-chip reconfigurable waveform generator, while the measured data are digitized. The IC is realized in 0.18 μm CMOS technology. Electrical measurements show that the linear readout current range is ±1650 nA with 8-bit resolution. The cyclic voltammetry of potassium ferricyanide and the chronoamperometry of hydrogen peroxide have been successfully performed with the interface. The IC consumes 0.92 mW from 1.8 V supply voltage, making it suitable for remotely powered and implantable applications

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

Integrated Electronics to Control and Readout Electrochemical Biosensors for Implantable Applications

Biosensors can effectively be used to monitor multiple metabolites such as glucose, lactate, ATP and drugs in the human body. Continuous monitoring of these metabolites is essential for patients with chronic or critical conditions. Moreover, this can be used to tune the dosage of a drug for each individual patient, in order to achieve personalized therapy. Implantable medical devices (IMDs) based on biosensors are emerging as a valid alternative for blood tests in laboratories. They can provide continuous monitoring while reduce the test costs. The potentiostat plays a fundamental role in modern biosensors. A potentiostat is an electronic device that controls the electrochemical cell, using three electrodes, and runs the electrochemical measurement. In particular the IMDs require a low-power, fully-integrated, and autonomous potentiostats to control and readout the biosensors. This thesis describes two integrated circuits (ICs) to control and readout multi-target biosensors: LOPHIC and ARIC. They enable chronoamperometry and cyclic voltammetrymeasurements and consume sub-mW power. The design, implementation, characterisation, and validation with biosensors are presented for each IC. To support the calibration of the biosensors with environmental parameters, ARIC includes circuitry to measure the pHand temperature of the analyte through an Iridiumoxide pH sensor and an off-chip resistor-temperature detector (RTD). In particular, novel circuits to convert resistor value into digital are designed for RTD readout. ARIC is integrated into two IMDs aimed for health-care monitoring and personalized therapy. The control and readout of the embedded sensor arrays have been successfully achieved, thanks to ARIC, and validated for glucose and paracetamol measurements while it is remotely powered through an inductive link. To ensure the security and privacy of IMDs, a lightweight cryptographic system (LCS) is presented. This is the first ASIC implementation of a cryptosystem for IMDs, and is integrated into ARIC. The resulting system provides a unique and fundamental capability by immediately encrypting and signing the sensor data upon its creation within the body. Nano-structures such as Carbon nanotubes have been widely used to improve the sensitivity of the biosensors. However, in most of the cases, they introduce more noise into the measurements and produce a large background current. In this thesis the noise of the sensors incorporating CNTs is studied for the first time. The effect of CNTs as well as sensor geometry on the signal to noise ratio of the sensors is investigated experimentally. To remove the background current of the sensors, a differential readout scheme has been proposed. In particular, a novel differential readout IC is designed and implemented that measures inputcurrents within a wide dynamic range and produces a digital output that corresponds to the -informative- redox current of the biosensor

A high performance ASIC for electrical and neurochemical traumatic brain injury monitoring

Traumatic Brain Injury (TBI) can be defined as a non-degenerative, non-congenital brain trauma due to an external mechanical force. TBI is a major cause of death and disability in all age groups and the leading cause of death and disability in working people and among young adults. This Thesis presents the first application specific integrated chip (ASIC) for monitoring patients suffering from TBI. The microelectronic chip was designed to meet the demands of processing physiological signals for an alternative method of TBI monitoring. It has been studied that by monitoring electrical (ECoG) and chemical (glucose, lactate and potassium) signals, the report of spreading depolarisation (SD) waves could be a good indicator for an upcoming secondary brain injury. The ultimate aim of this Thesis has been to support the idea of a “behind-the-ear” micro-platform, which could enable the monitoring of mobile (or mobilized) patients suffering a TBI who, currently, are not monitored. Switched-capacitor (SC) circuits have been adopted for the implementation of both current and voltage analogue front-ends (AFEs). Advanced techniques to minimise noise and improve the noise performance of the circuit were employed. Moreover, a digitally enabled automatic transimpedance gain control circuit, suitable for current analogue front-ends, was developed and tested in order to provide an automated way to adjust the gain and to counterbalance for the drop in sensitivity of the biosensors due to drift. Measured results confirming the operation of the TBI ASIC and its sub-circuits are reported. Finally, a novel circuit that mimics the Butler-Volmer dynamics is presented. The basic building blocks arise from the combination of Translinear (TL) Circuits and the Non- linear Bernoulli Cell Formalism (NBCF). The developed electrical equivalent circuit has been compared to an ideal model, which was developed in MATLAB. The robustness of the microelectronic system was evaluated by means of Monte Carlo simulations.Open Acces

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

Wired, wireless and wearable bioinstrumentation for high-precision recording of bioelectrical signals in bidirectional neural interfaces

It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Furthermore, electrical stimulation of specific target brain regions has been shown to alleviate symptoms of neurological disorders, such as Parkinson’s disease, essential tremor, dystonia, epilepsy etc. In recent years, the traditional practice of continuously stimulating the brain using static stimulation parameters has shifted to the use of disease biomarkers to determine the intensity and timing of stimulation. The main motivation behind closed-loop stimulation is minimization of treatment side effects by providing only the necessary stimulation required within a certain period of time, as determined from a guiding biomarker. Hence, it is clear that high-quality recording of local field potentials (LFPs) or electrocorticographic (ECoG) signals during deep brain stimulation (DBS) is necessary to investigate the instantaneous brain response to stimulation, minimize time delays for closed-loop neurostimulation and maximise the available neural data. To our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording ECoG signals, which are of particular importance in closed-loop DBS and epilepsy DBS. In addition, existing recording systems lack the ability to provide artefact-free high-frequency (> 100 Hz) LFP recordings during DBS in real time primarily because of the contamination of the neural signals of interest by the stimulation artefacts. To address the problem of limited mobility often encountered by patients in the clinic and to provide a wide variety of high-precision sensor data to a closed-loop neurostimulation platform, a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless multi-instrument (55 × 80 mm2) was designed and developed. The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile tool to be utilized in a wide range of applications and environments. Moreover, in order to offer the capability of sensing and stimulating via the same electrode, novel real-time artefact suppression methods that could be used in bidirectional (recording and stimulation) system architectures are proposed and validated. More specifically, a novel, low-noise and versatile analog front-end (AFE), which uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency, is presented. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, the performance of the realised AFE is assessed by conducting both in vitro and in vivo experiments using unipolar and bipolar DBS (monophasic pulses, amplitude ranging from 3 to 6 V peak-to-peak, frequency 140 Hz and pulse width 100 µs). Under both in vitro and in vivo experimental conditions, the proposed AFE provided real-time, low-noise and artefact-free LFP recordings (in the frequency range 0.5 – 250 Hz) during stimulation. Finally, a family of tunable hardware filter designs and a novel method for real-time artefact suppression that enables wide-bandwidth biosignal recordings during stimulation are also presented. This work paves the way for the development of miniaturized research tools for closed-loop neuromodulation that use a wide variety of bioelectrical signals as control signals.Open Acces