An Integrated Platform for Differential Electrochemical and ISFET Sensing

A fully-integrated differential biosensing platform on CMOS is presented for miniaturized enzyme-based electrochemical sensing. It enables sensor background current elimination and consists of a differential sensor array and a differential readout IC (DiRIC). The sensor array includes a four-electrode sensor for amperometric electrochemical sensing, as well as a differential ISFET-based pH sensor to calibrate the biosensors. The ISFET is biased in weak inversion and co-designed with DiRIC to enable pH measurements from 1 to 14 with resolution of 0.1 pH. DiRIC enables differential current measurement in the range of ¿¿100 ¿¿A with more than 120dB dynamic range

Robust low power CMOS methodologies for ISFETs instrumentation

I have developed a robust design methodology in a 0.18 [Mu]m commercial CMOS process to circumvent the performance issues of the integrated Ions Sensitive Field Effect Transistor (ISFET) for pH detection. In circuit design, I have developed frequency domain signal processing, which transforms pH information into a frequency modulated signal. The frequency modulated signal is subsequently digitized and encoded into a bit-stream of data. The architecture of the instrumentation system consists of a) A novel front-end averaging amplifier to interface an array of ISFETs for converting pH into a voltage signal, b) A high linear voltage controlled oscillator for converting the voltage signal into a frequency modulated signal, and c) Digital gates for digitizing and differentiating the frequency modulated signal into an output bit-stream. The output bit stream is indistinguishable to a 1st order sigma delta modulation, whose noise floor is shaped by +20dB/decade. The fabricated instrumentation system has a dimension of 1565 [Mu] m 1565 [Mu] m. The chip responds linearly to the pH in a chemical solution and produces a digital output, with up to an 8-bit accuracy. Most importantly, the fabricated chips do not need any post-CMOS processing for neutralizing any trapped-charged effect, which can modulate on-chip ISFETs’ threshold voltages into atypical values. As compared to other ISFET-related works in the literature, the instrumentation system proposed in this thesis can cope with the mismatched ISFETs on chip for analogue-to-digital conversions. The design methodology is thus very accurate and robust for chemical sensing

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

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

Low-power Wearable Healthcare Sensors

Advances in technology have produced a range of on-body sensors and smartwatches that can be used to monitor a wearer’s health with the objective to keep the user healthy. However, the real potential of such devices not only lies in monitoring but also in interactive communication with expert-system-based cloud services to offer personalized and real-time healthcare advice that will enable the user to manage their health and, over time, to reduce expensive hospital admissions. To meet this goal, the research challenges for the next generation of wearable healthcare devices include the need to offer a wide range of sensing, computing, communication, and human–computer interaction methods, all within a tiny device with limited resources and electrical power. This Special Issue presents a collection of six papers on a wide range of research developments that highlight the specific challenges in creating the next generation of low-power wearable healthcare sensors

Integrated impedance spectroscopy biosensors

textAffinity-based biosensors, or in short biosensors, are extremely powerful and versatile analytical tools which are used for the detection of a wide variety of bio-molecules. In recent times, there has been a need for developing low-cost and portable affinity-based biosensor platforms. Such systems need to have a high density of detection sites (i.e biosensing elements) in order to simultaneously detect multiple analytes in a single sample. This has led to the creation of integrated biosensors, which make use of integrated circuits (ICs) for bio-molecular detection. In such systems, it has been demonstrated that by taking advantage of the capabilities of semiconductor and very large scale integrated (VLSI) circuit fabrication processes, it is possible to build compact miniaturized biosensors, which can be used in wide variety of applications such as in molecular diagnostics and for environmental monitoring. Among the various detection modalities for biosensors, Electrochemical Impedance Spectroscopy (EIS) permits real-time detection and has label-free detection capabilities. EIS is fully electronic in nature. Hence, it can be implemented using standard IC technologies. The versatility and ease of integration of EIS makes it a promising candidate for developing integrated biosensor platforms. In this thesis, we first examine the underlying principles of EIS method of biosensing. By analyzing an immunosensor assay as an example, we show that EIS based biosensing is a highly sensitive detection method, which can be used for the detection of a wide variety of analytes. Since EIS relies on small impedance changes in order to perform detection, it requires highly accurate models for the electrode-electrolyte systems. Hence, we also introduce a compact modeling technique for the distributed electrode-electrolyte systems with non-uniform electric fields, which is capable of modelling noise and other non-idealities in EIS. In the second part of this thesis, we describe the design and implementation of an integrated EIS biosensor array, built using a standard complementary metal-oxide-semiconductor (CMOS) process. The chip is capable of measuring admittance values as small as 10nS and has a wide dynamic range (90dB) over a wide range of frequencies (10Hz-50MHz). We also report the results obtained from the DNA and protein detection experiments performed using this chip.Electrical and Computer Engineerin

Electrochemical sensor system architecture using the CMOS-MEMS technology for cytometry applications

This thesis presents the development process of an integrated sensor-system-on-chip for recording the parameters of blood cells. The CMOS based device consists of the two flow-through sensor arrays, stacked one on top of the other. The sensors are able to detect the biological cell in terms of its physical size and the surface charge on a cell’s membrane. The development of the measurement system was divided into several stages these were to design and implement the two sensor arrays complemented with readout circuitry onto a single CMOS chip to create an on-chip membrane with embedded flow-through micro-channels by a CMOS compatible post-processing techniques to encapsulate and hermeti-cally package the device for liquid chemistry experiments, to test and characterise the two sensor arrays together with readout electronics, to develop control and data acquisition software and to detect the biological cells using the complete measurement system. Cy-tometry and haematology fields are closely related to the presented work, hence it is envis-aged that the developed technology enables further integration and miniaturisation of the biomedical instrumentation. The two vertically stacked 4 x 4 flow-through sensor arrays, embedded into an on-chip membrane, were implemented in a single silicon chip device together with a readout circuitry for each of the sensor sets. To develop a CMOS-MEMS device the design and fabrication was carried out using a commercial process design kit (0.35 µm 4-Metal, 2-Poly, CMOS) as well as the foundry service. Thereafter the device was post-processed in-house to develop the on-chip membrane and open the sensing micro-apertures. The two types of sensor were integrated on the silicon dice for multi-parametric characterisation of the analyte. To read the cell membrane charge the ion sensitive field effect transistor (ISFET) was utilised and for cell size (volume) detection an impedance sensor (Coulter counter) was used. Both sensors rely on a flow-through mode of operation, hence the constant flow of the analyte sample could be maintained. The Coulter counter metal electrode was exposed to the solution, while the ISFET floating gate electrode maintained contact with the analyte through a charge sensitive membrane constructed of a dielectric material (silicon dioxide) lining the inside of the micro-pore. The outside size of each of the electrodes was 100 µm x 100 µm and the inside varied from 20 µm x 20 µm to 58 µm x 58 µm. The sense aperture size also varied from 10 µm x 10 µm to 16 µm x 16 µm. The two stacked micro-electrode arrays were layed out on an area of 5002 µm2. The CMOS-MEMS device was fit into a custom printed circuit board (PCB) chip carrier, thereafter insulated and hermetically packaged. Microfluidic ports were attached to the packaged module so that the analyte can be introduced and drained by a flow-through mode of operation. The complete microfluidic system and packaging was assembled and thereafter evaluated for correct operation. Undisturbed flow of the analyte solution is es-sential for the sensor operation. This is related to the fact that the electrochemical response of both sensors depends on the analyte flow through the sense micro-apertures thus any aggregation of the sample within the microfluidic system would cause clogging of the mi-cro-pores. The on-chip electronic circuitry was characterised, and after comparison with the simulated results found to be within an error margin of what enables it for reliable sensor signal readout. The measurement system is automated by software control so that the bias parame-ters can be set precisely, it also helped while error debugging. Analogue signals from the two sensor arrays were acquired, later processed and stored by a data acquisition system. Both control and data capture systems are implemented in a high level programming lan-guage. Furthermore both are integrated and operated in a one window based graphical user interface (GUI). A fully functional measurement system was used as a flow-through cytometer for living cells detection. The measurements results showed that the system is capable of single cell detection and on-the-fly data display

Crexens™: an expandable general-purpose electrochemical analyzer

2019 Fall.Includes bibliographical references.Electrochemical analysis has gained a great deal of attention of late due to its low-cost, easy-to-perform, and easy-to-miniaturize, especially in personal health care where accuracy and mobility are key factors to bring diagnostics to patients. According to data from Centers for Medicare & Medicaid Services (CMS) in the US, the share of health expenditure in the US has been kept growing in the past 3 decades and reached 17.9% of its overall Gross Domestic Product till 2016, which is equivalent to $10,348 for every person in the US per year. On the other hand, health care resources are often limited not only in rural area but also appeared in well-developed countries. The urgent need and the lack of health resource brings to front the research interest of Point-of-Care (PoC) diagnosis devices. Electrochemical methods have been largely adopted by chemist and biologist for their research purposes. However, several issues exist within current commercial benchtop instruments for electrochemical measurement. First of all, the current commercial instruments are usually bulky and do not have handheld feature for point-of-care applications and the cost are easily near$5,000 each or above. Secondly, most of the instruments do not have good integration level that can perform different types of electrochemical measurements for different applications. The last but not the least, the existing generic benchtops instruments for electrochemical measurements have complex operational procedures that require users to have a sufficient biochemistry and electrochemistry background to operate them correctly. The proposed Crexens™ analyzer platform is aimed to present an affordable electrochemical analyzerwhile achieving comparable performance to the existing commercial instruments, thus, making general electrochemical measurement applications accessible to general public. In this dissertation, the overall Crexens™ electrochemical analyzer architecture and its evolution are presented. The foundation of the Crexens™ architecture was derived from two separate but related research in electrochemical sensing. One of them is a microelectrode sensor array using CMOS for neurotransmitter sensing; the other one is a DNA affinity-based capacitive sensor for infectious disease, such as ZIKA. The CMOS microelectrode sensor array achieved a 320uM sensitivity for norepinephrine, whereas the capacitive sensor achieved a dynamic range of detection from 1 /uL to 105 /uL target molecules (20 to 2 million targets), which makes it be within the detection range in a typical clinical application environment. This dissertation also covers the design details of the CMOS microelectrode array sensor and the capacitive sensor design as a prelude to the development of the Crexens™ analyzer architecture. Finally, an expandable integrated electrochemical analyzer architecture (Crexens™) has been designed for mobile point-of-care (POC) applications. Electrochemical methods have been explored in detecting various bio-molecules such as glucose, lactate, protein, DNA, neurotransmitter, steroid hormone, which resulted in good sensitivity and selectivity. The proposed system is capable of running electrochemical experiments including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), electrochemical capacitive spectroscopy (ECS), amperometry, potentiometry, and other derived electrochemical based tests. This system consist of a front-end interface to sensor electrodes, a back-end user interface on smart phone and PC, a base unit as master module, a low-noise add-on module, a high-speed add-on module, and a multi-channel add-on module. The architecture allows LEGO™-like capability to stack add-on modules on to the base-unit for performance enhancements in noise, speed or parallelism. The analyzer is capable of performing up to 1900 V/s CV with 10 mV step, up to 12 kHz EIS scan range and a limit of detection at 637 pA for amperometric applications with the base module. With high performance module, the EIS scan range can be extended upto 5 MHz. The limit of detection can be further improved to be at 333 fA using the low-noise module. The form factor of the electrochemical analyzer is designed for its mobile/point-of-care applications, integrating its entire functionality on to a 70 cm² area of surface space. A glutamine enzymatic sensor was used to valid the capability of the proposed electrochemical analyzer and turned out to give good linearity and reached a limit of detection at 50 uM

Implantable Piezoresistive Microcantilever-based Wireless Cocaine Biosensors

Cocaine is a well-known, illegal, recreational drug that is addictive due to its effects on the mesolimbic reward pathway in the human body. Accurate and real-time measurement of the concentration of cocaine in the body as a function of time and physiological factors is a key requirement for the understanding of the use of this drug. Current methods for such measurements involve taking samples from the human body (such as blood, urine, and hair) and performing analytical chemistry tests on these samples. This techniques are relatively expensive, time consuming, and labor intensive. To address this issue, a new implantable sensor for the automated detection and measurement of the relative cocaine concentration is presented here. The device is more economical and provides for higher sampling frequencies than the current methods. The active sensor elements consist of piezoresistive microcantilever arrays, which are coated with an oligonucleotide-based aptamer, i.e. a short sequence of RNA with high affinity for specific target molecules, as the cocaine receptor. A Wheatstone bridge is used to convert the biosensor signal into an electronic signal. This signal is transmitted wireless at an operating frequency of 403.55 MHz, which complies with the US Medical Implant Communication System (MICS) FCC 47CFR Part 95. The limit of detection for the in vitro experiment is found to be 1 ng/ml. The device has successfully measured the relative concentration of cocaine upon implantation in the subcutaneous interstitial fluid of male Wistar rats

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