Digital CMOS ISFET architectures and algorithmic methods for point-of-care diagnostics

Over the past decade, the surge of infectious diseases outbreaks across the globe is redefining how healthcare is provided and delivered to patients, with a clear trend towards distributed diagnosis at the Point-of-Care (PoC). In this context, Ion-Sensitive Field Effect Transistors (ISFETs) fabricated on standard CMOS technology have emerged as a promising solution to achieve a precise, deliverable and inexpensive platform that could be deployed worldwide to provide a rapid diagnosis of infectious diseases. This thesis presents advancements for the future of ISFET-based PoC diagnostic platforms, proposing and implementing a set of hardware and software methodologies to overcome its main challenges and enhance its sensing capabilities. The first part of this thesis focuses on novel hardware architectures that enable direct integration with computational capabilities while providing pixel programmability and adaptability required to overcome pressing challenges on ISFET-based PoC platforms. This section explores oscillator-based ISFET architectures, a set of sensing front-ends that encodes the chemical information on the duty cycle of a PWM signal. Two initial architectures are proposed and fabricated in AMS 0.35um, confirming multiple degrees of programmability and potential for multi-sensing. One of these architectures is optimised to create a dual-sensing pixel capable of sensing both temperature and chemical information on the same spatial point while modulating this information simultaneously on a single waveform. This dual-sensing capability, verified in silico using TSMC 0.18um process, is vital for DNA-based diagnosis where protocols such as LAMP or PCR require precise thermal control. The COVID-19 pandemic highlighted the need for a deliverable diagnosis that perform nucleic acid amplification tests at the PoC, requiring minimal footprint by integrating sensing and computational capabilities. In response to this challenge, a paradigm shift is proposed, advocating for integrating all elements of the portable diagnostic platform under a single piece of silicon, realising a ``Diagnosis-on-a-Chip". This approach is enabled by a novel Digital ISFET Pixel that integrates both ADC and memory with sensing elements on each pixel, enhancing its parallelism. Furthermore, this architecture removes the need for external instrumentation or memories and facilitates its integration with computational capabilities on-chip, such as the proposed ARM Cortex M3 system. These computational capabilities need to be complemented with software methods that enable sensing enhancement and new applications using ISFET arrays. The second part of this thesis is devoted to these methods. Leveraging the programmability capabilities available on oscillator-based architectures, various digital signal processing algorithms are implemented to overcome the most urgent ISFET non-idealities, such as trapped charge, drift and chemical noise. These methods enable fast trapped charge cancellation and enhanced dynamic range through real-time drift compensation, achieving over 36 hours of continuous monitoring without pixel saturation. Furthermore, the recent development of data-driven models and software methods open a wide range of opportunities for ISFET sensing and beyond. In the last section of this thesis, two examples of these opportunities are explored: the optimisation of image compression algorithms on chemical images generated by an ultra-high frame-rate ISFET array; and a proposed paradigm shift on surface Electromyography (sEMG) signals, moving from data-harvesting to information-focused sensing. These examples represent an initial step forward on a journey towards a new generation of miniaturised, precise and efficient sensors for PoC diagnostics.Open Acces

Design, Fabrication, Testing of CNT Based ISFET and Characterization of Nano/Bio Materials Using AFM

A combination of Carbon Nanotubes (CNTs) and Ion Selective Field Effect Transistor (ISFET) is designed and experimentally verified in order to develop the next generation ion concentration sensing system. Micro Electro-Mechanical System (MEMS) fabrication techniques, such as photolithography, diffusion, evaporation, lift-off, packaging, etc., are required in the fabrication of the CNT-ISFET structure on p-type silicon wafers. In addition, Atomic Force Microscopy (AFM) based surface nanomachining is investigated and used for creating nanochannels on silicon surfaces. Since AFM based nanomanipulation and nanomachining is highly controllable, nanochannels are precisely scratched in the area between the source and drain of the FET where the inversion layer is after the ISFET is activated. Thus, a bundle of CNTs are able to be aligned inside a single nanochannel by Dielectrophoresis (DEP) and the drain current is improved greatly due to CNTs` remarkable and unique electrical properties, for example, high current carrying capacity. ISFET structures with or without CNTs are fabricated and tested with different pH solutions. Besides the CNT-ISFET pH sensing system, this dissertation also presents novel AFM-based nanotechnology for learning the properties of chemical or biomedical samples in micro or nano level. Dimensional and mechanical property behaviors of Vertically Aligned Carbon Nanofibers (VACNFs) are studied after temperature and humidity treatment using AFM. Furthermore, mechanical property testing of biomedical samples, such as microbubbles and engineered soft tissues, using AFM based nanoindentation is introduced, and the methodology is of great directional value in the area

Micro- and nano-devices for electrochemical sensing

Electrode miniaturization has profoundly revolutionized the field of electrochemical sensing, opening up unprecedented opportunities for probing biological events with a high spatial and temporal resolution, integrating electrochemical systems with microfluidics, and designing arrays for multiplexed sensing. Several technological issues posed by the desire for downsizing have been addressed so far, leading to micrometric and nanometric sensing systems with different degrees of maturity. However, there is still an endless margin for researchers to improve current strategies and cope with demanding sensing fields, such as lab-on-a-chip devices and multi-array sensors, brain chemistry, and cell monitoring. In this review, we present current trends in the design of micro-/nano-electrochemical sensors and cutting-edge applications reported in the last 10 years. Micro- and nanosensors are divided into four categories depending on the transduction mechanism, e.g., amperometric, impedimetric, potentiometric, and transistor-based, to best guide the reader through the different detection strategies and highlight major advancements as well as still unaddressed demands in electrochemical sensing

Ion camera development for real–time acquisition of localised pH responses using the CMOS based 64×64–pixel ISFET sensor array technology

This thesis presents the development and test of an integrated ion camera chip for monitoring highly localised ion fluxes of electrochemical processes using an ion sensitive sensor array. Ionic concentration fluctuations are shown to travel across the sensor array as a result of citric acid injection and the BZ-reaction. The imaging capability of non-equilibrium chemical activities is also demonstrated monitoring self-assembling micrometre sized polyoxometalate tubular and membranous architectures. The sufficient spatial resolution for the visualisation of the 10-60 µm wide growing trajectories is provided by the dense sensor array containing 64×64 pixels. In the case of citric acid injection and the BZ-reaction the ion camera chip is shown to be able to resolve pH differences with resolution as low as the area of one pixel. As a result of the transient and volatile ionic fluxes high time resolution is required, thus the signal capturing can be performed in real.time at the maximum sampling rate of 40 µs per pixel, 10.2 ms per array. The extracted sensor data are reconstructed into ionic images and thus the ionic activities can be displayed as individual figures as well as continuous video recordings. This chip is the first prototype in the envisioned establishment of a fully automated CMOS based ion camera system which would be able to image the invisible activity of ions using a single microchip. In addition the capability of detecting ultra-low level pH oscillations in the extracellular space is demonstrated using cells of the slime mould organism. The detected pH oscillations with extent of ~0.022 pH furthermore raise the potential for observing fluctuations of ion currents in cell based tissue environments. The intrinsic noise of the sensor devices are measured to observe noise effect on the detected low level signals. It is experimentally shown that the used ion sensitive circuits, similarly to CMOS, also demonstrate 1/f noise. In addition the reference bias and pH sensitivity of the measured noise is confirmed. Corresponding to the measurement results the noise contribution is approximated with a 28.2 µV peak-to-peak level and related to the 450 µV �+/- 70 µV peak-to-peak oscillations amplitudes of the slime mould. Thus a maximum intrinsic noise contribution of 6.2 �+/- 1.2 % is calculated. A H+ flickering hypothesis is also presented that correlates the pH fluctuations on the surface of the device with the intrinsic 1/f noise. The ion camera chip was fabricated in an unmodified 4-metal 0.35 µm CMOS process and the ionic imaging technology was based on a 64�×64-pixel ion sensitive field effect transistor (ISFET) array. The high-speed and synchronous operation of the 4096 ISFET sensors occupying 715.8×715.8 µm space provided a spatial resolution as low as one pixel. Each pixel contained 4 transistors with 10.2×10.2 µm layout dimensions and the pixels were separated by a 1 µm separation gap. The ion sensitive silicon nitride based passivation layer was in contact with the floating gates of the ISFET sensors. It allowed the capacitive measurements of localised changes in the ionic concentrations, e.g. pH, pNa, on the surface of the chip. The device showed an average ionic sensitivity of 20 mV/pH and 9 mV/pNa. The packaging and encapsulation was carried out using PGA-100 chip carriers and two-component epoxies. Custom designed printed circuit boards (PCBs) were used to provide interface between the ISFET array chip and the data acquisition system. The data acquisition and extraction part of the developed software system was based on LabVIEW, the data processing was carried out on Matlab platform

Integrated Circuit Design for Miniaturized, Trackable, Ultrasound Based Biomedical Implants

This thesis focuses on the design of an ultrasonography compatible implantable sensor platform, as a novel approach that implements a miniaturized, battery-less, real-time trackable parallel biosensing system. In addition to the frontend circuit, a sub-nW fully integrated pH sensor is designed in a way that can be easily integrated with the proposed sonography-compatible sensor platform. Combining the two integrated circuits together, the whole system will be able to map in vivo physiological information acquired from a distributed set of sensors on top of the ultrasound movie, leading to the idea envisioned as “augmented ultrasonography”. Implemented in a 0.18 μm technology, an ultrasound power and data frontend circuit is designed to enable medical sensing implants to operate in an ultrasonography compatible way. When placed within the field of view of an imaging transducer, the frontend circuit harvests the power through a piece of piezo crystal from a minimally modified brightness-mode (B-mode) ultrasound imaging process that is commonly adopted in modern medical practices. The implant can also establish bi-directional data communication channels with the imaging transducer, allowing data to be transmitted in a way synchronized to the frame rate of the B-mode film. The design of the circuit is made possible by a combination of ultra-low-power circuit techniques and novel frontend circuit topologies, as imaging ultrasound waves in the form of short pulses with extremely low duty cycle poses challenges that has not previously seen in other implantable sensor systems. The proposed prototype achieves a total area of 0.6mm² for the integrated circuit (IC), as well as 71mm theoretical maximum implantable depth (up to 40 mm is verified experimentally). These two together give opportunities for this design to become the next generation solution for deep-tissue bio-sensing implants. Realized using the same 0.18 μm technology, the fully integrated pH sensor is designed to deliver accurate pH readouts, at a reasonable speed of 1 sample per second, while consuming only 0.72 nW of power. Using an ion-sensitive field effect transistor (ISFET) and reference field effect transistor pair (REFET), the IC requires minimum additional post fabrication to deliver 10-bit resolution pH readouts at an end-to-end sensitivity of 65.8 LSB/pH. When working as a standalone device, this work advances the state-of-the-art of ISFET based pH sensor design. With an addition of 0.46 mm² of area, it is possible to integrate it with the ultrasound sonography compatible implant platform. This potential integration will further advance the vision of the augmented ultrasonography: real-time display of physiological information in a B-mode film, with the help from a distributed bio-sensor system for deep-tissue physiology monitoring

Ultra-thin and flexible CMOS technology: ISFET-based microsystem for biomedical applications

A new paradigm of silicon technology is the ultra-thin chip (UTC) technology and the emerging applications. Very thin integrated circuits (ICs) with through-silicon vias (TSVs) will allow the stacking and interconnection of multiple dies in a compact format allowing a migration towards three-dimensional ICs (3D-ICs). Also, extremely thin and therefore mechanically bendable silicon chips in conjunction with the emerging thin-film and organic semiconductor technologies will enhance the performance and functionality of large-area flexible electronic systems. However, UTC technology requires special attention related to the circuit design, fabrication, dicing and handling of ultra-thin chips as they have different physical properties compared to their bulky counterparts. Also, transistors and other active devices on UTCs experiencing variable bending stresses will suffer from the piezoresistive effect of silicon substrate which results in a shift of their operating point and therefore, an additional aspect should be considered during circuit design. This thesis tries to address some of these challenges related to UTC technology by focusing initially on modelling of transistors on mechanically bendable Si-UTCs. The developed behavioural models are a combination of mathematical equations and extracted parameters from BSIM4 and BSIM6 modified by a set of equations describing the bending-induced stresses on silicon. The transistor models are written in Verilog-A and compiled in Cadence Virtuoso environment where they were simulated at different bending conditions. To complement this, the verification of these models through experimental results is also presented. Two chips were designed using a 180 nm CMOS technology. The first chip includes nMOS and pMOS transistors with fixed channel width and two different channel lengths and two different channel orientations (0° and 90°) with respect to the wafer crystal orientation. The second chip includes inverter logic gates with different transistor sizes and orientations, as in the previous chip. Both chips were thinned down to ∼20m using dicing-before-grinding (DBG) prior to electrical characterisation at different bending conditions. Furthermore, this thesis presents the first reported fully integrated CMOS-based ISFET microsystem on UTC technology. The design of the integrated CMOS-based ISFET chip with 512 integrated on-chip ISFET sensors along with their read-out and digitisation scheme is presented. The integrated circuits (ICs) are thinned down to ∼30m and the bulky, as well as thinned ICs, are electrically and electrochemically characterised. Also, the thesis presents the first reported mechanically bendable CMOS-based ISFET device demonstrating that mechanical deformation of the die can result in drift compensation through the exploitation of the piezoresistive nature of silicon. Finally, this thesis presents the studies towards the development of on-chip reference electrodes and biodegradable and ultra-thin biosensors for the detection of neurotransmitters such as dopamine and serotonin

Wearable, low-power CMOS ISFETs and compensation circuits for on-body sweat analysis

Complementary metal-oxide-semiconductor (CMOS) technology has been a key driver behind the trend of reduced power consumption and increased integration of electronics in consumer devices and sensors. In the late 1990s, the integration of ion-sensitive field-effect transistors (ISFETs) into unmodified CMOS helped to create advancements in lab-on-chip technology through highly parallelised and low-cost designs. Using CMOS techniques to reduce power and size in chemical sensing applications has already aided the realisation of portable, battery-powered analysis platforms, however the possibility of integrating these sensors into wearable devices has until recently remained unexplored. This thesis investigates the use of CMOS ISFETs as wearable electrochemical sensors, specifically for on-body sweat analysis. The investigation begins by evaluating the ISFET sensor for wearable applications, identifying the key advantages and challenges that arise in this pursuit. A key requirement for wearable devices is a low power consumption, to enable a suitable operational life and small form factor. From this perspective, ISFETs are investigated for low power operation, to determine the limitations when trying to push down the consumption of individual sensors. Batteryless ISFET operation is explored through the design and implementation of a 0.35 \si{\micro\metre} CMOS ISFET sensing array, operating in weak-inversion and consuming 6 \si{\micro\watt}. Using this application-specific integrated circuit (ASIC), the first ISFET array powered by body heat is demonstrated and the feasibility of using near-field communication (NFC) for wireless powering and data transfer is shown. The thesis also presents circuits and systems for combatting three key non-ideal effects experienced by CMOS ISFETs, namely temperature variation, threshold voltage offset and drift. An improvement in temperature sensitivity by a factor of three compared to an uncompensated design is shown through measured results, while adding less than 70 \si{\nano\watt} to the design. A method of automatically biasing the sensors is presented and an approach to using spatial separation of sensors in arrays in applications with flowing fluids is proposed for distinguishing between signal and sensor drift. A wearable device using the ISFET-based system is designed and tested with both artificial and natural sweat, identifying the remaining challenges that exist with both the sensors themselves and accompanying components such as microfluidics and reference electrode. A new ASIC is designed based on the discoveries of this work and aimed at detecting multiple analytes on a single chip. %Removed In the latter half of the thesis, Finally, the future directions of wearable electrochemical sensors is discussed with a look towards embedded machine learning to aid the interpretation of complex fluid with time-domain sensor arrays. The contributions of this thesis aim to form a foundation for the use of ISFETs in wearable devices to enable non-invasive physiological monitoring.Open Acces

Light-Addressing and Chemical Imaging Technologies for Electrochemical Sensing

Visualizing chemical components in a specimen is an essential technology in many branches of science and practical applications. This book deals with electrochemical imaging techniques based on semiconductor devices with capability of spatially resolved sensing. Two types of such sensing devices have been extensively studied and applied in various fields, i.e., arrayed sensors and light-addressed sensors. An ion-sensitive field-effect transistor (ISFET) array and a charge-coupled device (CCD) ion image sensor are examples of arrayed sensors. They take advantage of semiconductor microfabrication technology to integrate a large number of sensing elements on a single chip, each representing a pixel to form a chemical image. A light-addressable potentiometric sensor (LAPS), on the other hand, has no pixel structure. A chemical image is obtained by raster-scanning the sensor plate with a light beam, which can flexibly define the position and size of a pixel. This light-addressing approach is further applied in other LAPS-inspired methods. Scanning photo-induced impedance microscopy (SPIM) realized impedance mapping and light-addressable electrodes/light-activated electrochemistry (LAE) realized local activation of Faradaic processes. This book includes eight articles on state-of-the-art technologies of light-addressing/chemical imaging devices and their application to biology and materials science

Chemical Bionics - a novel design approach using ion sensitive field effect transistors

In the late 1980s Carver Mead introduced Neuromorphic engineering in which various aspects of the neural systems of the body were modelled using VLSI1 circuits. As a result most bio-inspired systems to date concentrate on modelling the electrical behaviour of neural systems such as the eyes, ears and brain. The reality is however that biological systems rely on chemical as well as electrical principles in order to function. This thesis introduces chemical bionics in which the chemically-dependent physiology of specific cells in the body is implemented for the development of novel bio-inspired therapeutic devices. The glucose dependent pancreatic beta cell is shown to be one such cell, that is designed and fabricated to form the first silicon metabolic cell. By replicating the bursting behaviour of biological beta cells, which respond to changes in blood glucose, a bio-inspired prosthetic for glucose homeostasis of Type I diabetes is demonstrated. To compliment this, research to further develop the Ion Sensitive Field Effect Transistor (ISFET) on unmodified CMOS is also presented for use as a monolithic sensor for chemical bionic systems. Problems arising by using the native passivation of CMOS as a sensing surface are described and methods of compensation are presented. A model for the operation of the device in weak inversion is also proposed for exploitation of its physical primitives to make novel monolithic solutions. Functional implementations in various technologies is also detailed to allow future implementations chemical bionic circuits. Finally the ISFET integrate and fire neuron, which is the first of its kind, is presented to be used as a chemical based building block for many existing neuromorphic circuits. As an example of this a chemical imager is described for spatio-temporal monitoring of chemical species and an acid base discriminator for monitoring changes in concentration around a fixed threshold is also proposed