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

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

A 32 x 32 ISFET Chemical Sensing Array With Integrated Trapped Charge and Gain Compensation

This paper presents a CMOS-based 32 × 32 ion-sensitive field-effect transistor (ISFET) system-on-chip for real-time ion imaging. Fabricated in an unmodified 0.35-μm CMOS technology, the ISFET sensor array is based on a pixel topology, which uses capacitive feedback to improve signal attenuation due to passivation capacitance and a low-leakage floatinggate reset followed by a digital correlated double sampling to robustly remove unwanted trapped charge-induced dc offset. An automatic gain calibration (AGC) is used to perform realtime calibration and guarantee all sensors that have the same gain with a 99% accuracy, and combining all these mechanisms guarantees an average pixel voltage variation of 14.3 mV after gain is applied when measured over multiple dies. The full array is experimentally shown to be capable of real-time ion imaging of pH, with an intrinsic sensitivity of 39.6mV/pH and a scan rate of 9.3 frames/s when running the AGC, with a total power consumption of 10.2 mW

Classification of nucleic acid amplification on ISFET arrays using spectrogram-based neural networks.

The COVID-19 pandemic has highlighted a significant research gap in the field of molecular diagnostics. This has brought forth the need for AI-based edge solutions that can provide quick diagnostic results whilst maintaining data privacy, security and high standards of sensitivity and specificity. This paper presents a novel proof-of-concept method to detect nucleic acid amplification using ISFET sensors and deep learning. This enables the detection of DNA and RNA on a low-cost and portable lab-on-chip platform for identifying infectious diseases and cancer biomarkers. We show that by using spectrograms to transform the signal to the time-frequency domain, image processing techniques can be applied to achieve the reliable classification of the detected chemical signals. Transformation to spectrograms is beneficial as it makes the data compatible with 2D convolutional neural networks and helps gain significant performance improvement over neural networks trained on the time domain data. The trained network achieves an accuracy of 84% with a size of 30kB making it suitable for deployment on edge devices. This facilitates a new wave of intelligent lab-on-chip platforms that combine microfluidics, CMOS-based chemical sensing arrays and AI-based edge solutions for more intelligent and rapid molecular diagnostics

A 12.8 k current-mode velocity-saturation ISFET array for on-chip real-time DNA detection

This paper presents a large-scale CMOS chemical-sensing array operating in current mode for real-time ion imaging and detection of DNA amplification. We show that the current-mode operation of ion-sensitive field-effect transistors in velocity saturation devices can be exploited to achieve an almost perfect linearity in their input-output characteristics (pH-current), which are aligned with the continuous scaling trend of transistors in CMOS. The array is implemented in a 0.35-m process and includes 12.8 k sensors configured in a 2T per pixel topology. We characterize the array by taking into account nonideal effects observed with floating gate devices, such as increased pixel mismatch due to trapped charge and attenuation of the input signal due to the passivation capacitance, and show that the selected biasing regime allows for a sufficiently large linear range that ensures a linear pH to current despite the increased mismatch. The proposed system achieves a sensitivity of 1.03 A/pH with a pH resolution of 0.101 pH and is suitable for the real-time detection of the NDM carbapenemase gene in E. Coli using a loop-mediated isothermal amplification

A Flexible, Highly Integrated, Low Power pH Readout

Medical devices are widely employed in everyday life as wearable and implantable technologies make more and more technological breakthroughs. Implantable biosensors can be implanted into the human body for monitoring of relevant physiological parameters, such as pH value, glucose, lactate, CO2 [carbon dioxide], etc. For these applications the implantable unit needs a whole functional set of blocks such as micro- or nano-sensors, sensor signal processing and data generation units, wireless data transmitters etc., which require a well-designed implantable unit.Microelectronics technology with biosensors has caused more and more interest from both academic and industrial areas. With the advancement of microelectronics and microfabrication, it makes possible to fabricate a complete solution on an integrated chip with miniaturized size and low power consumption.This work presents a monolithic pH measurement system with power conditioning system for supply power derived from harvested energy. The proposed system includes a low-power, high linearity pH readout circuits with wide pH values (0-14) and a power conditioning unit based on low drop-out (LDO) voltage regulator. The readout circuit provides square-wave output with frequency being highly linear corresponding to the input pH values. To overcome the process variations, a simple calibration method is employed in the design which makes the output frequency stay constant over process, supply voltage and temperature variations. The prototype circuit is designed and fabricated in a standard 0.13-μm [micro-meter] CMOS process and shows good linearity to cover the entire pH value range from 0-14 while the voltage regulator provides a stable supply voltage for the system

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

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

Solid State Circuits Technologies

The evolution of solid-state circuit technology has a long history within a relatively short period of time. This technology has lead to the modern information society that connects us and tools, a large market, and many types of products and applications. The solid-state circuit technology continuously evolves via breakthroughs and improvements every year. This book is devoted to review and present novel approaches for some of the main issues involved in this exciting and vigorous technology. The book is composed of 22 chapters, written by authors coming from 30 different institutions located in 12 different countries throughout the Americas, Asia and Europe. Thus, reflecting the wide international contribution to the book. The broad range of subjects presented in the book offers a general overview of the main issues in modern solid-state circuit technology. Furthermore, the book offers an in depth analysis on specific subjects for specialists. We believe the book is of great scientific and educational value for many readers. I am profoundly indebted to the support provided by all of those involved in the work. First and foremost I would like to acknowledge and thank the authors who worked hard and generously agreed to share their results and knowledge. Second I would like to express my gratitude to the Intech team that invited me to edit the book and give me their full support and a fruitful experience while working together to combine this book