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

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

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

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

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

Application of Parylene C thin films in cardiac cell culturing

There are two main challenges when producing in vitro cell systems: first, to reconstitute the in situ cellular microenvironment, thus delivering more representative and reliable cell models for drug screening and disease modelling studies. Second, to record and quantify the electrical and chemical gradients across the culture. Ideally, both challenges should be accomplished within a single platform towards a lab-on-chip implementation. This research work investigates the application of Parylene C in cardiac cell scaffolding and its integrability with electrochemical monitoring technologies for measuring extracellular action potentials and pH. The surface properties of Parylene C in terms of water affinity, chemical composition and nanotopography were characterised before and after modifying the material's inherent hydrophobicity through oxygen plasma. A technology was developed to selectively alter the surface hydrophobicity of Parylene C through standard lithography and oxygen plasma, which is characterised by μm-resolution and long-term pattern stability, and can accurately control the extent of induced hydrophilicity, the pattern layout and 3-D geometry. The micro-engineered Parylene C films were employed as scaffolds for cardiac cells with immature physiological properties, such as neonatal rat ventricular myocytes (NRVM). The scaffolds promoted a more in situ cellular structure and organisation, while they improved important calcium (Ca2+) cycling parameters such as fluorescent amplitude, time to peak (Tp), time to 50% (T50) and 90% (T90) decay at 0.5-2 Hz field stimulation. The thickness of the patterned Parylene C films was found to regulate the shape of the cells by controlling their adhesion area on the Parylene substrate through a thickness-dependent hydrophobicity. NRVM on thin (2 μm) membranes tended to bridge across the hydrophobic areas and adopt a spread-out shape (average contact angle at the level of the nucleus was 64.51o). On the other hand, cells on thick (10 μm) films were mostly constrained on the hydrophilic areas and demonstrated a more elongated, cylindrical (in vivo-like) shape (average contact angle was 84.73o). The cylindrical shape and a significantly (p <0.05) denser microtubule structure in cells on thick films possibly suggest a more mature cardiomyocyte. However, there was no significant effect on the Ca2+ physiology between the two groups. The micro-patterning technology was able to deliver free-standing Parylene C thin films (2-10 μm) to study the effect of substrate elasticity and flexibility on the Ca2+ physiology of NRVM. Preliminary results showed that fluorescent amplitude and time to peak were improved in structured NRVM cultures on stand-alone Parylene films compared to rigid Parylene-coated glass surfaces. However, no such trend was present in Ca2+ release parameters (T50, T90). The flexibility of the culture substrate was also manipulated by employing free-standing micro-patterned Parylene C films of distinct thicknesses (2-10 μm), but did not affect the cellular Ca2+ physiology. Further biological validation is needed with a larger sample size to draw a certain conclusion. The cell patterning technology was transferred to commercially available planar Multi-Electrode arrays (MEAs) to demonstrate integrability of this method with existing monitoring tools. The micro-patterned MEAs induced anisotropic cardiomyocyte cultures, as they substantially increased the longitudinal-to-transverse velocity anisotropy ratios (1.09, n=4 to 1.69, n=2), promoting action potential propagation profiles that closer resembled native cardiac tissue. Furthermore, the micro-engineered MEAs were proven to be reusable, yielding a versatile and low-cost approach that is compatible with state-of-art recording equipment and can be employed as a more reliable, off-the-shelf tool for drug screening studies. Selective hydrophilic modification of Parylene C was also employed to activate locally the H+ sensing capacity of such films, implementing extended-gate pH sensors. The ability of Parylene C to act in a dual way - as an encapsulation material and as an active pH sensing membrane - was demonstrated. The material exhibited a distinguishable sensitivity dependent on the oxygen plasma recipe, relatively low drift rates and excellent encapsulation quality. Based on these principles, flexible Parylene-based high-density miniaturised electrode arrays were fabricated, employing Parylene as a flexible structure material and as a H+ sensing membrane for local detection of pH. The presented Parylene-based technology has the potential to deliver integrated lab-on-chip implementations for growing cells in vitro with controlled microtopography while monitoring the extracellular electrical and pH gradients across the culture in a non-invasive way, with application in drug screening and disease modelling.Open Acces

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

Development of a Proximal Soil Sensing System for the Continuous Management of Acid Soil

The notion that agriculturally productive land may be treated as a relatively homogeneous resource at thewithin-field scale is not sound. This assumption and the subsequent uniform application of planting material,chemicals and/or tillage effort may result in zones within a field being under- or over-treated. Arising fromthese are problems associated with the inefficient use of input resources, economically significant yield losses,excessive energy costs, gaseous or percolatory release of chemicals into the environment, unacceptable long-term retention of chemicals and a less-than-optimal growing environment. The environmental impact of cropproduction systems is substantial. In this millennium, three important issues for scientists and agrariancommunities to address are the need to efficiently manage agricultural land for sustainable production, the maintenance of soil and water resources and the environmental quality of agricultural land.Precision agriculture (PA) aims to identify soil and crop attribute variability, and manage it in an accurate and timely manner for near-optimal crop production. Unlike conventional agricultural management where an averaged whole-field analytical result is employed for decision-making, management in PA is based on site-specific soil and crop information. That is, resource application and agronomic practices are matched with variation in soil attributes and crop requirements across a field or management unit. Conceptually PA makes economic and environmental sense, optimising gross margins and minimising the environmental impact of crop production systems. Although the economic justification for PA can be readily calculated, concepts such as environmental containment and the safety of agrochemicals in soil are more difficult to estimate. However,it may be argued that if PA lessens the overall agrochemical load in agricultural and non-agricultural environments, then its value as a management system for agriculture increases substantially.Management using PA requires detailed information of the spatial and temporal variation in crop yield components, weeds, soil-borne pests and attributes of physical, chemical and biological soil fertility. However,detailed descriptions of fine scale variation in soil properties have always been difficult and costly to perform.Sensing and scanning technologies need to be developed to more efficiently and economically obtain accurate information on the extent and variability of soil attributes that affect crop growth and yield. The primary aim of this work is to conduct research towards the development of an 'on-the-go' proximal soil pH and lime requirement sensing system for real-time continuous management of acid soil. It is divided into four sections.Section one consists of two chapters; the first describes global and historical events that converged into the development of precision agriculture, while chapter two provides reviews of statistical and geostatistical techniques that are used for the quantification of soil spatial variability and of topics that are integral to the concept of precision agriculture. The review then focuses on technologies that are used for the complete enumeration of soil, namely remote and proximal sensing.Section two comprises three chapters that deal with sampling and mapping methods. Chapter three provides a general description of the environment in the experimental field. It provides descriptions of the field site,topography, soil condition at the time of sampling, and the spatial variability of surface soil chemical properties. It also described the methods of sampling and laboratory analyses. Chapter four discusses some of the implications of soil sampling on analytical results and presents a review that quantifies the accuracy,precision and cost of current laboratory techniques. The chapter also presents analytical results that show theloss of information in kriged maps of lime requirement resulting from decreases in sample size. The messageof chapter four is that the evolution of precision agriculture calls for the development of 'on-the-go' proximal soil sensing systems to characterise soil spatial variability rapidly, economically, accurately and in a timely manner. Chapter five suggests that for sparsely sampled data the choice of spatial modelling and mapping techniques is important for reliable results and accurate representations of field soil variability. It assesses a number of geostatistical methodologies that may be used to model and map non-stationary soil data, in this instance soil pH and organic carbon. Intrinsic random functions of order k produced the most accurate and parsimonious predictions of all of the methods tested.Section three consists of two chapters whose theme pertains to sustainable and efficient management of acid agricultural soil. Chapter six discusses soil acidity, its causes, consequences and current management practices.It also reports the global extent of soil acidity and that which occurs in Australia. The chapter closes by proposing a real-time continuous management system for the management of acid soil. Chapter seven reports results from experiments conducted towards the development of an 'on-the-go' proximal soil pH and lime requirement sensing system that may be used for the real-time continuous management of acid soil. Assessment of four potentiometric sensors showed that the pH Ion Sensitive Field Effect Transistor (ISFET)was most suitable for inclusion in the proposed sensing system. It is accurate and precise, drift and hysteresis are low, and most importantly it's response time is small. A design for the analytical system was presented based on flow injection analysis (FIA) and sequential injection analysis (SIA) concepts. Two different modes of operation were described. Kinetic experiments were conducted to characterise soil:0.01M CaCl2 pH(pHCaCl2) and soil:lime requirement buffer (pH buffer) reactions. Modelling of the pH buffer reactions described their sequential, biphasic nature. A statistical methodology was devised to predict pH buffer measurements using only initial reaction measurements at 0.5s, 1s, 2s and 3s measurements. The accuracy of the technique was 0.1pH buffer units and the bias was low. Finally, the chapter describes a framework for the development of a prototype soil pH and lime requirement sensing system and the creative design of the system.The final section relates to the management of acid soil by liming. Chapter eight describes the development of empirical deterministic models for rapid predictions of lime requirement. The response surface models are based on soil:lime incubations, pH buffer measurements and the selection of target pH values. These models are more accurate and more practical than more conventional techniques, and may be more suitably incorporated into the spatial decision-support system of the proposed real-time continuous system for the management of acid soil. Chapter nine presents a glasshouse liming experiment that was used to authenticate the lime requirement model derived in the previous chapter. It also presents soil property interactions and soil-plant relationships in acid and ameliorated soil, to compare the effects of no lime applications, single-rate and variable-rate liming. Chapter X presents a methodology for modelling crop yields in the presence of uncertainty. The local uncertainty about soil properties and the uncertainty about model parameters were accounted for by using indicator kriging and Latin Hypercube Sampling for the propagation of uncertainties through two regression functions; a yield response function and one that equates resultant pH after the application of lime. Under the assumptions and constraints of the analysis, single-rate liming was found to be the best management option

Modeling and Fundamental Design Considerations for Portable, Wearable and Implantable Electronic Biosensors

Chronic diseases such as cancer, diabetes, acquired immune deficiency syndrome (AIDS), etc. are leading causes of mortality all over the world. Portable, wearable and implantable biosensors can go a long way in preventing these premature deaths by frequent or continuous self-monitoring of vital health parameters