68 research outputs found

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

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    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

    Biocompatibility of a lab-on-a-pill sensor in artificial gastrointestinal environments

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    n this paper, we present a radiotelemetry sensor, designed as a lab-in-a-pill, which incorporates a two-channel microfabricated sensor platform for real-time measurements of temperature and pH. These two parameters have potential application for use in remote biological sensing (for example they may be used as markers that reflect the physiological environment or as indicators for disease, within the gastrointestinal tract). We have investigated the effects of biofouling on these sensors, by exploring their response time and sensitivity in a model in vitro gastrointestinal system. The artificial gastric and intestinal solutions used represent a model both for fasting, as well as for the ingestion of food and subsequent digestion to gastrointestinal chyme. The results showed a decrease in pH sensitivity after exposure of the sensors for 3 h. The response time also increased from an initial measurement time of 10 s in pure GI juice, to ca. 25 s following the ingestion of food and 80 s in simulated chyme. These in vitro results indicate that changes in viscosity in our model gastrointestinal system had a pronounced effect on the unmodified sensor

    A Flexible, Highly Integrated, Low Power pH Readout

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    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

    Ameliorating integrated sensor drift and imperfections: an adaptive "neural" approach

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

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    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

    A high aspect ratio Fin-Ion Sensitive Field Effect Transistor: compromises towards better electrochemical bio-sensing

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    The development of next generation medicines demand more sensitive and reliable label free sensing able to cope with increasing needs of multiplexing and shorter times to results. Field effect transistor-based biosensors emerge as one of the main possible technologies to cover the existing gap. The general trend for the sensors has been miniaturisation with the expectation of improving sensitivity and response time, but presenting issues with reproducibility and noise level. Here we propose a Fin-Field Effect Transistor (FinFET) with a high heigth to width aspect ratio for electrochemical biosensing solving the issue of nanosensors in terms of reproducibility and noise, while keeping the fast response time. We fabricated different devices and characterised their performance with their response to the pH changes that fitted to a Nernst-Poisson model. The experimental data were compared with simulations of devices with different aspect ratio, stablishing an advantage in total signal and linearity for the FinFETs with higher aspect ratio. In addition, these FinFETs promise the optimisation of reliability and efficiency in terms of limits of detection, for which the interplay of the size and geometry of the sensor with the diffusion of the analytes plays a pivotal role.Comment: Article submitted to Nano Letter

    Robust low power CMOS methodologies for ISFETs instrumentation

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    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

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

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    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

    In-line monitoring of electrolytes and urea during continuous renal replacement therapy

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    The individualization of dialysis treatment using a customized dialysate composition usually requires a continuous measurement of electrolytes and urea in blood. The current practices are spot measurements of blood samples either with blood gas analyzers or in the laboratory, involving considerable personnel effort. Furthermore, the measured values are time delayed and not available in a continuous fashion. In this paper we investigate an in-line concept for continuous monitoring of important blood parameters such as sodium, potassium, calcium and urea concentrations in blood serum using ion-selective electrodes. This concept is evaluated in a preclinical study with human packed red blood cells as a test medium over a period of 7 h. It has been shown that the electrolytes can be well monitored. In addition, we present first measurements with ion-sensitive field-effect transistors in a miniaturized sensor assembly. Therefore, new low-cost electronics for such ion-sensitive field-effect transistors have been developed

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

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    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
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