Circuits and Systems for Lateral Flow Immunoassay Biosensors at the Point-of-Care

Lateral Flow Immunoassays (LFIAs) are biosensors, which among others are used for the detection of infectious diseases. Due to their numerous advantages, they are particularly suitable for point of care testing, especially in developing countries where there is lack of medical healthcare centers and trained personnel. When the testing sample is positive, the LFIAs generate a color test line to indicate the presence of analyte. The intensity of the test line relates to the concentration of analyte. Even though the color test line can be visually observed for the accurate quantification of the results in LFIAs an external electronic reader is required. Existing readers are not fully optimized for point-of-care (POC) testing and therefore have significant limitations. This thesis presents the development of three readout systems that quantify the results of LFIAs. The first system was implemented as a proof of concept of the proposed method, which is based on the scanning approach without using any moving components or any extra optical accessories. Instead, the test line and the area around it, are scanned using an array of photodiodes (1 × 128). The small size of the pixels gives the system sufficient spatial resolution, to avoid errors due to positioning displacement of the strip. The system was tested with influenza A nucleoprotein and the results demonstrate its quantification capabilities. The second generation system is an optimized version of the proof of concept system. Optimization was performed in terms of matching the photodetectors wavelength with the maximum absorption wavelength of the gold nanoparticles presented in the tested LFIA. Ray trace simulations defined the optimum position of all the components in order to achieve uniform light distribution across the LFIA with the minimum number of light sources. An experimental model of the optical profile of the surface of LFIA was also generated for accurate simulations. Tests of the developed system with LFIAs showed its ability to quantify the results while having reduced power consumption and better limit of detection compared to the first system. Finally, a third generation system was realized which demonstrated the capability of having a miniaturized reader. The photodetector of the previous systems was replaced with a CMOS Image Sensor (CIS), specifically designed for this application. The pixel design was optimized for very low power consumption via biasing the transistors in subthreshold and by reusing the same amplifier for both photocurrent to voltage conversion and noise cancellation. With uniform light distribution at 525 nm and 76 frames/s the chip has 1.9 mVrms total output referred noise and a total power consumption of 21 μW. In tests with lateral flow immunoassay, this system detected concentrations of influenza A nucleoprotein from 0.5 ng/mL to 200 ng/mL

Contribution to time domain readout circuits design for multi-standard sensing system for low voltage supply and high-resolution applications

Mención Internacional en el título de doctorThis research activity has the purpose of open new possibilities in the design of capacitance-to-digital converters (CDCs) by developing a solution based on time domain conversion. This can be applied to applications related with the Internet-of-Things (IoT). These applications are present in any electronic devices where sensing is needed. To be able to reduce the area of the whole system with the required performance, micro-electromechanical systems (MEMS) sensors are used in these applications. We propose a new family of sensor readout electronics to be integrated with MEMS sensors. Within the time domain converters, Dual Slope (DS) topology is very interesting to explore a new compromise between performances, area and power consumption. DS topology has been extensively used in instrumentation. The simplicity and robustness of the blocks inside classical DS converters it is the main advantage. However, they are not efficient for applications where higher bandwidth is required. To extend the bandwidth, DS converters have been introduced into ΔΣ loops. This topology has been named as integrating converters. They increase the bandwidth compare to classical DS architecture but at the expense of higher complexity. In this work we propose the use of a new family of DS converters that keep the advantages of the classical architecture and introduce noise shaping. This way the bandwidth is increased without extra blocks. The Self-Compensated noise-shaped DS converter (the name given to the new topology) keeps the signal transfer function (STF) and the noise transfer function (NTF) of Integrating converters. However, we introduce a new arrangement in the core of the converter to do noise shaping without extra circuitry. This way the simplicity of the architecture is preserved. We propose to use the Self-Compensated DS converter as a CDC for MEMS sensors. This work makes a study of the best possible integration of the two blocks to keep the signal integrity considering the electromechanical behavior of the sensor. The purpose of this front-end is to be connected to any kind of capacitive MEMS sensor. However, to prove the concepts developed in this thesis the architecture has been connected to a pressure MEMS sensor. An experimental prototype was implemented in 130-nm CMOS process using the architecture mentioned before. A peak SNR of 103.9 dB (equivalent to 1Pa) has been achieved within a time measurement of 20 ms. The final prototype has a power consumption of 220 μW with an effective area of 0.317 mm2. The designed architecture shows good performance having competitive numbers against high resolution topologies in amplitude domain.Esta actividad de investigación tiene el propósito de explorar nuevas posibilidades en el diseño de convertidores de capacitancia a digital (CDC) mediante el desarrollo de una solución basada en la conversión en el dominio del tiempo. Estos convertidores se pueden utilizar en aplicaciones relacionadas con el mercado del Internet-de-las-cosas (IoT). Hoy en día, estas aplicaciones están presentes en cualquier dispositivo electrónico donde se necesite sensar una magnitud. Para poder reducir el área de todo el sistema con el rendimiento requerido, se utilizan sensores de sistemas micro-electromecánicos (MEMS) en estas aplicaciones. Proponemos una nueva familia de electrónica de acondicionamiento para integrar con sensores MEMS. Dentro de los convertidores de dominio de tiempo, la topología del doble-rampa (DS) es muy interesante para explorar un nuevo compromiso entre rendimiento, área y consumo de energía. La topología de DS se ha usado ampliamente en instrumentación. La simplicidad y la solidez de los bloques dentro de los convertidores DS clásicos es la principal ventaja. Sin embargo, no son eficientes para aplicaciones donde se requiere mayor ancho de banda. Para ampliar el ancho de banda, los convertidores DS se han introducido en bucles ΔΣ. Esta topología ha sido nombrada como Integrating converters. Esta topología aumenta el ancho de banda en comparación con la arquitectura clásica de DS, pero a expensas de una mayor complejidad. En este trabajo, proponemos el uso de una nueva familia de convertidores DS que mantienen las ventajas de la arquitectura clásica e introducen la configuración del ruido. De esta forma, el ancho de banda aumenta sin bloques adicionales. El convertidor Self-Compensated noise-shaped DS (el nombre dado a la nueva topología) mantiene la función de transferencia de señal (STF) y la función de transferencia de ruido (NTF) de los Integrating converters. Sin embargo, presentamos una nueva topología en el núcleo del convertidor para conformar el ruido sin circuitos adicionales. De esta manera, se preserva la simplicidad de la arquitectura. Proponemos utilizar el Self-Compensated noise-shaped DS como un CDC para sensores MEMS. Este trabajo hace un estudio de la mejor integración posible de los dos bloques para mantener la integridad de la señal considerando el comportamiento electromecánico del sensor. El propósito de este circuito de acondicionamiento es conectarse a cualquier tipo de sensor MEMS capacitivo. Sin embargo, para demostrar los conceptos desarrollados en esta tesis, la arquitectura se ha conectado a un sensor MEMS de presión. Se ha implementado dos prototipos experimentales en un proceso CMOS de 130-nm utilizando la arquitectura mencionada anteriormente. Se ha logrado una relación señal-ruido máxima de 103.9 dB (equivalente a 1 Pa) con un tiempo de medida de 20 ms. El prototipo final tiene un consumo de energía de 220 μW con un área efectiva de 0.317 mm2. La arquitectura diseñada muestra un buen rendimiento comparable con las arquitecturas en el dominio de la amplitud que muestran resoluciones equivalentes.Programa Oficial de Doctorado en Ingeniería Eléctrica, Electrónica y AutomáticaPresidente: Pieter Rombouts.- Secretario: Alberto Rodríguez Pérez.- Vocal: Dietmar Strãußnig

Low-power CMOS digital-pixel Imagers for high-speed uncooled PbSe IR applications

This PhD dissertation describes the research and development of a new low-cost medium wavelength infrared MWIR monolithic imager technology for high-speed uncooled industrial applications. It takes the baton on the latest technological advances in the field of vapour phase deposition (VPD) PbSe-based medium wavelength IR (MWIR) detection accomplished by the industrial partner NIT S.L., adding fundamental knowledge on the investigation of novel VLSI analog and mixed-signal design techniques at circuit and system levels for the development of the readout integrated device attached to the detector. The work supports on the hypothesis that, by the use of the preceding design techniques, current standard inexpensive CMOS technologies fulfill all operational requirements of the VPD PbSe detector in terms of connectivity, reliability, functionality and scalability to integrate the device. The resulting monolithic PbSe-CMOS camera must consume very low power, operate at kHz frequencies, exhibit good uniformity and fit the CMOS read-out active pixels in the compact pitch of the focal plane, all while addressing the particular characteristics of the MWIR detector: high dark-to-signal ratios, large input parasitic capacitance values and remarkable mismatching in PbSe integration. In order to achieve these demands, this thesis proposes null inter-pixel crosstalk vision sensor architectures based on a digital-only focal plane array (FPA) of configurable pixel sensors. Each digital pixel sensor (DPS) cell is equipped with fast communication modules, self-biasing, offset cancellation, analog-to-digital converter (ADC) and fixed pattern noise (FPN) correction. In-pixel power consumption is minimized by the use of comprehensive MOSFET subthreshold operation. The main aim is to potentiate the integration of PbSe-based infra-red (IR)-image sensing technologies so as to widen its use, not only in distinct scenarios, but also at different stages of PbSe-CMOS integration maturity. For this purpose, we posit to investigate a comprehensive set of functional blocks distributed in two parallel approaches: • Frame-based “Smart” MWIR imaging based on new DPS circuit topologies with gain and offset FPN correction capabilities. This research line exploits the detector pitch to offer fully-digital programmability at pixel level and complete functionality with input parasitic capacitance compensation and internal frame memory. • Frame-free “Compact”-pitch MWIR vision based on a novel DPS lossless analog integrator and configurable temporal difference, combined with asynchronous communication protocols inside the focal plane. This strategy is conceived to allow extensive pitch compaction and readout speed increase by the suppression of in-pixel digital filtering, and the use of dynamic bandwidth allocation in each pixel of the FPA. In order make the electrical validation of first prototypes independent of the expensive PbSe deposition processes at wafer level, investigation is extended as well to the development of affordable sensor emulation strategies and integrated test platforms specifically oriented to image read-out integrated circuits. DPS cells, imagers and test chips have been fabricated and characterized in standard 0.15μm 1P6M, 0.35μm 2P4M and 2.5μm 2P1M CMOS technologies, all as part of research projects with industrial partnership. The research has led to the first high-speed uncooled frame-based IR quantum imager monolithically fabricated in a standard VLSI CMOS technology, and has given rise to the Tachyon series [1], a new line of commercial IR cameras used in real-time industrial, environmental and transportation control systems. The frame-free architectures investigated in this work represent a firm step forward to push further pixel pitch and system bandwidth up to the limits imposed by the evolving PbSe detector in future generations of the device.La present tesi doctoral descriu la recerca i el desenvolupament d'una nova tecnologia monolítica d'imatgeria infraroja de longitud d'ona mitja (MWIR), no refrigerada i de baix cost, per a usos industrials d'alta velocitat. El treball pren el relleu dels últims avenços assolits pel soci industrial NIT S.L. en el camp dels detectors MWIR de PbSe depositats en fase vapor (VPD), afegint-hi coneixement fonamental en la investigació de noves tècniques de disseny de circuits VLSI analògics i mixtes pel desenvolupament del dispositiu integrat de lectura unit al detector pixelat. Es parteix de la hipòtesi que, mitjançant l'ús de les esmentades tècniques de disseny, les tecnologies CMOS estàndard satisfan tots els requeriments operacionals del detector VPD PbSe respecte a connectivitat, fiabilitat, funcionalitat i escalabilitat per integrar de forma econòmica el dispositiu. La càmera PbSe-CMOS resultant ha de consumir molt baixa potència, operar a freqüències de kHz, exhibir bona uniformitat, i encabir els píxels actius CMOS de lectura en el pitch compacte del pla focal de la imatge, tot atenent a les particulars característiques del detector: altes relacions de corrent d'obscuritat a senyal, elevats valors de capacitat paràsita a l'entrada i dispersions importants en el procés de fabricació. Amb la finalitat de complir amb els requisits previs, es proposen arquitectures de sensors de visió de molt baix acoblament interpíxel basades en l'ús d'una matriu de pla focal (FPA) de píxels actius exclusivament digitals. Cada píxel sensor digital (DPS) està equipat amb mòduls de comunicació d'alta velocitat, autopolarització, cancel·lació de l'offset, conversió analògica-digital (ADC) i correcció del soroll de patró fixe (FPN). El consum en cada cel·la es minimitza fent un ús exhaustiu del MOSFET operant en subllindar. L'objectiu últim és potenciar la integració de les tecnologies de sensat d'imatge infraroja (IR) basades en PbSe per expandir-ne el seu ús, no només a diferents escenaris, sinó també en diferents estadis de maduresa de la integració PbSe-CMOS. En aquest sentit, es proposa investigar un conjunt complet de blocs funcionals distribuïts en dos enfocs paral·lels: - Dispositius d'imatgeria MWIR "Smart" basats en frames utilitzant noves topologies de circuit DPS amb correcció de l'FPN en guany i offset. Aquesta línia de recerca exprimeix el pitch del detector per oferir una programabilitat completament digital a nivell de píxel i plena funcionalitat amb compensació de la capacitat paràsita d'entrada i memòria interna de fotograma. - Dispositius de visió MWIR "Compact"-pitch "frame-free" en base a un novedós esquema d'integració analògica en el DPS i diferenciació temporal configurable, combinats amb protocols de comunicació asíncrons dins del pla focal. Aquesta estratègia es concep per permetre una alta compactació del pitch i un increment de la velocitat de lectura, mitjançant la supressió del filtrat digital intern i l'assignació dinàmica de l'ample de banda a cada píxel de l'FPA. Per tal d'independitzar la validació elèctrica dels primers prototips respecte a costosos processos de deposició del PbSe sensor a nivell d'oblia, la recerca s'amplia també al desenvolupament de noves estratègies d'emulació del detector d'IR i plataformes de test integrades especialment orientades a circuits integrats de lectura d'imatge. Cel·les DPS, dispositius d'imatge i xips de test s'han fabricat i caracteritzat, respectivament, en tecnologies CMOS estàndard 0.15 micres 1P6M, 0.35 micres 2P4M i 2.5 micres 2P1M, tots dins el marc de projectes de recerca amb socis industrials. Aquest treball ha conduït a la fabricació del primer dispositiu quàntic d'imatgeria IR d'alta velocitat, no refrigerat, basat en frames, i monolíticament fabricat en tecnologia VLSI CMOS estàndard, i ha donat lloc a Tachyon, una nova línia de càmeres IR comercials emprades en sistemes de control industrial, mediambiental i de transport en temps real.Postprint (published version

Adaptive beam control and analysis in fluorescence microscopy

This thesis details three novel advances in instrumentation that are each related to performance improvement in wide-field visible-spectrum imaging systems. In each case our solution concerns the assessment and improvement of optical imaging quality. The three instruments are as follows: The first is a portable transmission microscope which is able to correct for artificially induced aberrations using adaptive optics (AO). The specimens and the method of introducing aberrations into the optical system can be altered to simulate the performance of AO-correction in both astronomical and biological imaging. We present the design and construction of the system alongside before-and-after AO-correction images for simulated astronomical and biological images. The second instrument is a miniature endoscope camera sensor we re-purposed for use as a quantitative beam analysis probe using a custom high dynamic range (HDR) imaging and reconstruction procedure. This allowed us to produce quantitative flux maps of the illumination beam intensity profile within several operational fluorescence microscope systems. The third and final project in this thesis was concerned with an adaptive modification to the light sheet illumination beam used in light sheet microscopy, specifically for a single plane illumination microscope (SPIM), embracing the trade-off between the thickness of the light sheet and its extent across the detection field-of-view. The focal region of the beam was made as small as possible and then matched to the shape of curved features within a biological specimen by using a spatial light modulator (SLM) to alter the light sheet focal length throughout the vertical span of the sheet. We used the HDR beam profiling camera probe mentioned earlier to assess the focal shape and quality of the beam. The resulting illumination beam may in the future be used in a modified SPIM system to produce fluorescence microscope images with enhanced optical sectioning of specific curved features

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

Characterisation of CMOS APS Technologies for Space Applications

In recent years, the performance of scientific CMOS active pixel sensors has been improved to the point that it is now approaching that of the current silicon sensor of choice, CCDs. For some applications, CMOS APSs is believed to present significant advantages over CCDs, such as improved radiation hardness. In this work, the effect of radiation damage on a ‘baseline’ commercial APS, e2v technologies’ Jade APS, is characterised in response to gamma, proton and heavy ion irradiation. Specific performance problems encountered during this radiation characterisation, such as dark current non-uniformity under gamma irradiation, random telegraph signals under proton irradiation, and single event effects under heavy ion irradiation are described and analyzed. The X-ray spectroscopic imaging performance of the device is measured and compared to the Ocean Colour Imager APS test array showing progress towards a high frame rate spectroscopic X-ray imager for space science. The implications of these results for using similar devices in space applications are considered. Furthermore, possible novel techniques for measuring inter-pixel responsivity non-uniformity, heavy ion detection and spectroscopy, and measuring the dynamics of radiation-induced trap formation are discussed

Development of CMOS active pixel sensors

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.This thesis describes an investigation into the suitability of complementary metal oxide semiconductor (CMOS) active pixel sensor (APS) devices for scientific imaging applications. CMOS APS offer a number of advantages over the established charge-coupled device (CCD) technology, primarily in the areas of low power consumption, high-speed parallel readout and random (X-Y) addressing, increased system integration and improved radiation hardness. The investigation used a range of newly designed Test Structures in conjunction with a range of custom developed test equipment to characterise device performance. Initial experimental work highlighted the significant non-linearity in the charge conversion gain (responsivity) and found the read noise to be limited by the kTC component due to resetting of the pixel capacitance. The major experimental study investigated the contribution to dark signal due to hot-carrier injection effects from the in-pixel transistors during read-out and highlighted the importance of the contribution at low signal levels. The quantum efficiency (QE) and cross-talk were also investigated and found to be limited by the pixel fill factor and shallow depletion depth of the photodiode. The work has highlighted the need to design devices to explore the effects of individual components rather than stand-alone imaging devices and indicated further developments are required for APS technology to compete with the CCD for high-end scientific imaging applications. The main areas requiring development are in achieving backside illuminated, deep depletion devices with low dark signal and low noise sampling techniques.Engineering and Physical Sciences Research Council; e2v Technologie

Low-power CMOS circuit design for fast infrared imagers

La present tesi de màster detalla novedoses tècniques circuitals per al disseny de circuits integrats digitals CMOS de lectura compactes, de baixa potència i completament programables, destinats a aplicacions d'IR d'alta velocitat operant a temperatura ambient. En aquest sentit, el treball recull i amplia notablement la recerca iniciada en el Projecte Final de Carrera "Tècniques de disseny CMOS per a sistemes de visió híbrids de pla focal modular" obtenint-se resultats específics en tres diferents àrees: Recerca de l'arquitectura òptima d'FPA, des del punt de vista funcional i de construcció física. Disseny d'un conjunt complet de blocs bàsics d'autopolarització, compensació de la capacitat d'entrada i del corrent d'obscuritat, conversió A/D i interfície d'E/S exclusivament digital, amb compensació de l'FPN. Aplicació industrial real: Integraciió de tres versions diferents de píxel per sensors PbSe d'IR i fabricació de mòduls ROIC monolítics i híbrids en tecnologia CMOS estàndard 0.35&·956;m 2-PoliSi4-metall. Caracterització elèctrica i òptica-preliminar de les llibreries de disseny

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

Primitives and design of the intelligent pixel multimedia communicator

Communication systems arc an ever more essential component of our modern global society. Mobile communications systems are still in a state of rapid advancement and growth. Technology is constantly evolving at a rapid pace in ever more diverse areas and the emerging mobile multimedia based communication systems offer new challenges for both current and future technologies. To realise the full potential of mobile multimedia communication systems there is a need to explore new options to solve some of the fundamental problems facing the technology. In particular, the complexity of such a system within an infrastructure framework that is inherently limited by its power sources and has very restricted transmission bandwidth demands new methodologies and approaches