Блок прецизійного вимірювання температури головного мозку у зоні оптичного опромінення

Тема магістерської дисертації: “Блок прецизійного вимірювання температури головного мозку у зоні оптичного опромінення”. Обсяг дисертації становить 63 сторінку, міститься 17 таблиць, 15 рисунків. Загалом опрацьовано 38 джерело. Актуальність: Робота є частиною проекту між двома науковими закладами Korea Institute of Science and Technology(KIST) та Korean advanced Institute of Science and Technology(KAIST), що включає в себе створення приладу з наступними функціями: ● запис електрофізіологічного сигналу головного мозку; ● реалізація оптичного опромінення ділянки головного мозку; ● вимірювання температури опромінюваної ділянки головного мозку за допомогою масиву фотодіодів. Завдання даної роботи є створення інтегральної мікросхеми для вимірювання струму та перетворення його в цифровий сигнал для вимірювання температури . Метою МД є розробка інтегральної мікросхеми для вимірювання струму датчиків температури. Завдання: • Розробка електрично-принципової схеми • Підтвердження виконання функції • Розташування та створення топології • Після топологічна симуляція • Виготовлення прототипу інтегральної мікросхеми • Створення програмного забезпечення для керування чіпом. • Лабораторні випробування створеного протопипу системи. Об’єкт дослідження: методи і засоби контролю температури ділянки мозку під час терапії оптичним опроміненням. Предмет дослідження: засоби перетворення температури у електричний сигнал, підсилення, фільтрації, перетворення у цифрову форму і технічна реалізація блоку вимірювання температури. Методи дослідження – використання пакетів прикладних програм для створення принципово електричної схеми, проведення симуляції роботи системи, створення топології системи. Основні результати: сформовано технічні вимоги до прототипу, розроблено принципову електричну схему, розроблено топологію інтегральної мікросхеми, розроблено топологію друкованої плати блоку, виготовлено прототип інтегральної мікросхеми, створено програмний продукт для роботи з розробленим прототипом, проведені випробування прототипу в лабораторії.Theme of the thesis: “Integrated circuit for brain temperature measurement in the area of optical stimulation” The amount of work is 63 pages long, contains 15 illustrations, 17 tables. In total, 38 sources were processed. Relevance: The work is part of a project between two research institutes, the Korea Institute of Science and Technology (KIST) and the Korean Advanced Institute of Science and Technology (KAIST), which includes the development of a device with the following functions: ● recording of a brain electrophysiological signal; ● implementation of optical irradiation of the brain; ● measuring the temperature of the irradiated area of the brain using an array of photodiodes. The purpose of this work is a development of an integrated circuit for detection of temperature sensors current. Tasks: • Schematic design • System level confirmation • Placement and layout • Post-layout simulation • Manufacturing of the system prototype. • Creating software to control the chip. • Laboratory tests of the created system prototype. Subject of research: means of temperature conversion into electrical signal, amplification, filtration, digital conversion and technical implementation of temperature measurement unit. Research methods: the use of application software packages to create a schematic of electrical circuit, simulation of the system, creating a system topology. Main results: technical requirements to the prototype are formed, the electric scheme is designed, the topology of the integrated circuit is developed, the topology of the printed circuit board of the block is designed, the prototype of the chip is manufactured; the software product to control the developed prototype is created.Тема магистерской диссертации: "Блок прецизионного измерения температуры головного мозга в зоне оптического излучения". Объем диссертации составляет 61 страницу, содержится 17 таблиц, 15 рисунков. В общем обработано 38 источник. Актуальность: Работа является частью проекта между двумя научными учреждениями Korea Institute of Science and Technology (KIST) и Korean advanced Institute of Science and Technology (KAIST), включающегов себя создание прибора со следующими функциями: ● запись электрофизиологического сигнала головного мозга ● реализация оптического излучения участки головного мозга ● измерения температуры облучаемого участка головного мозга с помощью массива фотодиодов. Задача данной работы является создание интегральной микросхемы для измерения тока и преобразования его в цифровой сигнал для измерения температуры. Целью МД является разработка интегральной микросхемы для измерения тока датчиков температуры. Задачи: • Разработка электрически принципиальной схемы • Подтверждение выполнения функции • Расположение и создания топологии • После топологическая симуляция •Изготовление прототипа чипа • Создание программного обеспечения для управления чипом. • Лабораторные испытания созданного протопип системы. Объект исследования: методы и средства контроля температуры участки мозга во время терапии оптическим облучением. Предмет исследования: средства преобразования температуры в электрический сигнал, усиления, фильтрации, преобразования в цифровую форму и техническая реализация блока измерения температуры. Методы исследования - использование пакетов прикладных программ для создания принципиально электрической схемы, проведения симуляции работы системы, создания топологии системы. Основные результаты: сформирована технические требования к прототипу, разработана принципиальная электрическая схема, разработаны топологию интегральной микросхемы, разработаны топологию печатной платы блока, изготовлено прототип чипа, создан программный продукт для работы с разработанным прототипом, проведены испытания прототипа в лаборатории

A Label Free CMOS-Based Smart Petri Dish for Cellular Analysis

RÉSUMÉ Le dépistage de culture cellulaire à haut débit est le principal défi pour une variété d’applications des sciences de la vie, y compris la découverte de nouveaux médicaments et le suivi de la cytotoxicité. L’analyse classique de culture cellulaire est généralement réalisée à l’aide de techniques microscopiques non-intégrées avec le système de culture cellulaire. Celles-ci sont laborieuses spécialement dans le cas des données recueillies en temps réel ou à des fins de surveillance continue. Récemment, les micro-réseaux cellulaires in-vitro ont prouvé de nombreux avantages dans le domaine de surveillance des cellules en réduisant les coûts, le temps et la nécessité d’études sur des modèles animaux. Les microtechniques, y compris la microélectronique et la microfluidique,ont été récemment utilisé dans la biotechnologie pour la miniaturisation des systèmes biologiques et analytiques. Malgré les nombreux efforts consacrés au développement de dispositifs microfluidiques basés sur les techniques de microscopie optique, le développement de capteurs intégrés couplés à des micropuits pour le suivi des paramètres cellulaires tel que la viabilité, le taux de croissance et cytotoxicité a été limité. Parmi les différentes méthodes de détection disponibles, les techniques capacitives offrent une plateforme de faible complexité. Celles-ci ont été considérablement utilisées afin d’étudier l’interaction cellule-surface. Ce type d’interaction est le plus considéré dans la majorité des études biologiques. L’objectif de cette thèse est de trouver des nouvelles approches pour le suivi de la croissance cellulaire et la surveillance de la cytotoxicité à l’aide d’un réseau de capteurs capacitifs entièrement intégré. Une plateforme hybride combinant un circuit microélectronique et une structure microfluidique est proposée pour des applications de détection de cellules et de découverte de nouveaux médicaments. Les techniques biologiques et chimiques nécessaires au fonctionnement de cette plateforme sont aussi proposées. La technologie submicroniques Standard complementary metal-oxide-Semiconductor (CMOS) (TSMC 0.35 μm) est utilisée pour la conception du circuit microélectronique de cette plateforme. En outre, les électrodes sont fabriquées selon le processus CMOS standard sans la nécessité d’étapes de post-traitement supplémentaires. Ceci rend la plateforme proposée unique par rapport aux plateformes de dépistage de culture cellulaire à haut débit existantes. Plusieurs défis ont été identifiés durant le développement de cette plateforme comme la sensibilité, la bio-compatibilité et la stabilité et les solutions correspondantes sont fournies.----------ABSTRACT High throughput cell culture screening is a key challenge for a variety of life science applications, including drug discovery and cytotoxicity monitoring. Conventional cell culture analysis is widely performed using microscopic techniques that are not integrated into the target cell culture system. Additionally, these techniques are too laborious in particular to be used for real-time and continuous monitoring purposes. Recently, it has been proved that invitro cell microarrays offer great advantages for cell monitoring applications by reducing cost, time, and the need for animal model studies. Microtechnologies, including microelectronics and microfluidics, have been recently used in biotechnology for miniaturization of biological and analytical systems. Despite many efforts in developing microfluidic devices using optical microscopy techniques, less attention have been paid on developing fully integrated sensors for monitoring cell parameters such as viability, growth rate, and cytotoxicity. Among various available sensing methods, capacitive techniques offer low complexity platforms. This technique has significantly attracted attentions for the study of cell-surface interaction which is widely considered in biological studies. This thesis focuses on new approaches for cell growth and cytotoxicity monitoring using a fully integrated capacitive sensor array. A hybrid platform combining microelectronic circuitry and microfluidic structure is proposed along with other required biological and chemical techniques for single cell detection and drug discovery applications. Standard submicron complementary metal–oxide–semiconductor (CMOS) technology (TSMC 0.35 μm) is used to develop the microelectronic part of this platform. Also, the sensing electrodes are fabricated in standard CMOS process without the need for any additional post processing step, which makes the proposed platform unique compared to other state of the art high throughput cell assays. Several challenges in implementing this platform such as sensitivity, bio-compatibility, and stability are discussed and corresponding solutions are provided. Specifically, a new surface functionalization method based on polyelectrolyte multilayers deposition is proposed to enhance cell-electrode adherence and to increase sensing electrodes’ life time. In addition, a novel technique for microwell fabrication and its integration with the CMOS chip is proposed to allow parallel screening of cells. With the potential to perform inexpensive, fast, and real-time cell analyses, the proposed platform opens up the possibility to transform from passive traditional cell assays to a smart on-line monitoring system

New Architectures and Circuits for Pushing the Dynamic Range and Multiplexing Boundaries of CMOS-Integrated Sensors

Over the last decades, CMOS-integrated sensors have made impressive progress in performance, form-factor, and energy-efficiency for various applications such as imaging, physical/chemical sensing, bio/health monitoring. In the era of the artificial intelligence (AI) and the internet-of-things (IoT), such CMOS-integrated sensors are essential for massive and comprehensive data acquisition, where sensing range (or dynamic range), signal fidelity (or signal-to-noise ratio), and data throughput are key factors. Towards pushing the boundaries of such sensing capabilities, in this dissertation, novel sensing architectures are presented with energy/area-efficient circuit design techniques for multi-channel CMOS optical sensors and neural interfaces. The first topic is a fully-integrated, wide linear dynamic range optical sensor array combining linear and single-photon avalanche diode operation within each pixel. A pulse-counting readout scheme provides in-pixel digitization in an area-efficient manner for both operation modes, enabling fully parallel measurement across the array. The proposed dual-mode optical sensor array alternately requires high-voltage(10-20 V) and low-voltage supply (2-5 V) for reverse bias of the photodiodes, which is provided by a reconfigurable, closed-loop high-voltage charge pump in the same substrate. An 8 x 8 array architecture along with the dual-mode bias generator is fabricated in a general purpose 180 nm CMOS process and demonstrates 129 dB dynamic range while maintaining linear photoresponse operating with a dual-mode frame rate of 20 Hz. The second topic is a new approach for applying code-division multiplexing (CDM) to current-mode and voltage-mode sensor arrays with analog-domain orthogonal encoding directly in a shared, single analog-front-end circuit, which enables simultaneous readout for multiple sensors. The approach is applied to a 8 x 16 array of CMOS-integrated photodetectors and implemented in a general purpose 180 nm CMOS process, where the 16 channel CDM-based oversampling readout achieves an SNR improvement of more than 12 dB compared with time-division multiplexing at the same sampling rate. In addition, a CDM-based neural recording architecture is presented, which offers a significant tolerance to interference that can be injected through long cables

High-precision fluorescence photometry for real-time biomarkers detection

Les derniers évènements planétaires et plus particulièrement l'avènement sans précédent du nouveau coronavirus augmente la demande pour des appareils de test à proximité du patient. Ceux-ci fonctionnent avec une batterie et peuvent identifier rapidement des biomarqueurs cibles. Pareils systèmes permettent aux utilisateurs, disposant de connaissances limitées en la matière, de réagir rapidement, par exemple dans la détection d'un cas positif de COVID-19. La mise en œuvre de l'élaboration d'un tel instrument est un projet multidisciplinaire impliquant notamment la conception de circuits intégrés, la programmation, la conception optique et la biologie, demandant tous une maîtrise pointue des détails. De plus, l'établissement des spécifications et des exigences pour mesurer avec précision les interactions lumière-échantillon s'additionnent au besoin d'expérience dans la conception et la fabrication de tels systèmes microélectriques personnalisés et nécessitent en elles-mêmes, une connaissance approfondie de la physique et des mathématiques. Ce projet vise donc à concevoir et à mettre en œuvre un appareil sans fil pour détecter rapidement des biomarqueurs impliqués dans des maladies infectieuses telles que le COVID-19 ou des types de cancers en milieu ambulatoire. Cette détection se fait grâce à des méthodes basées sur la fluorescence. La spectrophotométrie de fluorescence permet aux médecins d'identifier la présence de matériel génétique viral ou bactérien tel que l'ADN ou l'ARN et de les caractériser. Les appareils de paillasse sont énormes et gourmand énergétiquement tandis que les spectrophotomètres à fluorescence miniatuarisés disponibles dans le commerce sont confrontés à de nombreux défis. Ces appareils miniaturisés ont été découverts en tirant parti des diodes électroluminescentes (DEL) à semi-conducteurs peu coûteuses et de la technologie des circuits intégrés. Ces avantages aident les scientifiques à réduire les erreurs possibles, la consommation d'énergie et le coût du produit final utilisé par la population. Cependant, comme leurs homologues de paillasse, ces appareils POC doivent quantifier les concentrations en micro-volume d'analytes sur une large gamme de longueurs d'onde suivant le cadre d'une économie en ressources. Le microsystème envisagé bénéficie d'une approche de haute précision pour fabriquer une puce microélectronique CMOS. Ce procédé se fait de concert avec un boîtier personnalisé imprimé en 3D pour réaliser le spectrophotomètre à la fluorescence nécessaire à la détection quantitative d'analytes en microvolume. En ce qui a trait à la conception de circuits, une nouvelle technique de mise à auto-zeroing est appliquée à l'amplificateur central, celui-ci étant linéarisé avec des techniques de recyclage et de polarisation adaptative. Cet amplificateur central est entièrement différentiel et est utilisé dans un amplificateur à verrouillage pour récupérer le signal d'intérêt éclipsé par le bruit. De plus, l'augmentation de la sensibilité de l'appareil permet des mesures quantitatives avec des concentrations en micro-volume d'analytes ayant moins d'erreurs de prédiction de concentration. Cet avantage cumulé à une faible consommation d'énergie, un faible coût, de petites dimensions et un poids léger font de notre appareil une solution POC prometteuse dans le domaine de la spectrophotométrie de fluorescence. La validation de ce projet s'est fait en concevant, fabriquant et testant un prototype discret et sans fil. Son article de référence a été publié dans IEEE LSC 2018. Quant à la caractérisation et l'interprétation du prototype d'expériences in vitro à l'aide d'une interface MATLAB personnalisée, cet article a été publié dans IEEE Sensors journal (2021). Les circuits intégrés et les photodétecteurs ont été fabriqués ont été conçus et fabriqués par Cadence en 2019. Relativement aux solutions de circuit proposées, elles ont été fabriquées avec la technologie CMOS 180 nm et publiées lors de la conférence IEEE MWSCAS 2020. Tout comme cette dernière contribution, les expériences in vitro avec le dispositif proposé incluant la puce personnalisée et le boîtier imprimé en 3D ont été réalisés et les résultats électriques et optiques ont été soumis au IEEE Journal of Solid-State Circuits (JSSC 2022).The most recent and unprecedented experience of the novel coronavirus increases the demand for battery-operated near-patient testing devices that can rapidly identify the target biomarkers. Such systems enable end-users with limited resources to quickly get feedback on various medical tests, such as detecting positive COVID-19 cases. Implementing such a device is a multidisciplinary project dealing with multiple areas of expertise, including integrated circuit design, programming, optical design, and biology, each of which needs a firm grasp of details. Alongside the need for experience in designing and manufacturing custom microelectronic systems, establishing the specifications and requirements to precisely measure the light-sample interactions requires an in-depth knowledge of physics and mathematics. This project aims to design and implement a wireless point-of-care (POC) device to rapidly detect biomarkers involved in infectious diseases such as COVID-19 or different types of cancers in an ambulatory setting using fluorescence-based methods. Fluorescence spectrophotometry allows physicians to identify and characterize viral or bacterial genetic materials such as DNAs or RNAs. The benchtop devices that are currently available are bulky and power-hungry, whereas the commercially available miniaturized fluorescence spectrophotometers are facing many challenges. Many of these difficulties have been resolved in literature thanks to inexpensive semiconductor light-emitting diodes (LEDs) and integrated circuits technology. Such advantages aid scientists in decreasing the size, power consumption, and cost of the final product for end-users. However, like the benchtop counterparts, such POC devices must quantify micro-volume concentrations of analytes across a wide wave length range under an economy of resources. The envisioned microsystem benefits from a high-precision approach to fabricating a CMOS microelectronic chip combined with a custom 3D-printed housing. This implementation results in a fluorescence spectrophotometer for qualitative and quantitative detection of micro-volume analytes. In terms of circuit design, a novel switched-biasing ping-pong auto-zeroed technique is applied to the core amplifier, linearized with recycling and adaptive biasing techniques. The fully differential core amplifier is utilized within a lock-in amplifier to retrieve the signal of interest overshadowed by noise. Increasing the device's sensitivity allows quantitative measurements down to micro-volume concentrations of analytes with less concentration prediction error. Such an advantage, along with low-power consumption, low cost, low weight, and small dimensions, make our device a promising POC solution in the fluorescence spectrophotometry area. The approach of this project was validated by designing, fabricating, and testing a discrete and wireless prototype. Its conference paper was published in IEEE LSC 2018, and the prototype characterization and interpretation of in vitro experiments using a custom MATLAB interface were published in IEEE Sensors Journal (2021). The integrated circuits and photodetectors were designed and fabricated by the Cadence circuit design toolbox (2019). The proposed circuit solutions were fabricated with 180-nm CMOS technology and published at IEEE MWSCAS 2020 conference. As the last contribution, the in vitro experiments with the proposed device, including the custom chip and 3D-printed housing, were performed, and the electrical and optical results were submitted to the IEEE Journal of Solid-State Circuits (JSSC 2022)

Biosensor system with an integrated CMOS microelectrode array for high spatio-temporal electrochemical imaging, A

2019 Fall.Includes bibliographical references.The ability to view biological events in real time has contributed significantly to research in life sciences. While optical microscopy is important to observe anatomical and morphological changes, it is equally important to capture real-time two-dimensional (2D) chemical activities that drive the bio-sample behaviors. The existing chemical sensing methods (i.e. optical photoluminescence, magnetic resonance, and scanning electrochemical), are well-established and optimized for existing ex vivo or in vitro analyses. However, such methods also present various limitations in resolution, real-time performance, and costs. Electrochemical method has been advantageous to life sciences by supporting studies and discoveries in neurotransmitter signaling and metabolic activities in biological samples. In the meantime, the integration of Microelectrode Array (MEA) and Complementary-Metal-Oxide-Semiconductor (CMOS) technology to the electrochemical method provides biosensing capabilities with high spatial and temporal resolutions. This work discusses three related subtopics in this specific order: improvements to an electrochemical imaging system with 8,192 sensing points for neurotransmitter sensing; comprehensive design processes of an electrochemical imaging system with 16,064 sensing points based on the previous system; and the application of the system for imaging oxygen concentration gradients in metabolizing bovine oocytes. The first attempt of high spatial electrochemical imaging was based on an integrated CMOS microchip with 8,192 configurable Pt surface electrodes, on-chip potentiostat, on-chip control logic, and a microfluidic device designed to support ex vivo tissue experimentation. Using norepinephrine as a target analyte for proof of concept, the system is capable of differentiating concentrations of norepinephrine as low as 8µM and up to 1,024 µM with a linear response and a spatial resolution of 25.5×30.4μm. Electrochemical imaging was performed using murine adrenal tissue as a biological model and successfully showed caffeine-stimulated release of catecholamines from live slices of adrenal tissue with desired spatial and temporal resolutions. This system demonstrates the capability of an electrochemical imaging system capable of capturing changes in chemical gradients in live tissue slices. An enhanced system was designed and implemented in a CMOS microchip based on the previous generation. The enhanced CMOS microchip has an expanded sensing area of 3.6×3.6mm containing 16,064 Pt electrodes and the associated 16,064 integrated read channels. The novel three-electrode electrochemical sensor system designed at 27.5×27.5µm pitch enables spatially dense cellular level chemical gradient imaging. The noise level of the on-chip read channels allow amperometric linear detection of neurotransmitter (norepinephrine) concentrations from 4µM to 512µM with 4.7pA/µM sensitivity (R=0.98). Electrochemical response to dissolved oxygen concentration or oxygen partial pressure (pO2) was also characterized with deoxygenated deionized water containing 10µM to 165 µM pO2 with 8.21pA/µM sensitivity (R=0.89). The enhanced biosensor system also demonstrates selectivity to different target analytes using cyclic voltammetry to simultaneously detect NE and uric acid. In addition, a custom-designed indium tin oxide and Au glass electrode is integrated into the microfluidic support system to enable pH measurement, ensuring viability of bio-samples in ex vivo experiments. Electrochemical images confirm the spatiotemporal performance at four frames per second while maintaining the sensitivity to target analytes. The overall system is controlled and continuously monitored by a custom-designed user interface, which is optimized for real-time high spatiotemporal resolution chemical bioimaging. It is well known that physiological events related to oxygen concentration gradients provide valuable information to determine the state of metabolizing biological cells. Utilizing the CMOS microchip with 16,064 Pt MEA and an improved three-electrode system configuration, the system is capable of imaging low oxygen concentration with limit of detection of 18.3µM, 0.58mg/L, or 13.8mmHg. A modified microfluidic support system allows convenient bio-sample handling and delivery to the MEA surface for sensing. In vitro oxygen imaging experiments were performed using bovine cumulus-oocytes-complexes cells with custom software algorithms to analyze its flux density and oxygen consumption rate. The imaging results are processed and presented as 2D heatmaps, representing the dissolved oxygen concentration in the immediate proximity of the cell. The 2D images and analysis of oxygen consumption provide a unique insight into the spatial and temporal dynamics of cell metabolism

Lab-on-CMOS Sensors and Real-time Imaging for Biological Cell Monitoring

Monitoring biological cell growth and viability is essential for in vivo biomedical diagnosis and therapy, and in vitro studies of pharmaceutical efficacy and material toxicity. Conventional monitoring techniques involve the use of dyes and markers that can potentially introduce side effects into the cell culture and often function as end-point assays. This eliminates the opportunity to track fast changes and to determine temporal correlation between measurements. Particularly in drug screening applications, high-temporal resolution cell viability data could inform decisions on drug application protocols that could lead to better treatment outcomes. This work presents development of a lab-on-chip (LoC) sensor for real-time monitoring of biological cell viability and proliferation, to provide a comprehensive picture of the changes cells undergo during their lifecycle. The LoC sensor consists of a complementary metal-oxide-semiconductor (CMOS) chip that measures the cell-to-substrate coupling of adherent cells that are cultured directly on top. This technique is non-invasive, does not require biochemical labeling, and allows for automated and unsupervised cell monitoring. The CMOS capacitance sensor was designed to addresses the ubiquitous challenges of sensitivity, noise coupling, and dynamic range that affect existing sensors. The design includes on-chip digitization, serial data output, and programmable control logic in order to facilitate packaging requirements for biological experiments. Only a microcontroller is required for readout, making it suitable for applications outside the traditional laboratory setting. An imaging platform was developed to provide time-lapse images of the sensor surface, which allowed for concurrent visual and capacitance observation of the cells. Results showed the ability of the LoC sensor to detect single cell binding events and changes in cell morphology. The sensor was used in in vitro experiments to monitor chemotherapeutic agent potency on drug-resistant and drug-sensitive cancer cell lines. Concentrations higher than 5 μM elicited cytotoxic effects on both cell lines, while a dose of 1 μM allowed discrimination of the two cell types. The system demonstrates the use of real-time capacitance measurements as a proof-of-concept tool that has potential to hasten the drug development process

Imepdance Sensing Techniques for Integrated Circuits Sensor Applications

Impedance measurements are increasingly demanded in modern CMOS sensing systems as impedance is the most common electrical signal obtained from sensors, delivering physical, chemical and biomedical quantity changes. Impedance sensing for wide interested frequency, broad dynamic range, and various sensor interfaces has numerous challenges, especially targeted in CMOS miniaturization with power and area limitation. In this thesis, first, a low power impedance-based cytometer architecture for cell analysis applications is presented. Fabricated in 0.18μm CMOS process with 6pArms input-referred noise over 200Hz bandwidth at 0.5 MHz modulation frequency, the impedance sensor demonstrates in detecting 3μm diameter particles. Secondly, using impedance sensing technique, a low-power RC oscillator based on IQ-balanced impedance sensing FLL is designed and demonstrated, achieving 25.4ppm/°C across temperature variation and 0.27%/V across supply variation at 650kHz output frequency

Ultra-low noise, high-frame rate readout design for a 3D-stacked CMOS image sensor

Due to the switch from CCD to CMOS technology, CMOS based image sensors have become smaller, cheaper, faster, and have recently outclassed CCDs in terms of image quality. Apart from the extensive set of applications requiring image sensors, the next technological breakthrough in imaging would be to consolidate and completely shift the conventional CMOS image sensor technology to the 3D-stacked technology. Stacking is recent and an innovative technology in the imaging field, allowing multiple silicon tiers with different functions to be stacked on top of each other. The technology allows for an extreme parallelism of the pixel readout circuitry. Furthermore, the readout is placed underneath the pixel array on a 3D-stacked image sensor, and the parallelism of the readout can remain constant at any spatial resolution of the sensors, allowing extreme low noise and a high-frame rate (design) at virtually any sensor array resolution. The objective of this work is the design of ultra-low noise readout circuits meant for 3D-stacked image sensors, structured with parallel readout circuitries. The readout circuit’s key requirements are low noise, speed, low-area (for higher parallelism), and low power. A CMOS imaging review is presented through a short historical background, followed by the description of the motivation, the research goals, and the work contributions. The fundamentals of CMOS image sensors are addressed, as a part of highlighting the typical image sensor features, the essential building blocks, types of operation, as well as their physical characteristics and their evaluation metrics. Following up on this, the document pays attention to the readout circuit’s noise theory and the column converters theory, to identify possible pitfalls to obtain sub-electron noise imagers. Lastly, the fabricated test CIS device performances are reported along with conjectures and conclusions, ending this thesis with the 3D-stacked subject issues and the future work. A part of the developed research work is located in the Appendices.Devido à mudança da tecnologia CCD para CMOS, os sensores de imagem em CMOS tornam se mais pequenos, mais baratos, mais rápidos, e mais recentemente, ultrapassaram os sensores CCD no que respeita à qualidade de imagem. Para além do vasto conjunto de aplicações que requerem sensores de imagem, o próximo salto tecnológico no ramo dos sensores de imagem é o de mudar completamente da tecnologia de sensores de imagem CMOS convencional para a tecnologia “3D-stacked”. O empilhamento de chips é relativamente recente e é uma tecnologia inovadora no campo dos sensores de imagem, permitindo vários planos de silício com diferentes funções poderem ser empilhados uns sobre os outros. Esta tecnologia permite portanto, um paralelismo extremo na leitura dos sinais vindos da matriz de píxeis. Além disso, num sensor de imagem de planos de silício empilhados, os circuitos de leitura estão posicionados debaixo da matriz de píxeis, sendo que dessa forma, o paralelismo pode manter-se constante para qualquer resolução espacial, permitindo assim atingir um extremo baixo ruído e um alto debito de imagens, virtualmente para qualquer resolução desejada. O objetivo deste trabalho é o de desenhar circuitos de leitura de coluna de muito baixo ruído, planeados para serem empregues em sensores de imagem “3D-stacked” com estruturas altamente paralelizadas. Os requisitos chave para os circuitos de leitura são de baixo ruído, rapidez e pouca área utilizada, de forma a obter-se o melhor rácio. Uma breve revisão histórica dos sensores de imagem CMOS é apresentada, seguida da motivação, dos objetivos e das contribuições feitas. Os fundamentos dos sensores de imagem CMOS são também abordados para expor as suas características, os blocos essenciais, os tipos de operação, assim como as suas características físicas e suas métricas de avaliação. No seguimento disto, especial atenção é dada à teoria subjacente ao ruído inerente dos circuitos de leitura e dos conversores de coluna, servindo para identificar os possíveis aspetos que dificultem atingir a tão desejada performance de muito baixo ruído. Por fim, os resultados experimentais do sensor desenvolvido são apresentados junto com possíveis conjeturas e respetivas conclusões, terminando o documento com o assunto de empilhamento vertical de camadas de silício, junto com o possível trabalho futuro

Spectrally and temporally resolved single photon counting in advanced biophotonics applications

Biomedicine requires highly sensitive and efficient light sensors to analyse light-tissue or light-sample interactions. Single-photon avalanche diode (SPAD) sensors implemented with complementary metal-oxide-semiconductor (CMOS) technology have a growing range of applications in this field. Single-photon detection coupled with integrated timing circuits enables us to timestamp each detected photon with high temporal resolution (down to picoseconds). Arrays of SPAD based pixels and CMOS technology offer massively parallel time-resolved single-photon counting for spectrally and temporally resolved analysis of various light phenomena.This thesis examines how time-resolved CMOS SPAD based line sensors with per pixel timing circuits can be utilized to advance biophotonic applications. The study focuses on improving the existing techniques of fluorescence and Raman spectroscopy, and demonstrates for the first time CMOS SPAD based detection in optical coherence tomography (OCT). A novel detection scheme is proposed combining low-coherence interferometry and time-resolved photon counting. In this approach the interferometric information is revealed from spectral intensity measurements, which is supplemented by time-stamping of the photons building up the spectra.Two CMOS SPAD line sensors (Ra-I and its improved version, Ra-II) were characterized and the effect of their parameters on the selected techniques was analysed. The thesis demonstrates the deployment of the Ra-I line sensor in time-resolved fluorescence spectroscopy with indications of the applicability in time-resolved Raman spectroscopy. The work includes integration of the sensor with surrounding electrical and optical systems, and the implementation of firmware and software for controlling the optical setup. As a result, a versatile platform is demonstrated capable of micro- and millisecond sampling of spectral fluorescence lifetime changes in a single transient of fast chemical reactions.OCT operating in the spectral domain traditionally uses CMOS photodiode and charge-coupled device (CCD) based detectors. The applicability of CMOS SPAD sensors is investigated for the first time with focus on the main limitations and related challenges. Finally, a new detection method is proposed relying on both the wave and particle nature of light, recording time-resolved interferometric spectra from a Michelson interferometer. This method offers an alternative approach to analyse luminous effects and improves techniques based on the light’s time of flight. As an example, a proof of concept study is presented for the removal of unwanted reflections from along the sample and the optical path in an OCT setup