Development of a Portable CMOS Time-Domain Fluorescence Lifetime Imager

Modern laboratory equipments to measure the excited-state lifetime of fluorophores usually include an expensive picosecond pulsed-laser excitation source, a fragile photomultiplier tube, and a large instrument body for optics. A portable and robust device to make fluorescence lifetime measurement in nanosecond scale is of great attraction for chemists and biologists. This dissertation reports the development of a portable LED time-domain fluorimeter from an all-solid-state discrete-component prototype to its advanced CMOS integrated circuit implementation. The motivation of the research is to develop a multiplexed fluorimeter for point-of-care diagnosis. Instruments developed by this novel method have higher fill factor, are more portable, and are fabricated at lower cost

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

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

DESIGN OF SMART SENSORS FOR DETECTION OF PHYSICAL QUANTITIES

Microsystems and integrated smart sensors represent a flourishing business thanks to the manifold benefits of these devices with respect to their respective macroscopic counterparts. Miniaturization to micrometric scale is a turning point to obtain high sensitive and reliable devices with enhanced spatial and temporal resolution. Power consumption compatible with battery operated systems, and reduced cost per device are also pivotal for their success. All these characteristics make investigation on this filed very active nowadays. This thesis work is focused on two main themes: (i) design and development of a single chip smart flow-meter; (ii) design and development of readout interfaces for capacitive micro-electro-mechanical-systems (MEMS) based on capacitance to pulse width modulation conversion. High sensitivity integrated smart sensors for detecting very small flow rates of both gases and liquids aiming to fulfil emerging demands for this kind of devices in the industrial to environmental and medical applications. On the other hand, the prototyping of such sensor is a multidisciplinary activity involving the study of thermal and fluid dynamic phenomenon that have to be considered to obtain a correct design. Design, assisted by finite elements CAD tools, and fabrication of the sensing structures using features of a standard CMOS process is discussed in the first chapter. The packaging of fluidic sensors issue is also illustrated as it has a great importance on the overall sensor performances. The package is charged to allow optimal interaction between fluids and the sensors and protecting the latter from the external environment. As miniaturized structures allows a great spatial resolution, it is extremely challenging to fabricate low cost packages for multiple flow rate measurements on the same chip. As a final point, a compact anemometer prototype, usable for wireless sensor network nodes, is described. The design of the full custom circuitry for signal extraction and conditioning is coped in the second chapter, where insights into the design methods are given for analog basic building blocks such as amplifiers, transconductors, filters, multipliers, current drivers. A big effort has been put to find reusable design guidelines and trade-offs applicable to different design cases. This kind of rational design enabled the implementation of complex and flexible functionalities making the interface circuits able to interact both with on chip sensors and external sensors. In the third chapter, the chip floor-plan designed in the STMicroelectronics BCD6s process of the entire smart flow sensor formed by the sensing structures and the readout electronics is presented. Some preliminary tests are also covered here. Finally design and implementation of very low power interfaces for typical MEMS capacitive sensors (accelerometers, gyroscopes, pressure sensors, angular displacement and chemical species sensors) is discussed. Very original circuital topologies, based on chopper modulation technique, will be illustrated. A prototype, designed within a joint research activity is presented. Measured performances spurred the investigation of new techniques to enhance precision and accuracy capabilities of the interface. A brief introduction to the design of active pixel sensors interface for hybrid CMOS imagers is sketched in the appendix as a preliminary study done during an internship in the CNM-IMB institute of Barcelona

A 25 micron-thin microscope for imaging upconverting nanoparticles with NIR-I and NIR-II illumination.

Rationale: Intraoperative visualization in small surgical cavities and hard-to-access areas are essential requirements for modern, minimally invasive surgeries and demand significant miniaturization. However, current optical imagers require multiple hard-to-miniaturize components including lenses, filters and optical fibers. These components restrict both the form-factor and maneuverability of these imagers, and imagers largely remain stand-alone devices with centimeter-scale dimensions. Methods: We have engineered INSITE (Immunotargeted Nanoparticle Single-Chip Imaging Technology), which integrates the unique optical properties of lanthanide-based alloyed upconverting nanoparticles (aUCNPs) with the time-resolved imaging of a 25-micron thin CMOS-based (complementary metal oxide semiconductor) imager. We have synthesized core/shell aUCNPs of different compositions and imaged their visible emission with INSITE under either NIR-I and NIR-II photoexcitation. We characterized aUCNP imaging with INSITE across both varying aUCNP composition and 980 nm and 1550 nm excitation wavelengths. To demonstrate clinical experimental validity, we also conducted an intratumoral injection into LNCaP prostate tumors in a male nude mouse that was subsequently excised and imaged with INSITE. Results: Under the low illumination fluences compatible with live animal imaging, we measure aUCNP radiative lifetimes of 600 μs - 1.3 ms, which provides strong signal for time-resolved INSITE imaging. Core/shell NaEr0.6Yb0.4F4 aUCNPs show the highest INSITE signal when illuminated at either 980 nm or 1550 nm, with signal from NIR-I excitation about an order of magnitude brighter than from NIR-II excitation. The 55 μm spatial resolution achievable with this approach is demonstrated through imaging of aUCNPs in PDMS (polydimethylsiloxane) micro-wells, showing resolution of micrometer-scale targets with single-pixel precision. INSITE imaging of intratumoral NaEr0.8Yb0.2F4 aUCNPs shows a signal-to-background ratio of 9, limited only by photodiode dark current and electronic noise. Conclusion: This work demonstrates INSITE imaging of aUCNPs in tumors, achieving an imaging platform that is thinned to just a 25 μm-thin, planar form-factor, with both NIR-I and NIR-II excitation. Based on a highly paralleled array structure INSITE is scalable, enabling direct coupling with a wide array of surgical and robotic tools for seamless integration with tissue actuation, resection or ablation

Automotive Three-Dimensional Vision Through a Single-Photon Counting SPAD Camera

We present an optical 3-D ranging camera for automotive applications that is able to provide a centimeter depth resolution over a mbox{40}^{\circ} \times mbox{20}^{\circ} field of view up to 45 m with just 1.5 W of active illumination at 808 nm. The enabling technology we developed is based on a CMOS imager chip of 64 \times 32 pixels, each with a single-photon avalanche diode (SPAD) and three 9-bit digital counters, able to perform lock-in time-of-flight calculation of individual photons emitted by a laser illuminator, reflected by the objects in the scene, and eventually detected by the camera. Due to the SPAD single-photon sensitivity and the smart in-pixel processing, the camera provides state-of-the-art performance at both high frame rates and very low light levels without the need for scanning and with global shutter benefits. Furthermore, the CMOS process is automotive certified