INTEGRATED SINGLE-PHOTON SENSING AND PROCESSING PLATFORM IN STANDARD CMOS

Practical implementation of large SPAD-based sensor arrays in the standard CMOS process has been fraught with challenges due to the many performance trade-offs existing at both the device and the system level [1]. At the device level the performance challenge stems from the suboptimal optical characteristics associated with the standard CMOS fabrication process. The challenge at the system level is the development of monolithic readout architecture capable of supporting the large volume of dynamic traffic, associated with multiple single-photon pixels, without limiting the dynamic range and throughput of the sensor. Due to trade-offs in both functionality and performance, no general solution currently exists for an integrated single-photon sensor in standard CMOS single photon sensing and multi-photon resolution. The research described herein is directed towards the development of a versatile high performance integrated SPAD sensor in the standard CMOS process. Towards this purpose a SPAD device with elongated junction geometry and a perimeter field gate that features a large detection area and a highly reduced dark noise has been presented and characterized. Additionally, a novel front-end system for optimizing the dynamic range and after-pulsing noise of the pixel has been developed. The pixel is also equipped with an output interface with an adjustable pulse width response. In order to further enhance the effective dynamic range of the pixel a theoretical model for accurate dead time related loss compensation has been developed and verified. This thesis also introduces a new paradigm for electrical generation and encoding of the SPAD array response that supports fully digital operation at the pixel level while enabling dynamic discrete time amplitude encoding of the array response. Thus offering a first ever system solution to simultaneously exploit both the dynamic nature and the digital profile of the SPAD response. The array interface, comprising of multiple digital inputs capacitively coupled onto a shared quasi-floating sense node, in conjunction with the integrated digital decoding and readout electronics represents the first ever solid state single-photon sensor capable of both photon counting and photon number resolution. The viability of the readout architecture is demonstrated through simulations and preliminary proof of concept measurements

Challenges and Solutions to Next-Generation Single-Photon Imagers

Detecting and counting single photons is useful in an increasingly large number of applications. Most applications require large formats, approaching and even far exceeding 1 megapixel. In this thesis, we look at the challenges of massively parallel photon-counting cameras from all performance angles. The thesis deals with a number of performance issues that emerge when the number of pixels exceeds about 1/4 of megapixels, proposing characterization techniques and solutions to mitigate performance degradation and non-uniformity. Two cameras were created to validate the proposed techniques. The first camera, SwissSPAD, comprises an array of 512 x 128 SPAD pixels, each with a one-bit memory and a gating mechanism to achieve 5ns high precision time windows with high uniformity across the array. With a massively parallel readout of over 10 Gigabit/s and positioning of the integration time window accurate to the pico-second range, fluorescence lifetime imaging and fluorescence correlation spectroscopy imaging achieve a speedup of several orders of magnitude while ensuring high precision in the measurements. Other possible applications include wide-field time-of-flight imaging and the generation of quantum random numbers at highest bit-rates. Lately super-resolution microscopy techniques have also used SwissSPAD. The second camera, LinoSPAD, takes the concepts of SwissSPAD one step further by moving even more 'intelligence' to the FPGA and reducing the sensor complexity to the bare minimum. This allows focusing the optimization of the sensor on the most important metrics of photon efficiency and fill factor. As such, the sensor consists of one line of SPADs that have a direct connection each to the FPGA where complex photon processing algorithms can be implemented. As a demonstration of the capabilities of current lowcost FPGAs we implemented an array of time-to-digital converters that can handle up to 8.5 billion photons per second, measuring each one of them and accounting them in high precision histograms. Using simple laser diodes and a circuit to generate light pulses in the picosecond range, we demonstrate a ubiquitous 3D time-of-flight sensor. The thesis intends to be a first step towards achieving the world's first megapixel SPAD camera, which, we believe, is in grasp thanks to the architectural and circuital techniques proposed in this thesis. In addition, we believe that the applications proposed in this thesis offer a wide variety of uses of the sensors presented in this thesis and in future ones to come

Energy-Efficient and Reliable Computing in Dark Silicon Era

Dark silicon denotes the phenomenon that, due to thermal and power constraints, the fraction of transistors that can operate at full frequency is decreasing in each technology generation. Moore’s law and Dennard scaling had been backed and coupled appropriately for five decades to bring commensurate exponential performance via single core and later muti-core design. However, recalculating Dennard scaling for recent small technology sizes shows that current ongoing multi-core growth is demanding exponential thermal design power to achieve linear performance increase. This process hits a power wall where raises the amount of dark or dim silicon on future multi/many-core chips more and more. Furthermore, from another perspective, by increasing the number of transistors on the area of a single chip and susceptibility to internal defects alongside aging phenomena, which also is exacerbated by high chip thermal density, monitoring and managing the chip reliability before and after its activation is becoming a necessity. The proposed approaches and experimental investigations in this thesis focus on two main tracks: 1) power awareness and 2) reliability awareness in dark silicon era, where later these two tracks will combine together. In the first track, the main goal is to increase the level of returns in terms of main important features in chip design, such as performance and throughput, while maximum power limit is honored. In fact, we show that by managing the power while having dark silicon, all the traditional benefits that could be achieved by proceeding in Moore’s law can be also achieved in the dark silicon era, however, with a lower amount. Via the track of reliability awareness in dark silicon era, we show that dark silicon can be considered as an opportunity to be exploited for different instances of benefits, namely life-time increase and online testing. We discuss how dark silicon can be exploited to guarantee the system lifetime to be above a certain target value and, furthermore, how dark silicon can be exploited to apply low cost non-intrusive online testing on the cores. After the demonstration of power and reliability awareness while having dark silicon, two approaches will be discussed as the case study where the power and reliability awareness are combined together. The first approach demonstrates how chip reliability can be used as a supplementary metric for power-reliability management. While the second approach provides a trade-off between workload performance and system reliability by simultaneously honoring the given power budget and target reliability

High-Speed Wide-Field Time-Correlated Single-Photon Counting Fluorescence Lifetime Imaging Microscopy

Fluorescence microscopy is a powerful imaging technique used in the biological sciences to identify labeled components of a sample with specificity. This is usually accomplished through labeling with fluorescent dyes, isolating these dyes by their spectral signatures with optical filters, and recording the intensity of the fluorescent response. Although these techniques are widely used, fluorescence intensity images can be negatively affected by a variety of factors that impact the fluorescence intensity. Fluorescence lifetime imaging microscopy (FLIM) is an imaging technique that is relatively immune to intensity fluctuations and also provides the unique ability to directly monitor the microenvironment surrounding a fluorophore. Despite the benefits associated with FLIM, the applications to which it is applied are fairly limited due to long image acquisition times and high cost of traditional hardware. Recent advances in complementary metal-oxide-semiconductor (CMOS) single-photon avalanche diodes (SPADs) have enabled the design of low-cost imaging arrays that are capable of recording lifetime images with acquisition times greater than one order of magnitude faster than existing systems. However, these SPAD arrays have yet to realize the full potential of the technology due to limitations in their ability to handle the vast amount of data generated during the commonly used time-correlated single-photon counting (TCSPC) lifetime imaging technique. This thesis presents the design, implementation, characterization, and demonstration of a high speed FLIM imaging system. The components of this design include a CMOS imager chip in a standard 0.13 μm technology containing a custom CMOS SPAD, a 64-by-64 array of these SPADs, pixel control circuitry, independent time-to-digital converters (TDCs), a FLIM specific datapath, and high bandwidth output buffers. In addition to the CMOS imaging array, a complete system was designed and implemented using a printed circuit board (PCB) for capturing data from the imager, creating histograms for the photon arrival data using field-programmable gate arrays, and transferring the data to a computer using a cabled PCIe interface. Finally, software is used to communicate between the imaging system and a computer.The dark count rate of the SPAD was measured to be only 231 Hz at room temperature while maintaining a photon detection probability of up to 30\%. TDCs included on the array have a 62.5 ps resolution and a 64 ns range, which is suitable for measuring the lifetime of most biological fluorophores. Additionally, the on-chip datapath was designed to handle continuous data transfers at rates capable of supporting TCSPC-based lifetime imaging at 100 frames per second. The system level implementation also provides sufficient data throughput for transferring up to 750 frames per second from the imaging system to a computer. The lifetime imaging system was characterized using standard techniques for evaluating SPAD performance and an electrical delay signal for measuring the TDC performance. This thesis concludes with a demonstration of TCSPC-FLIM imaging at 100 frames per second -- the fastest 64-by-64 TCSPC FLIM that has been demonstrated. This system overcomes some of the limitations of existing FLIM systems and has the potential to enable new application domains in dynamic FLIM imaging

Miniaturized Optical Probes for Near Infrared Spectroscopy

RÉSUMÉ L’étude de la propagation de la lumière dans des milieux hautement diffus tels que les tissus biologiques (imagerie optique diffuse) est très attrayante, car elle offre la possibilité d’explorer de manière non invasive le milieu se trouvant profondément sous la surface, et de retrouver des informations sur l’absorption (liée à la composition chimique) et sur la diffusion (liée à la microstructure). Dans la gamme spectrale 600-1000 nm, également appelée gamme proche infrarouge (NIR en anglais), l'atténuation de la lumière par le tissu biologique (eau, lipides et hémoglobine) est relativement faible, ce qui permet une pénétration de plusieurs centimètres dans le tissu. En spectroscopie proche infrarouge (NIRS en anglais), de photons sont injectés dans les tissus et le signal émis portant des informations sur les constituants tissulaires est mesuré. La mesure de très faibles signaux dans la plage de longueurs d'ondes visibles et proche infrarouge avec une résolution temporelle de l'ordre de la picoseconde s'est révélée une technique efficace pour étudier des tissus biologiques en imagerie cérébrale fonctionnelle, en mammographie optique et en imagerie moléculaire, sans parler de l'imagerie de la durée de vie de fluorescence, la spectroscopie de corrélation de fluorescence, informations quantiques et bien d’autres. NIRS dans le domaine temporel (TD en anglais) utilise une source de lumière pulsée, généralement un laser fournissant des impulsions lumineuses d'une durée de quelques dizaines de picosecondes, ainsi qu'un appareil de détection avec une résolution temporelle inférieure à la nanoseconde. Le point essentiel de ces mesures est la nécessité d’augmenter la sensibilité pour de plus grandes profondeurs d’investigation, en particulier pour l’imagerie cérébrale fonctionnelle, où la peau, le crâne et le liquide céphalo-rachidien (LCR) masquent fortement le signal cérébral. À ce jour, l'adoption plus large de ces techniques optique non invasives de surveillance est surtout entravée par les composants traditionnels volumineux, coûteux, complexes et fragiles qui ont un impact significatif sur le coût et la dimension de l’ensemble du système. Notre objectif est de développer une sonde NIRS compacte et miniaturisée, qui peut être directement mise en contact avec l'échantillon testé pour obtenir une haute efficacité de détection des photons diffusés, sans avoir recours à des fibres et des lentilles encombrantes pour l'injection et la collection de la lumière. Le système proposé est composé de deux parties: i) une unité d’émission de lumière pulsée et ii) un module de détection à photon unique qui peut être activé et désactivé rapidement. L'unité d'émission de lumière utilisera une source laser pulsée à plus de 80 MHz avec une largeur d'impulsion de picoseconde.----------ABSTRACT The study of light propagation into highly diffusive media like biological tissues (Diffuse Optical Imaging) is highly appealing due to the possibility to explore the medium non-invasively, deep beneath the surface and to recover information both on absorption (related to chemical composition) and on scattering (related to microstructure). In the 600–1000 nm spectral range also known as near-infrared (NIR) range, light attenuation by the biological tissue constituents (i.e. water, lipid, and hemoglobin) is relatively low and allows for penetration through several centimeters of tissue. In near-infrared spectroscopy (NIRS), a light signal is injected into the tissues and the emitted signal carrying information on tissue constituents is measured. The measurement of very faint light signals in the visible and near-infrared wavelength range with picosecond timing resolution has proven to be an effective technique to study biological tissues in functional brain imaging, optical mammography and molecular imaging, not to mention fluorescence lifetime imaging, fluorescence correlation spectroscopy, quantum information and many others. Time Domain (TD) NIRS employs a pulsed light source, typically a laser providing light pulses with duration of a few tens of picoseconds, and a detection circuit with temporal resolution in the sub-nanosecond scale. The key point of these measurements is the need to increase the sensitivity to higher penetration depths of investigation, in particular for functional brain imaging, where skin, skull, and cerebrospinal fluid (CSF) heavily mask the brain signal. To date, the widespread adoption of the non-invasive optical monitoring techniques is mainly hampered by the traditional bulky, expensive, complex and fragile components which significantly impact the overall cost and dimension of the system. Our goal is the development of a miniaturized compact NIRS probe, that can be directly put in contact with the sample under test to obtain high diffused photon harvesting efficiency without the need for cumbersome optical fibers and lenses for light injection and collection. The proposed system is composed of two parts namely; i) pulsed light emission unit and ii) gated single-photon detection module. The light emission unit will employ a laser source pulsed at over 80MHz with picosecond pulse width generator embedded into the probe along with the light detection unit which comprises single-photon detectors integrated with other peripheral control circuitry. Short distance source and detector pairing, most preferably on a single chip has the potential to greatly expedites the traditional method of portable brain imaging

VLSI Design

This book provides some recent advances in design nanometer VLSI chips. The selected topics try to present some open problems and challenges with important topics ranging from design tools, new post-silicon devices, GPU-based parallel computing, emerging 3D integration, and antenna design. The book consists of two parts, with chapters such as: VLSI design for multi-sensor smart systems on a chip, Three-dimensional integrated circuits design for thousand-core processors, Parallel symbolic analysis of large analog circuits on GPU platforms, Algorithms for CAD tools VLSI design, A multilevel memetic algorithm for large SAT-encoded problems, etc

Miniature high dynamic range time-resolved CMOS SPAD image sensors

Since their integration in complementary metal oxide (CMOS) semiconductor technology in 2003, single photon avalanche diodes (SPADs) have inspired a new era of low cost high integration quantum-level image sensors. Their unique feature of discerning single photon detections, their ability to retain temporal information on every collected photon and their amenability to high speed image sensor architectures makes them prime candidates for low light and time-resolved applications. From the biomedical field of fluorescence lifetime imaging microscopy (FLIM) to extreme physical phenomena such as quantum entanglement, all the way to time of flight (ToF) consumer applications such as gesture recognition and more recently automotive light detection and ranging (LIDAR), huge steps in detector and sensor architectures have been made to address the design challenges of pixel sensitivity and functionality trade-off, scalability and handling of large data rates. The goal of this research is to explore the hypothesis that given the state of the art CMOS nodes and fabrication technologies, it is possible to design miniature SPAD image sensors for time-resolved applications with a small pixel pitch while maintaining both sensitivity and built -in functionality. Three key approaches are pursued to that purpose: leveraging the innate area reduction of logic gates and finer design rules of advanced CMOS nodes to balance the pixel’s fill factor and processing capability, smarter pixel designs with configurable functionality and novel system architectures that lift the processing burden off the pixel array and mediate data flow. Two pathfinder SPAD image sensors were designed and fabricated: a 96 × 40 planar front side illuminated (FSI) sensor with 66% fill factor at 8.25μm pixel pitch in an industrialised 40nm process and a 128 × 120 3D-stacked backside illuminated (BSI) sensor with 45% fill factor at 7.83μm pixel pitch. Both designs rely on a digital, configurable, 12-bit ripple counter pixel allowing for time-gated shot noise limited photon counting. The FSI sensor was operated as a quanta image sensor (QIS) achieving an extended dynamic range in excess of 100dB, utilising triple exposure windows and in-pixel data compression which reduces data rates by a factor of 3.75×. The stacked sensor is the first demonstration of a wafer scale SPAD imaging array with a 1-to-1 hybrid bond connection. Characterisation results of the detector and sensor performance are presented. Two other time-resolved 3D-stacked BSI SPAD image sensor architectures are proposed. The first is a fully integrated 5-wire interface system on chip (SoC), with built-in power management and off-focal plane data processing and storage for high dynamic range as well as autonomous video rate operation. Preliminary images and bring-up results of the fabricated 2mm² sensor are shown. The second is a highly configurable design capable of simultaneous multi-bit oversampled imaging and programmable region of interest (ROI) time correlated single photon counting (TCSPC) with on-chip histogram generation. The 6.48μm pitch array has been submitted for fabrication. In-depth design details of both architectures are discussed

CMOS system for high throughput fluorescence lifetime sensing using time correlated single photon counting

Fluorescence lifetime sensing using time correlated single photon counting (TCSPC) is a key analytical tool for molecular and cell biology research, medical diagnosis and pharmacological development. However, commercially available TCSPC equipment is bulky, expensive and power hungry, typically requiring iterative software post-processing to calculate the fluorescence lifetime. Furthermore, the technique is restrictively slow due to a low photon throughput limit which is necessary to avoid distortions caused by TCSPC pile-up. An investigation into CMOS compatible multimodule architectures to miniaturise the standard TCSPC set up, allow an increase in photon throughput by overcoming the TCSPC pile-up limit, and provide fluorescence lifetime calculations in real-time is presented. The investigation verifies the operation of the architectures and leads to the selection of optimal parameters for the number of detectors and timing channels required to overcome the TCSPC pile-up limit by at least an order of magnitude. The parameters are used to implement a low power miniaturised sensor in a 130 nm CMOS process, combining single photon detection, multiple channel timing and embedded pre-processing of the fluorescence lifetime, all within a silicon area of < 2 mm2. Single photon detection is achieved using an array of single photon avalanche diodes (SPADs) arranged in a digital silicon photomultiplier (SiPM) architecture with a 10 % fill-factor and a compressed 250 ps output pulse, which provides a photon throughput of > 700 MHz. An array of time-interleaved time-to-digital converters (TI-TDCs) with 50 ps resolution and no processing dead-time records up to eight photon events during each excitation period, significantly reducing the effect of TCSPC pile-up. The TCSPC data is then processed using an embedded centre-of-mass method (CMM) pre-calculation to produce single exponential fluorescence lifetime estimations in real-time. The combination of high photon throughput and real-time calculation enables advances in applications such as fluorescence lifetime imaging microscopy (FLIM) and time domain fluorescence lifetime activated cell sorting. To demonstrate this, the device is validated in practical bulk sample fluorescence lifetime, FLIM and simulated flow based experiments. Photon throughputs in excess of the excitation frequency are demonstrated for a range of organic and inorganic fluorophores for minimal error in lifetime calculation by CMM (< 5 %)

CMOS SPAD-based image sensor for single photon counting and time of flight imaging

The facility to capture the arrival of a single photon, is the fundamental limit to the detection of quantised electromagnetic radiation. An image sensor capable of capturing a picture with this ultimate optical and temporal precision is the pinnacle of photo-sensing. The creation of high spatial resolution, single photon sensitive, and time-resolved image sensors in complementary metal oxide semiconductor (CMOS) technology offers numerous benefits in a wide field of applications. These CMOS devices will be suitable to replace high sensitivity charge-coupled device (CCD) technology (electron-multiplied or electron bombarded) with significantly lower cost and comparable performance in low light or high speed scenarios. For example, with temporal resolution in the order of nano and picoseconds, detailed three-dimensional (3D) pictures can be formed by measuring the time of flight (TOF) of a light pulse. High frame rate imaging of single photons can yield new capabilities in super-resolution microscopy. Also, the imaging of quantum effects such as the entanglement of photons may be realised. The goal of this research project is the development of such an image sensor by exploiting single photon avalanche diodes (SPAD) in advanced imaging-specific 130nm front side illuminated (FSI) CMOS technology. SPADs have three key combined advantages over other imaging technologies: single photon sensitivity, picosecond temporal resolution and the facility to be integrated in standard CMOS technology. Analogue techniques are employed to create an efficient and compact imager that is scalable to mega-pixel arrays. A SPAD-based image sensor is described with 320 by 240 pixels at a pitch of 8μm and an optical efficiency or fill-factor of 26.8%. Each pixel comprises a SPAD with a hybrid analogue counting and memory circuit that makes novel use of a low-power charge transfer amplifier. Global shutter single photon counting images are captured. These exhibit photon shot noise limited statistics with unprecedented low input-referred noise at an equivalent of 0.06 electrons. The CMOS image sensor (CIS) trends of shrinking pixels, increasing array sizes, decreasing read noise, fast readout and oversampled image formation are projected towards the formation of binary single photon imagers or quanta image sensors (QIS). In a binary digital image capture mode, the image sensor offers a look-ahead to the properties and performance of future QISs with 20,000 binary frames per second readout with a bit error rate of 1.7 x 10-3. The bit density, or cumulative binary intensity, against exposure performance of this image sensor is in the shape of the famous Hurter and Driffield densitometry curves of photographic film. Oversampled time-gated binary image capture is demonstrated, capturing 3D TOF images with 3.8cm precision in a 60cm range

A centrifugal microfluidic platform for capturing, assaying and manipulation of beads and biological cells

Microfluidics is deemed a field with great opportunities, especially for applications in medical diagnostics. The vision is to miniaturize processes typically performed in a central clinical lab into small, simple to use devices - so called lab-on-a-chip (LOC) systems. A wide variety of concepts for liquid actuation have been developed, including pressure driven flow, electro-osmotic actuation or capillary driven methods. This work is based on the centrifugal platform (lab-on-a-disc). Fluid actuation is performed by the forces induced due to the rotation of the disc, thus eliminating the need for external pumps since only a spindle motor is necessary to rotate the disc and propel the liquids inside of the micro structures. Lab-on-a-disc systems are especially promising for point-of-care applications involving particles or cells due to the centrifugal force present in a rotating system. Capturing, assaying and identification of biological cells and microparticles are important operations for lab-on-a-disc platforms, and the focus of this work is to provide novel building blocks towards an integrated system for cell and particle based assays. As a main outcome of my work, a novel particle capturing and manipulation scheme on a centrifugal microfluidic platform has been developed. To capture particles (biological cells or micro-beads) I designed an array of V-shaped micro cups and characterized it. Particles sediment under stagnant flow conditions into the array where they are then mechanically trapped in spatially well-defined locations. Due to the absence of flow during the capturing process, i.e. particle sedimentation is driven by the artificial gravity field on the centrifugal platform, the capture efficiency of this approach is close to 100% which is notably higher than values reported for typical pressure driven systems. After capturing the particles, the surrounding medium can easily be exchanged to expose them to various conditions such as staining solutions or washing buffers, and thus perform assays on the captured particles. By scale matching the size of the capturing elements to the size of the particles, sharply peaked single occupancy can be achieved. Since all particles are arrayed in the same focal plane in spatially well defined locations, operations such as counting or fluorescent detection can be performed easily. The application of this platform to perform multiplexed bead-based immunoassays as well as the discrimination of various cell types based on intra cellular and membrane based markers using fluorescently tagged antibodies is demonstrated. Additionally, methods to manipulate captured particles either in batch mode or on an individual particle level have been developed and characterized. Batch release of captured particles is performed by a novel magnetic actuator which is solely controlled by the rotation frequency of the disc. Furthermore, the application of this actuator to rapidly mix liquids is shown. Manipulation of individual particles is performed using an optical tweezers setup which has been developed as part of this work. Additionally, this optical module also provides fluorescence detection capabilities. This is the first time that optical tweezers have been combined with a centrifugal microfluidic system. This work presents the core technology for an integrated centrifugal platform to perform cell and particle based assays for fundamental research as well as for point-of- care applications. The key outputs of my specific work are: 1. Design, fabrication and characterization of a novel particle capturing scheme on a centrifugal microfluidic platform (V-cups) with very high capture efficiency (close to 100%) and sharply peaked single occupancy (up to 99.7% single occupancy). 2. A novel rotation frequency controlled magnetic actuator for releasing captured particles as well as for rapidly mixing liquids has been developed, manufactured and characterized. 3. The V-cup platform has successfully been employed to capture cells and perform multi-step antibody staining assays for cell discrimination. 4. An optical tweezers setup has been built and integrated into a centrifugal teststand, and successful manipulation of individual particles trapped in the V-cup array is demonstrated