38 research outputs found

    A portable device for time-resolved fluorescence based on an array of CMOS SPADs with integrated microfluidics

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    [eng] Traditionally, molecular analysis is performed in laboratories equipped with desktop instruments operated by specialized technicians. This paradigm has been changing in recent decades, as biosensor technology has become as accurate as desktop instruments, providing results in much shorter periods and miniaturizing the instrumentation, moving the diagnostic tests gradually out of the central laboratory. However, despite the inherent advantages of time-resolved fluorescence spectroscopy applied to molecular diagnosis, it is only in the last decade that POC (Point Of Care) devices have begun to be developed based on the detection of fluorescence, due to the challenge of developing high-performance, portable and low-cost spectroscopic sensors. This thesis presents the development of a compact, robust and low-cost system for molecular diagnosis based on time-resolved fluorescence spectroscopy, which serves as a general-purpose platform for the optical detection of a variety of biomarkers, bridging the gap between the laboratory and the POC of the fluorescence lifetime based bioassays. In particular, two systems with different levels of integration have been developed that combine a one-dimensional array of SPAD (Single-Photon Avalanch Diode) pixels capable of detecting a single photon, with an interchangeable microfluidic cartridge used to insert the sample and a laser diode Pulsed low-cost UV as a source of excitation. The contact-oriented design of the binomial formed by the sensor and the microfluidic, together with the timed operation of the sensors, makes it possible to dispense with the use of lenses and filters. In turn, custom packaging of the sensor chip allows the microfluidic cartridge to be positioned directly on the sensor array without any alignment procedure. Both systems have been validated, determining the decomposition time of quantum dots in 20 nl of solution for different concentrations, emulating a molecular test in a POC device.[cat] Tradicionalment, l'anàlisi molecular es realitza en laboratoris equipats amb instruments de sobretaula operats per tècnics especialitzats. Aquest paradigma ha anat canviant en les últimes dècades, a mesura que la tecnologia de biosensor s'ha tornat tan precisa com els instruments de sobretaula, proporcionant resultats en períodes molt més curts de temps i miniaturitzant la instrumentació, permetent així, traslladar gradualment les proves de diagnòstic fora de laboratori central. No obstant això i malgrat els avantatges inherents de l'espectroscòpia de fluorescència resolta en el temps aplicada a la diagnosi molecular, no ha estat fins a l'última dècada que s'han començat a desenvolupar dispositius POC (Point Of Care) basats en la detecció de la fluorescència, degut al desafiament que suposa el desenvolupament de sensors espectroscòpics d'alt rendiment, portàtils i de baix cost. Aquesta tesi presenta el desenvolupament d'un sistema compacte, robust i de baix cost per al diagnòstic molecular basat en l'espectroscòpia de fluorescència resolta en el temps, que serveixi com a plataforma d'ús general per a la detecció òptica d'una varietat de biomarcadors, tancant la bretxa entre el laboratori i el POC dels bioassaigs basats en l'anàlisi de la pèrdua de la fluorescència. En particular, s'han desenvolupat dos sistemes amb diferents nivells d'integració que combinen una matriu unidimensional de píxels SPAD (Single-Photon Avalanch Diode) capaços de detectar un sol fotó, amb un cartutx microfluídic intercanviable emprat per inserir la mostra, així com un díode làser UV premut de baix cost com a font d'excitació. El disseny orientat a la detecció per contacte de l'binomi format pel sensor i la microfluídica, juntament amb l'operació temporitzada dels sensors, permet prescindir de l'ús de lents i filtres. Al seu torn, l'empaquetat a mida de l'xip sensor permet posicionar el cartutx microfluídic directament sobre la matriu de sensors sense cap procediment d'alineament. Tots dos sistemes han estat validats determinant el temps de descomposició de "quantum dots" en 20 nl de solució per a diferents concentracions, emulant així un assaig molecular en un dispositiu POC

    Direct Time of Flight Single Photon Imaging

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    Strategies towards high performance (high-resolution/linearity) time-to-digital converters on field-programmable gate arrays

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    Time-correlated single-photon counting (TCSPC) technology has become popular in scientific research and industrial applications, such as high-energy physics, bio-sensing, non-invasion health monitoring, and 3D imaging. Because of the increasing demand for high-precision time measurements, time-to-digital converters (TDCs) have attracted attention since the 1970s. As a fully digital solution, TDCs are portable and have great potential for multichannel applications compared to bulky and expensive time-to-amplitude converters (TACs). A TDC can be implemented in ASIC and FPGA devices. Due to the low cost, flexibility, and short development cycle, FPGA-TDCs have become promising. Starting with a literature review, three original FPGA-TDCs with outstanding performance are introduced. The first design is the first efficient wave union (WU) based TDC implemented in Xilinx UltraScale (20 nm) FPGAs with a bubble-free sub-TDL structure. Combining with other existing methods, the resolution is further enhanced to 1.23 ps. The second TDC has been designed for LiDAR applications, especially in driver-less vehicles. Using the proposed new calibration method, the resolution is adjustable (50, 80, and 100 ps), and the linearity is exceptionally high (INL pk-pk and INL pk-pk are lower than 0.05 LSB). Meanwhile, a software tool has been open-sourced with a graphic user interface (GUI) to predict TDCs’ performance. In the third TDC, an onboard automatic calibration (AC) function has been realized by exploiting Xilinx ZYNQ SoC architectures. The test results show the robustness of the proposed method. Without the manual calibration, the AC function enables FPGA-TDCs to be applied in commercial products where mass production is required.Time-correlated single-photon counting (TCSPC) technology has become popular in scientific research and industrial applications, such as high-energy physics, bio-sensing, non-invasion health monitoring, and 3D imaging. Because of the increasing demand for high-precision time measurements, time-to-digital converters (TDCs) have attracted attention since the 1970s. As a fully digital solution, TDCs are portable and have great potential for multichannel applications compared to bulky and expensive time-to-amplitude converters (TACs). A TDC can be implemented in ASIC and FPGA devices. Due to the low cost, flexibility, and short development cycle, FPGA-TDCs have become promising. Starting with a literature review, three original FPGA-TDCs with outstanding performance are introduced. The first design is the first efficient wave union (WU) based TDC implemented in Xilinx UltraScale (20 nm) FPGAs with a bubble-free sub-TDL structure. Combining with other existing methods, the resolution is further enhanced to 1.23 ps. The second TDC has been designed for LiDAR applications, especially in driver-less vehicles. Using the proposed new calibration method, the resolution is adjustable (50, 80, and 100 ps), and the linearity is exceptionally high (INL pk-pk and INL pk-pk are lower than 0.05 LSB). Meanwhile, a software tool has been open-sourced with a graphic user interface (GUI) to predict TDCs’ performance. In the third TDC, an onboard automatic calibration (AC) function has been realized by exploiting Xilinx ZYNQ SoC architectures. The test results show the robustness of the proposed method. Without the manual calibration, the AC function enables FPGA-TDCs to be applied in commercial products where mass production is required

    Miniature high dynamic range time-resolved CMOS SPAD image sensors

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    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

    A 1.9 ps-rms Precision Time-to-Amplitude Converter With 782 fs LSB and 0.79%-rms DNL

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    Measuring a time interval in the nanoseconds range has opened the way to 3-D imaging, where additional information as distance of objects light detection and ranging (LiDAR) or lifetime decay fluorescence-lifetime imaging (FLIM) is added to spatial coordinates. One of the key elements of these systems is the time measurement circuit, which encodes a time interval into digital words. Nowadays, most demanding applications, especially in the biological field, require time-conversion circuits with a challenging combination of performance, including sub-ps resolution, ps precision, several ns of measurement range, linearity better than few percent of the bin width (especially when complex lifetime data caused by multiple factors have to be retrieved), and operating rates in the order of tens of Mcps. In this article, we present a time-to-amplitude converter (TAC) implemented in a SiGe 350 nm process featuring a resolution of 782 fs, a minimum timing jitter as low as 1.9 ps-rms, a DNL down to 0.79% LSB-rms, and conversion rate as high as 12.3 Mcps. With an area occupation of 0.2 mm2 [without PADs and digital-to-analog converter (DAC)], a FSR up to 100 ns, and a power dissipation of 70 mW, we developed a circuit suitable to be the core element of a densely integrated, faster and high-performance system

    New frontiers in time-domain diffuse optics, a review

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    The recent developments in time-domain diffuse optics that rely on physical concepts (e.g., time-gating and null distance) and advanced photonic components (e.g., vertical cavity source-emitting laser as light sources, single photon avalanche diode, and silicon photomultipliers as detectors, fast-gating circuits, and time-to-digital converters for acquisition) are focused. This study shows how these tools could lead on one hand to compact and wearable time-domain devices for point-of-care diagnostics down to the consumer level and on the other hand to powerful systems with exceptional depth penetration and sensitivity
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