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

[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

AlGaN ultraviolet micro-LEDs

AlGaN-based UV LEDs have proven to have broad applications in many fields including sterilization, disinfection, purification, and phototherapy, but the performance still needs to be further improved. Benefiting from advantages such as better current spreading, lower self-heating effect and higher light extraction efficiency achieved by the reduced LED size, UV micro-LEDs are expected to improve quantum efficiency and thus can expand more potential applications. In this article, performance enhancement techniques and applications of UV micro-LEDs will be reviewed, providing an outlook for further development of AlGaN-based UV-LEDs. The micro-LED format offers possibilities to address fundamental issues that UV LEDs confront in general, but also demonstrates specific characteristics and performance advantages opening up new areas of application including high-speed optical communication, time-resolved fluorescence lifetime measurement, optical pumping, direct writing and charge management

Hardware implementation algorithm and error analysis of high-speed fluorescence lifetime sensing systems using center-of-mass method

A new, simple, high-speed, and hardware-only integrationbased fluorescence-lifetime-sensing algorithm using a center-of-mass method CMM is proposed to implement lifetime calculations, and its signal-to-noise-ratio based on statistics theory is also deduced. Compared to the commonly used iterative least-squares method or the maximum-likelihood-estimation–based, general purpose fluorescence lifetime imaging microscopy FLIM analysis software, the proposed hardware lifetime calculation algorithm with CMM offers direct calculation of fluorescence lifetime based on the collected photon counts and timing information provided by in-pixel circuitry and therefore delivers faster analysis for real-time applications, such as clinical diagnosis. A real-time hardware implementation of this CMM FLIM algorithm suitable for a single-photon avalanche diode array in CMOS imaging technology is now proposed for implementation on field-programmable gate array. The performance of the proposed methods has been tested on Fluorescein, Coumarin 6, and 1,8- anilinonaphthalenesulfonate in water/methanol mixture

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

Photodetectors

In this book some recent advances in development of photodetectors and photodetection systems for specific applications are included. In the first section of the book nine different types of photodetectors and their characteristics are presented. Next, some theoretical aspects and simulations are discussed. The last eight chapters are devoted to the development of photodetection systems for imaging, particle size analysis, transfers of time, measurement of vibrations, magnetic field, polarization of light, and particle energy. The book is addressed to students, engineers, and researchers working in the field of photonics and advanced technologies