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

Circuits and Systems for Lateral Flow Immunoassay Biosensors at the Point-of-Care

Lateral Flow Immunoassays (LFIAs) are biosensors, which among others are used for the detection of infectious diseases. Due to their numerous advantages, they are particularly suitable for point of care testing, especially in developing countries where there is lack of medical healthcare centers and trained personnel. When the testing sample is positive, the LFIAs generate a color test line to indicate the presence of analyte. The intensity of the test line relates to the concentration of analyte. Even though the color test line can be visually observed for the accurate quantification of the results in LFIAs an external electronic reader is required. Existing readers are not fully optimized for point-of-care (POC) testing and therefore have significant limitations. This thesis presents the development of three readout systems that quantify the results of LFIAs. The first system was implemented as a proof of concept of the proposed method, which is based on the scanning approach without using any moving components or any extra optical accessories. Instead, the test line and the area around it, are scanned using an array of photodiodes (1 × 128). The small size of the pixels gives the system sufficient spatial resolution, to avoid errors due to positioning displacement of the strip. The system was tested with influenza A nucleoprotein and the results demonstrate its quantification capabilities. The second generation system is an optimized version of the proof of concept system. Optimization was performed in terms of matching the photodetectors wavelength with the maximum absorption wavelength of the gold nanoparticles presented in the tested LFIA. Ray trace simulations defined the optimum position of all the components in order to achieve uniform light distribution across the LFIA with the minimum number of light sources. An experimental model of the optical profile of the surface of LFIA was also generated for accurate simulations. Tests of the developed system with LFIAs showed its ability to quantify the results while having reduced power consumption and better limit of detection compared to the first system. Finally, a third generation system was realized which demonstrated the capability of having a miniaturized reader. The photodetector of the previous systems was replaced with a CMOS Image Sensor (CIS), specifically designed for this application. The pixel design was optimized for very low power consumption via biasing the transistors in subthreshold and by reusing the same amplifier for both photocurrent to voltage conversion and noise cancellation. With uniform light distribution at 525 nm and 76 frames/s the chip has 1.9 mVrms total output referred noise and a total power consumption of 21 μW. In tests with lateral flow immunoassay, this system detected concentrations of influenza A nucleoprotein from 0.5 ng/mL to 200 ng/mL

MEMS Technology for Biomedical Imaging Applications

Biomedical imaging is the key technique and process to create informative images of the human body or other organic structures for clinical purposes or medical science. Micro-electro-mechanical systems (MEMS) technology has demonstrated enormous potential in biomedical imaging applications due to its outstanding advantages of, for instance, miniaturization, high speed, higher resolution, and convenience of batch fabrication. There are many advancements and breakthroughs developing in the academic community, and there are a few challenges raised accordingly upon the designs, structures, fabrication, integration, and applications of MEMS for all kinds of biomedical imaging. This Special Issue aims to collate and showcase research papers, short commutations, perspectives, and insightful review articles from esteemed colleagues that demonstrate: (1) original works on the topic of MEMS components or devices based on various kinds of mechanisms for biomedical imaging; and (2) new developments and potentials of applying MEMS technology of any kind in biomedical imaging. The objective of this special session is to provide insightful information regarding the technological advancements for the researchers in the community