Time resolved imaging is concerned with the measurement of photon arrival time. It has a wealth of emerging applications including biomedical uses such as fluorescence lifetime microscopy and positron emission tomography, as well as laser ranging and imaging in three dimensions. The impact of time resolved imaging on human life is significant: it can be used to identify cancerous cells in-vivo, how well new drugs may perform, or to guide a robot around a factory or hospital. Two essential building blocks of a time resolved imaging system are a photon detector capable of sensing single photons, and fast time resolvers that can measure the time of flight of light to picosecond resolution. In order to address these emerging applications, miniaturised, single-chip, integrated arrays of photon detectors and time resolvers must be developed with state of the art performance and low cost. The goal of this research is therefore the design, layout and verification of arrays of low noise Single Photon Avalanche Diodes (SPADs) together with high resolution Time-Digital Converters (TDCs) using an advanced silicon fabrication process. The research reported in this Thesis was carried out as part of the E.U. funded Megaframe FP6 Project. A 32x32 pixel, one million frames per second, time correlated imaging device has been designed, simulated and fabricated using a 130nm CMOS Imaging process from ST Microelectronics. The imager array has been implemented together with required support cells in order to transmit data off chip at high speed as well as providing a means of device control, test and calibration. The fabricated imaging device successfully demonstrates the research objectives. The Thesis presents details of design, simulation and characterisation results of the elements of the Megaframe device which were the author’s own work. Highlights of the results include the smallest and lowest noise SPAD devices yet published for this class of fabrication process and an imaging array capable of recording single photon arrivals every microsecond, with a minimum time resolution of fifty picoseconds and single bit linearity.

<p>Neutron stimulated emission computed tomography (NSECT) is a non-invasive, tomographic imaging technique with the ability to locate and quantify elemental concentration in a tissue sample. Previous studies have shown that NSECT has the ability to differentiate between benign and malignant tissue and diagnose liver iron overload while using a neutron beam tomographic acquisition protocol followed by iterative image reconstruction. These studies have shown that moderate concentrations of iron can be detected in the liver with moderate dose levels and long scan times. However, a low-dose, reduced scan time technique to differentiate various liver diseases has not been tested. As with other imaging modalities, the performance of NSECT in detecting different diseases while reducing dose and scan time will depend on the acquisition techniques and parameters that are used to scan the patients. In order to optimize a clinical liver imaging system based on NSECT, it is important to implement low-dose techniques and evaluate their feasibility, sensitivity, specificity and accuracy by analyzing the generated liver images from a patient population. This research work proposes to use Monte-Carlo simulations to optimize a clinical NSECT system for detection, localization, quantification and classification of liver diseases. This project has been divided into three parts; (a) implement two novel acquisition techniques for dose reduction, (b) modify MLEM iterative image reconstruction algorithm to incorporate the new acquisition techniques and (c) evaluate the performance of this combined technique on a simulated patient population. </p><p>The two dose-reduction, acquisition techniques that have been implemented are; (i) use of a single angle scanning, multi-detector acquisition system and (ii) the neutron-time resolved imaging (n-TRI) technique. In n-TRI, the NSECT signal has been resolved in time by a function of the speed of the incident neutron beam and this information has been used to locate the liver lesions in the tissue. These changes in the acquisition system have been incorporated and used to modify MLEM iterative image reconstruction algorithm to generate liver images. The liver images are generated from sinograms acquired by the simulated n-TRI based NSECT scanner from a simulated patient population.</p><p>The simulated patient population has patients of different sizes, with different liver diseases, multiple lesions with different sizes and locations in the liver. The NSECT images generated from this population have been used to validate the liver imaging system developed in this project. Statistical tests such as ROC and student t-tests have been used to evaluate this system. The overall improvement in dose and scan time as compared to the NSECT tomographic system have been calculated to verify the improvement in the imaging system. The patient dose was calculated by measuring the energy deposited by the neutron beam in the liver and surrounding body tissue. The scan time was calculated by measuring the time required by a neutron source to produce the neutron fluence required to generate a clinically viable NSECT image.</p><p>Simulation studies indicate that this NSECT system can detect, locate, quantify and classify liver lesions in different sized patients. The n-TRI imaging technique can detect lesions with wet iron concentration of 0.5 mg/g or higher in liver tissue in patients with 30 cm torso and can quantify lesions at 0.3 ns timing resolution with errors &#8804; 17.8%. The NSECT system can localize and classify liver lesions of hemochromatosis, hepatocellular carcinoma, fatty liver tissue and cirrhotic liver tissue based on bulk and trace element concentrations. In a small patient with a torso major axis of 30 cm, the n-TRI based liver imaging technique can localize 91.67% of all lesions and classify lesions with an accuracy of 88.23%. The dose to the small patient is 0.37 mSv a reduction of 39.9% as compared to the NSECT tomographic system and scan times are comparable to that of an abdominal MRI scan. In a bigger patient with a torso major axis of 50cm, the n-TRI based technique can detect 75% of the lesions, while localizing 66.67% of the lesions, the accuracy of classification is 76.47%. The effective dose equivalent delivered to the larger patient is 1.57 mSv for a 68.8% decrease in dose as compared to a tomographic NSECT system.</p><p>The research performed for this dissertation has two important outcomes. First, it demonstrates that NSECT has the clinical potential for detection, localization and classification of liver diseases in patients. Second, it provides a validation of the simulation of a novel low-dose liver imaging technique which can be used to guide future development and experimental implementation of the technique.</p> / Dissertation

Les technologies laser sont largement utilisées dans le contexte de l'impression 3D de matériaux de toute taille ainsique pour la bioimpression des constituants de tissue biologiques. Dans ce contexte, la bioimpression par laser (LAB), basée sur le procédé LIFT, a émergé comme une technique permettant de s'affranchir des inconvénients des technologies d'impression à jet d'encre(par exemple le colmatage). La bioimpression par Laser est une technique d'écriture directe de matériaux sous forme solide ou liquide dotée d'une haute résolution spatiale. La technique permet ainsi le transfert précis de microgouttelettes (volume de l'ordre du pL) de biomatériaux et de cellules sur un substrat de réception. Dans nos travaux de recherche, afin de mieux comprendre la dynamique du processus de transfert et d'utiliser la technique en ingénierie tissulaire, nous avons avons développé une approche expérimentale basée sur une méthode d'imagerie résolue en temps. Nous avons tout d'abord caractérisé les différents régimes d'éjection afin de définir des conditions appropriées à l'impressiond'éléments biologiques. Nous avons également exploré la fenêtre d'éjection, afin d'étudier l'influence de l'énergie laser sur la dynamique de jet. Ensuite, nous avons étudié une nouvelle de configuration bioimpression par laser pour laquelle des études paramétriques impliquant l'effet de la viscosité et de la distance d'impression sur la morphologie des gouttes imprimées ont été réalisées. Cette configuration permet d'imprimer des encres biologiques en obtenant des contours très lisses et uniformes jusqu’à une grande distance de séparation (≤10 mm). Les paramètres d'impression de cellules ont aussi été analysées par TRI en fonction de la concentration cellulaire des encres. Nos résultats fournissent des renseignements clés sur l'optimisation et devraient permettre un meilleur contrôle du mécanisme de transfert du processus de LAB. Enfin à la lumière de ces études, nous proposons un mécanisme complet pour la bioimpression par laser. / Laser-based approaches are among the pioneering works in cell printing. These techniques are being extensively focussed for two or three-dimensional structures of any size in transferring pattern materials including deposition of 3D biological constructs. In this context, Laser-Assisted Bioprinting (LAB), based on Laser-Induced Forward Transfer (LIFT) has emerged as a nozzleless method to surmount the drawbacks (e.g. clogging) of inkjet printing technologies. LAB is a laser direct-write technique that offers printing micropatterns with high spatial resolution from a wide range of solid or liquid materials, such as dielectrics, biomaterials and living cells. The technique enables controlled transfer of droplets onto a receiving substrate. A typical LAB setup comprises three key components: (i) a pulsed laser source, (ii) a ribbon coated with the material to be transferred and (iii) a receiving substrate. The ribbon integrates three layers: (i) a quartz disk support transparent to laser wavelength, (ii) a thin (1–100 nm) absorbing layer (like Ti or Au), and (iii) a bioink layer (few tens of microns) incorporating the material to print. The receiving substrate is faced to the bioink and placed at 100 μm to 1 mm distance from the ribbon. Rapid thermal expansion of metallic layer (on absorbing laser pulse) propels a small volume (~pL) of the ink towards a receiving substrate. Such a metallic interlayer eliminates direct interaction between the laser beam and the bioink. Volume of deposited material depends linearly on the laser pulse energy, and that a minimum threshold energy is required for microdroplet ejection. The thickness of the absorbing layer, viscosity and thickness of the bioink, different optical parameters such as the focus spot and the laser fluence are the controlling parameters to obtain a microscopic resolution and to limit the shock inflicted on the ejected cells. In our research works, we considered experimental approach to study the physical mechanism involved in the LAB using a time-resolved imaging method in order to gain a better insight into the dynamics of the transfer process and to use the technique for printing biomaterials. First we designed and implemented a novel configuration of LAB for upward printing. Then we characterized different ejection regimes to define suitable conditions for bioprinting. We further explored jetting window to study the influence of laser energy on jet dynamics. Ejection dynamics has been investigated by temporal evolution of the liquid jet for their potential use in cell printing. In addition parametric studies like effect of viscosity and printing distance on the morphology of the printed drops were conducted to explore jetting “window”. This configuration allows debris-free printing of fragile bioinks with extremely smooth and uniform edges at larger separation distance (ranging from 3 to 10mm). Material criteria required for realization of the cell printing are discussed and supported by experimental observations obtained by TRI investigation of cell printing from donors with different cell concentrations. These results provide key insights into optimization and better control of transfer mechanism of LAB. Finally, in the light of these studies, a comprehensive mechanism is proposed for printing micro-drops by LAB.

Parallèlement à l’impression jet d’encre et au bioplotting, l’impression d'éléments biologiques assistée par laser (Laser Assisted Bioprinting : LAB) qui utilise le transfert vers l’avant induit par laser (Laser Induced Forward Transfer : LIFT) a émergé comme une méthode alternative dans l’assemblage et la micro–structuration de biomatériaux et de cellules. Le LAB est une technique d’écriture directe qui offre la possibilité d’imprimer des motifs avec une haute résolution spatiale à partir d'une large gamme de matériaux solides ou liquides, tels que des diélectriques, des biomolécules et des cellules vivantes en solution.Dans nos travaux de recherche, nous avons considéré une approche expérimentale et numérique pour étudier les mécanismes physiques mis en jeu lors de la microimpression d’éléments biologiques assistée par laser. Dans un premier temps nous avons défini les paramètres rhéologiques des bioencres et les conditions de transfert (composition, épaisseur et viscosité de la bioencre et énergie laser). Puis nous avons mené une analyse statistique du volume des gouttelettes déposées pour quatre viscosités de bioencre, cinq épaisseurs de bioencre et cinq énergies laser. Ensuite nous avons conçu et mis en place un système d’imagerie résolue en temps pour étudier les effets de la viscosité sur la dynamique de l’éjection. Nous avons ainsi différencié trois régimes d'éjection en fonction de l'énergie laser déposée dans la couche absorbante, de la viscosité et de l'épaisseur de la bioencre. Parallèlement, un modèle numérique a été mis en place pour comprendre et prédire la dynamique de l’éjection en fonction de paramètres multiples : choix et épaisseur de la couche absorbante, épaisseur de la couche de bioencre, énergie laser déposée. Enfin, au regard de ces études, nous proposons un mécanisme d'éjection des microgouttelettes intervenant au cours du procédé de microimpression assistée par laser. / Over this decade, cell printing strategy has emerged as one of the promising approaches to organize cells in two and three dimensional engineered tissues. In parallel with ink-jet printing and bioplotting, Laser Assisted Bioprinting (LAB) using Laser-Induced Forward Transfer (LIFT) has emerged as an alternative method in the assembly and micropatterning of biomaterials and cells. LAB is a laser direct-write technique that offers the possibility of printing micropatterns with high spatial resolution from a wide range of solid or liquid materials, such as dielectrics, biomolecules and living cells in solution. In our research works, we considered an experimental and numerical approach to study the physical mechanisms involved in the biological elements microprinting laser assisted.First we defined the rheological parameters of bioinks and the transfer conditions (composition, thickness and viscosity of the bioink and laser energy). Then we led a statistical analysis of the volume of the transfer droplets for four viscosities of bioink, five thicknesses of bioink and five laser energies. Then we designed and implemented a system for time resolved imaging to study the effects of viscosity on the dynamics of the ejection. Thus we have differentiated three ejection regimes in function of the laser energy released in the absorbing layer, the visocsity and the thickness of the bioink. In parallel, a numerical model was developed to understand and predict the dynamics of the ejection parameters according to multiple choice and thickness of the absorbing layer, thickness of the layer bioencre, energy deposited. Finally, with regard to these studies, we propose a mechanism for ejecting droplets involved in the process of laser-assisted microprinting.

Les décharges en phase gazeuse couplées avec les liquides est une branche relativement nouvelle de la physique des plasmas. Le développement des applications technologiques basées sur les plasmas-liquides dans des domaines tels que la médecine, le traitement de matériaux, la remédiation environnementale, etc., est très prometteur. Cependant, la compréhension de la nature de l’interaction plasma-liquide est indispensable pour pouvoir développer les applications. Dans ce mémoire, composé de trois sections, nous avons étudié l’interaction d’un plasma d’air, généré par une décharge à courant alternatif (AC), et couplé directement avec l’eau. Tout d’abord, une présentation générale des systèmes plasmas-liquides et ses applications pour le traitement des eaux est faite dans le Chapitre 1. Chapitre 2, un article publié dans Journal of Physics D: Applied Physics, est une étude de la dynamique spatio-temporelle d’un plasma d’air produit par une décharge AC entre une électrode pointe et la surface de l’eau. Chapitre 3, un article publié dans Plasma Chemistry and Plasma Processing, représente une investigation sur les différents modes de décharges AC en contact avec l’eau et sur l’efficacité de chaque mode pour dégrader un polluant organique modèle (bleue de méthylène). / Gas phase discharges in contact with liquids is a relatively novel research field in plasma physics. Plasma-liquid systems are very promising for various technological applications, such as medicine, solid-state physics, and environmental remediation. However, further development of the applications requires understanding of plasma-liquid interactions. In this thesis, interaction between an air plasma directly coupled in contact with water is studied. This thesis includes three chapters. Chapter 1 presents a general introduction of the plasma-liquid interactions and their applications in water treatment. Chapter 2, an article published in Journal of Physics D: Applied Physics, is an investigation of the spatial and temporal dynamics of an air plasma produced by AC discharge between a pin electrode and water. Chapter 3, an article published in Plasma Chemistry and Plasma Processing, is an investigation of the various modes produced by an AC-driven air discharge in contact with water. The electrical characteristics of each discharge mode are presented in detail, and variations in water properties (namely water acidity and conductivity) are also discussed. The efficiency of each discharge mode on the degradation rate of methylene blue, a standard pollutant, is also reported.