The goal of this research was to demonstrate the potential of spectral CT for the discrimination of vulnerable atherosclerotic plaques. It was proposed that spectral CT has the potential to identify the presence of specific markers for vulnerable plaques: iron deposits and lipid core. A spectral micro-CT system incorporating the latest Medipix spectroscopic photon- counting detectors was commissioned for this purpose. Using spectroscopic methods developed with this system, it was possible to distinguish the presence of iron deposits and lipid core within ex vivo atherosclerotic plaques. Atherosclerosis or hardening of arteries is a systemic disease of the vessel wall that occurs in the aorta, carotid, coronary and peripheral arteries. It is characterised by the deposition of calcified plaques on the innermost layer of the artery wall. Vulnerable plaques are unstable, prone to rupture and put the person at risk of cardiovascular events and strokes. Factors that may lead to plaque instability are lipid content and iron deposits. This preclinical study is a precursor to the development of a clinical technique that will enable vulnerable atherosclerotic plaques to be identified in vivo prior to treatment or removal. Following a preliminary study on atherosclerotic plaques with a prototype system, the MARS-CT3 spectral micro-CT system incorporating Medipix3 was developed and commissioned for further plaque studies. The spectral CT data sets acquired by this system were assessed visually for morphology and analysed for material composition using a linear algebra method. The results were correlated with photography and histology (the histology is the current gold standard). The presence of iron and lipid can be differentiated from the background soft-tissue using a linear algebra method. However the quantification of iron in the presence of calcium is not currently possible without additional data or constraints. Nevertheless the presence of iron deposits within the plaques can be distinguished in the high resolution MARS-CT images and has been correlated with photographic and histological evidence. Thus, using the high spatial resolution spectral data from MARS-CT, the discrimination of lipid core and iron deposits within ex vivo advanced human atherosclerotic plaques is feasible. This may provide the basis for the development of a clinical technique that will identify vulnerable plaques in vivo by high resolution spectral CT.

Detecting elementary particles and observing accompanying events in particle colliders is one of the most important field of current research in experimental physics. TimePix and its successor TimePix3 are types of the currently used detectors which are placed beside other in ATLAS experiment conducted by Eu- ropean Organization for Nuclear Research. Such detectors can produce huge amount of data about passing particles at high rate. The goal of the thesis is to develop methods for detecting and classification of elementary particles observed by detector network ATLAS-TPX3. Suitable methods for clustering and/or classification based on semi-labelled data should be identified or new one should be developed. The proposed methods will be implemented and their performance on real data will be evaluated. The results will also include an implementation of framework for preprocessing low level data from detector network ATLAS-TPX3 in real-time and creating outputs that are suitable for subsequent physics investigation (e.g. ROOT framework files) includ- ing the proposed or future methods for particle classification. 5

This thesis is about the development of the MARS camera: a standalone portable digital x-ray camera with spectral sensitivity. It is built for use in the MARS Spectral system from the Medipix2 and Medipix3 imaging chips. Photon counting detectors and Spectral CT are introduced, and Medipix is identified as a powerful new imaging device. The goals and strategy for the MARS camera are discussed. The Medipix chip physical, electronic and functional aspects, and experience gained, are described. The camera hardware, firmware and supporting PC software are presented. Reports of experimental work on the process of equalisation from noise, and of tests of charge summing mode, conclude the main body of the thesis. The camera has been actively used since late 2009 in pre-clinical research. A list of publications that derive from the use of the camera and the MARS Spectral scanner demonstrates the practical benefits already obtained from this work. Two of the publications are first-author, eight are co-authored, and a further four acknowledge use of the MARS camera as part of the MARS scanner. The work has been presented at three MARS group meetings, two departmental conferences, and at an internal Medipix3 collaboration meeting hosted by ESRF in Grenoble.

This thesis is about simulation of semiconductor X-ray and particledetectors. The simulation of a novel coating for solid state neutrondetectors is discussed as well as the implementation of a simulationframework for hybrid pixel detectors.Today’s most common thermal neutron detectors are proportionalcounters, that use 3He gas in large tubes or multi wire arrays. Globalnuclear disarmament and the increase in use for homeland securityapplications has created a shortage of the gas which poses a problemfor neutron spallation sources that require higher resolution and largersensors. In this thesis a novel material and clean room compatible pro-cess for neutron conversion are discussed. Simulations and fabricationhave been executed and analysed in measurements. It has been proventhat such a device can be fabricated and detect thermal neutrons.Spectral imaging hybrid pixel detectors like the Medipix chipare the most advanced imaging systems currently available. Thesechips are highly sophisticated with several hundreds of transistors perpixel to enable features like multiple thresholds for noise free photoncounting measurements, spectral imaging as well as time of arrivalmeasurements. To analyse and understand the behaviour of differentsensor materials bonded to the chip and to improve development offuture generations of the chip simulations are necessary. Generally, allparts of the detector system are simulated independently. However, itis favourable to have a simulation framework that is able to combineMonte Carlo particle transport, charge transport in the sensor as wellas analogue and digital response of the pixel read-out electronics. Thisthesis aims to develop such a system that has been developed withGeant4 and analytical semiconductor and electronics models. Further-more, it has been verified with data from measurements with severalMedipix and Timepix sensors as well as TCAD simulations.Results show that such a framework is feasible even for imagingsimulations. It shows great promise to be able to be extended withfuture pixel detector designs and semiconductor materials as well asneutron converters to aim for next generation imaging devices.

Computed Tomography is one of the most important image modalities in medical imaging nowadays. Recent developments have led to a new acquisition technique called 'dual-energy', where images are taken with different x-ray spectra. This enables for the first time spectral information in the CT dataset. Our approach was to use an energy resolving detector (Medipix) and investigate its potential in the medical imaging domain. Images are taken in different energy bins. For acquisition of the data, a CT scanner called 'Medipix All Resolution System' (MARS) scanner was constructed. It was upgraded to achieve better image quality as well as faster scan time and a stable operation. In medical imaging, it is important to achieve a high contrast and a good detail recognition at a low dose. Therefore, it is common practice to use contrast agents to highlight certain regions of the body like e.g. the vascular system. But with a broad spectrum acquisition, it is often impossible to distinguish highly absorbing body elements like bones from the contrast agent. We target this problem by a contrast agent study using different energy bins. This so called spectral contrast agent study has been conducted with small animals using the MARS scanner. The data has been processed to create an optimal CT reconstruction. The image enhancement techniques consist of corrections for noisy pixels, intensity fluctuations and eliminating streaks in the sinograms to reduce ring artifacts. In order to evaluate the data, we used two methods of material identification. The material reconstruction method works on projection data and uses a maximum-likelihood estimation to reconstruct images of base materials. The second method, the principal component analysis (PCA), identifies the relevant information from the spectral dataset in a few derived variables that account for most of the variance in the dataset. This resulted in images with enhanced contrast and removed redundancies. It is possible to combine these images in one colour image where anatomical structures are shown in good detail and certain materials show up in different colors. Based on this new information from spectral data, we could show that it is possible to distinguish the spinal bone from contrast agent.

In this thesis a recently developed energy resolving x-ray detector (Medipix) is used to investigate potential medical applications of spectral x-ray imaging. Computed Tomography (CT) is one of the most important medical imaging modalities. Recent developments in CT techniques include dual-energy CT, where images are taken with two different x-ray spectra by either using two x-ray tubes operated at different voltages, or modulating the operating voltage of a single tube. These techniques provide spectral information in the CT dataset but are limited to what can be achieved by manipulating the x-ray source, since the detectors used in current CT systems are unable to provide spectral information about the detected x-rays. A preliminary investigation of the use of the Medipix detectors for two different medical applications is presented. The first, applications is imaging of blood vessels for diagnosis of vascular diseases, and the second, characterising and measuring the energy dependence of x-ray attenuation in fat and liver tissue using the Medipix2 detector. This second investigation is part of work towards (eventually) quantifying the fat content of liver tissue in vivo, which is important for the early diagnosis of fatty liver disease. While an early attempt to identify iron fluorescence x-rays in a Monte-Carlo simulation of blood vessel x-ray image was not successful, the potential for improving image contrast using the changes in x-ray attenuation at the iodine k-edge iodine have been investigated in a series of further simulations and appears to be feasible. The potential use of spectral imaging to differentiate and quantify tissues without the need for added contrast material has been investigated by using a Medipix2 detector to measure the energy dependence of x-ray absorption in fat and liver tissue. The results of this experimental work show significant differences in x-ray attenuation between these two tissues that suggest this form of spectral imaging may be useful in practice.

The goal of this research is to contribute to the development of MARS spectral CT and to demonstrate the feasibility of molecular imaging using the technology. MARS is a newly developed micro CT scanner, incorporating the latest spectroscopic Medipix photon counting detector. I show that the scanner can identify both drug markers and stenosis of atherosclerosis labelled with non-toxic nanoparticles. I also show that spectral computed tomography using Medipix x-ray detectors can give quantitative measurements of concentrations of gold nanoparticles in phantoms, mice and excised atheroma. The characterisation of the Medipix2 assemblies with Si and CdTe x-ray sensors using poly-energetic x-ray sources has been performed. I measure the inhomogeneities within the sensors; individual pixel sensitivity response; and their saturation effects at higher photon fluxes. The effects of charge sharing on the performance of Medipix2 have been assessed, showing that it compromises energy resolution much more than spatial resolution. I have commissioned several MARS scanners incorporating several different Medipix2 and Medipix3 cameras. After the characterization of x-ray detectors and the geometrical assessment of MARS-CT, spectral CT data has been acquired, using x-ray energies that are appropriate for human imaging. The outcome shows that MARS scanner has the ability to discriminate among low atomic number materials, and from various concentrations of heavy atoms. This new imaging modality, used with functionalized gold nanoparticles, gives a new tool to assess plaque vulnerability. I demonstrated this by using gold nanoparticles, attached to antibodies, which targeted to thrombotic events in excised plaque. Likewise, the imaging modality can be used to track drugs labelled with any heavy atoms to assess how much drug gets into a target organ. Thus the methodology could be used to accelerate development of new drug treatments for cancers and inflammatory diseases.

Medical imaging is a technique that allows us to visualize non surgically the internal structure of the human body in order to diagnose or treat medical conditions. It permits also monitoring of physical processes or functions of different organs inside the body. The medical imaging encompasses wide range of techniques based on different physical prin- ciples, including techniques using ionizing radiation. The quality of the images depends significantly on the quality of the used imaging detectors. There are many types of the detectors, from old analog devices (e.g. films) to fully digital detectors such as flat panels, that are the most widely used today. The newer technology is being developed and the techniques such as photon counting explored. However, the state of the art technology is the single photon counting, where the experimental detectors such as Medipix are able to count and process each individual photon. This works studies the properties, features and applications of the newest detector from the Medipix family Timepix3 in different imaging modalities. Firstly, a design of a new hardware readout interface for Timepix3 is presented together with data acquisition software and new analysis and calibration algorithms. Then, different applications of Timepix3 detector were explored: very...

Medipix2 (MPX) sont des détecteurs semi-conducteurs au silicium montés sur 256x256 pixels. Chaque pixel a une aire de 55x55μm2. L’aire active d’un détecteur MPX est d’environ 2 cm2. Avec deux modes de détection, un seuil et un temps d’exposition ajustables, leur utilisation peut être optimisée pour une analyse spécifique. Seize de ces détecteurs sont présentement installés dans l’expérience ATLAS (A Toroidal LHC ApparatuS) au CERN (Organisation Européenne pour la Recherche Nucléaire). Ils mesurent en temps réel le champ de radiation dû aux collisions proton-proton, au point d’interaction IP1 (Point d’Interaction 1) du LHC (Grand Collisionneur d’Hadrons). Ces mesures ont divers buts comme par exemple la mesure du champ de neutrons dans la caverne d’ATLAS. Le réseau de détecteurs MPX est complètement indépendant du détecteur ATLAS. Le groupe ATLAS-Montréal s’est intéressé à l’analyse des données récoltées par ces détecteurs pour calculer une valeur de la luminosité du LHC au point de collision des faisceaux, autour duquel est construit le détecteur ATLAS. Cette valeur est déterminée indépendamment de la luminosité mesurée par les divers sous-détecteurs d’ATLAS dédiés spécifiquement à la mesure de la luminosité. Avec l’augmentation de la luminosité du LHC les détecteurs MPX les plus proches du point d’interaction détectent un grand nombre de particules dont les traces sont impossibles à distinguer sur les images ("frames") obtenues, à cause de leur recouvrement. Les paramètres de mesure de certains de ces détecteurs ont été optimisés pour des mesures de luminosité. Une méthode d’analyse des données permet de filtrer les pixels bruyants et de convertir les données des images, qui correspondent à des temps d’exposition propres aux détecteurs MPX, en valeur de luminosité pour chaque LumiBlock. Un LumiBlock est un intervalle de temps de mesure propre au détecteur ATLAS. On a validé les mesures de luminosité premièrement en comparant les résultats obtenus par différents détecteurs MPX, et ensuite en comparant les valeurs de luminosité relevées à celles obtenues par les sous-détecteurs d’ATLAS dédiés spécifiquement à la mesure de la luminosité. / Medipix2 (MPX) devices are silicon semiconductor detectors consisting of 256x256 pixels. Each pixel has 55x55μm2. The MPX sensitive area is ~2 cm2. With two modes of operation, an adjustable threshold, and adjustable exposure time, their use can be optimized for a specific analysis. Sixteen of these detectors are currently installed in the ATLAS detector at CERN (European Organization for Nuclear Research). They perform real time measurement of the radiation field due to proton-proton collisions occurring at the interaction point IP1 (Interaction Point 1) of the LHC (Large Hadron Collider). These measurements have different purposes, for instance the measurement of the neutron field in the ATLAS cavern. The network of MPX detectors is completely independent from the ATLAS detector. The ATLAS-Montreal group has taken interest in analysing data provided by these detectors to calculate a value for the luminosity of the LHC at the collision point of the beams around which is build the ATLAS detector that is completely independent from the value measured by ATLAS sub-detectors specifically dedicated to luminosity measurements. With the increase of the luminosity in LHC the MPX detectors near the interaction point record a large number of particles leaving tracks with a large number of overlaps in the resulting frames. These tracks are thus difficult to separate. The measurement parameters of some of these MPX detectors have been optimised for luminosity study. A method to analyse the recorded data was developed. It first filters the noisy pixels, then converts data from a frame format (corresponding to a given MPX exposure time), into luminosity in a LumiBlock format. A LumiBlock is a time measurement period used by ATLAS detector. To verify the results, comparisons between different MPXs have been made, as well as comparison between MPX results and the results of ATLAS sub-detectors specifically dedicated to luminosity measurements.

Ce document résume mes activités entre 1995 et 2010. Dans un premier temps, le développement d'un détecteur à pixels de silicium pour l'amélioration du Forward Proton Spectrometer de l'expérience H1 à DESY est présenté. Ensuite, les développements des circuits de lecture du détecteur à pixels de l'expérience ATLAS au CERN sont détaillés, en particulier le développement de bancs de test de ces circuits ainsi que la simulaton de leur comportement dans un environnement réaliste. Puis, l'infrastructure de la digitization des détecteurs à silicium (Pixels et SCT) est présentée. Une deuxième partie décrit la production de l'électronique frontale de lecture du calorimètre hadronique à tuiles scintillantes d'ATLAS (TileCal), en particulier le développement du système de test MobiDICK. Les logiciels de contrôle du système de calibration du TileCal par laser sont aussi détaillés. Pour finir, mes activités d'enseignement, d'encadrement et de diffusion des connaissances (en particulier le Cosmophone) sont mentionnées.