Th.--Méd.--Reims, 1977. N°: 24.

Spin-exchange optical pumping (SEOP) is a hyperpolarisation method used in the hyperpolarisation of noble gases and can enhance nuclear spin polarisation by five orders of magnitude. Hyperpolarised (HP) 129-Xe has many properties that make it ideally suited to clinical lung imaging, but since its first demonstration in animals in 1994 and humans in 1996, translation to the clinic has been hampered by challenges associated with scaling up production. Within this thesis, construction and demonstration of a clinical-scale stopped-flow hyperpolariser is described, the design of which is based on the record holding XeUS and XeNA polarisers developed previously by our consortium, which had aimed to address the issue of production scale-up. Modifications enhancing the ease of operation and utility in-clinic are presented, as are modifications that reduce the capital cost of such a system. These include a re-design of the gas manifold and the development of a low-cost low-field NMR spectrometer which achieved an SNR of 125 at a cost of ~$300, a 13-fold improvement in cost/SNR compared with the existing spectrometer at a saving of ~$19,000. In continuous-flow 129-Xe polarisers there has long been a discrepancy in the polarisation achieved and that predicted by the standard model of SEOP which was shown recently to be due to the presence of rubidium clusters. Here, the standard model is applied to- and validated for the first time against the stopped-flow regime. The validated model is used to explore parameter space to identify the most effective ways to increase production yield in future stopped-flow polarisers. Stopped-flow SEOP in the xenon-rich regime presents unique thermal management problems due to the absence of gas flow and abundance of poorly thermally conductive, Rb spin destroying Xe. Raman spectroscopy is used to spatially examine in-cell thermal behaviour under steady-state and turbulent 'rubidium runaway' conditions as a function of temperature and Xe density and the beneficial impact of adding thermally conductive helium to the standard N2-Xe gas mix is demonstrated. Hybrid Rb-Cs-Xe SEOP is demonstrated for the first time and examined using in-situ NMR and Raman spectroscopies. High polarisations of ~50% were obtained. Finally, progress on the HP-Xe clinical trial is presented to illustrate the impact of the 4-fold increase in SNR that will come with the installation of the new N-XeUS stopped-flow polariser.

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There is increasing interest in the use of small field of view (SFOV) portable gamma cameras in medical imaging. A novel hybrid optical-gamma camera (HGC) has been developed through a collaboration between the Universities of Leicester and Nottingham. This system offers high resolution gamma and optical imaging and shows potential for use at the patient bedside, or in the operating theatre. The aim of this thesis was to translate the HGC technology from in vitro laboratory studies to clinical use in human subjects. Pilot studies were undertaken with the HGC as part of this thesis. Furthermore, efforts have been made to transform the HGC technologies into a new medical device, known as Nebuleye. Initial physical evaluation of the pre-production prototype camera was carried out as part of the device developmental process, highlighting some aspects of the design that require further modification. A complete and rigorous testing scheme to assess the pre-production prototype camera has been developed and successfully implemented. The newly introduced tests enabled the system uniformity, system sensitivity, detector head shielding leakage, optical-gamma image alignment and optical image quality of the hybrid camera to be assessed objectively. This harmonised testing scheme allows characterisation and direct comparison of SFOV gamma cameras. In vitro and in vivo preclinical imaging was undertaken to examine the performance of the SFOV gamma cameras for experimental animal studies. The results of animal study have shown for the first time the feasibility and performance of these SFOV gamma cameras for imaging mice injected with a newly developed 111In labelled hybrid tracer. Further investigations are needed to improve the system resolution and prepare the camera system for combined gamma-near infrared fluorescence imaging in future. A systematic in vitro laboratory assessment method has been established to examine the imaging performance of the SFOV gamma camera in radioguided sentinel lymph node biopsy (SLNB) and radioactive seed localisation procedures for breast cancer surgery. Further preparatory work was undertaken to carry out a pilot clinical trial of the use of the pre-production prototype camera in sentinel node localisation procedures during breast cancer surgery. The clinical study protocol and routine quality control procedures have been established and are suitable for future use. Baseline data on the camera performance assessed using the routine quality control scheme have been obtained. Finally, the capabilities of the SFOV gamma camera were assessed. This has provided baseline data on user feedback and the imaging consequences on operator motion effects, as well as examining the detectability of a range of radionuclides, including 99mTc, 111In, 123I, 125I and 75Se. The first clinical results of the use of the HGC in clinical hybrid optical-gamma imaging in patients administered with 99mTc and 123I labelled radiopharmaceuticals have been reported. This clinical study has demonstrated the feasibility and capability of HGC in various clinical applications performed at the patient bedside, which included patients undergoing bone, thyroid, lacrimal drainage and lymphatic imaging as well as DaTscan studies. In conclusion, the work in this thesis has demonstrated the successful translation of an SFOV hybrid gamma camera for clinical use. This system would be ideally suited for use in the operating theatre for radioguided procedures such as sentinel node detection and tumour localisation. This system also offers potential for use with the new generation of hybrid fluorescent-radionuclide tracers currently under development.

This overview reports 31 studies, which have been performed by the author since 1989 to define the diagnostic value of thermometry and infrared imaging in rehabilitation and rheumatology. Some investigations were designed to characterise either treatment modalities, to clarify the role of temperature measurements as a method for follow-up or treatment monitoring in certain diseases. Thermal imaging has an important impact in assisting the diagnosis of many diseases. A relationship between temperature and clinical signs was established in the following disorders: epicondylitis (correlation of hot spots with pain provocated by firm pressure or resisted movement, and pressure threshold), complex regional pain syndrome (elevated temperature is paralleled by swelling and pain, temperature elevation of the hand after radius fracture after plaster removal predicts typical X-ray changes), thoracic outlet syndrome (high correlation of the region of paresthesia and low temperature readings), muscular inactivity, acute stage of Herpes zoster and Raynaud's phenomenon. Thermal imaging is of little value for the assessment of disability in patients with knee pain and of questionable value in patients with carpal tunnel syndrome or fibromyalgia. Painful tendon insertions or acupuncture points on the auricle cannot be detected by thermal imaging. Temperature signs in epicondylitis, complex regional pain syndrome and thoracic outlet can be successfully used for treatment monitoring. This might be also the case in radiotherapy of malignant breast disease. Infrared thermography, performed immediately after physical exercise can help to identify activated muscles. The value of thermal imaging for monitoring patients with lymphedema remains questionable. Temperature signs in epicondylitis, complex regional pain syndrome and thoracic outlet can be successfully used for treatment monitoring. This might be also the case in radiotherapy of malignant breast disease. Infrared thermography, performed immediately after physical exercise can help to identify activated muscles. The value of thermal imaging for monitoring patients with lymphedema remains questionable. On the other hand as a result of these studies, it became quite clear that the heat regulatory system is connected with other regulation systems of the body. Many of these influence the perfusion of vessels, which can result in temperature changes on the surface. In addition to the circulation system, pain and muscle function are the most important links to temperature regulation. Therefore any change or therapeutic modification of these systems might be seen on thermal images.

When performing nuclear magnetic resonance (NMR) it is desirable to maximise the available polarisation of the spin system in order to achieve optimal signal-to-noise ratios. One method of achieving this is via the process of spin-exchange optical pumping (SEOP). SEOP can be used to produce hyperpolarised (HP) noble gases, which possess numerous applications in the fields of science and medicine, ranging from spectroscopic imaging of porous media to Magnetic Resonance Imaging (MRI) of the human lungs. The SEOP process involves transfer of angular momentum from circularly polarised laser photons to the electrons of an alkali metal vapour. Noble gas nuclei can then be polarised via collisions with the alkali metal vapour. Ultra-low frequency Raman Spectroscopy may be used to perform rotational temperature measurements of a nitrogen buffer gas in these SEOP experiments in real-time, in an attempt to understand the poorly understood and highly complex system dynamics and energy transport processes. The work contained in this thesis aims to investigate the co-dependence of these dynamics, in order to characterise the SEOP process in greater detail for a variety of gas mixtures, temperatures and alkali metal targets. With this, it is hoped that HP noble gases may be produced with greater efficiency, achieving faster build-up rates and higher net magnetisation. In addition to in situ Raman spectroscopy, additional diagnostic techniques were implemented in order to illustrate the co-dependence of variables during the thermal exchange processes present in SEOP. Low-field NMR spectroscopy was utilised to determine the 129Xe net spin polarisation (P_Xe) as a function of time and position within the SEOP vessel, whilst near-infra-red (NIR) optical absorption spectroscopy allowed an estimate of the alkali metal polarisation and global pump laser power absorption to be determined. Additionally, initial studies into the use of optical absorption spectroscopy at various wavelengths for determination of the alkali metal number density are discussed. A chronology of experiments conducted using an `in-line', optically filtered Raman probe arrangement will be presented, culminating in the development of a fully automated, single-axis translational stage to perform rapid measurement of the rotational nitrogen temperature (T_N2) within the optical pumping cell with a high degree of temporal and spatial precision. The automated nature of the system facilitates a >3-fold improvement in the rate of thermal data acquisition, with greater ease and reliability than the previous manual method. In addition to pure rubidium, rotational temperature determination via Raman spectroscopy is demonstrated in a variety of rubidium/caesium hybrid alloy mixtures. In this way it may be possible to more efficiently utilise the greater spin exchange rate of caesium with 129Xe to achieve hybrid Rb/Cs cross-polarisation. The result of this is the first observation of 129Xe polarisation in a hybrid Rb/Cs system exceeding that of an equivalent pure Rb system under otherwise identical experimental conditions.

Une maintenance prévisionnelle efficace repose d’une part sur une modélisation précise de connaissances expertes préexistantes (AMDEC, Arbre de défaillance, etc.) et d’autre part sur des outils de supervision et de pronostic sensibles aux évolutions du procédé. La performance de ces outils repose sur l’analyse et l’estimation en temps réel de l’état du procédé, mais également sur la prévision de ses états futurs. Sur cette base, des indicateurs tels que les valeurs probabilistes issues du pronostic de défaillances peuvent être exploités pour la planification efficiente d’actions de maintenance. En partant des connaissances expertes préétablies, nous proposons une approche de supervision adaptative basée sur une technique de reconnaissance des formes, AUDyC (AUto-adaptive and Dynamical Clustering), qui est particulièrement adapté aux systèmes dynamiques évolutifs et complexes. Cette approche permet de suivre en temps réel l’état de fonctionnement du procédé, avec un minimum de connaissances a priori sur ses caractéristiques physiques, de détecter et de diagnostiquer tout changement de son comportement, même si le système évolue vers un état jusqu’alors inconnu et d’actualiser la base de connaissance par intégration de nouveautés. Une approche de pronostic de défaillance couplée au processus de supervision adaptative est alors proposée afin de fournir en temps réel, l’état futur d’un procédé tout en estimant la probabilité qu’une défaillance survienne à un instant futur ainsi que la fiabilité de ce pronostic. Cette architecture de supervision adaptative et de pronostic proposée est utilisée pour la maintenance prévisionnelle des composants d’un système réel de thermorégulation. / An effective predictive maintenance relies on the one hand, on an accurate modeling of available expert knowledge (Failure Mode, Effects and Criticality Analysis, Fault Tree, etc) and on the other hand, on monitoring tools that are sensitive to changes in the process under consideration. The performance of the monitoring tools consists not only in their ability to estimate and analyze the process state in real-time, but also in their capability to predict the future states. On this basis, indicators derived from the probabilistic prediction of failure occurrences can be exploited for the efficient planning of maintenance actions. Based on the predefined expert knowledge, we propose an approach of supervision based on a pattern recognition technique, the AUDyC algorithm (Auto-adaptive and Dynamical Clustering), which is particularly suitable for dynamic and complex systems monitoring. The proposed supervision approach allows us to (i) monitor the operational status of the system in real-time, with a minimum prior physical knowledge, (ii) detect and diagnose any change in the system behavior, even if the system evolves to a previously unknown state, (iii) update the basis of knowledge about the system by integrating new features into it. In order to provide in real-time an estimate of the future state of the system, a prognosis technique is coupled with the above mentioned supervision unit. This makes it possible to compute, with a certain reliability, the probability that a failure occurs at a given future time. Finally, the whole architecture for both supervision and prognosis is applied for the predictive maintenance of a real thermoregulation system.

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