Cette thèse traite le développement de dispositifs, basés sur la technologie "laboratoire sur puce"(LOC) qui visent à contrôler l'environnement des systèmes biologiques pour des applications macro et microbiologiques. En effet, les caractéristiques de la microfluidique permettent de manipuler l'environnement cellulaire à un niveau supérieur à celui du degré de contrôle atteignable avec les techniques ordinaires. Dans ce travail de thèse sera explorée la possibilité de profiter de ces fonctions afin de développer des outils de diagnostic peu coûteux et pourtant efficaces. En particulier, on rapporte le développement de systèmes microfluidiques permettant une perfusion des médias fluide et rapide, ainsi qu'une plateforme LOC capable de réaliser des PCRq hautement multiplexes. Au sujet des systèmes de perfusion, le but était d'obtenir une substitution du médium entourant les particules afin d'augmenter les capacités de séparation des modules de tri microfluidiques couplés. L'efficacité de notre approche a été validée par les hauts taux de séparation obtenus (>90%) avec l'utilisation de notre système de perfusion microfluidique couplé à une puce d'acoustophorèse. De plus, nous avons conçu et développé un système de thermalisation microfluidique capable d'opérer des changements de température en moins de 1s. Plus spécifiquement, cette plateforme exploite l'échange de chaleur entre un liquide de thermalisation qui circule dans une puce microfluidique et l'échantillon. Ces performances de thermalisation, et le rapport surface/volume élevé typique des appareils microfluidiques, ont permis d'effectuer 50 cycles de PCRq et l'analyse de courbe de fusion en moins de dix minutes. / The topic of this manuscript is the development of microdevices, based on "lab on chip" (LOC) technology, aimed to the environmental control and regulation of biological systems for macro and microbiological applications. Indeed, microfluidics possesses some inherent features which allow the manipulation of the environment at the cell and sub-cell level which are superior than the degree of control achievable with standard techniques. In this thesis work the possibility to leverage these features to develop inexpensive yet effective diagnostic tools is explored. In particular, we report the development of microfluidic systems which allow seamless and fast media perfusion and a novel LOC platform capable of performing highly multiplexed real-time PCR assays. Concerning the microfluidic perfusion systems, the aim was to achieve in-flow substitution of the particles' surrounding media in order to enhance the separation capabilities of the coupled microfluidic sorting modules. The effectiveness of our approach was validated by obtaining high separation purities (>90%) using our microfluidic perfusion system coupled with an acoustophoresis chip to discern two population of micro-sized beads. Moreover, we conceived and developed a microfluidic thermalisation system capable of sub-second temperature switches. Specifically, this platform relies on conductive heat exchange between a thermalisation liquid flowing inside a microfluidic chip and the biological sample. These thermalisation performances, and the high surface to volume ratio typical of microfluidic devices, allowed to perform 50 qPCR cycles and subsequent melting curve analysis in less than ten minutes.

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Tracer based MRI perfusion measurements is a clinically useful tool to assess regional distributions of tissue blood flow and volume. The method may be based on any of the three relaxation mechanisms T1, T1 and T2*, the latter denoted DSC-MRI being the most common. The primary aim of this work was to study the feasibility of obtaining quantitative estimates using these methods. 1) Feasibility of DSC-MRI for kidneys using an iron oxide based contrast agent and the influence of secondary relaxation effects on the results, part of a clinical phase II trial: The method proved feasible and the underestimation induced by secondary relaxation can be corrected for by using a double echo sequence. 2) Influence of blood flow rate on risk factors for developing cerebral ischemia during cardio pulmonary bypass, measurements in pig with gadolinium based DSC-MRI: The results indicated an ischemic threshold level at a blood flow rate of approximately 6 ml/kg/min. 3) The ability of gadolinium based DSC-MRI to detect changes in global blood flow, experimental measurements in pig and numerical simulations: The results support that DSC-MRI can discriminate between global flow levels in the same subject given that all other parameters are kept constant. The results also indicate that calculated perfusion values are highly sensitive to the arterial deconvolution procedure. 4) Influence of differences in blood/tissue relaxivity and secondary relaxation for a gadolinium based contrast agent, measurements in pig and numerical simulations: The blood/tissue relaxivity ratio is not unity and the situation is complicated by secondary relaxation effects. Deconvolution regularization appears to partly counteract the overestimation induced by difference in blood/tissue relaxivity for DSC-MRI. In summary, the fundamental assumption of equal blood and tissue relaxivity is experimentally shown to be invalid and the influence of this discrepancy is substantial. Several factors contribute to measurement errors, a combination of these factors can incidentally lead to additive errors or error cancellation based on a variety of experimental and analysis conditions. Given that the differences in blood/tissue relaxivity cannot readily be accounted for in a clinical setting, absolute perfusion quantification by tracer based MRI remains challenging if not impossible.

Dynamic Contrast Enhanced Computed Tomography is an imaging tool that aids in evaluating functional characteristics in different stages of disease assessment: diagnostic, treatment effectiveness and monitoring. At the present time, following all the technological advances, there remains no universally validated method of quantitative, non-invasive, perfusion imaging. In order to address this challenge, certain quality assurance flow phantoms have been developed. This work presents the first step in the prospective framework of phantom simulations with the goal of enhancing the understanding of contrast agent kinetics. Existing knowledge about a two-compartmental fluid exchange phantom was used to validate the constructed computational fluid dynamics (CFD) simulation model. The sensitivity of various parameters, both in the geometric and computational domains, was determined. Finally, the model was employed to evaluate current perfusion parameter estimation models. This provides the groundwork for future phantom developments within the framework.

Dynamic Contrast Enhanced Computed Tomography is an imaging tool that aids in evaluating functional characteristics in different stages of disease assessment: diagnostic, treatment effectiveness and monitoring. At the present time, following all the technological advances, there remains no universally validated method of quantitative, non-invasive, perfusion imaging. In order to address this challenge, certain quality assurance flow phantoms have been developed. This work presents the first step in the prospective framework of phantom simulations with the goal of enhancing the understanding of contrast agent kinetics. Existing knowledge about a two-compartmental fluid exchange phantom was used to validate the constructed computational fluid dynamics (CFD) simulation model. The sensitivity of various parameters, both in the geometric and computational domains, was determined. Finally, the model was employed to evaluate current perfusion parameter estimation models. This provides the groundwork for future phantom developments within the framework.

Reproduction de : Thèse d'exercice : Médecine vétérinaire : Toulouse 3 : 2007. / Bibliogr. p. 54-56.

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Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.