Le développement de différentes formes colloïdales pour la thérapie et le diagnostic médical ultrasonore connait un intérêt croissant depuis de nombreuses années. En particulier, les microbulles de perfluorocarbone (PFC) sont des agents de contraste intéressants, car le gaz est un puissant réflecteur des ultrasons. Plus récemment, les gouttelettes de PFC ont été proposées pour de nouvelles applications acoustiques. Suite à une impulsion acoustique, les ultrasons induisent un changement de phase de l’état liquide à l’état gazeux. Ce phénomène est appelé la vaporisation acoustique de gouttelettes. Parallèlement à l’étude de nouvelles applications, le développement de nouvelles techniques de préparation offrant un meilleur contrôle lors de la production, reste un enjeu primordial. Ainsi, de nouvelles méthodes de préparation basées sur des dispositifs membranaires semblent être particulièrement intéressantes. L’objectif de la thèse porte donc sur le développement de nouvelles techniques à membrane pour la formulation de microbulles et de microgouttelettes de taille contrôlée pour des applications en imagerie et thérapie ultrasonore. Dans ce travail, l’émulsification membranaire directe avec un module membranaire de type cross-flow a été utilisé pour la préparation de microbulles stabilisées par des tensioactifs solubles, tandis qu’un module de type microkit a permis l’obtention de microbulles stabilisées par des phospholipides. Dans un second temps, l’émulsification membranaire par prémix a permis de formuler des microgouttelettes de PFC monodispersées. Pour les différentes formes colloïdales préparées, nous avons observé l’influence des paramètres du procédé (pression, débit et contrainte de cisaillement), des paramètres de formulation (molécules stabilisatrices, type de PFC de la phase dispersée) et des paramètres de la membrane (taille des pores) sur la formation des microbulles/ microgouttelettes. Par la suite, la caractérisation acoustique des microbulles/microgouttelettes a montré que ces systèmes présentent les propriétés nécessaires pour être utilisés comme agents de contraste ultrasonores / The development of various colloidal forms for therapy and diagnosis in ultrasound medical present a great interest for many years. In particular, microbubbles of perfluorocarbon (PFC) are interesting as contrast agents because the gas is a high ultrasound reflector. More recently, PFC droplets have been proposed for news acoustic applications. Indeed, after an acoustic pulse, the ultrasound waves induce a phase change from the liquid state to the gaseous state. This phenomenon is called the acoustic vaporization of droplets. In parallel with the study of new applications, the development of new process offering a better control during production, remains a key issue.Thus, the preparation using news methods based on membrane devices seem to be particularly interesting. The aim of the thesis is the development of new membrane process for the formulation of microbubbles and droplets with a size controlled for ultrasound applications in imaging and therapy. In this work, the direct membrane emulsification with a cross-flow membrane module was used for the preparation of microbubbles stabilized by soluble surfactants, while a microkit module allowed to obtain microbubbles stabilized by phospholipids. In a second step, the membrane emulsification by premix allowed to formulate monodispersed droplets of PFC. For the various colloidal forms prepared, we observed the influence of the process parameters (pressure, flow rate and shear stress), the formulation parameters (surfactants, type of PFC of the dispersed phase) and the membrane parameters (pore size) on the formation of microbubbles/droplets. Subsequently, the acoustic characterization of microbubbles/droplets has shown that these systems have the properties to be used as ultrasonic contrast agents

Introdução: As massas cardíacas (MC) podem ser tumores, trombos ou pseudotumores. A avaliação da vascularização poderá ser uma ferramenta adicional para o seu diagnóstico diferencial. Neste estudo, demonstrou-se o valor diagnóstico da ecocardiografia com perfusão na caracterização das MC or meio de análises qualitativas e quantitativas de perfusão. Métodos: Estudo prospectivo que envolveu 107 pacientes, classificados em quatro grupos: 33 trombos, 23 tumores malignos (TM), 24 tumores benignos (TB) e 6 pseudotumores; 21 pacientes foram excluídos por não terem diagnóstico definitivo confirmado. A avaliação de perfusão foi realizada pela ecocardiografia com perfusão em tempo real, utilizando contraste à base de microbolhas. Em um grupo selecionado de pacientes (32), o estudo foi complementado com dipiridamol para avaliação da reserva de fluxo da massa. A análise foi feita qualitativa e quantitativamente por dois observadores independentes. Na análise qualitativa, os parâmetros foram: intensidade da perfusão (escore 0 a 3), velocidade do repreenchimento microvascular (escore 0 a 2), padrão de perfusão central ou periférico (escore 0 a 2) e presença de áreas de necrose (escore 0 e 1). Os dois parâmetros de quantificação das massas foram: volume de sangue microvascular (A) e fluxo microvascular regional, que é o produto da velocidade de fluxo () e volume (A). Resultados: Na análise qualitativa, o padrão mais frequente para o grupo trombos foi: sem perfusão (81,9%), sem velocidade de perfusão (81,9%) e sem área de necrose (93,4%); nos tumores, predominou perfusão discreta (62,3%), com velocidade lenta (64,2%) e áreas de necrose (30,2%). Na análise qualitativa, a variação intraobservador para escore de perfusão e de velocidade foi de 20%, para áreas de necrose de 25% e para padrão de perfusão foi de 45%. Na análise quantitativa, o grupo trombos apresentou valores de A e Ax significativamente menores quando comparados ao grupo de tumores: Trombos: A = 0,08 (0,01-0,22dB); Ax = 0,03 (0,010,14dB/s-1); TM: A = 2,78 (1,31-7,0dB); Ax = 2,0 (0,995,58dB/s-1); TB: A = 2,58 (1,24-4,55dB); Ax = 1,18 (0,453,4dB/s-1). Quando comparados apenas os grupos de tumores com o uso de dipiridamol, os TM apresentaram volume sanguíneo microvascular (A) maiores: A = 4,18 (2,14-7,93dB); Ax = 2,46 (1,424,59dB/s-1), TB: A = 2,69 (1,11-4,26dB); Ax = 1,55 (0,555,50dB/s-1). Na análise com a curva ROC, a área sob a curva = 0,95, no parâmetro volume sanguíneo microvascular (A) < 0,65dB na ecocardiografia de perfusão com e sem uso de dipiridamol foi preditor para trombo, bem como o parâmetro fluxo sanguíneo microvascular (Ax) < 0,30dB/s-1, (área sob a curva = 0,94). Para distinguir entre TM de TB, o parâmetro volume sanguíneo microvascular (A), com o uso de dipiridamol > 3,28dB foi preditor de TM (área sob a curva = 0,75). Conclusão: O estudo ecocardiográfico para avaliação da perfusão das MC mostrou que a análise qualitativa é um método diagnóstico rápido e reprodutível para diagnosticar trombos. Os tumores cardíacos apresentam volume microvascular e fluxo sanguíneo regional maior se comparados com os trombos. O uso do dipiridamol foi útil na diferenciação entre os TM e TB / Background: Cardiac masses (CM) can be tumors, thrombi or pseudotumors. Evaluation of their vascularization might be an additional tool to perform a differential diagnosis. In the present study we demonstrated the diagnostic value of perfusion echocardiography for CM characterization, by qualitative and quantitative analyses of perfusion. Methods: We prospectively studied 107 patients, who were classified into 4 groups: 33 thrombus, 23 malignant tumors (MT), 24 benign tumors (BT) and 6 pseudotumors, of which 21 were excluded because no definitive diagnosis could be confirmed. Perfusion evaluation was performed by contrast echocardiography with real time perfusion imaging using microbubbles. A group of patients (32) was selected for a complementary study using dipyridamole to evaluate mass flow reserve. Qualitative and quantitative analyses were performed by two independent observers. Parameters for qualitative analysis were perfusion intensity (0-3 score), microvascular refilling velocity (0-2 score), central or peripheral perfusion pattern (0-2 score), and presence of areas of necrosis (0 or 1 score). The two parameters for quantification of masses were microvascular blood volume (A), and regional microvascular flow which is the product of blood flow velocity and vomume (A). Results: The most frequent pattern for the thrombi group in the qualitative analysis was absence of perfusion (81.9%), followed by no perfusion velocity (81.9%), and no areas of necrosis (93.4%), whilst among tumors there was predominance of discrete perfusion (62.3%), with slowed velocity (64.2%), and areas of necrosis (30.2%). Qualitative analysis, perfusion velocity showed intraobserver variability 20%, presence of areas of necrosis of 25% and perfusion pattern of 45%. In the quantitative analysis, the thrombi group was shown to have A and Ax values significantly smaller compared to the tumor group: Thrombi: A = 0.08 (0.01-0.22dB); Ax = 0.03 (0.010.14dB/s-1); MT: A = 2.78 (1.31-7.0dB); Ax = 2.0 (0.995.58dB/s-1); BT: A = 2.58 (1.24-4.55dB); Ax = 1.18 (0.453.4dB/s-1). When only the tumor groups with the use of dipyridamole were compared, MT was shown to have greater microvascular blood volume (A): A = 4.18 (2.14-7.93dB); Ax = 2.46(1.424.59dB/s-1), BT: A = 2.69 (1.11-4.265dB); Ax = 1.55 (0.555.50dB/s-1). Analysis of the ROC curve showed that an area of 0.95 for a microvascular blood volume of A < 0.65 dB predictive curve on perfusion echocardiography, both with and without dipyridamole, predicts thrombi, and so does a <0.30dB/s-1microvascular blood flow (Ax), area under curve = 0.94. In order to distinguish MT from BT, a >3.28dB microvascular blood volume (A) using dipyridamole was predictor of MT (area under curve = 0.75). Conclusion: The echocardiographic study to evaluate CM perfusion showed that qualitative analysis is reproducible diagnostic approach for diagnosing thrombi. Cardiac tumors show greater microvascular volume and regional blood flow when compared with thrombi. Dipyridamole quantitative stress mass perfusion was useful to differentiate MT from BT

Des bulles micrométriques sont utilisées dans divers domaines, notamment dans des applications médicales basées sur les ultrasons. Il est possible d’exploiter différents effets des bulles, comme par exemple leur résonance acoustique ou leur effet destructeur en cavitation inertielle. Un autre mécanisme exploitable est la génération de micro-écoulements, appelé microstreaming, induits autour d’une bulle. Ces écoulements sont relativement lents par rapport aux oscillations rapides de la bulle. Le microstreaming et les contraintes de cisaillement associées jouent un rôle important dans la perméabilisation d’une membrane cellulaire, mais il manque encore une compréhension détaillée de l’écoulement induit. Afin d’améliorer la compréhension des phénomènes physiques, ce travail se concentre sur les écoulements induits autour d’une bulle d’air dans piégée et excitée acoustiquement dans de l’eau et oscillante en modes de surface. La partie expérimentale se décompose de deux étapes. Dans un premier temps, il est nécessaire de contrôler la dynamique de la bulle, en particulier ses modes de surface et son orientation. Ceci est réalisé par coalescence entre deux bulles. Dans un second temps, le microstreaming est généré et enregistré simultanément à la dynamique de bulle. De cette manière il est possible de corréler les motifs d'écoulement aux oscillations de la bulle. Le grand nombre de motifs obtenus peut être classé selon le mode dominant et la taille de la bulle. Une étude plus détaillée de la dynamique de bulle permet de déduire les paramètres importants qui mènent à une telle variété de motifs de microstreaming. Afin de confirmer les résultats expérimentaux, un modèle analytique a été développé. Il est basé sur les équations de la mécanique des fluides de deuxième ordre et moyennées en temps, la dynamique d'interface de la bulle obtenue expérimentalement sert de donnée d’entrée au modèle. Ce manuscrit contient en supplément une section sur la génération de microjets par l'implosion d'agents de contraste. Ces jets peuvent apparaître en cas d’excitation acoustique suffisamment élevée. L’impact de ces jets sur parois présente un autre mécanisme responsable de la perméabilisation de membranes cellulaires. / Microbubbles find use in several domains, one of them being medical ultrasound applications. Different characteristics of those bubbles such as their acoustic resonance or their destructive effect during inertial cavitation can be exploited. Another phenomenon induced around acoustically excited bubbles is microstreaming, that means a relatively slow mean flow with respect to the fast bubble oscillations. Microstreaming and its associated shear stresses are commonly agreed to play a role in the permeabilization of cell membranes, a detailed understanding of the induced flows is however missing. To acquire basic physical knowledge, this work focuses on the characterization of streaming induced around an air bubble in water, more precisely around a single acoustically trapped and excited, nonspherically oscillating bubble. The experimental part consists of two steps. First, the bubble dynamics, in particular the triggered shape mode and the orientation of the bubble have to be controlled. For this, the use of bubble coalescence proves to be an adequate method. In a second step, the microstreaming is recorded in parallel to bubble dynamics. This allows to correlate the obtained streaming patterns to the respective shape oscillations. The large number of obtained pattern types can be classified, in particular with respect to the mode number and bubble size. A close investigation of the bubble dynamics allows furthermore deducing the important physical mechanisms which lead to such a variety of streaming patterns. In order to confirm the experimental findings, an analytical model has been developed. It is based upon time-averaged second-order fluid mechanics equations and the experimentally obtained bubble dynamics serves as input parameters. Supplementary to the microstreaming work, this manuscript contains a short section on directed jetting of contrast agent microbubbles, which might appear at high acoustic driving. The impact of those microjets on cell membranes presents another mechanism made responsible for the permeabilization of cell membranes.

Thesis deals with ultrasonographic contrast examinations, that are performed to assess tissue perfusion and non-invasive ultrasound method speckle tracking, overcoming the weaknesses of Doppler techniques used to scanning the movement of the tissue.

L'hypoxie est un mécanisme reconnu de résistance à la radiothérapie chez les tumeurs solides. Il a récemment été démontré que la cavitation de microbulles (MBs) ciblées par ultrasons (US) (UTMC) peut augmenter la perfusion sanguine dans les muscles squelettiques en déclenchant la signalisation du monoxyde d’azote (NO). Il est intéressant de noter que cet effet a été amplifié par une co-injection de nitrite de sodium et a réduit le spasme observé avec des ultrasons à haute pression et à long pulse. Comme il a été démontré que le nitrite de sodium montrait une synergie avec la radiothérapie, nous avons émis l'hypothèse que les MBSU avec une co-injection de nitrite de sodium pourraient radiosensibiliser davantage les tumeurs solides en augmentant la perfusion sanguine et ainsi réduire l'hypoxie tumorale. Nous avons évalué la capacité des MBSU avec et sans nitrite d’augmenter la perfusion dans les muscles (membres postérieurs de la souris) et les tumeurs en utilisant différentes longueurs de pulse et pressions et évalué l'efficacité de cette approche en tant que thérapie provasculaire administrée directement avant les traitements de radiothérapie. Des xénogreffes de prostate humaine (PC3) ont été cultivées bilatéralement chez des souris immunodéficientes : un côté a été traité avec des MBSU et le côté controlatéral a été utilisé comme témoin. Des transducteurs thérapeutiques (pulse long) ou cardiaques (pulse court) ont été utilisés pour traiter le tissu d'intérêt lors de l'injection de MBs par la veine caudale. Le nitrite a été injecté 5 minutes avant les MBSU lorsque cela était approprié. Les MBSU consistaient en 60 impulsions thérapeutiques, administrées à un intervalle (10-15 secondes) ajusté pour permettre le réapprovisionnement en MBs, tel que guidé par l'imagerie ultrasonore à contraste amélioré (CEUS) (Sequoia, Siemens), et était généralement administré en 15 minutes. L'augmentation de la perfusion dans la tumeur a été quantifiée par Burst Replenishment Imaging permettant une quantification longitudinale de la perfusion sanguine (A×β). Les souris ont été irradiées 10 minutes après les MBSU et la croissance tumorale a été suivie pendant 25 jours. Dans le muscle, l'augmentation de la perfusion sanguine après traitement de MBSU avec différents longs pulses était forte. 6 Dans les tumeurs soumises à de longs pulses, l'augmentation de la perfusion était significative à une faible pression (125 et 250 kPa) mais pas à plus haute pression (375, 500 et 750 kPa) par rapport au groupe contrôle (0 kPa). Lorsqu'associé à la radiothérapie, les MBSU avec des longs pulses à 250 kPa n'ont pas entraîné d'augmentation significative de l'efficacité du traitement. Les MBSU avec des pulses courts à haute pression (SONOS, 1500kPa) et co-injection de nitrite ont ensuite été validés dans le muscle. L'effet du traitement était fort. Cette augmentation de la perfusion était également visible dans les tumeurs soumises aux MBSU (SONOS) + nitrite et a duré au moins 10 minutes. Le nitrite seul n’a causé aucun changement de perfusion. De plus, les faibles réponses provasculaires observées pour les longs pulses à 750 kPa sans nitrite ont été renversées avec l'ajout de nitrite. Le SONOS a provoqué une augmentation de la perfusion, avec et sans nitrite. La validation histologique de la reperfusion dans les tumeurs traitées par SONOS + nitrite était également significative par rapport aux tumeurs recevant uniquement du nitrite. Enfin, il y a eu une amélioration de l'inhibition de la croissance pour le groupe 8 Gy + nitrite + MBSU (SONOS) lorsque comparé à 8 Gy + nitrite seul. Cet effet n'était pas significatif chez les souris traitées par MBSU (SONOS) + nitrite et recevant 0 Gy ou 2 Gy. En conclusion, la thérapie de MBSU + nitrite semble augmenter la perfusion sanguine conduisant à une efficacité accrue de la radiothérapie à 8 Gy dans notre modèle tumoral. / In solid tumors, hypoxia is a recognized mechanism of resistance to radiation therapy. It has recently been shown that ultrasound (US) targeted microbubbles (MBs) cavitation (UTMC) can increase blood perfusion in skeletal muscles by triggering nitric oxide signaling. Interestingly, this effect was amplified with a sodium nitrite co-injection and reduced the spasm observed with high pressure long tone burst ultrasound. Since sodium nitrite has been shown to synergize with radiotherapy, we hypothesized that UTMC with a sodium nitrite co-injection could further radiosensitize solid tumors by increasing blood perfusion and thus reduce tumor hypoxia. We evaluated the ability of UTMC with and without nitrite to increase perfusion in muscle (mouse hindlimbs) and tumors using different pulse lengths and pressure and evaluated the efficacy of this approach as a provascular therapy given directly before radiotherapy treatments. Human prostate xenografts (PC3) were grown bilaterally in immunodeficient mice: one side was treated with UTMC, and the contralateral side was used as a control. Therapeutic transducers (long pulses) or cardiac phased array (short pulses) were used to treat the tissue of interest during the injection of MBs via the tail vein. Nitrite was injected 5 minutes before UTMC when appropriate. UTMC consisted of 60 therapeutic pulses, given at a pulse interval (10-15 seconds) adjusted to allow MB replenishment, as guided by contrast enhanced US imaging (CEUS), and was typically given in 15 minutes. The increase in perfusion in the tumor was quantified by burst replenishment imaging allowing longitudinal quantification of blood perfusion (A×B). Mice were irradiated 10 minutes after UTMC, and tumor growth followed for 25 days. In muscle, the increase in blood perfusion following UTMC treatment with various long pulses was strong. In tumors subjected to long pulses, the increase in perfusion was significant at lower M.I. (125 and 250 kPa) but not at higher M.I. (375, 500 and 750 kPa) when compared to control (0 kPa). When combined with radiotherapy, UTMC with long pulses at 250 kPa did not result in a significant increase in treatment efficacy. UTMC with short pulses (SONOS, 1500 kPa) and nitrite co-injection was then validated in muscle. The effect of treatment was strong and significative. 8 This significant increase in perfusion was also visible in tumors subjected to UTMC (SONOS) + nitrite and lasted for at least 10 minutes but not for nitrite alone. The blunted provascular responses observed for long pulses at higher M.I. without nitrite was reversed with the addition of nitrite. SONOS with and without nitrite caused an increase in perfusion. Histological validation of reperfusion in SONOS + nitrite was also significant when compared to tumors receiving only nitrite alone. Finally, there was an improved growth inhibition for the 8 Gy + nitrite + UTMC group vs. 8 Gy + nitrite alone with the SONOS therapy. This effect was not significant with mice treated by UTMC + nitrite and receiving 0 Gy or 2 Gy. In conclusion, UTMC + nitrite seemed to increase blood flow leading to an increased radiotherapy efficacy at 8 Gy in our tumor model.

The research in this thesis considers novel innovative developments in established industrial processes that involve the use of recyclable polymeric particles as a partial replacement for aqueous media and chemicals. The application of the technology typically leads to water savings of over 80% and chemical savings of over 25%. These industrial processes may be characterised in that are considered inefficient and wasteful but nevertheless are considered economically vital. These diverse industries including laundry cleaning, leather manufacturing, textile garment processing, effluent treatment and metal beverage can manufacture. The outcomes of this research have made significant contributions to industrial best practice in such industries. In terms of academic research, the knowledge created in this thesis provides the basis for the application of CFD-DEM modelling to understand complex multi-phase and multi-component systems. In particular, the thesis advocates the application of the Free Surface Lattice Boltzmann Method for creating highly accurate simulations of multi-phase flow. In addition, the thesis offers opportunities for further research in novel plasma micro-reactors and their applications in diverse fields such as chemical synthesis, chemical engineering and biotechnology. The nature of the research is multi-disciplinary, and involved investigations across several fields including applied mathematics, biochemistry, chemistry, physics, and engineering. The projects also involved scale up from laboratory, pilot plant and full commercial scale production trials. Primary objectives were investigated through a series of six published patents. The three patents relating to the development of novel leather and textile processes were solely conceived and executed by the author. The patent related to the development of the plasma micro-reactor for ozone synthesis was conceived and executed jointly by the author and Professor Will Zimmerman (Sheffield University). The two patents related to the development of a novel metal cleaning and treatment process was conceived and executed jointly by the author and Dr. Robert Bird (Xeros Technology Group Limited).

No description available.

Current research within the field of ultrasound contrast agents (UCAs) aims at developing capsules which are not only acoustically active, but also have a chemically modifiable surface. This enables use in new areas, including targeted drug delivery and theranostics. For such purposes, air-filled microbubbles (MBs) with a polyvinyl alcohol (PVA) shell are being studied. Ultrasound imaging velocimetry (UIV) is a technique used to evaluate various types of liquid flows by tracking patterns caused by UCAs across ultrasound images, and has shown great potential for flow measurements in terms of accuracy. The aim of this thesis was to implement a basic UIV program in Matlab to investigate the flow behavior of air-filled PVA MBs being pumped through a phantom, mimicking a blood vessel. The images were acquired using the programmable Verasonics research system by plane wave imaging with coherent compounding, and UIV was implemented as a post-processing technique. Three parameters were varied to study how the UIV performance and flow behavior of the MBs were affected: the concentration of MBs, the flow velocity, and the transducer voltage. The resulting velocity vector fields showed that it is possible to track PVA MBs using the implemented UIV program, and that the concentration 5·106 MBs/ml gave the best results out of the five concentrations tested. The generated velocity vector fields indicated a turbulent and pulsatile flow behavior, which was in line with the predicted flow behavior, although there was a disparity between the measured average flow velocity of the MBs and the predicted flow velocity. It was also observed that the MBs were increasingly pushed in the axial direction with increasing voltage, as according to theory. Even though a more advanced UIV algorithm could improve the accuracy of the velocity measurements, the results show possible use of air-filled PVA MBs in combination with UIV. / Nuvarande forskning inom ultraljudskontrastmedel syftar till att utveckla kapslar som inte bara är akustiskt aktiva, utan som även har en kemiskt modifierbar yta. Detta möjliggör användning inom nya områden, så som målinriktade läkemedel och theanostics. För detta syfte studeras luftfyllda mikrobubblor med ett skal av polyvinylalkohol (PVA). Ultrasound imaging velocimetry (UIV) är en teknik som används för att analysera olika typer av vätskeflöden genom att spåra mönster orsakade av ultraljudskontrastmedel över ett antal ultraljudsbilder. Metoden har visats ha stor potential för flödesmätningar, och hög noggrannhet har uppnåtts. Detta projekt syftade till att implementera ett grundläggande UIV-program i Matlab för att undersöka flödesbeteenden hos luftfyllda PVA-mikrobubblor som pumpas genom en modell av ett blodkärl. Ultraljudsbilderna togs med hjälp av det programmerbara forskningssystemet Verasonics, genom att använda planvågsavbildning och coherent compounding, och UIV implementerades som ett efterbearbetningsprogram. Tre parametrar varierades för att studera hur prestandan av UIV-programmet och flödesbeteendet hos mikrobubblorna påverkades: koncentrationen av mikrobubblor, flödeshastigheten, och spänningsamplituden hos ultraljudsproben. De resulterande hastighetsvektorfälten visade det möjligt att evaluera flödesbeteenden hos PVA-mikrobubblor med hjälp av det implementerade UIV-programmet. Bäst resultat erhölls genom att använda koncentrationen 5·106 mikrobubblor/ml, av de fem testade koncentrationerna. De genererade hastighetsvektorfälten indikerade ett turbulent och pulserande flöde, vilket överensstämde med teorin, trots att det fanns skillnader mellan genomsnittliga uppmätta flödeshastigheter och den beräknade flödeshastigheten. Det kunde också observeras att mikrobubblorna trycktes i den axiella riktningen när spänningsamplituden ökade, vilket överensstämde med teorin. Trots att metodens noggrannhet skulle kunna ökas genom att använda ett mer avancerat UIV-program, visade resultaten på möjligheten att använda luftfyllda PVA-mikrobubblor i kombination med UIV.

Ultrasound imaging systems are a safe and affordable imaging modality with the disadvantage of low spatial resolution, especially for assessing smaller vessels. However, with the implementation of super-resolution ultrasound imaging techniques, studies have shown promising results in achieving a resolution below the diffraction limit. Super-resolution ultrasound imaging techniques takes advantage of the point spread function to localize the centroid of the ultrasound contrast agents in an image. By superimposing thousands of these images, a super-resolved image of the localized and tracked contrast agents can be created, which presents an image where vessels down to a few micrometers can be resolved. The purpose of this master’s thesis was to implement super-resolution ultrasound imaging, test different localization methods and analyze them by using different ultrasound contrast agent concentrations. Grayscale ultrasound images were acquired using the Verasonics system for three different microbubble concentrations. The super-resolution ultrasound imaging program was executed on the grayscale images using three different localization methods, Gaussian fit, No-shift and Interpolation based scheme. The microbubbles were localized and tracked over several frames to create a super-resolved image which had the pixel resolution of a 10th of the wavelength. Significant improvements were demonstrated in the super-resolved images compared to the grayscale images. The higher microbubble concentrations resulted in a higher number of localized and tracked microbubbles. While the low concentration exhibited lower values. Comparing the methods, Gaussian fit and No-shift detected higher number of microbubbles than the method Interpolation. Although further analysis is needed, the thesis concluded that using Gaussian fit as a localization method and higher microbubble concentrations, a super-resolved image can be produced even if the program is tested on fewer images. / Ultraljudsavbildning är en säker och billig avbildningsmodalitet med en låg spatial upplösning, framför allt vid avbildning av mindre kärl. Men med implementering av ultraljudsavbildningstekniker med superupplösning har studier visat lovande resultat för att uppnå en upplösning under diffraktionsgränsen. Ultraljudsavbildningstekniker med superupplösning utnyttjar punktspridningsfunktionen för att lokalisera ett ultraljudskontrastmedels centerpunkt i en bild. Genom att överlagra tusentals av dessa bilder skapas en superupplöst bild av det lokaliserade och spårade kontrastmedlet. Med hjälp av superupplösta bilden kan kärl som är några mikrometer urskiljas. Syftet med denna masteruppsats var att implementera ultraljudsavbildning med superupplösning, testa olika lokaliseringsmetoder och analysera de genom att använda olika koncentrationer av mikrobubblor. Gråskale ultraljudsbilder samlades in med hjälp av Verasonics systemet för tre olika koncentrationer av mikrobubblor. Superupplösningsprogrammet var exekverad på gråskalebilderna för tre olika lokaliseringsmetoder, Gaussian fit, No-shift och Interpolation based scheme. Mikrobubblorna lokaliserades och spårades över flera bilder för att skapa en superupplöst bild vilket hade en tiondel av våglängden som pixelupplösning. Resultatet presenterade en märkbar förbättring i de superupplösta bilderna jämfört med gråskalebilderna. De högre koncentrationerna med flera mikrobubblor resulterade i ett högre antal lokaliserade och spårade mikrobubblor, medan den lägre koncentrationen gav färre lokaliserade mikrobubblor. Metoderna Gaussian fit och No-shift detekterade flera mikrobubblor än metoden Interpolation. Slutsatsen visade att användningen av lokaliseingsmetoden Gaussian fit med högre koncentrationer av mikrobubblor ger en superupplöst bild även om programmet exekveras på färre bilder.

Nous proposons dans cette thèse une étude sur la stabilisation de bulles de gaz dispersées en solution aqueuse par des nanocapsules lipidiques (NCL). L’objectif est le développement d’un système de libération d’actifs pharmaceutiques provoquée par l’application d’un champ ultrasonore adéquat. Préalablement, est évaluée la potentialité des NCL à se comporter comme de vrais agents de stabilisation interfaciale air/eau. Les NCL sont capables de diminuer la tension de surface plus que le Solutol®, principal surfactif pégylé rentrant dans leur composition.La méthode d’agitation mécanique s’est révélée la mieux adaptée pour formuler des microbulles d’air stabilisées.Les microbulles générées ont une taille moyenne inférieure à 2μm avec une concentration de 2,72.1012/mL. La distribution de taille est assez homogène avec un indice de polydispersité acceptable. Le ratio d’incorporation d’air dans les bulles est de 0,17. Les microbulles sont entourées d’un film constitué principalement de Solutol® et de Lipoïd®. En dispersion aqueuse, la stabilité des bulles à température ambiante(20°C±2°C) est maintenue jusqu’à 7 jours au moins. Le fusidate sodique utilisé comme actif pharmaceutique modèle et comme traceur est encapsulé avec un taux de27-35%. Un taux de libération de 40-50% est obtenu dans des conditions normales de libération. Ce pourcentage atteint 50-55% après application d’ultrasons. / This work deals with the stabilization of gaz microbubbles dispersed in aqueous solutions by using LipidNanoCapsules (LNC). The main objective is the development of a Drug Delivery System where the release is triggered by ultrasonation. Firstly, we investigated the ability of LNC to behave as real air/water interfacial stabilization agents. It is shown that LNC can decrease the surface tension at the air/water interface more than the Solutol®, main pegylated surfactant of the LNC. Usual stirring method seems the more efficient to produce stabilized air microbubbles. Microbubbles are characterized by a mean size below 2μm and are concentrated at 2.72x1012 /mL. The size distribution ishomogeneous with a convenient polydispersity index.The gas holdup inherent to the microbubbles was estimated to 0.17. Microbubbles are surrounded by a film constituted by Solutol® and Lipoïd®. Their stability at room temperature was kept up to 7 days. Sodium Fusidate was chosen as a drug model with an encapsulation rate in a 27-35% range. The drug release upon ultrasound was between 50-55 % in comparison with 40-50 % without ultrasounds focusing.