Smart materials are intelligent materials that change their structural, chemical, mechanical, or thermal properties in response to an external stimulus such as heat, light, and magnetic and electric fields. With the increase in usage of smart materials in many sensitive applications, the need for a remote, wireless, efficient, and biologically safe stimulus has become crucial. This dissertation addresses this requirement by using high intensity focused ultrasound (HIFU) as the external trigger. HIFU has a unique capability of maintaining both spatial and temporal control and propagating over long distances with reduced losses, to achieve the desired response of the smart material. Two categories of smart materials are investigated in this research; shape memory polymers (SMPs) and piezoelectric materials. SMPs have the ability to store a temporary shape and returning to their permanent or original shape when subjected to an external trigger. On the other hand, piezoelectric materials have the ability to convert mechanical energy to electrical energy and vice versa. Due to these extraordinary properties, these materials are being used in several industries including biomedical, robotic, noise-control, and aerospace. This work introduces two novel concepts: First, HIFU actuation of SMP-based drug delivery capsules as an alternative way of achieving controlled drug delivery. This concept exploits the pre-determined shape changing capabilities of SMPs under localized HIFU exposure to achieve the desired drug delivery rate. Second, solving the existing challenge of low efficiency by focusing the acoustic energy on piezoelectric receivers to transfer power wirelessly. The fundamental physics underlying these two concepts is explored by developing comprehensive mathematical models that provide an in-depth analysis of individual parameters affecting the HIFU-smart material systems, for the first time in literature. Many physical factors such as acoustic, material and dynamical nonlinearities, acoustic standing waves, and mechanical behavior of materials are explored to increase the developed models' accuracy. These mathematical frameworks are designed with the aim of serving as a basic groundwork for building more complex smart material-based systems under HIFU exposure. / Doctor of Philosophy / Smart materials are a type of intelligent materials that have the ability to respond to external stimuli such as heat, light, and magnetic fields. When these materials respond, they can change their structural, thermodynamical, mechanical or chemical nature. Due to this extraordinary property, smart materials are being used in many applications including biomedical, robotic, space, microelectronics, and automobile industry. However, due to increased sensitivity and need for safety in many applications, a biologically safe, wireless, and efficient trigger is required to actuate these materials. In this dissertation, sound is used as an external trigger to actuate two types of smart materials: shape memory polymers (SMPs) and piezoelectric materials. SMPs have an ability to store a temporary (arbitrarily deformed) shape and return to their permanent shape when exposed to a trigger. In this dissertation, focused sound induced thermal energy acts as a trigger for these polymers. A novel concept of focused ultrasound actuation of SMP-based drug delivery capsules is proposed as a means to solve some of the challenges being faced in the field of controlled drug delivery. Piezoelectric materials have an ability to generate electric power when an external mechanical force is applied and vice versa. In this study, sound pressure waves supply the external force required to produce electric current in piezoelectric disks, as a method for achieving power transfer wirelessly. This study aims to solve the current problem of low efficiency in acoustic power transfer systems by focusing sound waves. This dissertation addresses the fundamental physics of high intensity focused ultrasound actuation of smart materials by developing comprehensive mathematical models and systematic experimental investigations, that have not been performed till now. The developed models enable an in-depth analysis of individual parameters including nonlinear material behavior, acoustic nonlinearity and resonance phenomena that affect the functioning of these smart systems. These mathematical frameworks also serve as groundwork for developing more complex systems.

No description available.

High intensity focused ultrasound (HIFU) is an emerging non-invasive thermal ablative modality that can be utilised for the treatment of solid organ tumours, including liver cancer. Acoustic cavitation is a phenomenon that can occur during HIFU and its presence can enhance heating rates. One major limitation of thermal ablative techniques in general, such as radiofrequency and microwave ablation, is the heat sink effect imparted by large vasculature. Thermal advection from blood flow in vessels ≥ 3 - 4 mm in diameter has been shown to significantly reduce heating rates and peak temperatures in the target tissue, potentially leading to treatment failure. With regards to HIFU therapy, a clearer understanding is required of the effects of blood flow on heating, cavitation and thermal tissue necrosis, which is the treatment endpoint in clinical thermal ablation. Therefore, the overall aim of this thesis project was to elucidate the effects of blood flow on HIFU-induced heating, cavitation and histological assessment of thermal ablation. A unique isolated, perfused porcine liver model was used in order to provide a relevant test bed, with physiological and anatomical characteristics similar to the in vivo human liver. The normothermic liver perfusion device used in all studies presented in this work can keep an organ alive in a functional state ex vivo for in excess of 72 hours. A further advantage of the liver perfusion device was that it allowed blood flow to be stopped completely and resumed rapidly, allowing studies to be conducted under zero flow conditions. A therapeutic HIFU system was used in order to deliver HIFU therapy to regions of hepatic parenchyma adjacent (≤ 3 mm) to large (≥ 5 mm) blood vessels or away from vasculature (≥ 1 cm) at either 1.06 MHz or at 3.18 MHz. Cavitation events during HIFU therapy were spatio-temporally monitored using a previously developed passive acoustic mapping (PAM) technique. The cavitation threshold at each frequency was determined through assessment of acoustic emissions acquired through PAM during HIFU exposure at a range of acoustic pressures. Real time thermal data during HIFU therapy were obtained using an implantable 400 μm thermocouple, aligned with the HIFU focus, in order to assess the effect of large vessel blood flow on peak tissue temperatures. Thermal data were obtained at 1.06 MHz, in the presence of acoustic cavitation and at 3.18 MHz, in the absence of cavitation, both in the presence and complete absence of blood flow. Finally, histological assessment of cell viability and cell death was performed in order to determine whether any heat sink effect could be overcome, with the achievement of complete tissue necrosis in treatment regions directly adjacent to large vasculature. This work demonstrated for the first time that in perfused, functional liver tissue, the presence of large vasculature and physiological blood flow does not significantly affect ablative HIFU therapy, both in terms of peak focal tissue temperatures attained and histological evidence of complete tissue necrosis. Therefore, HIFU may be superior to other ablative modalities in treating tumours in tissue regions adjacent to major vascular structures, but further work needs to be performed to correlate the experimental findings with clinical outcomes.

Les ultrasons focalisés de haute intensité (HIFU) représentent une modalité de traitement du cancer de la prostate dont la place est en évolution. La première partie de ce travail a porté sur l'étude des résultats cliniques obtenus d'une part en traitement de première intention, d'autre part en situation de rattrapage et enfin en situation clinique complexe. Ces résultats ont également été évalués en fonction des différentes évolutions techniques des appareils. Les données obtenues ont permis de préciser les résultats oncologiques et fonctionnels et de définir les points faibles des traitements par HIFU. La seconde partie de ce travail a porté sur le développement préclinique et clinique d'une nouvelle sonde de traitement à focalisation dynamique. Pour cela, un modèle animal a été mis au point afin de tester la capacité du système à préserver la paroi rectale tout en permettant de réaliser des traitements profonds et/ou de grand volume. Il s'agissait d'un modèle porcin avec utilisation du caecum détubulisé et fixé sur le foie. Les traitements par HIFU étaient appliqués au foie à travers le caecum vascularisé. Ces essais ont permis de définir les paramètres de traitement global de la glande et les paramètres de traitement focal avec tirs suspendus. Grâce à ces résultats, des études cliniques ont débuté d'abord avec un prototype puis avec la dernière version d'appareil de traitement par HIFU : le Focal One / High Intensity Focused Ultrasound (HIFU) is a therapeutic option for localized prostate cancer with an evolving place. The first part of this work include the clinical results of HIFU for prostate cancer as the first line treatment, salvage treatment, and in challenging clinical cases. Those results were also evaluated according to the technical evolution of the devices. Oncological, functional outcomes as well as weak point of HIFU have been drawn with the obtained data. The second part of this work was the preclinical and clinical development of the new dynamic focusing probe. For this, an animal model has been developed in order to evaluate the capacity of the probe to spear the rectal wall while treating large and deep lesion. It was a porcine model with a part of the caecum fixed onto the liver. HIFU treatments were applied on the liver through the vascularized colon. Treatment parameters for whole gland ablation as well as focal treatment were developed based on the pathology report. Clinical trial have been started based on those treatment parameters, first with the prototype and then with the Focal One®

Contactless ultrasonic power transfer (UPT), using piezoelectric transducers, is based on transferring energy using acoustic waves, in which the waves are generated by an acoustic source or transmitter and then transferred through an acoustic medium such as water or human tissue to a sensor or receiver. The receiver then converts the mechanical strain induced by the incident acoustic waves to electricity and delivers to an electrical load, in which the electrical power output of the system can be determined. The execution and efficiency of this technology can be significantly enhanced through patterning, focusing, and localization of the transmitted acoustic energy in space to simultaneously power pre-determined distributed sensors or devices. A passive 3D-printed acoustic hologram plate alongside a single transducer can generate arbitrary and pre-designed ultrasound fields in a particular distance from the hologram mounted on the transmitter, i.e., a target plane. This dissertation presents the use of these simple, cost-effective, and high-fidelity acoustic holograms in UPT systems to selectively enhance and pattern the electrical power output from the receivers. Different holograms are numerically designed to create single and multi-focal pressure patterns in a target plane where an array of receivers are placed. The incident sound wave from a transmitter, after passing through the hologram, is manipulated, hence, the output field is the desired pressure field, which excites the receivers located at the pre-determined focal points more significantly. Furthermore, multi-functional holograms are designed to generate multiple images at different target planes and driving frequencies, called, respectively, multi-image-plane and multi-frequency patterning holograms. The multiple desired pressure distributions are encoded on the single hologram plate and each is reconstructed by changing the axial distance and by switching the frequency. Several proof-of-concept experiments are performed to verify the functionality of the computationally designed holograms, which are fabricated using modern 3D-printers, i.e., the desired wavefronts are encoded in the hologram plates' thickness profile, being input to the 3D-printer. The experiments include measurement of output pressure fields in water using needle hydrophones and acquisition of receivers' voltage output in UPT systems. Another technique investigated in this dissertation is the implementation of acoustic impedance matching layers deposited on the front leading surface of the transmitter and receiver transducers. Current UPT systems suffer from significant acoustic losses through the transmission line from a piezoelectric transmitter to an acoustic medium and then to a piezoelectric receiver. This is due to the unfavorable acoustic impedance mismatch between the transducers and the medium, which causes a narrow transducer bandwidth and a considerable reflection of the acoustic pressure waves at the boundary layers. Using matching layers enhance the acoustic power transmission into the medium and then reinforce the input as an excitation into the receiver. Experiments are performed to identify the input acoustic pressure from a cylindrical transmitter to a receiver disk operating in the 33-mode of piezoelectricity. Significant enhancements are obtained in terms of the receiver's electrical power output when implementing a two-layer matching structure. A design platform is also developed that can facilitate the construction of high-fidelity acoustically matched transducers, that is, the material layers' selection and determination of their thicknesses. Furthermore, this dissertation presents a numerical analysis for the dynamical motions of a high-intensity focused ultrasound (HIFU)-excited microbubble or stable acoustic cavitation, which includes the effects of acoustic nonlinearity, diffraction, and absorption of the medium, and entails the problem of several biomedical ultrasound applications. Finally, the design and use of acoustic holograms in microfluidic channels are addressed which opens the door of acoustic patterning in particle and cell sorting for medical ultrasound systems. / Doctor of Philosophy / This dissertation presents several techniques to enhance the wireless transfer of ultrasonic energy in which the sound wave is generated by an acoustic source or transmitter, transferred through an acoustic medium such as water or human tissue to a sensor or receiver. The receiver transducer then converts the vibrational energy into electricity and delivers to an electrical load in which the electrical power output from the system can be determined. The first enhancement technique presented in this dissertation is using a pre-designed and simple structured plate called an acoustic hologram in conjunction with a transmitter transducer to arbitrarily pattern and shape ultrasound fields at a particular distance from the hologram mounted on the transmitter. The desired wavefront such as single or multi-focal pressure fields or an arbitrary image such as a VT image pattern can simply be encoded in the thickness profile of this hologram plate by removing some of the hologram material based on the desired shape. When the sound wave from the transmitter passes this structured plate, it is locally delayed in proportion to the hologram thickness due to the different speed of sound in the hologram material compared to water. In this dissertation, various hologram types are designed numerically to implement in the ultrasonic power transfer (UPT) systems for powering receivers located at the predetermined focal points more significantly and finally, their functionality and performances are verified in several experiments. Current UPT systems suffer from significant acoustic losses through the transmission from a transmitter to an acoustic medium and then to a receiver due to the different acoustic impedance (defined as the product of density and sound speed) between the medium and transducers material, which reflects most of the incident pressure wave at the boundary layers. The second enhancement technology addressed in this dissertation is using intermediate materials, called acoustic impedance matching layers, bonded to the front side of the transmitter and receiver face to alleviate the acoustic impedance mismatch. Experiments are performed to identify the input acoustic pressure from a transmitter to a receiver. Using a two-layer matching structure, significant enhancements are observed in terms of the receiver's electrical power output. A design platform is also developed that can facilitate the construction of high-fidelity acoustically matched transducers, that is, the material layers' selection and determination of their thicknesses. Furthermore, this dissertation presents a numerical analysis for the dynamical motions of a microbubble exposed to a high-intensity focused ultrasound (HIFU) field, which entails the problem of several biomedical ultrasound applications such as microbubble-mediated ultrasound therapy or targeted drug delivery. Finally, an enhancement technique involving the design and use of acoustic holograms in microfluidic channels is addressed which opens the door of acoustic patterning in particle and cell sorting for medical ultrasound systems.

La thérapie par faisceaux ultrasonores focalisés de forte intensité (HIFU / High Intensity Focused Ultrasound) est une nouvelle technique d’ablation tissulaire, fondée sur la focalisation de faisceaux ultrasonores de forte intensité pour réaliser une élévation de température capable de créer une nécrose thermique. Le cerveau a été jusqu’à présent peu accessible aux ultrasons car il est protégé par la boîte crânienne. Mais de nouvelles techniques de focalisation par correction des aberrations des faisceaux ultrasonores laissent espérer des applications prochaines en intracrânien, où l’HIFU pourrait constituer une intéressante alternative à la chirurgie et à la radiothérapie stéréotaxique. Le but général de ce travail a été de tester la thérapie HIFU contrôlée par Imagerie de Résonance Magnétique (IRM) pour le traitement des tumeurs cérébrales dans un modèle petit animal in vivo de tumeur cérébrale. Nous espérons ainsi fournir des apports sur la thérapie HIFU et ses effets biologiques sur le cerveau et les tumeurs cérébrales, connaissances nécessaires avant de passer à des études cliniques chez l’homme. Le plan de ce travail est le suivant : 1) développement d’un protocole de thérapie HIFU contrôlé par IRM sur le cerveau sain et sur un modèle de tumeur RG2 greffée en intracérébral chez le rat ; 2) étude des effets biologiques de l’HIFU par l’IRM et l’examen anatomo-pathologique sur le tissu cérébral sain et la tumeur RG2 en intracérébral, montrant une sensibilité variable des tissus à l’hyperthermie ; 3) étude de sécurité (tolérance et effets indésirables), démonstration d’efficacité sur la tumeur RG2 (ralentissement de l’évolution tumorale et augmentation de la survie des animaux traités). En conclusion, l’HIFU a montré sa précision et son efficacité dans le traitement de la tumeur RG2 greffée en intracérébral chez le rat. Cette technique n’est cependant pas exempte de complications, notamment un œdème périlésionnel et des hémorragies intratumorales. / High Intensity Focused Ultrasound (HIFU) therapy is an innovative approach for tissue ablation, based on high intensity focused ultrasound beams. At focus, HIFU induces a temperature elevation and the tissue can be thermally destroyed. For transcranial brain therapy, the skull bone is a major limitation but new adaptive techniques for focusing ultrasound through the skull are underway and in the near future HIFU therapy could be an interesting alternative to brain surgery and radiotherapy.The overall aim of this work is to test HIFU therapy guided by Magnetic Resonance Imaging (MRgHIFU) for the treatment of brain tumors in an in vivo brain tumor model in rodent in order to provide inputs for future regulatory approval for clinical trial with a clinical prototype. In this work: 1) a dedicated system for transcranial MRgHIFU in an in vivo rat brain tumor model was developed, and a full protocol was applied in healthy brain tissue of rats and in transplanted tumors; 2) the biological effects of HIFU therapy was evaluated using MRI and histology in healthy brain tissue and in RG2 brain tumor, showing a different tissue sensibility for hyperthermia; 3) tolerance and side effects were investigated and the treatment was shown to improve the animal survival time by 50%. In conclusion, HIFU therapy has proved its accuracy and efficacy in the treatment of the RG2 brain tumor transplanted intracerebral in rats. However this technique is not free of complications, in particular edema and hemorrhages.

Background: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensusbased German S3 guidelines for a possible international use. - Summary: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. Key Message: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and followup diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

La thèse s’articule autour du développement des thermothérapies hépatique et cardiaque guidées par Imagerie de Résonance Magnétique (IRM). La première partie est axée sur le développement d’une méthode permettant d’augmenter la taille des lésions induites par ultrasons focalisés de haute intensité (HIFU). Le seuil de d’intensité acoustique fut déterminé par IRM de la force de radiation acoustique et l’effet caractérisé par IRM de température ex vivo et in vivo dans le foie de porc. La deuxième partie présente le développement d’une méthode permettant une focalisation HIFU hépatique intercostale avec utilisation de la déflection électronique du faisceau pour le suivi du mouvement respiratoire ou /et une ablation multipoint. La méthode proposée repose sur une mise à jour des éléments du transducteur HIFU à désactiver en fonction du point de focalisation sélectionné, à partir d’une projection géométrique de l’ombre des côtes sur la surface du transducteur, mesurée sur des images IRM anatomiques. Nous avons montré qu’il est possible de réduire significativement le chauffage des côtes tout en conservant une élévation de température dans le foie suffisante pour induire une lésion thermique. La troisième partie expose la mise en place de l’IRM de température pour le monitoring des ablations par radiofréquences (RF) dans le cœur. Plusieurs aspects sont abordés, notamment la précision de la thermométrie, la possibilité de réaliser des ablations thermiques par cathéter RF sous IRM de température in vivo dans le cœur de brebis, ainsi que l’utilisation du cathéter comme sonde d’imagerie dans l’objectif d’accroitre la précision de la thermométrie cardiaque. / My manuscript studies the development of mini and non invasive thermotherapies guided by magnetic resonance imaging (MRI) in the treatment of hepatic and cardiac diseases. The first part was the development of a method to increase the lesion size, induced by HIFU, and based on bubble enhanced heating (BEH). The acoustic power threshold of the BEH was determined by MR acoustic radiation force imaging (MR-ARFI) and the thermal effect was characterized by MR thermometry on ex vivo and in vivo in pig livers. The second part developed a strategy to perform HIFU through the rib cage using beam steering to track the respiratory movement or to performed multipoint ablation while avoiding heating of ribs. Transducer elements localized in the geometric projection of the shadow of ribs, relatively to the targeted focal point, were switched off.The third part was the development of the MR thermometry on the heart for the monitoring of radiofrequency ablation (RFA). Several aspects were investigated, in particular the thermometry precision, the feasibility to perform catheter radiofrequency ablation under MR thermometry in vivo in a sheep heart, the possibility to use the catheter as an MR antenna to increase spatial resolution of MR thermometry images.

R??sum?? : Les copolym??res ?? blocs sensibles aux stimuli (SR-BCPs) et leurs assemblages, tels que les micelles, les v??sicules et les hydrogels, peuvent subir des changements physiques ou chimiques en r??ponse ?? l'??volution des conditions environnementales. Pour un excellent SR-BCP, habituellement, de l??g??res modifications de l'environnement sont suffisantes pour induire des modifications relativement drastiques dans la conformation, la structure ou les propri??t??s du polym??re. Ces polym??res sont aussi appel??s polym??res stimuli-r??actifs ou polym??res intelligents et ils ont un grand potentiel d'application dans de nombreux domaines. Au cours des deux derni??res d??cennies, un int??r??t de recherche et d??veloppement particulier a ??t?? port?? sur l'exploitation des SR-BCPs pour utilisation comme syst??mes de relargage de m??dicaments. Dans de nombreux cas, les changements induits par des stimuli dans la structure ou la morphologie des assemblages de BCPs peuvent entra??ner la lib??ration de l'esp??ce encapsul??e, parfois d'une mani??re contr??lable spatialement et temporellement par le choix d'un stimulus appropri?? et en ajustant les param??tres de la m??thode de stimulation utilis??e. De fa??on g??n??rale, le fait d???avoir un certain type de groupements r??actifs ?? un stimulus donn?? dans la structure permet aux SR-BCPs de reconna??tre et r??agir ?? ce stimulus. Malgr?? les ??normes progr??s r??alis??s sur les SR-BCPs, un certain nombre de questions fondamentales restent ?? r??soudre afin de leur permettre de se trouver dans des applications pratiques. Pour y arriver, la cl?? ou le d??fi r??side dans l???am??lioration du niveau et de la complexit?? de contr??le sur les SR-BCPs ainsi que la sensibilit?? avec laquelle ces polym??res r??agissent ?? des stimuli. G??n??ralement, il est souhaitable d'obtenir une r??action rapide sous l'action d'une stimulation mod??r??e. A cette fin, il est n??cessaire d???effectuer des recherches fondamentales sur la conception rationnelle de nouveaux SR-BCPs ainsi que sur le d??veloppement de m??thodes de stimulation qui peuvent amplifier l'effet d'un stimulus. Les travaux de recherche pr??sent??s dans cette th??se s'inscrivent dans ce domaine de recherche. Plus sp??cifiquement, nous avons ??tudi?? des micelles de BCPs qui r??pondent ?? deux types de stimuli. D'une part, nous avons ??tudi?? un m??canisme d'amplification bas?? sur l???effet des ultrasons combin?? ?? la thermosensibilit?? de BCPs. D'autre part, nous avons d??velopp?? une nouvelle conception de BCPs qui permet aux micelles d?????tre d??truites soit de mani??re photochimique, soit par des r??actions d'oxydo-r??duction, tout en ayant le nombre minimum des groupes stimuli-r??actifs dans la structure du polym??re. Notre recherche a g??n??r?? de nouvelles connaissances dans ce domaine et sugg??re de nouveaux moyens sur la fa??on dont les questions de sensibilit?? et de contr??le complexe des micelles SR-BCPs peuvent ??tre abord??es, contribuant ainsi ?? l'avancement des connaissances fondamentales. Le c??ur de cette th??se est compos?? de trois publications r??sultant des projets r??alis??s. Dans le premier projet, afin de coupler la sensibilit?? aux ultrasons et la thermosensibilit??, nous avons men?? une ??tude ayant pour but de trouver des structures possibles de polym??res qui sont susceptibles d'??tre affect??es par les ultrasons. Nous avons effectu?? une ??tude comparative sur la destruction des micelles form??es par divers BCPs et la lib??ration concomitante d'un colorant hydrophobe encapsul?? (rouge du Nil) par les ultrasons focalis??s de haute intensit?? (HIFU). Nous avons constat?? que toutes les micelles form??es par les quatre copolym??res diblocs synth??tis??s, ??tant constitu??s d'un m??me bloc du polyoxyde d'??thyl??ne (PEO) hydrophile et d???un bloc de polym??thacrylate hydrophobe diff??rent, peuvent ??tre perturb??es par les ultrasons. Toutefois, l'ampleur de la perturbation et la lib??ration du colorant encapsul?? dans la micelle est influenc??e par la structure chimique du block hydrophobe. En particulier, les micelles du PEO-b-PIBMA (poly(1-isobutoxym??thacrylate d'??thyle)) et du PEO-b-PTHPMA (poly(m??thacrylate de 2-t??trahydropyrannyle)), qui poss??dent une unit?? ac??tal labile dans le groupe lat??ral, subissent des perturbations plus importantes en raison, probablement, d???une r??action d???hydrolyse de l???ester induite par les ultrasons, donnant lieu ?? une lib??ration plus rapide du colorant. En revanche, les micelles du PEO-b-PMMA (poly(m??thacrylate de m??thyle)), dont le bloc polym??thacrylate est plus stable, sont plus r??sistantes aux ultrasons et pr??sentent une cin??tique de lib??ration du colorant plus lente que les autres micelles. De plus, l???analyse des spectres infrarouges des solutions micellaires, enregistr??s avant et apr??s l???exposition aux ultrasons, sugg??re une r??action d???hydrolyses pour le PEO-b-PIBMA et le PEO-b-PTHPMA, mais montre l'absence d???une quelconque r??action chimique pour le PEO-b-PMMA. L'effet de la structure de copolym??re ?? blocs sur la r??activit?? des micelles ?? l'irradiation HIFU ?? hautes fr??quences permet de mieux comprendre comment des micelles de BCPs sensibles aux ultrasons peuvent ??tre con??ues. Sur la base du premier projet, dans le deuxi??me projet, nous avons d??montr?? une nouvelle approche pouvant amplifier l'effet de HIFU sur la destruction des micelles de BCPs en solution aqueuse. L???id??e est d???introduire une petite quantit?? des unit??s comonom??res sensibles aux ultrasons dans le bloc thermosensible et initialement hydrophobe. On peut alors former une micelle dont le noyau est compos?? du polym??re sensible aux ultrasons. Si la r??action induite par les ultrasons sur le noyau permet d???augmenter la temp??rature de solution critique inf??rieure (LCST) du polym??re thermosensible au-dessus de la temp??rature de la solution micellaire, la micelle doit ??tre dissolue car tout le BCP est devenu soluble dans l???eau. Pour tester la validit?? de ce nouveau m??canisme, nous avons synth??tis?? et ??tudi?? un copolym??re dibloc de PEO-b-P(MEO[indice inf??rieur 2]MA-co-THPMA) (MEO[indice inf??rieur 2]MA repr??sente 2-(2-m??thoxy??thoxy) m??thacrylate d'??thyle), dans lequel le bloc thermosensible P(MEO[indice inf??rieur 2]MA-co-THPMA) est hydrophobe ?? T>LCST. Le THPMA a ??t?? choisi en raison de sa plus grande r??activit?? vis-??-vis des faisceaux HIFU que les autres monom??res ??tudi??s dans le premier projet. Les r??sultats montrent que les HIFU peuvent effectivement augmenter la LCST du bloc P(MEO[indice inf??rieur 2]MA-co-THPMA) et, par cons??quent, induire la dissociation des micelles ?? une temp??rature constante de la solution. Une analyse spectrale en RMN [indice sup??rieur 13]C a fourni des preuves montrant que l'hydrolyse des groupes THPMA se produit sous l???irradiation HIFU et que la destruction des micelles provient d'une augmentation de la LCST en raison de la conversion des motifs hydrophobes THPMA en motifs acides m??thacryliques (MAA) hydrophiles. Cette m??thode de modifier la LCST par une irradiation des ultrasons est g??n??rale et peut ??tre appliqu??e aux autres groupements sensibles aux ultrasons dans la conception de ce type de SR-BCPs. Cette ??tude a ainsi d??montr?? un nouveau m??canisme d'amplification et de contr??le des micelles de BCPs via la modification induite par les ultrasons de la temp??rature de transition de phase (LCST) du bloc constituant le noyau micellaire. Le troisi??me projet pr??sent?? dans cette th??se portait sur une conception rationnelle de BCPs ayant un but pr??cis: permettre aux micelles d?????tre perturb??es par deux types de stimuli en utilisant le nombre minimal des unit??s sensibles ?? des stimuli dans la structure de BCPs. Pour ce faire, nous avons con??u et synth??tis?? un nouveau copolym??re tribloc amphiphile de type ABC, soit le poly(oxyde d'??thyl??ne) - disulfure ??? polystyrene - o-nitrobenzyle - poly(2-(dim??thylamino) ??thylm??thacrylate) (PEO-S-S-PS-ONB-PDMAEMA). Il dispose d'une liaison disulfure redox-clivable entre les blocs PEO et PS ainsi que d'un groupe o-nitrobenzyle (ONB) photoclivable ?? la jonction des blocs PS et PDMAEMA. Nous avons montr?? que ce mod??le est une strat??gie utile pour permettre aux micelles de BCPs de r??pondre soit ?? un agent r??ducteur comme le dithiothr??itol (DTT) dans une solution, soit ?? l'exposition ?? la lumi??re UV, tout en ayant le nombre minimum des groups stimuli-r??actifs dans la structure du copolym??re (deux unit??s par cha??ne). Nos investigations ont r??v??l?? que les micelles de ce copolym??re tribloc peuvent ??tre perturb??es de diff??rentes fa??ons. Lorsqu'un seul stimulus est appliqu??, l'enl??vement d'un type des cha??nes de polym??re hydrophile ?? partir de la couronne de micelles, soit le PEO par clivage par oxydo-r??duction ou le PDMAEMA par photoclivage, entra??ne un effet limit?? de d??stabilisation sur la dispersion des micelles. L'agglom??ration de quelques micelles appara??t mais la dispersion reste essentiellement stable. En revanche, en cas d'utilisation combin??e des deux stimuli qui clivent ?? la fois le PEO et le PDMAEMA, une agr??gation importante du polym??re se produit ?? la suite de l'??limination de l'amphiphilicit?? du polym??re. // Abstract : Stimuli-responsive block copolymers (SR-BCPs) and their assemblies, such as micelles, vesicles and hydrogels, can undergo physical or chemical changes in response to changing environmental conditions. For an excellent SR-BCP, usually, slight changes in the environment are sufficient to induce relatively drastic changes in either the conformation or structure or properties of the polymer. Stimuli-reactive polymers are often referred to as smart polymers and they have great application potential in many fields. Over the past two decades, particular research and development interest has been focused on exploiting SR-BCP assemblies as drug delivery systems (DDSs). In many cases, stimuli-induced changes in the structure or morphology of BCP assemblies (drug carriers) can result in the release of loaded species, sometimes in a spatially and temporally controllable manner by choosing an appropriate stimulus and adjusting the parameters of the used stimulating method. Generally speaking, by having a certain type of stimuli-reactive moieties in the structure, SR-BCP assemblies have an ability to recognize a specific stimulus and react to its presence accordingly. Despite the tremendous progress achieved on SR-BCPs, a number of fundamental issues remain to be addressed in order to enable real-life applications of these smart polymers. Of them, an increasing level and complexity of control on SR-BCPs as well as the sensitivity with which these polymers react to stimuli are key and challenging. It is highly desirable to obtain a fast reaction under the action of a modest stimulation. To this end, fundamental research is necessary on rational and creative BCP structural design as well as on development of stimulation methods that can amplify the effect of a stimulus. The research work presented in this thesis falls into this important topic. More specifically, we studied BCP micelles that are responsive to two types of stimuli. On the one hand, we investigated an amplification mechanism based on coupling the ultrasound reactivity with the thermosensitivity of BCPs. On the other hand, we developed a BCP structural design that allows micelles to be disrupted by either light or redox agents while having the minimum number of stimuli-reactive moieties in the polymer structure. Our research provided new insights into and suggested new means on how the issues of sensitivity and complex control of SR-BCP micelles can be tackled, thus contributing to the advancement of fundamental knowledge. The core of this thesis is comprised of three publications resulting from the projects realized in our research work. In order to couple the ultrasound sensitivity and thermosensitivity, in the first project, we carried out studies to find possible polymer structures that are susceptible to be affected by ultrasound. We conducted a comparative study on the disruption of the micelles formed by various BCPs and the concomitant release of an encapsulated hydrophobic dye (Nile Red) by high-intensity focused ultrasound (HIFU). It was found that all micelles formed by the four synthesized diblock copolymers, being composed of a hydrophilic poly(ethylene oxide) (PEO) block and a different polymethacrylate hydrophobic block, could be disrupted by ultrasound. However, the extent of the micellar disruption and dye release was found to be influenced by the chemical structure of the micelle-core-forming hydrophobic polymethacrylate. In particular, micelles of PEO-b-PIBMA (poly(1-(isobutoxy)ethyl methacrylate)) and PEO-b-PTHPMA (poly(2-tetrahydropyranyl methacrylate)), whose hydrophobic blocks have a labile acetal unit in the side group and are more likely to undergo ester hydrolysis, could be disrupted more severely by ultrasound, giving rise to a faster release of Nile Red. By contrast, micelles of PEO-b-PMMA (poly(methyl methacrylate)), whose polymethacrylate block is more stable, appear to be more resistant to ultrasound irradiation and exhibit a slower rate of dye release than other BCPs. Moreover, infrared spectra recorded with micelles before and after ultrasound irradiation of the aqueous solution of the micelles give evidence for the occurrence of chemical reactions, most likely hydrolysis, for PEO-b-PIBMA and PEO-b-PTHPMA, but absence of chemical reactions for PEO-b-PMMA. The effect of BCP chemical structure on the reaction of micelles to high-frequency HIFU irradiation shows the perspective of designing and developing ultrasound-sensitive BCP micelles for ultrasound-based delivery applications. On the basis of the first project, in the second project, we demonstrated a new approach that could amplify the effect of HIFU on the disassembly of BCP micelles in aqueous solution. By introducing a small amount of ultrasound-labile comonomer units into the micelle core-forming thermosensitive polymer, the ultrasound-induced reaction of the comonomer could increase the lower critical solution temperature (LCST) of the thermosensitive polymer due to a polarity change, which renders the BCP soluble in water without changing the solution temperature and, consequently, results in disassembly of BCP micelles. To prove the validity of this new mechanism, we synthesized and investigated a diblock copolymer of PEO-b-P(MEO[subscript 2]MA-co-THPMA) (MEO[subscript 2]MA stands for 2-(2-methoxyethoxy)ethyl methacrylate). In the thermosensitive random copolymer block P(MEO[subscript 2]MA-co-THPMA), which is hydrophobic at T>LCST, THPMA was chosen due to its greater reactivity under HIFU than other monomer structures investigated in the first project. We found that HIFU could indeed increase the LCST of the P(MEO[subscript 2]MA-co-THPMA) block and, as a result, dissociate the BCP micelles at a constant temperature. A [superscript 13]C NMR spectral analysis provided critical evidence that hydrolysis of the THPMA groups occurs under HIFU irradiation and the micellar disassembly originates from an increase in the LCST due to the ultrasound-induced conversion of hydrophobic comonomer units of THPMA onto hydrophilic methacrylic acid (MAA). This ultrasound-changeable-LCST approach is general and can be applied by exploring other ultrasound-labile moieties in the BCP design. By transducing an ultrasound-induced effect into a changing thermosensitivity of the micelle core-forming block, this study demonstrated a new amplification and control mechanism for SR-BCP micelles. The third project presented in this thesis dealt with a rational BCP design that had a specific purpose: allowing BCP micelles to be disrupted by two types of stimuli while using the minimum number of stimuli-reactive moieties in the BCP structure. The unveiling of such BCP structures provides insight into how to make BCP micelles sensitive to stimuli. To do this, we designed and synthesized a new amphiphilic ABC-type triblock copolymer, namely, poly(ethylene oxide)-disulfide-polystyrene- o-nitrobenzyl-poly(2-(dimethylamino)ethylmethacrylate) (PEO-S-S-PS-ONB-PDMAEMA), which features a redox-cleavable disulfide linkage between the PEO and PS blocks as well as a photocleavable ONB group as the junction of the PS and PDMAEMA blocks. We demonstrated that this design is a useful strategy to allow BCP micelles to respond to both a reducing agent like dithiothreitol (DTT) in solution and exposure to UV light while having the minimum number of stimuli-reactive moieties in the block copolymer structure (two units per chain). Our investigations found that the micelles of this triblock copolymer could be disrupted in different ways. When only one stimulus is applied, the removal of one type of hydrophilic polymer chains from the micelle corona, either PEO by redox-cleavage or PDMAEMA by photocleavage, results in a limited destabilization effect on the dispersion of the micelles. The agglomeration between a few micelles appears but the dispersion remains essentially stable. By contrast, under combined use of the two stimuli that cleaves both PEO and PDMAEMA, severe polymer aggregation occurs as a result of elimination of the polymer amphiphilicity. Moreover, by loading the hydrophobic Nile Red in the micelles, the fluorescence quenching of the dye by aqueous medium under the different uses of the two stimuli appears to correlate with the different extents of the micellar disruption. // ?????? : ??????????????????????????????SR-BCPs???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????SR-BCP???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????-??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????SR-BCP?????????????????????????????????DDSs???????????????????????????????????????BCP?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????-????????????????????????SR-BCP??????????????????????????????????????????????????????????????????????????? ??????SR-BCPs?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????SR-BCPs?????????????????????????????????????????????????????????????????????SR-BCPs???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????BCP???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????BCP???????????????????????????BCPs???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????-???????????????BCP???????????????????????????????????????????????????????????????????????????????????????SR-BCP???????????????????????????????????????????????????????????????????????????????????????????????????????????? ??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????BCPs????????????????????????????????????????????????HIFU?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????PEO-b-PIBMA????????? 1-????????????????????????????????????????????? ??????PEO-b-PTHPMA?????????2-???????????????????????????????????? ??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? ??????????????????????????????????????????????????????????????????PEO-b-PMMA?????????????????????????????????????????????????????????????????????????????????????????????????????????PEO-b-PMMA????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????PEO-b-PIBMA???PEO-b-PTHPMA????????????????????????????????????????????????PEO-b-PMMA???????????????????????????????????????HIFU????????????BCP???????????????????????????????????????????????????????????????????????????-??????BCP????????????????????? ??????????????????????????????????????????????????????????????????????????????????????????????????????HIFU??????????????????BCP???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????LCST?????????????????????????????????????????????????????????BCP??????????????????????????????BCP??????????????????????????????????????????????????????????????????????????????????????????????????????PEO-b-P(MEO2MA-co-THPMA) ???MEO2MA ??????2-???2-??????????????????????????????????????????????????????T > LCST????????????????????????????????????P(MEO2MA-co-THPMA)?????????????????????THPMA?????????????????????????????????????????????????????????????????????????????????HIFU?????????????????????????????????????????????????????????????????? ??????HIFU???????????????????????????P(MEO2MA-co-THPMA)?????????LCST?????????BCP??????????????????????????????????????????13C NMR ???????????????????????????THPMA?????????????????????????????????????????????THPMA??????????????????????????????MAA?????????LCST?????????????????????????????????????????????????????????????????????LCST??????????????????????????????????????????????????????BCP???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????SR-BCP????????????????????????????????? ????????????????????????????????????????????????????????????????????????????????????????????????BCP????????????????????????????????????????????????????????????????????????BCP?????????????????????????????????????????????BCP?????????????????????????????????????????????????????????BCP????????????????????????????????????????????????????????????????????????ABC???????????????????????????????????????????????? - ???????????? - ???????????? - ??? - ???????????? - ?????? 2 - ???????????????????????????????????????????????? (PEO-S-S-PS-ONB-PDMAEMA)?????????PEO???PS???????????????????????????????????????????????????PS???PDMAEMA?????????????????????????????????ONB????????????????????????????????????????????????????????????-??????????????????????????????????????????????????????BCP????????????????????????????????????????????? ???DDT????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????PEO????????????????????????PDMAEMA?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????PEO???PDMAEMA?????????????????????????????????????????????????????????????????????????????????????????????????????? ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

La capacité de la force de Lorentz à relier un déplacement mécanique à un courant électrique présente un intérêt certain pour l'acoustique médicale, et trois applications ont été étudiées dans cette thèse. Dans la première partie de ce travail, un hydrophone a été développé pour effectuer des champs de vitesse acoustique. Cet hydrophone était constitué d'un fil de cuivre vibrant dans un champ magnétique. Un modèle a été élaboré pour déterminer une relation entre la pression acoustique et le courant électrique mesure, qui est induit par force de Lorentz lorsque le fil vibre dans un champ acoustique. Un prototype a ensuite été conçu et sa résolution spatiale, sa réponse fréquentielle, sa sensibilité, sa résistance et sa réponse directionnelle ont été examinées. Une méthode d'imagerie appelée Tomographie d'Impedance Electrique par Force de Lorentz a aussi été étudiée. Dans cette méthode, un tissu biologique est déplacé par ultrasons dans un champ magnétique, ce qui induit un courant électrique par force de Lorentz. L'impédance électrique du tissu peut ensuite être déduite de la mesure du courant. Cette technique a été appliquée pour réaliser des images d'un fantôme de gélatine, d'un muscle de bœuf, et d'une lésion thermique dans un échantillon de poulet. Cela a montré que la méthode est potentiellement utile pour fournir un contraste supplémentaire à des images ultrasonores classiques. Enfin, cette thèse a démontré que des ondes de cisaillement peuvent être générées dans des tissus mous par force de Lorentz. Cela a été réalisé en appliquant un courant électrique par deux électrodes dans un solide mou place dans un champ magnétique. Des ondes de cisaillement ont été observées dans des échantillons de gélatine et de foie. La vitesse des ondes de cisaillement a été utilisée pour calculer l'élasticité et leur source pour cartographier la conductivité électrique des échantillons / The ability of the Lorentz force to link a mechanical displacement to an electrical current presents a strong interest for medical acoustics, and three applications were studied in this thesis. In the first part of this work, a hydrophone was developed for mapping the particle velocity of an acoustic field. This hydrophone was constructed using a thin copper wire and an external magnetic field. A model was elaborated to determine the relationship between the acoustic pressure and the measured electrical current, which is induced by Lorentz force when the wire vibrates in the acoustic field of an ultrasound transducer. The built prototype was characterized and its spatial resolution, frequency response, sensitivity, robustness and directivity response were investigated. An imaging method called Lorentz Force Electrical Impedance Tomography was also studied. In this method, a biological tissue is vibrated by ultrasound in a magnetic field, which induces an electrical current by Lorentz force. The electrical impedance of the tissue can be deduced from the measurement of the current. This technique was applied for imaging a gelatin phantom, a beef muscle sample, and a thermal lesion in a chicken breast sample. This showed the method may be useful for providing additional contrast to conventional ultrasound imaging. Finally, this thesis demonstrated that shear waves can be generated in soft tissues using Lorentz force. This work was performed by applying an electrical current with two electrodes in a soft solid placed in a magnetic field. Shear waves were observed in gelatin phantom and liver sample. The speed of the shear waves were used to compute elasticity and their source to map the electrical conductivity of the samples