The thesis studies selected evolution systems to use in planning of high intensity focused ultrasound surgeries. Considered algorithms are statistically analyzed and compared by appropriate criteria to find the one that adds the most value to the potential real world medical problems.

La technique de haute intensité ultrasons focalisés (HIFU) est maintenant largement utilisée pour le traitement du cancer, grâce à son avantage non-invasif. Dans un système de HIFU, une matrice de transducteurs à ultrasons est pilotée en phase pour produire un faisceau focalisé d'ultrasons (1M ~ 10 MHz) dans une petite zone de l'emplacement de la cible sur le cancer dans le corps. La plupart des systèmes HIFU sont guidées par imagerie par résonance magnétique (IRM) dans de nos jours. Dans cette étude de doctorat, un amplificateur de puissance de classe D en demi-pont et un système d'accord automatique d'impédance sont proposés. Tous deux circuits proposés sont compatibles avec le système IRM. L'amplificateur de puissance proposé a été réalisé par un circuit imprimé (PCB) avec des composants discrets. Selon les résultats du test, il a rendement de conversion en puissance de 82% pour une puissance de sortie conçue de 1,25W à une fréquence de travail de 3MHz. Le système d'accord automatique d'impédance proposé a été conçu en deux versions: une version en PCB et une version en circuit intégré (IC). Contrairement aux systèmes d'accord automatique proposés dans la littérature, il n'y a pas besoin de l'unité de microcontrôleur (MCU) ou de l'ordinateur dans la conception proposée. D'ailleurs, sans l'aide de composants magnétiques volumineux, ce système d'auto-réglage est entièrement compatible avec l'équipement IRM. La version en PCB a été conçue pour vérifier le principe du système proposé, et il est également utilisé pour guider à la conception du circuit intégré. La réalisation en PCB occupe une surface de 110cm². Les résultats des tests ont confirmé la performance attendue. Le système d'auto-tuning proposé peut parfaitement annuler l'impédance imaginaire du transducteur, et il peut également compenser l'impédance de la dérive causée par les variations inévitables (variation de température, dispersion technique, etc.). La conception du système d'auto-réglage en circuit intégré a été réalisé avec une technologie CMOS (C35B4C3) fournies par Austrian Micro Systems (AMS). La surface occupée par le circuit intégré est seulement de 0,42mm². Le circuit intégré conçu est capable de fonctionner à une large gamme de fréquence tout en conservant une consommation d'énergie très faible (137 mW). D'après les résultats de la simulation, le rendement de puissance de ce circuit peut être amélioré jusqu'à 20% comparant à celui utilisant le réseau d'accord statique. / High intensity focused ultrasound (HIFU) technology is now broadly used for cancer treatment, thanks to its non-invasive property. In a HIFU system, a phased array of ultrasonic transducers is utilized to generate a focused beam of ultrasound (1M~10MHz) into a small area of the cancer target within the body. Most HIFU systems are guided by magnetic resonance imaging (MRI) in nowadays. In this PhD study, a half-bridge class D power amplifier and an automatic impedance tuning system are proposed. Both the class D power amplifier and the auto-tuning system are compatible with MRI system. The proposed power amplifier is implemented by a printed circuit board (PCB) circuit with discrete components. According to the test results, it has a power efficiency of 82% designed for an output power of 3W at 1.25 MHz working frequency. The proposed automatic impedance tuning system has been designed in two versions: a PCB version and an integrated circuit (IC) version. Unlike the typical auto-impedance tuning networks, there is no need of microprogrammed control unit (MCU) or computer in the proposed design. Besides, without using bulky magnetic components, this auto-tuning system is completely compatible with MRI equipment. The PCB version was designed to verify the principle of the proposed automatic impedance tuning system, and it is also used to help the design of the integrated circuit. The PCB realization occupies a surface of 110cm². The test results confirmed the expected performance. The proposed auto-tuning system can perfectly cancel the imaginary impedance of the transducer, and it can also compensate the impedance drifting caused by unavoidable variations (temperature variation, technical dispersion, etc.). The IC design of the auto-tuning system is realized in a CMOS process (C35B4C3) provided by Austrian Micro Systems (AMS). The die area of the integrated circuit is only 0.42mm². This circuit design can provide a wide working frequency range while keeping a very low power consumption (137 mW). According to the simulation results, the power efficiency can be improved can up to 20% by using this auto-tuning circuit compared with that using the static tuning network.

Dans la première partie de cette thèse, les ultrasons focalisés (HIFU) guidés par Imagerie par Résonance Magnétique (IRM) sont utilisés pour l’activation locale transgénique in vivo. Une souris transgénique avec un gène luciferase sous contrôle d’un promoteur thermosensible est utilisée comme modèle biologique. L’hyperthermie locale est induite par une sonde HIFU et contrôlée via un IRM. Dans la seconde partie de ce travail de thèse, les ultrasons sont utilisés pour améliorer le dépôt local de médicaments dans les cellules et les tissus. Le suivi du médicament est effectué à l’aide de différentes techniques d’imageries telles que l’IRM ou l’imagerie par fluorescence. / In the first part of the thesis magnetic resonance imaging (MRI) guided high intensity focused ultrasound (HIFU) is used for the local activation of a transgene in vivo. A transgenic mouse with a luciferase gene under control of a heat sensitive promoter is used as biological model. Local hyperthermia is induced by HIFU and monitored and controlled via MRI. In the second part of the thesis (focused) ultrasound is used for improving local drug delivery in cells and tissue. The fate of the drug is followed by different imaging techniques such as MRI and fluorescence imaging.

HIFU is the upcoming technology for noninvasive or minimally invasive tumor ablation via the localized acoustic energy deposition at the focal region within the tumor target. The presence of cavitation bubbles had been shown to improve the therapeutic effect of HIFU. In this study, we have investigated the effect of HIFU on temperature rise and cavitation bubble activity in ethanol-treated porcine liver and kidney tissues. We have also explored changes in the viability and proliferation rate of HepG2, SW1376, and FB1 cancer cells with their exposure to ethanol and HIFU. Tissues were submerged in 95% ethanol for five hours and then exposed to HIFU generated by a 1.1 MHz transducer or injected into focal spot before HIFU exposure. Cavitation events were measured by a passive cavitation detection technique for a range of acoustic power from 1.17 W to 20.52 W. The temperature around the focal zone was measured by type K or type E thermocouples embedded in the samples. In experiments with cancer cells, 2.7 millions cells were treated with concentration of ethanol at concentration 2%, 4%, 10%, 25%, and 50% and the cell were exposed to HIFU with power of 2.73 W, 8.72 W, and 12.0 W for 30 seconds. Our data show that the treatment of tissues with ethanol reduces the threshold power for inertial cavitation and increases the temperature rise. The exposure of cancer cells to various HIFU power only showed a higher number of viable cells 24 to 72 hours after HIFU exposure. On the other hand, both the viability and proliferation rate were significantly decreased in cells treated with ethanol and then HIFU at 8.7 W and 12.0 W even at ethanol concentration of 2 and 4 percent. In conclusion, the results of our study indicate that percutaneous ethanol injection (PEI) and HIFU have a synergistic effect on cancer cells ablation. / acase@tulane.edu

Pas de résumé / Propagation of nonlinear acoustic waves in inhomogeneous media is an important problem inmany research domains of modern theoretical and applied acoustics. For example, studies onpropagation of high amplitude N-waves in turbulent atmosphere are relevant to the sonic boomproblem which involves high interest due to development of new civil supersonic aircrafts. Inrelation to sonic boom problem, many studies on spark-generated N-wave propagation through aturbulent layer were carried out in model laboratory-scale experiments which are more controlledand reproducible than field measurements. Propagation of high intensity focused ultrasound intissue (HIFU) is intensively studied for medical applications. HIFU is a basis of new surgicaldevices for noninvasive thermal and mechanical ablation of tumors.In this thesis, the problem of characterization of high amplitude N-waves generated in air byan electric spark was studied using combined acoustical and optical methods. The fine structureof shocks was deduced from the shadowgraphy images with a resolution that cannot be obtainedusing condenser microphones. It was shown that the combination of optical and acoustical methodsallows complete characterization of the N-waves.N-wave propagation through a layer of thermal turbulence was further studied in a laboratoryexperiment. The evolution of statistical distributions and average values of the most importantN-wave parameters was investigated at different propagation distances. Experimental results werecompared to data obtained in another experiment known in literature, where N-wave was propagatedthrough kinematic turbulence. It was shown that in the case of almost the same widths ofthe turbulent layers, values of the characteristic scales and rms of refractive index fluctuations, thekinematic turbulence leads to stronger distortions of the peak pressure and the shock rise time ofthe N-wave and to 2-3 greater probabilities to observe intense focusing in caustics.Effects of nonlinear propagation and random focusing on the statistics of N-wave amplitudewere studied theoretically using the KZK equation and the phase screen model. The phase screenwas characterized by the correlation length and the refraction length – the distance where firstcaustics occur. Probability distributions, mean values and standard deviations of the N-wave peakpressure were obtained from the numerical solutions and were presented as functions of the propagationdistance and the nonlinear length. Statistical results from the KZK model were comparedwith analytical predictions of the nonlinear geometrical acoustics approach (NGA). It was shown,that NGA approach is valid only up to the distance of one third of refraction length of the screen.Strong nonlinear effects were shown to suppress amplitude fluctuations. The effect of the scale ofinhomogeneities on amplitude statistics was also investigated.The problem of focusing of ultrasound beam through inhomogeneous medium is importantfor medical diagnostics and nondestructive testing problems. The inhomogeneities of biologicaltissue or of industrial materials can destroy beam focusing. In the thesis, distortions of a weaklynonlinear diagnostic beam focused through a phase layer of special configuration were consideredexperimentally and theoretically. Feasibility of selective destruction of focusing of differentharmonics in the beam was predicted in the modeling and confirmed in experiment.The most modern HIFU devices rely on using two-dimensional multi-element phased arrayswith elements randomly distributed over a segment of a spherical surface. Numerical experimentis an important tool to characterize pressure fields created by HIFU radiators. Intensity levels atthe focus of HIFU radiators can reach several tens of thousands of W/cm2, causing nonlinearpropagation effects and formation of shocks [...]

This work deals with the 2D and 3D visualization of simulation outputs from the k-Wave toolbox. This toolbox, designed to accurately model the propagation of ultrasound waves in the human body, usually generates immense amounts of output data (up to hundreds of GB). That is why new methods for both the visualization and the effective data representation are necessary to be developed to help users to easily understand the simulation results. This thesis elaborates on the data format, simulation outputs are stored in, with the use of the HDF5 library and looking for the best way to quickly read the simulation data. Finally, the thesis presents the design and the implementation of the console-based application for big simulation data pre-processing and the GUI-based application for interactive visualization of the pre-processed data. The most significant features of these applications are downsampling data, changing the format of storing, viewing 2D sections, planar and volumetric visualization and animation of the simulation process. The proposed implementation allows parts of the simulation domain to be visualised within tens of milliseconds even if the simulation domain comprises GBs of data - This significantly streamlines the work of scientists and clinicians in the field of HIFU.

High Intensity Focussed Ultrasound (HIFU) ablation is a promising technology for the non-invasive, targeted treatment of certain types of cancer. The technique functions by subjecting tumours to a cytotoxic level of intense, localised heating, while leaving the surrounding tissue unharmed. However, a number of limitations in the available HIFU treatment monitoring methods are currently hampering the effectiveness and clinical adoption of the therapy. This work aims to develop improved metrics of HIFU-induced biological damage that are specifically suited to monitoring and controlling HIFU ablation. Firstly, an optical method that enables straightforward quantification of thermal damage in protein-embedding hydrogels is developed. Secondly, hydrogels embedded with different cell lines are used to assess the performance of common temperature-based metrics of cell death across a range of HIFU-relevant conditions. Finally, a novel, passive acoustic detector designed for the real-time monitoring of HIFU-induced tissue damage is proposed. The detector is shown to predict lesioning with over 80% accuracy in regimes that are very likely to create lesions (60 J of acoustic energy or more), with an error rate of less than 6% for exposures that are too short to cause lesioning (up to 1 s long). The proposed detector could therefore provide a low-cost means of effectively monitoring clinical HIFU treatments passively and in real time.

Cavitation is a phenomenon present during many ultrasound therapies, including the thermal ablation of malignant tissue using high intensity focused ultrasound (HIFU). Inertial cavitation, in particular, has been previously shown to result in increased heat deposition and to be associated with broadband noise emissions that can be readily monitored using a passive receiver without interference from the main ultrasound signal. The present work demonstrates how an array of passive receivers can be used to generate maps of cavitation distribution during HIFU exposure, uncovering a new potential method of monitoring HIFU treatment. Using a commercially available ultrasound system (z.one, Zonare, USA), pulse transmission can be switched off and data from 64 elements of an array can be simultaneously acquired to generate passive maps of acoustic source power. For the present work, a 38 mm aperture 5-10 MHz linear array was used, with the 64 elements chosen to span the entire aperture. Theory and simulations were used to show the spatial resolution of the system, the latter showing that the broadband nature of inertial cavitation makes passive maps robust to interference between cavitating bubbles. Passive source mapping was first applied to wire scatterers, demonstrating the ability of the system to resolve broadband sources. With the array transversely placed to the HIFU axis, high-resolution passive maps are generated, and emissions from several cavitating bubbles are resolved. The sensitivity of passive mapping during HIFU exposure is compared with that of an active cavitation detector following exposure. The array was then placed within a rectangular opening in the centre of the HIFU transducer, providing a geometric setup that could be used clinically to monitor HIFU treatment. Cavitation was instigated in continuous and disjoint regions in agar tissue mimicking gel, with the expected regions of cavitation validating the passive maps obtained. Finally, passive maps were generated for samples of ox liver exposed to HIFU. The onset of inertial cavitation as detected by the passive mapping approach was found to provide a much more robust indicator of lesioning than post-exposure B-mode hyperecho, which is in current clinical use. Passive maps based on the broadband component of the received signal were able to localize the lesions both transversely and axially, however cavitation is generally indicated 5 mm prefocal to the lesions. Further work is needed to establish the source of this discrepancy. It is believed that with use of an appropriately designed cavitation detection array, passive mapping will represent a major advance in ultrasound-guided HIFU therapy. Not only can it be utilized in real-time during HIFU exposure, without the need to turn the therapeutic ultrasound field off, but it has also been shown in the context of the present work to provide a strong indicator of successful lesioning and high signal-to-noise compared to conventional B-mode ultrasound techniques.

Side effects of current chemotherapeutics limit their use in cancer therapy. Although many current drugs are highly toxic and potent, the effects they have on non-cancerous tissue are unbearable for patients. Targeting these drugs may provide a means to restrict their toxic effects to only cancer tissue while leaving healthy tissue unaffected. This approach requires that the drug is only available in cancer tissue, which has been achieved here by encapsulating drugs into liposomal nano-capsules which are capable of passively accumulating in cancerous tissue via the enhanced permeability and retention effect (EPR). In addition to localisation, a threshold dose must be achieved to deliver the desired toxic effect to the target tumour tissue. Previous strategies have relied on passive 'leaching' of the drug from liposomes, however this 'leaching' does not necessarily achieve the threshold dose required. In the present work, a new generation of liposomes has been developed whereby release is solely achieved in the presence of ultrasound triggered cavitation. Instigation of such cavitation events would normally require the target tissue be exposed to high and possibly damaging ultrasound pressures. To remove the need for these high pressures, cavitation nuclei have been developed to lower the cavitation threshold of surrounding media. To allow for improved co-localisation and treatment deeper into cancer tissue, cavitation nuclei were developed to be in the nanoscale size range. Two types of novel cavitation nuclei were produced, a rough surfaced carbon nanoparticle (CNP, ~180 nm) and smooth shaped polymeric nano-cup particle (NC, ~150, 470, or 770 nm). Both types of particle are solid nanoparticles with gas entrapped on their surface which was capable of cavitating in response to ultrasound without greatly affecting the particle itself. These particles are classified as cavicatalytic nanoparticles due to their ability to reduce the cavitation threshold of their surrounding media without being destroyed themselves. Finally, an entirely nanoscale release system was developed and tested in vitro and in vivo. The drug carrier (the liposome) and effector agent (the cavicatalytic nanoparticle) were used to demonstrate ultrasound triggered drug release, specifically in response to the generation of cavitation events. These cavitation events could be non-invasively monitored and characterised, adding to the potential clinical utility of the technologies developed and described here.

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