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Focused ultrasound (FUS) is an emerging technology, and it plays an essential role in clinical and contactless acoustic energy transfer applications. These applications have critical criteria for the acoustic pressure level, the creation of complex pressure patterns, spatial management of the complicated acoustic field, and the degree of nonlinear waveform distortion at the focal areas, which have not been met to date. This dissertation focuses on introducing experimentally validated novel numerical approaches, optimization algorithms, and experimental techniques to fill existing knowledge gaps and enhance the functionality of holographic acoustic lenses (HALs) with an emphasis on applications related to biomedical-focused ultrasound and ultrasonic energy transfer. This dissertation also aims to investigate the dynamics of nonlinear acoustic beam shaping in engineered HALs. First, We will introduce 3D-printed metallic acoustic holographic mirrors for precise spatial manipulation of reflected ultrasonic waves. Optimization algorithms and experimental validations are presented for applications like contactless acoustic energy transfer. Furthermore, a portion of the present work focuses on designing holographic lenses in strongly heterogeneous media for ultrasound focusing and skull aberration compensation in transcranial-focused ultrasound. To this end, we collaborated with the Biomedical Engineering and Mechanics Department as well as Fralin Biomedical Research Institute to implement acoustic lenses in transcranial neuromodulation, targeting to improve the quality of life for patients with brain disease by minimizing the treatment time and optimizing the ultrasonic energy into the region of interest. We will also delve into the nonlinear regime for High-Intensity Focused Ultrasound (HIFU) applications, this study is structured under three objectives: (1) establishing nonlinear acoustic-elastodynamics models to represent the dynamics of holographic lenses under low- to high-intensity acoustic fields; (2) validating and leveraging the resulting models for high-fidelity lens designs used in generating specified nonlinear ultrasonic fields of complex spatial distribution; (3) exploiting new physical phenomena in acoustic holography. The performed research in this dissertation yields experimentally proven mathematical frameworks for extending the functionality of holographic lenses, especially in transcranial-focused ultrasound and nonlinear wavefront shaping, advancing knowledge in the burgeoning field of the inverse issue of nonlinear acoustics, which has remained underdeveloped for many years. / Doctor of Philosophy / Ultrasonic waves are sound waves that have frequencies higher than the upper audible limit of human hearing. The versatility and non-invasive nature of ultrasonic waves make them a valuable tool in numerous scientific, medical, and industrial applications. In healthcare, ultrasonic waves are employed in diagnostic imaging techniques, such as ultrasound scans, to create images of internal body structures. Ultrasonic waves are also used for non-destructive testing (NDT) of materials, detecting flaws or cracks within structures without causing any damage. Furthermore, this technology finds applications in the field of material science for the manipulation of particles and in biomedical research for drug delivery systems. Focused ultrasound sound is an emerging non-invasive therapeutic modality that uses focused ultrasound waves to target tissue within the body without damaging the surrounding tissue. This technology allows for precise delivery of ultrasound energy to a specific region, where it can induce various desired therapeutic effects depending on the targeting location and parameters. Therapeutic focused ultrasound has the advantage of being non-invasive, reducing the risks and recovery time associated with traditional surgery. It can be precisely controlled and monitored in real-time with imaging techniques such as ultrasound or MRI, ensuring the targeted treatment of pathological tissues while sparing healthy ones. Applications of therapeutic are broad and include tumor ablation, facilitation of drug delivery across the blood-brain barrier, relief of chronic pain, and treatment of essential tremor and other neurological disorders. The domain of therapeutic focused ultrasound is continually advancing, driven by research that seeks to extend its applications. Recent developments in acoustic engineering and 3D printing have led to the creation of acoustic holograms, or holographic acoustic lenses, which allow for more refined control over the spatial structure of the acoustic field. These technological advancements hold the promise of enhancing FUS by improving the accuracy of acoustic field localization and providing a more cost-effective solution compared to conventional systems like phased array transducers. However, the accuracy and applicability of existing models and techniques are constrained by assumptions, including the uniformity of the propagation medium and the linearity of the acoustic field, which limits the functionality and restricts the potential applications of acoustic holograms. In this dissertation, we present novel numerical techniques, algorithms, and proof-of-concept experiments to fill those knowledge gaps and expand the functionality of acoustic holograms in crucial applications.

Brain diseases including neurological disorders and tumors remain undertreated due to the challenge in accessing the brain, and blood-brain barrier (BBB) restricting drug delivery, which also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with acoustic agents including microbubbles and nanodroplets remains as the only method to open the BBB noninvasively, locally, and transiently to assist drug delivery. For an ideal medical system to serve a broad patient population, it requires precise and flexible targeting with simulation to personalize treatment, real-time monitoring to ensure safety and effectiveness, and rapid application, as repetitive pharmacological treatment is often required. Since none of current systems fulfills all the requirements, here we designed a neuronavigation-guided FUS system with protocol assessed in in vivo mice, in vivo non-human primates, and human skulls from in silico preplanning, online FUS treatment and real-time acoustic monitoring and mapping, to post-treatment assessment using MRI. Both sedate and awake non-human primates were evaluated with total treatment time averaging 30 min and 3-mm targeting accuracy in cerebral cortex and subcortical structures. The FUS system developed would enable transcranial FUS in patients with high accuracy and independent of MRI guidance.

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

<p>Ultrasound can be used for a variety of therapeutic purposes. High-intensity focused ultrasound (HIFU) has progressed over the past decade to become a viable therapeutic method and is valuable as a non-invasive alternative to many surgical procedures. Ultrasonic thermal therapies can also be used to release thermally sensitive liposomes encapsulating chemotherapeutic drugs. In the brain, the permeability of the blood-brain barrier to drugs, antibodies, and gene transfer can be increased with a mechanical mechanism using ultrasound and contrast agent.</p><p>The work presented in this dissertation tests the hypothesis that a diagnostic system can be used for combined imaging and therapeutic applications. In order to evaluate the effectiveness of a diagnostic system for use in therapeutic applications, a set of non-destructive tests is developed that can predict the potential for high acoustic output. A rigorous, nondestructive testing regimen for standard, diagnostic transducers to evaluate their potential for therapeutic use is formulated. Based on this work, transducer heating is identified as the largest challenge. The design and evaluation of several custom diagnostic transducers with various modifications to reduce internal heating are described. These transducers are compared with diagnostic controls using image contrast, face heating, hydrophone, and ARFI displacement measurements. From these results, we conclude that the most promising design is a passively and actively cooled, PZT-4 multilayer composite transducer, while the acoustically lossless lens and capactive micro-machined transducers evaluated herein are determined to be ineffective.</p><p>Three therapeutic applications are evaluated for the combined system. Image-guided spot ablations, such as in the treatment of early stage liver cancers, could not be successfully performed; however, the additional acoustic output requirements are determined to be on the order of 2.4 times those that can be currently produced without transducer damage in a clinically relevant amount of time (10-20 seconds per spot). The potential of a diagnostic system for a hyperthermia application is shown by producing temperatures for the duration necessary to release chemotherapeutic agents from thermally-activated liposomes without damage to the transducer. Finally, a mechanically-based therapeutic method for opening the BBB with ultrasonic contrast agent and specialized sonication regimes under ultrasonic B-mode guidance is demonstrated.</p><p>These studies indicate that a diagnostic system is capable of both moderate thermal and mechanical therapeutic applications under co-registered image-guidance.</p> / Dissertation

Das Verschließen besitzt als finaler qualitätsbestimmender Prozess besondere Bedeutung in der Verpackungstechnik. Da nach wie vor Kunststoff der am häufigsten eingesetzte Packstoff in der Lebensmittel- und Pharmaindustrie ist, sind insbesondere für das stoffschlüssige Fügen polymerer Packstoffe zahlreiche Verfahren etabliert. Alle bekannten Verfahren besitzen jedoch Einschränkungen bei deren Anwendung oder stellen spezifische Anforderungen an den Packstoff wie beispielsweise das Vorhandensein polarer oder elektrisch leitender Schichten im Verbundaufbau. Wissenschaftliche Untersuchungen haben das Ziel, die bestehenden Einschränkungen durch die Schaffung von Prozessverständnis und darauf aufbauender Optimierung der Verfahren und Prozesse zu verringern oder zu beseitigen. Alternativ dazu erscheint es sinnvoll, neue, bisher nicht in der Verarbeitungstechnik eingesetzte Verfahren auf deren Anwendbarkeit für verpackungstechnische Prozesse im Bereich des Fügens hin zu prüfen. Hochintensiver fokussierter Ultraschall (HIFU) ist ein solches interessantes Verfahren, welches bisher als nichtinvasive Methode zur Tumorbehandlung auf Basis von ultraschallinduzierter Gewebeerwärmung und -zerstörung im medizinisch-therapeutischen Bereich eingesetzt wird. Die prinzipielle Eignung des Verfahrens zur Erwärmung von Kunststoffen ist nur in wenigen wissenschaftlichen Veröffentlichungen beschrieben. Als Fügeverfahren zum Bauteilschweißen von mehreren Millimetern dicken Kunststoffplatten wurde das Prinzip in den 1970er Jahren erprobt. Eine industrielle Nutzung ist jedoch nicht bekannt und der publizierte Stand der Technik ist weit von den Anforderungen des modernen Verarbeitungsmaschinenbaus entfernt. Daraus ergibt sich die Motivation zur Schaffung einer Wissensbasis für dieses Fügeverfahren und die Abschätzung dessen Potential unter verarbeitungstechnischen Maßstäben. Dabei fließen physikalische Grundlagen zur Akustik und Erkenntnisse zu den Wirkzusammenhängen in der Medizin ebenso wie verpackungstechnische Grundlagen ein. Die Ergebnisse der Arbeit stellen die Grundlage für weiterführende Untersuchungen zum stoffschlüssigen Fügen polymerer Packstoffe mittels hochintensivem fokussierten Ultraschall dar.

Le glaucome est une pathologie fréquente principalement due à une élévation de la pression intraoculaire. La pression intraoculaire est le fruit d’un équilibre entre la production du liquide qui remplit la portion antérieure de l’œil - l’humeur aqueuse - et son élimination. Les traitements du glaucome peuvent donc agir selon deux mécanismes : la réduction de la production d’humeur aqueuse par la destruction partielle ou l’inhibition pharmacologique du corps ciliaire, structure responsable de la production de l’humeur aqueuse, ou la facilitation de l’évacuation de l’humeur aqueuse en dehors de l’oeil. De nombreuses méthodes physiques peuvent être utilisées pour détruire le corps ciliaire : lasers, cryothérapie, micro-ondes, etc. Néanmoins, toutes ces méthodes ont deux inconvénients majeurs qui limitent leur utilisation : elles sont peu sélectives de l’organe à traiter, entraînant souvent des dommages des structures adjacentes, et elles présentent une relation effet-dose très inconstante, empêchant de prévoir avec précision l’effet du traitement. L’objectif de ce travail de thèse est le développement d’un dispositif ultrasonore de coagulation du corps ciliaire circulaire, comprenant 6 transducteurs piézoélectriques en forme de segments de cylindre, et générant 6 lésions segmentaires s’inscrivant dans un anneau de diamètre similaire à celui formé par le corps ciliaire. Les expérimentations animales ont montré une nécrose de coagulation sélective des zones du corps ciliaire traitées par le dispositif. Le premier essai clinique a montré que cette méthode était bien tolérée et permettait une réduction importante, prédictible et maintenue dans le temps de la pression intraoculaire / Glaucoma is a common disease mainly due to an increase of the pressure inside the eye. Intraocular pressure is the result of a balance between the production of liquid that fills the anterior part of eye - aqueous humor - and its elimination. All treatments for glaucoma aim to reduce the intraocular pressure and can therefore have two mechanisms of action: reducing aqueous humor production by the partial destruction or medical inhibition of the ciliary body - anatomical structure responsible for the production of aqueous humor - or facilitating the evacuation of aqueous humor out of the eye. Several physical methods can be used to destroy the ciliary body: laser, cryotherapy, microwave, etc. However, all these methods have two major drawbacks limiting their use: they are non-selective of the organ to be treated, often resulting in damage to the adjacent structures, and they have an unpredictable dose-effect relationship, preventing to accurately predict the treatment effect. The objective of this thesis is the development of a circular ultrasonic device incorporating six transducers producing high-intensity focused ultrasound for a selective coagulation of the ciliary body. A circular device with 6 piezoelectric transducers having a geometry of a segment of a cylinder was used to generate six segmental lesions entering in a ring of diameter similar to that formed by the ciliary body. Animal experiments have shown a selective coagulation necrosis of the treated ciliary body. The first clinical trial in humans showed that this method was well tolerated and allowed a significant, predictable and sustained reduction of the intraocular pressure

Das Verschließen besitzt als finaler qualitätsbestimmender Prozess besondere Bedeutung in der Verpackungstechnik. Da nach wie vor Kunststoff der am häufigsten eingesetzte Packstoff in der Lebensmittel- und Pharmaindustrie ist, sind insbesondere für das stoffschlüssige Fügen polymerer Packstoffe zahlreiche Verfahren etabliert. Alle bekannten Verfahren besitzen jedoch Einschränkungen bei deren Anwendung oder stellen spezifische Anforderungen an den Packstoff wie beispielsweise das Vorhandensein polarer oder elektrisch leitender Schichten im Verbundaufbau. Wissenschaftliche Untersuchungen haben das Ziel, die bestehenden Einschränkungen durch die Schaffung von Prozessverständnis und darauf aufbauender Optimierung der Verfahren und Prozesse zu verringern oder zu beseitigen. Alternativ dazu erscheint es sinnvoll, neue, bisher nicht in der Verarbeitungstechnik eingesetzte Verfahren auf deren Anwendbarkeit für verpackungstechnische Prozesse im Bereich des Fügens hin zu prüfen. Hochintensiver fokussierter Ultraschall (HIFU) ist ein solches interessantes Verfahren, welches bisher als nichtinvasive Methode zur Tumorbehandlung auf Basis von ultraschallinduzierter Gewebeerwärmung und -zerstörung im medizinisch-therapeutischen Bereich eingesetzt wird. Die prinzipielle Eignung des Verfahrens zur Erwärmung von Kunststoffen ist nur in wenigen wissenschaftlichen Veröffentlichungen beschrieben. Als Fügeverfahren zum Bauteilschweißen von mehreren Millimetern dicken Kunststoffplatten wurde das Prinzip in den 1970er Jahren erprobt. Eine industrielle Nutzung ist jedoch nicht bekannt und der publizierte Stand der Technik ist weit von den Anforderungen des modernen Verarbeitungsmaschinenbaus entfernt. Daraus ergibt sich die Motivation zur Schaffung einer Wissensbasis für dieses Fügeverfahren und die Abschätzung dessen Potential unter verarbeitungstechnischen Maßstäben. Dabei fließen physikalische Grundlagen zur Akustik und Erkenntnisse zu den Wirkzusammenhängen in der Medizin ebenso wie verpackungstechnische Grundlagen ein. Die Ergebnisse der Arbeit stellen die Grundlage für weiterführende Untersuchungen zum stoffschlüssigen Fügen polymerer Packstoffe mittels hochintensivem fokussierten Ultraschall dar.

Treatment of brain diseases remains extremely challenging partly due to the fact that critical drug delivery is hindered by the blood-brain barrier (BBB), a specialized and highly selective barrier lining the brain vasculature. Focused ultrasound (FUS), combined with systematically administered microbubbles (MBs), has been established as a technique to noninvasively, locally, and transiently open the BBB. The primary mechanism for temporarily opening the BBB using FUS is microbubble cavitation, a phenomenon that occurs when the circulating microbubbles interact with the FUS beam in the brain vasculature. Over the past two decades, many preclinical and clinical applications of FUS-induced BBB opening have been developed, but certain challenges, such as drug delivery route, cavitation control, inflammation onset, and overall accessibility of the technology, have affected its efficient translation to the clinic. This dissertation focuses on optimizing three aspects of FUS-induced BBB opening for therapeutic applications. The first specific aim investigated FUS-induced BBB opening for drug delivery through the intranasal route. Optimal sonication parameters were determined and applied to FUS-enhanced intranasal delivery of neurotrophic factors in a Parkinson’s Disease mouse model. In the second specific aim, cavitation levels affecting the inflammatory response due to BBB opening with FUS were optimized. The relationship between cavitation during FUS-induced BBB opening and the local inflammation was examined, and a cavitation-based controller system was developed to modulate the inflammatory response. In the third specific aim, the devices used for FUS-induced BBB opening were streamlined. A conventional system for FUS-induced BBB opening includes two transducers: one for therapy and another for cavitation monitoring (single element) or imaging (multi-element). In this aim, a single linear array transducer capable of synchronous BBB opening and cavitation imaging was developed, creating a cost-effective and highly accessible “theranostic ultrasound” device. The feasibility of theranostic ultrasound (TUS) was demonstrated in vivo in both mice and non-human primates. In summary, the findings and methodologies in this dissertation optimized FUS-enhanced intranasal delivery across the BBB, developed a cavitation-controlled system to modulate inflammation in the brain, which has been advantageous in reducing pathology and designed a new system for theranostic ultrasound for drug delivery to the brain. Taken altogether, this thesis contributes to the efficient advancement and optimization of FUS-induced BBB opening technology, thus enhancing its clinical adoption in the fight to treat many challenging brain diseases.