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Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Cavitation is the formation of vapor bubbles in a liquid that is a consequence of tensions acting on the liquid. It is of great interest to lots of different scientific fields such as fluid mechanics, acoustics, hydraulic engineering and biology. Although widely studied in macroscale and microscale confined liquids, heterogeneous cavitation at the nanoscale has only been experimentally observed recently in 2-D nanofluidic channels during an evaporation process, where vapor bubbles form and expand inside the nanochannels instead of menisci receding along the channels. Such evaporation-induced cavitation shows a strong correlation with the nanochannel cross-section non-uniformity and exhibited lots of interesting phenomena, including fast evaporation rate and self-controlled bubble dynamics. In this work, we further investigated this new cavitation phenomenon using a series of specially designed 2-D multi-section nanochannels. Each of these channels includes two or three sections of nanochannel with heights of 25 and/or 35 nm and the same width of 3 μm. A modified sacrificial layer etching method was developed to fabricate these nanochannel devices. Water evaporation processes in these channels were recorded using a high-speed camera mounted on an inverted microscope. We observed that cavitation only occurred in multi-section nanochannels with a “Low to High” channel design. In such nanochannels, when menisci receded to the “Low to High” step, bubbles occurred in the higher channel section and started expansion until they occupied the whole section. We explored the origin of these cavitation phenomena and discovered that that initial bubbles were formed during a snap-off process, where meniscus curvature difference induced reverse liquid flows cause air trapping right at the step. The following bubble expansion is a result of evaporation-induced negative pressure (up to -58 bars) as water inside the nanochannels is in a metastable state. We also analyzed water evaporation rates (bubble growth rates) in these nanochannels in the presence of cavitation. While most evaporation rates can be explained by classic vapor diffusion theories or the kinetic limit of evaporation, water evaporation rates in nanochannels with a Low-High-Low design in the presence of cavitation were as high as 630 μm/s, which is even much higher than the kinetic limit of evaporation and cannot be explained by any current theories. This study further expands our understanding of cavitation and provides new insights and explanations for phase-change phenomena at the nanoscale, including cavitation in plants and quick drying process in nanoporous media. The discovered ultra-high evaporation rates in the Low-High-Low nanochannels also offer a new solution to address thermal management needs for next generation electronic devices. / 2031-01-01

Le cancer est reconnu comme l'un des principaux enjeux de santé actuels. Même si de grands progrès ont été réalisés dans ce domaine, les effets systémiques des chimiothérapies et le caractère invasif des procédures actuelles de potentialisation (agents physiques) sont autant d'éléments limitants. Les ultrasons se démarquent néanmoins par leur faible morbidité. Appliqués de façon extracorporelle, ils peuvent pénétrer en profondeur dans les tissus et y induire effets thermiques et mécaniques, incluant entre autres la cavitation. La cavitation peut se définir comme la formation et l'oscillation de bulles dans le milieu de propagation. Il a été montré de potentiels bénéfices de ce mécanisme dans la potentialisation d'agents thérapeutiques. Bien que la génération de cavitation puisse être aidée par l'ajout d'agents de nucléation extérieurs, le travail présenté ici s'en affranchit afin de rendre la procédure plus versatile. Des simulations ont montré qu'un dispositif ultrasonore basé sur deux faisceaux confocaux permettait des conditions favorables à l'obtention de cavitation dans ces conditions. De plus, études in vivo ont montré l'innocuité du phénomène en regard de la stabilité de la doxorubicine, des effets histologiques sur tissus sains ainsi que sur l'éventuelle diffusion métastatique. L'efficacité du traitement combiné n'a en revanche pas pu être démontrée. Pour investiguer la combinaison de chimiothérapie avec de la cavitation stable, une stratégie de régulation est mise en place. Bien que la synergie ait pu être démontrée in vitro, l'étude préclinique ne permet pas de conclure sur l'effet in vivo. Dans l'hypothèse d'un défaut de localisation du nuage de cavitation, une méthode de localisation spatiale est mise en place et validée / Cancer is recognized as one of the major health issues of this beginning century. Even if great achievements have been performed, chemotherapies induce systemic toxicity and combinable physical agents are invasive. Ultrasound has shown a great potential as an external physical agent. Applied extracorporeally, it can penetrate in depth in tissue and induce various biological effects, mechanical of thermal. Notably, cavitation, which is the formation and oscillatory motion of bubbles in a media, has effects providing the possibility to enhance the delivery of chemotherapeutic agents. This effect can be induced in biological tissues by using external nucleation agents such as ultrasound contrast agents. However, to avoid diffusion issues, this work focuses on cavitation without external nucleation agents. For this purpose, a particular setup based on two confocal transducers was designed. Simulations showed its advantages for cavitation applications. A developed preclinical device demonstrated the safety of using unseeded inertial cavitation for the potentiation of doxorubicin (DOX) regarding the drug stability, the effect on healthy tissues and the metastatic spreading. Unfortunately, no effect of combining inertial cavitation with DOX in could have been demonstrated in vivo. To investigate stable cavitation phenomenon, a control process was developed. It permitted to evidence in vitro the synergistic interaction between DOX and stable cavitation. Again, preclinical studies were not able to prove this synergy in vivo. To assess the correct tissue exposures to stable cavitation, a localization method was developed and validated

High-intensity focused ultrasound (HIFU) is rapidly emerging as a viable alterna- tive to conventional therapies in the treatment of deep-seated, solid tumours. In contrast to surgical methods, extracorporeal HIFU transducers non-invasively tar- get pathogenic tissue deep beneath the skin, inducing thermal necrosis of a volume of tissue typically coincident with the ultrasound focus. More recently, cavitation activity has been observed to enhance focal heating, whilst providing a unique op- portunity for real-time treatment monitoring. Unfortunately, the stochastic nature of cavitation makes it difficult to initiate and sustain the level of cavitation activity required for enhanced heating, and to confine the spatial extent of cavitation to the focal volume. The overall aim of this thesis is to design and implement a real-time, closed- loop controller for sustaining thermally relevant cavitation within the HIFU focal region. This is intended to improve the speed and reproducibility of tissue ablation, whilst providing clinicians with real-time feedback as to the extent and location of the ablated region. A quantitative relationship between the level of cavitation activity and asso- ciated temperature rise is first sought experimentally, by investigating cavitation- enhanced heating in two different tissue-mimicking materials (TMM) that yield dif- ferent levels of cavitation for the same HIFU exposure conditions. It is found that a minimum level of inertial cavitation activity is required for cavitation-enhanced heating to dominate the heating process, which is achieved in the first material but not the second. However, the introduction of exogenous, artificial nuclei to the second material is seen to augment cavitation levels to the extent that cavitation- enhanced heating becomes dominant. Subsequently, HIFU experimentation is extended to non-perfused, ex vivo bovine liver, into which a variety of cavitation nuclei are introduced to augment cav- itation levels, and hence heating. Commercially available lipid-shelled microbub- bles are contrasted with custom-made sonosensitive nanoparticles for their ability to seed cavitation events, culminating in an empirical relationship between iner- tial cavitation and heating that is common to both types of exogenous nuclei, and which agrees with the in vitro results. Moreover, the abnormally large lesions pro- duced are found to correlate with a broad spatial distribution of inertial cavitation events, as seen on two-dimensional passive acoustic maps. Based on these encouraging results, a novel negative-feedback, real-time con- trol system is implemented to sustain inertial cavitation within the focal region for extended periods of time. The controller is designed to be both asymmetric and adaptive, deploying different feedback gains to adjust the peak rarefactional focal pressure (PRFP), depending on whether cavitation activity is above or below the level required for cavitation-enhanced heating. With active cavitation control in vitro, the associated focal temperature elevation is maintained at a cytotoxic level for 20 seconds using less than half the energy input required in the absence of cavi- tation control. In order to test the applicability of the novel controller to a near-physiological environment, HIFU exposures are eventually performed in a unique normothermic perfused liver model that accounts for both heat advection and nuclei replenish- ment. Following preliminary experimentation, the controller is modified to account for the inherent variability in the cavitation threshold of perfused tissue, whilst the cavitation demand is also increased to account for heat advection. Following these modifications, use of the controller is found to enable greatly improved re- producibility of HIFU-induced lesions compared to those achieved without cavita- tion control, with a lesion size that is directly related to the cavitation demand. A cost-effective method for enabling caviation-enhanced, cavitation-controlled and cavitation-monitored HIFU therapy has thus been developed, which enables suc- cessful tissue ablation at acoustic energies lower than in current clinical use.

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