京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21643号 / 医博第4449号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 坂井 義治, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The search for a convenient connection between vibration patterns on a structure and the sound radiated from that structure is ongoing in structural acoustics literature. Common techniques are wavenumber domain methods, or representation of the vibration in terms of some basis, such as structural modes or elementary radiators, and calculating the sound radiation in terms of the basis. Most choices for a basis in this situation exhibit strong coupling between the basis functions, but there is one choice which does not: Acoustic radiation modes are by definition the basis that orthogonalizes the radiation operator, meaning the radiation modes do not exhibit any coupling in radiation of sound.Acoustic radiation modes are coming up on their 30th anniversary in the literature, but still have not found wide use. This is largely due to the fact that most radiation modes must be calculated through the computationally intensive boundary element method or boundary integral equations. Analytical expressions for radiation modes, or for the radiation resistance matrix from which they are derived, are only available for a few geometries. This thesis meets this problem head on, to develop additional analytical expressions for radiation resistance matrices of cylindrically curved structures.Radiation modes are developed in the context of their use to calculate sound power. Experimental and computational sound power calculations are presented in order to validate the use of the modes developed here. In addition, the properties and trends of the developed modes are explored.

Tendon injuries are prevalent, debilitating and difficult to treat. Common interventions such as anti-inflammatory medication, growth factor injections and surgery are associated with short-term efficacy and long rehabilitation periods. Tendons possess an incomplete healing response which is reparative (scar-mediated) rather than regenerative, resulting in a 'healed' tissue that is mechanically inferior to the native tendon. While it is widely accepted that mechanical-loading based treatments offer long-term symptomatic resolution and improved functionality, the exact mechanisms of action of such mechanotransduction-based healing cascades remain unclear. Nevertheless, there is significant motivation for the development of non-invasive and efficient rehabilitative treatments that mechanically stimulate the injured tendons to achieve functional healing responses. Focused Ultrasound (FUS) methods are an attractive treatment option as they are non-invasive, utilize higher intensities for shorter durations and are targeted to a very specific treatment volume, hence inducing significant bio-effects in the tissue without affecting surrounding structures. Herein, we present a body of work that includes the development of FUS pulsing to precisely target murine Achilles tendons and emphasize distinct bioeffects (thermal-dominant and mechanical-dominant). We investigated the feasibility of applying FUS pulsing to murine Achilles tendons ex vivo and in vivo and demonstrated that FUS can be safely applied without any deleterious effects in the tendons and surrounding tissues. The animals showed no symptoms of distress after multi-session treatments. Overall, results suggest that tendon material properties are not adversely altered by FUS pulsing. Histological analyses showed mild matrix disorganization, suggesting the need for slight modifications in the ultrasound pulsing parameters and treatment durations. When applied to injured tendons, mechanical dominant schemes seemed to drive larger improvements in material properties compared to thermal-dominant pulsing, confirming our original hypothesis that mechanical stimulation may play a bigger role in tendon healing compared to purely thermal-dominant stimulation. Additionally, feasibility of histotripsy ablation in murine Achilles tendons was successfully investigated ex vivo and in vivo and experimentation to further optimize these methods are ongoing. Such (non-thermal) ablative paradigms will be extremely useful when conservative treatment options are unavailable and debridement of scar tissue is warranted to interrupt the degenerative process and stimulate healing. Finally, a pilot investigation into FUS-induced strains was performed to guide our parameter selection process and deliver controlled strains to achieve healing responses (similar to current clinical rehabilitation protocols). We were able confirm that strains between 1% and 6% (or higher) can be induced by manipulating ultrasound treatment parameters. Overall, or results reiterate the potential of FUS in eliciting the desired bioeffects and thus achieve healing in tendons and provide a snapshot of the expected effects of using such pulsing methods to treat tendon injuries. / Doctor of Philosophy / Tendons are tissues that connect muscles to bones, and are unfortunately prone to injuries. Such injuries are prevalent and difficult to treat. Effective treatment options remain limited, as common methods such as surgery, anti-inflammatory medications and corticosteroid injections do not provide long-term relief. One of the few treatments that has been proven to provide symptomatic relief and improved the functionality of chronically (over a long period of time) injured tendons is physical therapy. However, researchers are still investigating the reasons for this successful healing response. Some limitations of physical therapy are long rehabilitation and recovery periods, and the need for patient compliance (i.e., performing painful exercises while already being under significant pain). In this research, we explore the use of a non-invasive modality known as ultrasound to treat tendon injuries. Ultrasound is commonly thought of as a diagnostic tool, i.e., to detect injuries in musculoskeletal medicine. It, however, is also an attractive therapeutic (treatment) modality, as sound waves can be concentrated in the required area of interest which results in different types of effects in the chosen tissue, such as heating. A huge advantage is that ultrasound is non-invasive, painless, and safe, as the energy is only applied to the chosen volume of interest and surrounding structures are unaffected. To examine the utility of therapeutic ultrasound in treating tendon injuries, we used a mouse model that has been previously used in our lab, and designed different types of ultrasound treatments that elicit two main types of effects in the tissue, namely, thermal, or heating effects and mechanical, or physical therapy-like effects. Prior to applying these treatments, we measured how much heating is produced in mouse Achilles tendons via these treatments, to establish safety. Once we identified safe thermal and mechanical treatment sets, we treated mouse Achilles tendons ex vivo, i.e., after euthanasia. We tested the mechanical properties of the treated tendons and determined that treatments do not alter the mechanical properties of tendons, which is encouraging, given that we do not want treatments to interfere with the properties of native tendons. We also examined the influence of treatments on structure of Achilles tendons after treatments and deducted that the structure was not damaged due to treatments. We followed up these studies with treatments conducted in live mice, which received four treatment sessions in one week. These studies were conducted to further determine the safety and tolerance to these procedures and also examine the healing effects of treatments in injured Achilles tendons. Results suggest that focused ultrasound treatments are safe and tolerable to mice and seem to elicit improvements in tendon properties. In other studies, we also examined a different ultrasound method named histotripsy, as a non-invasive alternative to dry needling (which is another methodology used to treat tendon injuries) and scar debridement (removal of scar tissue to stimulate a new healing response). This research establishes that therapeutic ultrasound is a novel, non-invasive alternative with good potential to treat tendon injuries. Future studies will investigate the effects of ultrasound treatments over longer durations and also aim to clarify the exact type and magnitude of physical therapy-like forces that are produced by ultrasound treatments. This understanding will enhance our treatment design process to be able to mimic clinical treatments that are known to be effective.

Studying the effects of free stream turbulence on noise, vibration, and heat transfer on structures is very important in engineering applications. The problem of the interaction of large scale turbulence with a flat-plate cascade is a model of important problems in propulsion systems. Addressing the problem of large scale turbulence interacting with a flat plate cascade requires flow simulation over a large number of plates (6-12 plates) in order to be able to represent numerically integral length scales on the order of blade-to-blade spacing. Having such a large number of solid surfaces in the simulation requires very large computational grid points to resolve the boundary layers on the plates, and that is not possible with the current computing resources. In this thesis we develop a computational technique to predict the distortion of homogeneous isotropic turbulence as it passes through a cascade of thin flat plates. We use Large-Eddy Simulation (LES) to capture the spatial development of the incident turbulence and its interaction with the plates which are assumed to be inviscid walls. The LES is conducted for a linear cascade composed of six plates. Because suppression of the normal component of velocity is the main mechanism of distortion, we neglect the presence of mean shear in the boundary layers and wakes, and allow slip velocity on the plate surfaces. We enforce the zero normal velocity condition on the plates. This boundary condition treatment is motivated by rapid distortion theory (RDT) in which viscous effects are neglected, however, the present LES approach accounts for nonlinear and turbulence diffusion effects by a sub-grid scale model. We refer to this type of turbulence-blade interaction as shear-free interaction. To validate our calculations, we computed the unsteady loading and radiated acoustic pressure field from flat plates interacting with vortical structures. We consider two fundamental problems: (1) A linear cascade of flat plates excited by a vortical wave (gust) given by a 2D Fourier mode, and (2) The parallel interaction of a finite-core vortex with a single plate. We solve the nonlinear Euler equations by a high-order finite-differece method. We use nonreflecting boundary conditions at the inflow and outflow boundaries. For the gust problem, we found that the cascade response depends sensitively on the frequency of the convicted gust. The unsteady surface pressure distribution and radiated pressure field agree very well with predictions of the linear theory for the tested range of reduced frequency. We have also investigated the effects of the incident gust frequency on the undesirable wave reflection at the inflow and outflow boundaries. For the vortex-plate interaction problem, we investigate the effects of the internal structure of the vortex on the strength and directivity of radiated sound. Then we solved the turbulence cascade interaction problem. The normal Reynolds stresses and velocity spectra are analyzed ahead, within, and downstream of the cascade. Good agreement with predictions of rapid distortion theory in the region of its validity is obtained. Also, the normal Reynolds stress profiles are found to be in qualitative agreement with available experimental data. As such, this dissertation presents a viable computational alternative to rapid distortion theory (RDT) for the prediction of noise radiation due to the interaction of free stream turbulence with structures. / Ph. D.

Sound pressure radiating from vibrating structures submerged in fluid, as in the case of a vibrating panel in a submarine hull, is usually undesirable. An optimal control methodology for the suppression of far-field acoustic radiation pressure from submerged structures has been developed by Meirovitch (ref. 1). The linear modal state feedback control law developed implies that the full state (displacements and velocities) is available, perhaps through measurements. However, in practice, it is not always feasible to measure the full modal state vector for feedback. To permit practical implementation of the feedback control law, an optimal stochastic state estimator, or Kalman-Bucy filter, has been developed here for incorporation into the control system design. The development has been specialized to a uniform simply supported rectangular plate. / Master of Science

Die vorliegende medizinische Dissertation untersucht nicht-invasive bildgebende Verfahren wie die konventionelle Sonographie, die Acoustic radiation force impulse (ARFI)-Elastographie sowie die Transiente Elastographie (TE) zur Detektion von Komplikationen in der Frühphase nach allogener Stammzelltransplantation. Dem kurativen Therapieansatz der Stammzelltransplantation steht ein hohes Komplikationspotential gegenüber. Besonders hepatobiliär treten Graft-versus-host Erkrankungen (GvHD) sowie Gefäßkomplikationen (VOD) auf. Der bisherige diagnostische Goldstandard, die Leberbiopsie, ist als invasives Verfahren mit einer hohen Intra- und Inter-Untersucher-Variabilität sowie der geringen Repräsentativität als Screeningmethode ungeeignet. Die Elastographieverfahren ARFI und TE als nicht-invasive Alternativen ermitteln die Lebergewebesteifigkeit als Surrogatparameter fibrotischer Veränderungen und wurden bereits in zahlreichen Studien als geeignete Diagnoseverfahren für Leberfibrose und -zirrhose unterschiedlicher Ätiologie definiert. Ziel dieser prospektiven Pilotstudie war die Evaluation der genannten Methoden zur Detektion von Frühkomplikationen nach allogener Stammzelltransplantation. Die Ergebnisse der Studie zeigen, dass sowohl die konventionelle Sonographie als auch die Transiente Elastographie pathologische Organveränderungen vor allem des hepatobiliären Systems detektieren können. Allerdings erscheinen diese Veränderungen unspezifisch. Es bestehen keine signifikanten Unterschiede zwischen Patienten mit und ohne Komplikationen. Anders bei der ARFI-Elastographie. Hier zeigten die Messwerte im linken Leberlappen signifikant höhere Werte bei Patienten mit Komplikationen. Zusammenfassend ist die ARFI-Elastographie zur Prädiktion möglicher Komplikationen nach allogener Stammzelltransplantation geeignet, sollte allerdings mit anderen diagnostischen Verfahren ergänzt werden.:III. Inhaltsverzeichnis I. Vorbemerkungen 2 II. Bibliographische Beschreibung 3 III. Inhaltsverzeichnis 4 IV. Abkürzungsverzeichnis 5 1. Einleitung 1.1. Hämatopoetische Stammzelltransplantation 6 2. Komplikationen nach allogener Stammzelltransplantation und deren Diagnostik 2.1. Akute Komplikationen 8 2.2. Akute und chronische Graft-versus-host Erkrankung 9 2.3. Hepatobiliäre Komplikationen 12 2.3.1. Veno-occlusive disease 12 2.3.2. Drug-induced liver injury 14 2.3.3. Problematik der Diagnostik 16 3. Risikostratifizierung bei Stammzelltransplantation 16 3.1. Karnovsky Index und Eastern Cooperative Oncology Group Index 16 3.2. Hematopoietic cell transplantation comorbidity index 17 3.3. Leberspezifisches Risikoassessment 18 4. Nicht-invasive Leberdiagnostik 19 4.1. Konventionelle Sonographie 19 4.2. Elastographie 20 4.2.1. Transiente Elastographie 21 4.2.2. Acoustic radiation force impulse imaging 22 5. Prospektive Studie: Sonographische Evaluation von Komplikationen in der Frühphase nach allogener Stammzelltransplantation 23 5.1. Methodik 24 5.2. Eigener Arbeitsanteil 24 6. Publikationsmanuskript 25 7. Zusammenfassung 32 8. Literaturverzeichnis 36 9. Selbständigkeitserklärung 44 10. Lebenslauf 45 11. Danksagung 46

Abstract not available. / by Wong Lai-hung, Grace. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 218-252). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

<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

The concept of tailored force fields is seen as an enabler for the construction of large scale space structures. Manufacturing would take place in space using in-situ resources thereby eliminating the size and weight restriction commonly placed on space vehicles and structures. This thesis serves as the first investigation of opening the way to a generalized fabrication technology by means of force fields. Such a technology would be non-contact, flexible, and automated. The idea is based on the principle that waves carry momentum and energy with no mass transport. Scattering and gradient forces are generated from various types of wave motion. Starting from experiments on shaping walls using acoustic force fields, this thesis extends the technology to electromagnetic fields. The interaction physics of electromagnetic waves with dielectric material is studied. Electromagnetic forces on neutral dielectric material are shown to be analogous to acoustic forces on sound-scattering material. By analogy to the acoustic experiments, force fields obtained by optical tweezers are extended to longer wavelength electromagnetic waves while remaining in the Rayleigh scattering regime. Curing of the surface formed takes place by use of a higher frequency beam that scans the surface and melts a subsurface layer enabling a sintering effect to take place between the particles. The resulting capability is explored at its extremes in the context of building massive structures in Space. A unification of these areas is sought through a generalization of the various theories provided in the literature applicable for each field.