[pt] A maioria dos métodos de avaliação de ondas vibratórias é realizada através do contato entre o sensor e o objeto a ser analisado. Esse requisito de contato impõe algumas limitações de quais objetos podem ser avaliados, como por exemplo, o tamanho do mesmo. Uma técnica que expandiu a capacidade de medição se comparado aos sensores tradicionais de vibração é a vibrometria laser doppler. Ela possibilita medições não intrusivas com alta resolução espacial e tempo de teste reduzido. Dentre as várias aplicações que se beneficiam das aquisições com o vibrômetro laser doppler, o imageamento fotoacústico se encontra no centro do objetivo deste trabalho. O imageamento fotoacústico é uma tecnologia emergente que supera o alto espalhamento óptico em amostras biológicas utilizando o efeito fotoacústico. Ele combina aspectos de imageamento óptico e ultrassom e, consequentemente, algumas de suas vantagens: imagear certos componentes biológicos em profundidades de alguns centímetros e com alto contraste. A técnica mais direta de obter imagens em um sistema fotoacústico é a excitação pontual da amostra e a detecção por varredura. O foco deste trabalho é analisar e implementar uma técnica óptica para detecção das vibrações ultrassonoras em um sistema fotoacústico. Foram avaliados diferentes sistemas interferométricos experimentais, tanto por mapeamento pontual quanto por campo pleno. O princípio da interferometria e a teoria das medições quantitativas são apresentados para explicar as técnicas experimentais utilizadas para aquisição das ondas vibratórias. Igualmente, a técnica de processamento do sinal vibratório é discutida. Dentre as técnicas testadas experimentalmente, duas foram implementadas, analisadas e discutidas em detalhe e seus resultados foram apresentados e comparados entre si. A primeira técnica discutida é o Laser Optical Feedback Imaging (LOFI), um interferômetro heteródino que utiliza a dinâmica do laser e a sua grande sensibilidade ao fenômeno de reinjeção óptica para realizar medições de alta precisão do sinal retroespalhado da amostra. Essa técnica realiza suas aquisições ponto a ponto, através do do escaneamento do feixe do laser na superfície da amostra. Esse modo de aquisição possui um tempo de teste e processamento elevado, mas com alta resolução espacial e com a possibilidade de medir a região transitória. A segunda técnica utilizada para a aquisição de medidas de vibrações ultrassonoras é o estroboscópio Mach-Zehnder, um interferômetro de campo pleno que possibilita a aquisição do padrão de speckle de toda a região de interesse da amostra com baixo tempo de aquisição e processamento. Dessa forma, essa técnica tem um grande potencial para aplicações em tempo real. Os resultados experimentais de ambos os sistemas são apresentados e discutidos em detalhe. Um transdutor piezoelétrico é utilizado para as medições com os dois sistemas, com as mesmas características de teste. Adicionalmente, são apresentados os resultados com a técnica LOFI quando o ganho não-linear é compensado. Esse tipo de teste não é possível no sistema estroboscópico Mach-Zehnder campo pleno, considerando que apenas o LOFI é capaz de realizar medidas transitórias. Para concluir o trabalho, são discutidos e comparados os principais parâmetros para as técnicas testadas: ruído, potência do laser, resolução espacial, resolução temporal, e tempo de aquisição. / [en] Photoacoustic imaging combines aspects of optical and ultrasound imaging and, consequently, combines some of their particular advantages: imaging of specific tissue components in a depth up to several centimeters becomes possible with a high image contrast. The most straightforward strategy to produce photoacoustic images is point-wise excitation and detection in a scanning mode. The main focus of this work is to analyze and implement optical techniques to detect ultrasound vibrations in a photoacoustic system. We evaluate different interferometric systems, both point scanning and full field. Two techniques that were implemented and further discussed are the Laser Optical Feedback Imaging (LOFI), which is a sensitive, point scanning, heterodyne interferometer that uses the dynamics of the laser, and a full field, stroboscopic Mach-Zehnder to acquire ultrasound vibration measurements.We discuss the results from each system and its advantages with the intended application.

Atherosclerosis accounts of 50% of the deaths in the western world leading to a plethora of diseases that include myocardial infarction, stroke, and peripheral artery disease. Currently available imaging modalities have inherent limitations, including ionizing radiation, lack of compositional information, and difficulty acquiring volumetric data that constrain their use in studying cardiovascular disease. Photoacoustic Tomography (PAT) has emerged as a promising modality that could address these limitations to improve the characterization and diagnosis of atherosclerosis-related conditions. Non-ionizing pulsed laser light is delivered to tissue leading to thermoelastic expansion followed by propagation of a pressure transient that can be detected with an ultrasound transducer. The magnitude of the ultrasonic PAT signal is proportional to the optical absorption at that location, revealing physiologically relevant compositional information of the tissue. The objective of this work is to therefore develop advanced volumetric imaging techniques to characterize disease progression in a murine model of atherosclerosis. The novelty of this work lies in the methodology and validation presented towards characterization of small animal vascular lipid accumulation with a high-resolution PAT system that utilizes the second near-infrared window (1100-1300nm). Additionally, we utilized <i>in situ </i>PAT to cross-sectionally assess lipid deposition and <i>in vivo</i>ultrasound to longitudinally assess hemodynamic, kinematic, and morphological changes during atherosclerosis progression. Together, this dissertation lays the foundation towards utilizing dual-modality PAT and ultrasound for various applications including understanding atherosclerosis pathophysiology, evaluation of novel therapeutics, and translation of clinically relevant techniques.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第19232号 / 人健博第29号 / 新制||人健||3(附属図書館) / 32231 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 杉本 直三, 教授 精山 明敏, 教授 戸井 雅和 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Nano and nanostructured materials offer unique physical and chemical properties that differ considerably from their bulk counterparts. For decades, due to their fascinating properties, they have been extensively explored and found to be beneficial in numerous applications. These materials are key components in many cutting-edge optic and photonic technologies, including photovoltaics, waveguides and sensors. In this dissertation, the uses of nano and nanostructured materials for optical applications are investigated in the context of optical limiting, three dimensional displays, and optical sensing. Nanomaterials with nonlinear optical responses are promising candidates for self-activating optical limiters. In the first part of this study, optical limiting properties of unexplored nanomaterials are investigated. A photoacoustic detection technique is developed as an alternative characterization method for studying optical nonlinearities. This was done with an indigenously developed setup for measuring the photoacoustic signals generated from samples excited with a pulse laser. A theoretical model for understanding the experimental observations is presented. In addition, the advantages of this newly developed technique over the existing methods are demonstrated. Blending optical sensitizers with photoconducting polymers and chromophores results in a polymer composite that is able to record a light grating. This composite can be used as recording media in 3D holographic display technology. Here, 2D nano materials, like graphenes, are used as optical sensitizers to improve the response time of a photorefractive polymer. The addition of graphenes to a PATPD/ECZ/7-DCST composite results in a three-fold enhancement in response time and therefore faster recording speed of the medium. The faster build-up time is attributed to better charge generation and mobility due to the presence of graphenes in the composite. Lastly, a facile nanofabrication technique is developed to produce metallic nanostructures with a tunable plasmonic response. The enhancement of the light-matter interactions due to these nanostructures in sensing an analyte is demonstrated.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult type of cancer to treat, due to late diagnosis which is a result of vague symptoms and lack of biomarkers, as well as refractory behavior toward current treatment protocols. Imaging of the disease progression therefore plays a crucial role in identifying potentially curable PDAC patients at an early stage. Nanoparticle-based contrast agents have shown multimodal capabilities and potential to enhance the contrast of previously undetectable pathological changes, including PDAC. In this master’s thesis study, an iron oxide nanoparticle (IONP) was evaluated as a potential multimodal contrast agent for both photoacoustic imaging (PAI) and magnetic resonance imaging (MRI). The investigated particle was composed of Fe3O4 with a hydrodynamic size of 418.5 nm and a zeta potential of -27.7 mV. In the agarose suspended IONP phantom studies, the IONP demonstrated a two-fold higher T2 contrast compared to commercial IONP VivoTrax (Magnetic Insight), as well as generating strong and stable photoacoustic signal throughout the first near-infrared window (700 to 1000 nm). Based on this thesis’ proof of concept study, Fe3O4 IONP showed good potential as multimodal contrast agent for MRI and PAI. Future work consists of modification of the particle composition and in vivo imaging on animals to evaluate the application in PDAC diagnostics.

To address the paucity of available molecularly targeted photoacoustic imaging probes (PIPs) and to generate meaningful data to support the ongoing effort to refine diagnostic photoacoustic imaging (PAI) applications, the work presented here focuses on the design, synthesis, and evaluation of novel PIPs. To this end, various light-absorbing small molecule dyes, targeting strategies, and disease-targeting molecules were evaluated. First, a near-infrared photoacoustic probe was used to image bone in vivo through active and bioorthogonal pre-targeting strategies by utilizing a coupling between a tetrazine-derived cyanine dye and a trans-cyclooctene-modified bisphosphonate. In vitro hydroxyapatite binding and in vivo bone imaging studies showed significant localization of the agent to the target using both active and pre-targeting strategies. The tetrazine-dye building block was then used to create a first-generation bacteria-targeting PIP, using a trans-cyclooctene-modified Zinc (II)-dipicolylamine (ZnDPA). The PIP demonstrated poor aqueous solubility and overlapping photoacoustic (PA) signal with deoxyhemoglobin. Therefore, a commercially available ZnDPA-derived fluorophore, PSVue794, was then repurposed for use as a PIP. PSVue794 demonstrated the ability to differentiate between bacterial infection, sterile inflammation, and healthy tissue in a mouse model, via PA imaging, which prompted its use in a series of proof-of-concept studies towards the generation of a model of implant infection. The feasibility of detecting the PIP in the presence of a PA signal-emitting metallic implant, which was deemed a significant hurdle due to the intensity of the PA signal of the metal, was verified. Although the work requires some follow-up evaluations to demonstrate the practical use of the model, ZnDPA-based PIPs have remained promising candidates for PAI of bacterial infection. Finally, a novel general-purpose dye was designed to possess properties ideal for in vivo PAI. To evaluate the modifications made, the general-purpose dye was conjugated with ZnDPA, and was tested alongside the non-targeted counterpart and PSVue794. Through the studies conducted, it was evident that the rationale that contributed to the design of the general-purpose dye did lead to highly soluble PIP with promising PA properties, however, the PIP did not demonstrate target-specificity, in vivo. Therefore, investigations using the non-targeted PIP with higher affinity targeting vectors for PA-compatible diseases, such as surgical-site/implant infections and prostate cancer, is warranted. / Thesis / Doctor of Philosophy (PhD) / The work conducted within this thesis aims to outline the process of developing photoacoustic diagnostic agents for the detection of various diseases, including bone disease and bacterial infection. To this end, various small molecule, near-infrared absorbing dyes, disease-targeting molecules, and assembly methods were selected to generate several diagnostic agents. To demonstrate their utility, the diagnostic agents were each evaluated in a series of studies designed to assess their ability to generate detectable photoacoustic signal, interact specifically with disease-markers, and localize the sites of disease in living systems. Significant attention was placed on comprehensively evaluating the diagnostic agents through the development of methodology and generating a standard procedure for photoacoustic data production and reporting, which was practiced throughout the work.

Biomedical optical imaging is capable of providing functional information of the soft bi-ological tissues, whose applications include imaging large tissues, such breastand brain in-vivo. Biomedical optical imaging uses near infrared light (600nm-900nm) as the probing media, givin ganaddedadvantageofbeingnon-ionizingimagingmodality. The tomographic technologies for imaging large tissues encompasses diffuse optical tomogra-phyandphotoacoustictomography. Traditional image reconstruction methods indiffuse optical tomographyemploysa �2-norm based regularization, which is known to remove high frequency no is either econstructed images and make the mappearsmooth. Hence as parsity based image reconstruction has been deployed for diffuse optical tomography, these sparserecov-ery methods utilize the �p-norm based regularization in the estimation problem with 0≤ p<1. These sparse recovery methods, along with an approximation to utilizethe �0-norm, have been used forther econstruction of diffus eopticaltomographic images.The comparison of these methods was performed by increasing the sparsityinthesolu-tion. Further a model resolution matrix based framework was proposed and shown to in-duceblurinthe�2-norm based regularization framework for diffuse optical tomography. This model-resolution matrix framework was utilized in the optical imaged econvolution framework. A basis pursuitdeconvolution based on Split AugmentedLagrangianShrink-ageAlgorithm(SALSA)algorithm was used along with the Tikhonovregularization step making the image reconstruction into a two-step procedure. This new two-step approach was found to be robust with no iseandwasabletobetterdelineatethestructureswhichwasevaluatedusingnumericalandgelatinphantom experiments. Modern diffuse optical imaging systems are multi-modalin nature, where diffuse optical imaging is combined with traditional imaging modalitiessuc has Magnetic Res-onanceImaging(MRI),or Computed Tomography(CT). Image-guided diffuse optical tomography has the advantage of reducingthetota lnumber of optical parameters beingreconstructedtothenumber of distinct tissue types identified by the traditional imaging modality, converting the optical image-reconstruction problem fromunder-determined innaturetoover-determined. In such cases, the minimum required measurements might be farless compared to those of the traditional diffuse optical imaging. An approach to choose these measurements optimally based on a data-resolution matrix is proposed, and it is shown that it drastically reduces the minimum required measurements (typicalcaseof240to6) without compromising the image reconstruction performance. In the last part of the work , a model-based image reconstruction approaches in pho-toacoustic tomography (which combines light and ultra sound) arestudied as it is know that these methods have a distinct advantage compared to traditionalanalytical methods in limited datacase. These model-based methods deployTikhonovbasedregularizationschemetoreconstruct the initial pressure from the boundary acoustic data. Again a model-resolution for these cases tend to represent the blurinduced by the regularization scheme. A method that utilizes this blurringmodelandper forms the basis pursuit econ-volution to improve the quantitative accuracy of the reconstructed photoacoustic image is proposed and shown to be superior compared to other traditional methods. Moreover, this deconvolution including the building of model-resolution matrixis achievedvia the Lanczosbidiagonalization (least-squares QR) making this approach computationally ef-ficient and deployable inreal-time. Keywords Medical imaging, biomedical optical imaging, diffuse optical tomography, photoacous-tictomography, multi-modalimaging, inverse problems,sparse recovery,computational methods inbiomedical optical imaging.

Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (Dil). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 mu g/ml, and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE)

Les nanomatériaux suscitent depuis quelques décennies de plus en plus d’intérêt tant sur le plan des études fondamentales que sur celui des applications. Parmi ces nouveaux matériaux, les nanotubes de carbone ont attiré beaucoup d’attention au sein de la communauté scientifique à cause de leurs propriétés physiques remarquables. Les travaux présentés dans cette thèse, concernent l’élaboration et la caractérisation de composites solides à base de nanotubes de carbone. Le choix des matériaux s’est porté sur une matrice solide à base de Bromure de Potassium (KBr) et des nanotubes de carbone mono et multifeuillets (SWNT, MWNT). L’étude de ces composites concerne deux aspects : dans un premier temps, l’effet de la charge et de la nature des nanotubes de carbone sur les propriétés électriques et thermiques ont été étudiés. L’étude des propriétés thermiques a été réalisée à l’aide d’une technique photothermique, la photoacoustique, qui présente un grand avantage pour ce type de composites. L’évolution des propriétés thermiques en fonction de la charge a montré un comportement atypique, une augmentation puis une diminution, avec un maximum autour de 2% de charge en nanotubes. Un modèle physique permettant de décrire cette évolution a été proposé. Concernant les propriétés électriques, cette étude a permis de mettre en évidence le phénomène de percolation et d’en déterminer le seuil. Dans un deuxième temps, l’étude a porté sur l’influence du gaz environnant sur les propriétés thermiques et électriques, et sur l’éventuelle utilisation de ces composites comme capteurs de gaz. La caractérisation thermique en présence d’éthanol n’a pas permis de mettre en évidence un changement notable des propriétés thermiques des composites. En revanche, la caractérisation électrique a montré une bonne réponse à ce gaz. L’évolution de la sensibilité en fonction de la charge en nanotubes dans les composites a montré une augmentation pour des charges inférieures à 4% et une stabilisation au-delà. L’influence d’autre gaz comme le dioxyde d’azote et le toluène a été aussi étudié. La réponse électrique au dioxyde d’azote a montré une forte interaction du gaz avec les composites. La réponse au toluène n’a pas montré d’influence de ce gaz sur les propriétés électriques des composites à base de SWNT, cependant, dans le cas des composites à base de MWNT, une réponse électrique comparable à celle de l’éthanol a été observée. / In the recent decades, nanomaterials arouse a growing interest both in their fundamental studies and in their applications. Among these new materials, carbon nanotubes have attracted much attention within the scientific community because of their remarkable physical properties.The work presented in this thesis, involve the preparation and characterization of solid composites based on carbon nanotubes. A solid matrix containing potassium bromide (KBr) and carbon nanotubes, single and multiwalled (SWNT, MWNT) was chosen. The study of these composites involves two aspects: initially, the effect of the loading fraction and the nature of carbon nanotubes on the electrical and thermal properties were investigated. The study of thermal properties was carried out by a photothermal technique, the photoacoustic, which offers great advantages for this type of composites. The evolution of thermal properties according to the loading fraction of nanotubes showed an atypical behavior, an increase followed by a decrease, with a maximum around 2% of nanotubes loading fraction. A physical model describing this evolution has been proposed. Regarding the electrical properties, this study has highlighted the phenomenon of percolation and allowed the determination of the percolation threshold. In a second step, the study focused on the influence of surrounding gas on the thermal and electrical properties, and the possible use of these composites as gas sensors. The thermal characterization with ethanol did not reveal a significant change in thermal properties of composites. However, the electrical characterization showed a good response to this gas. The evolution of the sensitivity depending on the nanotubes loading fraction in the composites showed an increase for loads below 4% and a stabilization beyond this value. The influence of other gases such as nitrogen dioxide and toluene were also studied. The electrical response to nitrogen dioxide showed a strong interaction of the gas with composites. The response to toluene did not show any influence of this gas on the electrical properties of SWNT-based composites, however, in the case of MWNT-based composite, an electrical response similar to that of ethanol was observed.

Apresentaremos nesta tese três novos tipos de dosímetros de radiação, projetados para medir radiação X, na faixa de diagnóstico: o dosímetro de radiação fotoacústico pulsado, o dosímetro de radiação piroelétrico e o dosímetro de radiação piroelétrico pulsado. Estudamos também o dosimetro de radiação fotoacústico com o objetivo de compará-lo com os novos dosímetros desenvolvidos. Propomos uma metodologia para calibração de um dosímetro fotoacústico que prescinde da calibração de sua resposta em um campo conhecido de radiação ionizante. Apresentaremos um modelo teórico para explicar os resultados obtidos com o dosímetro de radiação piroelétrico pulsado. Os resultados encontrados mostram que os dosímetros desenvolvidos são do tipo calorimétrico, sendo a resposta deles linear com a taxa de fluência de energia da radiação X. / In this thesis we present three new types of radiation dosimeters, designed to measure X-rays in its diagnostic region: the pulsed photo acoustical radiation dosimeter, the pyroeletric radiation dosimeter and the pulsed pyroelectric radiation dosimeter. We also study the photo acoustical radiation dosimeter with the scope of to compare its characteristics with the characteristics of the new developed dosimeters. We propose a methodology for calibration of a photo acoustical dosimeter which doesn´t require the calibration of its response in a known field of ionizing radiation. We present a theoretical model to explain the results produced by the pulsed pyroelectric radiation dosimeter. The obtained results show that the developed dosimeters are of calorimetric type, being linear its response with the X-ray energy fluency rate.