Final publication is available at http://www.sciencedirect.com/science/article/pii/S0002939414000488 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19586号 / 医博第4093号 / 新制||医||1014(附属図書館) / 32622 / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 宮本 享, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20271号 / 医博第4230号 / 新制||医||1021(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 木村 剛, 教授 富樫 かおり, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Laser-based photo-thermal therapies can provide minimally-invasive treatment of cancers. Their effectiveness is limited by light penetration depth in tissue due to its highly scattering properties. The highly disordered refractive index distribution in tissue leads to multiple-scattering of incident light. It has been hypothesized that mechanical compression has a great potential to enhance the capabilities of laser therapy by inducing localized water transport, decreasing the refractive index mismatch, and decreasing the scattering coefficient of tissue. To better understand this process, we investigated the refractive index change of ex-vivo dog skin during mechanical compression using a swept-source optical coherence tomography (OCT) device built in our lab. The Lorentz-Lorenz rule of mixtures was applied to evaluate the water and protein weight fraction of tissue simultaneously. Results show that the refractive index of skin increased from 1.38 to 1.52 during compression and water content decreased about 60%-70% when the skin sample was compressed by 70%. In addition, we conducted compression experiments on human finger, palm, back of hand, and front of forearm in vivo. OCT images of these skin sites before and after compression by 1 minute were compared. Optical thickness of epidermis and light penetration depth in the dermis were measured. The extended Huygens-Fresnel model was applied to measure the scattering coefficient μs of skin specimens. μs of skin was measured to be about 10-17 mm-1 before compression and decreased 60%-80% after compression, which increases the averaged light intensity by 2-7 dB and almost doubles light penetration depth in dermis. It is quite significant in laser therapies especially for treating epithelia cancers which originate at 1-2 mm beneath the tissue surface. In the OCT imaging of skin dehydration experiment, we conclude that dehydration is an important mechanism of mechanical clearing. / Master of Science

[pt] Foram desenvolvidas fontes ópticas para obtenção de imagens por tomografia de coerência óptica com alta resolução. Dois tipos de abordagens foram realizados, uma com um laser contínuo sintonizável, que neste trabalho foi instrumentado com marcadores de frequência óptica, outra com uma fonte óptica pulsada de banda larga. Mediante um processo de calibricação desenvolvido neste trabalho, a fonte contínua forneceu resoluções de 8 μm e alcances até 0,5 mm, enquanto que a fonte pulsada forneceu resoluções de 3 μm e alcances de 300 μm. A fonte pulsada permitiu ainda a obtenção de imagens em tempo real com capacidade de captura de movimento do objeto. / [en] Optical sources to obtain images through high resolution optical coherence tomography were developed. Two approaches were taken, one with a continuously tunable external cavity laser which, in this work, was modified to produce optical frequency markers, the other with an ultra-wideband pulsed source. Using a calibration process we developed in this work the continuously tunable source continued to achieve resolutions 8 μm and ranges of 0.5 mm, while the pulsed source achieved resolutions of 3.3 μm and ranges of 300 μm. The pulsed source has the capacity to capture real time images.

Glaucoma is the second leading cause of blindness in the world. The disease is characterized by irreversible damage to retinal ganglion cells. Once glaucoma is detected, further vision loss can be prevented by pharmacological or surgical treatment. However, current diagnostic methods lack the necessary sensitivity and up to 40% of vision maybe irreversibly lost before detection occurs. A Swept Source Polarization-Sensitive Optical Coherence Tomography (SS-PSOCT) instrument for high sensitivity cross-sectional imaging of optical anisotropy in turbid media has been designed, constructed, and verified. A multiple-state nonlinear fitting algorithm was used to measure birefringence of the retinal nerve fiber layer with less than 1%± average uncertainty. To perform eye imaging efficiently a slit-lamp based interface for the SS-PSOCT instrument with a Line Scanning Laser Ophthalmoscope (LSLO) was used. This interface allowed for repeatable, stable, and registered measurements of the retina. A fixation target was used to stabilize the volunteer’s eye and image desired areas of the retina. The LSLO allowed for an optimization of the location of OCT scans on the retina and provided a fundus blood vessel signature for registration between different imaging sessions. The SS-PSOCT system was used to measure depth-resolved thickness, birefringence, phase retardation and optic axis orientation of the retinal nerve fiber layer in normal volunteers. The peripapillary area around the optic nerve head (ONH) is most sensitive to glaucoma changes and hence data was acquired as concentric ring scans about the ONH with increasing diameters from 2mm to 5mm. Imaging of normal patients showed that higher values of phase retardation occurred superior and inferior to the optic nerve head especially next to blood vessels and thicker parts of the retinal nerve fiber layer. / text

<p>Optical coherence tomography (OCT) is a non-invasive optical imaging modality that provides micron-scale resolution of tissue micro-structure over depth ranges of several millimeters. This imaging technique has had a profound effect on the field of ophthalmology, wherein it has become the standard of care for the diagnosis of many retinal pathologies. Applications of OCT in the anterior eye, as well as for imaging of coronary arteries and the gastro-intestinal tract, have also shown promise, but have not yet achieved widespread clinical use.</p><p>The usable imaging depth of OCT systems is most often limited by one of three factors: optical attenuation, inherent imaging range, or depth-of-focus. The first of these, optical attenuation, stems from the limitation that OCT only detects singly-scattered light. Thus, beyond a certain penetration depth into turbid media, essentially all of the incident light will have been multiply scattered, and can no longer be used for OCT imaging. For many applications (especially retinal imaging), optical attenuation is the most restrictive of the three imaging depth limitations. However, for some applications, especially anterior segment, cardiovascular (catheter-based) and GI (endoscopic) imaging, the usable imaging depth is often not limited by optical attenuation, but rather by the inherent imaging depth of the OCT systems. This inherent imaging depth, which is specific to only Fourier Domain OCT, arises due to two factors: sensitivity fall-off and the complex conjugate ambiguity. Finally, due to the trade-off between lateral resolution and axial depth-of-focus inherent in diffractive optical systems, additional depth limitations sometimes arises in either high lateral resolution or extended depth OCT imaging systems. The depth-of-focus limitation is most apparent in applications such as adaptive optics (AO-) OCT imaging of the retina, and extended depth imaging of the ocular anterior segment.</p><p>In this dissertation, techniques for extending the imaging range of OCT systems are developed. These techniques include the use of a high spectral purity swept source laser in a full-field OCT system, as well as the use of a peculiar phenomenon known as coherence revival to resolve the complex conjugate ambiguity in swept source OCT. In addition, a technique for extending the depth of focus of OCT systems by using a polarization-encoded, dual-focus sample arm is demonstrated. Along the way, other related advances are also presented, including the development of techniques to reduce crosstalk and speckle artifacts in full-field OCT, and the use of fast optical switches to increase the imaging speed of certain low-duty cycle swept source OCT systems. Finally, the clinical utility of these techniques is demonstrated by combining them to demonstrate high-speed, high resolution, extended-depth imaging of both the anterior and posterior eye simultaneously and in vivo.</p> / Dissertation

Cette thèse décrit le design, la simulation et la fabrication d’une matrice 4x4 de micro-miroirs actionnée verticalement et munie d’un capteur de position. Le micro-scanneur vertical a pour vocation à être intégré au sein d’un micro-interféromètre de Mirau de type matriciel, réalisé àbase de composants micro-optiques fabriqués grâce à des méthodes collectives. Le mouvement du micro-scanneur, développé dans cette thèse, génère un signal de référence utilisé pour l’implémentation de l’interférométrie à modulation de phase dans un système de tomographie par cohérence optique (OCT). Dans un premier temps, la thèse introduit le besoin d’un système d’imagerie adapté pour la détection précoce des cancers de la peau et établit les spécifications optiques requises par cette application. A partir de ces spécifications, le design du système OCT basé sur le micro-interféromètre de Mirau est présenté. En parallèle, l’état de l’art des technologies de micro-actionnement est décrit et un actionnement électrostatique à base de peignes interdigités est choisi pour actionner et lire la position de la matrice de micro-miroirs. En effet ce type d’actionnement bénéficie d’une bonne compatibilité avec le design du micro-interféromètre de Mirau. Dans un second temps, le cœur de la thèse expose le développement du micro-scanneur vertical, c.à.d le design et les simulations ainsi que la fabrication et la caractérisation. / This thesis describes the design, simulation and fabrication of a vertically actuated 4x4 array ofmicromirrors with embedded position sensing function. The vertical microscanner is meant to beintegrated within an array-type Mirau microinterferometer realized with optical microcomponentsfabricated using collective techniques. The microscanner, developed in this thesis, provides areference signal that is used for the implementation of phase modulation interferometery in an opticalcoherence tomography (OCT) system. This thesis first introduces the need for adapted imagingsystems for the early diagnosis of skin cancer and establishes the optical specifications requiredby this specific application. Based on these specifications, the design of the OCT system based onthe Mirau microinterferometer is presented. In parallel, the state of the art of the microactuationtechnologies is discussed and comb drive electrostatic actuation is chosen, for its compatibilitywith the design of the Mirau microinterferometer, to actuate and sense the position of the array ofmicromirrors. Then, the core of the thesis deals with the development of the vertical microscanner,i.e. its design and simulations, its fabrication and its characterization.

Les sources laser accordables se distinguent par leur capacité à changer leur longueur d’onde d’émission de façon continue dans le temps. Elles sont utilisées dans de nombreuses applications comme les télécommunications, la spectroscopie et la tomographie optique cohérente. Elles sont caractérisées principalement par une faible largeur de raie instantanée, une grande fréquence de balayage et une large plage d’accord. Les avantages des sources accordables ouvrent la voie vers d’autres types d’applications comme la caractérisation des impulsions ultra-courtes par exemple. Généralement, ces impulsions sont caractérisées via des méthodes non linéaires, lentes et trop compliquées à mettre en place. Nous avons donc proposé une nouvelle approche basée sur les sources accordables pour la caractérisation des impulsions ultra-courtes. En utilisant un laser à semi-conducteur accordable linéairement, type SG-DBR (Sampled-Grating Distributed Bragg Reflector), nous pouvons balayer en une seule mesure tout le spectre optique des impulsions sous test. Le signal de battement entre la source accordable et le laser pulsé permet de mesurer l’amplitude et la phase spectrales des différents modes ce qui nous donne accès à la forme temporelle de l’impulsion. L’avantage de notre approche est que tout le processus de caractérisation se fait en une seule mesure très rapide. En effet, la grande fréquence de balayage du laser accordable permet d’avoir des temps de mesure très faibles (< 10 μs), ce qui offre la possibilité d’avoir des mesures en temps réel. De plus, grâce à la large plage d’accord, cette technique est complétement indépendante de l’impulsion sous test, elle ne nécessite aucune connaissance au préalable des différentes propriétés de cette dernière telles que la fréquence de répétition, le nombre de modes ou la fréquence de chaque mode / Optical swept sources are distinguished by the ability to change their output wavelength in a continuous manner over time. They are used in many applications such as telecommunications, spectroscopy and optical coherence tomography. They are mainly characterized by a narrow instantaneous linewidth, a high sweep rate and a wide tuning range. The advantages of swept sources open the way to other types of applications such as the characterization of ultrashort pulses for example. Generally, these pulses are characterized using nonlinear methods which are slow and too complicated. We have proposed a novel approach based on swept sources for the characterization of ultrashort pulses. By using a linearly wavelength-swept semiconductor laser like SG-DBR (Sampled-Grating Distributed Bragg Reflector), we can scan the entire optical spectrum of the pulses under test in a single measurement. The beat signal between the swept source and the pulsed laser is then used to measure the spectral amplitude and phase of all modes which gives access to the temporal shape of the pulse. The main advantage of our approach is that the entire characterization process is done in a single fast measurement. Indeed, the high sweep rate of the swept source offers the possibility of having real time measurements. In addition, thanks to the wide tuning range, this technique is completely independent of the pulse under test, it requires no prior knowledge of the various properties of the pulse such as the repetition frequency, the number of modes or the frequency of each mode

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18855号 / 医博第3966号 / 新制||医||1007(附属図書館) / 31806 / 京都大学大学院医学研究科医学専攻 / (主査)教授 河野 憲二, 教授 黒田 知宏, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Ce manuscrit de thèse de doctorat présente la conception et la réalisation d’un système d’imageriepour le diagnostic précoce des pathologies de la peau. Un diagnostic précoce permet de réduire lesactes chirurgicaux inutiles. Il est important de mettre en avant que seulement 20% des pathologiesfaisant office d’une opération chirurgicale, sont malignes. De plus, les pronostics de l’année 2015avançaient trois millions de nouveaux cas de cancer de la peau diagnostiqués aux ´ Etats-Unis. Basésur la tomographie par cohérence optique à balayage en longueur d’onde et une configuration pleinchamp et multi-canaux, le système d’imagerie médicale est capable d’imager en volume les couchesinternes de la peau et donc de fournir un diagnostic médical pour le professionnel de santé. Pourune fabrication en série du système portatif, les composants optiques sont micro-fabriqués sur dessubstrats et assemblés verticalement. Ces micro-composants optiques requièrent une caractérisationspécifique. Pour cela, deux systèmes ont ainsi été développés pour estimer leurs performancesoptiques. Ce travail a été réalisé dans le cadre du projet Européen VIAMOS (Vertically IntegratedArray-type Mirau-based OCT System). / The manuscript concerns the optical design and the development of a non-invasive new imagingsystem for the early diagnosis of skin pathologies. Indeed, an early diagnosis can make the differencebetween malignant and benign skin lesion in order to minimize unnecessary surgical procedure.Furthermore, prognosis for the year 2015 was that more than three millions new skin cancer caseswill be diagnosed in the United States. Based on the swept source optical coherence tomographytechnique in full-field and multiple channels configuration, the imaging system is able to perform avolumetric image of the subsurface of the skin, and thus can help in taking a better medical decision.Furthermore, for a batch-fabrication of the hand-held device, micro-optical components were made atwafer-level and vertically assembled using multi-wafer bonding. This miniaturized system requiresspecific characterization. Thus, two systems were also developed for imaging quality evaluation ofmicro-optical elements. This work has been supported by the VIAMOS (Vertically Integrated ArraytypeMirau-based OCT System) European project.