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

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This work presents an effective methodology for measuring the depth-resolved 3D full-field deformation of semitransparent, light scattering soft tissues such as vertebrate eye cornea. This was obtained by performing digital volume correlation on optical coherence tomography volume reconstructions of silicone rubber phantoms and porcine cornea samples. Both the strip tensile tests and the posterior inflation tests have been studied. Prior to these tests, noise effect and strain induced speckle decorrelation were first studied using experimental and simulation methods. The interpolation bias in the strain results has also been analyzed. Two effective approaches have been introduced to reduce the interpolation bias. To extract material constitutive parameters from the 3D full-field deformation measurements, the virtual fields method has been extended into 3D. Both manually defined virtual fields and the optimized piecewise virtual fields have been developed and compared with each other. Efforts have also been made in developing a method to correct the refraction induced distortions in the optical coherence tomography reconstructions. Tilt tests of different silicone rubber phantoms have been implemented to evaluate the performance of the refraction correction method in correcting the distorted reconstructions.

Optical coherence tomography systems are used to image the retina in 3D to allow ophthalmologists diagnose ocular disease. These systems yield large data sets that are often labor-intensive to analyze and require significant expertise in order to draw conclusions, especially when used over time to monitor disease progression. Spectral Domain Optical Coherence Tomography (SD-OCT) instantly acquires depth profiles at a single location with a broadband source. These systems require mechanical scanning to generate two- or three-dimensional images. Instead of mechanically scanning, a beamlet array was used to permit multiple depth measurements on the retina with a single snapshot using a 3x 3 beamlet array. This multi-channel system was designed, assembled, and tested using a 1 x 2 beamlet lens array instead of a 3 x 3 beamlet array as a proof of concept prototype. The source was a superluminescent diode centered at 840nm with a 45nm bandwidth. Theoretical axial resolution was 6.92um and depth of focus was 3.45mm. Glass samples of varying thickness ranging from 0.18mm to 1.14mm were measured with the system to validate that correct depth profiles can be acquired for each channel. The results demonstrated the prototype system performed as expected, and is ready to be modified for in vivo applicability.

Amblyopia is the leading cause of monocular visual impairment in children. Therapy for amblyopia is extremely beneficial in some children but ineffective in others. It is critical that the reasons for this discrepancy are understood. Emerging evidence indicates that current clinical protocols for the diagnosis of amblyopia may not be sufficiently sensitive in identifying individuals who, on more detailed examination, exhibit subtle structural defects of the eye. Presently, the magnitude of this problem is unknown. The aim of this study was to establish the prevalence of subtle retinal/optic nerve head defects in eyes diagnosed with amblyopia, to distinguish between possible explanations for the origin of such defects and to investigate the relationship between quantitative measures of retinal structure, retinal nerve fibre layer thickness and optic nerve head dimensions. Using the imaging technique of Optical Coherence Tomography (OCT) retinal structure has been investigated in detail, following the visual pathway across the retina from the fovea, via the paramacular bundle to the optic disc, where peripapillary retinal nerve fibre thickness has been imaged and subjected to detailed measures along with optic disc size and shape. The study formed two phases, the first imaging the eyes of visually normal adults and children, comparing them to amblyopes, both adults and children who had completed their treatment. The second phase, a longitudinal study, investigated retinal structure of amblyopic children undertaking occlusion therapy for the first time. By relating pre-therapy quantitative measures to the visual outcome the second phase of the study aimed to examine whether OCT imaging could identify children achieving a poor final outcome. The results show a clear picture of inter-ocular symmetry structure in all individuals, visually normal and amblyopic. Optic disc characteristics revealed no structural abnormalities in amblyopes, in any of the measured parameters, nor was there any association between the level of visual acuity and the measured structure. At the fovea differences were shown to occur in the presence of amblyopia, with thickening of the fovea and reduction of the foveal pit depth. The structural changes were found to be both bilateral and symmetrical with the fellow eye also affected. In the longitudinal phase of the study these changes were demonstrated to a greater extent in children who 'failed' to respond to treatment. This bilateral, symmetrical structural change found at the fovea, which has not been previously reported, cannot therefore be the primary cause of the visual loss which has been diagnosed as amblyopia.

Glaucoma is an ophthalmic pathology that is the second leading cause of blindness. The laboratory design of a Polarization Sensitive Spectral Domain Optical Coherence Tomographic System aims to detect early glaucoma symptoms and prevent vision loss that occurs due to late or no glaucoma diagnosis. In order to perform human clinical trials at partner hospitals across the country, a miniaturized and portable version of the laboratory system was developed. The system facilitates easy transportation and clinical testing of the otherwise voluminous laboratory system across different eye centers. Significant consideration was given for performance optimization, cost reduction, design improvements and providing a friendly user-patient interface. / text

Optical Coherence Tomography (OCT) is a non-invasive three-dimensional imaging technique. OCT synthesizes a cross-sectional image from a series of lateral adjacent depth scans, and with a two-dimensional scanning scheme, three-dimensional intensity image of sample can be constructed. Due to its non-invasive capability, OCT has been widely applied in ophthalmology, cardiology and dermatology; and in addition to three-dimensional intensity image construction, various functional OCT imaging techniques have been developed for clinical application. My research is focused on developing functional OCT systems for application in ophthalmology, including polarization-sensitive optical coherence tomography (PS-OCT) for retinal nerve fiber layer (RNFL) birefringence measurement and dual-wavelength photothermal optical coherence tomography (DWP-OCT) for microvasculature blood oxygen saturation (SO2) measurement. In the study, a single-mode-fiber based polarization-sensitive swept-source OCT (PS-SS-OCT) with polarization modulator, polarization-sensitive bulk-optics balanced detection module is constructed and polarization processing methods based on Stokes vectors are applied to determine birefringence. PS-OCT is able to provide human subject's RNFL thickness, phase retardation, and birefringence information. Degradation in the degree of polarization (DOP) along depth is investigated and its difference between four quadrants of RNFL (superior, temporal, inferior and nasal) indicates the structural property difference. DWP-OCT is a novel functional OCT system consisting of a phase-sensitive optical coherence tomography system (PhS-OCT) and two photothermal excitation lasers. PhS-OCT is based on a swept-source laser operating in the 1060 nm wavelength range; the two photothermal excitation lasers with wavelength 770 nm and 800 nm are intensity modulated at different frequencies. PhS-OCT probe beam and two photothermal excitation beams are combined and incident on the sample, optical pathlength (op) change on the sample introduced by two photothermal excitation beams are measured and used for blood SO2 estimation. A polarization microscope is proposed for future study. The polarization microscope is an imaging technique providing molecular structure and orientation based on probe light's polarization state information. The polarization microscope uses a wavelength tunable light source, and can achieve any incident polarization state by a retarder-rotator combination. Specimen's birefringence can be determined based on the changing of detected light amplitude. / text

A multi-modality imaging system intended for clinical utilization has been developed. It is constructed around an existing fiber-bundle-based fluorescence confocal microendoscope. Additional imaging modalities have been implemented to expand the capabilities of the system and improve the accuracy of disease diagnosis. A multi-spectral mode of operation is one such modality. It acquires fluorescence images of a biological sample across a spectral range of sensitivity and explores the collected image data at any specified wavelength within that spectral range. Cellular structures can be differentiated according to their spectral properties. The relative distribution and concentration of the different cellular structures can potentially provide useful pathologic information about the imaged tissue. A spectral-domain optical coherence tomography (SDOCT) modality is another imaging technique integrated into the system. It provides a cross-sectional imaging perspective that is comparable to microscopic images obtained from histology slides and complementary to the en face view obtained from the confocal imaging modality. The imaging system uses a parallelized architecture (fiber-optic bundle, line of illumination) to increase the data acquisition speed. A one-dimensional scan is needed to capture 2D images in the confocal modality or a 3D data cube (two spatial dimensions and one spectral dimension) in the multi-spectral mode of operation. No scanning is required to capture a 2D OCT image. The fiber-bundle design is particularly critical for the SDOCT modality as it paves the way to novel fast endoscopic OCT imaging that has a high potential for translation into the clinic. The integrated multi-modality imaging system can readily switch between different imaging modalities, which will make it a powerful diagnostic tool in a clinical environment. It can provide valuable information about the morphology, the spectral and biochemical features, and the macroscopic architecture of tissue. It is believed that fast and accurate disease diagnosis can potentially be made based on all these characteristics.

Optical coherence tomography (OCT) is a minimally-invasive imaging modality that generates high resolution cross-sectional images of tissue. The present study employed a 2 mm diameter endoscopic spectral domain OCT system in the in vivo evaluation of the drugs α-Difluoromethylornithine and Sulindac as chemopreventive and chemotherapeutic agents in a mouse model of sporadic colorectal cancer. 30 mm lateral images of each colon at eight different rotations were obtained at five different time points. Visual analysis of the images was performed to determine the number and size of discrete adenomas, with gross photos and histology serving as gold standard confirmation of the final imaging time point. When applied for chemoprevention, DFMO and Sulindac both significantly reduced the incidence of adenoma, appearing to interact additively in the prevention of tumorigenesis. For chemotherapy, however, only Sulindac had a significant effect on the number of adenoma and neither DFMO nor Sulindac significantly affected tumor growth.

<p>Optical coherence tomography (OCT) is a non-invasive imaging modality that uses low coherence interferometry to generate three-dimensional datasets of a sample's structure. OCT has found tremendous clinical applications in imaging the retina and has demonstrated great utility in the diagnosis of various retinal diseases. However, such diagnoses rely upon the ability to observe abnormalities in the structure of the retina caused by pathology. By the time an ocular disease has progressed to the point of affecting the morphology of the retina, irreversible vision loss in the eye may already occur. Changes in the functionality of the tissue often precede changes to the structure. Thus, if imaging methods are developed to provide additional functional information about the behavior and response of the retinal tissue and vasculature, earlier treatment for disease may be prescribed, thus preserving vision for the patient. </p><p>Within the last decade, significant technological advances in OCT systems have enabled high-speed and high sensitivity image acquisition using either spectral domain OCT (SDOCT) or swept-source OCT (SSOCT) configurations. Such systems use Fourier processing to extract structural information of a sample from interferometric principles. But such systems also have access to the optical phase information, which allows for functional analysis of sample dynamics. This dissertation details the development and application of methods using both intensity and phase information as a tool for studying interesting biological phenomena. The goal of this work is an extension of techniques to image the vasculature in the retina and enhance the clinical utility of OCT.</p><p>I first outline basic theory necessary for understanding the principles of OCT. I then describe OCT phase imaging in cellular applications as a demonstration of the ability of OCT to provide functional information on biological dynamics. Phase imaging methods suffer from an artifact known as phase wrapping, and I have developed a software technique to overcome this problem in OCT, thus extending its usefulness in providing quantitative information. I characterize the limitations in measuring moving scatterers with Doppler OCT in both SDOCT and SSOCT system. I also show the ability to image the vasculature in the retina using variance imaging with a high-speed retinal imaging system and software based methods to correct for patient motion and create a widefield mosaic in an automated manner. Finally, future directions for this work are discussed.</p> / Dissertation