Live volumetric (4D) visualization and guidance of in vivo human ophthalmic surgery with intraoperative optical coherence tomography.

Minimally-invasive microsurgery has resulted in improved outcomes for patients. However, operating through a microscope limits depth perception and fixes the visual perspective, which result in a steep learning curve to achieve microsurgical proficiency. We introduce a surgical imaging system employing four-dimensional (live volumetric imaging through time) microscope-integrated optical coherence tomography (4D MIOCT) capable of imaging at up to 10 volumes per second to visualize human microsurgery. A custom stereoscopic heads-up display provides real-time interactive volumetric feedback to the surgeon. We report that 4D MIOCT enhanced suturing accuracy and control of instrument positioning in mock surgical trials involving 17 ophthalmic surgeons. Additionally, 4D MIOCT imaging was performed in 48 human eye surgeries and was demonstrated to successfully visualize the pathology of interest in concordance with preoperative diagnosis in 93% of retinal surgeries and the surgical site of interest in 100% of anterior segment surgeries. In vivo 4D MIOCT imaging revealed sub-surface pathologic structures and instrument-induced lesions that were invisible through the operating microscope during standard surgical maneuvers. In select cases, 4D MIOCT guidance was necessary to resolve such lesions and prevent post-operative complications. Our novel surgical visualization platform achieves surgeon-interactive 4D visualization of live surgery which could expand the surgeon's capabilities.

Infrared image enhancement based on hybrid-domain consideration and data fusion methods

Au cours des dernières décennies, l’effort sur les applications de capteurs infrarouges a largement progressé dans le monde. Mais, une certaine difficulté demeure, en ce qui concerne le fait que les objets ne sont pas assez clairs ou ne peuvent pas toujours être distingués facilement dans l’image obtenue pour la scène observée. L’amélioration de l’image infrarouge a joué un rôle important dans le développement de technologies de la vision infrarouge de l’ordinateur, le traitement de l’image et les essais non destructifs, etc. Cette thèse traite de la question des techniques d’amélioration de l’image infrarouge en deux aspects, y compris le traitement d’une seule image infrarouge dans le domaine hybride espacefréquence, et la fusion d’images infrarouges et visibles employant la technique du nonsubsampled Contourlet transformer (NSCT). La fusion d’images peut être considérée comme étant la poursuite de l’exploration du modèle d’amélioration de l’image unique infrarouge, alors qu’il combine les images infrarouges et visibles en une seule image pour représenter et améliorer toutes les informations utiles et les caractéristiques des images sources, car une seule image ne pouvait contenir tous les renseignements pertinents ou disponibles en raison de restrictions découlant de tout capteur unique de l’imagerie. Nous examinons et faisons une enquête concernant le développement de techniques d’amélioration d’images infrarouges, et ensuite nous nous consacrons à l’amélioration de l’image unique infrarouge, et nous proposons un schéma d’amélioration de domaine hybride avec une méthode d’évaluation floue de seuil amélioré, qui permet d’obtenir une qualité d’image supérieure et améliore la perception visuelle humaine. Les techniques de fusion d’images infrarouges et visibles sont établies à l’aide de la mise en oeuvre d’une mise en registre précise des images sources acquises par différents capteurs. L’algorithme SURF-RANSAC est appliqué pour la mise en registre tout au long des travaux de recherche, ce qui conduit à des images mises en registre de façon très précise et des bénéfices accrus pour le traitement de fusion. Pour les questions de fusion d’images infrarouges et visibles, une série d’approches avancées et efficaces sont proposés. Une méthode standard de fusion à base de NSCT multi-canal est présente comme référence pour les approches de fusion proposées suivantes. Une approche conjointe de fusion, impliquant l’Adaptive-Gaussian NSCT et la transformée en ondelettes (Wavelet Transform, WT) est propose, ce qui conduit à des résultats de fusion qui sont meilleurs que ceux obtenus avec les méthodes non-adaptatives générales. Une approche de fusion basée sur le NSCT employant la détection comprime (CS, compressed sensing) et de la variation totale (TV) à des coefficients d’échantillons clairsemés et effectuant la reconstruction de coefficients fusionnés de façon précise est proposée, qui obtient de bien meilleurs résultats de fusion par le biais d’une pré-amélioration de l’image infrarouge et en diminuant les informations redondantes des coefficients de fusion. Une procédure de fusion basée sur le NSCT utilisant une technique de détection rapide de rétrécissement itératif comprimé (fast iterative-shrinking compressed sensing, FISCS) est proposée pour compresser les coefficients décomposés et reconstruire les coefficients fusionnés dans le processus de fusion, qui conduit à de meilleurs résultats plus rapidement et d’une manière efficace.

Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11

Purpose Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.

In vivo microvascular oximetry using multispectral imaging

This thesis describes the application of multispectral imaging to several novel oximetry applications. Chapter 1 motivates optical microvascular oximetry, outlines oxygen transport in the body, describes the theory of oximetry, and describes the challenges associated with in vivo oximetry, in particular imaging through tissue. Chapter 2 reviews various imaging techniques for quantitative in vivo oximetry of the microvasculature, including multispectral and hyperspectral imaging, photoacoustic imaging, optical coherence tomography, and laser speckle techniques. Chapter 3 describes a two-wavelength oximetry study of two microvascular beds in the anterior segment of the eye: the bulbar conjunctival and episcleral microvasculature. This study reveals previously unseen oxygen diffusion from ambient air into the bulbar conjunctival microvasculature, altering the oxygen saturation of the bulbar conjunctiva. The response of the bulbar conjunctival and episcleral microvascular beds to acute mild hypoxia is quantified and the rate at which oxygen diffuses into bulbar conjunctival vessels is measured. Chapter 4 describes the development and application of a highly novel non-invasive retinal angiography technique: Oximetric Ratio Contrast Angiography (ORCA). ORCA requires only multispectral imaging and a small perturbation of blood oxygen saturation to produce angiographic sequences. A pilot study of ORCA in human subjects was conducted. This study demonstrates that ORCA can produce angiographic sequences with features such as sequential vessel filling and laminar flow. The application and challenges of ORCA are discussed, with emphasis on comparison with other angiography techniques, such as fluorescein angiography. Chapter 5 describes the development of a multispectral microscope for oximetry in the spinal cord dorsal vein of rats. Measurements of blood oxygen saturation are made in the dorsal vein of both healthy rats, and in rats with the Experimental autoimmune encephalomyelitis (EAE) disease model of multiple sclerosis. The venous blood oxygen saturation of EAE disease model rats was found to be significantly lower than that of healthy controls, indicating increased oxygen uptake from blood in the EAE disease model of multiple sclerosis. Chapter 6 describes the development of video-rate red eye oximetry; a technique which could enable stand-off oximetry of the blood-supply of the eye with high temporal resolution. The various challenges associated with video-rate red eye oximetry are investigated and their influence quantified. The eventual aim of this research is to track circulating deoxygenation perturbations as they arrive in both eyes, which could provide a screening method for carotid artery stenosis, which is major risk-factor for stroke. However, due to time constraints, it was not possible to thoroughly investigate if video-rate red eye can detect such perturbations. Directions and recommendations for future research are outlined.

Structure of the N-terminal oligomerization domain of DnaD reveals a unique tetramerization motif and provides insights into scaffold formation

DnaD is a primosomal protein that remodels supercoiled plasmids. It binds to supercoiled forms and converts them to open forms without nicking. During this remodeling process, all the writhe is converted to twist and the plasmids are held around the periphery of large scaffolds made up of DnaD molecules. This DNA-remodeling function is the sum of a scaffold-forming activity on the N-terminal domain and a DNA-dependent oligomerization activity on the C-terminal domain. We have determined the crystal structure of the scaffold-forming N-terminal domain, which reveals a winged-helix architecture, with additional structural elements extending from both N- and C-termini. Four monomers form dimers that join into a tetramer. The N-terminal extension mediates dimerization and tetramerization, with extensive interactions and distinct interfaces. The wings and helices of the winged-helix domains remain exposed on the surface of the tetramer. Structure-guided mutagenesis and atomic force microscopy imaging indicate that these elements, together with the C-terminal extension, are involved in scaffold formation. Based upon our data, we propose a model for the DnaD-mediated scaffold formation.

Endoscopic optical coherence tomography : design and application

This thesis presents an investigation on endoscopic optical coherence tomography (OCT). As a noninvasive imaging modality, OCT emerges as an increasingly important diagnostic tool for many clinical applications. Despite of many of its merits, such as high resolution and depth resolvability, a major limitation is the relatively shallow penetration depth in tissue (about 2∼3 mm). This is mainly due to tissue scattering and absorption. To overcome this limitation, people have been developing many different endoscopic OCT systems. By utilizing a minimally invasive endoscope, the OCT probing beam can be brought to the close vicinity of the tissue of interest and bypass the scattering of intervening tissues so that it can collect the reflected light signal from desired depth and provide a clear image representing the physiological structure of the region, which can not be disclosed by traditional OCT. In this thesis, three endoscope designs have been studied. While they rely on vastly different principles, they all converge to solve this long-standing problem.

A hand-held endoscope with manual scanning is first explored. When a user is holding a hand- held endoscope to examine samples, the movement of the device provides a natural scanning. We proposed and implemented an optical tracking system to estimate and record the trajectory of the device. By registering the OCT axial scan with the spatial information obtained from the tracking system, one can use this system to simply ‘paint’ a desired volume and get any arbitrary scanning pattern by manually waving the endoscope over the region of interest. The accuracy of the tracking system was measured to be about 10 microns, which is comparable to the lateral resolution of most OCT system. Targeted phantom sample and biological samples were manually scanned and the reconstructed images verified the method.

Next, we investigated a mechanical way to steer the beam in an OCT endoscope, which is termed as Paired-angle-rotation scanning (PARS). This concept was proposed by my colleague and we further developed this technology by enhancing the longevity of the device, reducing the diameter of the probe, and shrinking down the form factor of the hand-piece. Several families of probes have been designed and fabricated with various optical performances. They have been applied to different applications, including the collector channel examination for glaucoma stent implantation, and vitreous remnant detection during live animal vitrectomy.

Lastly a novel non-moving scanning method has been devised. This approach is based on the EO effect of a KTN crystal. With Ohmic contact of the electrodes, the KTN crystal can exhibit a special mode of EO effect, termed as space-charge-controlled electro-optic effect, where the carrier electron will be injected into the material via the Ohmic contact. By applying a high voltage across the material, a linear phase profile can be built under this mode, which in turn deflects the light beam passing through. We constructed a relay telescope to adapt the KTN deflector into a bench top OCT scanning system. One of major technical challenges for this system is the strong chromatic dispersion of KTN crystal within the wavelength band of OCT system. We investigated its impact on the acquired OCT images and proposed a new approach to estimate and compensate the actual dispersion. Comparing with traditional methods, the new method is more computational efficient and accurate. Some biological samples were scanned by this KTN based system. The acquired images justified the feasibility of the usage of this system into a endoscopy setting. My research above all aims to provide solutions to implement an OCT endoscope. As technology evolves from manual, to mechanical, and to electrical approaches, different solutions are presented. Since all have their own advantages and disadvantages, one has to determine the actual requirements and select the best fit for a specific application.

A Diagnostic Calculator for Detecting Glaucoma on the Basis of Retinal Nerve Fiber Layer, Optic Disc, and Retinal Ganglion Cell Analysis by Optical Coherence Tomography

Purpose: The purpose of this study was to develop and validate a multivariate predictive model to detect glaucoma by using a combination of retinal nerve fiber layer (RNFL), retinal ganglion cell-inner plexiform (GCIPL), and optic disc parameters measured using spectral-domain optical coherence tomography (OCT). Methods: Five hundred eyes from 500 participants and 187 eyes of another 187 participants were included in the study and validation groups, respectively. Patients with glaucoma were classified in five groups based on visual field damage. Sensitivity and specificity of all glaucoma OCT parameters were analyzed. Receiver operating characteristic curves (ROC) and areas under the ROC (AUC) were compared. Three predictive multivariate models (quantitative, qualitative, and combined) that used a combination of the best OCT parameters were constructed. A diagnostic calculator was created using the combined multivariate model. Results: The best AUC parameters were: inferior RNFL, average RNFL, vertical cup/disc ratio, minimal GCIPL, and inferior-temporal GCIPL. Comparisons among the parameters did not show that the GCIPL parameters were better than those of the RNFL in early and advanced glaucoma. The highest AUC was in the combined predictive model (0.937; 95% confidence interval, 0.911–0.957) and was significantly (P = 0.0001) higher than the other isolated parameters considered in early and advanced glaucoma. The validation group displayed similar results to those of the study group. Conclusions: Best GCIPL, RNFL, and optic disc parameters showed a similar ability to detect glaucoma. The combined predictive formula improved the glaucoma detection compared to the best isolated parameters evaluated. The diagnostic calculator obtained good classification from participants in both the study and validation groups.

Hallazgos tomográficos como predictores del resultado funcional en edema macular secundario a oclusiones venosas retinianas

INTRODUCCIÓN: El Edema Macular (EM) es la principal causa de perdida de agudeza visual en pacientes con Oclusión Venosa Retiniana (OVR); luego del tratamiento, algunos pacientes persisten con mala agudeza visual. OBJETIVO: Realizar una Revisión Sistemática de la Literatura (RSL), para identificar la evidencia existente sobre factores tomográficos que predicen el resultado visual en pacientes con EM secundario a OVR. FUENTE DE LA INFORMACIÓN: PUBMED, MEDLINE, EMBASE, LILACS, COCHRANE, literatura gris. SELECCIÓN DE LOS ESTUDIOS: Ensayos Clínicos Controlados (ECC) y estudios observacionales analíticos. EXTRACCIÓN Y SÍNTESIS DE LOS DATOS: Dos investigadores seleccionaron los artículos de forma independiente. Se realizó una síntesis cualitativa de la información siguiendo las recomendaciones de la declaración PRISMA 2009. MEDIDAS Y DESENLACE PRINCIPAL: Grosor Retiniano Central (GRC), integridad de Banda Elipsoide e Integridad de Membrana Limitante Externa (MLE), determinados por SD OCT. El desenlace principal es la Agudeza Visual Mejor Corregida (AVMC) a los 6, 12,18 y/o 24 meses. RESULTADOS: Se identificaron 872 abstract y se incluyeron 8 artículos en el análisis cualitativo. Seis estudios evaluaron el GRC sin encontrar asociación con resultado visual final. Solo 2 estudios evaluaron y encontraron asociación estadísticamente significativa de la integridad de la MLE con el desenlace visual, Kang, H 2012 (r2 0,51 p 0,000), Rodriguez, F 2014 (p< 0,001). La integridad de la BE fue asociada a pronostico visual en 4 de 5 estudios que evaluaron esta variable, con resultados estadísticamente significativos. La AVMC de base también se asocio con desenlace visual en 4 de 5 estudios que la evaluaron. El mejor modelo que predice el resultado funcional según el estudio de Kang, H 2012 fue: Integridad de MLE, integridad de BE y AVMC de base (R2 0,671 p 0,000), a los 12 meses de seguimiento. CONCLUSION: La evidencia actual sugiere que la integridad de la BE y la MLE son predictores del resultados funcional en pacientes con EM secundario a OVR después de 6 o mas meses de seguimiento. Es necesario la realización de estudios controlados para llegar a resultados mas concluyentes.

Effective Cell-Centred Time-Domain Maxwell's Equations Numerical Solvers

This research work analyses techniques for implementing a cell-centred finite-volume time-domain (ccFV-TD) computational methodology for the purpose of studying microwave heating. Various state-of-the-art spatial and temporal discretisation methods employed to solve Maxwell's equations on multidimensional structured grid networks are investigated, and the dispersive and dissipative errors inherent in those techniques examined. Both staggered and unstaggered grid approaches are considered. Upwind schemes using a Riemann solver and intensity vector splitting are studied and evaluated. Staggered and unstaggered Leapfrog and Runge-Kutta time integration methods are analysed in terms of phase and amplitude error to identify which method is the most accurate and efficient for simulating microwave heating processes. The implementation and migration of typical electromagnetic boundary conditions. from staggered in space to cell-centred approaches also is deliberated. In particular, an existing perfectly matched layer absorbing boundary methodology is adapted to formulate a new cell-centred boundary implementation for the ccFV-TD solvers. Finally for microwave heating purposes, a comparison of analytical and numerical results for standard case studies in rectangular waveguides allows the accuracy of the developed methods to be assessed.