Intraoperative Fourier domain optical coherence tomography for microsurgery guidance and assessment

In this dissertation, advanced high-speed Fourier domain optical coherence tomography (FD-OCT)systems were investigated and developed. Several real-time, high resolution functional Spectral-domain OCT (SD-OCT) systems capable of imaging and sensing blood flow and motion were designed and developed. The system were designed particularly for microsurgery guidance and assessment. The systems were tested for their ability to assessing microvascular anastomosis and vulnerable plaque development. An all fiber-optic common-path optical coherence tomography (CP-OCT) system capable of measuring high-resolution optical distances, was built and integrated into di fferent imaging modalities. First, a novel non-contact accurate in-vitro intra-ocular lens power measurement method was proposed and validated based on CP-OCT. Second, CP-OCT was integrated with a ber bundle based confocal microscope to achieve motion-compensated imaging. Distance between the probe and imaged target was monitored by the CP-OCT system in real-time.The distance signal from the CP-OCT system was routed to a high speed, high resolution linear motor to compensate for the axial motion of the sample in a closed-loop control. Finally a motion-compensated hand-held common-path Fourier domain optical coherence tomography probe was developed for image-guided intervention. Both phantom and ex vivo models were used to test and evaluate the probe. As the data acquisition speed of current OCT systems continue to increase, the means to process the data in real-time are in critically needed. Previous graphics processing unit accelerated OCT signal processing methods have shown their potential to achieve real-time imaging. In this dissertation, algorithms to perform real-time reference A-line subtraction and saturation artifact removal were proposed, realized and integrated into previously developed FD-OCT system CPU-GPU heterogeneous structure. Fourier domain phase resolved Doppler OCT (PRDOCT) system capable of real-time simultaneous structure and flow imaging based on dual GPUs was also developed and implemented. Finally, systematic experiments were conducted to validate the system for surgical applications. FD-OCT system was used to detect atherosclerotic plaque and drug effi ciency test in mouse model. Application of PRDOCT for both suture and cu ff based microvascular anastomosis guidance and assessment was extensively stuided in rodent model

Optical Coherence Tomography as a Diagnostic Tool in Renal Transplant and Cancer Imaging

This dissertation aims to investigate optical coherence tomography (OCT) as a diagnostic technology in renal imaging through two main arenas: renal transplantation and renal cancer. Part 1: Ischemia-reperfusion injury, which frequently occurs after kidney transplant, is a major contributing factor in delayed-graft function leading to varying degrees of early renal dysfunction. Real-time assessment of graft morphological and hemodynamic changes could help to evaluate graft condition and offer valuable information to predict the prognosis of graft injury for patient-specific management strategies. Previous studies have shown the ability of OCT to monitor structural changes associated with ischemia-reperfusion injury in vivo. Therefore, we investigated the ability of Doppler OCT (DOCT) to image microcirculatory changes in real time in the kidney glomerulus in vivo in an animal model and quantified observed changes in blood flow in 3D. Then, we translated OCT/DOCT technology into clinical testing for renal imaging during transplantation procedures and demonstrated the ability of OCT/DOCT to reveal renal tubular morphology and blood flow immediately following reperfusion. Part 2: For solid renal masses, nephron sparing procedures have been developed as an alternative to radical nephrectomy. However, achieving a negative tumor margin is critical to ensuring the best oncological efficacy for precluding tumor recurrence. OCT is a high-resolution, real-time imaging technology that has shown the ability to distinguish cancerous tissue from normal in several systems of the body based on changes in tissue optical properties. Therefore, we investigated the capability of OCT to quantify differences in optical properties between tumor and normal renal tissue. However, we did not observe a significant difference in optical attenuation between tumor and normal tissue in ex vivo specimens. These results suggest that further studies or possible alternative metrics need to be investigated to determine if OCT is able to detect renal neoplasms

OPTICAL COHERENCE TOMOGRAPHY OPHTHALMIC SURGICAL GUIDANCE

Optical coherence tomography (OCT) performs high-resolution cross-sectional and volumetric tissue imaging in situ through the combination of confocal gating, coherence gating, and polarization gating. Because it is noninvasive, OCT has been used in multiple clinical applications such as tissue pathology assessment and interventional procedure guidance. Moreover, OCT can perform functional measurements such as phase-sensitive measurement of blood flow and polarization-sensitive measurement of tissue birefringence. These features made OCT one of the most widely used imaging systems in ophthalmology. In this thesis, we present several novel OCT methods developed for microsurgery guidance and OCT image analysis. The thesis mainly consists of five parts, which are shown as follows. First, we present a BC-mode OCT image visualization method for microsurgery guidance, where multiple sparsely sampled B-scans are combined to generate a single cross-sectional image with an enhanced instrument and tissue layer visibility and reduced shadowing artifacts. The performance of the proposed method is demonstrated by guiding a 30-gauge needle into an ex-vivo human cornea. Second, we present a microscope-integrated OCT guided robotic subretinal injection method. A workflow is designed for accurate and stable robotic needle navigation. The performance of the proposed method is demonstrated on ex-vivo porcine eye subretinal injection. Third, we present optical flow OCT technique that quantifies accurate velocity fields. The accuracy of the proposed method is verified through phantom flow experiments by using a diluted milk powder solution as the scattering medium, in both cases of advective flow and turbulent flow. Fourth, we present a wrapped Gaussian mixture model to stabilize the phase of swept source OCT systems. A closed-form iteration solution is derived using the expectation-maximization algorithm. The performance of the proposed method is demonstrated through ex-vivo, in-vivo, and flow phantom experiments. The results show its robustness in different application scenarios. Fifth, we present a numerical landmark localization algorithm based on a convolutional neural network and a conditional random field. The robustness of the proposed method is demonstrated through ex-vivo porcine intestine landmark localization experiments

3D printing of biomedical devices with soft and biocompatible elastomers

Additive manufacturing (AM) which is commonly known as 3D printing is evolving quickly during the last decades. It has been utilized in various areas including biomedical applications, such as tissue engineering, therapeutic delivery, surgical planning and implant designs. The possibility to fabricate complex geometries allows us to solve many problems that cannot be done using traditional methods. In this thesis, we explored possible applications of 3D printing in biomedical engineering. The first application was using 3D printing to address challenges in treatments for congenital heart diseases (CHD). 1.35 million infants are born with CHD each year in the world, reconstruction of right ventricle–to–pulmonary artery (RVPA) continuity is an integral part of various surgical procedures commonly performed in neonates and young infants to treat CHD. However, these conduits need multiple open-chest replacement surgeries because the size of the conduits cannot grow as infants grow. We addressed the lack of growth potential of RV-PA conduits using novel 3D-printed conduits that can change their shape in response to the physiological changes during pediatric growth. We utilized thermoplastic polycarbonate-based polyurethane as a filament material in a fused filament fabrication printing process. We characterized the material to determine the suitable printing parameters, then developed a customized bench-top fluidic set up to study the in-vitro functionalities of the 3D-printed conduits. The conduits can increase the effective diameters as the RV pressure increases during growth to accommodate increased blood flow rate. The second application was utilizing the same material to address the technique difficulties in vascular and microvascular anastomosis. Traditional suture method requires surgeons to have a long-time training before they can perform vascular anastomosis, and the surgeries usually last for hours, the sewing material may cause further damage to blood vessels after the surgery. To address these issues, we developed a 3D-printed device that can connect blood vessels together and allow a broader access of vascular and microvascular anastomosis by making the process simpler, faster, and safer. We believe that using 3D printing technology, we can provide new aspects in designing patient specific biomedical devices and develop experience of both patients and surgeons

Real-time tissue viability assessment using near-infrared light

Despite significant advances in medical imaging technologies, there currently exist no tools to effectively assist healthcare professionals during surgical procedures. In turn, procedures remain subjective and dependent on experience, resulting in avoidable failure and significant quality of care disparities across hospitals. Optical techniques are gaining popularity in clinical research because they are low cost, non-invasive, portable, and can retrieve both fluorescence and endogenous contrast information, providing physiological information relative to perfusion, oxygenation, metabolism, hydration, and sub-cellular content. Near-infrared (NIR) light is especially well suited for biological tissue and does not cause tissue damage from ionizing radiation or heat. My dissertation has been focused on developing rapid imaging techniques for mapping endogenous tissue constituents to aid surgical guidance. These techniques allow, for the first time, video-rate quantitative acquisition over a large field of view (> 100 cm2) in widefield and endoscopic implementations. The optical system analysis has been focused on the spatial-frequency domain for its ease of quantitative measurements over large fields of view and for its recent development in real-time acquisition, single snapshot of optical properties (SSOP) imaging. Using these methods, this dissertation provides novel improvements and implementations to SSOP, including both widefield and endoscopic instrumentations capable of video-rate acquisition of optical properties and sample surface profile maps. In turn, these measures generate profile-corrected maps of hemoglobin concentration that are highly beneficial for perfusion and overall tissue viability. Also utilizing optical property maps, a novel technique for quantitative fluorescence imaging was also demonstrated, showing large improvement over standard and ratiometric methods. To enable real-time feedback, rapid processing algorithms were designed using lookup tables that provide a 100x improvement in processing speed. Finally, these techniques were demonstrated in vivo to investigate their ability for early detection of tissue failure due to ischemia. Both pre-clinical studies show endogenous contrast imaging can provide early measures of future tissue viability. The goal of this work has been to provide the foundation for real-time imaging systems that provide tissue constituent quantification for tissue viability assessments.2018-01-09T00:00:00

Structural and functional brain imaging using extended-focus optical coherence tomography and microscopy

Neuroimaging techniques aim at revealing the anatomy and functional organisation of cerebral structures. Over the past decades, functional magnetic resonance imaging (fMRI) has revolutionized our understanding of human cerebral physiology through its ability to probe neural activity throughout the entire brain in a non-invasive fashion. Nevertheless, despite recent technological improvements, the spatial resolution of fMRI remains limited to a few hundreds of microns, restricting its use to macroscopic studies. Microscopic imaging solutions have been proposed to circumvent this limitation and have enabled revealing the existence of various cerebral structures, such as neuronal and vascular networks and their contribution to information processing and blood flow regulation within the brain. Optical imaging has proven, through its increased resolution and available contrast mechanisms, to be a valuable complement to fMRI for cellular-scale imaging. In this context, we demonstrate here the capabilities of an extension of optical coherence tomography, termed extended-focus optical coherence tomography (xf-OCT), in imaging cerebral structure and function at high resolution and very high acquisitions rates. Optical coherence tomography is an interferometric imaging technique using a low-coherence illumination source to provide fast, three-dimensional imaging of the back-scattering of tissue and cells. By multiplexing the interferometric ranging over several spectral channels, Fourier-domain OCT performs depth-resolved imaging at very high acquisition rates and high sensitivity. Increasing the lateral resolution of optical systems typically reduces the available depth-of-field and thus hampers this depth multiplexing advantage of OCT. Extended-focus systems aim at alleviating this trade-off between imaging depth and lateral resolution through the use of diffraction-less beams such as Bessel beams, providing high resolution imaging over large depths. The xf-OCT system therefore combines fast acquisition rates and high resolution, both characteristics required to image and study the structure and function of microscopic constituents of cerebral tissue. In this work, we performed functional brain imaging using the ability of xf-OCT to obtain quantita- tive measurements of blood flow in the brain. Changes in blood velocity evoked by neuronal activation were monitored and maps of hemodynamic activity were generated by adapting tools routinely used in fMRI to xf-OCT imaging. Additionally, three novel xf-OCT instruments are presented, wherein the advantages of different spectral ranges are exploited to reach specific imaging parameters. The increased contrast and resolution afforded by an illumination in the visible spectral range was used in two extended-focus optical coherence microscopy (xf-OCM) implementations for subcellular imaging of ex-vivo brain slices and cellular imaging of neurons, capillaries and myelinated axons in the superficial cortex in-vivo. Subsequently, an xf-OCT system is presented, operating in the infrared spectral range, wherein the reduced scattering enabled imaging the smallest capillaries deep in the murine cortex in-vivo

Anatomical Modeling of Cerebral Microvascular Structures: Application to Identify Biomarkers of Microstrokes

Les réseaux microvasculaires corticaux sont responsables du transport de l’oxygène et des substrats énergétiques vers les neurones. Ces réseaux réagissent dynamiquement aux demandes énergétiques lors d’une activation neuronale par le biais du couplage neurovasculaire. Afin d’élucider le rôle de la composante microvasculaire dans ce processus de couplage, l’utilisation de la modélisation in-formatique pourrait se révéler un élément clé. Cependant, la manque de méthodologies de calcul appropriées et entièrement automatisées pour modéliser et caractériser les réseaux microvasculaires reste l’un des principaux obstacles. Le développement d’une solution entièrement automatisée est donc important pour des explorations plus avancées, notamment pour quantifier l’impact des mal-formations vasculaires associées à de nombreuses maladies cérébrovasculaires. Une observation courante dans l’ensemble des troubles neurovasculaires est la formation de micro-blocages vascu-laires cérébraux (mAVC) dans les artérioles pénétrantes de la surface piale. De récents travaux ont démontré l’impact de ces événements microscopiques sur la fonction cérébrale. Par conséquent, il est d’une importance vitale de développer une approche non invasive et comparative pour identifier leur présence dans un cadre clinique. Dans cette thèse,un pipeline de traitement entièrement automatisé est proposé pour aborder le prob-lème de la modélisation anatomique microvasculaire. La méthode de modélisation consiste en un réseau de neurones entièrement convolutif pour segmenter les capillaires sanguins, un générateur de modèle de surface 3D et un algorithme de contraction de la géométrie pour produire des mod-èles graphiques vasculaires ne comportant pas de connections multiples. Une amélioration de ce pipeline est développée plus tard pour alléger l’exigence de maillage lors de la phase de représen-tation graphique. Un nouveau schéma permettant de générer un modèle de graphe est développé avec des exigences d’entrée assouplies et permettant de retenir les informations sur les rayons des vaisseaux. Il est inspiré de graphes géométriques déformants construits en respectant les morpholo-gies vasculaires au lieu de maillages de surface. Un mécanisme pour supprimer la structure initiale du graphe à chaque exécution est implémenté avec un critère de convergence pour arrêter le pro-cessus. Une phase de raffinement est introduite pour obtenir des modèles vasculaires finaux. La modélisation informatique développée est ensuite appliquée pour simuler les signatures IRM po-tentielles de mAVC, combinant le marquage de spin artériel (ASL) et l’imagerie multidirectionnelle pondérée en diffusion (DWI). L’hypothèse est basée sur des observations récentes démontrant une réorientation radiale de la microvascularisation dans la périphérie du mAVC lors de la récupéra-tion chez la souris. Des lits capillaires synthétiques, orientés aléatoirement et radialement, et des angiogrammes de tomographie par cohérence optique (OCT), acquis dans le cortex de souris (n = 5) avant et après l’induction d’une photothrombose ciblée, sont analysés. Les graphes vasculaires informatiques sont exploités dans un simulateur 3D Monte-Carlo pour caractériser la réponse par résonance magnétique (MR), tout en considérant les effets des perturbations du champ magnétique causées par la désoxyhémoglobine, et l’advection et la diffusion des spins nucléaires. Le pipeline graphique proposé est validé sur des angiographies synthétiques et réelles acquises avec différentes modalités d’imagerie. Comparé à d’autres méthodes effectuées dans le milieu de la recherche, les expériences indiquent que le schéma proposé produit des taux d’erreur géométriques et topologiques amoindris sur divers angiogrammes. L’évaluation confirme également l’efficacité de la méthode proposée en fournissant des modèles représentatifs qui capturent tous les aspects anatomiques des structures vasculaires. Ensuite, afin de trouver des signatures de mAVC basées sur le signal IRM, la modélisation vasculaire proposée est exploitée pour quantifier le rapport de perte de signal intravoxel minimal lors de l’application de plusieurs directions de gradient, à des paramètres de séquence variables avec et sans ASL. Avec l’ASL, les résultats démontrent une dif-férence significative (p <0,05) entre le signal calculé avant et 3 semaines après la photothrombose. La puissance statistique a encore augmenté (p <0,005) en utilisant des angiogrammes capturés à la semaine suivante. Sans ASL, aucun changement de signal significatif n’est trouvé. Des rapports plus élevés sont obtenus à des intensités de champ magnétique plus faibles (par exemple, B0 = 3) et une lecture TE plus courte (<16 ms). Cette étude suggère que les mAVC pourraient être carac-térisés par des séquences ASL-DWI, et fournirait les informations nécessaires pour les validations expérimentales postérieures et les futurs essais comparatifs.----------ABSTRACT Cortical microvascular networks are responsible for carrying the necessary oxygen and energy substrates to our neurons. These networks react to the dynamic energy demands during neuronal activation through the process of neurovascular coupling. A key element in elucidating the role of the microvascular component in the brain is through computational modeling. However, the lack of fully-automated computational frameworks to model and characterize these microvascular net-works remains one of the main obstacles. Developing a fully-automated solution is thus substantial for further explorations, especially to quantify the impact of cerebrovascular malformations associ-ated with many cerebrovascular diseases. A common pathogenic outcome in a set of neurovascular disorders is the formation of microstrokes, i.e., micro occlusions in penetrating arterioles descend-ing from the pial surface. Recent experiments have demonstrated the impact of these microscopic events on brain function. Hence, it is of vital importance to develop a non-invasive and translatable approach to identify their presence in a clinical setting. In this thesis, a fully automatic processing pipeline to address the problem of microvascular anatom-ical modeling is proposed. The modeling scheme consists of a fully-convolutional neural network to segment microvessels, a 3D surface model generator and a geometry contraction algorithm to produce vascular graphical models with a single connected component. An improvement on this pipeline is developed later to alleviate the requirement of water-tight surface meshes as inputs to the graphing phase. The novel graphing scheme works with relaxed input requirements and intrin-sically captures vessel radii information, based on deforming geometric graphs constructed within vascular boundaries instead of surface meshes. A mechanism to decimate the initial graph struc-ture at each run is formulated with a convergence criterion to stop the process. A refinement phase is introduced to obtain final vascular models. The developed computational modeling is then ap-plied to simulate potential MRI signatures of microstrokes, combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). The hypothesis is driven based on recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially oriented, and op-tical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n=5) before and after inducing targeted photothrombosis, are analyzed. The computational vascular graphs are exploited within a 3D Monte-Carlo simulator to characterize the magnetic resonance (MR) re-sponse, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. The proposed graphing pipeline is validated on both synthetic and real angiograms acquired with different imaging modalities. Compared to other efficient and state-of-the-art graphing schemes, the experiments indicate that the proposed scheme produces the lowest geometric and topological error rates on various angiograms. The evaluation also confirms the efficiency of the proposed scheme in providing representative models that capture all anatomical aspects of vascular struc-tures. Next, searching for MRI-based signatures of microstokes, the proposed vascular modeling is exploited to quantify the minimal intravoxel signal loss ratio when applying multiple gradient di-rections, at varying sequence parameters with and without ASL. With ASL, the results demonstrate a significant difference (p<0.05) between the signal-ratios computed at baseline and 3 weeks after photothrombosis. The statistical power further increased (p<0.005) using angiograms captured at week 4. Without ASL, no reliable signal change is found. Higher ratios with improved significance are achieved at low magnetic field strengths (e.g., at 3 Tesla) and shorter readout TE (<16 ms). This study suggests that microstrokes might be characterized through ASL-DWI sequences, and provides necessary insights for posterior experimental validations, and ultimately, future transla-tional trials