京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22037号 / 医博第4522号 / 新制||医||1038(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 髙橋 良輔, 教授 湊谷 謙司, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.

An intracranial aneurysm (IA) is a balloon-like focal lesion on the cerebral arterial wall. IAs are poorly understood, but are commonly considered to be a disease caused by multiple factors. Current interventional treatments are accompanied with risks. Given the low incidence of rupture, it would be ideal to only treat aneurysms identified with rupture risk. Numerical models of aneurysm development may provide insight into the disease mechanisms, and contribute to the prediction of disease progression. Better understanding of the disease aetiology will also guide clinical decision making. Different hypotheses have been proposed on the influence of haemodynamic stimuli on IA inception. We investigate this influence by examining the haemodynamic stimuli of the 'pre-aneurysmal' vasculature in the locations of IA formation in 22 clinical cases. The 'pre aneurysmal' geometries are obtained by applying a novel numerical vessel reconstruction method on the aneurysmal geometries. This automated reconstruction method propagates a closed curve along the vessel skeleton using the local Frenet frames to smoothly morph the upstream boundary into the downstream boundary. We observe that locally elevated wall shear stress (WSS) and gradient oscillatory number (GON) are highly correlated with regions susceptible to sidewall IA formation, whilst haemodynamic indices associated with the oscillation of the WSS vectors have much lower correlations. A common assumption made in the literature on arterial growth and remodelling (G&R) is that the 'state of stretch' (denoted as the attachment stretch) at which collagen fibres are configured in the extracellular matrix (ECM) is assumed to be constant. This will lead to an unrealistically thickened arterial wall in modelling aneurysm evolution. We propose a novel 1D mathematical model of collagen microstructural adaption during IA evolution. We assume new collagen fibres are configured into the ECM in a state of attachment stretch distribution which can be temporally adaptive. We explicitly define the functional form of this distribution and model its temporal adaption during IA evolution. This model is then implemented into two 3D models of IA evolution: a solid structural model and Fluid-Solid-Growth (FSG) model. In the solid structural model, the artery is modelled as a two-layer, nonlinear elastic cylindrical membrane using a physiologically realistic constitutive model. The development of the aneurysm is considered as a consequence of the growth and remodelling of its material constituents: elastinous constituents are prescribed to degrade in a localised circular patch; collagen concentration and recruitment variables enable the growth and remodelling of collagen fabric to be simulated; adaption of the attachment stretch distribution is confined locally within the region of aneurysm evolution. The sophisticated solid model predicts stabilised saccular IAs with realistic sizes and wall thicknesses. The FSG model simulates the IA development on patient-specific vasculature: the updated 3D solid structural model is integrated into a patient-specific geometry of the vasculature and the growth and remodelling of the constituents is now linked to the local haemodynamic stimuli obtained from a rigid-wall computational fluid dynamics analysis. Adaption of the attachment stretch distribution is also confined locally in the region where the constituents degrade. An illustrative case of IA development on patient specific geometry is provided. Based on our study, we conclude that incorporating the adaption of attachment stretch distribution is necessary to simulate IA evolution with physiological evolving wall thicknesses. However, how vascular cells confine this adaption heterogeneously needs further investigation. Improved understanding and modelling of the biology of the arterial wall is needed for more sophisticated models of aneurysm evolution. It will in turn assist in understanding the aetiology of IA formation. Ultimately we hope to have a patient-specific growth model that could have the potential be used to assist diagnostic decisions.

<p>Accurately assessing the risk and growth of rupture among intracranial aneurysms (IA) remains a challenging task for clinicians. Hemodynamic factors are known to play a critical role in the development of IAs, but the specific mechanisms are not well understood. Many studies have sought to correlate specific flow metrics to risk of growth and rupture but have reported conflicting findings. Computational fluid dynamics (CFD) has predominantly been the methodology used to study IA hemodynamics. Yet, CFD assumptions and limitations coupled with the lack of CFD validation has precluded clinical acceptance of IA hemodynamic assessments and likely contributed to the contradictory results among previous studies. Experimental particle image velocimetry (PIV) studies have been noticeably limited in both scope and number among IA studies, in part due to the complexity associated with such experiments. Moreover, the limited understanding of the robustness of hemodynamic metrics across varying flow and measurement environments and the effect of transitional flow in IAs also remain open issues. In this work, techniques to enhance IA PIV capabilities were developed and the first volumetric pulsatile IA PIV study was performed. A novel blood analog solution—a mixture of water, glycerol and urea— was developed and an autonomous methodology for reducing experimental noise in velocity fields was introduced and demonstrated. Both of these experimental techniques can also be used in PIV studies extending beyond IA applications. Further, the onset and development of transitional flow in physiological, pulsatile waveforms was explored. The robustness of hemodynamic metrics such as wall shear stress, oscillatory shear index, and relative residence time across varying modalities, spatiotemporal resolutions, and flow assumptions was explored. Additional hemodynamic metrics which have been demonstrated to be influential in other cardiovascular flows but yet to be tested in IA studies were also identified and considered. Ultimately this work provides a framework for future IA PIV studies as well as insight on using hemodynamic evaluations to assess the risk of growth and rupture of an IA, thereby taking steps towards enhancing the clinical utility of such analysis.</p>

No description available.

An intracranial aneurysm can be a serious, life-threatening condition which may go undetected until the aneurysm ruptures causing hemorrhaging within the brain. The typical treatment method for large aneurysms is by embolization using platinum coils. However, in about 15% of the cases treated by platinum coils, the aneurysm eventually re-opens. The solution to the problem of aneurysm recurrence may be to develop more bio-active materials, including certain polymers, to use as coil implants. In this research, a shape memory polymer (SMP) was investigated as a potential candidate for aneurysm coils. The benefit of a shape memory polymer is that a small diameter fiber can be fed through a micro-catheter and then change its shape into a three-dimensional configuration when heated to body temperature. The SMP was tested to determine its thermo-mechanical properties and the strength of the shape recovery force. In addition, composite specimens containing tantalum filler were produced and tested to determine the mechanical effect of adding this radio-opaque metal. Thermo-mechanical testing showed that the material exhibited a shape recovery force a few degrees above Tg. The effects of the metal filler were small and included depression of Tg and recovery force. SMP coils deployed inside a simulated aneurysm model demonstrated that typical hemodynamic forces would not hinder the shape recovery process. The x-ray absorption capability the tantalum-filled material was characterized using x-ray diffractometry and clinical fluoroscopy. Diffractometry revealed that x-ray absorption increased with tantalum concentration, however, not as the rule of mixtures would predict. Fluoroscopic imaging of the composite coils in a clinical setting verified the radio-opacity of the material.

Over the last decade, there has been a growing interest in assessing cerebral aneurysmal wall motion, because of its potential connections to the biomechanical conditions of the vessel wall, which could eventually aid the prediction of aneurysmal rupture risk. Such quantification could provide a valid surrogate for the vascular wall status and integrity. However, the vast majority of current morphological indices used in the literature to predict growth and rupture in cerebral aneurysms do not take into account the temporal changes that occur during the cardiac cycle. This is because these indices are derived from image modalities that do not provide sufficient temporal and/or spatial resolution to obtain dynamic aneurysm information, which is expected to be similar to or below image resolution. Among currently available vascular imaging techniques, 3D rotational angiography (3DRA) and digital subtraction angiography (DSA) have the highest spatial (and temporal) resolution. Still, for a human operator relying solely on qualitative visual observation, even when using images from these modalities, to objectively analyze the small motion and shape changes of the cerebrovasculature of an individual throughout the cardiac cycle is difficult, if not impossible. Therefore, the availability of a robust morphodynamic analysis tool is needed. In this context, this thesis focuses on developing techniques to estimate, quantify and analyze cerebrovascular wall motion, particularly aneurysmal wall motion, using such modalities. The main contributions of the thesis are: 1) a first methodology to estimate and model patient-specific cerebrovascular morphodynamics over one cardiac cycle, through a proposed multiple 2D to 3D image registration framework; 2) an extension of this methodology to provide robust and efficient estimates of cerebrovascular wall motion for clinical evaluation and for further biomechanical modeling of the cerebrovascular wall; 3) a patient study that demonstrates the validity of the developed techniques from clinical practice, through an analysis of 3DRA and DSA images. Each of these contributions is published in or submitted to a peerreviewed international journal. / Durante la última década se ha dado un creciente interés en la evaluación del movimiento de la pared vascular en aneurismas cerebrales. Éste hecho ha sido motivado en gran medida por la relación existente entre dicha motilidad y sus condiciones biomecánicas, pudiendo éstas llegar a ser útiles en la predicción del riesgo de ruptura del aneurisma cerebral analizado. De este modo, de ésta cuantificación, se podría llegar a derivar un indicador indirecto del estado e integridad de la pared vascular. Sin embargo, la gran mayoría de los índices morfológicos utilizados en la actualidad para predecir crecimiento y ruptura de aneurismas cerebrales no consideran los cambios que se producen en el tiempo a lo largo del ciclo cardíaco. Esto se debe a que dichos índices se obtienen a partir de modalidades de imagen que no proporcionan suficiente resolución espacial y/o temporal para obtener información dinámica del aneurisma, cuyo rango de variación se espera sea similar o inferior a la resolución de la imagen. Entre las técnicas de imagen vascular disponibles en la actualidad, la angiografía rotacional 3D (3DRA) y la angiografía de substracción digital (DSA) son las que ofrecen la mayor resolución espacial (y temporal). De todos modos, aún utilizando imágenes de estas modalidades, el análisis objetivo de pequeñas diferencias de forma y movimiento en los vasos cerebrales de un individuo a lo largo de un ciclo cardíaco es difícil, si no imposible para un operador humano utilizando únicamente medidas cualitativas guiadas por inspección visual. Por lo tanto, la disponibilidad de herramientas robustas para el análisis morfodinámico de la vasculatura cerebral resulta necesaria. En este contexto, la investigación de esta tesis se concentra en el desarrollo de técnicas para estimar, cuantificar y analizar el movimiento de las paredes de los vasos cerebrales, con particular énfasis en el movimiento de la pared en aneurismas, utilizando las modalidades indicadas anteriormente. En líneas generales, esta tesis presenta tres contribuciones principales: 1) una primera metodología de estimación y modelado morfodinámico de vasos cerebrales a lo largo de un ciclo cardíaco, utilizando una técnica de registrado de imágenes 2D-3D; 2) una metodología extendida para proporcionar una estimación robusta y eficiente del movimiento de las paredes de los vasos cerebrales para su evaluación clínica y posterior modelado biomecánico de dichas paredes; 3) un estudio sobre una población de pacientes que demuestra la validez de las técnicas desarrolladas en la práctica clínica, a través del análisis en imágenes de 3DRA y DSA. Cada una de estas contribuciones ha sido publicada o se encuentra en fase de revisión en revistas internacionales indexadas.

1 Abstract: Time-dependent and three-dimensional flow of Newtonian fluid is studied in context of two biomechanical applications, flow in cerebral aneurysms and flow in stenotic valves. In the first part of the thesis, the computational meshes obtained from the medical imaging techniques are used for the computation of hemodynamic parameters associated with the rupture potency of the cerebral aneurysms. The main result is the computation within twenty geometries of aneurysms. It is shown that the aneurysm size has more important role in wall shear stress distribution than the fact whether the aneurysm is ruptured or unruptured. The second part of the thesis is addressed to the flow in stenotic valves. It is shown that the method cur- rently used in medical practice is based on assumptions which are too restrictive to be apply to blood flow in the real case. The full continuum mechanics model is presented with physiologically relevant boundary conditions and it is shown that results are consistent with measured data obtained from literature. Then we focus on the obtaining the pressure field from the velocity field. The presented method provides more accurate pressure approximation than commonly used Pressure Poisson Equation. The last chapter of the thesis is dedicated to Nitsche's method for treating slip boundary...

Le risque individuel de rupture des anévrismes cérébraux est un enjeu majeur dans la prise en charge clinique des anévrismes asymptomatiques. La rupture anévrismale se produit lorsque la contrainte intra-pariétale dépasse la contrainte à rupture du matériau composant la paroi. Notre étude a pour objectif d'être un pas vers une nouvelle mesure biomécanique du risque individuel de rupture des anévrismes cérébraux. Dans un premier temps, une étude expéri- mentale fut menée pour caractériser le comportement biomécanique de la paroi anévrismale sur 16 échantillons d'anévrismes prélevés chirurgicalement. L'expérimentation sur les échan tillons de poche anévrismale a permis de dégager trois grandes classes de tissus pour chaque sexe (homme et femme) : souple, rigide et intermédiaire. Il apparaît que tous les anévrismes non rompus appartiennent à la catégorie rigide ou intermédiaire et que tous les anévrismes rompus correspondent à la catégorie souple. Ceci permet de mettre en évidence une corrélation entre le risque de rupture et les propriétés du matériau composant la paroi anévrismale. Dans un deuxième temps, des simulations d'interaction fluide/structure (FSI) ont été réalisées pour comparer les déformations d'un anévrisme " patient spécifique " constitué d'un matériau dégradé et non dégradé. Les résultats montrent que les propriétés du matériaux ont un impact majeur sur l'ampleur de la variation de volume anévrismale diastolosystolique. Les changements en terme de variations de volume en fonction des caractéristiques du tissu sont potentiellement visualisables à l'aide de l'imagerie médicale. Une analyse des incertitudes des paramètres est aussi présentée et montre la robustesse des résultats aux incertitudes des données d'entrée. Il a ensuite été démontré sur 12 cas " patient-spécifique " d'anévrismes différents (forme, taille, localisation et conditions aux limites différentes) qu'il existe toujours une différence significative en terme de variation de volume au cours du cycle cardiaque entre un anévrisme dont la paroi est composé d'un matériau rigide et d'un matériau souple. Cette étude suggère donc que la variation de volume anévrismale pourrait être utilisée comme une base pour une évaluation individuelle du risque de rupture des anévrismes cérébraux. / The individual risk of rupture of cerebral aneurysm is a major stake in the clinical treatment. The aneurismal rupture occurs when the intra-parietal stress exceeds the rupture stress of the material of the aneurismal wall. The goal of our study is to be a step toward a new biomechanical measure of an individual risk of rupture of cerebral aneurysm. First, an experimental study was performed to characterize the biomechanical behavior of the aneurismal wall on 16 samples of aneurysms removed by neurosurgery. The experimentation on the samples allowed us to reach three main categories of tissues for each sex (female and male): soft, intermediate and stiff. All the unruptured aneurysms belong to the stiff category or the intermediate category and all the ruptured aneurysms belong to the soft category. This is allowed us to give prominence to the correlation between the risk of rupture and the properties of the material of the aneurismal wall. Then, Fluid/Structure interaction computations (FSI) were performed to compare the strain of a “patient-specific” aneurysm composed of a degraded and undegraded material. The results show that the properties of the material have a major impact on the scope of the aneurismal volume variation over the cardiac cycle. The volume variation changes depending on the properties of the tissue are potentially viewable by medical imaging. A study of the uncertainties of the parameters is also proposed and shows the robustness of the results. We also demonstrated on 12 cases of “patient-specific” aneurysms that a significant difference stiff exists in terms of volume variation over the cardiac cycle between an aneurysm composed of a stiff and a soft material. This study suggests that the aneurismal volume variation could be used as a basis for an evaluation of the individual risk of rupture of cerebral aneurysms.

Les avancées technologiques endovasculaires des dernières décennies ont été nombreuses ; la diversion de flux en fait partie. Lorsqu’une nouvelle approche permet de traiter de façon efficace et sûre un certain nombre de patients présentant des défis jusque-là difficiles à surmonter, son adoption en pratique clinique peut-être précoce, voire prématurée. Nous avons dans un premier travail réalisé une revue systématique sur les stents dits «Flow Diverters» (FD) et les modèles animaux. Puis nous avons mené quatre expérimentations animales évaluant l’efficacité des FDs dans différents modèles d’anévrismes canins adaptés à l’hypothèse de travail par l’application d’une méthodologie rigoureuse. Nous avons été en mesure de montrer que la technique de diversion de flux est plus à même d’occlure les anévrismes avec de petits collets, des anévrismes dont la branche couverte par le FD est occluse, ou encore quand la porosité du FD en regard de l’anévrisme est diminuée par l’opérateur. Dans le sixième travail, nous avons expérimenté les résultats de la mise en place d’un clip chirurgical sur ces FDs avant d’en déconseiller la pratique. Puis nous avons étudié la variabilité dans la décision des opérateurs d’implanter un FD pour le traitement d’un anévrisme à l’aide d’un questionnaire et ainsi montré l’importante variabilité présente. Enfin nous rapportons le design de l’étude randomisée, pragmatique, multicentrique FIAT (Flow diversion In Aneurysm Treatment) ainsi que ces résultats. / Flow Diversion is one of the relevant technical improvements of the past decade in the endovascular treatment of cerebral aneurysms. When the efficacy and safety of a new tool allow treating challenging aneurysms, this adoption in daily practice can be fast even if the benefit of use is not clearly, scientifically show. We performed a systematic review of studies of these stents called “Flow Diverters” (FD) in animal models. Then we performed 4 animal studies in models we create in order to isolate the propriety of the FD we wanted to study. By using this methodology, we have been able to show that Flow Diversion is more likely to occlude small neck aneurysms, aneurysms in which the jailed branch has been occluded, or when the operator compact the FD in order to decrease the porosity of the device. In a 6th study, we test the result of the use of a clip to occlude a FD. Regarding the results of the test, we recommand to avoid clipping FDs.Then by using a questionaire; we showed the poor agreement of using FD in daily practice by using clinical vignettes. Then we presented the design and the result of the first randomized clinical study on flow diverters FIAT (Flow diversion In Aneurysm Treatment).