Thesis (M.Med.(Diagnostic Radiology))--University of the Witwatersrand, Faculty of Health Sciences, 2000.

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Identification of material properties for elastic materials is important in mechanics, material sciences, mechanical engineering and biomedical engineering. Although the principle and techniques have been long established, the application in living biology still faces challenges. The biological materials are in general nonlinear, anisotropic, heterogeneous, and subject-specific. The difficulty is compounded sometimes by the requirement of non-destructiveness in medical applications. Recently, the pointwise identification method (PWIM) was proposed to address some of the needs of soft tissue characterization. PWIM is a non-invasive identification method, designed for thin materials; it can sharply characterize arbitrary heterogeneous property distributions. The primary goal of this thesis is to extend the pointwise identification method , originally developed for membranes which by default is of convex shape in pressurized states, to thin structures of arbitrary geometry. This work consists of four parts. The first part investigates the insensitivity of stress solution to material parameters in thin shell structures. This is an important first step, because PWIM hinges on the static determinacy property of the equilibrium problem of membranes. Before introducing the shell element into PWIM, it is necessary to test to what extent the assumption of static determinacy remains reasonable. It is shown that saccular structure which bending stress is small compared to in-plane stress, can still be treated as a statically determined structure. The second part focuses on developing finite element formulations of forward and inverse shell methods for a hyperelastic material model specifically proposed for cerebral aneuryms tissues. This is a preparatory step for the core development. The third part is the development of pointwise identification method for thin shell structures. Methods for stress solution, strain acquisition, and parameter regression will be discussed in detail. The entire process is demonstrated using an example of a geometrically realistic model of aneurysm. The fourth part is testing the applicability on geometrically realistic cerebral aneurysms. Six models were selected in the study; the emphasis is placed on cerebral aneurysm with concave or saddle surface region for which the use of shell theory is a must. The identification results of all six human cerebral aneurysms successfully demonstrate that the shell PWIM can be applied to realistic cerebral aneurysms. Four types of heterogeneous property distributions are considered in the study. It is found that the method can accurately back out the property distributions in all cases. Fiber directions can also be accurately estimated. The robustness of the method at the presentence of numerical noise is also investigated. It is shown that the shell PWIM still works when small perturbations exist in displacements.

This is the peer reviewed version of the following article: Tominari, S., Morita, A., Ishibashi, T., Yamazaki, T., Takao, H., Murayama, Y., Sonobe, M., Yonekura, M., Saito, N., Shiokawa, Y., Date, I., Tominaga, T., Nozaki, K., Houkin, K., Miyamoto, S., Kirino, T., Hashi, K., Nakayama, T. and for the Unruptured Cerebral Aneurysm Study Japan Investigators (2015), Prediction model for 3-year rupture risk of unruptured cerebral aneurysms in Japanese patients. Ann Neurol., 77: 1050–1059. doi: 10.1002/ana.24400, which has been published in final form at http://dx.doi.org/10.1002/ana.24400. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19585号 / 医博第4092号 / 新制||医||1014(附属図書館) / 32621 / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 小泉 昭夫, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A cerebral aneurysm (CA) is an abnormal distension of the wall of an artery in the brain, which results from arterial wall weakening. CAs are poorly understood, but are believed to be the result of a combination of biological and life-style factors. The low incidence of rupture coupled with risks of interventional treatments provide motivation for identifying and treating only those aneurysms at risk of rupture. Computational models of aneurysm evolution may provide great insight into CA disease mechanisms, and guide clinical decision-making. It is well known that vascular cells sense mechanical forces exerted by bloodflow (i.e. haemodynamic forces), which are translated into a myriad of intra- and inter-cellular responses. In this thesis, hypotheses on the role of the patient-specific haemodynamic environment on the evolution of CAs is examined. Arterial geometries are obtained from images of patient-specific vasculature, and the physiological aneurysm is virtually removed and replaced by a novel, fluid-solid-growth (FSG) model. The model incorporates a constitutive model for the artery, growth and remodelling (G&R) hypotheses for arterial wall constituents, and links between G&R and the haemodynamic environment, which is simulated utilising computational fluid dynamics. It is observed that coupling G&R to the patient-specific haemodynamic environment profoundly impacts the shape and size of the evolving aneurysm geometry; in some cases, the model aneurysm is qualitatively similar to the corresponding physiological aneurysm. This provides tentative support for the hypotheses on haemodynamics-induced G&R investigated here, and motivates the need for improved understanding of arterial adaptation to physiological conditions. This will facilitate the improvement and validation of the model, and may ultimately lead to predictive models with clinical application on a patient-specific basis.

Cerebral aneurysm is a pathology of the circulatory system in the brain in which an arterial wall balloons into a blood-filled sac. If the aneurysm ruptures, stroke can occur and has a high probability of causing permanent disability or death. Aneurysm surgery carries a high rate of morbidity and mortality compared to the natural rate of aneurysm rupture, so physicians must take care in recommending surgery for an aneurysm patient. However, very little is known about the etiology of brain aneurysm rupture and what prognostics exist. The International Study for Intracranial Aneurysms suggested that large aneurysm size and posterior location are important factors in identifying high rupture risk. However, many small aneurysms and aneurysms in other portions of the circulation still rupture. Many studies have assessed morphological traits, identified from aneurysm appearance on diagnostic medical images, and found such traits to be different in aneurysms that ruptured and aneurysms that did not rupture. In fact, more than 50 such morphological indices have been introduced in the literature, and many of them redundantly quantify particular morphological characteristics. In order to demonstrate the prognostic ability of morphology as an indicator of rupture risk, however, a large longitudinal cohort study must be carried out. A study such as this is time-consuming and expensive, and each additional hypothesis that a particular morphological index is predictive of rupture risk would require increasing the study population size in order to fulfill the necessary statistical power requirements for a rigorous test. Thus, a minimal set of physically meaningful, independent metrics that fully describe the aneurysm morphology is needed. In this dissertation an automated protocol was developed to process segmented medical images and extract an exhaustive set of morphological indices that quantify all relevant morphological features. Each morphological index was then analyzed for robustness to inter-user variability and for sensitivity to the particular morphological characteristic that it was designed to quantify. A factor analysis was then performed using the most robust, sensitive metrics on a population of unruptured aneurysms from five data centers and 276 patient-specific aneurysms. The results from the factor analysis were utilized to ascertain what morphological features those metrics truly described, if there were any redundancies in definition, and the variance each morphological trait described in the population. Four underlying morphological constructs were uncovered through the factor analysis. The first factor, sac size, was highly aligned with morphological indices that measured volume and one-dimensional size measurements. Sac size described 50% of the variance in the data set. The second factor, sac irregularity, was highly aligned with morphological indices that described various aspects of irregular shape. A set of variables that all were implicated in causing irregular shape, but in reality measured sac-neck size relation, also merited inclusion of a second metric to describe the variance seen in the second factor. Sac irregularity described 20% of the variance in the data set. The third factor, sac ellipticity, aligned highly with morphological indices that described the overarching ellipticity of the aneurysm sac independent of other non-spherical characteristics. Sac ellipticity described 13% of the variance in the data set. The fourth factor, sac-vessel size relation, aligned highly with morphological indices that described the size of the aneurysm sac in relation to its parent vessel. Sac-vessel size relation described 7% of the variance in the data set. All four of these factors in combination described 91% of the variance in the data set. Five morphological indices – non-planar isolation sac volume (Vnp), Voronoi diagram core evolution irregularity index (IRRvdc), tissue stretch ratio (TSR), Voronoi diagram core evolution ellipticity index (EIvdc) and size ratio (SRang) were determined to be the key indices for describing aneurysm morphology. Finally, the proposed metrics were used to test the hypothesis that aneurysms that are chosen for untreated observation are morphologically different than those that are treated – commonly referred to as selection bias. Study population was 27 patient-specific aneurysms that were placed on untreated observation (observation group) and 27 patient specific aneurysms that were size- and location-matched but were chosen for treatment (treated group). A significant difference was found in the morphological index that measured ellipticity between the two groups, indicating that physicians already commonly select highly elliptical aneurysms for treatment. This result may give insight into physicians’ choices, and merits further investigation with a larger data set for confirmation. Additionally, because the same result was replicated in both of the metrics chosen to quantify ellipticity (for both manual and automated methods), this highlighted the use of the morphological factors in determining an minimal set of independent, robust morphological indices.

abstract: Treatment of cerebral aneurysms using non-invasive methods has existed for decades. Since the advent of modern endovascular techniques, advancements to embolic materials have largely focused on improving platinum coil technology. However, the recent development of Onyx®, a liquid-delivery precipitating polymer system, has opened the door for a new class of embolic materials--liquid-fill systems. These liquid-fill materials have the potential to provide better treatment outcomes than platinum coils. Initial clinical use of Onyx has proven promising, but not without substantial drawbacks, such as co-delivery of angiotoxic compounds and an extremely technical delivery procedure. This work focuses on formulation, characterization and testing of a novel liquid-to-solid gelling polymer system, based on poly(propylene glycol) diacrylate (PPODA) and pentaerythritol tetrakis(3-mercaptopropionate) (QT). The PPODA-QT system bypasses difficulties associated with Onyx embolization, yet still maintains non-invasive liquid delivery--exhibiting the properties of an ideal embolic material for cerebral aneurysm embolization. To allow for material visibility during clinical delivery, an embolic material must be radio-opaque. The PPODA-QT system was formulated with commercially available contrast agents and the gelling kinetics were studied, as a complete understanding of the gelling process is vital for clinical use. These PPODA-QT formulations underwent in vitro characterization of material properties including cytotoxicity, swelling, and degradation behaviors. Formulation and characterization tests led to an optimized PPODA-QT formulation that was used in subsequent in vivo testing. PPODA-QT formulated with the liquid contrast agent ConrayTM was used in the first in vivo studies. These studies employed a swine aneurysm model to assess initial biocompatibility and test different delivery strategies of PPODA-QT. Results showed good biocompatibility and a suitable delivery strategy, providing justification for further in vivo testing. PPODA-QT was then used in a small scale pilot study to gauge long-term effectiveness of the material in a clinically-relevant aneurysm model. Results from the pilot study showed that PPODA-QT has the capability to provide successful, long-term treatment of model aneurysms as well as facilitate aneurysm healing. / Dissertation/Thesis / Ph.D. Bioengineering 2011

abstract: Cerebral aneurysms are pathological balloonings of blood vessels in the brain, commonly found in the arterial network at the base of the brain. Cerebral aneurysm rupture can lead to a dangerous medical condition, subarachnoid hemorrhage, that is associated with high rates of morbidity and mortality. Effective evaluation and management of cerebral aneurysms is therefore essential to public health. The goal of treating an aneurysm is to isolate the aneurysm from its surrounding circulation, thereby preventing further growth and rupture. Endovascular treatment for cerebral aneurysms has gained popularity over traditional surgical techniques due to its minimally invasive nature and shorter associated recovery time. The hemodynamic modifications that the treatment effects can promote thrombus formation within the aneurysm leading to eventual isolation. However, different treatment devices can effect very different hemodynamic outcomes in aneurysms with different geometries. Currently, cerebral aneurysm risk evaluation and treatment planning in clinical practice is largely based on geometric features of the aneurysm including the dome size, dome-to-neck ratio, and parent vessel geometry. Hemodynamics, on the other hand, although known to be deeply involved in cerebral aneurysm initiation and progression, are considered to a lesser degree. Previous work in the field of biofluid mechanics has demonstrated that geometry is a driving factor behind aneurysmal hemodynamics. The goal of this research is to develop a more combined geometric/hemodynamic basis for informing clinical decisions. Geometric main effects were analyzed to quantify contributions made by geometric factors that describe cerebral aneurysms (i.e., dome size, dome-to-neck ratio, and inflow angle) to clinically relevant hemodynamic responses (i.e., wall shear stress, root mean square velocity magnitude and cross-neck flow). Computational templates of idealized bifurcation and sidewall aneurysms were created to satisfy a two-level full factorial design, and examined using computational fluid dynamics. A subset of the computational bifurcation templates was also translated into physical models for experimental validation using particle image velocimetry. The effects of geometry on treatment were analyzed by virtually treating the aneurysm templates with endovascular devices. The statistical relationships between geometry, treatment, and flow that emerged have the potential to play a valuable role in clinical practice. / Dissertation/Thesis / Doctoral Dissertation Bioengineering 2016

abstract: A cerebral aneurysm is an abnormal ballooning of the blood vessel wall in the brain that occurs in approximately 6% of the general population. When a cerebral aneurysm ruptures, the subsequent damage is lethal damage in nearly 50% of cases. Over the past decade, endovascular treatment has emerged as an effective treatment option for cerebral aneurysms that is far less invasive than conventional surgical options. Nonetheless, the rate of successful treatment is as low as 50% for certain types of aneurysms. Treatment success has been correlated with favorable post-treatment hemodynamics. However, current understanding of the effects of endovascular treatment parameters on post-treatment hemodynamics is limited. This limitation is due in part to current challenges in in vivo flow measurement techniques. Improved understanding of post-treatment hemodynamics can lead to more effective treatments. However, the effects of treatment on hemodynamics may be patient-specific and thus, accurate tools that can predict hemodynamics on a case by case basis are also required for improving outcomes.Accordingly, the main objectives of this work were 1) to develop computational tools for predicting post-treatment hemodynamics and 2) to build a foundation of understanding on the effects of controllable treatment parameters on cerebral aneurysm hemodynamics. Experimental flow measurement techniques, using particle image velocimetry, were first developed for acquiring flow data in cerebral aneurysm models treated with an endovascular device. The experimental data were then used to guide the development of novel computational tools, which consider the physical properties, design specifications, and deployment mechanics of endovascular devices to simulate post-treatment hemodynamics. The effects of different endovascular treatment parameters on cerebral aneurysm hemodynamics were then characterized under controlled conditions. Lastly, application of the computational tools for interventional planning was demonstrated through the evaluation of two patient cases. / Dissertation/Thesis / Ph.D. Bioengineering 2013