Saccular aneurysms are the abnormal plastic deformation of veins and arteries that can lead to lethal thrombus genesis or internal hemorrhaging. Medication and surgery greatly reduce the mortality rates, but treatment is limited by predicting who will develop aneurysms. A common location for saccular aneurysm genesis is at the main middle cerebral artery (MCA) bifurcation. The main MCA bifurcation is comprised of the M1 MCA segment, parent artery, and two M2 segments, daughter arteries. Studies have found that the lateral angle (LA) ratio of the MCA bifurcation is correlated with aneurysm formation. The LA ratio is defined as the angle between the M1 and the larger M2 divided by the angle between the M1 and the smaller M2. When the LA ratio is equal to 1, perfectly symmetrical, no aneurysms are found at the MCA bifurcation. When the LA ratio is greater than 1.6, aneurysms are commonly found at the MCA bifurcation. In the research described here, varying MCA bifurcation angles were compared to uncover any changes to fluid flow and wall shear stress that could stimulate aneurysm growth. Eight pre-aneurysm MCA bifurcation models were created in SolidWorks® using 120 degrees, 90 degrees, and 60 degrees as the angle between the M1 and the larger M2. LA ratios of 1, 1.6 and 2.2 were then used to characterize the other branch angle (60 degrees with a LA ratio of 1 was excluded). These models were imported into COMSOL Multiphysics® where the laminar fluid flow module was used to simulate non-Newtonian blood flow. Fluid flow profiles showed little to no change between the models. Shear stress changed when the LA ratio was increased, but the changed varied between the 120, 90 and 60 degree models. 120 degree models had a 3.87% decrease in max shear stress with a LA ratio of 2.2 while the 90 degree models had 7.5% decrease in max shear stress with a LA ratio of 2.2. Each daughter artery had distinct areas of high shear stress when the LA ratio equaled 1. Increasing the LA ratio or decreasing the bifurcation angle caused the areas of shear stress to merge together. Increasing LA ratio caused shear stress to decrease and spread around the MCA bifurcation. The reduction in max wall shear stress for high LA ratios supports current aneurysm genesis hypothesizes, but additional testing is required before bifurcation geometries can be used to predicted aneurysm genesis.

The interaction between fluid dynamics and biofilm growth plays a key role in both medical and industrial applications. Biofilms, or bacteria that are embedded in a protective matrix of extracellular polymeric substances, settle on interfaces such as on implanted devices or ship hulls. These biofilms canthen cause infectious diseases or significantly increase drag. In this thesis, we investigate the influence of flow, specifically shear stress, on the development of biofilm. The first paper presents a new facility to investigate biofilm growth in laminar flow cells over extended periods of up to several weeks. Optical coherence tomography is used to obtain three-dimensional scans of the biofilm structure at regular intervals. From these time series, we derive a simple model that relates the growth of an individual microcolony to the growth of the full biofilm depending on the wall shear stress. Additionally, we show that biofilm streamers, thin, flexible filaments that extend into the bulk flow, can form on sharp biofilm structures in laminar flow, even if the substratum is a flat surface. The second contribution is a report detailing preliminary studies on biofilm experiments. We investigate the formation of biofilm in the shear layer behinda backward-facing step. The results indicate a maximum shear stress, beyond which biofilm growth is inhibited. We also provide guidelines for the design of experimental setups for the investigation of the influence of fluid dynamics on biofilm and vice-versa. / Samspelet mellan fluiddynamik och biofilmtillväxt spelar en nyckelroll i både medicinska och industriella tillämpningar. Biofilmer, eller bakterier som är inbäddade i en skyddande matris av extracellulära polymera substanser, sätter sig på ytor som på implanterade enheter eller fartygsskrov. Dessa biofilmer kan sedan orsaka infektionssjukdomar eller avsevärt öka vattenmotståndet. I den här avhandlingen undersöker vi hur flöde, speciellt skjuvspänning, påverkar utvecklingen av biofilm. I den första artikeln presenteras en ny uppställning för att undersöka biofilmstillväxt i flödesceller med laminärt flöde under längre perioder på upp till flera veckor. Optisk koherenstomografi används för att få tredimensionella skanningar av biofilmstrukturen vid regelbundna intervall. Från dessa tidsserier härleder vi en enkel modell som relaterar tillväxten av en enskild mikrokoloni till tillväxten av hela biofilmen beroende på väggskjuvspänning. Dessutom visar vi att biofilm filament som sträcker sig in i bulkflödet, kan bildas på skarpa biofilmstrukturer i laminärt flöde, även om substratum är en plan yta.  Det andra bidraget är en rapport som beskriver preliminära studier av biofilmsexperiment. Vi undersöker bildandet av biofilm i skjuvskiktet bakom ett bakåtvänt steg. Resultaten indikerar en maximal skjuvspänning, bortom vilken biofilmstillväxt hämmas. / <p>QC 240314</p>

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Coronary tortuosity is the abnormal curving and twisting of the coronary arteries. Although the phenomenon of coronary tortuosity is frequently encountered by cardiologists its clinical significance is unclear. It is known that coronary tortuosity has significant influence on the hemodynamics inside the coronary arteries, but it is difficult to draw definite conclusions due to the lack of patient-specific studies and an absence of a clear definition of tortuosity. In this work, in order to investigate a relation of coronary tortuosity to such diseases as atherosclerosis, ischemia, and angina, a numerical investigation of coronary tortuosity was performed. First, we studied a correlation between a degree of tortuosity and flow parameters in three simplified vessels with curvature and zero torsion. Next, a statistical analysis based on flow calculations of 23 patient-based real tortuous arteries was performed in order to investigate a correlation between tortuosity and flow parameters, such as pressure drop, wall shear stress distribution, and a strength of helical flow, represented by a helicity intensity, and concomitant risks. Results of both idealized and patient-specific studies indicate that a risk of perfusion defects grows with an increased degree of tortuosity due to an increased pressure drop downstream an artery. According to the results of the patient-specific study, a risk of atherosclerosis decreases in more tortuous arteries - a result different from an outcome of the idealized study of arteries with zero torsion. Consequently, a modeling of coronary tortuosity should take into account all aspects of tortuosity including a heart shape that introduces additional torsion to arteries. Moreover, strength of a helical flow was shown to depend strongly on a degree of tortuosity and affect flow alterations and accompanying risks of developing atherosclerosis and perfusion defects. A corresponding quantity, helicity intensity, might have a potential to be implemented in future studies as a universal single parameter to describe tortuosity and assess congruent impact on the health of a patient. / Master of Science

Computational Fluid Dynamic Simulation of Intracranial Aneurysms Analysis of time-dependent changes of hemodynamic parameters - the road the clinical use Hemodynamics are involved in the genesis of intracranial aneurysms and time- dependent changes of their parameters lead to aneurysm growth, stabilization or rupture. Definition of these changes using computational fluid hemodynamics could significantly contribute to the understanding of aneurysmal development and rupture and could enable the routine use of mathematical simulations. In this study, computational fluid dynamics were performed for nine incidental aneurysms. Five aneurysms were monitored throughout time and factors leading to aneurysm rupture were analyzed. In four aneurysms the influence of the hemodynamics on the growth was defined. Major growth occurred in areas of low wall shear stress and oscillatory index. These areas increased in size during growth time. Contrary to this, neck shape remodeling occurred in areas with large wall shear stress and pressure. Throughout the follow-up of ruptured aneurysms, the minimal wall shear stress decreased, and the area of low wall shear stress increased significantly. The results indicate that decreasing values of minimal wall shear stress and increasing values of low wall shear stress area...

O presente estudo foi realizado para investigar a relação entre forças hemodinâmicas locais e remodelamento intimal e medial nos segmentos pré-estenose e pós-estenose da parede da aorta abdominal de ratos submetidos à estenose acentuada. Foram utilizados ratos Wistar machos divididos em dois grupos: sham-operado, grupo controle em que a aorta foi apenas manipulada, e grupo estenosado, animais submetidos à cirurgia de estenose da aorta abdominal. As aortas demonstraram duas respostas remodeladoras distintas e diferentes ao estímulo hemodinâmico induzido pela coarctação infra-diafragmática. A primeira é o remodelamento no segmento pré-estenótico hipertensivo com tensão circunferencial da parede aumentada associada com estresse tensional normal, fluxo laminar e tensão de cisalhamento normal. As células endoteliais eram heterogêneas, aumentadas em tamanho e alongadas em direção ao fluxo. Além disso, observou-se conspícuas placas neointimais difusamente distribuídas e espessamento medial. Nossos achados sugerem que a tensão circunferencial da parede aumentada devido a hipertensão tem papel fundamental no remodelamento desse segmento através de efeitos biomecânicos sobre o estresse oxidativo e expressão aumentada de TGF-?. A segunda é o remodelamento no segmento pós-estenótico normotenso com fluxo turbilhonar e baixa tensão de cisalhamento na parede associados a tensão circunferencial da parede e estresse tensional normais. As células endoteliais apresentavam-se semelhantes aos controles, exceto por alterações fenotípicas focais associadas à presença de conspícuas placas neointimais focalmente distribuídas, similares mas muito maiores que as encontradas no segmento pré-estenose. Mais estudos são necessários para se determinar como as forças mecânicas do fluxo turbilhonar e da baixa tensão de cisalhamento na parede são detectadas e traduzidas em sinais bioquímicos para as células e convertidas em alterações fenotípicas patofisiologicamente relevantes. / The present investigation was carried out to evaluate the relationship between local hemodynamic forces and intimal and medial remodeling in the proximal and distal segments of the arterial walls of rats in relation to severe stenosis of the aorta. Male Wistar young rats were divided randomly into: operated group, animals submitted to surgical abdominal aorta stenosis, and sham-operated group, a control group of animals submitted to sham operation to simulate abdominal aorta stenosis. Constricted aortas showed two distinct adaptive remodeling responses to hemodynamic stimuli induced by coarctation. The first is remodeling in the hypertensive prestenotic segment with increased circumferential wall tension associated with normal tensile stress, laminar flow/normal wall shear stress. The remodeling in this segment is characterized by enlarged heterogeneous endothelial cells, elongated in the direction of the blood flow, diffusely distributed neointimal plaques, appearing as discrete bulging toward the vascular lumen, and medial thickening. Our findings suggest that increased circumferential wall tension due to hypertension play a pivotal role in the remodeling of the prestenotic segment through biomechanical effects on oxidative stress and increased TGF-? expression. The second is remodeling in the normotensive poststenotic segment with turbulent flow/low wall shear stress and normal circumferential wall tension and tensile stress. The remodeling in this segment is characterized by groups of endothelial cells with phenotypic alterations and focally distributed neointimal plaques, similar but many of them larger than those found in the prestenotic segments. Further studies are needed to determine how the mechanical forces of turbulent flow/low shear stress are detected and transduced into biochemical signaling by the cells of the artery walls and then converted into pathophysiologic relevant phenotypic changes.

Ischaemic heart disease remains the single leading cause of death throughout the world. Rupture of an advanced atheromatous coronary plaque precipitates the majority of these clinical events, resulting in thrombosis and myocardial infarction. Post-mortem studies have identified thin-cap fibroatheroma (TCFA) as the plaque subtype most prone to rupture with prospective virtual-histology intravascular ultrasound (VH-IVUS) studies linking VH-TCFA to future adverse clinical events. VH-TCFA are however common along the coronary tree with the majority remaining clinically silent, suggesting that factors other than plaque phenotype play an important role in determining rupture and future plaque behaviour. Rupture is thought to occur when the structural stress within the plaque exceeds the material strength of the overlying fibrous cap. Previous histological work has demonstrated that ruptured plaques are associated with higher stress compared to non-ruptured controls, with in vivo VH-IVUS studies linking higher plaque structural stress (PSS) with the presentation of acute coronary syndrome. Wall shear stress (WSS) on the other hand has been implicated in early plaque development and plaque growth suggesting that both PSS and WSS can influence future plaque behaviour. The work presented in this thesis is associated with a number of novel findings. First, it is the only work to demonstrate that in vivo PSS is higher in coronary atherosclerotic plaques with rupture vs. no rupture across a range of plaque subtypes and irrespective of whether analysis of the entire plaque or of regions close to the minimal luminal area is performed. Second, it shows that the pattern and extent of plaque progression and regression defined as an increase and decrease in plaque area, respectively, are associated with specific biomechanical environments at baseline, in the only study that examines the role of both PSS and WSS in this process. More specifically, high PSS is associated with changes consistent with increased vulnerability both in areas of progression and regression. On the other hand, lower WSS at baseline is associated with greater increases in plaque area and burden in areas that progress and with smaller decreases in areas that regress largely due to changes in fibrous tissue. Although the role of WSS in determining future plaque behaviour has been previously examined, this is the first time that this is assessed specifically in areas of progression and regression, particularly important in view of the dynamic nature of atherosclerotic plaques. More importantly, the work presented in this thesis demonstrates that the interplay of these biomechanical forces is associated with specific patterns of plaque progression and regression despite the fact that PSS and WSS are independent of each other. This has never been previously demonstrated and further suggests that incorporation of biomechanical analysis can play role in the identification of plaques that lead to future clinical events. Finally, the ability of PSS to identify plaques that lead to adverse clinical events was assessed through a propensity core matched analysis of the PROSPECT (A Prospective Natural-History Study of Coronary Atherosclerosis) study. The analysis presented here is the largest, most extensive and thus most significant work to ever examine this with results suggesting that incorporation of PSS and associated parameters can improve the capability of VH-IVUS to identify plaques that lead to such events. In summary, the results of this thesis suggest that coronary PSS plays an important role in the pathophysiology of plaque rupture, and that its incorporation in routine plaque assessment may improve our current ability to identifying coronary plaques that lead to future adverse clinical events. The interplay between PSS and WSS may also affect future plaque behaviour and in particular progression and regression. Prospective studies are now required to fully evaluate the role of these biomechanical forces in plaque development, and whether their incorporation in plaque evaluation can be of clinical significance.

O presente estudo foi realizado para investigar a relação entre forças hemodinâmicas locais e remodelamento intimal e medial nos segmentos pré-estenose e pós-estenose da parede da aorta abdominal de ratos submetidos à estenose acentuada. Foram utilizados ratos Wistar machos divididos em dois grupos: sham-operado, grupo controle em que a aorta foi apenas manipulada, e grupo estenosado, animais submetidos à cirurgia de estenose da aorta abdominal. As aortas demonstraram duas respostas remodeladoras distintas e diferentes ao estímulo hemodinâmico induzido pela coarctação infra-diafragmática. A primeira é o remodelamento no segmento pré-estenótico hipertensivo com tensão circunferencial da parede aumentada associada com estresse tensional normal, fluxo laminar e tensão de cisalhamento normal. As células endoteliais eram heterogêneas, aumentadas em tamanho e alongadas em direção ao fluxo. Além disso, observou-se conspícuas placas neointimais difusamente distribuídas e espessamento medial. Nossos achados sugerem que a tensão circunferencial da parede aumentada devido a hipertensão tem papel fundamental no remodelamento desse segmento através de efeitos biomecânicos sobre o estresse oxidativo e expressão aumentada de TGF-?. A segunda é o remodelamento no segmento pós-estenótico normotenso com fluxo turbilhonar e baixa tensão de cisalhamento na parede associados a tensão circunferencial da parede e estresse tensional normais. As células endoteliais apresentavam-se semelhantes aos controles, exceto por alterações fenotípicas focais associadas à presença de conspícuas placas neointimais focalmente distribuídas, similares mas muito maiores que as encontradas no segmento pré-estenose. Mais estudos são necessários para se determinar como as forças mecânicas do fluxo turbilhonar e da baixa tensão de cisalhamento na parede são detectadas e traduzidas em sinais bioquímicos para as células e convertidas em alterações fenotípicas patofisiologicamente relevantes. / The present investigation was carried out to evaluate the relationship between local hemodynamic forces and intimal and medial remodeling in the proximal and distal segments of the arterial walls of rats in relation to severe stenosis of the aorta. Male Wistar young rats were divided randomly into: operated group, animals submitted to surgical abdominal aorta stenosis, and sham-operated group, a control group of animals submitted to sham operation to simulate abdominal aorta stenosis. Constricted aortas showed two distinct adaptive remodeling responses to hemodynamic stimuli induced by coarctation. The first is remodeling in the hypertensive prestenotic segment with increased circumferential wall tension associated with normal tensile stress, laminar flow/normal wall shear stress. The remodeling in this segment is characterized by enlarged heterogeneous endothelial cells, elongated in the direction of the blood flow, diffusely distributed neointimal plaques, appearing as discrete bulging toward the vascular lumen, and medial thickening. Our findings suggest that increased circumferential wall tension due to hypertension play a pivotal role in the remodeling of the prestenotic segment through biomechanical effects on oxidative stress and increased TGF-? expression. The second is remodeling in the normotensive poststenotic segment with turbulent flow/low wall shear stress and normal circumferential wall tension and tensile stress. The remodeling in this segment is characterized by groups of endothelial cells with phenotypic alterations and focally distributed neointimal plaques, similar but many of them larger than those found in the prestenotic segments. Further studies are needed to determine how the mechanical forces of turbulent flow/low shear stress are detected and transduced into biochemical signaling by the cells of the artery walls and then converted into pathophysiologic relevant phenotypic changes.