Vascular stents are medical devices used to treat stenoses blockages in arteries that restrict blood flow. Most commonly, stents are made out of stainless steel or nitinol, and are delivered to the afflicted sites via catheter-based delivery systems. Usually, stents are balloon-expandable or self-expanding. In order for the treated vessel to remain patent, it is necessary that the stents be oversized to prevent flow-induced or pressureinduced stent migration. Furthermore, stents must be rigid enough to prevent the collapse of the vessel, allowing the free passage of blood. However, it has been observed that the presence of the stent in the artery triggers adverse biological responses such as neointinal hyperplasia, often times culminating in restenosis. Extensive research external to this investigation has elucidated evidence to suggest that the abnormally high stresses imparted to the arterial wall as a result of stenting are an important factor in the treatment and development of cardiovascular diseases. Furthermore, normal physiologic diameter flcutuations between systole and diastole produce beneficial biological responses in the artery wall. The primary purpose of this study was to investigate specific stent design criteria that minimize the stress field in the arterial wall to mitigate the impact of restenosis. Commerically available finite element software was used to design the stents parametrically, and perform the stress analysis on a hyperelastic arterial model, including the effects of contact between the artery and stent. Seven stent geometries were uniquely defined by varying strut-spacing, ring amplitude, and crown radii of curvature. Stent designs with large strut spacing, large ring amplitude and a greater than zero radius of curvature imparted the less severe stress field in the arterial wall as well as maximizing vessel deflection between systole and diastole. In contrast, stents with small strut spacing, small amplitudes and zero radius of curvature at the crowns imparted significantly higher stresses. The small strut spacing and small amplitude created stiffer stents, prventing the artery from experiencing physiologic diameter fluctuations between systole and diastole. Evidence presented herein suggests that strut spacing should be as wide as possible without causing pillowing of the arterial wall into the stent.

This research forms part of an interdisciplinary project that aims to improve the understanding of haemodynamics and vascular mechanics in arteriovenous shunting. To achieve the high flow rates that enable patients with renal disease to receive haemodialysis, a fistula is created between an artery and a vein. The patency rate of fistulas, especially those located in the upper arm, is low. The approach adopted here makes use of new magnetic resonance image (MRI) technology and computational modelling of blood flow, with a view to improving therapeutic strategies of disease requiring vascular interventions. This thesis presents the construction and development of a 3D finite element model of the fluid-structure interaction in a brachial–cephalic patient–specific fistula. An overview of the mathematical models that describe the vessel wall and fluid behaviour as well their interaction with each other is given. An Arbitrary Lagrangian- Eulerian (ALE) framework is used together with a transversely isotropic hyperelastic constitutive model for the vessel walls, while blood flow is modelled as a Newtonian fluid. A three-element Windkessel model is used to allow the fluid to move through the outlets of the computational domain without causing non–physical reflections. Flow data acquired from MRI is used to prescribe the flow at the inlet. The parameters of the Windkessel-model at the two outlets are calibrated to resemble the flow acquired from the 2D MRI. The model is validated against the flow patterns acquired from the 4D MRI. The flow patterns of the blood, and stress present in the vessel are investigated. Of special significance are the flow and wall shear stress at the anastomosis. An area of very high velocity in the anastomosis is followed by an area of recirculation and low velocity. The propagation of pressure waves and their reflection at the anastomosis are studied. Areas that are subjected to low wall shear stress, high oscillatory wall shear stress or flow circulation are identified as areas where intimal hyperplasia may develop. The flow results from the simulation show good qualitative agreement with the MRI data.

The overall goals of this project were to develop microstructurally based constitutive models to characterize the mechanical behavior of arteries and to investigate the effects of HIV proteins and antiretroviral drugs on the microstructure and mechanical behavior. To this end we created several constitutive models in aim 1 using a rule of mixtures approach, investigated the role of viral proteins in aim 2 through the use a transgenic mouse model, and studied the effects of the antiretroviral drug AZT administered to mice in aim 3. It is well known that the local mechanical environment which cells experience mediates growth and remodeling and that subsequent growth and remodeling can change that mechanical environment. This remodeling includes changes in the content and organization of the constituents of arteries (collagen, elastin, and smooth muscle cells). The first aim thus created models that incorporated the content and organization of these constituents using a rule-of-mixtures approach. The models we developed were able to capture the mechanical behavior of the arteries as well as previously developed phenomenological models while providing more physical meaning to the parameters, some which can be measured experimentally for incorporation into future models. Aims 2 and 3 investigated the mechanical and microstructural changes to murine arteries in response to HIV proteins or the drug AZT. While the development of antiretroviral therapy has greatly increased the life expectancy of patients with HIV, a number of other complications and co-morbidities including cardiovascular disease have become apparent. While clinical data has implicated both the virus and the antiretroviral drugs as playing roles, this work addressed the need of investigating these effects in a controlled manner. Specifically we used mouse models and focused on the two subclinical markers of increased intima-media thickness and arterial stiffening. Aim 2 used a transgenic mouse that expressed most of the human HIV proteins. We observed both intima-media thickening and arterial stiffening in alignment with clinical data. Other changes that also support a proatherogenic phenotype included decreased elastin content and changes in cathepsin activity. Aim 3 administered the antiretroviral drug AZT to healthy mice and we also observed the same subclinical markers of atherosclerosis including intima-media thickening and arterial stiffening as well as the other proatherogenic changes of decreased elastin and changes in cathepsin activity. Several other parameters including axial behavior, opening angles, collagen content, and collagen fiber angles were also quantified. These were important to fully characterize the vessel and may also be incorporated in the future into the constitutive models developed in aim1. In conclusion, in aim 1 we developed a microstructurally based constitutive model of arteries that effectively captures the mechanical behavior and includes parameters that have more physical meaning and some of which are experimentally tractable. Aims 2 and 3 both observed several subclinical markers of atherosclerosis in mice that express HIV proteins or were given AZT, providing a good model for future work and suggesting that both the HIV virus and antiretroviral drugs may play roles in the development of atherosclerosis in HIV.

Arterial wall morphology depends strongly on the hemodynamic environment experienced in vivo. The mammalian heart pumps blood through rhythmic contractions forcing blood vessels to undergo cyclic, mechanical stimulation in the form of pulsatile blood pressure and flow. While it has been shown that stepwise, chronic increases in blood pressure and flow modify arterial wall thickness and diameter respectively, few studies on arterial remodeling have examined the influences that pulsatility (i.e., the range of cyclic stimuli) may have on biaxial wall morphology. We experimentally studied the biaxial behavior of carotid arteries from 8 control (CCA), 15 transgenic, and 21 mechanically altered mice using a custom designed mechanical testing device and correlated those results with hemodynamic measurements using pulsed Doppler. In this dissertation, we establish that increased pulsatile stimulation in the right carotid artery after banding (RCCA-B) has a strong affect on wall morphological parameters that peak at 2 weeks and include thickness (CCA=24.8±0.878, RCCA-B=99.0±8.43 μ m), inner diameter (CCA=530±7.36, RCCA-B=680±32.0μ m), and in vivo axial stretch (CCA=1.7±0.029, RCCAB= 1.19±0.067). These modifications entail stress and the change in stress across the cardiac cycle from an arterial wall macro-structural point of view (i.e., cellular and extracellular matrix) citing increases in collagen mass fraction (CCA=0.223±0.056, RCCA-B=0.314±0.011), collagen to elastin ratio (CCA=0.708±0.152, RCCA-B=1.487±0.26), and cross-sectional cellular nuclei counts (CCA=298±58.9, RCCA-B=578±28.3 cells) at 0, 7, 10, 14, and 42 post-banding surgery. Furthermore, we study the biomechanical properties of carotid arteries from a transgenic mouse of Marfan Syndrome. This arterial disease experiences increased pulse transmission and our findings indicate that alterations occur primarily in the axial direction. The above results are all applied to a predictive biaxial model of Cauchy stress vs. strain.

Cardiovascular disease is the leading cause of mortality in diabetic patients, and diabetes is one of the main causes of cardiovascular disease. Risk factors for cardiovascular disease result in structural and functional changes in the vascular wall. Arterial stiffness is a prominent structural change observed in the arterial wall that can be measured in clinical settings. The purpose of this thesis was to create a static model of the changes in arterial stiffness seen in diabetes. Elastic tubes with varying wall thicknesses were used to create artificial arteries for this purpose. Compliance (inverse of stiffness) of the arteries was determined using a pressurevolume model and a mathematical model. The compliance curves generated using the pressurevolume model exhibited trends predicted by the mathematical model. These trends were comparable to arterial stiffness changes seen in diabetes. Compliance obtained from pressurevolume measurements of elastic tubes with varying wall thickness can therefore be used to model the general trends of arterial stiffness in diabetes.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-06-21T19:41:07Z No. of bitstreams: 1 Renata Kelly da Palma.pdf: 5650038 bytes, checksum: 27a64e62c897fb5ab5e43cf7a98e3250 (MD5) / Made available in DSpace on 2018-06-21T19:41:07Z (GMT). No. of bitstreams: 1 Renata Kelly da Palma.pdf: 5650038 bytes, checksum: 27a64e62c897fb5ab5e43cf7a98e3250 (MD5) Previous issue date: 2015-10-07 / Organ biofabrication is a potential future alternative for obtaining viable organs for transplantation. Achieving intact scaffolds to be recellularized is a key step in lung bioengineering. The decellularizing agent perfusion technique via the pulmonary artery (PA) has been shown very effective in the process however; vascular perfusion pressure and flow vary along the pulmonary decellularization process. These factors are not fully understood it being very important in the optimization process, ensuring the integrity of the scaffold. The objectives were to characterize the pressure / pulmonary vascular flow associated with variation in vascular resistance (VR), according to the control of the infusion (pressure or flow) at the time of the infusion of different decellularizing agents in PA and determine the VR's behavior in relation to different pressures of lung inflation (tracheal pressure) and perfusion (pulmonary artery). For the first study, were used 43 lungs of the healthy mice (C57/BL6) with 7–8 weeks old and in the second study, lungs of the 5 healthy rat (Sprague- Dawley) with 7-8 weeks old. In the first study, after excision and tracheal cannulation, lungs were inflated at 10 cmH2O airway pressure and subjected to conventional decellularization process being perfused through PA. For the second study, the decellularized lungs were subjected to variations in tracheal pressure (0 to 15 cmH2O) and vascular pressure (5 to 30 cmH2O). Pressure (PPA) and flow (V’PA) at the pulmonary artery were continuously measured. The VR (VR=PPA/V’PA) considerably varied throughout lung decellularization, particularly for pressure controlled perfusion, as compared with flow-controlled perfusion. This study shows that monitoring perfusion mechanics throughout decellularization provides information relevant for optimizing the process time while ensuring that vascular pressure is kept within a safety range to preserve the organ scaffold integrity. Moreover, arterial lung pressure has more influence on behavior of vascular resistance in decellularized lungs than positive airway pressure, providing information that could be relevant for future cell repopulation by using the vascular resistance as a facilitator cell distribution throughout pulmonary circuit. / A geração artificial de órgãos é uma alternativa potencial na obtenção de órgãos viáveis para o transplante humano. Obter scaffolds perfeitos para serem recelularizados é um grande desafio e um passo fundamental na bioengenharia de pulmões. A técnica de perfusão de agentes descelularizantes através da artéria pulmonar (AP) tem se apresentado muito eficaz no processo entretanto, a pressão e o fluxo de perfusão vascular variam ao longo do processo de descelularização pulmonar. Estes fatores ainda não se encontram totalmente compreendidos, sendo muito importantes na otimização do processo, assegurando a integridade dos scaffolds. Os objetivos foram caracterizar a relação pressão/fluxo vascular pulmonar associado a variação de resistência vascular (RV), de acordo com o controle da perfusão (pressão ou fluxo) no momento da infusão de diferentes agentes descelularizantes na AP e determinar o comportamento da RV em relação a diferentes pressões de insuflação pulmonar (pressão traqueal) e de perfusão (artéria pulmonar). Para o primeiro estudo, foram utilizados 43 pulmões de camundongos machos saudáveis (C57/BL6) com idade de 7-8 semanas e no segundo estudo, pulmões de 5 ratos machos saudavéis (Sprague- Dawley) com idade de 7-8 semanas. No primeiro estudo, após excisão e canulação da traqueia e da artéria pulmonar, os pulmões foram insuflados a uma pressão de 10 cmH2O na via aérea e submetidos ao processo convencional de descelularização sendo perfundidos através da AP. Para o segundo estudo, os pulmões descelularizados foram submetidos a variações de pressão traqueal (0 à 15 cmH2O) e pressão vascular (5 à 30 cmH2O). A pressão na artéria pulmonar (PPA) e o fluxo da artéria pulmonar (V’PA) foram continuamente mensurados. A RV (Rv=PPA/V`PA.Rv) variou consideravelmente ao longo do processo de descelularização pulmonar, particularmente na perfusão por pressão controlada, quando comparado a perfusão controlada por fluxo. Concluimos que o monitoramento da mecânica de perfusão ao longo do processo de descelularização fornece informações relevantes na otimização do processo, assegurando um limite para pressão vascular, preservando a integridade do scaffold. Somado a estes achados um resultado relevante demonstrou que a pressão arterial pulmonar tem mais influência no comportamento da RV nos pulmões descelularizados do que pressão positiva nas vias aéreas, fornecendo informações importantes para futuro manejo no processo de recelularização utilizando a RV como um facilitador na distribuição celular através do arcabouço celular pulmonar.

Le travail présenté dans ce manuscrit concerne la fabrication de fantômes d'aorte patient spécifiques utilisant une technique de fabrication additive par impression 3D. Ces répliques sont fabriquées en matériaux synthétiques dont les caractéristiques morphologiques et les propriétés mécaniques doivent être proches de celles déterminées sur un patient. Elles permettent d'optimiser ou de développer les techniques d'imagerie médicale, de comprendre les relations entre le comportement mécanique de la paroi aortique et les caractéristiques hémodynamiques du flux sanguin mais aussi de réaliser des entrainements préopératoires aux interventions chirurgicales, telles que le traitement endovasculaire. Dans cette étude, le comportement mécanique hyper-viscoélastique de la paroi aortique est modélisé par un modèle de Maxwell solide généralisé, dont les paramètres ont permis la sélection et le développement de matériaux élastomères de type silicone aux comportements mécaniques contrôlés. Ces matériaux ont été élaborés à partir de mélanges de formulations existantes et des lois de mélange ont été comparées pour guider la définition de la composition idéale permettant d'imiter le comportement mécanique désiré. Nous avons mis au point une méthode basée sur l'imagerie médicale par ultrason, capable d'identifier les paramètres hyper-viscoélastiques d'une paroi vasculaire. Cette méthode a été validée sur des tubes réalisés avec ces formulations de silicone, dont les propriétés mécaniques ont été mesurées avec des méthodes de référence. Puis, ces silicones ont été utilisés dans un processus de fabrication additive utilisant l'impression 3D par voie indirecte. Un travail de conception assistée par ordinateur a été réalisé pour produire un fantôme d'aorte patient-spécifique présentant un anévrisme fusiforme et non-thrombosé dans la région thoracique / The present work deals with the producing of patient-specific aortic phantoms using an additive manufacturing technique by 3D printing. Phantoms are manufactured from synthetic materials with morphological and mechanical characteristics which should be close to these identified on a patient. They can be used to develop techniques of medical imaging, to understand the relationship between aortic mechanical behavior and hemodynamic properties of blood flow, as well as to perform a preoperative training of interventions, such as endovascular treatment. In this study, the hyper-viscoelastic aortic mechanical behavior was described using a generalized solid Maxwell model. Silicone materials were developed based on the model’s mechanical parameters to mimic various aortic mechanical behaviors. These materials were formulated from commercials silicones, and then mixing rules were compared to define the ideal mixture which can mimic the specific mechanical behavior. A nondestructive method based on medical imaging by ultrasound was developed to identify the parameters of a blood vessel hyper-viscoelastic model. Silicone tubes made of our formulations with known reference mechanical parameters, were used to validate this method. Then, these silicone materials were used in an additive manufacturing process using indirect 3D printing. A work of computer aided design was done to produce a patient-specific aortic phantom with a thoracic fusiform aneurysm without thrombosis