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.

Arterial pulse pressure is critically important to a number of diseases such as isolated systolic hypertension, coronary artery disease and heart failure. Determining the cause of increased pulse pressure has been hampered for two reasons. First, pulse pressure results from contraction of the heart and the load formed by the complex arterial tree. Pressure pulses travel from the heart to the peripheral arteries. As they reach a bifurcation or change in arterial wall properties, some of the pulses get reflected and propagate retrograde towards the heart. Second, two different modeling approaches (0-D and 1-D) describe the arterial system. The Windkessel model ascribed changes in pulse pressure to changes in total arterial compliance (Ctot) and total arterial resistance, whereas the transmission model ascribed them to changes in the magnitude, timing and sites of reflection. Our investigation has addressed both these limitations by finding that a complex arterial system degenerates into a simple 2-element Windkessel model when wavelength of the propagated pulse increases. This theoretical development has yielded three practical results. First, isolated systolic hypertension can be viewed as a manifestation of a system that has degenerated into a Windkessel, and thus increased pulse pressure is due to decreased Ctot. Second, the well-discussed Augmentation Index does not truly describe augmentation of pulse pressure by pulse reflection. Third, the simple 2-element Windkessel can be used to characterize the interaction among heart, arterial system and axial-flow left ventricular assist device analytically. The fact that arterial systems degenerate into Windkessels explains why it becomes much easier to estimate total arterial compliance in hypertension?total arterial compliance is the dominant determinant of pulsatile pressure.

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Lors d'une lésion vasculaire, les plaquettes adhèrent, s’activent et agrègent pour former un clou hémostatique qui stoppe le saignement. Dans un contexte pathologique, l’agrégation plaquettaire mène à la formation d’un thrombus qui peut obstruer une artère malade et entrainer des pathologies ischémiques graves. Les agents antiplaquettaires actuels, qui ciblent l’activation et l’agrégation des plaquettes, ont une efficacité reconnue, mais ont pour limites, la récurrence d'événements ischémiques et le risque hémorragique. L’objectif central de ma thèse a été d’explorer l’importance des étapes initiales d’adhérence des plaquettes aux protéines sous-endothéliales et du rôle du flux sanguin dans l’agrégation des plaquettes. J’ai pu montrer qu’un anticorps dirigé contre la GPIbβ, RAM.1, réduit la signalisation du complexe GPIb-V-IX et la formation de thrombi sans affecter l'hémostase. J’ai également mis en évidence que la fibronectine cellulaire fibrillaire est une surface thrombogène qui assure l’adhérence, l'activation, l'agrégation et l'activité pro-coagulante des plaquettes. Enfin, mes travaux indiquent que la pulsatilité du flux sanguin possède un rôle inverse sur la croissance des thrombi en conditions physiologique et pathologique. En conclusion, ce travail met en lumière l’importance des étapes initiales d’adhérence des plaquettes et de la pulsatilité du flux sanguin dans l’agrégation plaquettaire. / Following vascular injury, blood platelets adhere, become activated and aggregate to form a hemostatic plug which stops the bleeding. In a pathological context, platelet aggregation can also lead to the formation of an occlusive thrombus, responsible for lifethreatening ischemic events. Current antiplatelet drugs targeting platelet activation and aggregation, have a recognized efficacy, but also present some limitations including the recurrence of ischemic events and the risk of bleeding. The aim of my thesis was to explore the importance of the initial step of platelet adhesion to subendothelial proteins and the role of pulsatile blood flow in platelet aggregation. I provided evidence that RAM.1 an antibody directed against GPIbβ, reduces GPIb signaling and thrombus formation without affecting hemostasis. My work also showed that fibrillar cellular fibronectin is a thrombogenic surface which supports efficient adhesion, activation, aggregation and procoagulant activity of platelets. Finally, I observed that the pulsatility of the blood flow has an inverse role in the growth of thrombi in physiological and pathological settings. In conclusion, this work highlights the importance of initial stages of platelet adhesion and of the blood flow pulsatility in platelet aggregation.

Le coeur et les vaisseaux sanguins sont directement issus de l'endothélium et dépendent de sa fonction. Le coeur ne représente pas la seule force motrice de notre système circulatoire, la plupart des stratégies thérapeutiques actuelles des maladies cardiovasculaires sont encore focalisées sur le coeur, négligeant l'ensemble du système circulatoire et le système endothélial. Par exemple, le développement de Dispositifs d'Assistance Cardiaque (DAC) est influencé par le coeur, conçu pour suivre,obéir et doit être synchronisé avec un organe malade.De nombreux « signaux » de nature différente sont capables d’activer les cellules endothéliales : les forces de cisaillement créées par le flux sanguin parallèle à la surface de la paroi des vaisseaux, mais également les forces perpendiculaires provoquées par l’étirement de la paroi artérielle par les variations de la pression et la qualité cyclique de ces forces. L’activation de cellules endothéliales est due à la pulsatilité du flux mais aussi à l’action de substances vasoactives et des médiateurs de l’inflammation.Dans notre travail de thèse, nous proposons une nouvelle approche thérapeutique,basée sur une révision fondamentale de l'ensemble du système circulatoire: exposer les défauts de la gestion courante des maladies cardiovasculaires (MCV). Notre nouveau concept se concentre sur la dynamique des flux sanguins pour stimuler,restaurer et maintenir la fonction endothéliale, et compris le coeur lui-même. Nous avons développé et évalué une nouvelle génération de DAC pulsatiles, testée in vitro et in vivo.Pendant le déroulement de cette thèse nous avons effectué les études suivantes:1. Etude d’un prototype de cathéter pulsatile. Il est testé de manière isolée dans un modèle expérimental d’ischémie aiguë du myocarde et dans un modèle d’hypertension pulmonaire aiguë.2. Etude d’un prototype de tube pulsatile à double lumière. Il est testé in-vitro dans un circuit de circulation extracorporelle, et in vivo comme assistance ventriculaire gauche.73. Etude d’un prototype de combinaison pulsatile. Il est testé sur un modèle animal présentant une défaillance aiguë du ventricule droit. Des prototypes de masques et de pantalons pulsatiles sont en développement.En conclusion, notre approche est basée sur l’activation de la fonction endothéliale plutôt qu’en une assistance cardiaque directe. Ce concept permet une meilleure gestion thérapeutique des maladies circulatoires et cardio-pulmonaires. / The “Heart” is still considered as the main organ to be dealt with, in case ofcardiovascular disease. Nevertheless, the heart is not the only driving force in ourcirculatory system. In fact, the heart and blood vessels are the direct issues of theendothelium and depend on its function. Moreover, almost all current therapeuticstrategies are still focusing on the heart and neglecting the entire circulatoryendothelialsystem. For example, development of cardiac assist devices (CAD) is stillrestrained by the heart, designed to follow, obey and must be synchronized with adiseased organ.Many "signals" of different nature are capable of activating endothelial cells: the shearforces created by the blood flow parallel to the surface of the vessel wall, but alsoforces caused by stretching perpendicular to the artery wall by the cyclic pressuregradient and the quality of these forces. The activation of endothelial cells is due tothat pressurized flow dynamic forces, but also to the action of vasoactive substancesand inflammatory mediators.In this thesis we are proposing a new therapeutic approach, based on a fundamentalrevision of the entire systems: exposing those defects of current management ofcardiovascular diseases (CVD). A concept that focuses on flow dynamics to stimulate,restore and maintain endothelial function including the heart itself. This includespreliminary results of new generations of pulsatile CAD that promote endothelial shearstress (ESS) enhancement. Devices prototypes were tested.During this thesis, pulsatile devices prototypes were tested in vivo, in vitro as well aswith pre-clinical volunteers as follow:1. A pulsatile catheter prototype was tested in 2 pediatric animal models (piglets) of:acute myocardial ischemia; and acute pulmonary arterial hypertension.2. A pulstile tube prototype was tested in vitro (mock circuit) and in vivo (piglets) as aleft ventricular assist device (ongoing).3. Pulsatile suit prototypes were tested: in vivo (piglets) for acute right ventricularfailure treatment. Prototypes of pulsatile mask and trousers are currently in plannedfor pre-clinical studies.9Conclusion, Think endothelial instead of cardiac is our policy for better management ofCVD.

La thèse « Arrêt cardiaque réfractaire aux traitements pharmacologiques: quelle solution proposer pour améliorer la circulation systémique et cérébrale? » a montré que l'amélioration de la fonction circulatoire peut être obtenue à plusieurs étapes de la prise en charge de l'arrêt cardiaque. La première étude du travail, sous la forme d'une étude expérimentale à double randomisation, a montré que l'assistance circulatoire type extracorporeal life support ECLS apporte un bénéfice sur la mortalité dans la prise en charge de l'arrêt cardiaque réfractaire chez le cochon, et que l'adrénaline administrée en intraveineux lors de la résuscitation prolongée n'améliore pas la survie des animaux. La deuxième étude a montré que la canulation pour l'ECLS peut être réalisée rapidement par voie percutanée à l'aide d'un repérage échographique et en utilisant des guides rigides en salle de cathétérisme cardiaque chez les patients en arrêt cardiaque réfractaire, permettant l'initiation de l'ECLS dans des centres dotés de salle de cathétérisme sans chirurgie cardiovasculaire. La troisième étude a retrouvé que l'état de choc et le pH artériel<7,11 sont des critères pronostiques identifiant les patients qui, après un arrêt cardiaque, présentent une reprise d'une circulation spontanée mais sont à risque de décéder d'insuffisance circulatoire réfractaire au traitement par catécholamines. La quatrième étude à montré que la stabilisation de la fonction circulatoire par l'ECLS peut être suivie par une meilleure récupération de la fonction ventriculaire gauche en modulant la postcharge, par un dispositif pulsatile diminuant le débit de l'ECLS lors de la systole cardiaque. Enfin, l'optimisation de la circulation cérébrale nécessite en plus de l'optimisation de la circulation systémique, le contrôle de l'interaction entre la pression en gaz carbonique et le débit sanguin cérébral qui est amélioré par une normalisation de la pression en gaz carbonique en stratégie pH-stat. Cette stratégie mesure la pression en gaz carbonique à la température réelle du patient au lieu de la température de référence 37° comme dans la stratégie alpha-stat. L’ensemble de ces résultats, pouvant être appliqués à différentes étapes de la prise en charge d'un patient présentant un arrêt cardiaque, pourraient permettre l'amélioration du pronostic des patients. / The doctoral dissertation « Cardiac arrest refractory to pharmacological treatments : what solution to propose to improve systemic and cerebral circulation ? » showed that circulatory function improvement can be achieved at several stages of the management of cardiac arrest patients. The first study of the dissertation, a double randomization experimental study, showed that extracorporeal life support - ECLS type circulatory assistance improves mortality in refractory cardiac arrest in pigs, and intravenous administration of epinephrine during prolonged resuscitation does not improve survival.The second study showed that cannulation for ECLS can be performed rapidly by the percutaneous technique using echography guidance and stiff wires in the catheterization laboratory in refractory cardiac arrest patients allowing for ECLS initiation in centres with catheterization laboratories but without cardiovascular surgery.The third study found that circulatory shock and arterial pH<7.11 are prognostic criteria identifying patients who, after a cardiac arrest, have return of spontaneous circulation but are at risk of death from circulatory failure refractory to catecholamine treatment.The fourth study showed that hemodynamic stabilization by ECLS can be followed by a better recovery of the left ventricular function by modulating afterload using a pulsatile device lowering ECLS output during systole.Finally, optimization of the cerebral circulation requires besides optimization of the systemic circulation, the control of the interaction between carbon dioxyde partial pressure and cerebral circulatory output, which is improved by normalizing carbon dioxyde partial pressure in pH-stat strategy. This strategy measures partial pressure of carbon dioxyde at the real temperature of the patients instead of the theoretical 37° reference temperature as in alpha-stat strategy.All these results can be applied at different stages of the management of cardiac arrest patients and may improve their prognosis.

Turbocharging the internal combustion (IC) engine is a common technique to increase the power density. If turbocharging is used with the downsizing technique, the fuel consumption and pollution of green house gases can be decreased. In the turbocharger, the energy of the engine exhaust gas is extracted by expanding it through the turbine which drives the compressor by a shaft. If a turbocharged IC engine is compared with a natural aspirated engine, the turbocharged engine will be smaller, lighter and will also have a better efficiency, due to less pump losses, lower inertia of the system and less friction losses. To be able to further increase the efficiency of the IC engine, the understanding of the highly unsteady flow in turbochargers must be improved, which then can be used to increase the efficiency of the turbine and the compressor. The main objective with this thesis has been to enhance the understanding of the unsteady flow in turbocharger and to assess the sensitivity of inflow conditions on the turbocharger performance. The performance and the flow field in a radial turbocharger turbine working under both non-pulsatile and pulsatile flow conditions has been assessed by using Large Eddy Simulation (LES). To assess the effects of different operation conditions on the turbine performance, different cases have been considered with different perturbations and unsteadiness of the inflow conditions. Also different rotational speeds of the turbine wheel were considered. The results show that the turbine cannot be treated as being quasi-stationary; for example,the shaft power varies for different frequencies of the pulses for the same amplitude of mass flow. The results also show that perturbations and unsteadiness that are created in the geometry upstream of the turbine have substantial effects on the performance of the turbocharger. All this can be summarized as that perturbations and unsteadiness in the inflow conditions to the turbine affect the performance. The unsteady flow field in ported shroud compressor has also been assessed by using LES for two different operational points. For an operational point near surge, the flow field in the entire compressor stage is unsteady, where the driving mechanism is an unsteadiness created in the volute. For an operational point far away from surge, the flow field in the compressor is relatively much more steady as compared with the former case. Although the stable operational point exhibits back-flow from the ported shroud channels, which implies that the flow into the compressor wheel is disturbed due to the structures that are created in the shear layer between the bulk flow and the back-flow from the ported shroud channels. / QC20100622

<p>Non-pulsatile and pulsatile flow in bent pipes and radial turbine has been assessed with numerical simulations. The flow field in a single bent pipe has been computed with different turbulence modelling approaches. A comparison with measured data shows that Implicit Large Eddy Simulation (ILES) gives the best agreement in terms of mean flow quantities. All computations with the different turbulence models qualitatively capture the so called Dean vortices. The Dean vortices are a pair of counter-rotating vortices that are created in the bend, due to inertial effects in combination with a radial pressure gradient. The pulsatile flow in a double bent pipe has also been considered. In the first bend, the Dean vortices are formed and in the second bend a swirling motion is created, which will together with the Dean vortices create a complex flow field downstream of the second bend. The strength of these structures will vary with the amplitude of the axial flow. For pulsatile flow, a phase shift between the velocity and the pressure occurs and the phase shift is not constant during the pulse depending on the balance between the different terms in the Navier- Stokes equations.</p><p>The performance of a radial turbocharger turbine working under both non-pulsatile and pulsatile flow conditions has also been investigated by using ILES. To assess the effect of pulsatile inflow conditions on the turbine performance, three different cases have been considered with different frequencies and amplitude of the mass flow pulse and different rotational speeds of the turbine wheel. The results show that the turbine cannot be treated as being quasi-stationary; for example, the shaft power varies with varying frequency of the pulses for the same amplitude of mass flow. The pulsatile flow also implies that the incidence angle of the flow into the turbine wheel varies during the pulse. For the worst case, the relative incidence angle varies from approximately −80° to +60°. A phase shift between the pressure and the mass flow at the inlet and the shaft torque also occurs. This phase shift increases with increasing frequency, which affects the accuracy of the results from 1-D models based on turbine maps measured under non-pulsatile conditions.</p><p>For a turbocharger working under internal combustion engine conditions, the flow into the turbine is pulsatile and there are also unsteady secondary flow components, depending on the geometry of the exhaust manifold situated upstream of the turbine. Therefore, the effects of different perturbations at the inflow conditions on the turbine performance have been assessed. For the different cases both turbulent fluctuations and different secondary flow structures are added to the inlet velocity. The results show that a non-disturbed inlet flow gives the best performance, while an inflow condition with a certain large scale eddy in combination with turbulence has the largest negative effect on the shaft power output.</p>

Multiple dose regimens are frequently required to optimize therapy; however, such therapy is frequently undermined by poor patient adherence. In fact, patient adherence is inversely related to the number of doses a patient is asked to take each drug. Consequently, great efforts are under way to develop drug delivery systems that are able to release drugs over an extended time interval; this could offer considerable benefits including reducing administration frequency. This dissertation describes multiple dose platforms designed to deliver a variety of drugs as a single oral administration are described in this dissertation. We believe these drug delivery systems can be used to enhance patient compliance and achieve better therapeutic outcomes. We developed and tested a novel gastroretentive pulsatile drug delivery platform. This platform could deliver multiple unit doses of a drug in a pulsatile pattern and be controlled by dissolution/erosion of a lag-time interval layer. The platform was designed to be retained in the stomach whilst pulsing drug at various timed intervals. This would allow each dose of the drug to release above or within an optimized absorption window over an extended period of time. To assure the robustness and reproducibility of the platform, various in vitro dissolution studies and physical stability tests were performed and evaluated through drug release characteristics, buoyancy, and structural integrity evaluations. The applicability of the novel multiple dose platform was demonstrated by providing repeated release profiles of ciprofloxacin and verapamil in a single, once-daily delivery system. Ultimately, this dissertation demonstrates that a novel multiple dose platform could be a suitable alternative dosing strategy for a variety of drugs to improve patient adherence and treatment efficacy. / text

Following a head concussion the intracranial pressure increases due to the impact, which cannot be adequately relieved because of the stiffness of the skull. Popular strategies aimed at decompressing the head consist in the administration of osmotic agents and skull removal. The mechanical properties of bone can be affected by the administration of different solutions. If the malleability of skull is influenced by the osmotic agents that are administered to the patient then the pressure and volume in the intracranial cavity can also be modified following the treatment. In this thesis research, we hypothesize that administered osmotic agents can influence the mechanical properties of the skull, which can also impact the volume the cavity can hold and subsequently the pressure in the head. This premise was tested by modifying existing mathematical models compiled through two general MATLAB codes that allow the computation of a non-symbolic differential-algebraic initial value problem. Three main features were changed in comparison to current models: the skull's influence on the pressure and volume modulation was tested (inputs were obtained from skull tested under different solutions); pulsatile flow was accounted for on the creation and movement of cerebrospinal fluid; and the input on the mechanical behavior of the cranial vessels was accounted for through previously published continuum-mechanics vessel-behavior models. To complete the model, materials and mechanical properties were obtained through laboratory experiments as well as data collection from existing literature. From our bone test we were able to conclude that there are different factors that affect the mechanical properties of bone in various degrees. There is a mild statistical correlation (p-value 0.05) between the mechanical properties of bone obtained from different regions of the skull samples (2-14mm) and the DPBS and hDPBS solutions. Additionally there is a strong statistical difference (p-value 0.05) between the mechanical properties obtained from cross head speed (0.02, 0.002, and 0.004 (mm/s)) and solution variation (DI, DPBS and hDPBS). Finally, we were able to see that there seems to be a correlation between the mechanical properties of bone, the solution treatments and hypertension; although more test need to be developed to affirm this premise since our results are preliminary.