Orientador: Reinaldo Wilson Vieira / Tese (doutorado)- Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T08:18:06Z (GMT). No. of bitstreams: 1 VieiraJunior_FranciscoUbaldo_D.pdf: 9716061 bytes, checksum: 94d31e9715d7d77c249963888ed77562 (MD5) Previous issue date: 2009 / Resumo: Introdução: Dentre os equipamentos utilizados em circulação extracorpórea, as bombas de roletes têm grande importância, com modelos disponíveis de vários fabricantes. O ajuste dos roletes é um fator importante nas taxas de hemólise e o potencial hemolítico difere em cada um deles. Pesquisadores nem sempre abordam detalhes sobre os perfis do leito rígido supondo que as formas padronizadas de ajuste garantem valores iguais e comparáveis para todos os modelos de bombas de roletes. Dispomos principalmente de dois métodos para o ajuste de bombas de roletes e nenhum deles considera as características de impulsão do fluido, definida pelo perfil do leito rígido. Objetivo: O objetivo desse trabalho é analisar o perfil hidrodinâmico de três diferentes modelos de bombas de roletes comercializados no Brasil e sua influência no fluxo e refluxo. Materiais e Métodos: Foram utilizados tubos de silicone de 9,5x1,6; 9,5x2,4; 13x2,4 mm de diâmetro de dois fornecedores diferentes. Os testes foram realizados em solução fisiológica e solução análoga ao sangue. O perfil hidrodinâmico de três bombas de roletes foi realizado por medidas de velocidade de queda e calibração dinâmica. Foi investigada a variação das medidas de velocidade de queda com o tempo e testes de compressão em equipamento servo-hidráulico. Os refluxos foram visualizados em aspirador de sangue e reservatório de cardiotomia com medidas simultâneas. Resultados: Os perfis hidrodinâmicos apresentaram diferenças em suas variâncias para medidas de velocidade de queda (P<0,01) e calibração dinâmica (P<0,0001). A tensão residual nos tubos de silicone ocasionou redução nas medidas de velocidade de queda com o tempo (P<0,0002) e foram confirmadas pelos testes de compressão (P<0,0001). Conclusão: Os ajustes realizados pelos métodos de velocidade de queda e calibração dinâmica são dependentes da forma do leito rígido. Comparações envolvendo bombas de roletes devem ser feitas com cautela. A tensão residual em tubos de silicone compromete a repetitividade dos ajustes feitos pelo método de velocidade de queda. / Abstract: Introduction: Among the equipment used in cardiopulmonary bypass, roller pumps have great importance, with models available from several manufacturers. The roller adjustment is an important factor in the rates of hemolysis and the hemolytic potential differs in adjustment. Researchers do not always address details on the profiles of the raceway accepting that the forms of standardized settings ensure equal and comparable values for all models of roller pumps. There are two methods for setting roller pumps and none considers the dynamic characteristics of the fluid, defined by the profile of the raceway. Objective: The aim of this study is to analyze the hydrodynamic profile of three different models of roller pumps commercialized in Brazil and its influence on the flow and back flow. Materials and methods: We used silicone tubes of 9.5x1.6, 9.5 x2.4 and 13x2.4 mm in diameter from two different suppliers. The tests were performed in saline and solution analogous to blood. The hydrodynamic profile in three roller pumps was achieved by measurements of drop rate and dynamic calibration. The drop rate variations were investigated in silicone tubes by measurements of drop rate and the compression tests in servo-hydraulic equipment. Retrograde flows were viewed in blood aspirator and cardiotomy reservoir. Results: The hydrodynamic profiles showed differences in their variances for measurements of drop rate (P <0.01) and dynamic calibration (P <0.0001). The residual stress in the silicone tubes caused reduction in drop rate with time (P<0.0002) and were confirmed by compression tests (P <0.0001). Conclusion: The adjustments made by the methods of drop rate and dynamic calibration are dependent on the raceway profile. Comparisons involving roller pumps must be made with caution. The residual stress in the silicone tubes compromises repeatability of adjustments made by the drop rate method. / Doutorado / Pesquisa Experimental / Doutor em Cirurgia

<div>The thesis includes two application studies of computational fluid dynamics. The first is new and efficient drug delivery to the posterior part of the eye, a growing health necessity worldwide. Current treatment of eye diseases, such as age related macular degeneration (AMD), relies on repeated intravitreal injections of drug-containing solutions. Such a drug delivery has significant drawbacks, including short drug life, vital medical service, and high medical costs. In this study, we explore a new approach of controlled drug delivery by introducing unique porous implants. Computational</div><div>modeling contains physiological and anatomical traits. We simulate the IgG1 Fab drug delivery to the posterior eye to evaluate the effectiveness of the porous implants to control the drug delivery. The computational model was validated by established computation results from independent studies and experimental data. Overall, the results indicate that therapeutic drug levels in the posterior eye are sustained for</div><div>eight weeks, similar to those performed with intravitreal injection of the same drug. We evaluate the effects of the porous implant on the time evaluation of the drug concentrations in the sclera, choroid, and retina layers of the eye. Subsequent simulations were carried out with varying porosity values of a porous episcleral implant.</div><div>Our computational results reveal that the time evolution of drug concentration is distinctively correlated to drug source location and pore size. The response of this porous implant for controlled drug delivery applications was examined. A correlation between porosity and fluid properties for the porous implants was revealed in this study. The second application lays in the computational modeling of the oscillating flow in rectangular ducts. This computational study has further applications in investigating the fluid flow motion in bodily organs. It can be useful in studying the</div><div>response of bone cells to the wall shear stress in the human body. </div>

This present thesis comprise two major parts both experimental and numerical study which have been conducted in four distinct steps as following: (1) Design, construction, and evaluation of control and hydrodynamic of a bioreactor system. (2) Visualization of fluid flow perfusion in the hollow fibre membrane bioreactor (HFMB) using a biomedical noninvasive imaging technique, i.e. positron emission tomography (PET). (3) Development of a mathematical model for analyzing a hybrid hollow fibre membrane bioreactor (hHFMB) and (4) Development of a dynamic and two-porous media model for analyzing the HFMB with the aid of computational fluid dynamics (CFD), specifically for bone tissue engineering application. The experimental part includes the steps 1 and 2. In the step 1, the flow perfusion bioreactor system has been designed and constructed. The experimental evaluations of hydrodynamic, and control were performed. In this system, mean pressure, mean flow rate, frequency and waveform of the pulsatile pressure and flow rate can be modulated and controlled over the time to simulate both physiological and non-physiological conditions. The temperature, dissolved oxygen, and pH can be controlled.This bioreactor system can be applied to a variety of scaffold configurations, geometries, and sizes as the cell/tissue culture chamber is adjustable in length.This system is autoclavable, and compatible with noninvasive medical imaging techniques. Designing of the inlet and outlet manifold of the bioreactor were performed according to data obtained from CFD simulation of the flow distribution to achieve high efficiencies in the uniformity of flow perfusion. In the second step, PET was proposed for the very first time and a small animal PET system was used to obtain new information about steady and pulsatile flow patterns in the HFMB for tissue engineering applications. The non-homogeneous tracer distribution, as found with PET imaging, implies the occurrence of non-efficient regions with respect to mass transfer. In steady inlet flow condition, a non-uniform distribution of radioactive tracer was obtained. In contrast, the pulsatile inlet flow generated more uniform perfusion than that of steady flow. Further, it was found that in the case of pulsatile flow, the accumulation of the tracer within the bioreactor was efficiently less than that of steady inlet flow at the same condition. Therefore, in one hand these findings have the potential to improve bioreactor design and in the other hand can explore a very important rout to employ PET in developing bioreactors for tissue engineering applications. The numerical part includes the step 3 and 4 in which the numerical study has been performed for 3-D bone tissue growth in HFMB as a case study for large-scale tissue culture. In the step 3, the feasibility of utilizing newly proposed hHFMB for the growth of mesenchymal stem cells (MSCs) to form bone tissue was investigated using numerical simulations. To this aim, a mathematical model using a CFD code was developed to optimize the design and operation parameters of hHFMB for the growth of MSCs. The volume averaging method was used to formulate mass balance for the nutrients and the cells in the porous extracapillary space (ECS) of the hHFMB. The cell-scaffold construct in the ECS of the hollow fibres and membrane wall were treated as porous medium. Cell volume fraction dependent porosity, permeability, and diffusivity of mass were used in the model. The simulations allowed the simultaneous prediction of nutrient distribution and nutrient-dependent cell volume fraction. In addition, this model was used to study the effects of the operating and design parameters on the nutrient distribution and cell growth within the bioreactor. The modeling results demonstrated that the fluid dynamics within the ECS and transport properties and uptake rates in hHFMB were sufficient to support MSCs required for clinical-scale bone tissue growth in vitro and enabled to solve nutrition difficulties because of high cell density and scaffold size. In the step 4, the new dynamic and two-porous media model has been used for analyzing the nutrient-dependent MSCs growth in order to form the bone tissue in the HFMB. In the present model, hollow fibre scaffold within the bioreactor was treated as a porous domain. The domain consists of the porous lumen region available for fluid flow and the porous ECS region, filled with collagen gel containing cells, for growing tissue mass. Furthermore, the contributions of several design and process parameters, which enhance the performance of the bioreactor, were studied. In addition, the dynamic evaluation of cell growth, oxygen and glucose distributions were quantitatively analyzed. The obtained information can be used for better designing of the bioreactor, determining of suitable operational conditions and scale up of the bioreactor for engineering of clinical-scale bone tissue.--Résumé abrégé par UMI.

INTRODUCTION : L’utilisation de la circulation extracorporelle durant la chirurgie cardiaque est associée à des problèmes pulmonaires chez certains patients. L’utilisation d’une pression pulsatile induite par un ballon intra-aortique (BIA) pourrait diminuer la dysfonction endothéliale et la survenue de tels événements. MATÉRIEL ET MÉTHODE : 12 porcs Landrace-Yorkshire ont subi une circulation extracorporelle et ont été divisés en deux groupes et 4 porcs ont servi de contrôles sans CEC. Le premier groupe (n=6) a bénéficié d’un flot pulsatile créé par un BIA en mode interne à 80 battements par minute durant les 90 minutes de l’opération alors que le second groupe (n=6) a subi une CEC standard. Après 60 minutes de reperfusion suivant la CEC, les valeurs hémodynamiques ont été évaluées dont les pressions artérielles, les pressions pulmonaires, l’index cardiaque et la concentration de glucose et de lactate. Les artères pulmonaires sont ensuite montées en chambre d’organe pour évaluer la fonction endothéliale. RÉSULTATS : Les porcs avec pression pulsatile ont tendance à produire moins de lactate sanguin après 60 minutes de reperfusion. Les autres valeurs hémodynamiques sont semblables. Finalement, la relaxation à la bradykinine est significativement meilleure dans le groupe pression pulsatile alors que la relaxation à l’acétylcholine n’est pas significativement différente. CONCLUSION : Ces résultats démontrent que la perfusion pulsatile produite par un BIA protège l’endothélium pulmonaire lors d'une CEC. Cet effet pourrait être dû à une augmentation du flot bronchique qui diminuerait l’ischémie pulmonaire ou à une diminution de la libération de cytokines et de bradykinine qui réduirait les dommages de reperfusion. / INTRODUCTION : Cardiopulmonary bypass (CPB) during cardiac surgery leads to postoperative pulmonary complications. The use of pulsatile pressure with an intra-aortic balloon pump (IABP) could preserve the endothelial function and decrease the occurence of pulmonary problems. MATERIAL AND METHODS : Twelve Landrace-Yorkshire swine were divided into two groups, one group (n=6) received pulsatile perfusion under CPB from an IABP in an internal mode at 80 beats per minute (bpm) and the other (n=6) had a standard CPB of 90 minutes. A third group (n=4) has been used as controls without CPB. The two first groups underwent aortic clamping for 80 minutes with administration of intermittent blood cardioplegia. After 60 minutes of reperfusion following of bypass, swine were sacrificed and pulmonary arteries were harvested. Haemodynamic values were calculated including pulmonary arterial pressures (PAP), mean arterial pressures (mAP), lactate production, blood glucose and cardiac index. Pulmonary arteries were placed in organ chambers and vascular reactivity studies were performed. RESULTS : There was a trend towards lower lactate production with use of pulsatile perfusion after 60 minutes of reperfusion. All other hemodynamics were not significally different in both groups. Relaxation to bradykinin was greater in pulsatile group while relaxation to acetylcholine did not differ. CONCLUSION : IABP induced pulsatile pressure protect the pulmonary endothelium during CPB. This could be explained by an increase in blood flow through the bronchial arteries or by a decreased release of cytokines or bradykinin which could reduce reperfusion damage.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Objetivo: Medir a pulsatilidade da parede do aneurisma de aorta humano antes e depois de sua correção endoluminal. Método: Cinco aneurismas foram submetidos à perfusão pulsátil antes e depois do implante de uma endoprótese. Resultado: o nível da coluna de água oscilou durante a pulsação com variações de 17, 16, 13, 7 e 25 cm antes da colocação da endoprótese. Depois da prótese, a oscilação diminuiu em todos os casos para 13, 12, 9, 3,5 e 23 cm, respectivamente. Conclusão: A pulsação da endoprótese é transmitida à parede do aneurisma / Objective: To measure the pulsatility of human aortic aneurysms before and after exclusion with endograft. Method: Five aneurysms were submitted to pulsatile perfusion before and after implantation of a bifurcated endograft. Result: The level of the water column oscillated during pulsation, in each case, with an amplitude of 17, 16, 13, 7 and 25 cm before the endograft insertion. After that, the amplitudes dropped to, respectively 13, 12, 9, 3.5 and 23 cm.Conclusion: Pulsation of an endograft is transmitted to the aneurysm wall even in the absence of endoleak

Die vorliegende Untersuchung stellt sich die folgenden Fragen: Welchen Stand hat die Entwicklung von mechanischen Kreislaufunterstützungssystemen für Kinder, worin unterscheiden sich die eingesetzten Verfahren? Wie beeinflusst der Blutkontakt mit Fremdmaterial das Kapillarleck beim Kind? Welche Erfahrungen gibt es mit dem pulsatilen Ventrikelunterstützungssystem Berlin Heart beim Kind, welche Schwierigkeiten und Nebenwirkungen sind für das Kindesalter spezifisch? Wann profitieren Kinder von einer mechanischen Kreislaufunterstützung? Die bei Kindern am häufigsten eingesetzten Verfahren, Herzlungenmaschine (HLM), extrakorporale Membranoxygenierung (ECMO) und pneumatisch pulsatiles ventrikuläres Assist device (VAD) unterscheiden sich in Technik, Indikation, Nebenwirkung und möglicher Einsatzdauer erheblich. Die HLM dient der intraoperativen Kreislaufunterstützung. ECMO haben wir seit 1990 zur mittelfristigen Kreislaufunterstützung bei mehr als 70 Kindern für eine Dauer von ein bis zwei, selten bis zu drei Wochen eingesetzt. Mit VAD''s haben wir seit 1990 bei 56 Kindern die Herzfunktion teils monatelang ersetzt. Es bestehen multiple Unterschiede bei dem Einsatz von VAD zwischen Säuglingen, Kindern und Erwachsenen sowohl in der Indikation, Physiologie, Technik, Antikoagulation, der Familienbetreuung und hinsichtlich der Komplikationen. Bei jeder mechanischen Kreislaufunterstützung aktiviert der Fremdflächenkontakt des Blutes das Kontaktsystem, zu dem Gerinnungs- und Komplementsystem gehören. Klinische Äquivalente sind Thrombosen, Thrombozytenverlust und Kapillarleck. Insbesondere Säuglinge neigen zu diesen Komplikationen, weil das Verhältnis von Blutvolumen zu Fremdfläche ungünstig ist und der kontaktabhängige alternative Weg der Komplementaktivierung im jungen Alter vorherrscht. - Wir untersuchten prospektiv den prä- und postoperativen Verlauf von Kontakt- und Komplementsystem (C1q, C3, C4, C1-Inhibitor, Faktor B, Faktor XIIa) bei 11 herzoperierten Säuglingen ohne und 24 Säuglingen mit HLM. Es konnte nachgewiesen werden, dass obwohl bei allen Kindern eine Komplementaktivierung vorhanden war, diese signifikant ausgeprägter in der HLM-Gruppe stattfand. Die Kontaktaktivierung (Faktor XIIa, Präkallikrein) ließ sich nur in der HLM-Gruppe nachweisen, so dass belegt war, dass es nicht die Anästhesie oder die Operation an sich, sondern die HLM ist, die die inflammatorische Reaktion hervorruft. - Bei 27 mit HLM operierten Säuglingen untersuchten wir prospektiv die CLS-Entstehung und die Komplement- und Kontaktaktivierung. Bei den 10 Kindern, die im späteren Verlauf ein Kapillarlecksyndrom (CLS) entwickelten, waren bereits 30 Minuten nach HLM-Beginn die C1-INH-Konzentration und -Aktivität niedriger und Faktor XIIa, C3a und C5a höher als bei den 17 Kindern, die später kein CLS entwickelten. Die Aktivierung korrelierte mit dem Alter der Kinder und der HLM-Zeit, nicht mit der Tiefe der Hypothermie. - Retrospektiv untersuchten wir 28 Kinder (6 Tage - 16 Jahre alt), bei denen im terminalen Herzversagen nach Reanimation die Herzfunktion mit dem parakorporalen pneumatischen VAD Berlin Heart 1-98 Tage lang unterstützt wurde. Zwölf dieser Kinder wurden unter laufender Reanimation mit Herzdruckmassage in den Operationssaal gebracht. 13 Patienten erreichten eine Herztransplantation, 3 Kinder wurden mit dem eigenen Herzen vom System entwöhnt. 12 Kinder starben am System, Todesursachen waren Schock, Multiorganversagen, Sepsis und Blutungen. - Bei 95 herztransplantierten Kindern untersuchten wir retrospektiv die Verläufe in Abhängigkeit davon, ob die Kinder (I) vor der Transplantation in relativ stabilem Zustand zuhause waren (n=33), ob sie (II) kritisch krank hospitalisiert waren (n= 44), oder ob sie (III) nach Reanimation mit einem VAD kreislaufunterstützt wurden (n=18, Dauer 4-111 Tage). Die Überlebensraten nach 1Mo/1J/5J betrugen in Gruppe I 88/88/80 %, Gruppe II 88/82/79 %, Gruppe III 72/72/72 %. Der frühpostoperative Verlauf nach Transplantation war bei Gruppe III nur wenig komplizierter, was den Erfolg der Transplantation nicht minderte. - Retrospektiv untersuchten wir den Verlauf von 4 Kindern mit schwerer Myokarditis, die bei kardiogenem Schock mit biventrikulärem VAD kreislaufunterstützt wurden. Das schockbedingte Multiorganversagen und die Thrombozytopenie bildete sich während der Unterstützung mit dem VAD zurück. Drei Kinder konnten nach Erholung des Myokards vom VAD entwöhnt werden, eines wurde erfolgreich transplantiert. - Ausserdem untersuchten wir den Verlauf von 84 Kindern, die wegen Kardiomyopathie auf der Intensivstation behandelt wurden. Von den 69 (= 82 %), bei denen eine kreislaufstützende medikamentöse Therapie ausreichend war, konnten 32 herztransplantiert werden, 36 besserten sich und wurden nach Hause entlassen und ein Kind verstarb akut. Fünfzehn der 84 Kinder (= 18 %) ließen sich nicht stabilisieren und erhielten nach Reanimation eine mechanische Kreislaufunterstützung mit VAD (Dauer 1 – 98 Tage). Von diesen konnten 12 transplantiert werden. Die in dieser Habilitationsschrift ausgeführten Arbeiten haben weiterführende Fragestellungen und Grenzbereiche des mechanischen Kreislaufersatzes im Kindesalter aufgezeigt und neue Therapiestrategien dargestellt. Dadurch ist es möglich, die Überlebenschancen von Kindern mit terminalem Herzversagen erheblich zu verbessern. Sei es durch Zeitgewinn bis zur Erholung des Myokards oder zum Organangebot auf der HTx-Warteliste. Durch den Zeitgewinn, den die VAD`s den zur HTx gelisteten Kindern bieten, brauchen zur Transplantation freigegebene Kinderherzen seltener verworfen werden, mehr Kinder können überleben und die Ausnutzung der angebotenen Organe gelingt besser. / This scientific work addresses the following questions: what is the state of the art in mechanical circulatory support (MCS) in infants and children? How do the different techniques differ? How does mechanical circulatory support influence the systemic inflammatory response after cardiac surgery? What are the indications for use of the pneumatic pulsatile ventricular support system Berlin Heart in children and what do our experience and the results of its use show? The MCS systems most often used for children of all ages are cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), centrifugal pumps and the pneumatic pulsatile ventricular assist device (VAD). These systems vary in indications, results, side effects and potential supporting time. CPB is used to replace the circulation during cardiac surgery. ECMO has been used in our hospital since 1990 for circulatory support in cases of cardiac failure and of pulmonary failure and has been applied in more than 70 children over a period of 1 to 3 weeks. The VAD (Berlin Heart) has been used since 1990 in 56 children for long-term support, when the heart function had to be supported for up to several months. In VAD use there are multiple differences in indication, physiology, underlying disease, technique, anticoagulation and complications between infants, children and adults. In every case of MCS there is contact and complement activation as a reaction of the blood to foreign surfaces, resulting in capillary leak and activation of coagulation and anticoagulation systems with the risk of thrombosis or bleeding. In particular, young infants are prone to systemic inflammatory response in the form of capillary leak. In a prospective study we compared the complement activation after cardiac operations with or without CPB in 35 infants and measured serially the complement function and concentrations or activity of C1q, C3, C4, C1 esterase inhibitor, factor B, the activated split product C3a, prekallikrein and factor XIIa of the contact system. We found that complement activation occurs in all infants but is significantly higher in the group with CPB. Contact activation occurred only in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia. In 27 infants with CPB surgery we prospectively investigated the early clinical parameters that predict the development of capillary leak syndrome (CLS) and examined the relationship between CLS and complement and contact activation and C1 esterase inhibitor during and after bypass. We found that contact and complement activation occurs during CPB and contributes to CLS more frequently in infants of a younger age and with a prolonged bypass time. This activation and decrease in C1 esterase inhibitor was strongly expressed in the CLS group. Although MCS in intractable heart failure in children has normally been limited to centrifugal pumps and ECMO, we implanted 28 children with the pediatric sized pulsatile air-driven Berlin Heart VAD. Our aim was to keep the children alive and allow recovery from shock sequeale until later transplantation or myocardial recovery. Twelve children were brought to the operating room under cardiac massage. In total 12 children died on the system, but thirteen children were transplanted and three were sucessfully weaned from the system. Acute myocarditis appears to be a promising precondition for complete recovery during VAD support and in patients with cardiomyopathy support until transplantation is the goal for the future. We reviewed the course of 95 children who had undergone heart transplantation in our center to investigate whether previous VAD support has an impact on long-term outcome after transplantation. Three groups were compared and we found that bridging to transplantation with a pulsatile pneumatic VAD is a safe procedure in pediatric patients. After transplantation the overall survival rate is 86 % at 1 month, 82 % at 1 year and 75 % at 5 years. The survival of children previously supported with a VAD is similar to that of patients who were bridged with inotropes or who awaited heart transplantation electively. In 4 children with fulminant myocarditis and cardiogenic shock in whom all aggressive medical treatment failed we found that artificial replacement of the heart with complete unloading was followed by total recovery; 3 patients were successfully weaned from the device. No patient died and heart transplantation was necessary in only one child. Retrospectively we examined the course of 84 children who were treated at the ICU, presenting severe cardiac failure due to cardiomyopathy. In 15 of them medical treatment failed and the disease progressed so rapidly that they would have died during the waiting period before a suitable donor organ was found. After resuscitation these 15 children were supported with a VAD. Only 3 died during the waiting period and 12 (80%) underwent later heart transplantation. Progress has been rapid towards individualized choice of mechanical circulatory support systems for children of different ages and with different indications. With the Berlin Heart VAD prolonged circulatory support until myocardial recovery or until heart transplantation is effective in children and infants. It offers time to restore organ function, allows extubation, mobilization and neurological examination and increases the chances for successful transplantation. It can be used with low device-related morbidity and satisfactory results especially in the myocarditis and the cardiomyopathy groups. Complete recovery from secondary organ dysfunction should be achieved before heart transplantation is considered. We expect not only that children with end-stage heart failure will benefit from long-term VAD support, but also that fewer organs from young donors will be lost. Of particular importance is our experience with myocardial recovery in children with acute myocarditis in whom the devices could be explanted.

Native heart valves with limited functionality are commonly replaced by a bileaflet mechanical heart valve (BMHV). However, despite their widespread use, BMHVs still cause major complications, including hemolysis, platelet activation, and thromboembolic events. These complications are believed to be due to the non-physiologic hemodynamic stresses imposed on blood elements by the hinge flows. Three-dimensional characterization of the hinge flows is therefore crucial to ultimately design BMHVs with lower complication rates. This study aims at simulating the pulsatile 3D hinge flows of various BMHVs placed and estimating the thromboembolic potential associated with each hinge. The hinge and leaflet geometries of clinical BMHVs are reconstructed from micro-computed tomography scans. Simulations are conducted using a Cartesian sharp-interface immersed-boundary methodology combined with a second-order accurate fractional-step method. Physiologic flow boundary conditions and leaflet motion are extracted from the Fluid-Structure-Interaction simulations of the BMHV bulk flow. The accuracy of the solver is assessed by comparing the results with experimental data. The numerical results are analyzed using a particle tracking approach coupled with existing blood damage models to relate the flow structures to the risk for blood damage. Calculations reveal complex, unsteady, and highly 3D flow fields. Zones of flow stagnation and recirculation, favorable to thrombosis and regions of elevated shear stresses, which may induce platelet activation, are identified throughout the hinge and cardiac cycle. The hinge gap width and, more importantly, the shape of the hinge recess and leaflet are found to impact the flow distribution. Avoiding sharp corners or sudden shape transitions appear as key geometrical design parameters to minimize flow disturbances and thromboembolic potential. The computed flows underscore the need to perform full 3D pulsatile simulations throughout the cardiac cycle to fully capture the complexity and unsteadiness of the hinge flows. Though based only on three different designs, this study provides general guidelines to optimize the hinge design based on hemodynamic performance and thromboembolic potential. The developed framework enables rapid and cost-efficient pre-clinical evaluation of prototype BMHV designs prior to valve manufacturing. Application to a wide range of hinges with varying design parameters will eventually help in determining the optimal hinge design.

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.

Objetivo: Medir a pulsatilidade da parede do aneurisma de aorta humano antes e depois de sua correção endoluminal. Método: Cinco aneurismas foram submetidos à perfusão pulsátil antes e depois do implante de uma endoprótese. Resultado: o nível da coluna de água oscilou durante a pulsação com variações de 17, 16, 13, 7 e 25 cm antes da colocação da endoprótese. Depois da prótese, a oscilação diminuiu em todos os casos para 13, 12, 9, 3,5 e 23 cm, respectivamente. Conclusão: A pulsação da endoprótese é transmitida à parede do aneurisma / Objective: To measure the pulsatility of human aortic aneurysms before and after exclusion with endograft. Method: Five aneurysms were submitted to pulsatile perfusion before and after implantation of a bifurcated endograft. Result: The level of the water column oscillated during pulsation, in each case, with an amplitude of 17, 16, 13, 7 and 25 cm before the endograft insertion. After that, the amplitudes dropped to, respectively 13, 12, 9, 3.5 and 23 cm.Conclusion: Pulsation of an endograft is transmitted to the aneurysm wall even in the absence of endoleak