MULTI-SCALE MODELING OF THE FONTAN CIRCULATION USING A MOCK CIRCULATORY SYSTEM

The Fontan circulation is the result of a series of operations performed to save the lives of children born with univentricular circulations. The Fontan procedure achieves venous return to the pulmonary circulation without a ventricular power source. The load on the heart is reduced to normal, and these patients can lead a normal life into adulthood, although late complications continue to prevent normal lifespan. A unique feature of the Fontan circulation is the dependency of inferior vena cava flow on respiration. The Fontan circulation has been modeled experimentally using an adjustable mock circulatory system, which for the first time includes the influence of respiration. A multi-scale model based on a realistic, 3D patient-specific test section coupled with a lumped parameter model tuned to patient-specific parameters is used to simulate the pressure and flow found in the Fontan circulation. For the first time, the clinically observed respiratory effects in TCPC venous physiology were successfully simulated in an experimental model, where venous flow increased during inspiration and decreased during expiration. Clinically observed hepatic vein flow reversal was also seen in the model. This reverse flow was accentuated when the pulmonary vascular resistance was increased on the venous side

Development of a prosthetic heart valve with inbuilt sensing technology, to aid in continuous monitoring of function under various stenotic conditions

In spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design.In spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design

DESIGN AND EVALUATION OF A NOVEL PULSATILE BIOREACTOR FOR BIOLOGICALLY ACTIVE HEART VALVES

Biologically active replacement heart valves (tissue engineered, recellularized xenograft) offer enhanced function compared to current valve therapies by possessing the capacity for remodeling and growth to meet the hemodynamic needs of the patient and eliminating the need for chronic medication. However, many fundamental questions remain as to how these valves will function in vivo, and new in vitro tools need to be created to address these questions. Traditional in vitro heart valve testing devices (mock flow loops) are designed to subject valves to physiologic and pathologic hemodynamic conditions. These devices offer a heart valve designer a useful tool with which to evaluate the mechanical functioning of their device in a variety of well-controlled hemodynamic situations. Unfortunately, these devices have not been designed for testing valves built of biologically active materials which require proper nutrient and waste exchange, pH, temperature, and freedom from attacks by microbial organisms in order to function. Pulsatile bioreactors have been developed to provide the aforementioned biological requirements to developing tissue engineered valves [1, 2], but these systems offer very limited hemodynamic control in comparison to mock flow loops. Therefore, in order to better understand the role of hemodynamics in the function of biologically active heart valves (BAHV), and to thereby create better BAHV designs, a new type of pulsatile bioreactor should be created that also incorporates more of the hemodynamic control found in mock circulatory loops. This thesis details the both the development of such a device and evaluating its functionality

Nouvelle Théorie Hémodynamique Flux et Rythme Concept et applications précliniques en utilisant des nouveaux dispositifs d'assistance circulatoire Directeur

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.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Fluid-structure interaction analysis of the aortic valve in young healthy, ageing and post treatment conditions

Optimal aortic valve function, limitation of blood damage, and frequency of thromboembolic events are all dependent upon the haemodynamics within the aortic root. Improved understanding of the young healthy physiological state via investigation of the fluid dynamics around and through the aortic valve is essential to identify detrimental changes leading to pathologies and develop novel therapeutic procedures. The aim of this study is to develop a numerical model that can support a better comprehension of the valve function and serve as a reference to identify the changes produced by specific pathologies and treatments. A Fluid-structure interaction (FSI) numerical model was developed and adapted to accurately replicate the conditions of a previous in vitro investigation into aortic valve dynamics, performed by means of particle image velocimetry (PIV). The model was validated on equivalent physical settings, in a pulse duplicator replicating the physiological healthy flow and pressure experienced in the left heart chambers. The resulting velocity fields and hydrodynamic valve performance indicators of the two analyses were qualitatively and quantitatively compared to validate the numerical model. The validated FSI model was then used to describe realistic young healthy, ageing and post treatment conditions, by eliminating the experimental and methodological limitations and approximations. In detail, in terms of treatments, both surgical and transcatheter valve replacement procedures were investigated. In terms of pathologies, typical alterations frequently due to ageing, namely thickening of the valve leaflets and progressive dilation of the aortic chamber, were studied. The analysis was performed by comparing the data obtained for the ageing and post treatment configurations with those of the young healthy root environment. The results were analysed in terms of leaflets kinematics, flow dynamics, pressure and valve performance parameters. The study suggests a new operating mechanism for the young healthy aortic valve leaflets considerably different from what reported in the literature to date and largely more efficient in terms of hydrodynamic performance

Development of an In Vitro System for Evaluation of Prosthetic Vein Valves

Chronic venous insufficiency is a chronic disorder where venous pressure is not reduced during exercise. In a healthy individual, the vein valves and muscle pumps of the extremities combine to allow for a reduction in venous pressure during exercise. Consistent high pressure in the leg can lead to disability, pain, and ulcer formation. Typical causes of chronic venous insufficiency are venous reflux and acute venous obstruction. Research is under way to develop a prosthetic vein valve that can easily be implanted with a minimally invasive catheter procedure which addresses chronic venous insufficiency. This thesis discusses development of an in vitro test system in order to evaluate new prosthetic venous valves. A lumped parameter model of the leg venous system is developed which can simulate venous pressure and flow during calf muscle action while standing. A table top representation of the lumped parameter model is constructed, and the system is tuned to have a physiological ankle pressure response during exercise. The effects of an ideal venous valve, a missing or incompetent venous valve, and an acute thrombosis are all used as baseline conditions to ensure a physiological response. During tuning, system parameters are adjusted in order to match physiological ambulatory venous pressures and pressure recovery times. After the system has been tuned to have an accurate pressure response, based for all baseline test sections, ambulatory venous pressure and flow rate through each test section is in a physiological range. This is the first time physiological pressure response has been modeled for patients with chronic venous insufficiency, both due to high reflux and acute thrombosis. High reflux flow rate in the biological test section paired with an ambulatory venous pressure in the range sufficient to reduce risk of venous ulceration suggests that reflux flow rate may be an inappropriate parameter for in vitro evaluation of prosthetic valves when not paired with simulation of physiological pressure response

Development and evaluation of a catheter deliverable artificial aortic heart valve prosthesis and delivery system

Currently, malfunctioning heart valves are replaced via highly invasive and costly open-heart procedures. A new alternative approach is a catheter deliverable or percutaneous heart valve. Current PHV prototypes utilize fixed animal tissue as valves. This research investigated the feasibility of an artificial PHV and the development of a delivery system. A left hea11 simulator and a tensile tester were used to characterize the hydrodynamics and mechanics of a novel artificial PHV. Test results showed equal or better in vitro hydrodynamic performance when compared to a St. Jude mechanical valve and an Edwards-Sapien PHV, with a mean pressure drop of \u3c15 mmHg and a mean regurgitation of \u3c5%. The PHV\u27s exceeded requirements for fixation and radial force. The 24 F delivery system successfully delivered and deployed a PHV. The work described herein proves the feasibility of an artificial PHV and delivery system and justifies further investigation into its design and function