Optimisation de stents actifs

Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern of DES, mainly due to delayed healing of the wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the healing process. To this end, we have developed a computational model of blood flow and drug transport in stented arteries which provides a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that minimizes the DES performance metric to identify optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Optimal paclitaxel-eluting stents release the drug either within a few hours or slowly within a year at concentrations considerably lower than current DES. Optimal sirolimus-eluting stents require a slow drug release. Optimal strut shapes for DES are elongated and can be streamlined only if the drug release occurs quickly. The results offer explanations for the performance of recent DES designs, demonstrate the potential for large improvements in DES design relative to the current state of commercial devices, and define guidelines for implementing these improvementsL'utilisation de stents actifs (DES) a révolutionné le traitement de l'athérosclérose. Le relargage contrôlé de médicaments anti-prolifératifs dans la paroi artérielle (PA) a permis de réduire fortement le taux de resténose intra-stent. Mais le risque de thromboses intra-stents tardives demeure un enjeu majeur des DES en partie lié au retard de cicatrisation de la PA endommagée lors de l'implantation. Cette thèse présente une méthode d'optimisation du design des DES afin d'inhiber la resténose sans affecter la cicatrisation. Pour quantifier la performance des différents designs, un modèle numérique décrivant l'écoulement sanguin et le transport de médicaments dans les artères stentées a été développé. Il prend en compte la structure multi-couches de la PA et les interactions du médicament avec les cellules. Un algorithme d'optimisation est couplé au modèle afin d'identifier les DES optimaux. L'optimisation du temps de relargage ainsi que de la concentration initiale du médicament dans le revêtement du DES ont un effet significatif sur la performance. Lorsque le médicament utilisé est le paclitaxel, les solutions optimales consistent à relarguer le produit à des concentrations nettement inférieures à celles des DES actuels soit pendant quelques heures, soit pendant une durée d'un an. Pour le sirolimus, un relargage lent est nécessaire. Les formes optimales des spires du DES sont toujours allongées mais profilées seulement lorsque le relargage est rapide. Ces résultats permettent d'expliquer en partie les performances des différents DES récents et révèlent un fort potentiel d'amélioration dans la conception des DES par rapport aux dispositifs commerciaux actuels

Optimization of Drug Delivery by Drug-Eluting Stents

International audienceDrug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices

Optimisation de stents actifs

L'utilisation de stents actifs (DES) a révolutionné le traitement de l'athérosclérose. Le relargage contrôlé de médicaments anti-prolifératifs dans la paroi artérielle (PA) a permis de réduire fortement le taux de resténose intra-stent. Mais le risque de thromboses intra-stents tardives demeure un enjeu majeur des DES en partie lié au retard de cicatrisation de la PA endommagée lors de l'implantation. Cette thèse présente une méthode d'optimisation du design des DES afin d'inhiber la resténose sans affecter la cicatrisation. Pour quantifier la performance des différents designs, un modèle numérique décrivant l'écoulement sanguin et le transport de médicaments dans les artères stentées a été développé. Il prend en compte la structure multi-couches de la PA et les interactions du médicament avec les cellules. Un algorithme d'optimisation est couplé au modèle afin d'identifier les DES optimaux. L'optimisation du temps de relargage ainsi que de la concentration initiale du médicament dans le revêtement du DES ont un effet significatif sur la performance. Lorsque le médicament utilisé est le paclitaxel, les solutions optimales consistent à relarguer le produit à des concentrations nettement inférieures à celles des DES actuels soit pendant quelques heures, soit pendant une durée d'un an. Pour le sirolimus, un relargage lent est nécessaire. Les formes optimales des spires du DES sont toujours allongées mais profilées seulement lorsque le relargage est rapide. Ces résultats permettent d'expliquer en partie les performances des différents DES récents et révèlent un fort potentiel d'amélioration dans la conception des DES par rapport aux dispositifs commerciaux actuelsDrug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern of DES, mainly due to delayed healing of the wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the healing process. To this end, we have developed a computational model of blood flow and drug transport in stented arteries which provides a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that minimizes the DES performance metric to identify optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Optimal paclitaxel-eluting stents release the drug either within a few hours or slowly within a year at concentrations considerably lower than current DES. Optimal sirolimus-eluting stents require a slow drug release. Optimal strut shapes for DES are elongated and can be streamlined only if the drug release occurs quickly. The results offer explanations for the performance of recent DES designs, demonstrate the potential for large improvements in DES design relative to the current state of commercial devices, and define guidelines for implementing these improvementsPALAISEAU-Polytechnique (914772301) / SudocSudocFranceF

Modeling the transport of drugs eluted from stents: physical phenomena driving drug distribution in the arterial wall

International audienceDespite recent data that suggest that the overall performance of drug-eluting stents (DES) is superior to that of bare-metal stents, the long-term safety and efficacy of DES remain controversial. The risk of late stent thrombosis associated with the use of DES has also motivated the development of a new and promising treatment option in recent years, namely drug-coated balloons (DCB). Contrary to DES where the drug of choice is typically sirolimus and its derivatives, DCB use paclitaxel since the use of sirolimus does not appear to lead to satisfactory results. Since both sirolimus and paclitaxel are highly lipophilic drugs with similar transport properties, the reason for the success of paclitaxel but not sirolimus in DCB remains unclear. Computational models of the transport of drugs eluted from DES or DCB within the arterial wall promise to enhance our understanding of the performance of these devices. The present study develops a computational model of the transport of the two drugs paclitaxel and sirolimus eluted from DES in the arterial wall. The model takes into account the multilayered structure of the arterial wall and incorporates a reversible binding model to describe drug interactions with the constituents of the arterial wall. The present results demonstrate that the transport of paclitaxel in the arterial wall is dominated by convection while the transport of sirolimus is dominated by the binding process. These marked differences suggest that drug release kinetics of DES should be tailored to the type of drug used

Modeling Arterial Drug Transport from Drug-eluting Stents: Effect of Blood Flow on the Concentration Distribution close to the Endothelial Surface

International audienceDrug-eluting stents (DES) are commonly used for treating coronary atherosclerosis. Despite the broad effectiveness of DES, ~5% of treated patients experience complications including in-stent restenosis and late-stent thrombosis. Furthermore, drugs used in DES not only inhibit proliferation of smooth muscle cells but also affect re-endothelialization. We have developed a computational model of the transport of drugs eluted from DES within stented arteries. Previous models have typically treated the arterial wall as one homogeneous porous medium and have often ignored drug reaction with cells in the arterial wall or used an equilibrium assumption. Our model incorporates the multi-layer structure of the arterial wall and accounts for the reaction of the eluted drug with cells of the arterial wall

Dynamics of Arterial Wall Transport for Small Hydrophobic Drugs

International audienceDrugs used in drug-eluting stents (DES) to inhibit proliferation of smooth muscle cells (SMCs) also limit re-endothelialization at the site of stent implantation [1]. Thus, treated patients face an increased risk of late-stent thrombosis. Avoiding this adverse side effect represents one of the major challenges in the design of next-generation DES

Verification of an electron-carbon interaction model for DSMC schemes

International audienceThe Direct Simulation Monte Carlo module of a fully kinetic 3D plasma particle code is currently under development at the Institute of Space Systems (IRS). As the complete discharge simulation of a non-stationary magnetoplasmadynamic thruster is intended, improved models for the DSMC (direct simulation monte carlo) based interaction evaluation in a highly rarefied and strongly disturbed plasma need to be used. For that purpose it is essential to avoid macroscopic quantities (like temperature) in the model approach. Therefore, a collision and reaction evaluation approach was developed and implemented which is based on energy dependent cross section data only. As the thruster propellant is Polytetrafluorethylen (PTFE) a large cross section data base was built, implemented, and verified based on the assumption of an initially fully dissociated and partially ionized plasma. The electron - heavy particle interactions of interest are elastic scattering (including polarization), collisional excitation, de-excitation, and recombination. In this work we present the model approach, details on the implemented Carbon related cross sections as well as the verification procedure which is based on the reproduction of rate coefficients in the range of 20.000 - 200.000 K. © 2010 by the authors

Modeling Arterial Wall Transport for Drug-Eluting Stents

International audienceDrug-eluting stents (DES) are very commonly used for treating coronary atherosclerotic lesions. Despite the broad effectiveness of DES, ∼5% of treated patients experience complications including in-stent restenosis and late-stent thrombosis. The occurrence of these complications depends on various factors including the concentration of the eluted drug in the arterial wall and the rate of arterial re-endothelialization. Drug concentration in the arterial wall needs to be sufficiently high to be efficacious while remaining sufficiently low to avoid compromising wall stability (leading to stent malapposition). Furthermore, because drugs used in DES modulate proliferation rates of not only smooth muscle cells but also endothelial cells, the drug concentration affects re-endothelialization rates. Drug concentration in the arterial wall is determined by the transport and metabolism of the drug and may also be affected by the flow field in the lumen of the stented vessel. In the present study, we develop a computational model of drug transport in the arterial wall. Previous models have typically treated the arterial wall as a homogeneous porous medium [1] and have often ignored drug reaction with cells in the arterial wall [2]. In the present study, we have developed a model that incorporates the multi-layer structure of the arterial wall and have compared its predictions for the distribution of an eluted drug within the arterial wall with those of the single-layer homogeneous wall model. Copyright © 2011 by ASM