L’objectif de ce travail est d’évaluer la biocompatibilité d’un copolymère de Dextrane- Polybutylmethacrylate utilisé comme revêtement de stent métallique en Cobalt-Chrome. L’étude s’est déroulée en trois phase : 1/La production du polymère et la caractérisation physico-chimique, 2/L’évaluation in vitro et 3/L’évaluation in vivo dans plusieurs modèles. Dans un premier temps deux copolymères de concentrations distinctes ont été synthétisés et mis en forme pour les différentes expériences. Leur caractérisation par FTIR, mesure d’angle de contact et une première implantation in vivo évaluant la réaction à corps étranger a permis d’ensélectionner un : le Dex-PBMA. Aucune réaction inflammatoire chronique n’a été observée. Desépreuves dynamiques et une observation des stents recouverts au MEB ont permis de confirmer la présence et la tenue du film de Dex-PBMA sur les stents. Des tests in vitro ont montré une faible d’adhésion bactérienne et plaquettaire ainsi qu’une thrombogénicité modérée. Un dispositif sous flux ex vivo et l’utilisation d’une molécule modèle - le Tacrolimus – ont montré la faisabilité d’utiliser le Dex-PBMA comme plateforme de libération de substances. In vitro, l’adhésion et la prolifération des progéniteurs endothéliaux ainsi que des cellules souches mésenchymateuses étaient faibles mais aucun effet toxique n’a été noté. Finalement les stents recouverts de Dex-PBMA ont été implantés in vivo dans un modèle d’aorte saine de rat puis dans un modèle de resténose chez le lapin. Chez le rat, après 30 jours, une hyperplasie limitée, l’absence de macrophage et une réendothélialisation des mailles ont été observées. Les premières implantations chez le lapin ont confirmé ces tendances mais l’étude doit être élargie afin d’en tirer une conclusion plus fiable. En conclusion, ces données démontrent que le Dex-PBMA est un matériau intéressant pour le revêtement de stent. / The purpose of this work was to study the biocompatibility of a dextran-graft-polybutylmethacrylate copolymer coated on cobalt chromium metallic stent. This study was divided in 3 parts: 1/the production of the copolymer and its physico-chemical characterization; 2/ its in vitro evaluation and 3/ its in vivo evaluation in several models. In the first step, 2 copolymers with different concentrations were synthetized and shaped for the following experiments. Their FTIR examination, contact angle measurement and a first in vivo implantation to evaluate foreign body reaction lead to the selection of one copolymer: the Dex-PBMA. No chronicle inflammatory reaction was noticed. Dynamic tests and SEM observations of coated stents confirmed the presence and the resistance of the Dex-PBMA coating. In vitro tests showed both low bacterial and platelet adhesions and a moderate thrombogenicity. An ex vivo test under flow with a model molecule – the Tacrolimus – showed the ability of Dex-PBMA to deliver drug. In vitro, the human endothelial progenitors and mesenchymal stem cells adhesion and proliferation were low but didn’t reveal any toxic effect. Finally Dex-PBMA coated stent were implanted in vivo in a healthy rat aorta model of stenting then in a rabbit model of restenosis. In rat, the intimal hyperplasia was moderate and an endothelium was present 30 days after stent implantation. First rabbit implantation confirmed these trends nevertheless this study must be extended to obtain significant results. In conclusion, these data demonstrate that Dex-PBMA is an interesting material for stent coating.

Este estudo foi desenvolvido no Instituto de Pesquisas Energéticas e Nucleares IPEN mais especificamente, no Centro de Ciência e Tecnologia dos Materiais CCTM com apoio da empresa Innovatech. Foram estudados tubos de Co-Cr (L605) usados para fabricação de stents coronarianos, aplicação esta que pede um comportamento mecânico específico e biocompatibilidade. Os tubos de CoCr (L605) podem ser adquiridos em duas condições de história térmica: Trabalhado a frio ou com encruamento ou recozido. O tubo recozido se não estiver em condições para a aplicação, dificilmente será possível atingi-las com um novo tratamento térmico. O tubo encruado abre possibilidades para acertar as condições de tratamento térmico e obter a condição ideal de comportamento mecânico, sem comprometer outros aspectos importantes para a aplicação como biocompatibilidade. Foi selecionado um tubo de CoCr (L605) encruado e com uma quantidade grande de precipitados para os testes, foram selecionadas três faixas de temperatura para o tratamento térmico de recozimento uma abaixo do ponto de solubilização (1000°C), uma dentro da temperatura (1175°C) e uma terceira, mais próxima do ponto de fusão alcançável pelo forno (1250°C). Em cada temperatura foram usados quatro períodos de exposição ao forno( 4, 7, 10 e 15 minutos) totalizando uma matriz com 12 condições de tratamento térmico. Em cada tratamento térmico foram incluídas amostras para ensaio de tração e metalografia. O objetivo deste trabalho é estudar os efeitos dos tratamentos térmicos no comportamento mecânico e na microestrutura do material afim de levantar critérios para determinar os melhores parâmetros de tratamento térmico para a aplicação. / This study was developed at IPEN Institute of Energy and Nuclear Research more specifically in CCTM Materials Cience and Tecnology Center, with support of Innovatech Medical. It was studied Co-Cr (L605) tubes used for manufacture of coronary stents, this application require a specific mechanical behavior and biocompatibility. The tubes CoCr (L605) can be acquired in two conditions of thermal history: Cold worked or annealed. If the annealed tube doesn´t have the conditions for the application it is hardly possible to reach them with a new heat treatment. Hardened tube opens up more possibilities to adjust the conditions of thermal treatment and obtain the optimum condition of mechanical behavior without compromising other aspects important for application as biocompatibility. A tube CoCr (L605) Hardened and a relatively large amount of precipitates were selected for the tests, three temperature tracks have been selected for the thermal annealing treatment: below the temperature of solution aneealing(1000 ° C), at solution aneealing(1175 ° C) and a third temperature closest achievable by furnace (1250 ° C). For each temperature four periods of exposure where selected (4, 7, 10 and 15 minutes) totaling a matrix of 12 heat treatment conditions. In each heat treatment, samples for tensile testing and metallography were included. The objective of this work is to study the effects of heat treatment on mechanical behavior and microstructure of the material in order to raise criteria to determine the best heat treatment for the application.

La resténose intra-stent (RIS) est une complication importante du traitement endovasculaire des sténoses et occlusions artérielles dont l’incidence est réduite par les stents actifs. Ces derniers entraînent un retard de cicatrisation de la paroi vasculaire et parfois une réaction d’hypersensibilité au polymère, pouvant être responsable d’une thrombose aigue tardive. En raison de l’absence de modèle ex vivo validé, le modèle animal est actuellement obligatoire pour l’étude de la RIS. Ces modèles posent des problèmes éthiques et ne permettent pas une étude satisfaisante des stents actifs en raison de l’impossibilité d’effectuer des prélèvements réguliers. Le but de ce travail est d’une part l’exploration de deux nouvelles cibles thérapeutiques dans la RIS, l’hémine et EP224283, et d’autre part la mise au point d’un bioréacteur pour l’étude ex vivo hémodynamique de la RIS. Analyse in vivo. Les modèles de RIS utilisés étaient le stenting d’aorte de rat et le stenting d’artères iliaques de lapins hypercholestérolémiques. Sept ou 28 jours après l’implantation du stent, les artères stentées étaient prélevées puis soit incluses en résine pour analyse morphologique, soit congelées pour analyse de l’expression protéique. L’hémine était administrée par voie intrapéritonéale et EP224283 par voie sous cutanée toutes les 48 heures. Les témoins recevaient du sérum physiologique. L’analyse histomorphométrique après traitement par hémine montrait une réduction significative de 30% de la formation de néointima chez le rat et de 48% chez le lapin. La ré-endothélialisation des mailles du stent, analysée en microscopie électronique, était comparable à celle des témoins. L’analyse protéique montrait chez les rats traités par hémine : une réduction de l’expression des cytokines inflammatoires et des protéines impliquées dans la prolifération et la migration des CMLV (ERK1/2 et RhoA), associée à une augmentation de l’expression des protéines régulatrices de la prolifération (p21 et p27), et une réduction de l’apoptose. L’analyse histomorphométrique montrait chez les rats traités par EP224283 une réduction significative de formation de néointima de 20%. L’analyse protéique montrait une réduction de l’expression des protéines impliquées dans la prolifération des CMLV (ERK1/2 et Akt) associée à une augmentation de la forme active de p38, régulatrice de la prolifération. L’expression de Ki67 était réduite chez l’ensemble des rats traités témoignant d’une réduction de prolifération cellulaire. Analyse ex vivo : En partenariat avec l’ENSAM (Paris), nous avons confectionné et breveté un bioréacteur pour l’étude ex vivo de la RIS en conditions hémodynamiques et biologiques semblables au vivant. Ce bioréacteur fait circuler un flux pulsé dans 6 artères branchées en dérivation et immergées dans du milieu de culture cellulaire. Ce circuit est logé dans un incubateur afin de maintenir les tissus vivants durant l’expérimentation. Son objectif est d’affiner l’étude des nouveaux stents actifs par la possibilité de prélèvements multiples, d’analyser les écoulements, de travailler avec des artères humaines (prélevées lors de dons d’organes) et de s’affranchir en partie du modèle animal. Ces travaux montrent l’intérêt de deux nouvelles molécules thérapeutiques dans la RIS. Celles-ci limitent la prolifération cellulaire sans empêcher la cicatrisation de la paroi vasculaire. Notre modèle d’étude ex vivo hémodynamique de la RIS n’a jamais été décrit dans la littérature et permettra une analyse précise des nouveaux stents. Ce modèle va réduire le recours à l’expérimentation animale. Nos travaux futurs comprendront la mise au point de nouveaux stents actifs à l’hémine et à EP224283, ainsi que la validation et l’exploitation du modèle de RIS hémodynamique ex vivo. / In stent restenosis (ISR) is a major complication of endovascular treatment due to an excessive healing of the arterial wall. Drug eluting stents (DES) reduce the rate of ISR but expose to late stent thrombosis, related to a delayed or incomplete healing of the arterial wall, and also to hypersensitivity reactions induced by the polymer. Currently animal models are mandatory to investigate ISR as there is no reliable in vitro model. Nevertheless, these models are often far from human ISR, because of the underlying atherosclerosis process. They are also not suitable for testing DES because several experimentations and multiple samples are required. In this work, we assess the effects of two new therapeutic molecules to reduce ISR, hemin and EP224283, and we developed a new in vitro model of ISR, reproducing a hemodynamic and biological physiological environment. In vivo analysis. In stent restenosis models were stent implantation in rat abdominal aorta or in hypercholesterolemic rabbit iliac arteries. Seven or 28 days after stent implantation, the stented arteries were removed and either frozen for protein analysis or placed in fixative for morphological analysis with optical or electronical microscopy. Animals received hemin intraperitoneally or EP224283 subcutaneously every 48 hours. Control animals received saline. Histomorphological analysis at day 28 revealed that in the hemin treated group, the extent of neointima area was significantly reduced compared to the control group. A 30% decrease was observed in rats and 40% in rabbit. Endothelial coverage in electronic microscopy was similar in hemin-treated rats and rabbit when compared to their controls. The protein analysis in rats revealed that hemin limited the early inflammatory response and cellular mechanisms implicated in VSMC proliferation (ERK1/2 and p21 p27), in VSMC migration (RhoA) and reduce apoptosis. At day 28, EP224283 significantly reduced neointima growth around 20% in rats. Protein analysis revealed that EP224283 reduced vascular smooth muscle cells proliferation pathways: both ERK1/2 and Akt activated form were down-regulated in the treated rats, and p38 activated form were up-regulated. Expression of Ki67 was also reduced in both hemin and EP224283 treated group, indicating a reduced proliferation of vascular cells.Ex vivo experiments. In association with ParisTech, we developed a bioreactor for ex vivo study of ISR, providing physiologic pulsatile flow. This bioreactor will be a major tool in the research on future pro-healing DES. The bioreactor will allow: to perform numerous blood samples; study several stents at the same time; analyze flows and their effects on ISR; work directly with human arteries, collected during organ donation; and reduce the need for animal experimentation. This work demonstrated the significance of two new therapeutic molecules to prevent ISR, hemin and EP224283. Both reduced ISR without stopping the physiological healing of the arterial wall. We developed a bioreactor providing physiological and hemodynamical conditions. It will be a useful tool for the development of new DES. Our perspectives are now to create a new drug eluting stent releasing hemin or EP224283, as well as to validate our novel ex vivo hemodynamic model of ISR, in order to test our new DES in both animal models and ex vivo hemodynamic conditions.

Les stents sont aujourd’hui le traitement le plus courant des stades avancés de l’athérosclérose. Le concept de stents bioresorbables (BRS) est basé sur l’idée qu’un stent n’est nécessaire que jusqu’à la guérison de l’artère – suite à quoi il serait préférable que le stent disparaisse, afin de retrouver un état plus physiologique. Le déploiement d’un stent altère significativement les contraintes mécaniques exercées sur la paroi artérielle, or celles-ci jouent un rôle important dans l’incidence de complications telle que la resténose et l’hyperplasie néointimale. Dans le cas d’un BRS, les contraintes mécaniques dans le stent comme dans la paroi artérielle évoluent au fur et à mesure que le stent se dégrade. De plus, la dégradation du stent par hydrolyse peut être accélérée par ces contraintes : un couplage supplémentaire qui doit être pris en compte. Nous nous intéressons à la détermination de l’évolution des contraintes dans le stent et dans l’artère pendant le déploiement puis la dégradation du stent, ainsi qu’à l’influence de ces contraintes sur la dégradation du stent et sur le remodelage de la paroi, qui est également influencé par la dénudation de l’endothélium et par l’inflammation induite par l’implantation d’un BRS. Pour atteindre ces objectifs, nous avons développé un modèle 3D par éléments finis du déploiement et de la dégradation d’un BRS en acide polylactique tenant compte du couplage entre l’artère et le stent. Il permet notamment de prédire les zones de démantèlement dustent et l’évolution de l’épaisseur de la paroi artérielle en réponse à l’implantation d’un BRS. Etant donné que le modèle repose fortement sur des paramètres qui doivent être déterminés expérimentalement, nous nous sommes intéressés au développement d’une méthode expérimentale pour suivre la dégradation d’un BRS. Nous avons utilisé la tomographie par cohérence optique (OCT) pour suivre régulièrement la dégradation de stents déployés dans des tubes et immergés dans du sérum physiologique à 37°C pendant deux ans. Nous avons ensuite développé une méthode qui détecte automatiquement les struts des stents sur les images OCT et quantifie leur intensité de niveau de gris. Les résultats suggèrent que cette méthode automatisée d’analyse d’images OCT est un outil prometteur pour évaluer quantitativement l’état de dégradation d’un BRS. Enfin, nous nous sommes intéressés à la capacité d’une artère stentée à s’adapter à une modification du cisaillement ressenti. Nous avons étudié l’évolution de la lumière artérielle de porc stentés suivis in vivo par OCT ainsi que le cisaillement associé. Alors qu’un stent métallique bloque le remodelage artériel, nous avons observé qu’un BRS – probablement grâce au démantèlement du stade final de la dégradation – libère le vaisseau et permet ainsi l’adaptation de son diamètre de manière à diminuer le cisaillement et l’inadéquation avec l’artère non stentée. L’adaptation de la lumière artérielle permise par le démantèlement du stent pourrait être prise en compte dans de futurs modèles numériques. / Today, sent deployment is the most common treatment for symptomatic atherosclerosis. Bioresorbable stents (BRS) are based on the premise that a stent is needed only until arterial wound healing occurs after which it would be desirable for the stent to degrade so that the arterial wall recovers its natural compliance. Deployment of a stent profoundly alters the mechanical environment in the arterial wall, and these alterations play an important role in regulating the incidence of complications such as restenosis and neointimal hyperplasia. In the case of a BRS, the mechanical stresses in both the stent and the arterial wall evolve as the stent degrades. Furthermore, the hydrolysis-driven degradation of the stent can be accelerated by mechanical stresses in the stent, an additional coupling that needs to be taken into account. We are interested in determining the evolution of stresses in both the stent and the arterial wall during the stent deployment and degradation process and in elucidating the effect of these stresses on the stent degradation and on the remodeling process in the wall, which would also be influenced by the loss of endothelial cells and the amount of inflammation induced by the stent deployment and degradation. To this end, we have developed a 3D finite element model of the deployment and degradation of a polylactic acid (PLA) BRS that integrates the coupling between the stent and the artery.This allows one to predict the zones of dismantling of the stent and the evolution of the arterial thickness in response to a BRS stenting procedure. Since the model relies strongly on parameters that need to be determined experimentally, we became interested in developing methods to follow stent degradation. With this aim, we used optical coherence tomography (OCT) to image several BRS that were deployed into tubes and allowed to degrade in a saline solution at 37°C over a period of two years. We subsequently developed a versatile method for automatically detecting stent struts on the OCT images and quantifying the strut gray scale intensity. The results suggest that this automated method of OCT image analysis represents a promising tool to quantitatively assessing BRS degradation states. Lastly, we were interested in establishing the ability of a stented artery to adapt to a modification in its wall shear stress. Studying the in vivo evolution of the lumen of stented mini-swine arteries followed by OCT imaging allowed us to demonstrate that whereas a bare metal stent cages the artery, a BRS, presumably due to its degradation-induced dismantling, frees the vessel and enables it to adapt its lumen diameter in order to decrease its absolute level of shear stress and the compliance mismatch with the unstented portion of the artery. This lumen adaptation allowed by the stent dismantling could be taken into account in future computational models.

No description available.

The purpose of this study is to evaluate the endothelialization, exclusion of the aneurysm from circulation and intra-aneurysmal thrombus formation induced by the implantation of endovascular flow divertors for the purpose of bridging aneurysms. The design of the flow divertors was based on previous in vitro hemodynamic experiments in aneurysm models. The significance of this work is manifested in the development of a minimally invasive technology that may be employed for aneurysm treatment. Divertors with two different filament sizes and three different porosities were implanted in the rabbit elastase-induced aneurysm model and their effectiveness evaluated both angiographically and histologically. Preliminary results demonstrated that it is possible to achieve substantial reduction in intraaneurysmal flow immediately after device deployment. Angiographically, the aneurysms were excluded from the circulation with the medium and low porosity devices. In addition, the device performed as expected: smooth deployment, no intralumenal clot formation, and exclusion of aneurysm from the circulation without occluding other arterial branches. Additional data is needed to make definitive conclusions regarding endothelialization and the formation of a neointima.

No description available.

Introduction: This study describes the patterns of use and processes of care following colonic stent insertion for patients with colorectal cancer (CRC) in clinical practice. Methods: Ontario residents who had a colonic stent placed for CRC between 2000–2009 were identified using linked administrative databases. Baseline patient, physician, and institutional characteristics were extracted. The cohort was followed for death and health services utilization post-stent. Results: Two hundred twenty-five patients were identified. Median overall survival post-stent insertion was 199 days (interquartile range [IQR] 153-282). Eighty-five (38%) patients required a subsequent intervention (abdominal surgery, restenting, and/or dilatation). Median intervention-free survival was 75 days (IQR 59-91). Following stent insertion, the average rate of ER visits was 2.4 visits per person-year of follow up (95% CI, 2.2-2.7) and the overall average days spent in hospital was 19 inpatient days per person-year (95% CI, 18-19). Conclusions: In clinical practice, many patients required another intervention shortly after stent insertion; however, the rate of post-stent ER visits and inpatient hospital days was low.

Introduction: This study describes the patterns of use and processes of care following colonic stent insertion for patients with colorectal cancer (CRC) in clinical practice. Methods: Ontario residents who had a colonic stent placed for CRC between 2000–2009 were identified using linked administrative databases. Baseline patient, physician, and institutional characteristics were extracted. The cohort was followed for death and health services utilization post-stent. Results: Two hundred twenty-five patients were identified. Median overall survival post-stent insertion was 199 days (interquartile range [IQR] 153-282). Eighty-five (38%) patients required a subsequent intervention (abdominal surgery, restenting, and/or dilatation). Median intervention-free survival was 75 days (IQR 59-91). Following stent insertion, the average rate of ER visits was 2.4 visits per person-year of follow up (95% CI, 2.2-2.7) and the overall average days spent in hospital was 19 inpatient days per person-year (95% CI, 18-19). Conclusions: In clinical practice, many patients required another intervention shortly after stent insertion; however, the rate of post-stent ER visits and inpatient hospital days was low.

Abdominal aortic aneurysms (AAA) are an expansion in diameter of the abdominal aorta and their rupture is a leading cause of mortality. One of the treatments for AAA is the implantation of an endograft (also called a stent graft), a combination of fabric and metal stents, to provide a new conduit for blood and shield the aneurysm sac from direct pressurization. After implantation of the stent graft, the aneurysm may shrink, grow, or stabilize in diameter ? even in the absence of apparent flow into the sac ? in some cases resulting in graft failure through component separation, kinking, or loss of seal at its ends. Greater understanding of AAA and treated AAA could provide insight on how treatment might be modified to improve treatment methods and/or design devices to be more effective in a wider range of patients. Computational models provide a means to investigate the biomechanics of endografts treating AAA through analysis of the endografts, the AAA, and the combination of them. Axisymmetric models of endograft-treated AAA showed that peak von Mises stress within the wall varied between 533 kPa and 1200 kPa when different material properties for the endograft were used. The patient-specific models, built from time series of patient CT scans with similar patient history but different outcomes, show that wall shrinkage and stability can be related to the level of stresses within the vessel wall, with the shrinking AAA showing a greater reduction by endograft treatment and a lower final value of average von Mises stress. The reduction in pressure felt by the wall is local to the central sac region. The inclusion of thrombus is also essential to accurate stress estimation. The combination of axisymmetric and patient-specific computational models explains in further detail the biomechanics of endograft treatment. The patient-specific reconstruction models show that when effectively deployed and reducing the pressure felt in the AAA wall, the graft is under tension in the sac region and compression at its ends.