The incorporation of drugs into phosphorylcholine (PC) polymers coated onto coronary stent surfaces is one potential method of treatment for reducing restenosis, the reclosure of the artery after angioplasty treatment. This work on the characterisation of the swelling performance of thin PC polymer films represents a further extension of the study on biocompatible polymers. The broad aim of this work is to relate the PC polymer structure and film processing conditions to their swelling, drug loading and release kinetics. As the two highly sensitive and powerful techniques in film structure determination, both ellipsometry and neutron reflection have proved to be useful in characterising PC polymer films and drug release processes. Following an established ellipsometry measurement method, a two stage process consisting of diffusion and relaxation has been observed during the PC film swelling: this suggests an anomalous mechanism, and this performance is well described by the coupled diffusion and relaxation model developed by Berens and Hopfenberg. Furthermore, the swelling of PC polymer films was investigated as a function of cross-linking, annealing temperature, chemical composition, hydrophilic/hydrophobic ratios, film thickness and environmental conditions by ellipsometry measurements, and their effects on swelling kinetics well quantified. The structures of the PC polymer films (PC100B) with cross-linking groups have been further characterised by neutron reflection. The segregation of hydrophobic and hydrophilic domains was found in the PC films with different dimensions. The PC100B with deuterated dodecyl chains was used to highlight the interfacial structures of the PC films. The hydrophilic segments, including phosphorylcholine groups and hydroxypropyl groups, are preferentially adsorbed at the polymer/substrate interface. The hydrophobic dodecyl chains are expelled away from the silicon oxide surface. The main part of PC100B films is the middle uniform region with 40% of water in the sample annealed at 150°C, and 55% of water in the sample annealed at 50°C. The combination of the ellipsometry results and the drug release profiles from UV measurements indicates that the drug release pattern is strongly affected by the film swelling kinetics when the drug molecules and polymer matrix interact weakly. Otherwise, a strong interaction between the drug and the polymer will dominate the drug release behaviour from the PC polymer films.

Coronary stent placement is a routine treatment of coronary artery disease, the leading cause of death worldwide. Intravascular Optical Coherence Tomography (IVOCT) is a superior imaging assessment technique in coronary stenting. To characterize IVOCT artifacts, phantom blood vessels were constructed and metallic and bioabsorable coronary stents were deployed with and without phantom neointima. High resolution Micro-CT images of the stent strut were recorded as a gold standard and utilized to create a three-dimensional representation of a strut that was imported into computer optical simulations. Simulated IVOCT images were computed that include the IVOCT catheter, light reflection from stent struts with varying neointimal thickness and scattering in the vessel lumen. The simulation results along with IVOCT images of the phantom vessels were utilized to elucidate the mechanisms underlying the “sunflower effect”, bending of stent struts toward the imaging catheter and “merry-go-round” effect, variable apparent strut size of metallic stents. Atomic force microscopy was used to examine surface properties of metallic and bioabsorbale stents, revealing sources of the distinctive appearance of bioabsorable stents in IVOCT images. The model formed a basis to develop a correction algorithm to remove stent artifacts in clinical IVOCT images. / text

Au cours des dernières décennies, les stents coronaires et les stents déviateurs de flux intracrâniens ont révolutionné le traitement endovasculaire de deux pathologies artérielles différentes : la maladie coronarienne et les anévrismes intracrâniens. Ces deux types d’endoprothèses métalliques ont des mécanismes de fonctionnement différents, mais ils sont tous deux associés à des complications qui découlent de problèmes de biocompatibilité. En particulier, la couverture rapide de ces endoprothèses par des cellules endothéliales présentant un phénotype anti-inflammatoire et anti-thrombotique est cruciale pour leur intégration à l’interface vaisseau/sang. Par conséquent, le développement de solutions visant à améliorer l’endothélialisation et l’intégration de ces deux types de stents dans la paroi vasculaire représenterait un progrès majeur dans leur domaine respectif.Dans ce contexte, cette thèse porte sur l’immobilisation d’une molécule bioactive à la surface de stents coronaires et de stents déviateurs de flux, afin de résoudre leurs problèmes de biocompatibilité. La molécule bioactive utilisée est un peptide synthétique, appelé P8RI, qui promeut les fonctions régulatrices de la glycoprotéine transmembranaire CD31 : l’inhibition de l’activation des plaquettes et des leucocytes, ainsi que l’amélioration de la survie, de la migration et de la fonction de barrière des cellules endothéliales.La première partie de ce travail de thèse a consisté à développer un procédé d’immobilisation du P8RI sur des stents métalliques. Nous avons successivement adopté trois approches : l’immobilisation directe du peptide sur des surfaces d’alliage fonctionnalisées par plasma ; le dépôt chimique en phase vapeur assisté par plasma d’une couche intermédiaire de polymère ; et le dépôt d’une couche de polydopamine par auto-polymérisation, suivi de l’immobilisation d’un bras d’ancrage et de la liaison du P8RI par chimie click sans cuivre.Nous avons ensuite réalisé une évaluation in vitro de la biocompatibilité des surfaces d’alliage ainsi revêtues, en termes de propriétés anti-thrombotiques, anti-inflammatoires et pro-endothélialisation. Les surfaces sur lesquelles le P8RI avait été immobilisé ont montré une tendance à diminuer l’adhésion plaquettaire, à améliorer l’adhérence et la fonction de barrière de cellules endothéliales vasculaires humaines, et à promouvoir un phénotype anti-inflammatoire et anti-thrombotique chez ces dernières. Enfin, nous avons évalué in vivo des stents coronaires et déviateurs de flux recouverts de P8RI. Les stents coronaires ont été implantés dans des artères coronaires de porcs, et les résultats préliminaires ont montré une endothélialisation plus complète et une moindre densité de leucocytes adhérents sur les stents recouverts de P8RI que sur les témoins. Quant aux stents déviateurs de flux recouverts de P8RI, implantés dans un modèle d’anévrisme carotidien induit par incubation d'élastase chez le lapin, ils ont été associés à la formation d’une néointima plus épaisse et mieux organisée que sur les témoins, en particulier au niveau du collet anévrismal, ce qui implique de moindres risques de persistance du flux sanguin et de rupture d’anévrisme. / Over the last decades, coronary stents and intracranial flow diverting stents have revolutionized the endovascular treatment of two different arterial pathologies: coronary artery disease and intracranial aneurysms. The working mechanisms of these metallic endoprostheses are different but both are associated with complications stemming from biocompatibility issues. In particular, the rapid covering by endothelial cells presenting an anti-inflammatory and anti-thrombotic phenotype is key to the integration of the endoprosthesis at the blood/vessel interface. Thus, the development of solutions to improve the endothelialization and the integration of these two types of stents in the vessel wall would represent a major progress in their respective field.In this context, this thesis work deals with the immobilization of a bioactive molecule on coronary stents and flow diverting stents in order to solve their biocompatibility issues. The bioactive molecule that we used is a synthetic peptide, named P8RI, which promotes the regulatory functions of the transmembrane glycoprotein CD31 : the inhibition of platelets and leukocytes activation, as well as the enhancement of endothelial cell survival, migration and barrier function.The first part of this thesis work consisted in the development of a process for the immobilization of P8RI on metallic stents. We adopted three successive approaches: the direct immobilization of the peptide on plasma-functionalized alloy surfaces; the plasma-enhanced chemical vapor deposition of an intermediate polymeric layer; and the deposition of a polydopamine coating by self-polymerization, followed with the immobilization of a linker and the binding of P8RI by copper-free click chemistry.We then carried out an in vitro evaluation of the biocompatibility of the resulting coated alloy surfaces, in terms of anti-thrombotic, anti-inflammatory, and pro-endothelialization properties. The surfaces on which P8RI had been immobilized were shown to exhibit a tendency to decrease platelet adhesion, increase endothelial cell adhesion and barrier function, and promote an anti-inflammatory and anti-thrombotic phenotype in human vascular endothelial cells.Finally, coronary stents and flow diverting stents were evaluated in vivo. Coronary stents were implanted in the coronary arteries of farm pigs, and preliminary results showed a more complete endothelialization and a lesser density of adherent leukocytes on ‘P8RI-coated’ stents than on the controls. ‘P8RI-coated’ flow diverting stents were implanted in a rabbit elastase-induced carotid aneurysm model. Compared with the controls, they were associated with the formation of a thicker and better organized neointima, in particular on the stent struts in front of the aneurysm neck, which implies lesser risks of persistence of blood flow and aneurysm rupture.

Cardiovascular diseases are among the leading causes of deaths worldwide, but the fluid mechanics of many of these conditions and the devices used to treat them are only partially understood. This goal of this dissertation was to develop new experimental techniques that would enable translational research into two of these conditions. The first set of experiments examined <i>in-vitro</i> the changes in Wall Shear Stress (WSS) and Oscillatory Shear Index (OSI) caused by the implantation of coronary stents into the arteries of the heart using Particle Image Velocimetry. These experiments featured one-to-one scaling, commercial stents, and realistic flow and pressure waveforms, and are believed to be the most physiologically accurate stent experiments to date. This work revealed distinct differences in WSS and OSI between the different stent designs tested, and showed that changes in implantation configuration also affected these hemodynamic parameters. Also, the production of vortices near the stent struts during flow reversal was noted, and an inverse correlation between WSS and OSI was described. The second set of experiments investigated Left Ventricular Diastolic Dysfunction (LVDD) using phase contrast magnetic resonance imaging (pcMRI). Using this technique, ten patients with and without LVDD were scanned and a 2D portrait of blood flow through their heart was obtained. To augment this data, pressure fields were calculated from the velocity data using an omni-directional pressure integration scheme coupled with a proper-orthogonal decomposition-based smoothing. This technique was selected from a variety of methods from the literature based on an extensive error analysis and comparison. With this coupled information, it was observed that healthy patients exhibited different flow patterns than diseased patients, and had stronger pressure differences during early filling. In particular, the ratio of early filling pressure to late filling pressure was a statistically significant predictor of diastolic dysfunction. Based on these observations, a novel hypothesis was presented that related the motion of the heart walls to the observed flow patterns and pressure gradients, which may explain the differences observed clinically between healthy and diseased patients. / Ph. D.