Le contrôle des propriétés physico-chimiques de surfaces des matériaux à base de titane est souvent requis pour améliorer leurs performances, leur activité biologique ou encore pour concevoir de nouveaux matériaux intelligents. Dans ce contexte, le greffage de (macro)molécules à propriétés spécifiques est une solution pertinente pour élaborer des matériaux stimulables aux propriétés physico-chimiques modulables. Dans ce travail de thèse, nous avons conçu plusieurs plateformes de fonctionnalisation du titane en exploitant les propriétés adhésives du motif catéchol combinées au concept de chimie « click » afin d’immobiliser des polymères fonctionnels préparés par polymérisation radicalaire contrôlée. Ainsi, des surfaces de titane recyclables à la mouillabilité programmable sur demande et des matériaux stimulables par la température ou par rayonnement ultra-violet ont pu être élaborés. Enfin, les propriétés adhésives de la polydopamine ont été exploitées pour concevoir une nouvelle génération de stent « actif » utilisé en chirurgie cardiovasculaire pour lutter contre le phénomène de resténose intra-stent. / The control of physico-chemical properties of titanium based materials is frequently needed with the aim of enhancing their capabilities, their biological activity or to design new « smart » materials. In this context, tethering of specific (macro)molecules seems to be a relevant method to develop stimuli responsive materials with predictable or commutable physico-chemical properties. In this work, we have elaborated numerous platforms for the functionalization of titanium surfaces by a combination of catechol adhesives properties and very efficient coupling reactions in order to graft functional polymers prepared by controlled radical polymerization. This approach allowed us to create reusable titanium surfaces with programmable wettability and materials capable of responding to external stimuli such as temperature or UV light. Finally, versatile polydopamine coating has been used to design a new generation of drug eluting stent which might be employed in cardiovascular surgery to struggle against in-stent restenosis.

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

Atualmente, as doenças cardiovasculares são apontadas como as principais causas de mortes no Brasil e no mundo. Essas doenças são causadas pelo comprometimento das artérias, principalmente as artérias coronárias. Essas artérias possuem a importante função de transportar nutrientes ao próprio coração, possibilitando que o mesmo exerça sua tarefa de suprir todo o resto do corpo com elementos essenciais à sobrevivência do indivíduo. Este trabalho é sobre um estudo do comportamento dessas artérias quando ocorre a difusão de um fluido através de suas paredes. Primeiramente, estudou-se a composição das artérias coronárias, suas funções e patologias, para extrair elementos para compor um modelo fisicamente realístico e analiticamente tratável. Devido à sua composição histológica em três túnicas, a artéria coronária foi modelada como um cilindro elástico composto de cilindros ocos e concêntricos. Investigou-se então a solução do problema da difusão de um fluido em duas e três camadas, sendo esta última configuração geométrica mais próxima da realidade. Por fim, estudou-se a difusão de um fármaco contido em um stent farmacológico, cuja função é desobstruir uma artéria aterosclerosada e evitar sua reestenose. / Currently, cardiovascular diseases are known to be the primary cause of death in Brasil and worldwide. These diseases are caused by the malfunction of the arteries, especially the coronary arteries. These arteries have the important role of transporting nutrients to the heart itself, allowing it to exert its main task of providing the rest of the body with essential elements to the survival of an individual. This work is about a study of the diffusion of a fluid through the walls of a coronary artery. First, the composition of the coronary arteries, their functions, and pathologies were studied to extract elements that could be used to construct a model that is both physically realistic and analytically amenable to analysis. Due to its histologic composition in three layers, a coronary artery was modeled as an elastic cylinder composed of hollow and concentric cylinders. The solution of the diffusion problem of a fluid in two and three layers was studied, being this last geometrical configuration the closest to reality. Finally, the diffusion of a drug contained in a pharmacological stent was investigated. The main task of this type of stent is to clear an atherosclerotic artery and to avoid its restenosis.

Atualmente, as doenças cardiovasculares são apontadas como as principais causas de mortes no Brasil e no mundo. Essas doenças são causadas pelo comprometimento das artérias, principalmente as artérias coronárias. Essas artérias possuem a importante função de transportar nutrientes ao próprio coração, possibilitando que o mesmo exerça sua tarefa de suprir todo o resto do corpo com elementos essenciais à sobrevivência do indivíduo. Este trabalho é sobre um estudo do comportamento dessas artérias quando ocorre a difusão de um fluido através de suas paredes. Primeiramente, estudou-se a composição das artérias coronárias, suas funções e patologias, para extrair elementos para compor um modelo fisicamente realístico e analiticamente tratável. Devido à sua composição histológica em três túnicas, a artéria coronária foi modelada como um cilindro elástico composto de cilindros ocos e concêntricos. Investigou-se então a solução do problema da difusão de um fluido em duas e três camadas, sendo esta última configuração geométrica mais próxima da realidade. Por fim, estudou-se a difusão de um fármaco contido em um stent farmacológico, cuja função é desobstruir uma artéria aterosclerosada e evitar sua reestenose. / Currently, cardiovascular diseases are known to be the primary cause of death in Brasil and worldwide. These diseases are caused by the malfunction of the arteries, especially the coronary arteries. These arteries have the important role of transporting nutrients to the heart itself, allowing it to exert its main task of providing the rest of the body with essential elements to the survival of an individual. This work is about a study of the diffusion of a fluid through the walls of a coronary artery. First, the composition of the coronary arteries, their functions, and pathologies were studied to extract elements that could be used to construct a model that is both physically realistic and analytically amenable to analysis. Due to its histologic composition in three layers, a coronary artery was modeled as an elastic cylinder composed of hollow and concentric cylinders. The solution of the diffusion problem of a fluid in two and three layers was studied, being this last geometrical configuration the closest to reality. Finally, the diffusion of a drug contained in a pharmacological stent was investigated. The main task of this type of stent is to clear an atherosclerotic artery and to avoid its restenosis.

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Made available in DSpace on 2015-07-22T20:50:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-05-30. Added 1 bitstream(s) on 2015-08-11T03:26:18Z : No. of bitstreams: 1 Publico-13256.pdf: 2482735 bytes, checksum: eaf78b153b33731b3ff4250c42b843ae (MD5) / Introdução: não há consenso na literatura a respeito do impacto que angioplastia com implante de stents teria sobre a função endotelial vasomotriz. Inúmeros trabalhos têm mostrado piora da função endotelial após o implante de stents farmacológicos quando comparados aos stents convencionais. Objetivos: o principal objetivo deste trabalho foi avaliar o impacto dos stents convencionais e do Sirolimus, administrado por via oral, sobre a função endotelial vasomotriz. Material e métodos: foram selecionados pacientes em três grupos: grupo 1 - stent convencional com alta dose de Sirolimus (15 mg de ataque seguidos de 6 mg diariamente por 4 semanas); grupo 2 - stents convencionais com baixa dose de Sirolimus (6 mg de dose de ataque seguidos de 2 mg diariamente por 4 semanas) e grupo 3 - stent convencional sem Sirolimus. Modificações na vasomotricidade foram avaliadas com uso de infusão de acetilcolina intracoronariana em doses crescentes. A função vasomotriz independente do endotélio foi avaliada com uso de nitroglicerina. O segmento alvo de análise foram os 15 mm distais à borda do stent. Este segmento também foi avaliado com ultrassonografia intracoronariana. Resultados: os três grupos apresentavam características clínicas e angiográficas semelhantes. A porcentagem de variação do diâmetro foi semelhante em todos os três grupos nos dois momentos da avaliação (4 horas após implante do stent e aos 8 meses de acompanhamento) (p=0,469). Quatro horas após implante dos stents o segmento alvo apresentou disfunção endotelial leve a moderada caracterizada por vasoconstrição em média de -3% que se manteve aos oito meses e foi semelhante entre os grupos. Não houve correlação do volume de placa pela ultrassonografia com o grau de disfunção endotelial nos dois momentos da avaliação. A função vasomotriz independente do endotélio encontrava-se preservada nos dois momentos da avaliação nos três grupos. Conclusão: a disfunção endotelial foi semelhante entre os grupos nos dois momentos da avaliação e não sofreu alteração com implante dos stents e nem com o uso do Sirolimus oral por 4 semanas. Não houve correlação do volume de placa com disfunção endotelial. / Rationale: There is no consensus regarding the impact of stenting on long-term endothelial function. There have been reports of increased endothelial dysfunction with Sirolimus-eluting stents as compared to bare metal stenting (SC). Objectives: This study aims to assess the impact of SC and the effect of oral Sirolimus on endothelial function. Methods: Forty-five patients were randomized into three groups: SC + high-dose oral Sirolimus (initial dose of 15 mg, followed by 6 mg/day during four weeks); SC + lowdose Sirolimus (6 mg followed by 2 mg daily during four weeks); and SC without Sirolimus. Changes in vasoconstriction or vasodilation in a 15 mm segment starting at the distal stent end in response to acetylcholine and nitroglycerin were assessed by quantitative angiography. Results: The groups had similar angiographic characteristics. The percent variation in diameter in response to acetylcholine was similar in all groups at the two time points (p = 0.469). Four hours after stenting, the target segment presented an endothelial dysfunction that was maintained after eight months in all groups. In all groups, endothelium-independent vasomotion in response to nitroglycerin was similar at four hours and eight months, with increased target segment diameter after nitroglycerin infusion (p = 0.001). Conclusions: The endothelial dysfunction was similarly present at the 15 mm segment distal to the treated segment, at 4 hours and 8 months after stenting. Sirolimus administered orally during 4 weeks to prevent restenosis did not affect the status of endothelium-dependent and independent vasomotion. / TEDE / BV UNIFESP: Teses e dissertações

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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.

Até o momento, pouco se sabe sobre a influência da modificação na composição do ateroma nas bordas dos stents e a ocorrência de alterações na geometria vascular. Este estudo objetiva correlacionar, utilizando de maneira seriada (pós-implante do stent e reestudo aos nove meses) o ultrassom monocromático e a Histologia Virtual®, as modificações na composição dos ateromas nas bordas proximais e distais de stents nãofarmacológicos e farmacológicos e as alterações ocorridas nas dimensões do vaso, luz e placa que possam explicar a ocorrência da reestenose nestes segmentos. Estudo prospectivo, de centro único, que randomizou (1:1) pacientes com síndrome coronária aguda para receberem stents nãofarmacológicos (Driver®, n=20 pacientes) ou farmacológicos (Cypher®, n=20 pacientes). Após a realização do procedimento, todos os pacientes submeteram-se a avaliação com ultrassom e Histologia Virtual®, que foi repetido ao final de nove meses de seguimento. O objetivo primário foi avaliar as modificações na área do vaso, luz e placa ao ultrassom e na composição do ateroma pela Histologia Virtual® no período entre o implante e o reestudo, buscando correlacionar as alterações no ateroma com as modificações na geometria vascular. Observou-se que na borda proximal, stents farmacológicos e não-farmacológicos tem um comportamento semelhante na avaliação ultrassonográfica, com tendência a remodelamento expansivo da área do vaso para compensar o crescimento na área da placa. Por outro lado, na borda distal, há menor crescimento da área da placa entre os pacientes tratados com stents farmacológicos, resultando em maior área da luz no reestudo de nove meses. Do ponto de vista da análise com Histologia virtual, nos dois grupos e em ambas as bordas houve redução do componente fibroso e núcleo necrótico com aumento no conteúdo fibrolipidico. Observou-se ainda importante correlação entre a variação do componente fibrótico e o aumento na área da placa (r=0.78, p=0.01). O uso de stents farmacológicos não se correlaciona com \"efeito de borda\". Ao contrário, parece haver menor crescimento da placa na borda distal destas endopróteses quando comparadas às sem fármaco. A modificação na composição do ateroma, com aumento do conteúdo fibro-lipídico pode explicar em parte estes achados. / To the present, little is known about the correlation between modifications in plaque composition at stent edges and the changes in vessel geometry. This study sought to evaluate, by serial grey-scale intravascular ultrasound (IVUS) and Virtual Histology(TM), the modifications in plaque composition at the edges of drug-eluting and bare-metal stents and the correlation of these findings with changes in the measuremntes of vessel, lumen and plaque area at those segments. Single-center, prospective and randomized (1:1) evaluation of 40 patients with acute coronary syndrome treated with bare-metal (Driver(TM), n=20 patients) or drug-eluting stents (Cypher(TM), n=20 patients). Following stent deployment, all individuals underwent gray scale IVUS and Virtual Histology(TM) evaluation, which were repeated at nine months. Primary endpoint included the modification in vessel, lumen and plaque area and in the composition of the plaque in the mean time between the baseline and follow-up procedure. Additionally, we tried to determine a correlation between plaque composition variation and changes in vessel geometry. At the proximal edge of both drug-eluting and bare-metal stents there was a trend to positive vessel remodeling which compensated the modest increase in plaque area. At the distal edge, patients treated with drug-eluting stents had less plaque growth resulting in a larger lumen area at follow-up. By Virtual Histology, there was a marked reduction in the % of fibrotic tissue and necrotic core in both edges of the two stents and a positive, strong correlation was seen between increase in % of fibrofatty component and augmentation in plaque area(r=0.78, p=0.01). The use of drug-eluting stents was not associated with \"edge effect\". On the contrary, patients treated with these devices experienced less plaque growth, especially at the distal edge of the stents. Modifications in plaque composition, with increase in fibrofatty content, might partially explain these findings.