Dissertations / Theses on the topic 'Stent coating'

The long-term efficacy of coronary or peripheral stenting is limited by in-stent restenosis (ISR), which occurs in 15 to 30% of patients and is attributed primarily to neointimal hyperplasia. By adding a drug-eluting coating, this rate has been reduced to about 5% or less. However, recently longer-term follow-up data has highlighted problems with drug-coated stents, including late stage thrombosis. A bio-stable poly(carbonate-urea)urethane has been used for stent coating and the surface properties of the polymer have been optimised by incorporating the polyhedral oligomeric silsesquioxane molecule. These POSS polymers improve the adhesion and the growth of endothelial cells. The work described in this thesis, presents an innovative approach in self-expanding/balloon expandable coronary stent design that incorporates a NiTi/stainless steel alloy scaffold with a polyhedral oligomeric silsesquioxane- poly (carbonate-urea) urethane nanocomposite polymer (POSS-PCU) coating. Electrohydrodynamic spraying and ultrasonic atomization spraying of the non-biodegradable nanocomposite polyhedral oligomeric silsesquioxane (POSS) polymer have been investigated in detail for coating metallic stent materials and compared with dip coating. Because of the tight geometry of coronary stents, these new coating techniques have been shown to offer advantages over traditional coating techniques. These advantages include, reduced polymer consumption, precise coating thickness as low as 10 μm and a highly controllable spray which leads to consistent reproducible results. However, poor adhesion, or bond deterioration over the lifespan/ deployment of the device could reduces the efficiency and could impart even more complexity to the implant including formation of debris which can induce thrombus formation. Changing the surface physical property/chemical composition through the proposed protocol has been shown to increase the bonding strength by up to three times. This study has identified a new process and conditions which can be used in stent coating research.

Metal-organic frameworks have a wide range of applications including gas separation, gas capture, catalysis and drug delivery. Due to the in-stent thrombosis of the current drug-eluting stents we propose replacing the toxic polymer with a more biodegradable MOF thin film consisting of MIL-88b. The MIL-88b thin film was formed on functionalized gold through a direct crystallization method and was confirmed using x-ray diffraction (XRD) and Fourier- transform infrared spectroscopy (FTIR). Possible ibuprofen encapsulation and elution was confirmed through FTIR and UV-VIS spectroscopy. The MIL-88b thin film was also formed on medical grade stainless steel to mimic conditions of the current DES. The surface area, using N₂ gas isotherm at 770K, of MIL-88b and MIL-53 was compared to validate the favorable porosity for drug delivery application.

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

Introdução: Apesar dos avanços significativos no tratamento endovascular das doenças arteriais coronarianas e periféricas, a reestenose intra-stent continua sendo o principal limitante a médio prazo desses procedimentos. O mecanismo da reestenose intra-stent é principalmente a hiperplasia intimal, já que o stent impede a retração elástica aguda e resiste ao remodelamento geométrico negativo tardio. A hiperplasia intimal ocorre basicamente em resposta à formação de trombo local, à inflamação e às dissecções intimais e mediais secundárias à injúria causada pelo stent, sendo o grau de resposta intimal a base dos efeitos a longo prazo. O uso de stents com hastes menores e revestidos com drogas ou polímeros tem sido considerado uma nova alternativa para a prevenção da reestenose intra-stent. Objetivo: Analisar a resposta arterial ao implante de stent de cromo-cobalto sem e com revestimento de polímero Camouflage® em artérias carótidas de suínos, utilizando os seguintes parâmetros histológicos: grau de endotelização, conteúdo de células musculares lisas, grau de angiogênese, conteúdo de fibrina, grau de inflamação e injúria; além da análise histomorfométrica. Método: Stents balões-expansíveis de cromo-cobalto ( 8 stents CC Flex e 5 stents CC Flex Proactive) de 4 x 16 mm foram implantados em artérias carótidas comuns de oito suínos jovens, sendo um stent liberado em cada artéria. Após 30 dias, as artérias contendo os stents foram removidas, fixadas e coradas pelos métodos de hematoxilina/eosina e Verhoeff/Van Giesson. O segmento arterial contendo o stent foi dividido em 3 blocos distintos: proximal, médio e distal. Os cortes histológicos foram obtidos utilizando-se micrótomo de impacto (Polycut S, Leica, Alemanha) equipado com navalha de tungstênio de 16 cm, tipo D (Leica, Alemanha), com 5 ^m de espessura. A navalha de tungstênio mantém as hastes dos stents intactas nas secções transversas, minimizando os artefatos potenciais causados pela retirada dos stents. A avaliação foi realizada através de critérios histológicos e histomorfométricos. Resultados: Todos os stents foram implantados com sucesso e sem dificuldades técnicas. A análise histológica em 30 dias evidenciou alto grau de endotelização em todos os segmentos avaliados e leve à moderada infiltração de células musculares na íntima. Observou-se baixo grau de angiogênese em cerca de 50% dos segmentos avaliados e ausência completa de deposição de fibrina em pelo menos 80%, com distribuição semelhante entre os grupos. A resposta inflamatória e o grau de injúria causadas pelas hastes dos stents também foram discretas e similares entre os grupos e não houve correlação entre resposta inflamatória e injúria e desses parâmetros com a área de neoíntima. O grau de obstrução neo-intimal identificada neste período foi pequeno (15,1% +/- 8,38 CC Flex x 15,5%+/- 5,39 CC Flex ProActive) e estatisticamente não significativo entre os grupos (p=0,785). Conclusão: Os achados deste estudo experimental sugerem que o uso de stents de cromo-cobalto revestidos com polímero Camouflage® em artérias carótidas de suínos parece estar associado, pelo menos no curto prazo, a uma resposta histológica semelhante àquela encontrada após o implante de stents de cromo-cobalto não revestidos. Neste período não se observou uma menor hiperplasia intimal em virtude do revestimento de polímero.
Introduction: Despite all the advances in the endovascular treatment of coronary and peripheral artery diseases, in-stent restenosis is still the main limiting factor of these procedures in the medium and long-term. The mechanism of in-stent restenosis is mainly the intimal hyperplasia, as the stent prevents acute elastic recoil and later negative geometric arterial remodeling. Intimal hyperplasia occurs basically in response to the formation of local thrombus, inflammation and intimal and medial dissections secondary to the injury caused by the stent, with the degree of intimal response being the cause of long-term effects. Coating drug-eluting stents with polymers and drugs with thinner struts have been considered a new alternative for in-stent restenosis prevention. Objective: Analyse the arterial response to the cobalt-chromium stent implant with and without polymer coating Camouflage® in carotid arteries of pigs, using the following histological parameters: degree of endothelialization, smooth muscle cells (SMC) content, degree of angiogenesis, intimal fibrin content, degree of inflammation and injury; plus histomorphometric analysis. Method: Cobaltchromium balloon-expandable stents (8 CC Flex stents and 5 CC Flex Proactive), 4 x 16 mm, were deployed in common carotid arteries of 8 young pigs, with one stent being deployed in each artery. After 30 days, the arteries containing the stents were removed and underwent fixation and staining using the hematoxilin/eosin and Verhoeff /Van Giesson methods. The arterial segment containing the stent was divided into 3 distinct portions: proximal, middle and distal. The histological sections were obtained using impact microtome (Polycut S, Leica, Germany), equipped with a 16 cm, type D, 5 ^m thick tungsten knife (Leica, Germany). The tungsten knife maintains the stent shaft intact in cross sections, minimizing the potential artifacts caused by stent removal. The evaluation was carried out using histological and histomorfometric criteria. Results: All the stents were deployed with success and with no technical difficulties. The histological analysis performed after 30 days showed a high level of endothelialization in all the evaluated portions and mild to moderate infiltration of the SMC in the intima layer. A low level of angiogenesis of about 50% of the evaluated portions was observed and a complete absence of fibrin deposition in at least 80% of the portions, with similar distribution among the groups. The inflammatory response and the level of injury caused by the struts of the stents were also minimum and this was similar among the groups. There was no correlation between inflammatory response and injury and between the two latter parameters and the neo-intima area. The level of neo-intimal obstruction identified in this period was small (15,1% +/- 8,38 CC Flex x 15,5%+/- 5,39 CC Flex ProActive ) and no statistical significance between the groups (p=0,785). Conclusion: The findings of this experimental study suggest the use of balloonexpandable cobalt-chromium stents coated with polymer Camouflage® in carotid arteries of pigs seems to be associated, at least in the short-term, with a similar histological response to that found in the implantation of non-coated cobalt-chromium stents. In this period, a lower intimal hyperplasia was not observed with polymer coating stents.

An intracranial aneurysm is a local dilation of an artery in the cerebral circulation. While the etiology of intracranial aneurysms is unknown, they likely result from a combination of factors including the weakening and degeneration of the collagen fibers and the internal elastic lamina comprising the arterial wall, as well as hemodynamic-associated stress resulting from blood pulsation inside the aneurysm sac. Intracranial aneurysm rupture leads to a devastating sequela, as 50% of patients die. In the U.S. alone there are approximately 30,000 cases of subarachnoid hemorrhage annually, a prevalence which has pushed practitioners to aggressively treat the aneurysm disease. Traditionally, intracranial aneurysms were managed with open craniotomy and microsurgical clipping; however, these treatment modalities carry relatively high morbidity and mortality depending upon the aneurysm location and surgical experience. In 2002 the International Subarachnoid Hemorrhage Aneurysm Trial established the superiority of the endovascular coiling of intracranial aneurysms compared to microsurgical clipping. This trial led to a paradigm shift in treating intracranial aneurysms with marked use of intracranial stenting, including devices used to assist endovascular coiling and stand-alone flow diverting devices. However, the placement of intracranial devices in the cerebral circulation mandates the adjunctive application of dual anti-platelet pharmaceuticals to minimize thromboembolic events, despite being associated with increased patient risk. This dissertation proposes a novel multilayer, nanometer-scale coating technology suitable for commercially available intracranial stents and flow diverting devices to minimize the use of dual anti-platelet therapy in the elective setting and expand the use of intracranial devices in the acute setting of ruptured intracranial aneurysms. A combination of qualitative and quantitative chemical characterization techniques was used to assess the composition, uniformity, and thickness of each coating layer on commercially available flow diverting devices; overall the coating was found to be relatively uniform and conformal to the device wires. Furthermore, in-vitro and in-vivo testing on commercially available intracranial devices suggest some hemocompatible and antithrombotic properties. Finally, the proposed coating technology can be modified for use as a platform for the attachment of FDA-approved molecules. With further optimization and testing this technology has the potential to minimize the adjunctive use of dual-antiplatelet therapy in the endovascular treatment of intracranial aneurysms.

Thesis(Ph.D.)--Case Western Reserve University, 2010
Title from PDF (viewed on 2009-12-22) Department of Macromolecular Science and Engineering Includes abstract Includes bibliographical references and appendices Available online via the OhioLINK ETD Center

Made available in DSpace on 2014-07-29T15:07:09Z (GMT). No. of bitstreams: 1 Dissertacao Harley Fernandes Rodrigues.pdf: 5566711 bytes, checksum: 484423a034c8d6a3a3f34650b5036af1 (MD5) Previous issue date: 2011-08-23
In this work we developed a Dip Coating method that could control the temperature gradient between a substrate and the material that one wants to adsorb at its surface. In particular, the adsorption of biocompatible magnetic nanoparticles at the surface of bare metal Stents, under different experimental conditions, was investigated. The magnetic nanoparticles consisted of magnetite coated with tripoliphosphate (mean diameter 7.68 nm and standard deviation 1.88 nm) dispersed in water at physiological conditions, while the Stent was a CoCr based-one (Cronus stent from Scitech with 16 mm length). Nine series of experiments were performed where it was controlled parameters as: time of adsorption, stent temperature and magnetic fluid temperature. The stents coated with nanoparticles were magnetically characterized using a vibrating sample magnetometer (VSM), which allowed us to determine the number of nanoparticles at the stent surface. The increase of the magnetic moment of the stent with the increase of the adsorption time was theoretically modeled, with an excellent experimental agreement, as a transient diffusion process of nanoparticles at the interface stent-magnetic fluid, which clearly indicates an important diffusive contribution. Strong evidences of thermal diffusion (Soret effect), i.e. nanoparticle diffusion due to temperature gradient between the stent and the magnetic fluid, were shown, suggesting the possibility of nanostructures vectorization through thermal induced mechanisms. The spatial distribution of nanoparticles at the surface of the stent was investigated by Scanning Electron Microscopy (SEM) and X-ray Spectroscopy by Dispersive Energy (EDS). Measurements of the compositional mapping and images of SEM revealed that the nanoparticles are not homogeneously distributed, being concentrated at the edges of the stents for the experimental conditions investigated in this work. As the VSM data, the EDS of the stents revealed an increase of the quantity of adsorbed magnetic nanoparticles at the surface with the increase of the adsorption time. The same theoretical model, know considering the amount of 26Fe in the chemical composition of the coated stent, was able to explain the experimental data. Finally, a comparison was made, using the compositional mapping study of the coated stents, between the Dip Coating and the Spray technique. The later showed a more homogeneous distribution of nanoparticles at the surface of the stent, suggesting that this technique is more adequate on the development of a biomedical nanoproduct for clinical tests.
Neste trabalho foi desenvolvida uma técnica de Dip Coating (deposição por via líquida) que permite controlar o gradiente de temperatura entre o substrato e o material que se quer depositar em sua superfície. Em particular, foi investigado o efeito de adsorção de nanopartículas magnéticas biocompatíveis na superfície de Stents nus em diversas condições experimentais. As nanopartículas magnéticas consistiam de magnetita recobertas com tripolifosfato (diâmetro médio ) dispersas em água em pH fisiológico, enquanto as endopróteses eram Stents de CoCr (Stent Cronus da empresa Scitech com 16mm). Ao todo foram realizadas 9 séries de experimentos onde controlou-se parâmetros como: tempo de adsorção, temperatura do Stent e temperatura do fluido magnético. Os Stents recobertos com nanopartículas foram então caracterizados magneticamente pela técnica de magnetometria de amostra vibrante (VSM Vibrating Sample Magnetometer ), que permitiu determinar o número de nanopartículas magnéticas adsorvidas na superfície da endoprótese. O aumento do momento magnético do Stent com o aumento do tempo de adsorção foi modelado teoricamente, com grande concordância experimental, como um processo de difusão transiente de nanopartículas na interface Stent-fluido magnético, evidenciando a forte contribuição difusiva. Fortes evidências de efeitos termodifusivos (efeito de Soret), ou seja mecanismos de difusão mássica de nanopartículas devido ao gradiente de temperatura entre Stent e FM, foram apresentados, sugerindo a possibilidade de vetorização de nanoestruturas por meio de fenômenos termoinduzidos. A distribuição das nanopartículas na superfície dos Stents foi investigada por medidas de Microscopia Eletrônica de Varredura (MEV) e espectroscopia de raios-X por energia dispersiva (EDS). As medidas de mapeamento composicional e imagens de MEV revelaram que as nanopartículas estão distribuídas de maneira não homogênea, estando concentradas nas bordas dos Stents para as condições experimentais utilizadas neste trabalho. Assim como os dados de MAV, o EDS dos Stents recobertos revelou um aumento da quantidade de nanopartículas magnéticas adsorvidas em sua superfície com o aumento do tempo de adsorção. O mesmo modelo teórico, agora considerando o percentual de 26Fe na composição química do revestimento, foi capaz de explicar os dados experimentais. Finalmente, foi feita uma comparação, por meio do mapeamento composicional de Stents recobertos, entre as técnicas de Dip Coating e Spray. Esta última apresentou uma distribuição de nanopartículas mais homogênea na superfície da endoprótese, sugerindo que possa ser mais adequada para a confecção de um nanoproduto médico voltado a testes clínicos.

A l’exception du chapitre bibliographique, cette thèse a été rédigée sous forme d’articles avec des résumés et des discussions tout en comparant les résultats obtenus à d’autres résultats de la littérature dans la même thématique de recherche. Ce travail s’organise en trois axes de recherche : la synthèse organique et la chimie des polymères, la physicochimie de la surface et l’étude de la réponse biologique et de la dégradation des polymères. La problématique de ce sujet de thèse s’articule autour de la resténose intra-stent qui représente la complication majeure de l’angioplastie par pose de stent dans les artères sténosées. Les stents actifs restent la solution actuellement utilisée pour le traitement de la resténose. Ce sont des stents métalliques recouverts d’un polymère qui comporte une substance bioactive généralement un antiprolifératif. Le rôle du polymère est de créer une barrière protectrice entre le métal et la paroi artérielle. Cette barrière doit améliorer la rugosité et la composition chimique du stent métallique, réparer l’endothélium par la prolifération des cellules endothéliales et inhiber la prolifération et la migration des cellules musculaires lisses qui sont responsables d’une façon directe de la reformation de la plaque d’athérome. Les propriétés de surface du polymère lui confèrent un fort pouvoir d’adhérence au métal et de biocompatibilité vis-à-vis de la paroi artérielle. Les interactions créées entre le revêtement polymère et les cellules vasculaires sont modulées par les propriétés physicochimiques de la surface. C’est dans cette optique que mon sujet de thèse est organisé en deux thématiques
With the exception of bibliographic chapter, this thesis was written in the format of collection of articles with abstracts and discussions while comparing the results with other’s in the literature in the same research theme. This work is organized in three tasks: organic synthesis and stereochemistry of polymers, surface physicochemical properties and biological response and degradation study of polymers. The issue of this thesis is based on in-stent restenosis which represents the major complications of angioplasty with stent placement. Drug-eluting stents are currently the solution used for the restenosis treatment. These are metal stents coated with a polymer having a bioactive substance which is generally an antiproliferative agent. The polymer role is to create a protective barrier between the metal and the arterial wall. This barrier must improve the roughness and the chemical composition of the metallic stent, repair the endothelium by the proliferation of endothelial cells and inhibit the proliferation and the migration of smooth muscle cells which are responsible to the reformation of atheroma plaque. The surface properties confer to polymer a strong adhesiveness to the metal and biocompatibility vis-a-vis of the arterial wall. Interaction created between the polymer coating and vascular cells are modulated by the physicochemical properties of the surface. It is in this context that my thesis is organized into two themes.The first aim of my thesis is to develop a series of amorphous polymers and study their physicochemical (wettability, roughness ...) and biological properties (adhesion, cell behavior and proliferation) and then correlate these properties to choose the promising coating coronary stent. A degradation study was also conducted on elaborate systems. The second is dedicated to chemical synthesis and stereochemistry of polymers. Indeed, new optically active monomers and the corresponding stereopolyesters were synthesized and characterized in order to compare their physicochemical properties with those of amorphous polyesters studied as a coating of the stent and enhance the biomaterials field

The persistence of thrombosis and restenosis owing to inflammation and poor endothelialisation of cardiovascular stents in patients highlights the need for new biomaterials with in situ endothelialisation capability. This thesis describes the development of a novel chemical curing procedure using poly(carbonate)urethane pre-polymers (PCU-PP), and subsequent immobilisation of biomolecules to promote in situ endothelialisation. PCU-PP coatings were chemically cured with ethylenediamine (EDA), propargylamine (PPA) and 3-mercaptopropionic acid (MPA). Anti-CD34 antibodies, which can capture endothelial progenitor cells (EPCs), were immobilised on to EDA coatings (EDA-CD34Ab). Cyclic REDV peptides (cycREDV), which are ligands selective towards endothelial cells (ECs), were immobilised on to PPA coatings (PPA-cycREDV). EDA-curing yielded coatings with surface amine (-NH2) functionality alongside micro-ridges (~8 μm) and nanofeatures (~90 nm). MPA-curing yielded carboxyl (-COOH) functionalised coatings with submicron ridges (~0.5 μm), while PPA-curing produced alkyne (-C≡C) functionalised coatings with micro-islands (~15 μm) and nanofibrous morphology (< 120 nm). Human umbilical vein ECs (HUVEC) showed differential responses to these combinatorial chemistry and nanotopography platforms. Cell adhesion and proliferation were influenced primarily by surface chemistry, but were further regulated by nanotopography. Optimal cell adhesion and proliferation were impeded on EDA surfaces with 35 nm high nanofeatures, but was enhanced on 15 nm high nanofeatures. EDA-CD34Ab supported optimal adhesion and proliferation of HUVECs and endothelial colony forming cells (ECFCs), but reduced platelet adhesion and activation. ECFCs with higher CD34 expression demonstrated improved long-term survivability on EDA-CD34Ab. PPA-cycREDV enhanced HUVEC adhesion and survival compared to linear REDV chains, while also reduced platelet adhesion. Finally, combinatorial EDA-PPA curing yielded multifunctional coatings for co-immobilisation of anti-CD34Ab and cycREDV. The combined coatings did not show synergistic enhancement in HUVEC density, suggesting further optimisation in its formulation might be needed. In conclusion, PCU-PP was developed to produce coatings with tuneable chemistry and topography. Immobilisation of biomolecules enhances EC selectivity over platelets, which is vital to promote in situ endothelialisation and circumvent clinical complications including thrombosis and restenosis. The tailorability of combinatorial surface properties of such coatings is important for discovery of next generation biomaterials with pro-healing capabilities.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 178-190).
Drug-eluting stents (DES) are commonly used in coronary angioplasty procedures. A DES elutes drug compounds from a thin polymeric coating into the surrounding coronary artery tissue to reduce in-stent restenosis (a significant lumen loss due to growth of vascular tissue). Biodurable (non-erodible) polymers are often used in the current DES coatings, which stay permanently in the patients. While promising treatment results were obtained, in-stent restenosis remains an issue and late in-stent thrombosis, which is associated with hypersensitivities to the polymer coatings, is also reported. Increasing interests have been raised towards the design of a more biocompatible coating, in particular a poly(lactic acid-co-glycolic acid) (PLGA) coating, for DES applications to improve the drug delivery and reduce adverse outcomes in patients. This dissertation aims to develop a mathematical model for describing the process of drug release from a biodegradable PLGA stent coating, and subsequent drug transport, pharmacokinetics, and distribution in the arterial wall. A model framework is developed in the first part of the dissertation, where a biodurable stent coating is considered, and the intravascular delivery of a hydrophobic drug from an implanted DES in a coronary artery is mathematically modeled. The model integrates drug diffusion in the coating with drug diffusion and reversible drug binding in the arterial wall. The model was solved by the finite volume method. The drug diffusivities in the coating and in the arterial wall were investigated for the impact on the drug release and arterial drug uptake. In particular, anisotropic vascular drug diffusivities result in slightly different average arterial drug levels but can lead to very different spatial drug distributions, and is likely related to the reported non-uniform restenosis thickness distribution in the artery cross-section. The second part of the dissertation focuses on modeling drug transport in a biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) coating. A mathematical model for the PLGA degradation, erosion, and coupled drug release from PLGA stent coating is developed and validated. An analytical expression is derived for PLGA mass loss. The drug transport model incorporates simultaneous drug diffusion through both the polymer solid and the liquid-filled pores in the coating, where an effective drug diffusivity model is derived taking into account factors including polymer molecular weight change, stent coating porosity change, and drug partitioning between solid and aqueous phases. The model predicted in vitro sirolimus release from PLGA stent coating, and demonstrated the significance of the developed model by comparing with existing drug transport models. An integrated model for intravascular drug delivery from a PLGA-coated DES is developed in the last part of the dissertation. The integrated model describes the processes of drug release in a PLGA coating and subsequent drug delivery, distribution, and drug pharmacokinetics in the arterial wall. Model simulations first compared a biodegradable PLGA coating with a biodurable coating for stent-based drug delivery. The simulations further investigated drug internalization, interstitial fluid flow in the arterial wall, and stent embedment for impact on the drug release and arterial drug distribution of a PLGA-coated stent. These three factors greatly change the average drug concentrations in the arterial wall. Each factor leads to significant and distinguished alterations in the arterial drug distribution that can potentially influence the treatment outcomes. The developed model here provides the basis of a design tool for evaluating and studying a PLGA coating for stent applications. Simulations using the model helped to provide insights into the potential impacts of various factors that can affect the efficacy of drug delivery. With the developed model, optimization of the model parameters can also be performed for future exploration on the design of PLGA-coated drug-eluting stents.
by Xiaoxiang Zhu.
Ph. D.

Owing to an increased risk of aging population and a higher incidence of coronary artery disease (CAD), there is a need for more reliable and safer treatments. Numerous varieties of durable polymer-coated drug eluting stents (DES) are available in the market in order to mitigate in-stent restenosis. However, there are certain issues regarding their usage such as delayed arterial healing, thrombosis, inflammation, toxic corrosion by-products, mechanical stability and degradation. As a result, significant amount of research has to be devoted to the improvement of biodegradable polymer-coated implant materials in an effort to enhance their bioactive response. In this investigation, magneto-electropolished (MEP) and a novel biodegradable polymer coated ternary Nitinol alloys, NiTiTa and NiTiCr were prepared to study their bio and hemocompatibility properties. The initial interaction of a biomaterial with its surroundings is dependent on its surface characteristics such as, composition, corrosion resistance, work of adhesion and morphology. In-vitro corrosion tests such as potentiodynamic polarization and electrochemical impedance spectroscopic (EIS) studies were conducted to determine the coating stability and longevity. In-vitro hemocompatibility studies and HUVEC cell growth was performed to determine their thrombogenic and biocompatibility properties. Critical delamination load of the polymer coated Nitinol alloys was determined using Nano-scratch analysis. Sulforhodamine B (SRB) assays were performed to elucidate the effect of metal ions leached from Nitinol alloys on the viability of HUVEC cells. Scanning Electron Microscopy (SEM), X-ray Photoelectron Spectroscopy (XPS), contact angle meter and X-ray diffraction (XRD) were used to characterize the surface of the alloys. MEP treated and polymer coated (PC) Nitinol alloys displayed a corrosion resistant polymer coating as compared to uncoated alloys. MEP and PC has resulted in reduced Ni and Cr ion leaching from NiTi5Cr and subsequently low cytotoxicity. Thrombogenicity tests revealed significantly less platelet adhesion and confluent endothelial cell growth on polymer coated and uncoated ternary MEP Nitinol alloys. Finally, this research addresses the bio and hemocompatibility of MEP + PC ternary Nitinol alloys that could be used to manufacture blood contacting devices such as stents and vascular implants which can lead to lower U.S. healthcare spending.

Les malalties d'artèria coronària són el tipus més comú de malaltia cardíaca, matant a més de 385,000 persones anualment. Fins a la data, s'han provat moltes estratègies diferents a l'hora de plantejar tractaments que mantinguin les respostes inflamatòries al mínim. Entre aquests, l'ús de nanopartícules, recobriments multicapa i teràpia gènica destaquen com algunes de les estratègies terapèutiques noves més prometedores. L'ús de stents cardíacs s'ha mantingut al llarg dels anys amb diferents dissenys i recobriments, aconseguint millors resultats amb cada nova generació. Encara que el seu ús està justificat, els seus resultats no són òptims, creant la necessitat de desenvolupar millors estratègies per tractar aquest tipus de malalties. Entenem que un control total de l'alliberament de la càrrega farmacològica d'un dispositiu mèdic pot canviar profundament els resultats d'un pacient, convertint-se així en una prioritat del nostre treball. Presentem una forma de produir recobriments, a escala industrial i de laboratori, orientats per a dispositius mèdics i que s'utilitzen per produir recobriments multicapa a mida per stents amb alliberament de fàrmac. A més d'això, també es presenta un enfocament per tractar malalties d'artèria coronària a través de la teràpia gènica amb nanoportadors, el que obre noves possibilitats per a tractaments localitzats emprant stents amb alliberament de fàrmac. Començant amb l'elaboració de metodologies i instruments necessaris per a produir recobriments a mida, es creen i estudien nous dissenys de stent al llarg d'aquest treball. Això permet la producció de nous recobriments i sistemes d’alliberació els quals són provats in-vitro i in-vivo per demostrar la seva efectivitat. En conclusió, aquesta tesi demostra que es pot aconseguir un alliberament de fàrmacs a mida mitjançant dissenys multicapa i alliberament amb nanoportadors, aplicable a stents amb alliberament de fàrmac per obtenir una reducció en les taxes de reestenosi amb resultats prometedors.
Las enfermedades de arteria coronaria son el tipo más común de enfermedad cardíaca, matando a más de 385,000 personas anualmente. Hasta la fecha, se han probado muchos enfoques distintos a la hora de plantear tratamientos que mantengan las respuestas inflamatorias al mínimo. Entre estos, el uso de nanoparticulas, recubrimientos multicapa y terapia génica destacan como algunas de las estrategias terapéuticas novedosas más prometedoras. El uso de stents cardíacos se ha mantenido a lo largo de los años con diferentes diseños y recubrimientos, logrando mejores resultados con cada nueva generación. Aunque su uso está justificado, sus resultados no son óptimos, creando la necesidad de desarrollar mejores estrategias para tratar este tipo de enfermedades. Entendemos que un control total de la liberación de la carga farmacológica de un dispositivo médico puede cambiar profundamente los resultados de un paciente, convirtiéndose así en una prioridad de nuestro trabajo. Presentamos una forma de producir recubrimientos, a escala industrial y de laboratorio, orientados para dispositivos médicos y que se utilizan para producir recubrimientos multicapa a medida para stents con liberación de fármaco. Además de esto, también se presenta un enfoque para tratar enfermedades de arteria coronaria a través de la terapia génica con nanoportadores, lo que abre nuevas posibilidades para tratamientos localizados empleando stents con liberación de fármaco. Comenzando con la elaboración de metodologías e instrumentos necesarios para producir recubrimientos a medida, se crean y estudian nuevos diseños de stent a lo largo de este trabajo. Esto permite la producción de nuevos recubrimientos y sistemas de liberación los cuales son probados in-vitro e in-vivo para demostrar su efectividad. En conclusión, esta tesis demuestra que se puede lograr una liberación de fármacos a medida mediante diseños multicapa y liberación con nanoportadores, aplicable a stents con liberación de fármaco para obtener una reducción en las tasas de reestenosis con resultados prometedores.
Coronary artery disease is the most typical type of heart disease, killing more than 385,000 people annually. Up to date, many different approaches have been tested in order to treat patients while trying to keep inflammatory responses to a minimum. Among these, the use of nanocarriers, multilayered coatings and gene therapy stand out as some of the most promising novel therapeutic strategies tested lately. Stents have been used throughout the years with different designs and coatings, achieving enhanced healing results with every new generation. Although their use is justified their results are not optimal, creating a need to develop better strategies to treat coronary artery diseases. We understand that a total liberation control of the pharmacological drug load from a medical device can profoundly change a patient’s outcome, therefore, becoming a priority of our work. Here, we present a way of producing in-lab and industrial scaled coatings for medical devices which are used to produce tailored multilayered coatings for drug eluting stents. Apart from this, an approach to treat coronary artery disease through gene therapy with nanocarriers is also introduced, opening new possibilities for localized treatments with drug eluting stents. Starting with the elaboration of methodologies and instrumentation required to produce tailored coatings, novel stent designs are created and studied in this work. This enables the production of new coatings and delivery systems which are tested in-vitro and in-vivo in order to prove their effectiveness. In conclusion, this thesis demonstrated that a tailored drug release can be achieved through multilayered designs and nanoparticle liberations, which can be applied to drug eluting stents to obtain a reduction in restenosis rates with promising results.

Metallic cardiovascular stents are medical devices (implants) that can provide endovascular scaffolding in order to relieve a vascular obstruction and minimize the risk of myocardial infarction (heart attack). However, current stents are considered to offer poor bio/hemocompatibility, since their surface provokes undesirable tissue reaction upon implantation. In most cases, this results in in-stent restenosis (re-blocking of the blood vessel at the implantation site). Thus, various surface characteristics of stents play a determinant role in their bio/hemocompatibility, and hence their functionality and safety. Therefore, in order to increase the bio/hemocompatibility of stents, an appropriate surface-modification method can be employed to tune the stent's surface texture and physico-chemical properties in a way to promote desirable cell/platelet-surface interactions and render the stent surface more electrochemically stable (corrosion resistant). The aim of this work was to investigate a possibility of increasing a bio/hemocompatibility of a metal surface by employing two surface-modification approaches: (i) formation of IrxTi1-x-oxide coatings (x=0, 0.2, 0.4, 0.6, 0.8 and 1) on a Ti substrate and on a commercial 316L stainless steel (316L-SS) coronary stent and (ii) electrochemical polishing of a 316L-SS surface. The former approach was also employed with the aim of increasing the stent's radiopacity (visibility). Electrochemical and surface-characterization results showed that the physic-chemical properties were highly depended on the coating composition. All the coatings were found to be electrochemically stable (corrosion resistant) under experimental conditions employed in the research. 316L-SS coronary stents modified by Ir/Ti-oxide coatings were found to be more radiopaque than the bare (naked) 316L-SS stent. The Ir0.4Ti0.6-oxide coating showed to be the most uniform, corrosion resistant and radiopaque. Electrochemical polishing (EP) of a 316L-SS surface in an electrolyte of a new chemical composition was investigated at different cell voltages. The influence of the EP cell voltage on the topographical/morphological and physico-chemical properties of resulting passive oxide films formed on the surface was studied. A particularly high enrichment with Cr species was recorded at the outermost layer of the EP oxide films. As a result of the increase in the oxide film thickness and relative Cr enrichment, the EP-treated 316L-SS surfaces offered a notable improvement in general and pitting corrosion resistance. The influence of the employed surface-modification methods on the resulting bio/hemocompatibility was further investigated. This was implemented by examining the interaction of platelets, endothelial cells (ECs) and smooth muscle cells (SMCs) with the modified surfaces. A significant decrease in platelet adhesion and activation was obtained on Ir0.2Ti0.8-oxide and Ir0.4Ti0.6-oxide coatings (among Ir/Ti-oxide surfaces) and on the surfaces electrochemically polished at the cell voltages of 4 and 10 V (among electropolished surfaces), rendering the surfaces more blood compatible, in comparison to the control (316L-SS). Moreover, ECs and SMCs showed a desirable response to the modified surfaces (the Ir/Ti-oxide coated and the electropolished surfaces). The cell/surface interaction experiments revealed a a higher affinity of ECs towards attachment to the modified surfaces, relative to the attachment of SMCs. Hence, the modified surfaces would enable faster endothelialization, rendering them potentially superior for coronary stenting applications.
Endoprothèses vasculaires métalliques sont des dispositifs médicaux (implantes) qui peuvent fournir des échafaudages endovasculaire afin de soulager une obstruction vasculaire et minimiser le risque d'infarctus du myocarde (crise cardiaque). Cependant, les prothèses actuels sont considérés d'offrir mauvais bio/hémocompatibilité, car leur surface provoque une réaction tissulaire indésirable lors de l'implantation.Dans la plupart des cas, cela se traduit par une resténose intra-prothèses (re-blocage des vaisseaux sanguins au niveau du site d'implantation). Alors, diverses caractéristiques de surface des prothèses jouent un rôle déterminant dans leur biocompatibilité et subséquemment leur fonctionnalité et sécurité. Par conséquent, afin d'augmenter la bio/hémocompatibilité de prothèses s, une méthode de modification de surface appropriée peut être utilisée pour ajuster la texture de la surface du stprothèses et les propriétés physico-chimiques de manière à favoriser les interactions cellulaires/surface souhaitables et rendre la surface des prothèses plus électrochimique stable (résistant à la corrosion).Le but de ce travail était d'étudier la possibilité d'augmenter un bio/hémocompatibilité d'une surface métallique en utilisant deux approches de modification de surface: (i) la formation de revêtements IrxTi1-x-oxyde (x = 0, 0,2, 0,4, 0,6, 0.8 et 1) sur un substrat de Ti et sur une base commerciale acier inoxydable 316L (316L-SS) prothèses coronariens et (ii) le polissage électrochimique d'une surface 316L-SS. La première approche a également été utilisée dans le but d'augmenter la radio-opacité des prothèses (visibilité). Des techniques électrochimiques et surface-caractérisation ont été utilisées pour étudier la topographie/morphologie de la surface, la structure et la composition chimique des revêtements Ir/Ti-oxyde, ainsi que leurs propriétés électrochimiques et des radio-opacité. Ces propriétés ont été trouvés fortement dépendent de la composition de revêtement. Tous les revêtements ont été jugées électrochimiquement stables dans les conditions expérimentales utilisées dans la recherche. 316L-SS prothèses coronaires modifiés par des revêtements Ir/Ti-oxyde ont été trouvés à être plus radio-opaque que celui sans revêtements 316L-SS prothèses. Le revêtement Ir0.4Ti0.6-oxyde a été montré pour être le plus uniforme, résistant à la corrosion et radio-opaque. Spectrométrie photoélectron du rayon-X résultats de spectroscopie de photoélectrons ont révélé que les films d'oxyde du EP ont été caractérisées par une proportion beaucoup plus élevé atomique Cr/Fe et d'épaisseur de film, par rapport au film d'oxyde passif naturellement développée formée sur la surface non traitée 316L-SS. Un particulièrement enrichissement élevé avec des espèces Cr a été enregistré à la couche la plus externe des films d'oxyde EP. En raison de l'augmentation de l'épaisseur du film d'oxyde et enrichissement relatif Cr, les surfaces 316-SS EP-traités offert une amélioration notable de la résistance à la corrosion générale et piqûres. L'influence des méthodes de modification de surface utilisés sur la bio/hémocompatibilité a été étudiée. Ceci a été implémenté en examinant l'interaction des plaquettes, des cellules endothéliales (EC) et les cellules musculaires lisses (SMC) avec les surfaces modifiées. Les expériences sur l'interaction entre la cellule et la surface ont révélé un plus grand ratio de fixation EC/SMC pour Ir0.2Ti0.8-oxyde, Ir0.4Ti0.6-oxyde et les trois surfaces du EP, lorsque en comparant avec la contrôle 316L-SS. Ceci. Ainsi, les surfaces modifiées permettront une endothélialisation plus rapide, ce qui les rend potentiellement supérieure pour les applications de prothèses coronaire.

Au cours de 15 dernières années, les maladies coronariennes et les accidents vasculaires cérébraux demeurent les causes principales de décès dans le monde. Selon l'Organisation Mondiale de la Santé, en 2015, ces deux maladies ont causé 15 millions des décès sur les 56,4 millions dans le monde. Des traitements chirurgicaux ont été élaborés et améliorés pour soigner ces maladies en maintenant les vaisseaux sanguins ouverts. Parmi les traitements chirurgicaux, l'angioplastie avec utilisation d’un stent est le traitement le plus populaire et le moins invasif. Les stents, qui sont des tubes métalliques en treillis, vont soutenir mécaniquement les vaisseaux sanguins après l’implantation et les maintenir ouverts pour améliorer le flux sanguin. Ceux-ci sont principalement composés d’acier inoxydable AISI316L (SS316L), d'alliage de cobalt-chrome et d'alliage de titane. Depuis plus d'un demi-siècle, lorsqu'un stent a été implanté pour la première fois, ils ont été considérablement améliorés. Cependant, la libération d'ions métalliques, potentiellement toxiques, et la détérioration des propriétés mécaniques à cause de la corrosion ainsi que la diminution de l'adhérence des revêtements, dans le cas de stents avec les revêtements en polymère, constituent encore des préoccupations majeures lors de l’utilisation des stents. Dans le cas des stents en SS316L, afin d’éviter la libération d'ions métalliques, au laboratoire de biomatériaux et de bioingénierie de l'Université Laval (LBB), lors de précédentes recherches, un revêtement fluorocarboné (CFx) a été étudié pour isoler complètement le stent de l'environnement biologique. Ce revêtement permet également le greffage ultérieur de molécules bioactives pour améliorer son intégration dans le corps. Cependant, l'interface de SS316L / CFx devait être améliorée pour augmenter l’adhésion du revêtement CFx sur le SS316L. Dans mon projet de doctorat, l’oxydation au plasma a été utilisé pour élaborer une nouvelle interface entre le substrat SS316L et le revêtement. Les propriétés de cette nouvelle interface, qui est composée d’une couche d'oxyde, ont été modifiées en faisant varier les paramètres du procédé plasma afin de préserver les propriétés de cette couche d’oxyde lorsqu’elle subit une déformation plastique de 25%, c’est-à-dire le pourcentage de déformation maximale que subira le stent lors de son implantation. Cette interface a permis de diminuer la libération des ions du substrat SS316L en réduisant son taux de corrosion plus que trois fois et d’améliorer l’adhérence adéquate du revêtement CFx sur le substrat, après déformation et après immersion dans une solution aqueuse saline. La nouvelle couche d'oxyde sur SS316L est une couche d'oxyde amorphe avec une épaisseur d'environ 6 nm qui se distincte bien de la microstructure polycristalline du substrat. L'amélioration des propriétés de l'interface a été attribuée à cette couche d'oxyde amorphe nano-épaisse, qui est résistante aux déformations plastiques. Cette couche d'oxyde peut être appliquée sur des stents métalliques nus composés de métaux passivables. En outre, elle crée une interface favorable pour les revêtements en polymère, qui sont utilisés pour les stents à relargage de principes actifs ainsi que pour améliorer l'intégration des stents dans le corps humain.
Over the past 15 years, ischemic heart disease and stroke have remained the leading causes of death, worldwide. According to the World Health Organization, 15 million of the 56.4 million global deaths, in 2015, were caused only by ischemic heart disease or stroke. For the treatment of these diseases, surgical treatments have been introduced and improved to hold the blood vessels open. Among the surgical treatments, angioplasty with stenting is the most popular and the least invasive treatments. Stents, which are wire mesh tubes, prepare a mechanical support for blood vessels and hold them open to restore the blood flow. They are mostly made up of AISI316L stainless steel (SS316L), cobalt-chromium, and titanium alloys. More than half a century ago, when a stent first used, it has considerably evolved. However, release of potentially-toxic metallic ions and deterioration of mechanical properties due to corrosion, and decrease of polymeric coatings adhesion, in case of coated stents, still constitute major concerns in SS316L stents. In the case of SS316L stents, to circumvent the release of metallic ions, in the laboratory for biomaterials and bioengineering of Université Laval (LBB), a fluorocarbon (CFx) coating was previously investigated to isolate the stent completely from the biological environment. The coating also enables subsequent grafting of bioactive molecules to improve its integration in the body. The results were promising; however, the interface of SS316L/CFx needed to be modified to improve the adhesion of the CFx coating. In this Ph.D. research project, a new interface between the SS316L substrate and the CFx coating was created by plasma oxidation. The properties of this new interface, which was an oxide layer, was modified by varying the plasma-process parameters in order to preserve its properties after a 25% plastic deformation. This deformation is the maximum plastic deformation that imposes on a stent during its implantation. The new interface decreased the release of ions by decreasing the corrosion rate of the SS316L substrate by a factor of three. It was also found that the new interface produced an adequate adhesion of the CFx coating to the substrate after deformation as well as after immersion in an aqueous saline solution. The new oxide layer on SS316L was an amorphous oxide layer with an approximately 6 nm thickness, which was clearly distinguished from the polycrystalline microstructure of the substrate. The enhancement of the interface properties was ascribed to this nano-thick amorphous oxide layer, which was found to be more resistant to plastic deformation. This new oxide layer can be produced on bare-metal stents made of passivating metals. Moreover, it can create a favorable interface for coated stents, which have been used in drug-eluting stents, and also to improve stents integration in the human body.

La réparation endovasculaire (EVAR) est une technique minimalement invasive permettant de traiter l’anévrisme de l’aorte abdominale (AAA) par l’entremise d’un stent- graft (SG). L’utilisation d’EVAR est actuellement limitée par de fréquentes complications liées à une guérison inadéquate autour de l’implant. Ce manque de guérison est principalement dû au type de recouvrement polymérique des SG, au milieu pro-apoptotique des AAA et à l’accès réduit aux nutriments et à l’oxygène après EVAR. L’objectif de cette thèse consistait à concevoir un revêtement bioactif permettant d’inhiber l’apoptose et stimuler la croissance des cellules musculaires lisses vasculaires (CMLV), pour ainsi favoriser la guérison des tissus vasculaires autour des SG. La chondroïtine-4-sulfate (CS) a d’abord été choisie, car elle a été identifiée comme un médiateur important de la réparation vasculaire. Il a été démontré que la CS en solution influence directement la résistance à l’apoptose des CMLV, en plus de favoriser la différenciation myofibroblastique chez les fibroblastes. Dans le cadre de ce projet, un premier revêtement à base de CS et de collagène a été créé. Bien que le revêtement permettait d’induire une résistance à l’apoptose chez les CMLV, il se désintégrait trop rapidement dans des conditions aqueuses. Une nouvelle méthodologie a donc été adaptée afin de greffer la CS directement sur des surfaces aminées, à l’aide d’un système utilisant un carbodiimide. Dans le but d’accroître la croissance des CMLV à la surface des revêtements, le facteur de croissance de l’épiderme (EGF) a ensuite été sélectionné. En plus de ses propriétés mitogéniques et chimiotactiques, l’EGF stimule la production d’éléments de la matrice extracellulaire, comme le collagène et la fibronectine. De plus, l’activation du récepteur de l’EGF inhibe également l’apoptose des CMLV. L’EGF a donc été greffé sur la CS. Le revêtement de CS+EGF a démontré une bonne uniformité et bioactivité sur des surfaces de verre aminé. iii iv Dans une 3ème étape, afin de permettre de transposer ce revêtement bioactif sur des implants, plusieurs méthodes permettant de créer des groupements d’amines primaires sur les biomatériaux polymériques comme le PET ou le ePTFE ont été étudiées. La polymérisation par plasma a été choisie pour créer le revêtement CS+EGF à la surface de PET. Une fois de plus, celui-ci a permis d’inhiber l’apoptose des CMLV, dans des conditions pro-apoptotiques, et de favoriser la croissance des cellules. Le revêtement de CS et d’EGF, déposé sur des surfaces aminées, possède des caractéristiques biologiques intéressantes et semble donc prometteur pour favoriser une meilleure guérison autour des SG.
Endovascular aneurysm repair (EVAR) is a minimally invasive technique performed to treat abdominal aortic aneurysm (AAA) through the use of a stent-graft (SG). The usage of EVAR is presently limited by postoperative complications related to an incomplete healing of the surrounding tissues. The materials currently used in SG, the pro- apoptotic phathophysiology of AAA and the limited access to nutrients and oxygen, all limit the wound healing process and proper tissue ingrowth around the implant. The main objective of this thesis was to create of a bioactive coating inhibiting cell apoptosis and increasing vascular smooth muscle cells (VSMC) growth, to promote healing of the vascular tissues surrounding SG. Chondroitin sulfate (CS) was chosen since recent findings have shown that this polysaccharide triggers key mechanisms involved in vascular repair. CS in solution was shown to inhibit apoptosis of VSMC, as well as stimulate myofibroblast differentiation. A coating of CS and collagen was first created for the purpose of this work. Although the coating was shown to increase cell resistance to apoptosis with VSMC, it was not stable enough, since it rapidly disintegrated in aqueous solutions. A new methodology was thus proposed, where CS was grafted right on aminated surfaces, through carbodiimide chemistry. Epidermal growth factor (EGF) was then chosen to increase VSMC growth on the coatings. EGF is a known mitogenic and chemotactif growth factor for VSMC. It also stimulates the production of extracellular matrix elements, such as collagen and fibronectin. The activation of EGF receptor (EGFR) also triggers various cell signalling pathways modulating VSMC resistance to apoptosis. EGF was thus grafted on CS. CS+EGF coating on aminated glassed slides was shown to be uniform and bioactive. Finally, several methodologies to produce primary amines on polymeric biomaterials, such as PET and ePTFE, were studied in order to eventually transfer the v vi coating on implants. Plasma polymerization was chosen to create the CS+EGF coating. Once again the coating was shown to decrease VSMC apoptosis, in apoptotic conditions, and favour cell growth. Overall, the CS and EGF coating on aminated surfaces possesses interesting biological features and is a promising avenue to stimulate vascular healing around SG.

Calcium phosphate ceramic coatings, especially hydroxyapatite (HA), have attracted much attention in the orthopedics and dentistry due to their excellent biocompatibility and bioactivity. Among the different methods of calcium phosphate coatings processing, electrochemical deposition (ECD) is a relatively low cost and flexible process technology. In this study, electrochemical deposition was used to deposit uniform calcium phosphate coatings on 316L stainless steel coronary stents. The influence of the ECD process parameters (deposition time, current density, electrolyte temperature, pH, and Ca/P ratio) on the resulting deposition morphology was investigated. Scanning electron microscopy (SEM) and X-Ray diffractometry (XRD) were used to analyze the coatings. The results demonstrated that both dicalcium phosphate dihydrate (CaHP0₄·2H₂0, DCPD) and hydroxyapatite (Ca₁₀(P0₄)(OH)₂, HA) were present in the uniform [tilde]0.5 [micro sign]m thick as-deposited coating. However, a post-treatment process, including a O.1N NaOH(aq) phase conversion at 75°C and a 500°C heat treatment produced a pure phase HA coating. The final deposit revealed a highly porous surface morphology which could be useful for drug encapsulation. With the application of the substrate surface modification and the post-treatment processes, sufficient coating adhesion was achieved as demonstrated by the in-vitro stent deployment tests without visible damage to the coating. Commercial in-vitro 40 million cycles fatigue tests demonstrated that the coatings exhibit good adhesion to the stent substrate, with no coating cracking or delamination. It was confirmed that the ECD-HA coating process for coronary stents is reliable and reproducible.
Applied Science, Faculty of
Materials Engineering, Department of
Graduate

碩士
國立中興大學
材料科學與工程學系所
102
Some limitations like the hypersensitivity reaction, the long-term impairment of endothelial response, and the late stent thrombosis for drug-eluting stents using percutaneous transluminal coronary angioplasty (PTCA) are still found. Though the degradable magnesium alloy used to construct an absorbable stent could be another candidate, the poor corrosion resistance is relatively a serious impediment against wider applications of magnesium alloys. In this study, the coatings of zirconia (ZrO2) bottom layer and calcium phosphate (CaP) top layer are carried out on pure magnesium specimens by electrochemical deposition and subsequent annealing, leading to the corrosion current density reduced from 13.3 to 3.86 μA/cm2 derived by potentiodynamic polarization tests in artificial blood plasma at 37 °C. Furthermore, calcium phosphate (CaP), gelatin (Gel) and heparin (Hep) are co-deposited on post CaP/ZrO2 coated specimens in order to fabricate the heparin sustaining release system for promoting the hemocompatibility of magnesium. Heparin loaded composite coatings are analyzed by X-Ray diffractometry (XRD), field emission scanning electron microscope (FESEM), focused ion beam system (FIB), toluidine blue colorimetric assay, UV-visible spectrometer, and indirect endothelial cell viability tests. The drug content increases from 243.56±55.18 μg/cm2 for single layer (CaP-Hep) to 484.19±19.26 μg/cm2 for multilayer (CaP-Gel-Hep/CaP-Hep/CaP/ZrO2) and the sustaining release of the latter lasting for more than 28 days compared with that of the former for 1 day in PBS solution. The cell viability, related to Mg2+ ions in medium extracts which are still toxic to endothelial cells at high concentrations, is 63 % for the uncoated, 97 % for the ZrO2 coated, and 110 % for the CaP/ZrO2 and CaP-Gel-Hep/CaP-Hep/CaP/ZrO2 coated specimens compared with 100 % for the negative control. All results indicate that ZrO2 coated, CaP/ZrO2 coated, and CaP-Gel-Hep/CaP-Hep/CaP/ZrO2 coated magnesium specimens are potential for biodegradable cardiovascular stents.

碩士
國立中興大學
材料科學與工程學系所
100
Although the initial success of bare metal stents (BMS) has significantly reduced the restenosis rate from 35% for Percutaneous transluminal coronary angioplasty (PTCA) to 25%, the biological mechanism such as smooth muscle cell proliferation and neointimal hyperplasia may still induce in-stent restenosis (ISR). Therefore, some drug eluting stents have been introduced to reduce ISR. In this study, heparin (Hep) combined with calcium phosphate (CaP) and gelatin (Gel) is co-deposited on NiTi alloy in order to promote the hemocompatibility of NiTi substrate and fabricate the sustained heparin releasing system. Polarization tests are carried out in several solutions to investigate deposition mechanisms. Heparin contained composite coatings are characterized by X-ray diffractometry (XRD), Field emission scanning electron microscope (FESEM), Fourier transform infrared spectroscopy (FTIR), toluidine blue colorimetric assay, UV-visible spectrometer and kinetic clotting tests. The consequences indicate that heparin accompanied with CaP, and Gel through ionic bonds can be loaded on the NiTi alloy, respectively. The porous post HA coating can enhance drug content from 147.06±68.66 μg/cm2 of single layer coating (CaP-Hep) to 191.58±11.87 μg/cm2 of bilayer coating (HA/CaP-Hep) and further to 324.87±4.94 μg/cm2 of trilayer coating (HA/CaP-Hep/Gel-Hep) by adding the third layer which also results in the in vitro heparin release prolonging from 1 day burst to more than 35 days sustaining. As the result of clotting tests, drug loaded composite coatings reveal good anticoagulant property which is proportional to the cumulative content of drug release in an hour, indicating no denaturalization of heparin found during the electrochemical process.