Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-02-13T18:50:27Z No. of bitstreams: 1 thiagodossantosribeiro.pdf: 1282702 bytes, checksum: 3d347e1f5b2c2d1d122a47e12f71fc48 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-02-15T13:49:43Z (GMT) No. of bitstreams: 1 thiagodossantosribeiro.pdf: 1282702 bytes, checksum: 3d347e1f5b2c2d1d122a47e12f71fc48 (MD5) / Made available in DSpace on 2017-02-15T13:49:43Z (GMT). No. of bitstreams: 1 thiagodossantosribeiro.pdf: 1282702 bytes, checksum: 3d347e1f5b2c2d1d122a47e12f71fc48 (MD5) Previous issue date: 2016-09-16 / Este trabalho tem como objetivo efetuar uma análise da sensibilidade da perfusão sanguínea e da condutividade térmica ao se simular processos de queimadura de pele devido a uma fonte de calor externa, considerando diferentes condições de contorno e utilizando o método dos elementos finitos (MEF) para discretizar a equação de Pennes. O modelo 2D aqui empregado considera um tecido biológico formado pelas camadas de epiderme, derme e subcutânea, e considera também funções não lineares para perfusão sanguínea e condutividade térmica. A hipótese não linear se explica pelo fato que para a perfusão sanguínea observa-se um aumento seguido de uma diminui¸ca˜o acima das temperaturas específicas resultantes de danos induzidos pelo aumento de temperatura nos capilares sanguíneos, e que a condutividade térmica varia linearmente com o aumento da temperatura. O sistema de equações diferenciais ordinárias não lineares oriundo da discretização via MEF é resolvido empregando-se o método de Euler implícito em conjunto com o método de Picard. Uma vez determinado a distribuição de temperatura, o modelo de Arrhenius será utilizado para calcular o dano térmico e classificar a queimadura quanto ao seu grau (ou seja, primeiro, segundo ou terceiro grau). / This paper aims at performing a sensitivity analysis of blood perfusion and thermal conductivity when simulating skin burning process due to an external heat source, considering different boundary conditions and using the finite element method (FEM) to discretize Pennes’s equation. The 2D model employed here considers a biological tissue formed by epidermis, dermis and subcutaneous layers, and also considers nonlinear functions for blood perfusion and thermal conductivity. The nonlinear assumption is explained by the fact that for the blood perfusion it is observed an increase followed by a decrease greater than the specific temperatures resulting from damage induced by temperature increase in blood capillaries, and also that the thermal conductivity varies linearly with temperature growth. The system of nonlinear ordinary differential equations arising from the discretization by FEM is solved by employing the implicit Euler method in conjunction with the method of Picard. Once the distribution of temperature is determined, the Arrhenius model is used to calculate the thermal damage and classify the burn degree (i.e., first, second or third degree).

L'objectif de cette thèse était de mettre en oeuvre le développement d'une thérapie des plaies cutanées profondes basée sur l'utilisation de nanoparticules (NP) biodégradables de poly(acide lactique) (NP-PLA) vectrices de médiateurs de la cicatrisation. Le but était d'accélérer la cicatrisation cutanée et de favoriser la reconstruction d'un derme fonctionnel. La méthode a été de (i) réduire la réaction inflammatoire pour en contenir les effets délétères et (ii) stimuler la réépithélialisation pour accélérer la cicatrisation et réduire le risque infectieux. Les moyens ont été l'utilisation d'un antioxydant, la vitamine E (VE) et d'un facteur de croissance des fibroblastes (le FGF2) vectorisés par des nanoparticules biocompatibles et biodégradables de poly(acide lactique) (PLA). Nos NP-PLA contiennent l'antioxydant (VE) dans leur coeur hydrophobe, et portent le facteur de croissance fibroblastique (FGF2) à leur surface. Ces formulations ont été (i) caractérisées par des méthodes physico-chimiques et (ii) testées par des méthodes in vitro pour évaluer leurs effets potentiels, en tant que système de délivrance de VE et de FGF2, sur la cicatrisation des plaies. Des modèles expérimentaux in vivo ont été développés et caractérisés pour mettre en évidence l'efficacité des NP-PLA fonctionnalisées pour la cicatrisation cutanée et la reconstruction dermique fonctionnelle. Nos résultats montrent que l'activité antioxydante de la VE n'est pas perturbée par l'encapsulation dans des NP-PLA et qu'elle est légèrement supérieure à celle de la VE libre dans un système in vitro. De même, l'activité biologique du FGF2 sur la prolifération et la migration des fibroblastes dans un système in vitro n'est pas altérée par son adsorption sur des NP-PLA. Aucune de ces deux NP-PLA fonctionnalisées n'a de cytotoxicité avérée in vitro. Deux modèles expérimentaux de plaies cutanées profondes ont été développés sur souris sans poils SKH1 saines : (i) Un modèle robuste de brûlure cutanée thermique de 3ème degré qui se caractérise par une inflammation massive de la plaie et par un stade de granulation tardif après 16 jours de cicatrisation. (ii) Un modèle de plaie d'excision cutanée a également été utilisé. Un modèle de cicatrisation retardée a été obtenu par induction chimique d'un diabète de type I stable avant réalisation des plaies d'excision ou de brûlure. Ces modèles de plaies cutanées ont été caractérisés tout au long du processus de cicatrisation par des études (i) macroscopiques de cinétique de fermeture des plaies, (ii) histologiques d'inflammation, de nécrose et de réépithélialisation, (iii) physiologiques de perfusion sanguine cutanée. L'expression de 84 gènes impliqués dans le processus de cicatrisation a été étudiée sur le tissu cicatriciel 14 jours après formation de la plaie. Pour conclure, nos résultats mettent en évidence le potentiel de vectorisation de molécules thérapeutiques des NP de PLA pour le développement de futures stratégies de délivrance ciblée de VE et de FGF2 dans les plaies cutanées profondes. Les modèles expérimentaux in vivo développés et caractérisés, ouvrent la voie aux études précliniques d'efficacité des NP-PLA fonctionnalisées dans le processus de cicatrisation des plaies profondes / The objective of this thesis was to develop a therapy of cutaneous deep wounds based on biodegradable poly (lactic-acid) nanoparticles (PLA-NP) releasing wound healing mediators. The goal was to accelerate wound healing and to promote the reconstruction of a functional dermis. Our method was (i) to reduce the inflammatory reaction in the aim of limiting its deleterious effects, (ii) to stimulate reepithelialization to accelerate wound healing and to reduce the risk of infections. The implementation of means was based on the use of an antioxidant (vitamin E, VE) and a fibroblast growth factor (FGF2) carried by biocompatible and biodegradable poly(lactic-acid) based nanoparticles. Our PLA-NP contained the antioxidant (VE), in their hydrophobic core and carried the fibroblastic growth factor (FGF2) on their surface. These formulations were (i) characterized by physico-chemical methods and (ii) tested by in vitro methods to evaluate their effects as a delivery system of VE and FGF2 on wound healing. Experimental in vivo models have been developed and characterized in the aim of studying the potential beneficial effect of functionalized PLA-NP on wound healing and functional reconstruction of dermis. Our results show that the antioxidant activity of VE was not inhibited by encapsulation into PLA-NP and was lightly increased compared with free VE in an in vitro system. The biological activity of FGF2 on proliferation and migration of fibroblasts in an in vitro system was not altered by adsorption onto PLA-NP as well. No cytotoxicity of these functionalized PLA-NP was detected in vitro. Two experimental models of deep cutaneous wounds were developed on the healthy SKH1 hairless mouse: (i) A robust third degree thermal burn model that was characterized by massive inflammation of the wound and a late granulation stage after 16 days of healing. (ii) A model of excisional skin wound was also used. A model of delayed wound healing was established by chemical induction of stable type I diabetes prior to excision and burn injuries. The healing process of these models of cutaneous wounds was characterized by (i) macroscopic studies of wound closure, (ii) histological studies of inflammation, necrosis and reepithelialization, and (iii) by physiological studies of cutaneous blood perfusion. A study of the expression of 84 genes involved in the healing process was carried out on the scar tissue 14 days post-wound. In conclusion, our results highlight the potential efficacy of PLA-NP as a vector of therapeutic molecules for the development of future strategies for targeted delivery of VE and FGF2 in deep skin wounds. The developed and characterized in vivo experimental models open the way to preclinical studies of efficacy of functionalized PLA-NP on the healing process of deep wounds

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