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La guérison des plaies cutanées appendiculaires chez le cheval, à la différence de celle des plaies corporelles, se complique régulièrement. Un retard de cicatrisation s’y observe et un tissu de granulation exubérant tend à s’y développer, le tout menant à une cicatrice pathologique hypertrophiée. La pathogénie exacte du tissu de granulation exubérant chez le cheval demeure inconnue à ce jour. Une hypoxie tissulaire pourrait favoriser son développement tout comme elle semble contribuer au développement de cicatrices cutanées pathologiques similaires observées chez l’Homme. L’objectif de cette étude était d’évaluer la perfusion vasculaire et la disponibilité locale en oxygène de plaies cutanées appendiculaires et corporelles en cours de cicatrisation normale et pathologique chez le cheval, à l’aide de la thermographie infrarouge et de la spectroscopie par réflectance dans le proche infrarouge. Six juments âgées de 3 à 4 ans ont été utilisées. Trois plaies cutanées ont été créées à l’aspect dorso-latéral du canon des membres thoraciques (plaies appendiculaires), et sur la paroi costale de l’un des hémithorax (plaies corporelles). Chez chaque jument, un canon a été aléatoirement bandé dans le but d’induire la formation de tissu de granulation exubérant dans les plaies s’y trouvant, tel que rapporté. La perfusion vasculaire et la disponibilité locale en oxygène ont été évaluées séquentiellement par thermographie infrarouge et spectroscopie par réflectance dans le proche infrarouge pour chaque plaie de chaque site (thorax; membre bandé; membre non bandé) au cours du processus de cicatrisation cutanée. Un modèle linéaire à doubles mesures répétées associé à une correction séquentielle de Bonferroni a révélé des différences significatives de perfusion vasculaire et de disponibilité locale en oxygène entre les plaies appendiculaires et corporelles. Ainsi la perfusion vasculaire et la disponibilité locale en oxygène étaient significativement plus élevées dans les plaies corporelles (P<0.05) et la perfusion vasculaire était significativement plus élevée dans les plaies appendiculaires non bandées que dans celles bandées (P<0.05). Nous avons récemment rapporté une plus grande occlusion de la micro-vascularisation au niveau des plaies appendiculaires chez le cheval. Nous rapportons maintenant que la perfusion vasculaire et la disponibilité locale en oxygène sont significativement inférieures dans les plaies appendiculaires, en particulier lorsqu’un tissu de granulation exubérant s’y développe. Compilés, ces résultats sous-tendent l’hypothèse que les plaies appendiculaires souffrent d’une altération de la perfusion vasculaire à l’origine possible d’une hypoxie tissulaire qui pourrait favoriser une cicatrisation cutanée anormale, telle la formation d’un tissu de granulation exubérant. / Cutaneous wound healing in horse limbs is often perturbed by the development of exuberant granulation tissue while body wounds tend to repair uneventfully. A delay in healing is usually observed in horse limb wounds, which tend to develop exuberant granulation tissue and excessive scarring. The events leading to exuberant granulation tissue formation in horses are not fully elucidated. Tissue hypoxia has been proposed as a major contributing factor as it appears to contribute to the development of similar abnormal skin scarring in human. The objective of this study was to investigate skin blood flow and tissue oxygen availability in normal / abnormal healing of full-thickness wounds created on the horse limb and body, using infrared thermography and near infrared reflectance spectroscopy. Six healthy, 3- to 4-year-old mares were used for the experiment. Three full-thickness cutaneous wounds were surgically created on the dorso-lateral surface of each metacarpal area (limb wounds) and on the lateral thoracic wall (body wounds). One randomly chosen distal forelimb was then left to heal by second intention without bandage, while the contralateral limb was bandaged postoperatively to induce the formation of exuberant granulation tissue and lead to excessive scarring. Thermal and spectroscopic data were collected from both anatomic sites (limb without bandage, bandaged limb, thoracic wall) at specific times following wounding. Mean changes in skin blood flow and tissue oxygen availability at specific wound sites over time were compared by use of repeated measures ANOVA with anatomical location and wound management as within-subject factors. A priori contrasts, submitted to Bonferroni sequential correction, were then used to compare pre-selected individual means. The statistical analysis revealed that there were significant differences in skin blood flow and tissue oxygen availability within wounds. Skin blood flow and tissue oxygen availability were significantly increased within body over limb wounds (P<0.05). Skin blood flow was significantly increased within unbandaged limb over bandaged limb wounds (P<0.05). We have recently reported a greater occlusion of microvessels in limb wounds in horses. We report here that skin blood flow and tissue oxygen availability are significantly inferior in limb wounds in horses, especially when exuberant granulation develops. Taken together, these results suggest that equine limb wounds may suffer from altered vascular perfusion and tissue hypoxia, which could favor abnormal skin healing and exuberant granulation tissue development.

Dans ce travail, le traitement des nutriments et plus particulièrement celui de l’azote en procédé de granulation aérobie a été étudié. L’approche expérimentale a dans un premier temps eu pour objet de comparer la stabilité des caractéristiques physiques et microbiologiques d’agrégats développés dans deux réacteurs fonctionnant en alternances de phases anaérobie / aérobie ou anoxie / aérobie. L’opération d’un procédé de granulation aérobie en alternance de phases anoxie / aérobie a favorisé la stabilisation des performances de traitement de l’azote et notamment celle de la nitrification. Le développement d’une boue hybride comprenant une fraction de flocs et de granules a été observé. Dans le but d’évaluer comment le caractère hybride de la boue obtenue en conditions anoxie/aérobie oriente les performances et vitesses de transformation de l’azote, une caractérisation ex-situ des limitations au transfert d’oxygène au sein des flocs, granules et boue hybride a été réalisée par respirométrie. En complément, la localisation des espèces nitrifiantes par la technique d’hybridation fluorescente in situ (FISH) a été réalisée. Les résultats obtenus indiquent que la présence de flocs au sein d’une boue granulaire permet d’augmenter la vitesse de la nitrification, en particulier pour de faibles concentrations en oxygène dissous. D’autre part, il est ici mis en évidence la nécessité de contrôler simultanément le ratio floc/granules et la taille des granules en vue de l’optimisation du traitement de l’azote.Enfin un outil mathématique permettant de décrire les phénomènes réactionnels ayant lieu au sein d’une biomasse hybride a été développé. Celui-ci a été employé dans le but d’optimiser le fonctionnement du procédé hybride par l’évaluation de l’effet des propriétés physiques de la biomasse, et plus particulièrement de la proportion de granules en présence, pouvant conduire à une élimination efficace de l’azote et à l’augmentation de la robustesse du procédé vis-à-vis de diminutions ponctuelles de l’oxygène dissous / In this work, the treatment of nutrients, especially that of nitrogen in aerobic granulation process was studied.The experimental approach has initially been intended to compare the stability and the physical and microbiological characteristics of aggregates developed in two reactors operating in alternating anaerobic / aerobic or anoxic / aerobic conditions. The presence of a pre-anoxic phase promoted the stabilization of nitrogen removal performances and especially those of nitrification. The development of a hybrid sludge process containing a fraction of flocs and granules was observed.In order to evaluate and quantify the influence of the simultaneous presence of flocs and granules in the nitrifying activity of the hybrid sludge developed in the alternating anoxic / aerobic conditions, the nitrification rate and oxygen limitation of flocs, granules and hybrid sludge was assessed using respirometric assays at different dissolved oxygen concentrations. The spatial distribution of nitrifying bacteria was investigated using fluorescence in situ hybridization (FISH). Results indicated that the presence of flocs with granules could increase the rate of nitrification to transitory reductions of aeration. On the other hand, the optimization of nitrogen removal requires the simultaneous control of the floc to granule ratio and granule size.Finally, a mathematical model to describe the reaction phenomena taking place in the hybrid biomass was developed. It was used in order to optimize the operation of the hybrid process through the evaluation of the effect of physical properties of biomass, specifically the ratio of granules and flocs in the reactor that can lead to efficient removal of nitrogen and increase the robustness of the process

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L'homogénéité des caractéristiques est garantie par une présence en fibres constante en tout point du matériau. La dispersion d'une espèce dans une autre est régie par des mécanismes de convection et/ou de diffusion. Pour des objets de la taille d'une fibre métallique, ces deux phénomènes trouvent leur origine dans le cisaillement appliqué au matériau, une donnée souvent inconnue et difficile à mesurer dans des malaxeurs à béton. Dans un premier temps, nous proposons une méthode permettant d'estimer l'efficacité d'un malaxeur. Elle est basée sur la mesure du diamètre moyen de granules de ciment fabriqués dans ce malaxeur. Nous montrons que la mesure de ce diamètre moyen permet de quantifier le cisaillement moyen. Dans un second temps, nous présentons un moyen de mesurer la dispersion des fibres pendant le malaxage des bétons à base de mesures de résistivité électrique. Puis, dans un troisième temps, nous mesurons la présence en fibres pendant le malaxage et relions le temps nécessaire à l'obtention d'une répartition homogène à la capacité de cisaillement du malaxeur / Fibers are added to the concrete to give it news properties. The homogeneity of these characteristics is assured by a constant presence of fiber as the whole material. The dispersion of one species within another is governed by convection and/or diffusion mechanisms. Concerning objects having the size of steel fiber, these two phenomena are caused by the shearing applied to the material, an unknown and difficult to measure datum in the case of concrete mixer. To begin, a method allowing to estimate the mixer's shearing is suggested. This method is based on the measurement of the medium diameter of cement aggregates produced in the mixer. The link between the medium diameter and the mean shearing is established. In a second time, a mean to measure fiber dispersion from electrical resistivity measurements during the concrete mixing is presented. Then, in a third time, fiber dispersion are measured during mixing. The link between necessary time to obtain an homogeneous distribution and the mixer's shearing ability is established

L’hypoxie contribue à la guérison cutanée via l’induction de HIF-1 (hypoxia-inducible factor-1). HIF-1 gère l’expression de VEGFA (vascular endothelial growth factor A) en se liant au HRE (hypoxia response element) présent au niveau de son promoteur. Par contre, dans le contexte de la guérison cutanée il est incertain si l’hypoxie et HIF-1 contribuent à l’augmentation de l’expression de VEGFA. Pour vérifier cette hypothèse, la guérison cutanée et l’expression de VEGFA ont été étudiées dans un modèle murine, Vegfa/, possédant un HRE non-fonctionnel dans le promoteur de Vegfa. De manière inattendue, le niveau d’ARNm de Vegfa présent dans la peau intacte des souris mutantes était diminué. Par contre, le niveau d’ARNm de Vegfa dans le tissu de granulation n’était pas altéré par rapport à celui de souris normales. Similairement, le niveau d’ARNm des gènes ciblés par Vegfa, Pdgfb et Sdf-1, étaient aussi comparativement diminués dans la peau intacte des souris mutantes mais aucune différence significative ne fut observée dans le tissu de granulation de plaies. L’analyse histologique des plaies en guérison chez les souris mutantes a démontré un tissu de granulation altéré en quantité et qualité (densité de capillaires). Par contre, la différence dans l’épithélialisation et le taux de guérison cutanée entre les deux populations de souris était non-significative. Les résultats démontrent qu’HIF-1 n’est pas un facteur majeur dans la régulation de Vegfa dans le contexte de la guérison cutanée. Cependant, HIF-1 est nécessaire pour maintenir un niveau d’expression basale (Vegfa et ses gènes cibles) adéquate et est aussi nécessaire pour la formation d’un tissu de granulation de qualité optimal suivant une blessure cutanée. / Hypoxia in skin wounds is thought to contribute to healing through the induction of hypoxia-inducible factor-1 (HIF-1), a key transcriptional regulator of genes associated with healing. HIF-1 regulates the expression of vascular endothelial growth factor A (VEGFA) by binding a hypoxia response element (HRE) in its promoter. Although VEGFA is a key regulator of angiogenesis during healing, whether hypoxia and HIF-1 serve to induce its expression in this context is unknown. To test this hypothesis, we studied VEGFA expression and wound healing in the Vegfa/ mouse model, which lacks a functional HRE in the Vegfa promoter. Unexpectedly, decreased levels of Vegfa mRNA were found in intact skin in Vegfa/ mice, whereas levels in granulation tissue during wound healing were not altered. Likewise, mRNA levels of VEGFA target genes Pdgfb and Sdf-1 were decreased in skin but unchanged in granulation tissue in the Vegfa/ mice. Decreased Vegfa levels in skin could not be attributed to decreased HIF-1 protein expression in the skin of Vegfa/ mice, and were therefore the consequence of a loss of HIF-1 responsiveness of the Vegfa promoter. Histologic analyses of healing wounds in Vegfa/ mice revealed significant defects in granulation tissue, both in terms of quantity and capillary density, although epithelialization and healing rates were unaltered. It can be concluded that HIF-1 is not a major regulator of Vegfa during wound healing. Rather, HIF-1 serves to maintain basal levels of Vegfa and VEGFA target genes in intact skin, required for optimal granulation tissue formation in response to wounding.

Twin screw wet granulation has been proved as a feasible alternative for traditional batch granulation process due to its continuous processing feature; considered as a significant processing method especially in the pharmaceutical industry. This thesis will explore the processibility of twin screw wet granulation with various formulations. The first section of the thesis focused on examining the processibility of wet granulation in a twin screw while using various grades of hydroxypropyl methylcellulose (HPMC) as an extended-release excipient. The method to find the processibility was by modifying the liquid-to-solid ratio for each formulation. The process window was defined by examining the amount of granules that fall in a pre-determined acceptable size range. This part focused on three substitution types of HPMC (Type 2910, Type 2208, and Type 2906) that varied in molecular weights. It was found that only Type 2910 HPMC showed a shift in the process window (also known as granulation range) in relation to the molecular weight of the formulations. A higher demand for binder liquid was found for higher molecular weight Type 2910 HPMC in order to form granules with acceptable sizes. The second part of this thesis was focused on understanding the process variables that might influence the processibility of the HPMC formulations. This part examined the impact of feed rate on the granulation range of Type 2910 HPMC specifically was examined. Multiple feed rates were tested, and it was found that the granulation range for lower molecular weight Type 2910 HPMC was easier to shrink when higher feed rates were applied. A transition in the granule formation method from liquid-bridging to compaction with respect to the feed rate was found for low molecular weight HPMC, whereas the high molecular weight HPMC always formed granules through compaction at all feed rates due to strong water retainability. / Thesis / Master of Applied Science (MASc)

High shear melt granulation (HSMG) is an established technology for a production of densified granules. In this project, it was used as a novel solvent-free method for the preparation of cocrystals. Cocrystals produced by HSMG were compared to those prepared by Hot Melt Extrusion (HME) to investigate the influence of variable parameters and conditions on the process of cocrystal conversion. The potential for the active control of cocrystals polymorphism utilising the intrinsic properties of lipids was also investigated in this project. Different cocrystal pairs were prepared by both cocrystallisation methods using glycol derivative polymers. Thermal analysis, powder X-ray diffraction and Raman spectroscopy were used as analytical techniques to determine the cocrystal yield and purity. The results obtained from HSMG suggest that sufficient binder concentrations (above 12.5% w/w) in a molten state and continuous shearing force are necessary to achieve a complete cocrystals conversion. Further increase in binder concentration (15% w/w) was found to provide more regular shape and smooth surface to the prepared spherical granules. Cocrystals preparation by HME was achievable after introducing a mixing zone to the extruder configuration (Conf B and Conf C) providing densified extrudates containing pure cocrystals. In conclusion, HSMG was found as a versatile technique for the preparation of pure pharmaceutical cocrystals embedded in polymer matrix within a spherical shape granule of smooth surfaces, providing additional desirable characteristics. Intensive surface interaction, enhanced by sufficient mixing under optimal parameters, was found as a key influencing factor in cocrystallisation. Cocrystals polymorphism was actively controlled by employing the intrinsic properties of polymers and lipids.

Orientador: Andrigo Barboza De Nardi / Resumo: As feridas de pele apresentam alta prevalência no atendimento clínico de pequenos animais. Para o tratamento dessas lesões, por segunda intenção, inúmeros produtos já foram descritos buscando-se características como: melhor qualidade e redução no tempo do processo de cicatrização. O objetivo desse trabalho foi avaliar a solução de Tartarato de ketanserina (0,345%) e Asiaticosídeo (0,20%) como opção terapêutica, aplicada via tópica, no processo de cicatrização de lesões cutâneas em cães atendidos no Hospital Veterinário “Governador Laudo Natel” (Unesp-FCAV) de Jaboticabal-SP. Para isso, foi acompanhado o processo de cicatrização de dezenove feridas em cães, divididos em dois grupos de tratamento, o grupo controle (GC) com dez feridas e o grupo tratado (GT) com nove feridas. Os pacientes do GT receberam o produto teste, via tópica, e os pacientes do GC a solução salina 0,9% em momentos pré-determinados. As feridas foram avaliadas quanto às suas características macroscópicas e redução da área em diferentes momentos (T0: início do tratamento; T3: terceiro dia de tratamento; T7: sétimo dia de tratamento; T14: décimo quarto dia de tratamento). A mensuração da área foi realizada por planimetria digital do decalque das feridas, pelo programa computacional “ImageJ”. As variáveis da avaliação macroscópica foram analisadas por correspondência múltipla, com aplicação do teste qui-quadrado, com nível de significância P<0,05. Os dados obtidos da área nos diferentes momentos, foram submetid... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Skin wounds present high prevalence in the clinical care of small animals. For the treatment of these lesions, by means of second intention, numerous products have already been described looking for characteristics such as: better quality and reduction in the time of the healing process. The objective of this study was to evaluate the solution of ketanserin tartrate (0.345%) and Asiaticosídeo (0.20%) as a therapeutic option, applied topically, in the healing process of cutaneous lesions in dogs attended at the Veterinary Hospital "Governador Laudo Natel" (Unesp-FCAV) of Jaboticabal-SP. For this, the cicatrization process of nineteen wounds in dogs was divided into two treatment groups, the control group (GC) with ten wounds and the treated group (WG) with nine wounds. The GT patients received the test product, topical, and the patients of the GC received saline solution 0.9% at predetermined times. The wounds were evaluated for their macroscopic characteristics and reduction of the area at different times (T0: beginning of treatment, T3: third day of treatment, T7: seventh day of treatment, T14: fourteenth day of treatment). The measurement of the area was performed by digital planimetry of the wound decal, by the computer program "ImageJ". The variables of the macroscopic evaluation were analyzed by multiple correspondence, with application of the chi-square test, with significance level P <0.05. The data obtained from the area at the different moments were submitted to anal... (Complete abstract click electronic access below) / Mestre

A modernização dos equipamentos de granulação por via úmida permitiu o desenvolvimento de diversas técnicas a partir do método tradicional. Dentre as técnicas desenvolvidas, a granulação por solidificação de materiais fundidos (GSMF) elimina o uso de solventes e diminui o tempo de processo. O presente trabalho teve por objetivo estudar o processo de granulação por solidificação de materiais fundidos usando um misturador/granulador do tipo high-shear (HSMG) e avaliar a influência das variáveis do processo nas características farmacotécnicas dos granulados e comprimidos obtidos. O artesunato foi escolhido para realização do estudo de granulação devido ao seu alto grau de cristalinidade e instabilidade química. Foi realizado um estudo de compatibilidade fármaco-excipiente usando técnicas de DSC, FTIR associada a técnicas estatísticas multivariadas (PCA e HCA) e cromatografia líquida de alta eficiência. Os parâmetros de HSMG estudados foram o tipo de diluente, a quantidade de PEG 6000 adicionada, o tempo de massificação, a velocidade do misturador e a velocidade do chopper, usando um planejamento experimental fatorial fracionário 25-1. Os granulados obtidos foram avaliados quanto a densidade, propriedades de fluxo e distribuição granulométrica. Os granulados de manitol apresentaram teor de umidade <1% e span de 1,690. Aqueles com lactose apresentaram teor de umidade > 2% e span de 2,814. A velocidade do misturador e do chopper não apresentaram efeitos significativos nas características dos granulados. O manitol foi escolhido como diluente para o artesunato que foi granulado com misturador a 100 rpm e chopper em 1000 rpm seguindo planejamento experimental fatorial completo 32 em duplicata para estudar variáveis de formulação: a razão artesunato/manitol e a quantidade de PEG 6000 adicionada. A quantidade PEG 6000 adicionada aos granulados contribuiu para o aumento da densidade (aparente e compactada) e do tamanho de partícula, e também para a diminuição da friabilidade, da formação de finos e do span. O perfil compressional dos granulados foi determinado graficamente através das curvas força-tempo e força-deslocamento. O tempo de desintegração dos comprimidos obtidos aumentou com a quantidade de artesunato na formulação enquanto a dureza diminuiu. O PEG 6000 aumentou a resistência mecânica e diminuiu o tempo de desintegração. Foram adicionados 2% de croscarmelose às amostras duplicadas e foi observado uma diminuição do tempo de desintegração dos comprimidos obtidos em 70% e o processo de compressão ficou mais uniforme sem alterar outras características do comprimido como resistência mecânica, trabalho útil, trabalho elástico e plasticidade da formulação. / The modernization of the equipment for wet granulation has enabled the development of different techniques from the traditional method. Among the techniques developed, hot - melt granulation eliminates the use of solvents and reduces the process time. The present work aimed to study the process of granulation by solidification of molten materials using a high-shear mixer/granulator (HSMG) and evaluate the influence of process parameters on particle size distribution, flowability and tableting characteristics of material produced. The artesunate was chosen to carry out the granulation study due to its high degree of crystallinity and chemical instability. A drug-excipient compatibility study was performed by DSC, FTIR combined with multivariate statistical techniques (PCA and HCA) and high performance liquid chromatography. The HSMG parameters investigated were the type of diluent, the amount of PEG 6000 added, massification time, the mixer speed and chopper speed, using a fractional factorial experimental design 25-1. Density, flow properties and particle size distribution of the granules were evaluated. The granular mannitol showed moisture content < 1% and span of 1.690. Granular lactose showed moisture content > 2% and span of 2.814. The mixer and chopper speed did not show significant effects on granule characteristics. Mannitol was chosen as more suitable diluent for artesunate. HSMG was carried out with the mixer speed 100 rpm and chopper speed 1000 rpm according to a full factorial experimental design 32 in duplicate to study formulation variables: artesunate/mannitol proportion and the amount of PEG 6000 added. The amount of PEG 6000 added contributed to increase the granules density (bulk and tapped), mean particle size and also to reduce friability, formation of fine particles and span. The granules compressional profile was determined graphically through force-time and force-displacement plots showing differences in work of compaction, compression and elastic recovery. The disintegration time of tablets obtained increased with the amount of artesunate in formulation while the tensile strength decreased. The amount of PEG 6000 increased hardness and decreased disintegration time. To the duplicate samples were added 2% of croscarmellose and a decrease of 70% in disintegration time of tablets was noted and also compression process become more uniform without changing other tablet features as mechanical resistance, compaction, elastic recovery and formulation plasticity.