The synthesis, characterization and photophysical properties of three Zr-based Metalorganic frameworks (MOFs) assembled from 2,6-anthracenedicarboxylic acid (2,6-ADCA, 2,6- MOF) and 1,4-anthracenedicarboxylic (1,4-ADCA, 1,4-MOF), and 9,10-anthracenedicarboxylic acid (9,10-ADCA, 9,10-MOF) are described. The crystal structure of the 9,10-MOF was elucidated by synchrotron powder X-ray diffraction (PXRD) analysis and is isostructural with the well-known UiO-66 framework. The 2,6-MOFs also form highly crystalline, octahedral-shaped structures and was characterized by PXRD. Le Bail refinement of the powder pattern revealed that the 2,6-MOF also has UiO-type crystal structure. Conversely, incorporation of the 1,4-ADCA ligand results in large rod-shaped crystals. The excited-state properties of the MOFs were examined using steadstate diffuse reflectance, steady-state emission spectroscopy and time-correlated single photon counting (TCSPC) spectroscopy and are compared to those of the corresponding ligand in solution. Both the unique fluorescent properties of the ligand as well as individual framework structure, result in distinctive luminescent behavior and dictate the extent of intermolecular interactions. Specifically, the 2,6-MOF displays monomeric emission with a fluorescence lifetime (t) of 16.6 ± 1.1 and fluorescence quantum yield (Ff). On the other hand, the 1,4-MOF displays both monomeric and excimeric emission, with corresponding lifetime values of 7.5 ± 0.01 and 19.9 ± 0.1, respectively and a quantum yield of 0.002 ± 0.0001. The propensity for photon upconversion through sensitized triplet-triplet annihilation (TTA-UC) was probed in the three anthracene-based MOFs. The MOFs were surface-modified with Pd(II) mesoporphyrin IX (PdMP) as the triplet sensitizer. Upconverted emission from the 9,10-MOF was observed, with a quantum efficiency (FUC) of 0.46 % and a threshold intensity (Ith) of 142 mW/cm2 . The variation of the spacing between the anthracene units in the MOFs was found to have significant impact on TTA-UC. As a result, upconverted emission is only displayed by the 9-10-MOF. The distance between anthracene linkers in the 2,6-MOF are too large for TTA to occur, while the short distances in the 1,4-MOF inhibit upconversion through competitive excimer formation. To further explore the effects of chromophore spacing on energy transfer processes, a series of zinc-based mixed-ligand MOF were constructed from Zn(II) tetrakis(4- carboxyphenyl)porphyrin (ZnTCPP) and pyrazine, 2,2′-bipyridine (pyz) or 4,4′-bipyridyl (bpy) or 1,4-di(4-pyridyl)benzense (dpbz), comprising ZnTCPP/Zn paddlewheel layers. Across this series, the porphyrin spacing was approximately 6 Å, 11 Å and 16 Å for pyz, bpy and dpbz, respectively. The photophysical properties of the MOFs were explored using stead-state diffuse reflectance spectroscopy and steady-state and time-resolved emission spectroscopies. Florescence quenching studies examined the correlation between porphyrin spacing and efficiency of energy transfer. / Ph. D. / Metal-organic frameworks (MOFs) are crystalline materials composed of metal clusters connected by organic molecules. Their modular nature and synthetic tunability allows for rational design of MOFs with different functionalities and has afforded their application in a variety of fields including gas storage and separation, catalysis, optoelectronics, energy conversion and storage, chemical sensing and biomedicine. MOFs provide an ideal platform for studying the structure-property relationships that govern energy-transfer processes. Furthermore, efficient and long-ranging, directional energy transfer has been demonstrated in MOFs. The work presented in this dissertation focuses on MOFs with applications in solar energy conversion schemes. The design and synthesis of photoactive MOFs is described and the effects of their structure on energy-transfer processes is explored. Photovoltaic cells (PVCs) absorb sunlight and convert it into electricity. However, only photons that are high enough in energy are absorbed by the PVC, while the lower energy photons are not absorbed and therefore do not contribute to power production, resulting in decreased efficiency of the solar cell. One approach to enhancing solar cell efficiencies is to collect the lower energy photons and convert them into higher energy photons through a process called sensitized photon upconversion (UC). This process involves a molecule (sensitizer chromophore) that absorbs lower-energy photons and then transfers the absorbed energy to a second molecule (acceptor chromophore), which emits higher-energy photons. In order to understand how to optimize the efficiency of the UC process, we integrated sensitizer and acceptor chromophores into MOFs various molecular arrangements and probed UC in these materials. Close proximity and he appropriate orientation between chromophores resulted in UC from the framework. Natural photosynthetic systems contain highly ordered arrays of chromophores that efficiently absorb sunlight and funnel the energy to a reaction center. Energy-harvesting materials that mimic natural photosynthetic processes also have potential applications in solar energy conversion. Porphyrins are often used in artificial photosynthetic systems because of their similarity to chlorophyll pigments found in nature. In order to design highly efficient artificial photosynthetic systems, we first need to understand how energy transfer processes are influenced by the structure of the system. Therefore, we synthesized a series of MOFs containing Zn=porphyrin layers at varied distances and examined the effects of distance between porphyrin layers on the energy-transfer processes within the MOFs. This work provides insight into the structure-property relationships in photoactive MOFs that can serve as a guide for the rational design of light-harvesting MOFs in future studies.

In den letzten Jahren konzentriert sich die Entwicklung in der kommerziellen Informatik zunehmend auf den Einsatz von Standardsoftware, vorgefertigten Komponenten und Frameworks. Gleichzeitig stehen bei steigenden funktionalen Anforderungen regelmäßig geringere personelle und monetäre Ressourcen für die Anwendungsentwicklung zur Verfügung. Andererseits ist immer mehr Rechenleistung zu sinkenden Preisen verfügbar. Vorhandene, individuell entwickelte und an die Prozesse im Unternehmen angepasste Software muss häufig für den Einsatz im Intranet und Internet erweitert werden. Die technologischen Veränderungen und der Zwang zur Konsolidierung erfordern und erzwingen ein anderes Management von IT-Projekten. Die Diskussionen der letzten Jahre über leichtgewichtige Verfahren geben den Praktikern das theoretische Rüstzeug für die Umsetzung dieser Vorgehensweisen in die Hand [COC 03]. Nachfolgend werden die Aspekte dieser Veränderungen für das Projektmanagement diskutiert. In einem Großprojekt einer deutschen Versicherung wurden einige der betrachteten Verfahren und Methoden durch den Autor im praktischen Einsatz angewandt.

Les MOFs résultent de l’organisation de polyèdres métalliques reliés par des molécules organiques chélatantes pour former un réseau poreux. La construction de solides hybrides organiques/inorganiques permet d’imaginer un très grand nombre de matériaux aux propriétés structurales et physico-chimiques variées. Le confinement du substrat dans une structure rigide, associé à des propriétés particulières des clusters métalliques ainsi qu’à des parois pouvant être fonctionnalisées, fournissent un environnement catalytique unique, plaçant les MOF à la frontière entre les espèces types zéolites et les enzymes. Cependant, il existe aujourd’hui très peu de MOFs possédant plus d’une fonction catalytique. Néanmoins, les propriétés catalytiques des MOFs peuvent être améliorées de façons non négligeables grâce aux méthodes de post-fonctionalisation. Dans ce travail, nous reportons le développement d’une méthode de post-fonctionnalisation originale des amino-MOFs. La première étape consiste à convertir la fonction amine en fonction azoture. Puis, sans isolation ni purification, le MOF fonctionnalisé est obtenu par « Click Chemistry » en ajoutant l’alcyne correspondant. Cette méthode peut être appliquée à tous les types d’amino-MOFs et à quasi toutes les fonctions chimiques que l’on souhaite greffer. Une large librairie de nouveaux matériaux a ainsi été obtenue et complètement caractérisée. Cette méthode a aussi été utilisée pour créer des MOFs catalytiques à façon pour une réaction de transesterification, ainsi que pour l’investigation de nouvelles applications plus fines (niches industrielle) / MOFs result from the association of metallic clusters connected by organic linkers to form a net. It is acknowledged that ultimately MOFs could mimic “enzymes” using “molecular recognition” concept to allow high chemio-, regio-, enantio-selectivity. We could indeed anticipate MOFs as potential “artificial enzymes” that can combine several properties at the nanometer scale in a concerted fashion. However to date, the number of MOFs with more than one reactive “catalytic” function is rather scarce. A key to address advanced MOF materials suitable for more sophisticated applications is to add functionalities of greater complexity in a controlled manner. The ability to modify the chemical environment of the cavities within MOFs would allow tuning of the interactions with guest species, and serve as a route to tailor the chemical reactivity of the framework. However, the introduction of reactive chemical functions by self-assembly methods is not a trivial task. In this work, we report an original PSM method starting from amino derived MOFs. The first step consists in converting the amino group into azide (N3). Without isolation nor purification, the desired functionalized material is obtained by grafting the corresponding alkyne using “Clik Chemistry”. This method can be applied to all kind of amino-MOFs and to all kind of grafted chemical functions. A diverse library of original MOFs was synthesized and characterized. Finally, this method was used to engineer catalytic MOFs for the transesterification of ethyldecanoate with methanol or to investigate applications in specialized industrial niches

[pt] Com o crescimento dos sistemas de informação baseados na internet, empresas que mantém seus negócios eletrônicos através de sistemas web necessitam monitorar o andamento das atividades dos seus negócios. Várias técnicas para monitoramento e análise da execução de processos de negócio podem ser empregadas, dentre elas: (i) mineração de arquivos de log de servidores web, tais como o Apache; e (ii) inserção explícita de código de monitoramento diretamente no código da aplicação. Tais técnicas possuem várias limitações, entre elas, a dificuldade e falta de flexibilidade para corelacionar informação ocorrendo em diferentes requisições web, e/ou necessidade de várias modificações invasivas transversais diretamente no código de componentes/classes do sistema. Esse trabalho apresenta o projeto e implementação de um framework orientado a aspectos para monitoramento e análise de processos de negócio que ocorrem em sistemas web. Aspectos foram usados para implementar as variabilidades orientadas a aspectos de monitoramento de processos de negócio ocorrendo em sistemas web. O framework foi implementado usando as linguagens Java e AspectJ e foi validado por meio da sua instanciação para duas diferentes aplicações web. / [en] Over the last years, many mechanisms and techniques to monitor web applications have been proposed, such as, mining of log files from web servers and insertion of monitoring code directly in web applications. The adoption of these techniques presents several limitations such as: obstacles to correlate information from different web requests and/or requires several intrusive changes in the code of existing web applications. This dissertation presents an aspect-oriented framework to monitoring and analysing business processes. Aspect-oriented technologies are used to implement crosscutting variabilities of monitoring of web business processes. The framework has been developed using Java and AspectJ programming languages. It was instantiated and validated through the development of two different web applications.

Polímeros de coordenação têm atraído a atenção de pesquisadores na última década por conta de sua incrível versatilidade e virtualmente infinito número de possibilidades de combinação de ligantes orgânicos e centros metálicos. Estes compostos normalmente herdam as características magnéticas, eletrônicas e espectroscópicas de seus componentes base. Entretanto, apesar do crescente número de trabalhos na área, ainda são raros os polímeros de coordenação que apresentem condutividade elétrica. Para este fim, utilizou-se a N,N\'-bis(4-piridil)-1,4,5,8-naftaleno diimida, ou NDI-py, que pertence a uma classe de compostos rígidos, planares, quimicamente e termicamente estáveis e que já foram extensamente estudados por suas propriedades fotoeletroquímicas e semicondução do tipo n. O primeiro polímero de coordenação sintetizado, MOF-CoNDI-py-1, indicou ser um polímero linear, de estrutura 1D. O segundo, MOF-CoNDI-py-2, que conta com ácido tereftálico como ligante suporte, é um sólido cristalino com cela unitária monoclínica pertencente ao grupo espacial C2/c, determinado por difração de raios-X de monocristal. A rede apresenta um arranjo trinuclear de íons Co(II) alto spin com coordenados em uma geometria de octaedro distorcido, enquanto os ligantes NDI-py se encontram em um arranjo paralelo na estrutura, em distâncias apropriadas para transferência eletrônica. Com o auxílio de cálculo teóricos a nível de DFT, foi realizado um estudo aprofundado dos espectros eletrônicos e vibracionais, com atribuição das transições observadas, tanto para o MOF-CoNDI-py-2 quanto para o ligante NDI-py livre. A rede de coordenação absorve em toda a região do espectro eletrônico analisada, de 200 nm a 2500 nm, além de apresentar luminescência com característica do ligante. Dispositivos eletrônicos fabricados com um cristal do MOF-CoNDI-py-2 revelaram condutividades da ordem de 7,9 10-3 S cm -1, a maior já observada para um MOF. Além de elevada, a condutividade elétrica dos cristais demonstrou-se altamente anisotrópica, sendo significativamente menos condutor em algumas direções. Os perfis de corrente versus voltagem foram analisados em termos de mecanismos de condutividade, sendo melhores descritos por um mecanismo limitado pelo eletrodo to tipo Space-Charge Limited Current, concordando com a proposta de condutividade através dos planos de NDI-py na rede. A condutividade dos cristais também é fortemente dependente de luz, apresentando fotocondução quando irradiado por um laser vermelho, de 632 nm, enquanto apresenta um comportamento fotorresistivo frente a uma fonte de luz branca. Estes resultados, combinados, trazem um MOF em uma estrutura incomum e com elevada condutividade elétrica, modulada por luz, em medidas diretas de corrente. Não existem exemplos conhecidos de MOFs na literatura com estas características. / Coordination polymers have been a major topic in materials science during the past decade, thanks to their versatility and virtually infinite possible combinations between metal centers and organic ligands. These coordination polymers usually inherit the properties of their components, such as magnetic, spectroscopic and electronic characteristics. However, despite the increasing number of research papers in this topic, it is still hard to find coordination polymers featuring electronic conductivity. To achieve that, we used a naphthalene diimide derivative, N,N\'-bis(4-pyridyl)-1,4,5,8- naphthalene diimide or NDI-py, which belongs to a class of rigid, planar, thermally and chemically stable compounds, extensively studied due to their photoelectrochemical properties and their n-type semiconductivity. The first coordination polymer synthesised, MOF-CoNDI-py-1, was an amorphous linear polymer, with a 1D structure. Based on these observations, MOF-CoNDI-py-2 was synthesised by using terephthalic acid as a supporting ligand, and it is a crystalline solid which its monoclinic unit cell belongs to a C2/c space group, as determined by single crystal X-ray diffraction. This network features a trinuclear high-spin Co(II) unit, and each metal ion sits on a distorted octahedra coordination geometry, while the NDI-py ligands sit in a parallel arrangement, with distances suitable for electronic transfers. A detailed study of their vibrational and electronic spectra, supported by DFT calculations, was performed, as well as a full description and assignment of the observed bands. MOF-CoNDI-py-2 absorbs in the whole studied spectral region, from 200 nm to 2500 nm, while it also features a ligand-centered emission spectrum. Electronic devices built around its crystals revealed electric conductivities of 7.9 10 -3 S cm -1, which is, to the best of our knowledge, the highest for a MOF to this date. This conductivity is also highly anisotropic, being significantly less conductive in certain directions. The current versus voltage profiles were analysed in terms of known conduction mechanisms, with best fits when using an electrode-limited Space-Charge Limited Current mechanism, in agreement with the proposition that this conductivity happens through the NDI-py stacking planes. Additionally, this mechanism is influenced by an external light source, being a photoconductor with a red laser, 632 nm, and a photoresistor with a white light. Combined, these results bring a light-modulated, highly conductive MOF material with an unusual structure. As far as we know, there are no similar MOFs in the literature, which makes MOF-CoNDI-py-2 one of a kind.

[pt] Dispositivos portáteis dotados de computador são cada vez mais utilizados em diversos domínios de aplicações. Juntamente com as redes de telecomunicações provêem a base tecnológica para a computação móvel. Neste ambiente, os Sistemas de Gerência de Bancos de Dados (SGBDs) podem fornecer todos os mecanismos para confiança, segurança, disponibilidade, integridade e acesso eficiente a dados persistentes. Estes SGBDs podem estar localizados na rede com fio (fixa), desempenhando seu papel convencional de servidor de banco de dados, ou podem prover dados para computadores móveis e tecnologias relacionadas. Vários modelos para transações em banco de dados para o ambiente de computação móvel têm sido propostos. No entanto, não satisfazem plenamente as características únicas deste tipo de ambiente, tais como desconexões freqüentes, fraca conectividade na rede sem fio e a movimentação dos clientes. Esta tese tem por objetivo propor um modelo de computação que permita a integração de um SGBD a um ambiente de computação móvel. É apresentado um novo modelo de transações de banco de dados em múltiplos níveis no sentido de garantir o atendimento dos requisitos da computação móvel e as propriedades ACID de transações, onde há participação efetiva do SGBD. O modelo é definido em lógica de primeira ordem seguindo o formalismo ACTA. A implementação desse modelo de transações é apresentada em uma arquitetura que faz uso das abordagens de frameworks orientados a objetos e agentes de software, de forma a tratar com maior eficiência as especificidades do ambiente de computação móvel. Finalmente, é feita uma comparação entre alguns dos modelos mais relevantes de transações para bancos de dados no ambiente de computação móvel e o modelo proposto nesta tese, ressaltando o tratamento dado às propriedades ACID das transações de banco de dados. / [en] Portable computerized devices have become widely used in many different application domains and are, together with telecommunication networks, the underlying technology for mobile computing. In this environment Data- base Management Systems (DBMS) may provide reliability, security and availability, besides data integrity and efficiency persistent data access. These DBMS might be located either in conventional (fixed) networks, with the conventional data server role, or might serve global and local data for mobile computers and related technology. There are many transaction models for mobile database management. However, the particular characteristics of this mobile environment, such as frequent disconnections, weak and intermittent connectivity of wireless networks and clients movement, are not always well addressed. The goal of this thesis is to propose a computational model that enables the integration of a DBMS to a mobile environment. Indeed, we present a new multi-level database transactional model in order to handle mobile requirements and ACID transaction properties, where a DBMS is present. Our model is defined using the ACTA formalism based in first-order logic. The implementation of proposed transaction model becomes feasible through the use of object-oriented frameworks and software agents, with gave support to deal with the particularities of the mobile computing environment. Finally, we give a comparison between the most relevant transaction models for the mobile computing environment and our proposed model, emphasizing the treatment given to the ACID transactions properties.

Les Poly(HydroxyAlcanoates) (PHA) sont des polymères naturels, biodégradables et biocompatibles, synthétisés par de nombreux organismes, et plus particulièrement des procaryotes. Il existe à ce jour plus de 150 types de monomères de PHA différents, accumulés chez différents genres bactériens, en tant que source d’énergie et de carbone. En effet, les granules de PHA intracellulaires sont produites en réponse à un apport en excès de sources de carbone dans l’environnement (glucides, acides gras…), couplé à une carence en éléments azotés nécessaires à la division cellulaire. De par leur caractère biodégradable et biocompatible, les PHA sont employés depuis plus de 20 ans comme biomatériaux dans les domaines pharmaceutiques et biomédicaux, notamment comme micro/nanovecteurs à visée thérapeutique. Ce doctorat met en évidence des méthodes de criblage moléculaire par PCR pour la sélection de bactéries productrices de PHA, isolées de sites hydrothermaux des océans Atlantique et Pacifique au cours de campagnes océanographiques Ifremer. Selon des protocoles de fermentation standardisés et optimisés, des polymères de poly(3-hydroxybutyrate-4-hydroxybutyrate) P(3HB4HB) d’intérêt biomédical ont été produits, puis des études taxonomiques et phylogénétiques ont été menées pour explorer la biodiversité microbienne associée aux environnements marins profonds. Ensuite, des PHA ont été modifiés par réaction thiol-ène photoactivée afin d’obtenir des copolymères hydrosolubles, adaptés pour l’enrobage de nanoparticules poreuses de type Metal-Organic Frameworks (MOF). La caractérisation physicochimique a été réalisée par différentes techniques, et notamment par SEM et STEM-EDX. Les systèmes hybrides poreux MOF-PHA ont ensuite été évalués quant à leur biocompatibilité vis-à-vis de cellules immunitaires (macrophages), par des tests de cytotoxicité et de prolifération cellulaire. Cette étude met en lumière les potentialités de cette nouvelle génération de nanovecteurs, synthétisés pour augmenter le bénéfice thérapeutique tout en minimisant les effets secondaires sur l’organisme humain. / Poly(HydroxyAlkanoates) (PHA) are natural polymers, biodegradable and biocompatible, synthesized by many organisms, especially prokaryotes. There are over 150 kinds of these polyesters, accumulated in a wide variety of bacteria as carbon and energy storage material. PHA granules are deposited intracellularly when microorganisms are cultivated in the presence of an excess of carbon source (glucids, fatty acids...) together with a nitrogenous nutrient deficiency. Due to their biodegradability and biocompatibility, PHA can be used as biomaterials in medical or pharmaceutical fields, and numerous therapeutic micro/nanovectors have already been developed over the past two decades.The present PhD research project highlighted molecular screening methods by PCR for the PHA producing Bacteria selection, isolated during Ifremer cruises from hydrothermal vents in Atlantic and Pacific oceans.According to standardized and optimized fermentation protocols, poly(3-hydroxybutyrate-4-hydroxybutyrate) P(3HB4HB) polymers of biomedical interest were produced, then taxonomic and phylogenetic studies were performed to explore microbial biodiversity associated with deep-sea environments. Next, PHA were modified by ‘click chemistry’ to obtain hydrosoluble copolymers, suitable for coating high porous Metal-Organic Frameworks (MOF) therapeutic nanoparticles. Physico-chemical characterization was performed using different techniques, and more particularly by SEM and STEM-EDX. MOF-PHA hybrid porous systems were then evaluated for their biocompatibility against immune cells (macrophages), by cytotoxicity and cellular proliferation tests. This study highlights potentials of these new generations of nanovectors, synthesized to increase the therapeutic benefit while minimizing side effects on the human body.

O aumento no número de dispositivos móveis de alto desempenho e a disponibilidade de conexões sem fio permitiram o desenvolvimento de interfaces que são compartilhadas entre diversos dispositivos; tais interfaces são chamadas de Interfaces Distribuídas de Usuários. Esta pesquisa foca no desenvolvimento de um arcabouço que visa simplificar o desenvolvimento de jogos digitais que utilizem interfaces distribuídas, assim como analisar o atual estado da arte de outras tecnologias e arcabouços. É proposto um estudo de aceitação, utilizando parâmetros quantitativos e qualitativos, afim de comprovar as características necessárias para uma experiência fluída para o usuário. Tal tarefa é analisada através da criação de um jogo protótipo onde diversos jogadores podem jogar juntos e compartilhar informações entre diversos dispositivos. / The increasing number of high-end mobile devices and increased connection availability have allowed on the development of interfaces that can be shared between multiple devices; such interfaces are called Distributed User Interfaces. This research aims the development of a framework to simplify the development of games using distributed interfaces, as well as to assay the current state-of-art of technologies and frameworks. We propose a study of the acceptance, using both qualitative and quantitative parameters, in order to verify compliance with the necessary characteristics for a fluid user experience. This is accomplished through the creation of a prototype game in which several players can play together and share information through many devices.

Padrões, linguagens de padrões e frameworks são formas de reuso de software. A complexidade de frameworks, causada pela dificuldade tanto em construí-los quanto em utilizá-los, é um dos inibidores do uso dessa tecnologia. Um processo para facilitar a construção e instanciação de frameworks é apresentado. Uma linguagem de padrões é utilizada para apoiar todo o processo, desde a identificação da funcionalidade do framework, seu projeto, implementação, validação, até sua instanciação para sistemas específicos do domínio. O framework obtido é do tipo caixa-branca e sua instanciação é feita especializando-se suas classes para sistemas específicos. O processo inclui, também, a construção de uma ferramenta para automatizar a instanciação do framework, por meio da qual é possível obter um sistema específico fornecendo apenas informações sobre os padrões da linguagem utilizados na sua modelagem. O processo é ilustrado com a Linguagem de Padrões para Gestão de Recursos de Negócios (GRN), que serviu de base para construção do framework GREN. Apresenta-se também o GREN-Wizard, uma ferramenta para instanciação automática do GREN para sistemas no domínio da GRN. A avaliação do processo é feita por meio de alguns experimentos e vários relatos de uso dos diversos sub-processos que compõem o processo geral, usando o GREN, a GRN e o GREN-Wizard. / Patterns, pattern languages, and frameworks are ways of enhancing software reuse. The complexity of software frameworks, caused both by the difficulty to build and to use them, is one of the inhibitors of this technology. A process to ease the construction and instantiation of frameworks is presented, in which a pattern language is used to support the whole process, starting from the identification of the framework functionality, its design, implementation, validation, and its instantiation to domain-specific systems. The framework that results from applying the proposed process is white-box and its instantiation is done by specializing its abstract classes according to a specific system. The process includes the construction of a tool to automate the framework instantiation, through which it is possible to obtain a specific system only by supplying information about the language patterns used to model it. The proposed process is illustrated with the Pattern Language for Business Resource Management (GRN), which was used as the basis for the GREN framework construction. The GREN-Wizard is also presented, which is a tool to automatically instantiate the GREN framework to specific applications in the GRN domain. The proposed process is evaluated by a few experiments and several uses of the sub-processes that compose the general process, using GRN, GREN and the GREN-Wizard.

Ce travail de thèse est centré sur l’étude d’un nouveau type de matériau, les solideshybrides cristallins MOFs (ou Metal-Organic Frameworks) comme systèmes devectorisation de médicaments.Tout d’abord, les MOFs ont été synthétisés à l’échelle nanométrique (NP), en utilisant desméthodes biocompatibles, quand possible. Leur cytotoxicité, ainsi que celle de leursligands constitutifs, a été évaluée par le test MTT sur des macrophages murins (J774) etdu carcinome cervical (HeLa). Nous avons pu constater: (i) une faible cytotoxicité desMOFs, comparable à celle d’autres particules commercialisées, (ii) une influenceimportante de la composition du MOF (ordre de toxicité: Fe<Zr<Zn; ligandshydrophiles<hydrophobes), (iii) une toxicité plus élevée sur la lignée J774 que sur laHeLa, associée à sa plus grande activité phagocytique et (iv) le MIL-100(Fe)_NPs est uncandidat prometteur pour des bioapplications, montrant une très faible cytotoxicité(IC50=0,7 mg·mL-1) et une internalisation cellulaire rapide, voir immédiate dans les J774.Ensuite, le bioflavonoïde non-toxique génistéine (GEN), avec une activité antitumoralremarquable, a été encapsulé avec succès dans des carboxylates de Fe ou de Zr poreux,obtenant des capacités très élevées (160-340 μg GEN·mg formulation-1) en fonction de lastructure et composition du MOF. Ces capacités sont bien en dessus de celles reportéespar d’autres formulations. En autre, la GEN est libérée progressivement (de 2 jours àquelques semaines) sous des conditions physiologiques simulées, ce qui semble appropriépour son utilisation comme système de libération contrôlée (DDS). L’évaluation de lapharmacocinétique et de la biodisponibilité de la formulation à base du MIL-100(Fe)_NPs, a été réalisée et comparée à celle de la GEN libre après une administrationunique (30 mg·Kg-1) par voie oral aux souris. Nous avons conclu que cette formulationpermet d’y obtenir (i) des niveaux de GEN plus élevés et prolongés, (ii) unebiodisponibilité relative supérieure et (iii) une meilleure biodisponibilité orale et un tempsmoyenne de résidence. Les niveaux de GEN dans les organes ont été davantage plus élevéset prolongés, suggérant que le MOF puisse protéger la GEN de la métabolisation.Finalement, un nouveau MOF biologiquement actif (BioMIL-5), a été synthétise par unevoie totalement biocompatible à basé de deux composants antibactériens etdermatologiques, l’acide azélaïque (AzA) et le Zn. La libération progressive des deux aumilieu (l’eau ou le milieu bactérien) à travers de la dégradation du BioMIL-5, conduit a uneffet antibactérien sur S. aureus et S. epidermidis. En prime, un effet antibactérien additifa été mis en évidence, avec cependant des concentrations minimales inhibitoires (MIC) etminimales bactéricides (MBC) assez élevées et en accord avec celles des composants isolés. Enfin, le BioMIL-5 a montré une activité bactéricide (4.3 mg·mL-1) etbactériostatique (0.9 et 1.7 mg·mL-1) prolongée (7 jours) sur S. epidermidis. / In this work, a new type of particles denoted as MOFs or Metal-Organic Frameworks, havebeen studied as a new drug carriers.First, they were synthesised at the nanoscale (NPs) using, when possible, biofriendlymethods. Their cytotoxicity, as well as that from their constitutive linkers, was evaluatedby the MTT test in murine macrophage (J774) and in cervix carcinoma (HeLa) cell lines,observing: (i) a low cytotoxicity of MOFs, comparable with other described particulatedsystems, (ii) a strong influence of the composition (toxicity order: Fe<Zr<Zn;hydrophilic<hydrophobic linkers), (iii) a higher cytotoxicity in J774 than HeLa, due totheir higher phagocytosis activity and (iv) MIL-100(Fe)_NPs was an excellent candidatefor bioapplications (IC50=0.7 mg·mL-1). MIL-100(Fe)_NPs are rapidly cell-uptaken, beingimmediately internalised in J774 cells.Next, the non-toxic bioflavonoid genistein (GEN) with antitumoral properties wassuccessfully encapsulated in porous Fe or Zr carboxylate MOFs, achieving GEN payloads(160-340 μg GEN·mg formulation-1), higher than other existing formulations anddependent on their composition and topology. Furthermore, GEN was progressivelyreleased under simulated physiological conditions from 2 days to several weeks, beingappropriate as long release drug delivery systems (DDS). Finally, the pharmacokineticsand bioavailability evaluation of MIL-100(Fe)_NPs’ formulation was carried out incomparison with the free drug after its oral unique administration (30 mg·Kg-1) to mice,depicting (i) higher and longer plasmatic levels, (ii) an increase in the relative and (iii) abetter oral bioavailability and a mean residence time. Furthermore, higher and moreprolonged drug levels were detected in organs, suggesting that the MOF worked as a drugshelter, protecting GEN from metabolisation.Finally, a new biologically active MOF (denoted BioMIL-5), based on the antibacterial anddermatologically active azelaic acid (AzA) and Zn, was successfully synthesised by a totallybiofriendly route. Both active components BioMIL-5 were slowly released to the media,either pure water or bacteria medium, upon its structural degradation. Its antibacterialactivity was evidenced in S. aureus and in S. epidermidis, observing an interestingadditive effect with however high minimal inhibitory (MIC) and minimal bactericidalconcentrations (MBC), in agreement with the isolated components. Finally, BioMIL-5exhibited a lengthened bactericidal (4.3 mg·mL-1) and bacteriostatic (0.9 and 1.7 mg·mL-1)in contact with S. epidermidis for one week. / En este trabajo, se han estudiado un nuevo tipo de partículas denominadas MOFs oMetal-Organic Frameworks como transportadores de fármacos.Primero, se sintetizaron en escala nanométrica (NP) sustituyendo los disolventes tóxicoscuando fuese posible. Se evaluó su citotoxicidad, así como la de sus ligandos, mediante eltest de MTT en las líneas celulares J774 (macrófagos murinos) y en HeLa (carcinoma decérvix), observando: (i) una baja citotoxicidad de los MOFs, comparable a otros sistemasparticulados, (ii) una fuerte influencia de su composición (orden de toxicidad: Fe<Zr<Zn;ligandos hidrofílicos<hidrofóbicos), (iii) una toxicidad mayor en J774 que en HeLa,debido a una actividad fagocítica mayor y (iv) MIL-100(Fe)_NPs resultó ser un candidatoexcelente para bioaplicationes (IC50=0,7 mg·mL-1). Asimismo, éstas partículas seinternalizaron inmediatamente en J774.A continuación, se encapsuló satisfactoriamente un bioflavonoide no tóxico denominadogenisteína (GEN), con actividad antitumoral en unos carboxilatos porosos de Fe o Zr,alcanzando unas cargas (160-340 μg GEN·mg formulación-1) mayores que cualquier otraformulación y que dependían de su composición y topología. Además, GEN se liberóprogresivamente bajo condiciones fisiológicas simuladas desde 2 días a varias semanas,siendo un tipo de DDS (sistema de liberación controlada) adecuado. Finalmente, laevaluación farmacocinética y de biodisponibilidad de la formulación de MIL-100(Fe)_NPs, se realizó tras su comparación con GEN libre tras su administración única(30 mg·Kg-1) por vía oral a ratones, mostrando (i) unos niveles de GEN más elevadosdurante más tiempo, (ii) un aumento en la biodisponibilidad relativa y (iii) en labiodisponibilidad oral, así como del tiempo medio de resistencia. Además, se observaronniveles de fármaco más elevados y durante más tiempo en órganos, sugiriendo que elMOF servía como una protección al fármaco, protegiéndolo de su metabolización.Por último, se sintetizó satisfactoriamente y en condiciones biológicamente favorables, unnuevo MOF biológicamente activo (denominado BioMIL-5), basado en dos componentescon propiedades antibacterianas y para el cuidado de la piel, que son el ácido azelaico(AzA) y el Zn. Ambos componentes se liberaron de forma sostenida en solución (agua omedio de cultivo bacteriano), como consecuencia de la degradación del BioMOF. Suactividad antibacteriana se evidenció en S. aureus y en S. epidermidis, observandoasimismo un efecto sumatorio interesante con unas concentraciones mínimas inhibitorias(MIC) y mínimas bactericidas (MBC) altas, en concordancia con los componentes aisladosdel BioMOF. Finalmente, BioMIL-5 mostró una actividad bactericida (4.3 mg·mL-1) ybacteriostática (0.9 y a 1.7 mg·mL-1) prolongada durante una semana en S.epidermidis.