La presente tesis doctoral, titulada "Nanotecnología y química supramolecular en procesos de liberación controlada y reconocimiento molecular para aplicaciones biomédicas", se centra en dos temas importantes: el reconocimiento molecular y los procesos de liberación controlada. Esta tesis doctoral está estructurada en cuatro capítulos. El primer capítulo introduce el concepto de materiales híbridos orgánicos-inorgánicos funcionalizados con puertas moleculares y sus aplicaciones biomédicas como nanomateriales para dirigir y controlar la liberación controlada de fármacos. Además se introduce una breve descripción sobre sensors colorimétricos basados en la base de la quimica supramolecular, particularmente en los procesos de reconocimiento molecular. En particular, el capítulo 2 describe la preparacion de cinco nanodispositivos que responden a enzimas. Estos materiales híbridos se componen de dos unidades principales: un soporte mesoporoso basado en sílice inorgánica, capaz de encapsular moléculas orgánicas y un compuesto orgánico anclado en la superficie externa del soporte mesoporoso inorgánico que actúa como puerta molecular. Todos los sistemas propuestos utilizan puertas moleculares peptídicas que responden a temperatura o enzimas como estímulo. La segunda parte de esta tesis doctoral se centra en el diseño y desarrollo de un nuevo compuesto químico capaz de detectar monóxido de carbono in vivo. En resumen, para todos los resultados antes mencionados podemos decir que esta tesis doctoral constituye una contribución científica original al desarrollo de la química supramolecular. Sus resultados derivados de los estudios presentados dejan rutas abiertas para continuar el estudio y el desarrollo de nuevos materiales híbridos y sensors químicos más eficientes para aplicaciones biomédicas y terapeuticas. / This PhD thesis entitled "Nanotechnology and supramolecular chemistry in controlled release and molecular recognition processes for biomedical applications", is focused on two important subjects: molecular recognition and controlled delivery processes. This PhD thesis is structured in four chapters. The first chapter introduces the concept of organic-inorganic hybrid materials containing switchable "gate-like" ensembles and their biomedical applications as nanomaterials for targeting and control drug delivery. Furthermore, is introduced a short review about chromo-fluorogenic chemosensors based on basic principles of supramolecular chemistry, particulary in molecular recognition processes. In particular, in chapter 2 is focus on the development of enzymatic-driven nanodevices. These hybrid materials are composed of two main units: an inorganic silica based mesoporous scaffold, able to store organic molecules and an organic compound anchored on the external surface of the inorganic mesoporous support than acts as molecular gate. All the systems proposed use peptidic gates that respond to temperature or enzimatic stimulis. The second part of this PhD thesis is focused on the design and development of a new chemical compound capable of detecting carbon monoxide in vivo. In summary, for all the results above mentioned we can say that this PhD thesis constitutes an original scientific contribution to the development of supramolecular chemistry. Its results derived from the studies presented leaves open routes to continue the study and development of new hybrid materials and more efficient chemical sensors with biomedical and therapeutic applications. / La present tesi doctoral, titulada "Nanotecnologia i química supramolecular en processos d'alliberament controlat i reconeixement molecular per a aplicacions biomèdiques", es centra en dos temes importants de la química: el reconeixement molecular i els processos d'alliberament controlat. Aquesta tesi doctoral està estructurada en quatre capítols. El primer capítol introdueix el concepte de materials híbrids orgànics-inorgànics funcionalitzats amb portes moleculars i les seves aplicacions biomèdiques com nanomaterials per dirigir i controlar l'alliberament controlat de fàrmacs. A més s'introdueix una breu descripció sobre sensors colorimètrics fonamentats en la base de la química supramolecular, particularment en els processos de reconeixement molecular. En particular, el capítol 2 descriu la preparació de cinc nanodispositius que responen a enzims. Aquests materials híbrids es componen de dues unitats principals: un suport mesoporos basat en sílice inorgànica, capaç d'encapsular molècules orgàniques i un compost orgànic ancorat a la superfície externa del suport mesoporós inorgànic que actua com a porta molecular. La segona part d'aquesta tesi doctoral es centra en el disseny i desenvolupaent d'un nou compost químic capaç de detectar monòxid de carboni in vivo. En resum, per a tots els resultats abans mencionats podem dir que esta tesi doctoral constituïx una contribució científica original al desenvolupament de la química supramolecular. Els seus resultats derivats dels estudis presentats deixen rutes obertes per a continuar l'estudi i el desenvolupament de nous materials hibrids i sensors químics més eficients per a aplicacions biomèdiques i terapeutiques. / De La Torre Paredes, C. (2017). Nanotechnology and supramolecular chemistry in controlled release and molecular recognition proceses for biomedical applications" [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/94043 / TESIS

No description available.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Liberação transdérmica de fármacos apresenta várias vantagens na terapêutica quando comparada com administração oral ou parenteral. Não existe até o momento nenhum método previsto na Farmacopéia Brasileira para realizar testes de liberação de fármacos em adesivos transdérmicos, outros compêndios oficiais como Farmacopéia Americana, Britânica e Européia, descrevem o aparato de pás sobre disco, o cilindro rotatório e o suporte recíproco. Atualmente a literatura descreve diversos tipos de células de difusão para liberação transdérmica das quais a célula de difusão de Franz tem sido a mais empregada tanto para adesivos transdérmicos como formas semi-sólidas, utilizada no desenvolvimento farmacotécnico, caracterização biofarmacêutica e controle de qualidade. A proposta deste estudo tem por objetivo estipular critérios para a escolha mais adequada do equipamento e metodologias in vitro na avaliação da liberação transdérmicas de fármacos, utilizando a nicotina como fármaco modelo. Para tal, foram empregados ensaios in vitro de liberação e retenção cutânea utilizando métodos de pás sobre disco e método de célula de difusão de Franz modificada em sistema estático e fluxo contínuo. A validação dos fatores que influenciam a taxa de liberação in vitro da nicotina foram fundamentais para escolha do meio receptor, escolha da velocidade de agitação que promoveu mais semelhança no perfil de liberação em diferentes equipamentos assim como a escolha da membrana biológica mais adequada para o método proposto. Os resultados mais promissores foram selecionados para os ensaios in vitro de liberação, permeação e retenção cutânea. Os dados de liberação, tanto em quantidades de nicotina liberada como seu fluxo, demonstraram semelhança no uso de diferentes equipamentos, indicando possíveis intercambialidades entre os métodos propostos para liberação de nicotina transdérmica. Ensaios in vitro de permeação cutânea em célula de difusão vertical de Franz não demonstraram diferenças significativas em diferentes modelos de membranas biológicas utilizadas, as quais foram pele de orelha de porco, pele de camundongo sem pelo e pele de cobra cascavel hidratada por 24 horas. A quantidade de nicotina permeada em até 8 horas, assim como o fluxo de permeação foram significativamente menor para o método de pás sobre disco (FDA) quando comparado com os resultados obtidos utilizando célula de difusão vertical de Franz tanto em sistema estático com em fluxo contínuo. Estes resultados podem estar relacionados com a estrutura física do equipamento de célula de difusão vertical de Franz, uma vez que oferece um sistema oclusivo, dificultando o contato do adesivo com o meio receptor. Desta forma, os resultados deste projeto podem indicar o uso da célula de difusão vertical de Franz para ensaios in vitro de liberação e permeação cutânea da nicotina em formas farmacêuticas transdérmicas, podendo ser aplicado em pesquisas de desenvolvimento de formulações, controle da qualidade e testes de Equivalência Farmacêutica para produtos genéricos. Os resultados desta pesquisa apresentam-se podem ter importante influência nas discussões em torno dos medicamentos genéricos no Brasil, bem como na elaboração de diretrizes para testes de Equivalência Farmacêutica e Controle de Qualidade de medicamentos transdérmicos. Poderão ainda fornecer dados para indicações de protocolos para Farmacopéia Brasileira e pesquisa científica em torno dos sistemas de liberação transdérmicas de fármacos. / The aim of this work was to compare in vitro release and permeation of nicotine from transdermal patch (TDS) using three different methods such as, FDA paddle method and both Vertical Diffusion Cell (VCD) static and continuous flux. We evaluated different kinds of membrane (hairless mouse, porcine ear skin and snake skin), different composition and pH of acceptor phases (0.01N isotonic phosphate buffer pH 7.4 (± 0.2), water, and HCL 0.025N), agitation of acceptor phase and batches of the transdermal patches. Profiles of release and permeation from all methods evaluated were linked statistically using linear regression and one-way ANOVA nonparametric assay. The 0.01N isotonic phosphate buffer pH 7.4 (± 0.2) improved greater release rate of nicotine than those obtained using HCL and water as acceptor phase. Cumulative released and permeated amounts of nicotine were almost equal for all methods evaluated and there is not significantly different (one-way ANOVA p 0.05) were observed after 8 h. However nicotine permeated fluxes (J) after 8 h were significantly higher using VDC than those obtained using FDA paddle method. Cumulative permeated amounts (reported to the effective surface area of the cells) were overestimated when skin permeation experiments were prolonged to 12 h, indicating that the actual diffusion surface area of NiQuitinTM exceeded the effective diffusion surface area of the cells. Reducing the trimmed TDS surface area led not only to a reduction of the cumulative permeated amounts, but also to a reduction of the flux at 12 h. In order to evaluate the edge effect on drug release flux studies were performed using static VDC. In vitro penetration studies using different membranes showed not significantly difference for ear pig skin, hairless mouse and snake skin at 8 h. However data obtained without membrane were about 1.25 times smaller than those obtained with biological membranes. These results demonstrated that NiQuitinTM TDS had dependent release of membrane at 8 h of permeation. In conclusion there is not significantly different for in vitro release and permeation amounts of nicotine from NiQuitinTM using VDC and FDA method. In term of release efficiency all methods released up to 80% of nicotine after 8 h. The results suggested the use of VDC as potential method to evaluate both in vitro release and skin permeation of nicotine in transdermal patches.

There is a lack of knowledge on how alternative forms of sports facility provision influences end user's sports and physical activity behaviour, and the consequent impact this has on their health, well-being and social capital. To address this knowledge gap, this thesis has undertaken a multi-level analysis of the sport delivery system. It examines if strategic priorities and objectives pursued by different types of sport and fitness facilities, that are being influenced by macro level forces, along with their characteristics and ownership, influences individuals sport participation behaviour with a potential consequent impact on the policy outcomes of health, well-being and social capital. In the UK recently, sport policy objectives have focussed on increasing the population s participation in sport and physical activity to enhance a range of outcomes including health, well-being and social capital. Over the last three decades, there has also been significant changes in sport provision with the growth of private sector facilities, and public sector facilities being outsourced to private management. However, there is no evidence of the effectiveness of these alternative arrangements in delivering the policy objectives. There is limited knowledge on how different agents and actors in the sport delivery system function collectively to achieve these objectives or not, and a multi-level analysis of the sport delivery system i.e., from policy, through facilities, to end users does not exist. This gap in knowledge is addressed in this thesis through the adoption of a mixed methods case study of Leicestershire and Rutland Sport-County Sport Partnership (LRS-CSP) region in the midlands of England. The sport participation of individuals who use differently owned and managed sport and fitness facilities in the LRS-CSP region is examined, and the impact this has on their health, well-being and social capital, from macro level (policy), meso level (facilities), and micro level (end users) perspectives. Data collected at these levels involves, semi-structured interviews with the regional managers (macro level) who are responsible for the development and provision of sport in the region, a quantitative survey involving the facility managers (meso level) who are responsible for the day-to-day activities of the facilities, and quantitative survey and focus groups of end users in the region (micro level). Surveys done at the meso and the micro level are matched to the facilities of a variety of different ownership and characteristics to explore the influence this might have on individuals participation frequency and the impact this has on their health, well-being and social capital. The results show that government and public sport agencies priorities towards the sports sector which operate at the macro level of the sport delivery system influence the strategic objectives pursued by different types of sport and fitness facilities that are responsible for sport provision at the meso level of the sport delivery system. Public sport agencies and government bodies through their policies seem to have a significant influence over public sector including LMC facilities strategic decision making. However, this is not the case for the private sector facilities. Neither the strategic objectives of facilities nor their ownership and characteristics are shown to have a significant difference on the users sport participation behaviour, nor on the sport policy outcomes of their health, well-being and social capital. The largest influence on sport participation seems to be when individuals engage in sport with those they meet at the facility, indicating that facilitation of the co-creation of social capital among individuals could play a bigger role in increasing participation levels. Along with this, results also show that sport participation has a direct positive influence on individuals health which then enhances their well-being and social capital. This thesis contributes towards the long-standing debate about the relative value of different ownership types that span the public, private, and LMCs and their relationship with performance . The findings of the thesis suggest that, providing general availability of space for sport and fitness activities and by facilitating a network of opportunities with others and across activities is important in achieving the policy outcomes of improved participation and the consequent positive impact this has on health, well-being and social capital, and should be given priority in sport provision.

A trombose venosa profunda (TVP) é uma patologia grave de alta incidência mundial. Quando não diagnosticada precocemente e tratada adequadamente pode evoluir causando sérias complicações, como a embolia pulmonar e insuficiência venosa crônica, as quais são responsáveis por altas taxas de morbidade e mortalidade. Seu tratamento utiliza terapia com anticoagulantes pelas vias parenteral e oral (para manutenção) que estão associadas a prejuízos bem documentados limitando seu uso, além de resultar em baixa adesão do paciente ao tratamento. Os sistemas de liberação modificada de fármacos, tais como as micropartículas poliméricas, representam uma grande área em desenvolvimento, a qual tem recebido atenção de pesquisadores e indústrias de todo o mundo e recebido investimentos crescentes nas últimas três décadas. As micropartículas poliméricas possuem grande estabilidade, capacidade industrial e possibilitam ajustes para alcançar o perfil de liberação adequado e/ou o direcionamento para determinado sítio de ação. O estudo teve início com o desenvolvimento e validação do método analítico para a quantificação da enoxaparina sódica. A turbidimetria foi a técnica de escolha, pois os resultados utilizando CLAE não foram satisfatórios. Este estudo teve como objetivo a obtenção e caracterização físico-química de um sistema de liberação microparticulado para veiculação de uma heparina fracionada (HF), a enoxaparina sódica, muito utilizada no tratamento da TVP, visando um aumento da biodisponibilidade do fármaco com controle da sua biodistribuição. As micropartículas contendo a enoxaparina sódica foram preparadas utilizando o copolímero dos ácidos lático e glicólico (50:50) (PLGA), biodegradável, através do método da dupla emulsificação/ evaporação do solvente. As partículas obtidas foram caracterizadas pela técnica de microscopia eletrônica de varredura (MEV) e apresentaram forma esférica com superfície lisa e regular. As análises do tamanho e distribuição dos tamanhos de partícula foram realizadas por dispersão de luz laser e apresentaram perfil monomodal para a maioria das formulações. O perfil de liberação in vitro do fármaco encapsulado foi avaliado por 35 dias e apresentou cinética de liberação de pseudo ordem zero, modelo de Higuchi (1961), indicando que a difusão foi o principal mecanismo de liberação. A velocidade de degradação das micropartículas é, através da difusão do fármaco, um parâmetro muito importante e determinante da liberação in vivo. / Deep vein thrombosis (DVT) is a severe disease with high incidence worldwide. When it is not early diagnosed and properly treated it can develop and to cause serious complications, such as pulmonary embolism and chronic venous insufficiency, which are responsible for high morbidity and mortality rates. The treatment of DVT is accomplished with parenteral and oral (for maintenance) anticoagulants. They are associated to damage well documented that limit their use resulting in poor adherence of patients to treatment. Drug delivery systems, such as polymeric microparticles, represent a significant development area. It has received attention of researchers and industries around the world and increased investments in last three decades. The polymeric microparticles have great stability, industrial capacity and they allow adjustments to achieve the suitable release profile and / or direction for a particular site of action. The study started with development and validation from the analytical method to quantification of enoxaparin sodium. Turbidimetric technique was used because the results by HPLC were not satisfactory. The aim of this work was the preparation and physical-chemical characterization of a microparticle release system for delivery of a fractionated heparin (FH), enoxaparin sodium, widely used to the treatment of DVT to increase the drug bioavailability and control their biodistribution. The microparticles containing enoxaparin sodium were prepared from a biodegradable polymer poly (lactic-co-glycolic acid) (50:50) (PLGA) using double emulsification / evaporation of the solvent method. The particles obtained were characterized by scanning electron microscopy technique (SEM) and showed spherical shape with smooth and regular surface. The analysis of the size and distribution of particle sizes were performed by scattering of laser light and showed unimodal profile for the most of formulations. In vitro drug release profile from the microparticles was evaluated in 35 days showing pseudo zero order kinetics, Higuchi model (1961). This indicated that main mechanism of drug release was diffusion.

Infecções associadas a cepas da Escherichia coli enterohemorrágica (EHEC), podem causar manifestações clínicas sendo a Síndrome Hemolítica Urêmica (SHU), a complicação mais severa. SHU está relacionada a presença da toxina de Shiga do tipo 2 (Stx2) e até o momento não se dispõe de uma vacina ou tratamentos efetivos para uso em humanos. Assim, este trabalho teve por objetivo desenvolver uma vacina baseada no derivado atóxico contendo a subunidade B e a porção A2 da subunidade A denominado Stx2ΔAB. Após expressão em linhagens de E.coli e tentativas iniciais de purificação, resultaram na formação de agregados proteicos. Ajustes nas condições de cultivo e purificação permitiram obter a proteína na forma de monômero da subunidade B, mas sem a presença da porção A2. O antígeno foi incorporado a lipossomas multilamelares (MLVs), combinados ao lipídio A e administrados por via subcutânea a camundongos. Animais imunizados desenvolveram anticorpos sistêmicos específicos contra Stx2 capazes de neutralizar a toxina in vitro e conferir proteção parcial a animais desafiados com dose letal da toxina. Em conclusão, o trabalho confirmou o potencial vacinal do antígeno e validou a estratégia baseada na incorporação do antígeno às MLVs como estratégia de imunização. / Infections associated with strains of enterohaemorrhagic Escherichia coli (EHEC), can cause clinical manifestations are the hemolytic uremic syndrome (HUS), the most severe complication. HUS is related to the presence of Shiga toxin type 2 (Stx2) and yet do not have a vaccine or effective treatments for use in humans. This work aimed to develop a vaccine based on non-toxic derivative containing the B subunit and the A2 portion of the subunit called Stx2ΔAB. After expression in E. coli strains and initial purification attempts resulted in the formation of protein aggregates. Adjustments in the cultivation and purification conditions have enabled the protein as the monomer subunit B but without the presence of the A2 portion. The antigen was incorporated into multilamellar liposomes (MLVs), the combined lipid A and administered subcutaneously to mice. immunized animals develop systemic antibodies specific against Stx2 able to neutralize toxin in vitro and to confer partial protection when challenged with a lethal dose of toxin. In conclusion, the study confirmed the potential vaccine antigen and validated strategy based on antigen incorporation into MLVs as immunization strategy.

本研究之主要目的在探討：服務傳送系統的意義與內涵為何？有線電視系統業者的服務傳送系統應該如何設計，方可導致良好的企業經營績效？有線電視系統業者將來在關於服務傳送系統上，重要的發展計劃為何？ 　　針對上述研究目的，以全省有線電視系統業者為對象抽樣，發出問卷107份，回收有效問卷27份。經由文獻探討，以及因素分析、集群分析、單因子多變量變異數分析、主成份分析、變異數分析，獲致下列發現： 　　1. 服務傳送系統的意義是“用系統的觀點來看前場服務之提供”。就此系統的目標而言，是提供服務去滿足顧客的需求；就其組成要素而言，可以用7Ps來表示，包括：產品或服務、訂價、地點或通路（含實體設備、環境及氣氛）、促銷、銷售過程、顧客參與、服務人員，而這些要素彼此之間有交互影響的關係。 　　2. 影響CATV系統業者設計其服務傳送系統型態的七個重要因素：注重客戶服務因素、不走低價競爭因素、注重節目因素、注重促銷因素、注重播送設備優劣因素、跟隨競爭者訂價策略、注重頻道數目眾多因素。 　　3. 將CATV系統業者就其服務傳送方式予以分群，可得到下列主要的六大集群： 　　一、強調節目，跟隨訂價群 　　二、不注重服務傳送系統群 　　三、頻道數目多，畫質佳群 　　四、全面重視6Ps，且價格稍高群 　　五、重服務、頻道多，跟隨訂價群 　　六、注重軟體群 　　其中第一、四、五、六群的績效較佳（績優組），第二和三群的績效較差（不良組）。 　　4. 績優組與不良組在服務傳送系統的作為上，主要是在“注重客戶服務”、“不走低價競爭”與“注重節目”三個因素有顯著差異。 　　5. 未來CATV系統業者有關服務傳送系統的重要計劃 　　在節目方面，未來十分強調自製節目的重要性，並將朝地方性、顧客參與性、文化知性及常態化的方向來努力。 　　在客戶服務方面，較注重提供資訊服務，以及透過市調、開放外界人士參觀、參與地方活動等方式，來加強與地方的互動程度。 　　在訂價方面，部分業者表示未來將朝分級收費、合理訂價來努力。 　　在促銷方面，較注重發行刊物、與異業合作設立有線電視加盟店，以及透過舉辦地方性活動來塑造公司形象。 　　在服務人員方面，由於目前有線電視人才普遍不足，所以加強人才培訓為各家系統業者的當前要務。 　　在服務流程方面，業者正朝向制定出一套完善、確實、電腦化的作業流程而努力。 / The purposes of this paper are: What is the service delivery system? What's the relationdhip between the service delivery system and the business's performance? The discories are: 　　1. The meaning of service delivery system is: To view the providing of front offece service with the point of view of system. The objective of the system is to satisfy the customers' demand. The subsystems are: product, pricing, place, promotion, process, participant and people. 　　2. There are 7 factors to affact CATV system operators designing their service delivery systems: emphasizing client service factor, resisting low price competition factor, emphasizing programs factor, emphasizing promotion factor, emphasizing equipment factor, emphasizing the numbers of channel, price following factor. 　　3. The are 6 groups: 1)emphsizing program, price following group 2)taking little consider of service delivery system group 3)many channels group 4)good service delivery system ,and high pricing group 5)emphasing service and channel, price following group 6)emphasing software group

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal