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Multiplex Gene Synthesis and Error Correction from Microchips Oligonucleotides and High-throughput Gene Screening with Programmable Double Emulsion Microfluidics DropletsMa, Siying January 2015 (has links)
<p>Promising applications in the design of various biological systems hold critical implications as heralded in the rising field of synthetic biology. But, to achieve these goals, the ability to synthesize and screen in situ DNA constructs of any size or sequence rapidly, accurately and economically is crucial. Today, the process of DNA oligonucleotide synthesis has been automated but the overall development of gene and genome synthesis and error correction technology has far lagged behind that of gene and genome sequencing. What even lagged behind is the capability of screening a large population of information on a single cell, protein or gene level. Compartmentalization of single cells in water-in-oil emulsion droplets provides an opportunity to screen vast numbers of individual assays with quantitative readouts. However these single-emulsion droplets are incompatible with aqueous phase analysis and are not controllable through molecule transports. </p><p>This thesis presents the development of a multi-tool ensemble platform targeted at high-throughput gene synthesis, error correction and screening. An inkjet oligonucleotide synthesizer is constructed to synthesize oligonucleotides as sub-arrays onto patterned and functionalized thermoplastic microchips. The arrays are married to microfluidic wells that provide a chamber to for enzymatic amplification and assembly of the DNA from the microarrays into a larger construct. Harvested product is then amplified off-chip and error corrected using a mismatch endonuclease-based reaction. Bacterial cells baring individual synthetic gene variants are encapsulated as single cells into double-emulsion droplets where cell populations are enriched by up to 1000 times within several hours of proliferation. Permeation of Isopropyl-D-1-thiogalactopyranoside (IPTG) molecules from the external solution allows induction of target gene expression. The induced expression of the synthetic fluorescent proteins from at least ~100 bacteria per droplet generates clearly distinguishable fluorescent signals that enable droplets sorting through fluorescence-activated cell sorting (FACS) technique. The integration of oligo synthesis and gene assembly on the same microchip facilitates automation and miniaturization, which leads to cost reduction and increases in throughput. The capacity of double emulsion system (millions discrete compartments in 1ml solution) combined with high-throughput sorting by FACS provide the basis for screening complex gene libraries for different functionality and activity, significantly reducing the cost and turn-around time.</p> / Dissertation
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Bottom-up generation of synthetic cells and tissues using microfluidic devices for double emulsion generationRamsay, Kaitlyn E. E. 11 June 2021 (has links)
Synthetic cells and tissues engineered from the bottom-up using non-living building blocks have many potential applications in medicine and biochemistry. Nonetheless, the applications of these synthetic cells and tissues remain limited by virtue of the challenging, costly, and uncontrollable methodologies available for their construction. Droplet microfluidic techniques, which are powerful analytical tools that can be used for the accurate and precise control over micro-sized droplets, offer potential solutions to these problems. The development of these droplet microfluidic platforms is a burgeoning and challenging field, with room for many impactful innovations. In the following dissertation, I first show the development of two different droplet microfluidic platform for the generation of two variations of synthetic cells: the first from polymeric-based building blocks and the second from biomimetic lipid-based building blocks. I then use the former of these platforms for the bottom-up generation of functional synthetic tissues (also known as prototissues). Using these techniques, I am able to elicit previously elusive structural and behavioral information. These methods contribute towards the creation of superior mimics of sophisticated life-like structures as well as a better understanding of how bespoke microfluidic platforms can be engineered to yield reliable and reproducible results. I have shown that microfluidic technologies are an invaluable tool for the creation and study of life-like systems and that these synthetic cells and tissues open up new avenues for research into multidisciplinary applications. / Graduate / 2023-06-07
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Desenvolvimento e caracterização de microcápsulas de xilitol e mentol por coacervação complexa e sua aplicação em gomas de mascar / Development and characterization of menthol and xylitol microcapsules by complex coacervation and its application in chewing gumSantos, Milla Gabriela dos 18 July 2014 (has links)
O processo de microencapsulação vem sendo bastante aplicado em alimentos e um dos objetivos que vem se destacando atualmente é o controle da liberação do agente ativo no tempo e local desejado. Portanto, o objetivo do trabalho foi microencapsular agentes refrescantes (xilitol e mentol) a aplicá-los em gomas de mascar, objetivando prolongar a duração da sensação de refrescância. Xilitol e mentol foram microencapsulados utilizando o método de coacervação complexa. As microcápsulas foram caracterizadas quanto ao tamanho médio, morfologia (microscopia ótica, confocal e eletrônica de varredura), cor instrumental, higroscopicidade, umidade, atividade de água (Aw), solubilidade em água, isotermas de sorção, espectroscopia no infravermelho por transformada de Fourier (FTIR), comportamento térmico (por Caloria Diferencial de Varredura - DSC), eficiência de encapsulação e controle de liberação. As gomas de mascar foram produzidas no laboratório de pesquisa e desenvolvimento de uma indústria de alimentos. Oito formulações foram produzidas, sendo quatro com as microcápsulas e quatro com os ingredientes livres. As gomas foram analisadas em relação à umidade, Aw e cor instrumental; por meio da análise do perfil de textura (TPA) avaliou-se a dureza, elasticidade, mastigabilidade e a coesividade das gomas. Análise de tempo-intensidade (TI) das gomas de mascar foi realizada com 19 provadores treinados para avaliar a duração da sensação de refrescância fornecida por esses ingredientes. As microcápsulas obtidas apresentaram características adequadas para aplicação em alimentos, como tamanho médio de partículas de aproximadamente 100 µm e baixos valores de umidade, Aw, solubilidade e higroscopicidade. Por meio da microscopia confocal e da análise de FTIR confirmou-se que os núcleos foram completamente encapsulados pelo material de parede, demonstrando o sucesso da técnica empregada. A eficiência de encapsulação foi alta para o mentol, mas relativamente baixa para o xilitol. Por meio da análise de DSC constatou-se que o xilitol e o mentol passam do estado cristalino para o estado amorfo após o processo de microencapsulação, o que não interfere nas propriedades do mentol, mas no caso do xilitol sim, pois sua refrescância é atribuída ao seu calor de dissolução endotérmico. As gomas de mascar apresentaram baixos valores de Aw e umidade, o que favorece a estabilidade microbiológica. Em relação ao perfil de textura, observou-se que a presença do xilitol melhorou os parâmetros de textura das gomas, pois as gomas produzidas com este composto apresentaram os menores valores de dureza, mastigabilidade e elasticidade. A presença das microcápsulas não interferiu significativamente em nenhum dos parâmetros de textura analisados. A análise de TI confirmou que as microcápsulas foram hábeis para promover liberação gradual do mentol e do xilitol, pois a refrescância das gomas de mascar contendo as microcápsulas durou mais tempo que as gomas de mascar com os ingredientes livres. / The microencapsulation process has been widely applied in food and one of the aims that have been highlighted is to control the release of the active agent at the desired time and local. Therefore, the objective was to microencapsulate cooling agents (menthol and xylitol) to apply them in chewing gum, aiming to prolong the feeling of freshness. Xylitol and menthol were microencapsulated using complex coacervation method. The microcapsules were characterized by particle size, morphology (optical microscopy, confocal and scanning electron), instrumental color parameter, hygroscopicity, moisture, water activity (Aw), solubility, sorption isotherms, Fourier transform Infrared Spectroscopy (FTIR), thermal behavior (Differential Scanning Calorie -DSC), encapsulation efficiency and release control. The chewing gums were produced in the research and development laboratory of a food industry. Eight formulations were produced, four with microcapsules and four with free ingredients. The gums were analyzed for moisture, Aw and instrumental color parameter; by texture profile analysis (TPA) was evaluated hardness, springiness, chewiness and cohesiveness of the gum. Analysis of time-intensity (TI) of chewing gum was conducted with 19 trained panelists to evaluate the duration of the freshness sensation provided by such ingredients. The microcapsules obtained had characteristics suitable for application in foods such as average particle size of approximately 100 µm and low levels of humidity, Aw, solubility and hygroscopicity. By confocal microscopy and FTIR analysis it was confirmed that the cores were completely encapsulated by wall material, ensuring the success of the technique. The encapsulation efficiency was high in menthol microcapsules but relatively low for xylitol microcapsules. By the DSC analysis it was found that xylitol and menthol crystalline state transform to the amorphous state after the microencapsulation process, which does not affect the properties of menthol, but in the xylitol yes, because their freshness is attributed to its endothermic heat of dissolution. Chewing gums showed low values of Aw and moisture, which favors the microbiological stability. Through TPA, was observed that the presence of xylitol improved the texture parameters of the gums because the gums produced with this compound showed the lowest hardness, chewiness and elasticity. The presence of the microcapsules was not significantly influenced the texture parameters analyzed. Time-Intensity analysis confirmed that the microcapsules were able to promote gradual release of menthol and xylitol, because the freshness of chewing gum containing microcapsules lasted longer than the chewing gum free ingredients.
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Design, Scale-up and Optimization of Double Emulsion Processes / Conception, extrapolation et optimisation des procédés d'émulsion doubleKhadem Hamedani, Behnam 15 July 2019 (has links)
De nos jours, les émulsions doubles se trouvent dans de nombreuses applications dans différents domaines, tels que le domaine alimentaire, les produits cosmétiques, les produits chimiques ou biochimiques. Dans les produits alimentaires par exemple, les émulsions doubles peuvent permettre d’encapsuler des arômes ou de réduire la teneur en matières grasses. La littérature manque cependant de compréhension globale de ces systèmes. La modélisation peut améliorer la compréhension d'un système et permettre d'optimiser les conditions de fonctionnement afin d'améliorer la qualité du produit. Dans ces systèmes, la qualité du produit est déterminée par l'efficacité de l'encapsulation et la distribution de la taille des gouttes internes et externes, qui peuvent affecter la stabilité physique pendant le stockage. L'objectif de ce travail est de réaliser une étude théorique et expérimentale approfondie des phénomènes intervenant à la fois lors de la préparation et du stockage des émulsions doubles. La contribution du travail peut donc être divisée en deux parties. Dans un premier temps, nous étudions les paramètres affectant l’étape de préparation des émulsions doubles et nous proposons des modèles pour les décrire. Trois procédés ont été considérés pour l’émulsification des émulsions doubles, l’ultra-sonication, l’Ultra-Turrax et un réacteur agité. Le modèle est basé sur un modèle de bilan de population des gouttelettes externes, incluant les phénomènes de rupture et de coalescence, associé à un modèle de relargage des gouttes internes. Le relargage des gouttes internes est supposé être régi par la rupture des gouttes externes. Pour être applicables aux différents procédés, les modèles de rupture ont été adaptés aux différentes échelles de turbulence, de dissipation pour ultra-sonication et inertielle pour Ultra-Turrax. La deuxième contribution de ce travail concerne l’étude des phénomènes ayant lieu lors du stockage des émulsions doubles, notamment le gonflement et le relargage des gouttes. Dans ce cas, deux modèles de bilan de population des gouttelettes internes et externes ont été développés, comprenant les phénomènes de gonflement des gouttelettes internes, et donc externes, ainsi que le relagage des gouttelettes internes par diffusion et coalescence avec la phase continue externe. Le modèle de gonflement prend en compte la pression de Laplace qui contrebalance le gradient de pression osmotique et arrête le gonflement. Dans les différentes étapes de préparation ou de stockage, les modèles développés permettent de prédire les distributions de la taille des gouttelettes et le taux de libération / Double emulsions can nowadays be found in a number of applications in different domains, like food, cosmetics, chemicals or biochemical. In food for instance, double emulsions may allow to encapsulate flavors or reduce the fat content. Yet, the literature is still lacking a comprehensive understanding of these systems. Modelling may improve the understanding of a system and allow optimizing the operating conditions in order to improve the product quality. In these systems, the product quality is determined by the encapsulation efficiency and the inner and outer droplet size distribution, which may affect the physical stability during storage. The objective of this work is to handle theoretical and experimental investigations of the phenomena occurring during both the preparation and the storage of double emulsions. The contribution of the work can therefore be divided into two parts. First of all, investigations of the parameters affecting the preparation step of double emulsions are handled, and models are proposed to describe them. Three processes were considered for the emulsification of the double emulsions, ultrasonication, Ultra-Turrax and a stirred vessel. The model is based on a population balance model of the outer droplets, including the kernels of breakage and coalescence combined with a leakage model of the inner droplets. The leakage of inner droplets is assumed to be governed by the breakage of the outer droplets. In order to be applicable in the different processes, the breakage models were adapted to different scales of turbulence, the dissipation subrange for ultrasonication and the inertial subrange for the Ultra-Turrax. The second contribution of the work concerns the investigation of the phenomena taking place during the storage of the double emulsions, including swelling and release. In this case, two population balance models of the inner and outer droplets were considered, including the phenomena of swelling of the inner, and so of the outer, droplets as well as the escape of the inner droplets by diffusion and coalescence with the external continuous phase. The swelling model takes into account the Laplace pressure that counterbalances the osmotic pressure which is the driving force for swelling. In the different steps of preparation or storage, the developed models allow the prediction of the droplet size distributions and the release rate
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Microfluidic-generated Double Emulsions for Cell Study, Drug Delivery and Particle Therapeutics FabricationZHANG, YING January 2015 (has links)
<p>Droplet microfluidics is a powerful platform for both fundamental and applied biomedical research. The droplets are small in size with a diameter of 1-300 um. Thus, they could function as a miniaturized environment for quantitative and qualitative analysis. Each droplet composes of water shielded by an immiscible organic shell which enables independent control over different droplets. The large surface to volume ratio of spherical structure allows rapid mass and heat transfer, which could enable more homogeneous chemical reactions. Moreover, since multiple identical droplets could be generated simultaneously, parallel analysis for large amount of samples are possible. The use of microfluidics brings more power to droplet technology. The precise control over the flow allows droplet with preferable size and structure to be generated, which is critical for quantitative analysis, homogeneous chemical reaction as well as some in vivo applications. </p><p>Nonetheless, generation of stable, monodispersed and well controlled emulsions to meet specific biological functions are still challenging. First of all, to form more biocompatible W/O/W DE, the microfluidics devices must be patterned with desired surface wettability. W/O emulsion could only form in hydrophobic environment and the O/W emulsions could only form in hydrophilic environment. Differential patterning of the surface wettability to meet the needs are challenging. Second, DE are stabilized by two amphiphilic surfactants, one for the oil phase and the other for the water phase. Selection of appropriate surfactants should hook with specific biological application to ensure stability and biocompatibility. Third, the choice of fluid and contents in the fluid will affect the viscosity and capillary number of interfacial interaction, and eventually influences the droplet formation. The choice of biocompatible medium and buffer must take this into consideration. Fourth, the adoption of emulsions for the specific application requires optimization of the processing techniques in order to meet the needs for final analysis. For instance, control of droplet rupture for content release, modulation of oil phase permeability, quantitative analysis of content with flow cytometry, etc. </p><p>In this thesis, we will first demonstrate the design and fabrication of PDMS-based devices for automatic and high-throughput DE formation in Chapter 2. In the following chapters, we will demonstrate the successful adoption of the microfluidics generated DE for different biological applications. In chapter 3, we will illustrate the application of DE as a micro-incubator for cellular studies such genetic circuit behavior and performance in bacterial cells cultured in DE droplets and formation of 3D mammalian cell spheroid. In chapter 4, we will show the successful application of DE as drug carriers for intranasal drug delivery. In chapter 5, we showed the application of microfluidics generated DE as template for microparticle synthesis and the use of these microparticles as therapeutic agents in nucleic acid induced inflammations in autoimmune diseases.</p> / Dissertation
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Desenvolvimento e caracterização de microcápsulas de xilitol e mentol por coacervação complexa e sua aplicação em gomas de mascar / Development and characterization of menthol and xylitol microcapsules by complex coacervation and its application in chewing gumMilla Gabriela dos Santos 18 July 2014 (has links)
O processo de microencapsulação vem sendo bastante aplicado em alimentos e um dos objetivos que vem se destacando atualmente é o controle da liberação do agente ativo no tempo e local desejado. Portanto, o objetivo do trabalho foi microencapsular agentes refrescantes (xilitol e mentol) a aplicá-los em gomas de mascar, objetivando prolongar a duração da sensação de refrescância. Xilitol e mentol foram microencapsulados utilizando o método de coacervação complexa. As microcápsulas foram caracterizadas quanto ao tamanho médio, morfologia (microscopia ótica, confocal e eletrônica de varredura), cor instrumental, higroscopicidade, umidade, atividade de água (Aw), solubilidade em água, isotermas de sorção, espectroscopia no infravermelho por transformada de Fourier (FTIR), comportamento térmico (por Caloria Diferencial de Varredura - DSC), eficiência de encapsulação e controle de liberação. As gomas de mascar foram produzidas no laboratório de pesquisa e desenvolvimento de uma indústria de alimentos. Oito formulações foram produzidas, sendo quatro com as microcápsulas e quatro com os ingredientes livres. As gomas foram analisadas em relação à umidade, Aw e cor instrumental; por meio da análise do perfil de textura (TPA) avaliou-se a dureza, elasticidade, mastigabilidade e a coesividade das gomas. Análise de tempo-intensidade (TI) das gomas de mascar foi realizada com 19 provadores treinados para avaliar a duração da sensação de refrescância fornecida por esses ingredientes. As microcápsulas obtidas apresentaram características adequadas para aplicação em alimentos, como tamanho médio de partículas de aproximadamente 100 µm e baixos valores de umidade, Aw, solubilidade e higroscopicidade. Por meio da microscopia confocal e da análise de FTIR confirmou-se que os núcleos foram completamente encapsulados pelo material de parede, demonstrando o sucesso da técnica empregada. A eficiência de encapsulação foi alta para o mentol, mas relativamente baixa para o xilitol. Por meio da análise de DSC constatou-se que o xilitol e o mentol passam do estado cristalino para o estado amorfo após o processo de microencapsulação, o que não interfere nas propriedades do mentol, mas no caso do xilitol sim, pois sua refrescância é atribuída ao seu calor de dissolução endotérmico. As gomas de mascar apresentaram baixos valores de Aw e umidade, o que favorece a estabilidade microbiológica. Em relação ao perfil de textura, observou-se que a presença do xilitol melhorou os parâmetros de textura das gomas, pois as gomas produzidas com este composto apresentaram os menores valores de dureza, mastigabilidade e elasticidade. A presença das microcápsulas não interferiu significativamente em nenhum dos parâmetros de textura analisados. A análise de TI confirmou que as microcápsulas foram hábeis para promover liberação gradual do mentol e do xilitol, pois a refrescância das gomas de mascar contendo as microcápsulas durou mais tempo que as gomas de mascar com os ingredientes livres. / The microencapsulation process has been widely applied in food and one of the aims that have been highlighted is to control the release of the active agent at the desired time and local. Therefore, the objective was to microencapsulate cooling agents (menthol and xylitol) to apply them in chewing gum, aiming to prolong the feeling of freshness. Xylitol and menthol were microencapsulated using complex coacervation method. The microcapsules were characterized by particle size, morphology (optical microscopy, confocal and scanning electron), instrumental color parameter, hygroscopicity, moisture, water activity (Aw), solubility, sorption isotherms, Fourier transform Infrared Spectroscopy (FTIR), thermal behavior (Differential Scanning Calorie -DSC), encapsulation efficiency and release control. The chewing gums were produced in the research and development laboratory of a food industry. Eight formulations were produced, four with microcapsules and four with free ingredients. The gums were analyzed for moisture, Aw and instrumental color parameter; by texture profile analysis (TPA) was evaluated hardness, springiness, chewiness and cohesiveness of the gum. Analysis of time-intensity (TI) of chewing gum was conducted with 19 trained panelists to evaluate the duration of the freshness sensation provided by such ingredients. The microcapsules obtained had characteristics suitable for application in foods such as average particle size of approximately 100 µm and low levels of humidity, Aw, solubility and hygroscopicity. By confocal microscopy and FTIR analysis it was confirmed that the cores were completely encapsulated by wall material, ensuring the success of the technique. The encapsulation efficiency was high in menthol microcapsules but relatively low for xylitol microcapsules. By the DSC analysis it was found that xylitol and menthol crystalline state transform to the amorphous state after the microencapsulation process, which does not affect the properties of menthol, but in the xylitol yes, because their freshness is attributed to its endothermic heat of dissolution. Chewing gums showed low values of Aw and moisture, which favors the microbiological stability. Through TPA, was observed that the presence of xylitol improved the texture parameters of the gums because the gums produced with this compound showed the lowest hardness, chewiness and elasticity. The presence of the microcapsules was not significantly influenced the texture parameters analyzed. Time-Intensity analysis confirmed that the microcapsules were able to promote gradual release of menthol and xylitol, because the freshness of chewing gum containing microcapsules lasted longer than the chewing gum free ingredients.
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Stability of W1/O/W2 Double Emulsion Made With Milk Fat and a Simplified Make Procedure and Its Use in Reduced-Fat CheeseClayton, Daniel Bradley 01 May 2014 (has links)
As overweight and obesity numbers continue to climb around the world, consumers continue to search for reduced-fat alternatives to foods they often consume. Given that cheese is naturally high in fat, this is one food that is often targeted for fat reduction. However, as fat plays an important functional role in the texture of cheese by breaking up the continuous protein matrix, reduced-fat products tend to be very chewy and rubbery compared to their full-fat counterparts.
My study aimed at producing a reduced-fat cheese with improved texture compared to other reduced-fat cheese products by incorporating a double emulsion into the cheese in place of cream. The double emulsion consisted of small water droplets dispersed within oil droplets, which in turn were dispersed within a secondary water phase. The oil droplets that would then be incorporated into the cheese could essentially be made up of 40% water droplets and only 60% fat, allowing for a cheese to be designed with the same number of fat droplets as full-fat cheese while having a 40% fat reduction.
In my experiments, I made cheese with varying levels of fat using the double emulsion, along with reduced-fat and full-fat control cheeses that contained oil droplets composed entirely of fat. Though retention of double emulsion in the cheese due to its inherent instability was the key factor, I found that the double emulsion cheeses had similar to improved textural qualities compared to the control cheeses of higher fat.
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Macroscopic modeling in double emulsion systems / Modélisation macroscopique des émulsions doublesCervantes de la rosa, Abigail 17 May 2019 (has links)
Les procédés de séparation à l’aide de membranes liquides sous forme d’émulsions doubles (DE) ont fait l’objet d’un examen approfondi en vue d’applications potentielles dans des domaines tels que la récupération des métaux, la séparation des gaz, l’élimination des composés organiques, l’élimination des polluants et les bioséparations. Les difficultés d’application de ces procédés ne concernent pas le caractère sophistiqué des équipements ou des installations, mais réside plutôt dans une bonne compréhension des phénomènes complexes qui se produisent à l’intérieur de ces systèmes. Depuis leur invention, d’importants efforts ont permis d’améliorer la modélisation des procédés de séparation par émulsions doubles. Toutefois, une représentation mathématique détaillée des phénomènes de diffusion/réaction au sein de ces systèmes restait inachevée. C’est pourquoi, l’objectif de cette thèse est de décrire le transport réactif d’un soluté au sein d’une émulsion double, constituée de trois phases, au moyen d’une modélisation permettant d’intégrer à l’échelle macroscopique les mécanismes aux échelles locales. La méthode de prise de moyenne volumique est utilisée pour établir rigoureusement les équations à l’échelle d’un continu équivalent dans le contexte des transferts hors équilibre massique local (NLME). La modélisation proposée dans ce travail repose sur deux philosophies distinctes. Dans un premier temps, les DES sont considérées comme des systèmes constitués par trois phases où les changements de concentration dans chacune d’entre-elles se produisent à la même échelle de longueur. Dans un deuxième temps, les DES correspondent à deux régions homogènes où les changements de concentration se produisent à deux échelles de longueur différentes. Deux modèles macroscopiques différents sont ainsi obtenus : le modèle à trois phases et celui à deux régions. Dans les deux cas, ces modèles font intervenir les coefficients effectifs de transport comprenant l’information aux petites échelles. Ces derniers sont liés aux variables de fermeture dont la détermination est obtenue par la résolution des problèmes de fermeture associés. Enfin, une analyse d’un procédé de séparation par contact dans un réservoir agité a été effectuée en appliquant les deux modèles. / Liquid membrane separations as Double Emulsions (DE) have been extensively examined for potential application in fields such as metal recovery, gas separation, organic compound removal, pollutant removal, and bioseparations. The difficulties in the application of these processes do not consist in sophisticated equipment or installation but in a good understanding of the complex phenomena that occur inside these systems. Since its invention, efforts have been made for successful modeling of DE process separation; however, information about the diffusion and reaction phenomena inside the DE has not been included in the mathematical descriptions in detail yet. Therefore, the objective of this thesis is to describe the solute transport with chemical reaction through DE systems by means of rigorous modeling that can provide with valuable information from the micro-scale to be applied at the macro-scale.To accomplish this, a DE system has been analyzed as a three-phase system characterized by more than one disparate length scales.The method of volume averaging has been used to derive rigorous averaged equations in the context of the non-local mass equilibrium (NLME). The structure of the DES has been studied from two different perspectives: 1) the DES as a single domain where concentration changes occur in the same length scale and 2) the DES consists in two homogeneous regions where concentration changes occur at two different length scales. As a result of these different standpoints of representing the system, two different averaged macroscopic models were obtained: the three-phase and the two-region models. Both models present effective coefficients that include information about the micro-scale. These latter are related to closure variables which are solutions of associated boundary-value problems. Finally, an analysis of a DE-containing separation process in a stirred tank by applying both models was made.
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Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cellsHaggag, Y.A., Matchett, K.B., Dakir, El-Habib, Buchanan, P., Osman, M.A., Elgizawy, S.A., El-Tanani, Mohamed, Faheem, A.M., McCarron, P.A. 02 February 2017 (has links)
Yes / Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182–277 nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.
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Formulation and evaluation of polymeric micelles for improved oral delivery of tenofovir disoproxil fumarate and zidovudine using poly-lactic-co-glycolic acid nanoparticlesTenghe, Lovette Asobo January 2018 (has links)
Magister Pharmaceuticae - MPharm / Background: Tenofovir disoproxil fumarate (TDF) and Zidovudine (AZT) are both nucleotide and nucleoside analogue reverse transcriptase inhibitors (NtRTIs and NRTIs), respectively. They are used for the management and prevention of the Human Immunodeficiency Virus (HIV) infection. These drugs are faced with oral delivery challenges such as low intestinal permeability and extensive first pass liver metabolism for TDF and AZT, respectively. Their use may also be limited by dose-dependent adverse effects, which may result in treatment failure when patients become non-compliant and non-adherent to their prescribed antiretroviral (ARV) regimen. Non-compliance and non-adherence to ARV regimen may lead to drug resistance and a need for change in regimen, which can be very expensive, not only financially but in terms of morbidity and mortality. To solve such issues, a new drug can be formulated, or an existing drug can be modified. The development and formulation of a new drug is time consuming and expensive, especially with no available data and a high probability of failure. Modifying existing drugs is a cheaper, less time-consuming option with lower probability of failure. Such modification can be achieved via non-covalent interactions using various methods such as preparation of nano-particulates with polymeric micelles (a non-covalent interaction). Polymeric micelles offer a variety of polymers to choose from for drug modification purposes.
Purpose: The aim of this study was to formulate polymeric nanoparticles of TDF and AZT using different ratios of poly-lactic-co-glycolic acid (PLGA), characterize the formulated nanoparticles (using the following analyses: particle size, zeta potential, encapsulation efficiency, hot stage microscopy, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy and scanning electron microscopy), analyze for stability during storage (2-8˚C) and determine the release rate of the active pharmaceutical ingredients in the formulated nanoparticles.
Methods: Nanoparticles were prepared using a modified version of the double emulsion (water-in-oil-in-water) solvent evaporation and diffusion method. Two ratios of PLGA (50:50 and 85:15) were used to prepare four formulations (two each of TDF and AZT). Thereafter, the physicochemical and pharmaceutical properties of the formulations were assessed by characterizing the nanoparticles for particle size, zeta potential, polydispersity index, percentage yield, release profile and particle morphology, using the suggested analytical techniques.
Results: For TDF-PLGA 85:15, TDF-PLGA 50:50, AZT-PLGA 85:15 and AZT-PLGA 50:50, nanoparticles of 160.4±1.7 nm,154.3±3.1 nm,127.0±2.32 nm and 153.2±4.3 nm, respectively, were recovered after washing. The polydispersity index (PDI) values were ≤0.418±0.004 after washing, indicating that the formulations were monodispersed. The zeta potential of the particles was -5.72±1 mV, -19.1 mV, -12.2±0.6 mV and -15.3±0.5 mV for TDF-PLGA 85:15, TDF-PLGA 50:50, AZT-PLGA 85:15 and AZT-PLGA 50:50 respectively after washing. The highest percentage yield was calculated to be 79.14% and the highest encapsulation efficiency obtained was 73.82% for AZT-PLGA 50:50, while the particle morphology showed spherical nanoparticles with signs of coalescence and aggregation for all formulated nanoparticles. The release profiles were biphasic; that is, an initial burst which indicated the presence of surface API followed by sustained release. Comparing the release profiles of AZT and TDF at pH 1.2 and 7.4, it was indicative that more AZT was released at pH 1.2 while more TDF was released at pH 7.4. On computing the release data further into various mathematical models, the Weibull model was found to be the best fit. The loaded nanoparticles showed an increase in stability after washing; however, they showed signs of gradual decrease in stability after 10 days of storage at 2-8°C.
Conclusions: Relatively small, spherical and smooth nanoparticles were formulated. The nanoparticle release profile was indicative of sustained release; however, there was no conclusive indication that 48 hours duration was sufficient to release all encapsulated drug. Further studies with an increased API or polymer ratio in the formulation needs to be performed to determine if the encapsulation efficiency can be improved and in-vivo studies are required for a better understanding of the API release from formulations as well as its absorption in the body.
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