Tesi sul tema "Capsules"

Alginate is a popular candidate for encapsulation of cells due to the formation of gels with divalent ions under physiological conditions. Stable alginate gels can be formed by the selection of alginates with a high content of guluronic acid (G) and gelling in a mixture of calcium and barium. These alginate gels have been proposed as immune protective barriers for the transplantation of human pancreatic islets (insulin producing cells) for the treatment of type 1 diabetes where the alginate gel protects the transplant from the host immune system. Microencapsulation can thus provide a way to overcome the need for immunosuppressive drugs. Although showing promising results in animal models, there are potential limitations of the Ca2+/Ba2+-beads concerning growth of host cells on the surface of capsules in primate models. Development of coating strategies for alginate based capsules could thus be beneficial for reducing the attachment of host cells. Alginate microbeads/capsules were formed by electrostatic bead generator producing beads of 400µm. Afterward, the alginate beads were coated by fluoresceinamine labeled alginate that was visualized by confocal laser scanning microscopy (CLSM) and quantified by fluorescent spectroscopy. The binding of coating alginate to alginate-poly-L-lysine (PLL) capsules was also studied.In this project, in the optimalisation of coating of alginate beads some parameters were studies such as concentration of coating alginate, different gelling ions both for core and coating alginate, exposure time for gelling solution for fixation of coating layer and different washing solution.The long-term stability of coating layer of coated alginate beads was determined by measuring the fluorescent intensity of fluorescently labeled of coating alginate during a period of forty nine days. A stability study of alginate-alginate capsules revealed that Ca2+/Ba2+ alginate coated with high-G alginate and washed with saline and used Ca2+ and Ba2+ with ratio 50:1 for fixation of coating layer were more stable coating than other capsules. The alginate beads coated with high-M or epimerized alginate were produced. It shows higher intensity of coating layer in both capsules coated with high-M or epimerized alginate than alginate beads coated with high-G alginate. In continue of the study, the alginate-PLL capsules were coated with high-G, high-M, and epimerized and sulfated alginate. Alginate-PLL capsules coated with high-G, high-M and epimerized alginate shows no detective signal by confocal images and sulfated alginate coating shows some signal of coating. The stability of coating for alginate-PLL-alginate capsules and alginate beads coated with epimerized or high-M alginate revealed that both kind of coating have high-stability over one week screening.Three dimensional images of capsules, in confocal microscope, both epimerized and high-M coating alginates cover whole of capsules. However, in 3D images we have seen some fragment of coating gelling in the surround solution and attached to the capsules which can make disturbance in spectroscopy measurement. 3D images of alginate-PLL capsules coated with sulfated alginate show evenly distribution of coating.

This thesis investigates the transport and sorting of capsules (elastic membranes enclosing a liquid core) using viscous flow in complex vessel geometries. Of particular interest is passive sorting by deformability using only the fluid-structure interaction between the capsule, the viscous fluid and the geometry of the vessel. Millimetric alginate-ovalbumin capsules in the regime of negligible fluid inertia are used in this work. In order to characterise the elastic properties of the capsules, a novel numerical finite element model of the compression of a thick-shelled capsule between parallel plates is implemented. The constitutive model of the capsule membranes was determined by comparison to experimental data: a Yeoh constitutive model with the ratio of constants $C_1 = 1$, $C_2 = 0$ and $C_3 = 10$ describes the capsules used. Three geometries are investigated in this work. (i) A T-Junction bifurcation. Capsule deformation in the T-Junction bifurcation is characterised by the maximal length of the capsule $L_{max}$ and depends on the ratio of viscous to elastic forces, the capillary number $Ca$. The maximal length, $L_{max}$, is especially sensitive at distinguishing soft capsules by their deformability. The sensitivity of $L_{max}$ to capsule compliance and the large deformations that can be achieved makes the T-junction a promising geometry in which to measure elastic properties of the capsules. The rate of relaxation of the capsules after the bifurcation is independent of their deformation. (ii) A half-cylinder obstacle in a channel followed by a sudden expansion. We show that the half-cylinder obstacle causes capsule trajectories to vary depending on deformability. Capsules with a factor of three difference in deformability can be separated. A practical feature of the system is its relative insensitivity to the initial lateral position of the capsules in the channel. However, while the results are reproducible across different capsules, the variations in final position amount to 10 \% at fixed parameters. As these experiments were conducted with the same capsule under identical flow conditions, this is likely to represent the best case scenario. (iii) We adapt the pinched flow fractionation (PFF) geometry to the sorting of capsules. We show that the standard PFF device cannot be used to sort capsules. However, a novel mode of operation, termed the ``T-Junction'' mode, shows great promise for the sorting of capsules. The PFF device in the T-Junction mode separates capsules with a factor of 1.5 difference in deformability. This is twice as sensitive as the half-cylinder device, although larger variability was observed in the PFF device.

Ce travail de thèse consiste en la conception et l’utilisation d’un système d’analyse d’agrégats multicellulaires par mesure de l’atténuation de la lumière. La technologie des capsules cellulaires brevetée au sein de l’équipe d’accueil peut générer plusieurs milliers de sphéroïdes/organoïdes en quelques secondes. L’objectif est ici de caractériser ces échantillons submillimétriques encapsulés dans une coque transparente par une mesure de leur rayon et de leur coefficient d’atténuation, sans recourir à une technique d’imagerie intrinsèquement lente et bas débit. Pour exploiter le fait que la technique de production est à haut débit, nous proposons de développer un analyseur optofluidique inspiré dans son principe de fonctionnement des cytomètres classiques, mais sans marquage fluorescent des échantillons. Nous avons tout d’abord simulé l’interaction d’un faisceau laser gaussien avec une sphère de rayon et coefficient d’atténuation connus, puis développé le module optique de détection. Les mesures expérimentales ont été confrontées aux simulations pour valider notre approche. Ensuite, nous avons conçu un circuit microfluidique capable de convoyer les capsules cellulaires pesantes au travers du faisceau en utilisant une approche par impression 3D. Enfin, notre système optique a été combiné au module fluidique et modifié pour déterminer la vitesse de déplacement de chaque capsule convoyée au moment de son interaction avec le faisceau d’interrogation. Nous apportons la preuve de concept que le caractère haut-débit d’un tel instrument permet d’analyser un très grand nombre d’échantillons (plusieurs milliers) en peu de temps (quelques heures). L’instrument présenté a été utilisé pour déterminer les courbes de croissance de deux lignées cellulaires de lymphocytes tumoraux (tumeurs « liquides »), ainsi que des modifications de coefficient d’atténuation liées à la fixation sur cellules hépatiques tumorales ou à la stimulation chimique de cellules souches adipeuses qui génèrent des chapelets de gouttelettes lipidiques au cours de leur différenciation. La sensibilité de notre instrument laisse envisager son utilisation dans le cadre d’essais précliniques sur des agrégats de cellules tumorales, afin de déterminer la croissance de ces « micro-tumeurs » et donc estimer l’efficacité de traitements de chimiothérapie par exemple. Enfin, un aspect « open source » a été souhaité dans la conception de l’infrastructure électronique et informatique du prototype, ouvrant ce travail à la copie et l’amélioration, notamment par l’ajout d’un module de tri d’échantillons
This work consists in the design and use of a micro-device dedicated to the analysis of multicellular aggregates based on the measure of light attenuation. The celllular capsule technology, which was patented by the host team, can generate several thousand spheroids/organoids in a few seconds. Our objective is to characterize these submillimetric samples encapsulated in a transparent shell by measuring their radius and extinction coefficient without resorting to an inherently slow and low throughput imaging technique. To exploit the high throughput capabilities of the technique, we propose to develop a fluorescence-free optofluidic analyzer inspired from classical cytometers. We first simulated the interaction of a Gaussian laser beam with a sphere of known radius and extinction coefficient and developed the optical detection module. Experimental measurements were compared with simulations to validate our approach. Then, we designed a microfluidic device aimed at conveying the heavy cellular capsules through the beam using a 3D printing approach. Finally, our optical system was combined with the fluidic module and modified to determine the displacement speed of each conveyed capsule as it interacts with the laser beam. We provide a proof of concept that the high throughput of such an instrument allows the analysis of a very large number of samples (several thousands) in a short time (a few hours). The instrument was then used to determine the growth curves of two tumor lymphocyte cell lines ("liquid" tumors), as well as the modifications in the extinction coefficients when cancer cells are fixed and when adipose stem cells undergo differentiation into adipocytes that store lipid droplets. The sensitivity of our instrument is compatible with a further use in pre-clinical trials on tumour cell aggregates to estimate the efficacy of chemotherapy treatments for instance. Finally, an "open source" dimension was integrated into the design of the electronic and software parts of the project to promote copying and improvement, e.g through the addition of a sorting module

L’encapsulation est une technique employée couramment par le milieu industriel, notamment dans le domaine du médical, de la parfumerie ou de la cosmétique. Afin de répondre aux attentes et de proposer des capsules modulables pour tous types d’applications, des capsules de type coeur-écorce ont été élaborées au cours de cette thèse. Elles sont obtenues à partir d’émulsion dont le coeur huileux est enrobé par une coque de silice, via la minéralisation de l’interface eau-huile. Les émulsions de Pickering, stabilisées par des particules colloïdales, sont particulièrement stables et intéressantes pour cette étude. Le but de cette thèse est de comprendre, dans un premier temps, les mécanismes fondamentaux impliqués dans le processus de fabrication. Cela a permis d’élaborer, par la suite, des matériaux hybrides complexes à différentes échelles, du micrométrique au nanométrique,mais également d’établir les mécanismes de libération par un stimulus externe. Enfin, une encapsulation maîtrisée permet d’allier stabilité au stockage et destruction rapide ou contrôlée à l’utilisation. Ainsi, par diverses méthodes définies dès la formulation de l’émulsion initiale, le contenu huileux des capsules peut être libéré de manière provoquée par une action mécanique ou par l’augmentation de la température (macroscopique ou local par hyperthermie magnétique)
Encapsulation is a technique used in the industry, in particular in the field of medical,perfumery or cosmetics. In order to meet the expectations and propose adaptable capsules for all types of applications, core-shell capsules type were developed during this thesis.There were based on emulsions science with an oily core coated by a silica shell,synthetized by sol-gel chemistry at the oil-water interface. Pickering emulsions, which are emulsions stabilized by colloidal particles, are particularly stable and interesting for this study. The aim of this thesis is to understand, at first, the fundamental mechanisms involved in the manufacturing process. This made it possible to develop complex hybrid materials at different scales, from micrometric to nanometric, but also to establish the releasing mechanisms by an external stimulus. Thanks to a controlled encapsulation, it is possible to combine stability (storage) and rapid or controlled destruction when used. Thus, by various method, defined from the formulation of the initial emulsion, the releasing of the oily contentcan be caused by mechanical action or by an temperature increased (macroscopically orlocally by magnetic hyperthermia)

De nos jours, l’encapsulation est une technique très répandue dans le domaine de la parfumerie. En effet, elle permet une libération contrôlée du parfum et une protection des molécules de parfumerie qui peuvent s’oxyder avec le temps. L’objectif de cette thèse a été de mettre au point un nouveau concept de capsules fondé sur la formulation d’émulsions doubles huile-dans-eau-dans-huile et de polymériser la phase aqueuse intermédiaire. Les phases huiles, intérieure et extérieure, sont respectivement constituées du parfum et d’un solvant de parfumerie. La phase aqueuse est, elle, composée de monomères hydrophiles dont la polymérisation radicalaire permet l’obtention d’une matrice polymère plus ou moins diffusive vis-à-vis du parfum. L’intérêt de ce nouveau principe d’encapsulation est de séparer la polymérisation et les molécules de parfumerie qui peuvent être réactives en polymérisation radicalaire en les localisant dans des compartiments distincts et ainsi éviter toute interaction. Cette stratégie qui combine la Science des Emulsions, des Polymères et des Parfums et la Formulation a permis l’élaboration de capsules robustes possédant des propriétés de libération progressive par diffusion et de libération provoquée par application d'une contrainte mécanique sans altérer l'intégrité des capsules. Elles se comportent alors comme des micro-éponges capables de se déformer et de reprendre leur forme initiale. Dans ce schéma général, les propriétés peuvent être modulées plus finement par le choix et les concentrations des réactifs lors de la synthèse
Nowadays, encapsulation is a widespread technology in fragrance applications. Indeed, it allows control of the fragrance release as well as protection of the fragrance molecules with respect to oxidation. The objective of this PhD is the development of a new concept of encapsulation based on the formulation of double oil-in-water-in-oil emulsion and the polymerization of the intermediate aqueous phase. The two, internal and external, oil phases, , are respectively the fragrance and perfume solvent while the aqueous phase is composed of hydrophilic monomers leading to a more or less fragrance-diffusive polymer matrix after their radical polymerization. The main advantage of this encapsulation principle is to locate the polymerization and the possibly reactive fragrance’s molecules in separate compartments. This strategy which combines the Sciences of Emulsion, Polymers and Fragrance but also the Formulation allows obtaining robust capsules exhibiting both diffusive properties and a triggered release under a mechanical stress. These capsules behaves as micrometric sponges that can deform and restore their initial state.. In this general scheme, the capsules' properties can be tuned by an appropriate choice of the polymerization reactants and their concentrations

La industria de detergentes y suavizantes de ropas ha ido incorporado en sus procesos la tecnología de microencapsulación de perfumes. Esta tecnología permite proteger los compuestos volátiles antes, durante y después de los procesos industriales; además, también protege las fragancias durante el ciclo de lavado; asimismo, ofrece una liberación prolongada del perfume durante el secado y almacenamiento de la ropa, haciendo que la fragancia se perciba por más tiempo. Sin embargo, algunas de las cápsulas industriales presentan una serie de desventajas tales como una baja estabilidad del material de la cápsula, una baja capacidad de encapsulación y además con el método industrial de encapsulación que actualmente utilizan es extremadamente complicado encapsular compuestos polares. Con el propósito de resolver estos problemas, se ha propuesto el uso de cápsulas de polisulfona (PSf) con contenido de vainilla y preparadas por la técnica de precipitación por inversión de fases En esta investigación, han sido exitosamente preparadas y caracterizadas cápsulas de PSf/Vanillin. Los resultados muestran que estas cápsulas pueden asegurar una alta capacidad de encapsulación de perfume, una liberación prolongada de la fragancia, una buena estabilidad del material y una protección óptima del perfume. Por todas estas cualidades, las cápsulas de PSf/Vanillin presentan el potencial de ser usadas no solo en detergentes y suavizantes de ropas, sino que también en otros productos textiles.
Textile detergent and softener industries have been incorporating in their processes the perfume microencapsulation technology. This technology allows the protection of the fragrance before and during industrial processes, as well as in the product storage. Moreover, it protects the perfume during the laundry and it provides a long-lasting fragrance release after the drying and storage of fabrics. However, certain current industrial microcapsules present a number of drawbacks such as low material stability, low perfume encapsulation capacity and, in addition, with the industrial encapsulation method presently used it is extremely complicated to encapsulate polar perfumes. With the aim to solve these problems, polysulfone (PSf) capsules containing vanillin and prepared by phase inversion precipitation technique have been proposed. In this investigation, PSf/Vanillin capsules have been successfully prepared and characterized. Results show that PSf/Vanillin capsules may ensure a high perfume encapsulation capacity, a long lasting fragrance release, a good material stability, and an optimal perfume protection. Because all these qualities, PSf/Vanillin capsules have the potential to be used not only in detergents and softeners but also in other textile products.

The present work is devoted to establishing of a new generation of self-healing anti-corrosion coatings for protection of metals. The concept of self-healing anticorrosion coatings is based on the combination of the passive part, represented by the matrix of conventional coating, and the active part, represented by micron-sized capsules loaded with corrosion inhibitor. Polymers were chosen as the class of compounds most suitable for the capsule preparation. The morphology of capsules made of crosslinked polymers, however, was found to be dependent on the nature of the encapsulated liquid. Therefore, a systematic analysis of the morphology of capsules consisting of a crosslinked polymer and a solvent was performed. Three classes of polymers such as polyurethane, polyurea and polyamide were chosen. Capsules made of these polymers and eight solvents of different polarity were synthesized via interfacial polymerization. It was shown that the morphology of the resulting capsules is specific for every polymer-solvent pair. Formation of capsules with three general types of morphology, such as core-shell, compact and multicompartment, was demonstrated by means of Scanning Electron Microscopy. Compact morphology was assumed to be a result of the specific polymer-solvent interactions and be analogues to the process of swelling. In order to verify the hypothesis, pure polyurethane, polyurea and polyamide were synthesized; their swelling behavior in the solvents used as the encapsulated material was investigated. It was shown that the swelling behavior of the polymers in most cases correlates with the capsules morphology. Different morphologies (compact, core-shell and multicompartment) were therefore attributed to the specific polymer-solvent interactions and discussed in terms of “good” and “poor” solvent. Capsules with core-shell morphology are formed when the encapsulated liquid is a “poor” solvent for the chosen polymer while compact morphologies are formed when the solvent is “good”. Multicompartment morphology is explained by the formation of infinite networks or gelation of crosslinked polymers. If gelation occurs after the phase separation in the system is achieved, core-shell morphology is present. If gelation of the polymer occurs far before crosslinking is accomplished, further condensation of the polymer due to the crosslinking may lead to the formation of porous or multicompartment morphologies. It was concluded that in general, the morphology of capsules consisting of certain polymer-solvent pairs can be predicted on the basis of polymer-solvent behavior. In some cases, the swelling behavior and morphology may not match. The reasons for that are discussed in detail in the thesis. The discussed approach is only capable of predicting capsule morphology for certain polymer-solvent pairs. In practice, the design of the capsules assumes the trial of a great number of polymer-solvent combinations; more complex systems consisting of three, four or even more components are often used. Evaluation of the swelling behavior of each component pair of such systems becomes unreasonable. Therefore, exploitation of the solubility parameter approach was found to be more useful. The latter allows consideration of the properties of each single component instead of the pair of components. In such a manner, the Hansen Solubility Parameter (HSP) approach was used for further analysis. Solubility spheres were constructed for polyurethane, polyurea and polyamide. For this a three-dimensional graph is plotted with dispersion, polar and hydrogen bonding components of solubility parameter, obtained from literature, as the orthogonal axes. The HSP of the solvents are used as the coordinates for the points on the HSP graph. Then a sphere with a certain radius is located on a graph, and the “good” solvents would be located inside the sphere, while the “poor” ones are located outside. Both the location of the sphere center and the sphere radius should be fitted according to the information on polymer swelling behavior in a number of solvents. According to the existing correlation between the capsule morphology and swelling behavior of polymers, the solvents located inside the solubility sphere of a polymer give capsules with compact morphologies. The solvents located outside the solubility sphere of the solvent give either core-shell or multicompartment capsules in combination with the chosen polymer. Once the solubility sphere of a polymer is found, the solubility/swelling behavior is approximated to all possible substances. HSP theory allows therefore prediction of polymer solubility/swelling behavior and consequently the capsule morphology for any given substance with known HSP parameters on the basis of limited data. The latter makes the theory so attractive for application in chemistry and technology, since the choice of the system components is usually performed on the basis of a large number of different parameters that should mutually match. Even slight change of the technology sometimes leads to the necessity to find the analogue of this or that solvent in a sense of solvency but carrying different chemistry. Usage of the HSP approach in this case is indispensable. In the second part of the work examples of the HSP application for the fabrication of capsules with on-demand-morphology are presented. Capsules with compact or core-shell morphology containing corrosion inhibitors were synthesized. Thus, alkoxysilanes possessing long hydrophobic tail, combining passivating and water-repelling properties, were encapsulated in polyurethane shell. The mechanism of action of the active material required core-shell morphology of the capsules. The new hybrid corrosion inhibitor, cerium diethylhexyl phosphate, was encapsulated in polyamide shells in order to facilitate the dispersion of the substance and improve its adhesion to the coating matrix. The encapsulation of commercially available antifouling agents in polyurethane shells was carried out in order to control its release behavior and colloidal stability. Capsules with compact morphology made of polyurea containing the liquid corrosion inhibitor 2-methyl benzothiazole were synthesized in order to improve the colloidal stability of the substance. Capsules with compact morphology allow slower release of the liquid encapsulated material compared to the core-shell ones. If the “in-situ” encapsulation is not possible due to the reaction of the oil-soluble monomer with the encapsulated material, a solution was proposed: loading of the capsules should be performed after monomer deactivation due to the accomplishment of the polymerization reaction. Capsules of desired morphologies should be preformed followed by the loading step. In this way, compact polyurea capsules containing the highly effective but chemically active corrosion inhibitors 8-hydroxyquinoline and benzotriazole were fabricated. All the resulting capsules were successfully introduced into model coatings. The efficiency of the resulting “smart” self-healing anticorrosion coatings on steel and aluminium alloy of the AA-2024 series was evaluated using characterization techniques such as Scanning Vibrating Electron Spectroscopy, Electrochemical Impedance Spectroscopy and salt-spray chamber tests.
In Anlehnung an den Selbstheilungsmechanismus der menschlichen Haut entwickeln wir ein innovatives Verfahren zur Funktionalisierung von Korrosionsschutzbeschichtungen, um auch diese in die Lage zu versetzen Beschädigungen selbstständig „auszuheilen“. Dazu werden winzige Mikro- und Nanobehälter mit aktiven Substanzen (z. B. Korrosionshemmstoffen, Versiegelungsmitteln, Bioziden etc.) befüllt und anschließend in eine Korrosionsschutzbeschichtung eingebettet. Kommt es nun im Zeitablauf zu korrosionsauslösenden Beschädigungen der Schutzbeschichtung (z. B. durch Kratzer oder Risse) werden an der Defektstelle die eingebetteten Behälter zerstört und aktiv wirkende Gegensubstanzen freigesetzt. Dadurch wird die verletzte Stelle sofort wieder verschlossen und die Korrosionsgefahr eliminiert. Der entscheidende Vorteil derart funktionalisierter Schutzbeschichtungen ist ihre aktive Rückkopplung mit dem Korrosionsauslöser: Die aktive Schutzsubstanz wird nur an der Defektstelle und nur in der zur Korrosionsvermeidung erforderlichen Menge freigegeben. Somit werden eine länger anhaltende Wirkdauer sowie eine deutlich höhere Nachhaltigkeit der Beschichtungen ermöglicht. Dieses „intelligente Verhalten“ der neuen aktiven Korrosionsschutzbeschichtungen ist nur dank ihrer innovativen Mikrostruktur möglich. Die winzigen Mikro- und Nanobehälter beinhalten nicht nur aktive Substanzen in ihrem Inneren sondern besitzen auch eine intelligent konstruierte Hüllenstruktur, deren Durchlässigkeit sich je nach Art des Korrosionsauslösers ändert. Wird die eingekapselte aktive Substanz freigesetzt, fängt diese sofort an gegen die korrosionsverursachenden Einflüsse zu wirken. Ist die Gefahr beseitigt verringert sich die Durchlässigkeit der Behälterhülle wieder. Diese bedingte Reversibilität zwischen geschlossenem und geöffnetem Zustand des Behälters sorgt für einen sehr sparsamen Verbrauch der aktiven Substanz und für die stark verbesserte Schutzwirkung darauf basierender Antikorrosionsbeschichtungen. Diese Arbeit befasst sich mit dem Aufbau polymerer Kern-Schale-Mikrokapseln, die entsprechende Korrosionsinhibitoren und Biocide enthalten. Der Morphologie wird für zahlreiche Lösungsmittel und Polymere mit Hilfe der Hansen-Löslichkeitsparameter in guter Übereinstimmung mit elektronenmikroskopischen Experimenten beschrieben. Die Wirkungsweise in technischen Beschichtungen wird quantifiziert anhand von elektrochemischer Impedanzspektroskopie, Rastervibrationssondenmessungen und industrienahen Testverfahren.

Master of Science
Biochemistry and Molecular Biophysics Interdepartmental Program
John M. Tomich
Nanocapsules have become more popular as potential therapeutic agents in recent years. Though liposomes are the most popular and well-studied, nanocapsules made of peptides have their distinct advantages as the research behind them intensifies. Branched Amphiphilic Peptide Capsules (BAPCs) are a type of self-assembling nanocapsules that are made up of two similar branched, amphiphilic, chemically synthesized peptides. These peptides self-assemble into bilayer delimited capsules capable of encapsulating solutes and even small proteins in aqueous solution. Previous studies have shown that these nanocapsules are taken up by cells in culture without negative effects and can be given to an organism, distributed throughout the organism without cytotoxic effects, suggesting a possible future as a therapeutic nanoparticle. For use as a therapeutic system, the understanding of how these BAPCs behave in the presence of sodium and chloride, two very common biological ions, must be understood and characterized. Previously published work showed that the BAPC bilayer is semipermeable and excludes sodium and chloride ions. Current research has expanded on this. Besides being semipermeable, this bilayer is also a dynamic membrane that has the ability to expand and contract due to osmotic pressure from ions in solution. Eosin Y, an autoquenching dye, has been used for many of the studies to monitor the behavior and the amount of water within the BAPCs. Having insight into how the BAPCs change under physiological conditions is necessary if these nanoparticles are to be used in a clinical setting and may open doors to new uses.

Antigen expression through the Chloroplast Transformation Technology (CTT) produces bioencapsulated subunit-vaccines, capable of eliciting immune responses when delivered orally. Considerable challenges to effective plant-based vaccines are the normalization of dosage and preservation of accumulated antigen, which is complicated by variable high water content and protease activity. This study critically examines the efficacy of lyophilization in dehydrating plant-tissues and preserving plant-derived antigens with vaccine potential. Lyophilization was optimized through gravimetric analysis using lettuce expressing Protective Antigen (PA) of Bacillus anthracis (LS-HPAG) and the human autoantigen Proinsulin (Pins) fused to Cholera toxin subunit B (LS-CTB-Pins). Lyophilization for 48-hours was sufficient treatment to reduce lettuce to 4.57% of its original weight, which retained .058% water content in the bound state; these levels corresponded with oven-dried controls while antigen was stabilized for over a year of storage at room temperature. A simulated gastric fluid assay was applied to evaluate stability of plant derived antigens during digestion. It was observed that lettuce plant cells conferred protection through antigen bioencapsulation for up to an hour under enzymatic digestive conditions. LS-HPAG immunogenicity was then demonstrated through the induction of a PA-specific IgG response by through oral boosting of C57/BL6 test mice. Survival during toxin challenge demonstrated a protective immune response if 40% of animal immunized by plant-derived PA. Lastly, the inclusion of excipient and adjuvant additives will be considered and utilized for the development of prototype vaccine capsule formulations.
B.S.
Bachelors
Medicine
Molecular Biology and Microbiology

Thesis (M.S.) -- University of Maryland, College Park, 2008.
Thesis research directed by: Dept. of Chemical and Biomolecular Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

A biodisponibilidade é uma característica decisiva para a eficácia dos medicamentos, podendo sua intensidade ser estimada através da cedência "in vitro". Vários fatores são capazes de influenciá-la, entre eles a composição quali e quantitativa dos adjuvantes, assim como as características da substância ativa e da forma farmacêutica. A hidroclorotiazida é um diurético de amplo emprego, que apresenta problemas de biodisponibilidade e bioequivalência devido a sua baixa hidrossolubilidade. Através de planejamento fatorial 2 3 foram preparadas formulações de cápsulas de gelatina dura contendo 50 mg de hidroclorotiazida. Foi analisada a influência dos fatores material de enchimento (lactose e celulose microcristalina), reguladores de fluxo (dióxido de silício altamente disperso e estearato de magnésio) e hidrofilizante (polissorbato 80) sobre as características de qualidade dos complexos farmacêuticos e das cápsulas. O regulador de fluxo ou a interação entre este e o material de enchimento foram os fatores determinantes nas características de fluxo dos complexos farmacêuticos, analisadas através do ângulo de repouso e do índice de compressibilidade. A cedência "in vitro" das cápsulas, determinada com auxílio de aparelho de célula de fluxo e parametrizada pela eficiência de dissolução, foi influenciada preponderantemente pelo regulador de fluxo. Foram comparados os perfis de cedência "in vitro" entre as cápsulas e comprimido do mercado. O comportamento intermediário demonstrado pelo comprimido indica a necessidade de avaliação comparativa entre medicamentos contendo hidroclorotiazida a fim de assegurar sua bioequivalência.
The bioavailability is a decisive characteristic to drugs efficacy that can be predict by different "in vitro" dissolution methods. The bioavailability has been shown to be dependent on factors such as the drug, the dosage forms, type and quality of adjuvants. Hydrochlorothiazide is a widely used diuretic. Due to its limited aqueous solubility, this drug has potencial bioavailability problems. Eight differents hydrochlorothiazide hard gelatin capsules, containing 50 mg of the drug, were prepared according to a 2 3 factorial design. The influence of fillers (lactose or microcrystaline cellulose), glidants (magnesium stearate or coloidal silicon dioxide) and surfactant (polysorbate 80) on the pharmaceutical characteristics of powder mixtures and capsules were evaluated. The powder mixtures flow characteristics were evaluated through repose angle and compressibility index. It was determined that the glidant and its interaction with filler influenced this characteristic. The "in vitro" release of hydrochlorothiazide from capsules was carried out by a open flow-though dissolution method. The dissolution efficiency was the selected parameter to express the drug release. The glidant was the determinant factor. The dissolution profile of these capsules and marketed tablets was compared. The results evidenced the importance of comparative evaluation of hydrochlorothiazide dosage forms to assure their bioequivalence.

Software testing is an important part of modern system development. It is a collection of methods used to detect and correct bugs and faults found in software code. Unit testing is a widely used technique in software testing where individual units of source code are isolated, often divided up into classes and functions, and tested separately. When developing in a modeling environment, the system components and their respective behavior are expressed by models written in the Unified Modeling Language (UML). These model descriptions are then used to automatically generate programming code for compilation into real-time systems. The generated code can in turn be subjected to unit testing in order to aid in the verification of the systems behavior and functionality. The modeling tool Rational Software Architect RealTime Edition (RSARTE), developed by IBM, is one example of such an environment. The generated code from the UML models in RSARTE is designed to execute in a real-time computing C++ runtime environment. An essential building block for real-time functionality is the Capsule model. A capsule is an element with an internal state-machine and ports defining its behavior and communication with other capsules. This construction is of great help when programming concurrent real-time applications. Due to the complexity provided by the real-time runtime environment, it is difficult to isolate and unit test the behavior of designed capsules. In this thesis we will show that a capsule in this environment can be isolated and then subjected to unit testing with the help of an integrated third party unit test framework. Also, before integrating a suitable framework, we will select one by doing a review, discussion and a comparison of different mature and available unit test frameworks for use in the C++ language.

The external shell (exine) of plant spores and pollen grains is composed of sporopollenin, which is an organic polymer renowned for its exceptional resistance to physical and chemical attack. The resilience of sporopollenin to high temperature, pressures, acidic and basic corrosion is proved by its survival in some sedimentary rocks, which are 500 million years old. Solid phase organic synthesis is a process where molecules or reagents are used whilst attached to an insoluble and filterable solid support. Sporopollenin could have a series of advantages over commercial resins if it can be applied to solid phase synthesis as it has a constant chemical structure, constant pore size, and in particular chemical and physical stability. In this study sporopollenin was first extracted from fresh pollen and spores, and then modified to make a basic form by attachment of alkyldiamines, and an acidic form by treatment with chlorosulfonic or sulfuric acid. Detailed studies were undertaken regarding the use of the base form of sporopollenin in Schotten-Baumann type acylations and Knoevenagel condensations, and the acidic form of sporopollenin in the isopropylidene protection of mannose and preparation of cyclic acetal. As a result, aminated sporopollenin particles were shown to be effective scavengers in Schotten-Baumann acylation and they catalyse Knoevenagel condensation successfully. The sulfonated sporopollenin particles also reveal their ability in catalysing relative reactions. Raw spores and simply extracted sporopollenin has been investigated for the stabilization of Pickering emulsion by Binks et al. In this work, sporopollenin was aminated and their behaviour as emulsifiers has been studied. The amino groups on the surface of sporopollenin will change the hydrophilicity of the particles and affect their behaviour in the emulsions.

Research into inorganic supramolecular chemistry is burgeoning, in particular that which focuses on the formation of capsular molecules and the effects that these unique environments have on catalytic reactions. With the aim of producing new ligand designs that could not only support reactive metals, but also partake in supramolecular aggregation to provide a capsular microenvironment, new tripodal ligands and wide span imines and amines have been synthesised. Furthermore, the exploitation of hydrogen-bonding motifs formed through pyrrole-imine tautomerisation upon metallation of these ligands has been explored, with the aim of enhancing reactivity and stabilising reactive intermediates. In Chapter one, the concept of covalent and non-covalent capsules is introduced, and includes the different aspects affecting the encapsulation of molecules and their use as nanoreactors. The use of secondary interactions, e.g. hydrogen-bonding in metal complexes of tetrapodal and tripodal ligands is discussed. Chapter two describes the synthesis of a tripodal pyrrole-imine ligand and the formation of its multi-metallic complexes of Group one metals, transition metal and the f-block elements. The complete and partial tautomerisation of this ligand upon metal complexation is also examined. In Chapter three, the formation of hangman complexes of the tripodal pyrrole-imine ligand is described and is extrapolated to the chemistry of a new pyrrole-amide ligand. The synthesis of this latter ligand and its properties with regards to anion binding are also explored. Chapter four describes the formation of wide span diamine and diimine ligands and their propensity to form adducts with cobalt and zinc chlorometallates and unusual multimetallic palladium complexes. The final conclusions of the work presented in this thesis are drawn in Chapter five. Chapter six presents experimental details and characterising data for all of the new compounds presented in this thesis.

Cette thèse porte sur la formation de capsules par réticulation interfaciale entre un polysaccharide biodégradable, le chitosane et un agent réticulant. L’objectif est de former des capsules contenant un coeur lipophile dans des conditions chimiques douces pour encapsuler des principes actifs sensibles tels que les enzymes et les parfums. Nous avons opté pour un agent réticulant moins réactif que les dichlorures d’acide, et soluble dans une huile végétale pour éviter l’utilisation de solvants organiques. Les capsules sont formées dans une solution de chitosane à pH 6. La méthode de formation des capsules est également plus douce, car elle permet de former des capsules goutte à goutte avec une agitation modérée. Plusieurs techniques de caractérisation ont été mises en place pour déterminer les propriétés des capsules formées. La RMN 13C solide a permis de déterminer la structure chimique des membranes de chitosane réticulé. L’étude de la résistance mécanique sur les capsules a montré que les capsules ont des propriétés viscoélastiques. Une épaisseur homogène et une structure lisse de la membrane ont été observées en MEB en microscopie confocale, ce qui a montré l’absence de porosité. L’utilisation de la chromatographie liquide (CLHP) a permis de mettre en évidence les propriétés d’imperméabilité des membranes des capsules en utilisant un composé lipophile, le δ-tocophérol, d’où une libération de la substance par rupture mécanique de la membrane. Finalement, nous avons montré qu’il est possible de contrôler la formation de capsules par réticulation interfaciale et de moduler leurs propriétés
This thesis relates to the formation of capsules by interfacial cross-linking between a biodegradable polysaccharide, the chitosan and a cross linked agent. The objective is to form capsules containing a lipophilic core under soft chemical conditions to encapsulate active ingredients such as the enzymes and the perfumes. We chose a crosslinking agent less reactive than dichlorides of acid and which is soluble in an oil to avoid the use of organic solvents. The capsules are formed in a chitosan solution with pH 6. The method of formation of the capsules is also softer because it makes it possible to form capsules drop by drop with a moderate agitation. Several techniques of characterization were used to determine the properties of the formed capsules. The solid NMR 13C made it possible to determine the chemical structure of the membranes of chitosan cross linked. The study of the mechanical resistance on the capsules showed that capsules have the viscoelastic properties. A homogeneous thickness and a smooth structure of the membrane were observed in SEM and microscopy confocal, which showed the absence of porosity. The use of the liquid chromatography (HPLC), made it possible to showed the impermeability properties of the capsules membranes by using a lipophilic compound δ-tocopherol from where a release of the substance by mechanical rupture of the membrane. Finally, we showed that it is possible to control the formation of capsules by interfacial cross linking and to modulate their properties

L’objectif de cette thèse est d’étudier expérimentalement les deformations de microcapsules dans un écoulement confiné. Les microcapsules sont composées d’albumine du sérum humain avec des concentrations de 5 à 20 [g/100mL]. Leur taille varie de 50 à 1000 [μm]. Les capsules sont injectées dans des écoulements de Poiseuille produits dans des canaux microfluidiques présentant deux sections différentes : circulaire ou carrée.La mesure des caractéristiques géométriques de microcapsules déformées couplée à des simulations numériques mène à la détermination du module de cisaillement surfacique. Cette caractéristique mécanique augmente fortement tant avec la taille qu’avec la concentration en protéine de la capsule, et plus précisément avec le produit de ces deux paramètres.Le fluide est ensemencé avec des microparticules pour mesurer l’écoulement induit par une capsule dans un capillaire cylindrique par la méthode de la vélocimétrie par suivi de particules. Les zones de recirculation et de perturbation sont alors déduites et comparées avec la simulation numérique d’un objet rigide dans un capillaire et présentant le profil donné par les expériences. Finalement un système original de visualisation optique est consacré à l’observation simultanée de la vue de côté et de la vue de face des capsules pour obtenir sa forme entière. Ceux-ci révèlent l’existence des plis tout autour de la membrane des capsules. Le seuil de formation et l’évolution de ces plis sont étudiés en fonction de la vitesse, de la taille et du confinement, dans des canaux de section circulaire ou carrée
The objective of this thesis is to study experimentally microcapsule deformations in confined flows. The microcapsules are made of cross-linked proteins, the human serum albumin (HSA) with concentrations from 5 to 20 [g/100mL]. Their size vary from 50 to 1000 [μm]. Capsules are injected in Poiseuille flows generated within microfluidics channels with two different cross sections geometries : circular or square.The measurement of geometrical characteristics of deformed microcapsules coupled with numerical simulations leads to the determination of the surface shear modulus. This mechanical characteristic increases strongly with both the size and the protein concentration of the capsule, and more precisely with the product of these two parameters.The flow is seeded with microparticles to measure the induced flow of a capsule in a cylindrical capillary by particle tracking velocimetry. The recirculation and perturbation zones are then deduced and compared with numerical simulation of a rigid body flowing in a capillary. Finally an original system of optical visualization is dedicated to the simultaneous observation of the side and the front view of the capsules to get its whole shape. These reveal radial wrinkles all around capsules membrane. The formation threshold and the evolution of these wrinkles are studied as function of the capsule velocity and size and the confinement within capillaries with circular or square cross–section

Thesis (M.S.) -- University of Maryland, College Park, 2009.
Thesis research directed by: Dept. of Chemical and Biomolecular Engineering . Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

An understanding of the motion of soft capsules in microchannels is useful for a number applications. This knowledge can be used to develop devices to sort biological cells based on their size and stiffness. For example, cancer cells have a different stiffness from healthy cells and thus can be readily identified. Additionally, devices can be developed to detect flaws in synthetic particles. Using a 3D hybrid lattice Boltzmann and lattice spring method, the motion of rigid and soft capsules in a pressure-driven microfluidic flow was probed. The effect of inertial drift is evaluated in channels different Reynolds numbers. Other system parameters such as capsule elasticity and channel size are also varied to determine their effect. The equilibrium position of capsules in the channel is also obtained. The equilibrium position of rigid and soft capsules depends on the relative particle size. If the capsule is small, the equilibrium position is found to be closer to the channel wall. Conversely, for larger capsules, the equilibrium position is closer to the channel centerline. The capsule stiffness affects the magnitude of the cross-stream drift velocity. For a given Reynolds number, the equilibrium position of softer capsules is closer to the channel centerline. However, It is found that the equilibrium position of soft capsules is insensitive to the magnitude of the Reynolds number.

In conclusion, the results obtained firstly indicated that the BP, EMEA and WHO were in fairly good agreement on the criteria and specifications that can be used to assesses the pharmaceutical quality of a traditional plant medicine such as Phela. Secondly, the Phela plant powders were found to have acceptable pharmaceutical properties that did not complicate or adversely affected the capsule manufacture. Thirdly, the Phela capsules produced were generally of acceptable pharmacopoeial standard. Fourthly, HPLC fingerprinting and pattern recognition analysis proved useful to examine the chemical stability of selected marker compounds of Phela and indicated that the capsules had no practical shelf life under elevated temperature and humid conditions. Overall, the Phela capsules should thus be suitable for use in a short time clinical trial, but for use in a long period trial the long term stability of the Phela capsules under ambient conditions must still be confirmed.

Des capsules métalliques, avec joint intégré, sont couramment utilisées dans l'industrie alimentaire pour assurer l'étanchéité des bouteilles de verre par sertissage. La performance de l'assemblage est mesurée par la pression de fuite. Dans cette thèse, la simulation par éléments finis du sertissage d'une capsule sur une bouteille de verre est réalisée pour obtenir la distribution des forces exercées sur le joint en fonction de la pression interne. La simulation du sertissage est réalisée à l'aide du logiciel de calcul par éléments finis Ansys®. L'analyse tridimensionnelle tient compte du comportement élasto-plastique de la capsule métallique, du comportement hyperélastique du joint polymère, et des phénomènes de contact entre les outillages rigides et la capsule. Des mesures réalisées en laboratoire pour caractériser le comportement du joint en fonction de la pression de fuite ont été combinées aux résultats numériques de la simulation pour prédire la pression de fuite d'un assemblage donné. La comparaison entre la géométrie finale de l'assemblage serti et la simulation est très acceptable. De plus la prédiction de la pression de fuite d'un assemblage est d'un accord raisonnable avec l'expérimentation.

Ce travail de thèse concerne l'étude des propriétés physico-chimiques de capsules millimétriques à cœur liquide possédant une membrane fine d'hydrogel d'alginate. Nous avons dans un premier temps caractérisé le transport de molécules à travers la coque d'hydrogel et estimé le rayon de coupure de cette membrane semi-perméable. De plus, il est possible de limiter la fuite de petits solutés hydrophiles en ajoutant une couche hydrophobe entre le cœur aqueux et la membrane d'alginate. Nous démontrons alors que le temps caractéristique de fuite est déterminé par la géométrie du système (épaisseur de la couche hydrophobe et rayon de la capsule) ainsi que la solubilité et le coefficient de diffusion du soluté dans la phase huileuse. D'autre part, le gonflement d'une capsule soumise à une différence de pression osmotique nous a permis d'identifier les régimes viscoélastique et viscoplastique de la membrane sous étirement. Nous en déduisons un module élastique de l'hydrogel, qui diminue au-delà du seuil de plasticité. A contrario, lors de la compression de capsules, l'hydrogel est concentré par expulsion irréversible de l'eau, ce qui entraîne une rigidification de sa structure. Enfin, nous nous sommes intéressés à l'écoulement d'une suspension concentrée de capsules à coeur huileux dans l'eau. Il existe une friction entre les capsules qu'il est possible de contrôler par ajout de tensioactif. Nous avons donc étudié son rôle dans l'écoulement de capsules dans une constriction de type sablier. Ainsi, nous démontrons que le flux est constant et qu'il ne dépend pas de la friction, mais qu'il est fixé par la taille de l'étranglement. En effet, l'écoulement est uniquement déterminé par l'hydrodynamique en phase fluide dans le col du sablier.

We have developed simplified microfluidic droplet generators and employed them to fabricate anisotropic polymer particles and capsules in the size range of 100–500 μm. We used cheap and generally available materials and equipment to design and assemble microfluidic devices. All our devices were made of standard wall borosilicate capillaries (OD 1.0mm, ID 0.58mm), steel dispensing needles without bevel (30 G, 32 G), microscopy glass slides, fast-curing epoxy glue (Araldite-80805) and diamond scribe to process the glass. We designed four different geometries for each device, which can be separated for two groups: single and double droplet generators. The performance of the devices was validated using computational fluid dynamics and laboratory experiments. First of all, we tried to fabricate intricate single emulsion droplets and then moved on to double emulsion droplets. The range of the fabricated particles and capsules includes anisotropically-shaped amphiphilic polymer “microbuckets”, biphasic particles, capsules with various fillers and stimuli responsive polymer vesicles. To produce such objects we employed different functional monomers, for instance “clickable” glycidyl methacrylate or hydrophilic 2-hydroxyethyl methacrylate. We also utilized several chemical and physical phenomena such as internal phase separation, wettability or polymer chain cross-linking to tune the properties of the synthesized particles. We investigated properties of the above mentioned particles and capsules. For example, “microbuckets” which are hydrophilic at the exterior surface, but hydrophobic inside the cavity, were able to withdraw oil droplets from an aqueous phase and “arrest” them inside the cavity.

Des capsules à cœur hydrophobe ont été produites par extrusion gouttes à gouttes d’une émulsion de chlorure de calcium/huile dans une solution d’alginate. Une gélification autour des gouttes d’huile se créée par la migration des ions calcium dans la solution d’alginate (gélification interne) permettant la formation d’une membrane. L’influence des conditions opératoires (concentrations en chlorure de calcium et en alginate et le temps de gélification) sur l'épaisseur de la membrane et la résistance mécanique des capsules ont été étudiées et ont permis d’obtenir des capsules stables et résistantes. Ces capsules ont été utilisées pour l'immobilisation de la lipase pancréatique porcine avec un taux d’encapsulation proche de 60% sans perte d’activité intrinsèque. L’immobilisation de la lipase a été étudiée en fonction du pH, de la température, des taux de réutilisation et de libération, de l?efficacité du stockage et des paramètres cinétiques de la réaction hydrolytique. Ce biocatalyseur a montré une activité catalytique plus élevée par rapport à l'enzyme libre. On observe toutefois une libération de la lipase à travers la membrane des capsules lors d?utilisations répétées et une faible stabilité au stockage à température ambiante et à 4°C. Pour y remédier, la porosité de la membrane d'alginate de calcium a été modifiée en utilisant une membrane composée d'alginate et de pectine. Ces nouvelles capsules ont montré une efficacité d'encapsulation supérieure et permettent de réduire la libération de la lipase au cours du temps. D’autre part, la stabilité du stockage de la lipase immobilisée dans ces capsules a été améliorée lorsqu’elles sont conservées dans un environnement présentant une faible activité de l’eau.

Thesis (Ph.D)--Computing, Georgia Institute of Technology, 2009.
Committee Chair: Ramachandran, Umakishore; Committee Member: Knobe Kathleen; Committee Member: Pande, Santosh; Committee Member: Prvulovic, Milos; Committee Member: Rehg, James M.. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Ce travail traite de la synthèse et de la caractérisation de nouvelles cages moléculaires discrètes riches en électrons préparées via la méthodologie d'auto-assemblage dirigée par les métaux, ainsi que de leurs propriétés redox et d’encapsulation. Les concepts généraux guidant la méthodologie d’auto-assemblage pilotée par les métaux sont présentés. Trois types de ligands tétratopiques rédox-actifs (L) constitués de tétrathiafulvalène (TTF), de dithiol-fluorène (DTF) ou de tétrathiafulvalène π étendu (exTTF) ont été conçus. Leur capacité à générer des cages auto-assemblées avec divers complexes (M) a été étudiée. Dans le premier cas, des métallacages M8L2 dont la géométrie offre une opportunité unique de favoriser des interactions inter-TTF étroites au cours du processus d’oxydation ont été décrites. Ces interactions ont été confirmées par des études électrochimiques ainsi que par DRX à partir d’un sel oxydé électrocristallisé. Dans le second cas, plusieurs auto-assemblages discrets MxLy (cages, clips) ont été obtenus à partir de nouveaux ligands électroactifs basés sur l'unité 9- (1,3-dithiol-2-ylidène) fluorène (DTF). Leurs propriétés rédox ainsi que leur capacité à complexer des unités électro-déficientes sont fortement dépendantes de la géométrie de l’auto-assemblage. Concernant le ligand exTTF, de grandes métallacages électroactives M12L6 (environ 4 000 Å3) ont été obtenus par combinaison avec des complexes trans de palladium ou d'argent. Ces dernières se désassemblent lors de l'oxydation, donnant lieu à une transformation sans précédent d'une cage métallique discrète en un polymère de coordination. Enfin, un nouveau squelette aromatique benzo[1,2-b:4,5-b'] dithiophène est décrit en tant qu’alternative aux dérivés riches en électrons π étendus. Le rôle critique des interactions non-covalentes 1,5 S ···S est démontré par une approche combinée expérimentale et théorique
This work deals with the synthesis and characterization of new electron-rich discrete molecular cages, prepared via the coordination-driven self-assembly methodology, as well as on evaluating their redox and host-guest properties. The general concepts guiding the metal-driven self-assembly methodology are presented. Three types of redox-active tetratopic ligands (L) featuring either a tetrathiafulvalene (TTF), a dithiol-fluorene (DTF) or a π-extended tetrathiafulvalene (exTTF) have been designed. Their ability to generate self-assembled cages upon combination with various metal complexes (M) has been studied. In the first case, M8L2 metallacages were obtained, whose geometry offers a unique opportunity to promote close inter-TTF interactions upon oxidation, as confirmed through electrochemical studies as well as from single-crystal DRX from an electrocrystallized oxidized salt. In the second case, several discrete self-assemblies MxLy (cages, clips) were obtained and characterized from new electro-active ligands based on the 9-(1,3-dithiol-2-ylidene)fluorene (DTF) unit. Their redox properties as well as their binding ability towards electro-deficient planar species show a strong dependence to the self-assembly geometry. Considering the exTTF ligand, large (ca. 4000 Å3) electroactive M12L6 metallacages were obtained from combining with trans palladium or silver complexes. Le latter exhibits a disassembling process upon oxidation, giving rise to an unprecedented redox-triggered transformation of discrete metalla-cage into a coordination polymer. Finally, a new benzo[1,2-b:4,5-b'] dithiophene aromatic scaffold is investigated as an alternative π-extended electron-rich derivative. The critical role of non-covalent 1,5 S···S interactions is demonstrated by a combined experimental and theoretical approach

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 189-201).
Macromolecule drugs such as insulin have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limits their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. In this thesis I will describe two oral capsules designed to systemically deliver macromolecules by inserting the drugs directly into the walls of the gastrointestinal tract. One device is designed to deliver to the stomach wall, while the other device is designed to deliver to the wall of the small intestine. Ex vivo studies on human GI tissue and in vivo studies in rats and swine support the devices' safety and high delivery efficiency. I perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to show that these new methods of oral macromolecule delivery should increase the quality-adjusted life expectancies of patients suffering from diabetes. Moreover, I demonstrate that electronic systems can be incorporated into these devices for communication and additional therapeutic applications. With the ability to load a multitude of drug formulations, the devices can serve as platform technologies to orally deliver therapeutic doses of macromolecule drugs.
"NSF for providing me with a fellowship towards pursuing my graduate degree, and I want to acknowledge a grant from the National Institutes of Health for funding part of the research as well (EB-000244)"
by Alex Gilbert Abramson.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineering

Enzymatic phenol removal from wastewater is an important treatment approach to promote environmental sustainability. Whilst free peroxidases demonstrate efficient phenol degradation capabilities, they are disadvantaged by long-term stability and reusability. This research develops a novel system of plant-based peroxidase encapsulated in polymeric capsules for continuous phenol removal in a fluidized bed column. The process demonstrated scalability and commercial viability with 95% phenol removal efficiency.

Stability studies were undertaken at ambient (25ºC/60%RH) and accelerated conditions (40ºC/75%RH) to determine the effect of changing of hard gelatin capsule supplier on a phenytoin sodium (100 mg) capsule formulation. Three hard gelatin capsule suppliers: RP Scherer (Supplier A), Capsugel (supplier B) and Associated Caps (Supplier C) were used in the study. Capsules were analyzed just after filling of the capsules (T0), after 1 month (T1), after 2 months (T2) and after 3 months (T3) after being stored in securitainers under the above-mentioned conditions. The moisture content of the empty shells as well as the capsule contents were analysed at each time-point. The capsule disintegration time was recorded at each time point. Multi-point dissolution testing was performed at each time point to determine the release of the active substance in each case. Based on the achieved results, the best capsule shell supplier was recommended, and other suggestions were made to improve the capsule formulation.

Cette thèse a pour objectif de comprendre les mécanismes physiques régissant la formation de capsules submillimétriques à coeur aqueux possédant une membrane fine d'hydrogel et ainsi de mieux maitriser ce procédé. Des bigouttes sont d'abord formées dans l'air par fragmentation d'un jet cylindrique composé d'un coeur aqueux enveloppé par une solution d'alginate. La coque est ensuite gélifiée après immersion dans une solution de calcium. L'étude du co-Écoulement au sein de l'injecteur a montré l'existence d'une instabilité élastique qui est amplifiée en présence de cations, du fait du caractère polyélectrolyte de l'alginate. Nous avons montré que cette instabilité était à l'origine d'un battement du jet composé en sortie d'extrusion. En provoquant un décentrage du coeur, l'instabilité induit une relaxation asymétrique du profil de vitesse, ce qui crée un couple qui courbe le jet. Nous avons mis en évidence cet effet en produisant des jets courbés à partir d'une pointe biseautée. La fragmentation du jet est ensuite contrôlée par une perturbation harmonique des débits d'injection. Nous observons une décroissance de la vitesse d'onde à la surface du jet pilotée par la tension de surface. La viscosité élevée des solutions d'alginate entraine une amplification de fluctuations de cette vitesse donnant lieu à des coalescences au sein du jet. L'ajout de tensioactifs peut exacerber cet effet en induisant une tension de surface dynamique à la surface du jet. Finalement, nous parvenons à produire des capsules submillimétriques de taille contrôlée, monodisperses, possédant une membrane fine, avec un taux d'encapsulation supérieur à 99%. Ces capsules trouvent des applications dans le domaine des biotechnologies comme nouvel outil pour la culture cellulaire
The purpose of this work is to understand physical mechanisms that control the formation of aqueous-Core submillimetric capsules with a thin hydrogel membrane. This comprehension will allow a better control of the process. Compound drops are first formed in the air by the break-Up of a cylindrical jet composed of an aqueous core surrounded by an alginate solution. The shell is then solidified after immersion in a gelling calcium solution. The study of the co-Flow inside the injector showed the existence of an elastic instability which is amplified in the presence of cations, due to the polyelectrolyte property of alginate. We showed that this instability causes the flapping of the compound jet out of the injector. The instability induces a displacement of the core fluid position which leads to an asymmetric velocity relaxation that creates a torque and finally bends the jet. We produced curved jets with a beveled capillary to demonstrate this effect. The jet break-Up is controlled by a harmonic perturbation of the injection flow rates. We measured a decrease of the wave speed on the jet surface which is controlled by the surface tension. The alginate solution high viscosity causes an amplification of speed fluctuations that induces coalescence inside the jet. This amplification is enhanced by the addition of surfactants which create a dynamic surface tension at the jet interface. Finally, we managed to produce submillimetric and monodisperse capsules with a thin membrane, an encapsulation yield above 99% and a size that we can tune. These capsules can be used in biotechnology applications as a new tool for cell culture

Thermal energy storage via the latent heat of suitable phase change materials has the advantages of higher energy storage density and relatively isothermal behaviour compared to sensible heat storage systems. Glauber's salt (Na₂S0₄∙10H₂0) is one of the most extensively studied phase change materials for solar energy systems because of its low price, suitable phase change temperature and high latent heat. However, segregation due to incongruent melting behaviour leading to loss in the heat storage efficiency upon repeated melting-freezing cycling is a serious problem which has severely limited application of Glauber's salt. In this study Glauber's salt was encapsulated in 25 mm diameter hollow spheres and agitated in different systems including a liquid fluidized bed, rotating drum and rotating tube to reduce or eliminate the Toss in its heat storage efficiency. The encapsulated mixture consisted of 96% Glauber's salt and 4% borax by weight with 5% by volume air space in the capsules. Some capsules containing 25%, 15% and 5% by weight excess sodium sulfate and 10% by weight excess water were also prepared, to test the effect of sodium sulfate concentration under different agitation conditions. The heat storage capacity of 5756 capsules, agitated by fluidizing with water in a pilot plant size (0.34 m diameter) column, showed a decrease over the first three cycles to about 60% of that theoretically possible, but there was no further decrease over the next 93 cycles under fluidization conditions. The heat storage efficiency was found to be improved by increasing the superficial water velocity and by decreasing the cooling rate. Heating rate had little or no effect. The fluidized capsules provide enhanced heat transfer rates to or from the heat storage medium, enabling the energy to be charged or discharged in about one hour with realistic inlet and outlet temperatures. The high heat transfer rates are an important advantage for the system and may open new areas of applications for thermal energy storage by encapsulated phase change material. Economic analysis of the liquid fluidized bed heat storage system shows that operating costs are almost negligible compared to fixed capital costs. The heat storage efficiency of capsules decreased to 38.4% of the theoretical capacity or 67% of the corresponding agitated (fluidized) system in only 7 cycles under fixed bed conditions, and the efficiency decreased with further cycling. 97.5% of the original heat storage-capacity was recovered within three cycles when these capsules were refluidized. Performances of the regular and different composition capsules were tested in the rotating tube, with rotation around a fixed horizontal axis passing through the capsules' centers, and in the rotating drum, with impact due to collisions in addition to rotation. The results showed that full rotation of a capsule around a horizontal axis improves the heat storage efficiency. However, full recovery of the theoretical capacity was not possible, even under vigorous mixing conditions. The efficiencies in the rotating tube were similar to those in the rotating drum for capsules subject to the same number of rotations around a horizontal axis. At high rotation speeds centrifugal force had a negative influence, especially in the rotating tube. On the basis of heat storage capacity per unit volume or weight of phase change material, 47% by weight sodium sulfate concentration was found to be optimal for the rotating drum and the rotating tube cases. Some small scale experiments were performed to determine the relative importance of different factors in the loss of heat storage capacity. Sodium sulfate concentration gradients in the capsules with different thermal cycling histories were found by thermogravimetric analysis. The results showed that bulk segregation of anhydrous sodium sulfate is not the only reason for the loss of heat storage capacity in systems using Glauber's salt. Microencapsulation of anhydrous sodium sulfate beneath a layer of Glauber's salt crystals is at least as important. Experiments to determine the degree of subcooling, believed to be another factor in the loss of heat storage capacity, showed that a mixture of 96% Glauber's salt and 4% borax by weight undergoes subcooling of about 5 K in gently agitated capsules. Nucleation and crystallization temperatures both increase with increased agitation.
Applied Science, Faculty of
Chemical and Biological Engineering, Department of
Graduate

COORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR
CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO
Um dispositivo experimental foi desenvolvido para o estudo do superresfriamento da água em cápsulas cilíndricas visando sua utilização em processos de termoacumulação. A bancada experimental é constituída basicamente por: seção de teste, sistema de resfriamento, sistema de visualização, sistema de aquisição e armazenamento de dados. A temperatura do fluido externo, ou fluido de transferência (FT), uma solução aquosa de álcool a 50% por volume, foimantida constante por um banho de temperatura controlada durante cada teste. O trabalho foi dividido em quatro etapas. A primeira trata do estudo estatístico do super-resfriamento e da nucleação, em que foram utilizados 3 materiais distintos (alumínio, acrílico e PVC) para cápsulas de 30 e 80 mm de diâmetro com diferentes tipos de rugosidade, e diferentes temperaturas do FT. A segunda etapa investiga a Taxa de Resfriamento, parâmetro que quantifica a queda da temperatura e influencia fortemente o super-resfriamento e a nucleação. Na terceira etapa, foi estudada a influência da rugosidade da parede interna da cápsula. Nesta etapa, quatro cápsulas de alumínio distintas, com diferentes rugosidades, foram utilizadas. Finalmente, na quarta etapa foram realizadas visualizações do fenômeno de nucleação. Os resultados obtidos indicam que o material da cápsula (condutividade e rugosidade) e a temperatura do FT têm grande influência nos fenômenos de super-resfriamento e nucleação da água em cápsulas cilíndricas, afetando fortemente o processo de mudança de fase.
An experimental device was developed for the super-cooling water in cylindrical capsules study, seeking its use in term- accumulation processes. The experimental set is constituted basically by: test section, cooling system, visualization system, and data logger system. The temperature of the external fluid, or transfer fluid (FT), an alcohol aqueous solution with 50% per volume, it was maintained unchangeably with a bath controlled temperature during each test. The work was divided in four stages. The first one is about the statistical study of the super-cooling and nucleation, where 3 distinct materials were used (aluminum, acrylic and PVC) for capsules of 30 and 80 mm diameter, different roughness type, with different temperatures of FT. The second stage investigates the Cooling Rate, parameter that quantifies the falling of the temperature and it influences strongly the super-cooling and the nucleation process. In the third stage, the influence of the internal wall of the capsule was studied. In this stage, four different capsules of aluminum, with different roughness were used. Finally, in the fourth stage, visualizations of the nucleation phenomenon were accomplished. The obtained results indicate that the capsule material (conductivity and roughness) and the FT temperature has great influence in the phenomena of super-cooling and nucleation of the water in cylindrical capsules, affecting, strongly, the process of phase change.

Rapid depletion of energy resources has immensely affected the transportation industry, where the cargo transportation prices are going considerably high. Efforts have been made to develop newer economic and environmental friendly modes of cargo transportation. One such mode is the use of energy contained within fluids that flows in the pipelines for transportation of bulk solids. Bulk solids can be transported for long distances effectively in pipelines. Raw materials can be stored in spherical containers (commonly known as capsules) transported through the pipeline. For economical and efficient design of any transportation mode, both the local flow characteristics and the global performance parameters need to be investigated. Published literature is severely limited in establishing the effects of local flow features on system characteristics of Hydraulic Capsule Pipelines (HCPs). The present study focuses on using a well validated Computational Fluid Dynamics (CFD) based solver to numerically simulate capsule flow in HCPs for both onshore and offshore applications, including pipe bends. A novel numerical model has been employed in the present study with the aid of the dynamic mesh technique for calculating the pressure and the velocity variations within HCPs with respect to time. The numerical model for capsule flow yields realistic results for the global flow parameters as compared to the experimental data from the test rig developed for capsule flow in the present study. In order to develop knowledge base covering a wide range of HCPs operating conditions, both horizontal and vertical pipelines including bends have been considered for numerical analysis. The numerical analysis is supported by experimental investigations. After carrying out detailed numerical analysis at component-level, a system-level optimisation study has been carried out in order to optimally design HCPs based on Least-Cost Principle.

Ce travail a pour objectif l'encapsulation des solutions aqueuses, et en particulier de solutions d'agents ignifugeants phosphorés. Les matériaux conventionnels sont peu à peu remplacés par des polymères synthétiques grâce à leurs nombreuses propriétés (densité, mise en œuvre, ), mais la plupart de ces matériaux sont hautement inflammables. Or, l'ignifugation des polymères modifie profondément leurs propriétés. Nous avons donc décidé d'encapsuler des agents ignifugeants dans des nanosphères, de manière à d'une part, éviter les modifications des propriétés des polymères à ignifuger et d'autre part, protéger les agents ignifugeants des agressions extérieures, notamment des eaux de lavage. Nous avons étudié dans un premier temps la formation du cœur réservoir de polyacrylamide obtenu par les procédés de polymérisation en émulsion inverse et miniémulsion inverse, afin d'obtenir des semences permettant d'envisager l'étape d'encapsulation dans des conditions optimales. L'influence de différents paramètres a pu être mise en évidence (amorçage, stabilisation, procédé). Dans un deuxième temps, nous nous sommes concentrés sur la formation de l'écorce protectrice. Des particules originales cœur-écorce (cœur hydrophile - écorce hydrophobe) contenant un agent ignifugeant phosphoré hydrosoluble et présentant différentes morphologies, ont pu être élaborées. Cependant, le confinement du principe actif dans les nanosphères en présence d'eau est encore insuffisant.

Une capsule est une goutte de liquide enveloppée par une membrane fine et déformable. Les propriétés mécaniques de la membrane sont essentielles pour le mouvement de la capsule. L'analyse de l'écoulement d'une suspension de capsules dans un canal microfluidique au moyen d'un modèle mécanique est une technique permettant de déterminer les propriétés élastiques de la membrane. Un modèle numérique tridimensionnel a été développé pour résoudre ce problème d'interaction fluide-structure en écoulement confiné. Il couple une méthode des intégrales de frontières pour les écoulements des fluides et une méthode éléments finis pour la déformation de la membrane. Le modèle est utilisé pour étudier l'écoulement d'une capsule initialement sphérique dans des canaux de différentes sections. Dans un canal cylindrique, on montre que l'effet de confinement du canal conduit à la compression de la capsule. Cela engendre la formation de plis sur la membrane autour de l'axe de l'écoulement, phénomène également observé expérimentalement. Dans un canal de section carrée, les effets de la loi constitutive de la membrane, du rapport de taille et du débit d'écoulement sur la déformation de la capsule sont systématiquement étudiés. La comparaison entre les résultats expérimentaux et numériques nous permet de déduire les propriétés mécaniques de la membrane d'une population de capsules artificielles. Ce travail démontre la faisabilité de la mesure de propriétés mécaniques d'une membrane en utilisant une technique microfluidique en canal carré. Il pourrait être étendu par l'étude d'écoulements instationnaires dans un canal de section variable ou avec bifurcations.