This thesis present a study of thermo-gelling polycaprolactone (PCL) dispersion which consist of a mixture of PCL microspheres (MSs) and thermo-responsive, graft cationic copolymer. The PCL microspheres are solid or colloidosomes (hollow). This study aims toward an injectable colloidal cell delivery system. The thermo-responsive copolymer used in this study is a new family of cationic graft copolymer. The cationic graft copolymer consisted of cationic poly(N,N-dimethylaminoethyl methacrylate) backbone and poly 2-(2-methoxyethoxy) ethyl methacrylate (PMA) side chains. A series of new cationic graft copolymers were synthesized with different PMA arm length and grafting density. A representative copolymer showed good cell viabililty. The solid PCL MSs were prepared using solvent evaporation method. The MSs were mixed with the thermo-responsive graft copolymer. At room temperature the mixture were liquid-like and gelled at body temperature (37 ˚C). This indicates that the mixture systems were injectable. The injectable route offers a minimal invasive route to fill defect void inside the body. Furthermore, a porous morphology was evident for the mixed gels at 37 ˚C and the porosity could be altered using different composition of the mixed components. The mixed system showed self-healing properties for low volume fraction of PMA. The mixed system particle gel was more ductile in electrolyte but showed similar morphology to the mixed system particle gels prepared in water. This part of the study was carried out using PCL MSs prepared by cetyltrimethylammonium bromide (CTAB) as surfactant. A brief study using polyvinyl alcohol (PVA) as the surfactant showed that the PCL MSs had similar diameter and gel morphology which suggests that the model systems studied using CTAB may be applicable to the PVA system. Microencapsulation attracts interest due to its ability to deliver and control release actives and also its application in many fields. Colloidosomes are one of the microcapsules/microspheres used for microencapsulation. In this study a two step, facile and scaleable colloidosome preparation method was introduced. The PCL colloidosome shell consisted of partially fused small nanoparticles. The PCL colloidosomes were birefringence under cross polarised light due to the stress applied during solvent evaporation. A brief study showed that the mixture system of colloidosomes and thermo-responsive graft copolymer are able to gel at 37 ˚C.

Orientador: Maria Isabel Felisberti / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T10:33:06Z (GMT). No. of bitstreams: 1 Almeida_Paulade_M.pdf: 6180977 bytes, checksum: f368e755fcabe313d658156fe84a828e (MD5) Previous issue date: 2015 / Resumo: Neste trabalho foram sintetizados copolímeros anfifílicos e em bloco baseados em metacrilato de sacarose (SMA) e nos metacrilatos de alquila (MAlq): metacrilato de etila (EMA), metacrilato de n-butila (BMA) e metacrilato de n-hexila (HMA), via polimerização radicalar por transferência de átomo (ATRP). Para tal, utilizou-se o sistema catalítico catalisador/desativador/iniciador/ligante constituído de CuBr/CuBr2/2,2,2-tribromoetanol/1,1,4,7,10,10-hexametiltrietilenotetramina. Este sistema catalítico é inédito para a polimerização do EMA, BMA e HMA e dos copolímeros. A polimerização dos MAlq pode ser considerada viva, pois seguiu cinética de polimerização de pseudo-primeira ordem, gerando-se polímeros com polidispersidade estreita (PDI<1,3), massa molar pré-determinada e funcionalizados. A constante de velocidade de polimerização segue a ordem kEMA>kBMA>kHMA, ordem inversa do relatado para a polimerização radicalar livre. Os copolímeros inéditos [P(MAlq-b-SMA)] foram sintetizados, apresentando distribuição bimodal de massa molar, devido à copolimerização parcial dos macroiniciadores. Supõe-se que as cadeias dos macroiniciadores fiquem encapsuladas em agregados dos copolímeros durante a síntese, impossibilitando sua reação. As análises de GPC utilizando os solventes DMF e THF para um mesmo copolímero resultaram em massas molares diferindo entre si de cerca de 10 vezes, sugerindo que os copolímeros se agregam ou se auto-organizam em solução de DMF/THF a 5DMF:95THF (v/v). O caráter anfifílico foi comprovado pela estabilização de uma emulsão de água e benzeno. Demais propriedades físico-químicas dos copolímeros, tais como solubilidade, intumescimento, temperatura de transição vítrea, variação da capacidade calorífica e estabilidade térmica, são distintas a dos respectivos macroiniciadores, evidenciando as mudanças de propriedades dos polímeros devido à inserção de SMA / Abstract: In the present work, amphiphilic block copolymers based on sucrose methacrylate (SMA) and the alkyl methacrylates (MAlq): ethyl methacrylate (EMA), n-butyl methacrylate (BMA) and n-hexyl methacrylate (HMA), were synthesized by atom transfer radical polymerization (ATRP), employing the CuBr/CuBr2/2,2,2-tribromoethanol/1,1,4,7,10,10-hexamethyltriethylenetetramine as a catalyst/ deactivator/initiator/ligant system. This is a novel system for polymerizing EMA, BMA, HMA and their copolymers. This MAlq polymerization may be considered "living", because it followed a pseudo-first order kinetics, which resulted in polymer with narrow polidispersity (PDI<1,3), controlled molar mass and preserved chain end functionality. The apparent rate constants of the polymerization were found to follow the kEMA>kBMA>kHMA order, which is the opposite order reported in free radical polymerization. The novel copolymers [P(MAlq-b-SMA)] were synthesized, showing bimodal molar mass distribution, due to partial PMAlq copolymerization. Possibly, PMAlq chains are encapsulated into copolymer aggregates during polymerization, stopping its reaction. GPC analysis with DMF and THF as solvents differed in molar mass about 10 times, suggesting that copolymers can organize in a 5DMF:95THF (v/v) DMF/THF solution. The stabilization of a water and benzene emulsion proved the copolymers amphiphilicity. Other copolymer physical-chemistry properties, such as solubility, swelling, glass transition temperature, heat capacity change and thermal stability are different when compared to the macroinitiators, which is an evidence of change in polymer properties due to SMA monomer insertion. / Mestrado / Físico-Química / Mestra em Química

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An efficient delivery system and patient compliance are two of the most important factors for any drug delivery system design to be successful. The current standard, particularly to the ocular anterior segment, are topical applications including eye drops. However, due to ocular physical barriers including blinking, the varying tear film layers, and the structure of the corneal epithelium, less that 5% of drug reach the target tissue from a single eye drop dose. While most treatment regiments combat this with increased frequency of dosage and higher than needed concentrations, the need for a more efficient and controlled system has been recognized to reduce the risk of possible side effects. Contact lenses (CL) have been a widely discussed potential drug delivery device given their accepted use in the population, their ability to hold drug, as well as their placement on the ocular surface. The current work focuses on testing a novel delivery system using CLs with the incorporation of drug specific oligonucleotide chains known as aptamers on the surface of the lenses. This application of contact lenses is aimed at capitalizing on the strong affinity of aptamers to hold drug on the surface of the lenses until they are applied to the eyes. The aptamers were covalently attached to the surface via the activation of the hydroxyl groups on pHEMA as a model lens material using 1’1-carbonyldiimidazone CDI chemistry and subsequent reaction with the amine group on the 5' end of the aptamer. The presence of aptamers was confirmed using 6-carbofluorescein (6-FAM) fluorescence detection and x-ray photoelectron spectroscopy (XPS). The release of kanamycin B in comparison to regular pHEMA gels using a soaking uptake method was assessed. In this work, aptamers were confirmed through fluorescence to have been successfully reacted onto the surface, however XPS was not able to confirm a consistent reading. This may have been due to low initial amounts of aptamer or uneven distributions along the surface. The efficiency of the aptamer reaction was not tested and would need to be further investigated. The contact angle had a significant change with increased hydrophilicity at 60.7 ± 1.55° compared to 66.6 ± 0.67°, however physically it should not affect wettability. The lower aptamer amounts resulted in no significant difference during drug release. Kanamycin B was detected using liquid chromatography mass spectroscopy (LCMS) with a reverse phase method using a C18 column however quite a few errors in the methodology led to the conclusion that this method of drug release requires further investigation. It is recommended an aptamer-surface reaction efficiency be determined with the use of a much larger starting aptamer amount, as well as a follow up drug release. / Thesis / Master of Applied Science (MASc)

Les polymères synthétiques sont largement utilisés aujourd’hui comme implants prothétiques. Malheureusement, ces implants sont invisibles en imagerie par résonance magnétique IRM. La visualisation de ces implants est une nécessité afin d'obtenir des informations concernant leur fixation dans le corps et leur situation post-opératoire.Un des défis est alors de fixer un agent de contraste sur l'implant médical. Pour cet objectif, un premier polymère va être fonctionnalisé avec un agent de contraste de manière covalente, puis on le dépose par enduction sur la surface de la prothèse. Les polymères seront fonctionnalisés par polymérisation radicalaire et par chimie "click". Dans une première étape, le poly(méthacrylate de méthyle-co-méthacrylate de propargyle) avec un faible rapport molaire en méthacrylate de propargyle (F <10%) est préparé par copolymérisation radicalaire du méthacrylate de méthyle et du méthacrylate de propargyle. Dans une deuxième étape, l'agent de contraste sera greffé avec par réaction de chimie « click » sur le poly(méthacrylate de méthyle) porteur de fonctions propargyles (PMMA-co-PMA). Sur ce squelette polymérique, un nouveau agent de contraste à base de gadolinium sera greffé. Le polymère obtenu sera déposé sur une maille de polypropylene commercial par la technique de l'aérographie et la maille sera évaluée pour l'IRM visualisation sur un7T instrument. Des tests de cytotoxicité et de cytocompatibilité seront effectuées pour évaluer l'utilisation de cet agent de contraste dans des applications biomédicales.En même temps, les techniques d'imagerie de fluorescence gagnent aussi en popularité . Pour cela, le même polymère synthétisé (PMMA–co-PMA) sera fonctionnalisé avec différents précurseurs fluorescents: anthracène , fluorescéine, complexe d’europium. / Synthetic polymers are widely used nowadays as prosthetic implants. Unfortunately, these implants are invsisble by magnetic resonance imaging (MRI). The visualization of these implants is a necessity in order to gain information concerning their fixation in the body and post-operation fate. One of the challenges is then to fix a contrast agent on the implant. Thus the objective is to develop novel strategies for the long-term visualization of prosthetic implants by MRI. For this goal, a polymer will first be functionalized with a contrast agent in a covalent way, and then it will be deposited by coating on the surface of the prosthesis. Polymers will be functionalized by free radical polymerization followed by “click chemistry. In a first step, poly(methyl methacrylate-co-propargyl methacrylate) with low molar ratio in propargyl methacrylate (F< 10 %) will be prepared by free radical copolymerization of methyl methacrylate with propargyl methacrylate. In a second step, a novel gadolinium based contrast agent will be grafted by click chemistry onto the propargylated poly(methyl methacrylate) (PMMA-co-PMA) polymer. The obtained polymeric contrast agent will be spread on a commercial polypropylene mesh by the airbrushing technique and the mesh will be assessed for MRI visualization on a 7T instrument. Cytocompatibility and cytotoxicity tests will be performed to evaluate the use of this contrast agent in biomedical applications.At the same time, fluorescence imaging techniques are also gaining popularity. For this, the same synthesized polymer (PMMA-co-PMA) will be attached to different fluorescent precursors: anthracene, fluoresceine, and europium complex.

Orientador: Leila Peres / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Química / Made available in DSpace on 2018-08-26T22:00:36Z (GMT). No. of bitstreams: 1 Lucente_AnaGlauciaBogalhos_D.pdf: 2114033 bytes, checksum: ddc1d7f9bcfcce3f7ddfd258b22465d3 (MD5) Previous issue date: 2015 / Resumo: A falta de um material que viabilize a confecção de uma prótese dentária em um menor número de etapas, economizando tempo e facilitando a vida dos pacientes foi a maior motivação para o desenvolvimento desta tese que se baseia na patente BR n. PI 0602107-7 A: Conjuntos de arcos dentais pré-fabricados, flexíveis e com dentes ajustáveis obtida pelo grupo de pesquisa onde se insere este trabalho, em que se propõe o uso do arco dental flexível pré-fabricado na confecção da prótese, que poderá ser produzida em um menor tempo, com um menor custo. O material usado para o arco dental flexível pré-fabricado por energia de micro ondas, bem como para a prótese dental final deverá conter uma base polimérica que permitirá a flexibilidade inicial do arco, que após receber ajustes na posição dos dentes, adequados a cada paciente, será incorporado à prótese final, sendo o conjunto reticulado de forma simultânea. Para tanto, foi investigada a viabilidade do uso do copolímero de metacrilato de metila-n-metacrilato de butila (PMMA-co-PBMA), sintetizado via técnica de miniemulsão, como a matriz polimérica base para a confecção de arcos dentais pré-fabricados, flexíveis e com dentes ajustáveis e da prótese final. Na síntese do copolímero pretendido, foram estudadas as características dos iniciadores, surfactante, estabilizador e temperatura de reação sobre a distribuição volumétrica (Dv) e populacional (DSD) de tamanhos de partícula, conversão global, temperatura de transição vítrea (Tg), massa molar média ponderal (Mw), massa molar média numérica (Mn) e polidispersividade (Mw/Mn). Verificou-se a influência da solubilidade dos iniciadores em baixas temperaturas na conversão global, Dv e DSD, fator que não interfere em altas temperaturas. Além das análises de Tg, Mw e Mw/Mn dos copolímeros e homopolímeros obtidos por mecanismo de adição. Realizaram-se também análises de Ressonância Magnética Nuclear (RMN) e Espectroscopia no Infravermelho com Transformada de Fourrier (FT-IR) indicando que o copolímero foi formado na configuração alternada ou aleatória. A resina formulada a partir do copolímero sintetizado para uso no arco dental pré-fabricado foi caracterizado, a partir de ensaios de resistência à flexão, microdureza, módulo de elasticidade, coeficiente de Poisson, da Tg do material e monômero residual. Os resultados mostram um material compatível com resinas comerciais em relação à microdureza e módulo de elasticidade / Abstract: The lack of a material that enables the production of a dental prosthesis in fewer steps, saving time and making life easier for the patients was the major motivation for developing this thesis is based on the patent BR n. PI 0602107-7 A: Sets of prefabricated dental arches, flexible and adjustable teeth obtained by the research group which includes this work, it is proposed the use of prefabricated flexible dental arch in the making of the prosthesis, which can be produced in less time, with less cost. The material used for the flexible prefabricated dental arch by microwave energy and for the final dental prosthesis should contain a polymer base which will allow the initial flexibility of the arch, after receiving adjustments to the position of the teeth, adequate to each patient will be incorporated into the final prosthesis being crosslinked together simultaneously. Therefore, it was investigated the feasibility of using n-butyl methyl methacrylate-methacrylate copolymer (PMMA-co-PBMA) synthesized via miniemulsion technique as the base polymer matrix for the manufacture of prefabricated dental arches, flexible and adjustable teeth and the final prosthesis. In the synthesis of the desired copolymer characteristics of primers were studied, surfactant, stabilizer and reaction temperature on the size distribution (Dv) and population (DSD) particle size, overall conversion, glass transition temperature (Tg), mass-average molecular weight (Mw), number-average molecular weight (Mn) and polydispersity (Mw/Mn). It has been found to influence the solubility of the initiators at low temperatures in the overall conversion, Dv and DSD factor that does not interfere at high temperatures. In addition to the analyzes Tg, Mw and Mw / Mn of the copolymers and homopolymers obtained by adding mechanism. Nuclear Magnetic Resonance analysis (NMR) spectroscopy and Fourier transform infrared (FT-IR) were also performed indicating that the copolymer was formed in alternating or random configuration. The resin made from copolymer synthesized for use in prefabricated dental arch was characterized as bending strength tests, hardness, modulus of elasticity, Poisson's ratio, the Tg of the material and residual monomer. The results show a material similar to commercial resins with regard to hardness and modulus of elasticity / Doutorado / Ciencia e Tecnologia de Materiais / Doutora em Engenharia Quimica

Dans ce travail, nous avons cherché à mettre en évidence l'influence de la méthode de préparation de films minces de polymère pour la biofonctionnalisation de surfaces planes. Dans un premier temps, un polymère réactif, le poly(méthacrylate de glycidyle) p(GMA) a été choisi et sa capacité de fixation vis-à-vis d'une biomolécule modèle l'albumine de sérum bovin a été étudiée. Deux stratégies principales de préparation du film polymère ont été utilisées : la technique du grafting onto et celle du grafting from avec deux voies de synthèse : la polymérisation radicalaire classique (PRC) avec l'amorceur en solution et la polymérisation initiée à partir de la surface avec un amorceur photochimique. Il a été montré que la méthode du « grafting from » permettait l'obtention de films d'épaisseur plus élevées que la technique du « grafting onto » avec une meilleure capacité de fixation de biomolécules de BSA. Ces films de p(GMA) se sont révélés relativement hydrophobes, ce qui nous incités à analyser l'influence de la balance hydrophobe/hydrophile des interfaces sur leurs propriétés, dans un second temps. Par la préparation de films copolymères poly(GMA-co-acrylamide) et poly(GMA-co-méthacrylate de glycérol) et la modification des films de poly(GMA) par de l'éthanolamine, l'influence de l'hydrophilie du film sur la capacité de fixation en molécules de BSA et l'activité de reconnaissance moléculaire de celles-ci ont été évaluées. Il a été démontré que par un choix judicieux de la méthode d'hydrophilisation du film polymère, il est possible de réduire considérablement l'adsorption non-spécifique de biomolécules d'où l'obtention de films polymères bioinertes. De plus, les résultats préliminaires ont montré qu'il est possible d'améliorer sensiblement la capacité de reconnaissance moléculaire entre la BSA et son anticorps l'anti-BSA / It is now well accepted that polymeric spacers permit to attach proteins to surfaces efficiently as they carry several binding sites. Moreover, direct attachment of proteins to surfaces might result in the decrease of bioactivity which is critical in the case of the development of biosensors. In this context, we modified gold substrates by polymer grafts via the so-called (i) grafting onto and (ii) grafting from strategies. In (i) preformed polymer chains were attached to the surface, whilst in (ii) surface-confined photopolymerization was performed on either acrylic monomer- or initiator-functionalized gold substrates. The polymer grafts were further biofunctionalized by covalent immobilization of an active protein (bovine serum albumin, BSA). Given the protein-polymer and polymer-gold covalent bonds, the gold/polymer/BSA hybrids permitted to design robust optical biosensors. The modified gold substrates were characterized in terms of chemical composition (X-ray photoelectron spectroscopy), hydrophobicity (contact angle measurements), and polymer coating thickness (surface plasmon resonance, SPR). SPR was also used to monitor in real time the interaction between the grafted antigen to the specific antibody (aBSA). Using unique reactive monomer, glycidyl methacrylate (GMA) in the present case, the implementation of these three methods is assumed to provide polymer films of similar chemical composition but varied interfacial chains conformation. In this respect, influence of polymer chains mobility on the performance of the immunosensing reaction was evaluated. In a further step, hydrophobic/hydrophilic balance of the polymer films was modulated through copolymerization of GMA with acrylamide, and with glycerol methacrylate. It was demonstrated that control over the surface chemical composition of the polymer grafts allows preparing bioinert films, i.e. resistant to non specific adsorption, with enhanced biospecific activity

Due to sensor -tissue interactions, currently none of the commercially available glucose sensors are capable of continuous, reliable monitoring of glucose levels during long-term implantation. In order to improve the lifetime of implanted glucose sensors, two series of biocompatible novel hydrogel coatings were designed, synthesized and the physical properties were measured. Different hydrogels with various 2,3-dihydroxypropyl methacrylate (DHPMA) compositions were coated onto glucose sensors. Results show that the higher freezable water content, swelling rate and uniform porosity that resulted from high DHPMA content increased the sensitivity and shortened the response time of glucose sensors. The linear range of a glucose sensor coated only with hydrogel is short, however, the range can be improved by coating the epoxy- polyurethane (PU) with a layer of hydrogel. Since the hydrogel minimizes the fibrosis and inflammation, it shows promise for use in implantable glucose sensors. However, the in vivo experiment shows only 25% of sensors still worked after 4 weeks. In order to overcome problems present in the first series of experiments, another series of novel hydrogels with various N-vinyl pyrolidone (VP) contents was developed. This study has provided a feasible approach to design and select the properties of the copolymer for coating implantable biosensors. The in vivo experiments demonstrate that a hydrogel coating significantly improved the performance of implanted glucose sensors. In order to suppress the acute inflammation caused by the surgery, dexamethasone-21 phosphate disodium salt (DX-21) was incorporated to a series of poly (HEMA-DHPMA-VP) hydrogels to investigate the drug delivery in vitro. All hydrogels showed a high initial release, followed by slow, long term release during the next hours to days. This release pattern is believed to be optimum for implanted glucose sensors suppressing the acute and chronic inflammation. Water structures in hydrogels swollen in different media water, PBS and DX-21 solution were also investigated. 1HEMA:1DHPMA copolymer and VP-HEMA-DHPMA copolymers imbibed higher freezable water fractions in DX-21 solution. The ratio of transporting water mass to DX-21 mass is 9.6 which is independent of the hydrogel composition.