Titanium bone plates and screws are commonly used in oral and maxillofacial surgery for internal fixation. Although titanium plate is good for fixation of bone fractures, there are still somemany disadvantages of the material. Biodegradable materials are considered to be good alternatives for treatment of the facial bone fractures. Poor wound healing in diabetic animals and human was well known. The aims of the studies were to compare the strength and tissue reaction of the poly lactic-co-glycolic acid ¡]PLGA¡^ with titanium plates used as fixation material in fractured-femora of diabetic and normal animals. The results of the studies show that the wounds of the control group healed quite well and there was no discharge around the wound. However, bullas formation was found in all the diabetic wounds fixed with PLGA. There was fistula with pus and gas discharge around the bullas. In the control group, the diameter of the PLGA-fixed femur was larger than the titanium-fixed femura. There was a large amount of callus formation around the PLGA-fixed fracture femur. At the 20th day, the defects of both groups of the PLGA treated were not healed. A large amount of new bone formation in normal titanium-treated rats was found, while in diabetic rats, mainly a fibrous tissue reaction. At the 40th day, the diabetic PLGA-fixed femora were poorly healed with a large amount of fibrous tissue. Similarly, after 40 days in the titanium-fixed femora of diabetic rats, extensive fibrosis of the defect was also present. In normal PLGA-fixed fractured femora, there was a large amount of cartilage present around the defect. Most of the normal PLGA-fixed fractured femora were distorted in shape. At the 40th day, lamellar bone formation was found around the screw in normal titanium-fixed femora and the defect was healed. In conclusion, the PLGA plate is not suitable for fixation in the fractured-femora of the rats in either normal or diabetic groups when compared with those from titanium plate treat groups. It is because of less strength of the PLGA plate and the material easily cause tissue reaction in the rat which result in the formation of large amount of fibrous tissue around the PLGA screw instead of bone.

Os grandes desafios da medicina contemporânea destacam a necessidade de uma intensa pesquisa para desenvolver novos tratamentos para muitas doenças crônicas, tais como as reumáticas, que sejam efetivos, seguros e com qualidade. Uma das novas ferramentas para o desenvolvimento de novos medicamentos é a nanotecnologia, a qual nos últimos anos tem aumentado a sua aplicação na área farmacêutica contemplando um crescente otimismo acerca do seu potencial uso para obter melhores oportunidades de diagnóstico e de terapias mais eficazes. No presente trabalho foram encapsulados dois antiinflamatórios em sistemas nanoparticulados, nanoesferas de acido poli-láctico co-glicólico (PLGA), a técnica utilizada permitiu a encapsulação de compostos hidrofílicos e hidrofóbicos na mesma nanopartícula polimérica, diclofenaco de sódio (DS) e dexametasona (DX), respectivamente, obtendo nanopartículas com potencial para o tratamento de doenças inflamatórias crônicas. Para o desenvolvimento das nanoesferas se utilizou a técnica de emulsão/evaporação do solvente. As nanoesferas foram caraterizadas por microscopia eletrônica de varredura (SEM), microscopia eletrônica de transmissão (TEM), medição do pH, medição do tamanho de partícula, potencial zeta e polidisversividade e espectroscopia vibracional de infravermelho (IR). A eficiência de encapsulação (EE) dos fármacos (diclofenaco de sódio e dexametasona) nas nanoesferas foi realizada pelas técnicas analíticas, cromatografia líquida de alta eficiência (HPLC) e eletroforese capilar (CE), previamente validadas. Na melhor formulação foi obtida encapsulação de 51,4 ± 5,5 % para o diclofenaco e 66,9 ± 8,4 para a dexametasona. / The great challenges of contemporary medicine emphasize the need for intensive research to develop new treatments for many chronic diseases, such as the rheumatic, to be effective, safe and of good quality. One of the new tools for the development of new drugs is the nanotechnology, which in recent years has increased its application in the pharmaceutical area contemplating a growing optimism about its potential use to get better opportunities for diagnosis and more effective therapies. In the present work were encapsulated two anti-inflammatories in nanoparticulate systems, nanospheres poly-lactic co-glycolic acid (PLGA), the technique used allows the encapsulation of hydrophilic and hydrophobic compounds in the same polymer nanoparticle, diclofenac sodium (DS) and dexamethasone (DX), respectively, obtaining nanoparticles with potential for the treatment of chronic inflammatory diseases. For the development of nanospheres the technique used was emulsion / solvent evaporation. The nanospheres were characterized by zeta potential infrared, particle size, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and pH. The encapsulation of the drug (diclofenac sodium and dexamethasone) in the nanospheres was performed by previously validated analytical techniques high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). In the best formulation was achieved encapsulation 51.4 ± 5.5% for diclofenac and 66.9 ± 8.4 for dexamethasone

Os grandes desafios da medicina contemporânea destacam a necessidade de uma intensa pesquisa para desenvolver novos tratamentos para muitas doenças crônicas, tais como as reumáticas, que sejam efetivos, seguros e com qualidade. Uma das novas ferramentas para o desenvolvimento de novos medicamentos é a nanotecnologia, a qual nos últimos anos tem aumentado a sua aplicação na área farmacêutica contemplando um crescente otimismo acerca do seu potencial uso para obter melhores oportunidades de diagnóstico e de terapias mais eficazes. No presente trabalho foram encapsulados dois antiinflamatórios em sistemas nanoparticulados, nanoesferas de acido poli-láctico co-glicólico (PLGA), a técnica utilizada permitiu a encapsulação de compostos hidrofílicos e hidrofóbicos na mesma nanopartícula polimérica, diclofenaco de sódio (DS) e dexametasona (DX), respectivamente, obtendo nanopartículas com potencial para o tratamento de doenças inflamatórias crônicas. Para o desenvolvimento das nanoesferas se utilizou a técnica de emulsão/evaporação do solvente. As nanoesferas foram caraterizadas por microscopia eletrônica de varredura (SEM), microscopia eletrônica de transmissão (TEM), medição do pH, medição do tamanho de partícula, potencial zeta e polidisversividade e espectroscopia vibracional de infravermelho (IR). A eficiência de encapsulação (EE) dos fármacos (diclofenaco de sódio e dexametasona) nas nanoesferas foi realizada pelas técnicas analíticas, cromatografia líquida de alta eficiência (HPLC) e eletroforese capilar (CE), previamente validadas. Na melhor formulação foi obtida encapsulação de 51,4 ± 5,5 % para o diclofenaco e 66,9 ± 8,4 para a dexametasona. / The great challenges of contemporary medicine emphasize the need for intensive research to develop new treatments for many chronic diseases, such as the rheumatic, to be effective, safe and of good quality. One of the new tools for the development of new drugs is the nanotechnology, which in recent years has increased its application in the pharmaceutical area contemplating a growing optimism about its potential use to get better opportunities for diagnosis and more effective therapies. In the present work were encapsulated two anti-inflammatories in nanoparticulate systems, nanospheres poly-lactic co-glycolic acid (PLGA), the technique used allows the encapsulation of hydrophilic and hydrophobic compounds in the same polymer nanoparticle, diclofenac sodium (DS) and dexamethasone (DX), respectively, obtaining nanoparticles with potential for the treatment of chronic inflammatory diseases. For the development of nanospheres the technique used was emulsion / solvent evaporation. The nanospheres were characterized by zeta potential infrared, particle size, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and pH. The encapsulation of the drug (diclofenac sodium and dexamethasone) in the nanospheres was performed by previously validated analytical techniques high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). In the best formulation was achieved encapsulation 51.4 ± 5.5% for diclofenac and 66.9 ± 8.4 for dexamethasone

The aim of this thesis was to develop biodegradable devices loaded with chemotherapy drug. The system is targeted for advanced ovarian cancer treatment through the intraperitoneal (IP) route of administration. Polylactide-co-glycolide (PLGA) was selected as the model biodegradable polymer to produce drug-loaded microsphere, hollow and solid fibres. Copolymer PLGA with three different lactic:glycolic acids ratios; 50:50, 65:35 and 75:25 were used in order to compare their drug loading capacities and in vitro drug release profiles. Cisplatin, a cytotoxic drug with proven activity against ovarian cancer was selected as the model chemotherapy drug. Intraperitoneal administration is often associated with abdominal pain therefore a local anaesthetic, lidocaine, was selected for the purpose of pain relief.

O desenvolvimento de scaffolds para a aplicação em biomateriais, seja na produção de tecidos biomiméticos ou mesmo em sistemas para liberação de drogas, tem sido fundamental tanto para o entendimento dos mecanismos de crescimento de tecidos biológicos e seu funcionamento, quanto para o desenvolvimento de biomateriais que possam ser incorporados aos tecidos naturais para seu reparo e para a efetiva aplicação de agentes terapêuticos. Dentre as várias técnicas para a produção destes scaffolds, a técnica de Electrospinning (ES) foi utilizada neste trabalho para a confecção de scaffolds poliméricos com a incorporação moléculas de interesse biotecnológico. Foram produzidos scaffolds e scaffolds compósitos pela adição de nanopartículas de óxido de cério, nanoargila haloisita e protoporfirina IX complexada à nanoargila haloisita, os quais foram estudados quanto à sua morfologia e propriedades tênseis, além de terem sidos testados quanto a sua viabilidade como sistemas biomiméticos de tecidos. Os scaffolds compósitos mostraram um ganho em ordenamento e homogeneidade, e os scaffolds compósitos contendo óxido de cério mostraram um leve aumento em sua capacidade elástica, além de terem sido viáveis para o crescimento de células HCat / The development of scaffolds for biomaterials applications, in biomimetic tissues production and drug-delivery systems, have been a fundamental tool for the understanding of biological tissues growing and repair mechanisms and for the development of biomaterials that can be incorporated to the natural tissues for both repair and effective application of therapeutic agents. Amongst the several techniques for scaffolds production, the Electrospinning (ES) methodology was applied in this work for developing polymeric scaffolds with the encapsulation of molecules of biotechnological interest. Scaffolds and blend scaffolds by cerium oxide nanoparticles and haloisite nanoclay addiction were produced and studied regarding its morphology, tensile properties and cell viability as biomimetic tissues. The blend scaffolds shoed an enhancement in order and homogeneity, and those within cerium oxide showed also an increase in elastic capacity and viable physical base for HCat cells

Esta tese envolveu o estudo de encapsulação de vacina bivalente contra difteria e tétano de uso adulto (dT) em microesferas de ácido poli(láctico-coglicólico) (PLGA), com o objetivo de desenvolver uma formulação que induzisse uma resposta protetora com um número reduzido de doses, ou preferencialmente de apenas uma dose. Para ter sucesso, uma formulação como tal deve ter um perfil de liberação de antígeno que simule as múltiplas doses que recebem o indivíduo. Assim, nesta tese são mostrados os resultados dos experimentos de caracterização bioquímica e imunológica da formulação citada, sem o uso de estabilizadores protéicos, a fim de reduzir a complexidade do sistema em estudo. Do ponto de vista das proteínas encapsuladas, tal caracterização envolveu estudos de fluorescência, de dicroísmo circular, de atividade antigênica e determinação por HPLC da degradação durante o processo de encapsulação. Do ponto de vista da formulação, foram realizados ensaios de degradação in vitro e de atividade imunogênica in vivo, em camundongos e cobaias. Os dados obtidos indicaram que a encapsulação em microesferas de PLGA de vacina dT, sem o uso de estabilizadores, permitiu a produção de uma formulação vacinal viável, capaz de estimular uma resposta imunológica protetora e de memória, abrindo caminho para o desenvolvimento da tecnologia de produção de vacinas polivalentes encapsuladas em microesferas de PLGA. / The study on encapsulating a bivalent single dose vaccine against diphtheria and tetanus for adults (dT) within PLGA microspheres is described in this thesis. A successful single dose vaccine must show an antigen release profile mimicking the several doses a person should receive during the life. Therefore, results from the immunological and biochemical characterization of the formulation, prepared without protein stabilizers, is showed here. From the encapsulated protein point of view the characterization involved fluorescence, circular dichroism, antigenicity and HPLC analysis. From the formulation point of view, there were performed in vitro release assays and immunogenicity on mice and on guinea-pigs. The results indicated that the dT microencapsulation within PLGA microspheres without protein stabilizers lead to the production of a viable vaccine formulation, able to elicit protective and memory immune response.

Made available in DSpace on 2014-07-29T16:11:51Z (GMT). No. of bitstreams: 1 Luciano Aparecido Stecanella.pdf: 1386754 bytes, checksum: 98d171bf870e6a2ec50ece485d0e203b (MD5) Previous issue date: 2011-12-23 / Grandisin, a tetrahydrofuranic lignan produced by Virola surinamensis seeds and leaves, is popularly used to treat erysipelas, colic and dyspepsia, and is active against Schistosoma mansoni, Plasmodium falciparum, Leishmania donovani and Trypanosoma cruzi. It also antinociceptive, anti-inflamatory and potential for protective (dose dependent) activities, preventing cyclophosphamide induced chromosomal fragmentation, being considered a potencial anti-cancer candidate. The encapsulation of grandisin in polymeric nanocapsules can increase its solubility in aqueous media, allowing drug administration by intravenous route. In the presente work, polymeric nanocapsules containing grandisin were produced by nanoprecipitation method (or interfacial pre-formed polymer deposition). The average diameter of these nanocapsules were around 160 nm, PdI < 0,2, zeta potential -15,73 mV and grandisin load of 6,54%, with encapsulation efficiency of (EE%) 98%. Stability study, comprising 30 days under refrigeration (4ºC ± 1ºC), showed that physicochemical characteristics of the formulation (color, bluish translucency, etc.) were the same as compared to the nanocapsules dispersion originally produced, so there were no alterations such as deposition of residues and/or crystals, lumps formation, creamming or supernatant oil, droplets adhered to the glass, flocculation or phase separation. Regarding encapsulated grandisin, during stability test, there was a reduction of 6,4% of the total encapsulated drug. Drug release study showed quick liberation in the first 48h (30,54%) and then kept slower, because only 52% after 21 days. Polymeric nanocapsules containing grandisin, obtained in this work, showed potential to be a drug release system to administration by intravenous route. / A grandisina, uma neolignana tetraidrofurânica obtida das sementes e folhas da planta Virola surinamensis, é popularmente utilizada no tratamento de erisipelas, cólicas e dispepsias, e possui ação comprovada contra Schistosoma mansoni, Plasmodium falciparum, Leishmania donovani e Trypanosoma cruzi. Apresenta também atividade antinociceptiva, anti-inflamatória e potencial ação quimioprotetora (dose dependente), prevenindo a fragmentação cromossômica induzida pela ciclofosfamida, sendo assim considerada potencial candidata a agente anti-câncer. A encapsulação da grandisina em nanocápsulas poliméricas pode aumentar sua solubilidade em meio aquoso, consequentemente, permitindo sua administração por via intravenosa. No presente trabalho foram produzidas nanocápsulas poliméricas contendo grandisina pelo método de nanoprecipitação (ou deposição interfacial de polímero pré-formado). Estas nanocápsulas apresentaram diâmetro médio em torno de 160 nm, PdI < 0,2, potencial zeta de 15,73 mV e carga de grandisina de 6,54%, com eficiência de encapsulação (EE%) de 98%. O estudo de estabilidade, realizado por um período de 30 dias sob refrigeração (4ºC ± 1ºC), mostrou que as características físicas da formulação (coloração, translucência azulada, etc.) foram mantidas em relação à dispersão de nanocápsulas originalmente produzida, não sendo observadas alterações como deposição de resíduos e/ou cristais, formação de grumos, cremagem ou nata sobrenadante, gotículas de óleo aderidas ao vidro, floculação ou separação de fases. Com relação à grandisina encapsulada, durante o estudo de estabilidade, foi verificada uma redução de 6,4% do total encapsulado. O estudo de liberação mostrou rápida liberação nas primeiras 48h (30,45%) e posteriormente manteve-se mais lenta, com 52% após 21 dias de ensaio. As nanocápsulas poliméricas contendo grandisina, obtidas neste trabalho, mostraram ser um potencial sistema de liberação para viabilizar uma forma de administração por via parenteral para esta substância.

Esta tese envolveu o estudo de encapsulação de vacina bivalente contra difteria e tétano de uso adulto (dT) em microesferas de ácido poli(láctico-coglicólico) (PLGA), com o objetivo de desenvolver uma formulação que induzisse uma resposta protetora com um número reduzido de doses, ou preferencialmente de apenas uma dose. Para ter sucesso, uma formulação como tal deve ter um perfil de liberação de antígeno que simule as múltiplas doses que recebem o indivíduo. Assim, nesta tese são mostrados os resultados dos experimentos de caracterização bioquímica e imunológica da formulação citada, sem o uso de estabilizadores protéicos, a fim de reduzir a complexidade do sistema em estudo. Do ponto de vista das proteínas encapsuladas, tal caracterização envolveu estudos de fluorescência, de dicroísmo circular, de atividade antigênica e determinação por HPLC da degradação durante o processo de encapsulação. Do ponto de vista da formulação, foram realizados ensaios de degradação in vitro e de atividade imunogênica in vivo, em camundongos e cobaias. Os dados obtidos indicaram que a encapsulação em microesferas de PLGA de vacina dT, sem o uso de estabilizadores, permitiu a produção de uma formulação vacinal viável, capaz de estimular uma resposta imunológica protetora e de memória, abrindo caminho para o desenvolvimento da tecnologia de produção de vacinas polivalentes encapsuladas em microesferas de PLGA. / The study on encapsulating a bivalent single dose vaccine against diphtheria and tetanus for adults (dT) within PLGA microspheres is described in this thesis. A successful single dose vaccine must show an antigen release profile mimicking the several doses a person should receive during the life. Therefore, results from the immunological and biochemical characterization of the formulation, prepared without protein stabilizers, is showed here. From the encapsulated protein point of view the characterization involved fluorescence, circular dichroism, antigenicity and HPLC analysis. From the formulation point of view, there were performed in vitro release assays and immunogenicity on mice and on guinea-pigs. The results indicated that the dT microencapsulation within PLGA microspheres without protein stabilizers lead to the production of a viable vaccine formulation, able to elicit protective and memory immune response.

L’objectif poursuivi au cours de ce travail est l’encapsulation de complexes métalliques au sein de nanoparticules biocompatibles, et ce pour des visées diagnostiques. Dans ce but, un protocole de double émulsion-diffusion de solvant Wi/O/We, n’utilisant que des composés biocompatibles, a été mis au point et optimisé pour obtenir, de façon quantitative et reproductible, des nanoparticules de PLGA de diamètre compatible avec une injection par voie parentérale. Cette formulation a été employée avec succès pour l’encapsulation de complexes modèles de Cu(II). Les formulations optimales permettent d’obtenir des nanoparticules possédant des diamètres hydrodynamiques moyens inférieurs à 200 nm avec des efficacités d’encapsulation entre 20 et 25 %. L’utilisation de cette formulation pour l’encapsulation de chélates de gadolinium ne permet pas d’obtenir des rendements d’encapsulation satisfaisants. La modification du protocole vers une méthodologie Wi/O1/O2ne permet pas d’améliorer l’encapsulation et dénote l’absence d’affinités entre le polymère hydrophobe et les complexes hydrophiles. L’utilisation de nanoparticules composées d’une matrice hydrophile permet d’obtenir des taux de charges nettement supérieurs. Ceci conforte l’hypothèse selon laquelle les interactions entre le complexe et la matrice des nanoparticules jouent un rôle crucial pour l’encapsulation. / The goal of this work was to encapsulate metal complexes into biocompatible nanoparticles for diagnostics. To reach this purpose, a double emulsion-solvent diffusion Wi/O/We technique was optimized, using only biocompatible compounds. It allowed the obtention of PLGA nanoparticles that are compatible with parenteral injections in a reproducible and quantitative way. This formulation was successfully applied to encapsulate model Cu(II)complexes. Optimal formulations showed mean diameters below 200 nm with encapsulation yields in the 20-25 % range. The use of this formulation for gadolinium chelates did not lead to satisfactory encapsulation yields. Thereafter, a Wi/O1/O2 methodology was developed but could not allow to raise the encapsulation efficiencies. This point showed the lack of affinity between the hydrophobic polymer and the hydrophilic chelates. The use of nanoparticles made of an hydrophilic matrix showed a ten-fold increase in the drug loading efficiency. This confirms the hypothesis in which interactions between chelates and nanoparticle matrices play a crucial role for encapsulation.

The objective of my thesis is to explore the use of the conducting polymer, polypyrrole, in neural applications. In addition a supplementary aspect of dissertation will involves understanding the effects of external stimuli on nervous system cells, with the ultimate goal of designing therapeutic systems for nerve regeneration. In normal development and peripheral nervous system repair, nerves encounter naturally occurring chemical, physical, and electrical stimuli. Polypyrrole (PPy) has attracted much attention for use in numerous biomedical applications as it presents chemical, physical and electrical stimuli. In addition, PPy is particularly exciting because the extent by which chemical, physical, and electrical cues are presented to the injured nerve can be easily tailored. Thus, conducting polymers are excellent scaffolds for the exploration of how the cellular components of the nervous system (i.e., Schwann cells and neurons) interact with chemical, topographical, and electrical stimuli. This dissertation covers three main objectives and is supplemented by two additional topics. The two additional topics explore the effect stimuli present on the conducting polymer PPy have on neural interfaces. These fundamental studies use computational modeling to gain a better understanding of cellular motility on substrates containing different stimuli. Both topics are covered in the appendices of this dissertation. With regards to the three main objectives, I first characterized and optimized the electrochemical synthesis of the conducting polymer, PPy, for Schwann cell biocompatibility. Next, I investigated the effect the application of electrical cues through PPy has on Schwann cell migration. In addition to investigating the effect of the direct electrical current on Schwann cells I also considered the effect that electrical stimulation provided by PPy has on protein adsorption. Finally, I developed a hybrid PPy material that will provide advantageous properties for neural interfaces. Specifically, I describe the development of a polypyrrole:poly-(lactic-co-glycolic) acid blend for neural applications. In summary the three specific objectives covered in my thesis are: Specific Aim 1: Characterize and optimize the electrochemical synthesis of the conducting polymer, polypyrrole, for Schwann cell biocompatibility Specific Aim 2: Determine the effect of electrical stimulation on Schwann cell migration Specific Aim 3: Develop polypyrrole:poly-(lactic-co-glyolic) acid blends for neural engineering applications. / text