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Advanced Polymeric Systems for Antibiotic Targeting
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Os ossos são órgãos mineralizados, que têm uma incrível capacidade de cicatrização e reparação, embora, quando o dano é grave ou os ossos não estão completamente saudáveis (por exemplo, devido a cancro ou a fraturas graves), o processo de cicatrização é lento e imperfeito. As cirurgias com recurso a scaffolds têm sido realizadas quando o osso não consegue reparar-se. A composição dos scaffolds e a sua estrutura porosa aumentam a capacidade de cicatrização e de crescimento do osso, o que leva a um melhor tratamento. Mas o fato dos scaffolds se apresentarem como um suporte para o crescimento celular, fungos e bactérias tendem a infetar o scaffold antes da cirurgia. Após a cirurgia, a infeção (agora chamada de Infeção óssea) crescerá, as colónias tenderão a criar um biofilme protetor, impermeável aos medicamentos, impedindo que estes administrados por via oral ou parentérica atuem. A maioria dos pacientes que sofrem esta cirurgia não estão preparados para uma segunda cirurgia, para a remoção do scaffold infetado, portanto, uma nova estratégia, não invasiva, deve ser apresentada para esses casos. Incorporar fármacos em scaffolds que previnam a infeção do scaffold em primeiro lugar é uma estratégia já estudada há algum tempo. Incorporar dois fármacos nos scaffolds, um antifúngico e um antibiótico é muito mais raro e inovador. O objetivo desta tese foi encontrar novas estratégias de entrega dos compostos, combinando dois por scaffold ou veiculando-os em nanopartículas de quitosano. Para tal, os scaffolds foram preparados por "solvent casting". Os dois fármacos testados foram: minociclina e voriconazol. A atividade microbiológica dos scaffolds foi estudada por ensaio de difusão em ágar contra Candida albicans e Staphylococcus aureus. As nanopartículas foram preparadas por gelificação ionotrópica e carregadas com os mesmos fármacos. As nanopartículas foram caracterizadas quanto a: distribuição de tamanho, potencial zeta e atividade microbiológica. Os scaffolds com fármacos inibiram o crescimento de colónias de S. aureus, e as nanopartículas apresentaram potencial zeta em torno de +20 mV, tamanho de distribuição em torno de 280 nm e também apresentaram efeitos antimicrobianos contra S. aureus. Os sistemas poliméricos de veiculação de fármacos apresentam potencial como nova estratégia terapêutica da infeção óssea. No entanto, serão necessários mais estudos in vitro e in vivo, com uma gama mais ampla de microorganismos e de fármacos e de outros polímeros.
Bones are mineralized organs, that have an amazing ability to heal and repair, although, when the damage is severe, or the bones are not completely healthy (for example due to cancers or an extreme fracture) the healing process is slow and imperfect. Surgeries resorting to scaffolds have been performed when the bone is unable to repair. Scaffolds composition and porosity structure enhance the healing and growing capacity of the bone, what leads to better treatment. But the fact that scaffolds present themselves as a good support for cellular growth bacteria and fungus tent to infect the scaffold before surgery. After surgery, the infection (now called Associated Bone Infection) will grow, the microorganism colonies tent to create a protective biofilm, impermeable to drugs, preventing drugs administered by the oral or parenteral route to act. Most patients that suffer this surgery are not prepared for a second surgery, for the removal of the infected scaffold, so a new strategy must be present for these cases. Loading scaffolds with drugs that prevent scaffold infection in the first place is a strategy, already being studied for some time. Loading the scaffolds with two drugs, an antifungal and one antibiotic is much rarer and novel strategy. The aim of this thesis was to find newer delivery strategies, by combining two drugs loaded per scaffold and by loading them in chitosan nanoparticles. To do so, scaffolds were prepared by solvent casting/particular leaching, and loaded with minocycline and voriconazole. The microbiological activity of the scaffolds was studied by the agar diffusion assay against Candida albicans and Staphylococcus aureus. The nanoparticles were prepared by ionotropic gelation and loaded with the same drugs. Nanoparticles were characterized with respect to: distribution size, zeta potential and microbiological activity. The loaded scaffolds did inhibit the growth of S. aureus colonies, and loaded nanoparticles presented a zeta potential around +20 mV, distribution size around 280 nm and they also presented antimicrobial effects against S. aureus. The proposed advanced polymeric delivery systems showed potential in the context of finding new therapeutic approaches against associated-bone-infections. However, more in vitro and in vivo studies, with a wider range of microbiological models and drugs, with other polymers should be conducted.
Bones are mineralized organs, that have an amazing ability to heal and repair, although, when the damage is severe, or the bones are not completely healthy (for example due to cancers or an extreme fracture) the healing process is slow and imperfect. Surgeries resorting to scaffolds have been performed when the bone is unable to repair. Scaffolds composition and porosity structure enhance the healing and growing capacity of the bone, what leads to better treatment. But the fact that scaffolds present themselves as a good support for cellular growth bacteria and fungus tent to infect the scaffold before surgery. After surgery, the infection (now called Associated Bone Infection) will grow, the microorganism colonies tent to create a protective biofilm, impermeable to drugs, preventing drugs administered by the oral or parenteral route to act. Most patients that suffer this surgery are not prepared for a second surgery, for the removal of the infected scaffold, so a new strategy must be present for these cases. Loading scaffolds with drugs that prevent scaffold infection in the first place is a strategy, already being studied for some time. Loading the scaffolds with two drugs, an antifungal and one antibiotic is much rarer and novel strategy. The aim of this thesis was to find newer delivery strategies, by combining two drugs loaded per scaffold and by loading them in chitosan nanoparticles. To do so, scaffolds were prepared by solvent casting/particular leaching, and loaded with minocycline and voriconazole. The microbiological activity of the scaffolds was studied by the agar diffusion assay against Candida albicans and Staphylococcus aureus. The nanoparticles were prepared by ionotropic gelation and loaded with the same drugs. Nanoparticles were characterized with respect to: distribution size, zeta potential and microbiological activity. The loaded scaffolds did inhibit the growth of S. aureus colonies, and loaded nanoparticles presented a zeta potential around +20 mV, distribution size around 280 nm and they also presented antimicrobial effects against S. aureus. The proposed advanced polymeric delivery systems showed potential in the context of finding new therapeutic approaches against associated-bone-infections. However, more in vitro and in vivo studies, with a wider range of microbiological models and drugs, with other polymers should be conducted.
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Bone associated infection Chitosan Nanoparticles Scaffolds