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New insights in permeability studies :
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Os transetossomas são um tipo de vesículas ultradeformáveis, que são adequadas para a administração transdérmica de fármacos. Os modelos in vitro de pele 3D são membranas muito interessantes uma vez que permitem eliminar os problemas éticos dos ensaios de permeação in vivo ou ex vivo necessários para a aprovação de fármacos de aplicação tópica ou cosméticos, enquanto a bioimpressão 3D é uma tecnologia recente que permite melhorar as características funcionais dos modelos in vitro de pele. No entanto, a literatura apresenta uma lacuna no que respeita a estudos de
caracterização dos modelos de pele 3D bioimpressos e a sua correlação com membranas biológicas, utilizadas nos ensaios de permeação. Assim, o objetivo principal desta dissertação é correlacionar um modelo in vitro de pele 3D produzido por bioimpressão 3D com a pele de porco ex vivo, uma membrana biológica.
Para atingir este objetivo, os transetossomas foram preparados com uma molécula lipofílica (Nile Red, NR) através do “cold method” e caracterizados. Na segunda parte deste trabalho, foram avaliadas e correlacionadas as propriedades da barreira formada pela pele de porco e pelo modelo in vitro 3D de pele humana obtido por bioimpressão 3D.
Os resultados demonstraram que as vesículas apresentam as características adequadas para serem aplicadas nas etapas seguintes do estudo, nomeadamente nos ensaios de permeação. Os ensaios de permeação realizados na pele de porco revelaram uma retenção superior de vesículas no estrato córneo, que foi confirmado por microscopia de fluorescência. Apesar da variabilidade, os valores de resistência elétrica da membrana permitiram corroborar que apresentava uma barreira íntegra. O modelo de pele obtido por bioimpressão 3D revelou uma permeabilidade superior e uma barreira não íntegra, embora as imagens obtidas por microscopia confocal refletissem uma distribuição do fluoróforo semelhante à observada na pele de porco.
Em conclusão, este estudo demonstrou que os transetossomas com NR podem ser utilizados como vesículas modelo para efetuar ensaios de permeação em diferentes modelos de pele 3D. No entanto, o modelo 3D desenvolvido neste projeto não demonstrou as características desejadas e seria necessário efetuar mais estudos para reduzir a sua permeabilidade. Não obstante, poderíamos tirar partido da permeabilidade superior para avaliar a absorção de um fármaco numa pele com uma barreira comprometida devido à ausência de um estrato córneo maturo.
Transethosomes are a type of ultradeformable vesicles (UDV) suitable for transdermal delivery. In vitro 3D skin models are very interesting membranes that can eliminate the ethical issues of in vivo or ex vivo permeation assays required for the approval of cosmetics or topical drugs, while 3D bioprinting is a recent technology that is emerging nowadays allowing to obtain 3D skin models with more specific functional characteristics. However, there is a lack in the characterization and correlation of these models with the biological skin used in delivery studies. Thus, the main goal of this work is to correlate the 3D skin models with a biological membrane (ex vivo newborn pig skin) used in in vitro delivery studies. In the first part of our work, transethosomes loaded with Nile red (NR) were prepared by the “cold method” and characterized. In the second part of our work, the barrier properties of the newborn pig skin and 3D full-thickness skin model obtained by 3D bioprinting were evaluated. The results of this study showed NR-loaded transethosomes with suitable characteristics for permeation studies. The skin delivery assays in newborn pig skin showed a greater retention of these vesicles in the stratum corneum rather than viable epidermis and dermis, confirmed by fluorescence images. In addition, the skin resistance measurements revealed some variability but a good barrier, as expected. The 3D skin model showed a less hydrophilic barrier. However, the resistance measurements collected demonstrated a non-integral barrier and the delivery studies revealed a higher permeability than the newborn pig skin. Although the fluorescence images reflect a distribution of the fluorophore similar to the pig skin. In conclusion, the NR-loaded transethosomes could be used as a DDS model to perform permeability studies in other 3D skin models but the model developed did not show the desired characteristics to correlate with a biological membrane and would need further refinement to achieve lower permeability. Nonetheless, the higher permeability could turn into an advantage by creating a model to evaluate the permeation in a skin with a less effective barrier due to a less matured stratum corneum.
Transethosomes are a type of ultradeformable vesicles (UDV) suitable for transdermal delivery. In vitro 3D skin models are very interesting membranes that can eliminate the ethical issues of in vivo or ex vivo permeation assays required for the approval of cosmetics or topical drugs, while 3D bioprinting is a recent technology that is emerging nowadays allowing to obtain 3D skin models with more specific functional characteristics. However, there is a lack in the characterization and correlation of these models with the biological skin used in delivery studies. Thus, the main goal of this work is to correlate the 3D skin models with a biological membrane (ex vivo newborn pig skin) used in in vitro delivery studies. In the first part of our work, transethosomes loaded with Nile red (NR) were prepared by the “cold method” and characterized. In the second part of our work, the barrier properties of the newborn pig skin and 3D full-thickness skin model obtained by 3D bioprinting were evaluated. The results of this study showed NR-loaded transethosomes with suitable characteristics for permeation studies. The skin delivery assays in newborn pig skin showed a greater retention of these vesicles in the stratum corneum rather than viable epidermis and dermis, confirmed by fluorescence images. In addition, the skin resistance measurements revealed some variability but a good barrier, as expected. The 3D skin model showed a less hydrophilic barrier. However, the resistance measurements collected demonstrated a non-integral barrier and the delivery studies revealed a higher permeability than the newborn pig skin. Although the fluorescence images reflect a distribution of the fluorophore similar to the pig skin. In conclusion, the NR-loaded transethosomes could be used as a DDS model to perform permeability studies in other 3D skin models but the model developed did not show the desired characteristics to correlate with a biological membrane and would need further refinement to achieve lower permeability. Nonetheless, the higher permeability could turn into an advantage by creating a model to evaluate the permeation in a skin with a less effective barrier due to a less matured stratum corneum.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
3D Bioprinting Nile red Permeation/penetration studies Skin models Transethosomes Mestrado integrado - 2022