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Cell-based in vitro models for dermal permeability studies

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Abstract

This chapter compiles available information about in vitro skin models to evaluate dermal permeability. The assessment of the dermal permeation of molecules is one of the main steps in the initial design. Later, it is also important for the evaluation of dermal delivery systems. Therefore, the choice of predictive in vitro penetration models is of utmost importance. Initially, the structure and function of human skin are described, discussing the contributions of the different skin layers and skin appendages to skin absorption. Particular attention is paid to the differences between the two- and three-monolayer models. Moreover, commercialized three-dimensional models are discussed as well as various models of reconstructed epidermis that already provide useful tools for assessment of the safety and efficacy of cosmetic products.

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... The use of in-vitro skin models of reconstructed human epidermis (e.g., EpiSkin™) has some limitations, but it should be performed as a first approach, particularly when the ingredient is only used as excipient and has no claims. Although this model is composed of highly differentiated multi-layer human epidermis cells, the network between the pilosebaceous units responsible for the regulation of dermal homeostasis is compromised [5,48]. Furthermore, this model did not reproduce entirely the hydrolipidic film in what concerns to the physiological properties of the constituents (e.g., urea and glycolic acid) and the occlusive effect of the lipid component (ceramides) [5,48]. ...
... Although this model is composed of highly differentiated multi-layer human epidermis cells, the network between the pilosebaceous units responsible for the regulation of dermal homeostasis is compromised [5,48]. Furthermore, this model did not reproduce entirely the hydrolipidic film in what concerns to the physiological properties of the constituents (e.g., urea and glycolic acid) and the occlusive effect of the lipid component (ceramides) [5,48]. Also, Episkin™ did not contain dendritic Langerhans' cells present in human skin [5,48]. ...
... Furthermore, this model did not reproduce entirely the hydrolipidic film in what concerns to the physiological properties of the constituents (e.g., urea and glycolic acid) and the occlusive effect of the lipid component (ceramides) [5,48]. Also, Episkin™ did not contain dendritic Langerhans' cells present in human skin [5,48]. These skin models may over-predict the irritability of the tested compounds due to the higher penetration rate of these tissues [5,48]. ...
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... Regarding safety assays, the model is validated by OECD for skin corrosion (OECD 431) (OECD, 2004b) and irritation (OECD 439) (OECD, 2015c). EpiSkin TM (L'Oreal, France) consists of a dermal substrate generated on type I bovine collagen matrix (representing the dermis), with a film of type IV human collagen, upon which a stratified differentiated epidermis derived from human keratinocytes is laid after 13 days in culture (Rodrigues and Oliveira, 2016). The model contains the epidermal layers of native skin. ...
... The protocol of EpiSkin TM use is based on a short treatment time (15 min) with the compound placed on the top of the model, followed by an extended 42-h post treatment incubation period. The prediction model is mainly based on the validate cell viability measurement (MTT) as endpoint (Rodrigues and Oliveira, 2016). Complementary assays can be performed, such as LDH leak quantification, cytokine release, histological analyses or gene arrays. ...
... The Epiderm TM model (MatTek Corporation, Massachusetts, USA) was introduced in 1993, being successfully used as an alternative in vitro toxicology test for dermal corrosivity, skin irritation and phototoxicity. It is composed by human epidermal keratinocytes as fully-differentiated epidermal tissue (fully-differentiated natural epidermis displaying a basement membrane, proliferating keratinocytes and a stratum corneum) at air-liquid interface on inert polycarbonate membranes (Rodrigues and Oliveira, 2016). The model tissue consists on metabolic and mitotic active cells organized into basal, spinous and granular layers, along with a multi-layered stratum corneum (Sarmento et al., 2012). ...
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... This type of hydrogel is applied directly on the skin of the affected region in the form of a patch and is commonly used for an external wound. After touching the skin, the drug infiltrates the dead stratum corneum and then arrives at the blood vessels, the dermis, and the viable epidermis [118]. By delivering the drug directly to the wound site with the mechanism of transepithelial drug delivery, the risk of systemic side effects can be avoided. ...
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... All these variables have a profound impact on the efficacy-safety profile of the product (Shah et al., 2015). Therefore, data on the skin absorption profile is essential as it reflects not only issues related to therapeutic efficacy but also the safety of the medicinal product (Rodrigues and Oliveira, 2016). ...
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