A Stratum corneum lipid model as a platform for biophysical profiling of bioactive chemical interactions at the skin level

Stratum Corneum (SC), the outermost layer of mammalian skin, provides the first and most challenging barrier to skin permeation of cosmetic and pharmaceutical compounds. SC barrier function relies primarily on the complex structure and organization of the intercellular lipid matrix. This matrix consists mainly of ceramides (CER), free fatty acids (FFA), and cholesterol (Chol) in an equimolar ratio, forming a multilamellar structure with short- and long-periodicity phases. Along with permeation studies, it becomes paramount the molecular investigation of the interaction between the lipid matrix and the compounds, towards a comprehensive picture of their biophysical impact, including lipid packing impairment, which can result in skin damage, and in consequences for their permeation and mechanism of action. In this study, a lipid-based model (CER[EOS]:CER[AP]:Chol:FFA) was developed to accurately resemble the barrier properties of the intercellular lipid matrix. In a monolayer assembly, this SC lipid model was characterized and applied as an in vitro platform to explore interactions with model compounds – caffeine and testosterone – following OECD recommendations. The SC model successfully mimicked different barrier properties of the SC’s lipid matrix, and its interactions with the model compounds were discussed closely aligned with existing data, including in vitro permeation studies using human and animal membranes. This SC model can be a step forward towards the development of new in vitro platforms for investigating the skin barrier function and the interactions with external molecules. Moreover, the composition of these platforms can be easily modified to mimic impaired lipid matrices to study different skin conditions, providing valuable insights for both cosmetic and pharmaceutical applications.