The outer part of the skin, stratum corneum, is essential to the skin's barrier function. Monolayer and bulk phase behavior of stratum corneum model lipids have thus been studied. Domain formation in Langmuir-Blodgett monolayers of synthetic ceramides (C16CerIII and C24CerIII), cholesterol, and free fatty acids (lignoceric acid, C24:0, and palmitic acid, C16:0) were investigated by atomic force microscopy. Binary, ternary, and more complex lipid mixtures were examined. It was shown that small amounts of ceramide are miscible in a cholesterol-rich phase with the miscibility dependent upon the ceramide chain length. Two phases are formed at low and intermediate cholesterol concentrations. In the ceramidecholesterol monolayers, very small rectangular-shaped ceramide domains thought to be two-dimensional single ceramide crystals are formed. Small domains were also found in more complex mixtures where the fatty acid is miscible in the ceramide phase, although these domains were not as regular in shape. Binary ceramide-cholesterol as well as ternary ceramide-cholesterol-lignoceric acid bulk mixtures were also studied by X-ray diffraction. The bulk lipid miscibility is consistent with the monolayer results.

Very small rectangular domains were observed by atomic force microscopy in binary monolayers of synthetic ceramides and cholesterol. When the cholesterol content is increased the domains are bigger although the rectangular shape is retained. The almost perfect shape of the domains indicates two-dimensional single ceramide crystals. Lipid domains in monolayers of this particular shape and size have to our knowledge not been reported in the literature previously.

This contribution summarises the results from a number of investigations undertaken in the spirit of the Domain Mosaic Model proposed by Forslind in 1994. Atomic Force Microscopy (AFM) studies on the two-dimensional phase behaviour of some stratum corneum lipids revealed phase separation of the lipids in the typical case and the ability of cholesterol to reduce the line tension between phases. A theoretical model was developed describing the response of an oriented stack of polar lipid bilayers in the presence of a gradient in water chemical potential (water solution to humid air). The gradient gives rise to an inhomogeneous water swelling, and presumably to a liquid crystal-to-gel transition in the lamellar region closest to humid air. Skin penetration enhancers such as Azone and oleic acid cause phase transformations in lipid bilayer systems which may be relevant in the context of skin permeation.