In order to appreciate the structure-function relationships of the skin barrier in vivo, it is of value to understand horny layer lipid formation, as the horny layer’s lipid structure may represent a “frozen-in” or “immobilized” open biological system rather than a primary minimum energy order equilibrium system. Skin lipid formation is also central from a dermatological standpoint, since barrier malformation may be an etiological factor in barrier-deficient skin conditions such as eczema, psoriasis, and “dry skin.”

It has recently been proposed that skin lipid formation proceeds via (1) membrane synthesis in the trans-Golgi of a membrane system with cubic-like symmetry, followed by (2) morphologically continuous (non-fusion-dependent) secretion of the cubic-like membrane system into the extracellular space, (3) phase transition from cubic-like to lamellar membrane morphology, (4) dehydration, (5) condensation, and (6) lipid chain rearrangement from a folded (hairpin) to an extended (splayed chain) stacked bilayer conformation (Norlén 2001a; Iwai et al. 2012). CEMOVIS supports the proposed continuity of the lipid secretion system as well as the proposed structural association of non-lamellar and lamellar lipid morphologies (Norlén et al. 2003; Al-Amoudi et al. 2005). However, structure determination of the intermediate stages of skin lipid formation may require access to native molecular resolution tomographic 3D data in situ (molecular tissue TOVIS (cf. Norlén et al. 2009)), a developing technology that may not yet have reached its full potential.

Current knowledge suggests that a stacked, fully extended (splayed chain) ceramide bilayer arrangement (Figs. 4.1 and 4.2) with a high cholesterol content and a heterogeneous, saturated, long-chain lipid composition represents an optimized barrier organization for skin. This is because it renders skin largely impermeable to water as well as to both hydrophilic and lipophilic substances due to its condensed chain packing and its alternating lipophilic (alkyl chain) and hydrophilic (headgroup) regions. Likewise, it is resistant to both hydration and dehydration because of its lack of exchangeable water between lipid leaflets. It is also resistant towards temperature and pressure changes because of its heterogeneous lipid composition and high cholesterol content, which stabilize gel-like chain packing and thereby prevent both lateral domain formation and induction of “pores” or non-lamellar morphologies. Further, this bilayer arrangement accounts for stratum corneum cell cohesion without advocating specialized intercellular adhesion structures such as desmosomes. The arrangement hence allows for sliding of stratum corneum cells to accommodate skin bending. Finally, as the interaction between the individual layers of the lipid structure involves only hydrocarbons, the layers may be relatively free to slide with respect to one another, making the lipid structure pliable. The fully extended ceramide bilayer arrangement with high cholesterol content and heterogeneous saturated long-chain lipid composition thus meets the barrier needs of the skin by being simultaneously impermeable and robust.