Microscopic models for the structure and permeability of the stratum corneum barrier layer of skin

A study addressing both structure and diffusion theory was carried out to better understand permeation of molecules through the stratum corneum (SC), the primary barrier layer of skin.; In the structural study (part I), analysis of micrographs of real skin sections led to quantitative determinations of key dimensions and—most significantly—the tortuosity of the intercellular lipid phase seen in 2-D cross section, quantifying the effective path length for diffusion. A geometrical model was subsequently developed to estimate the true tortuosity in 3-D space, which is not directly observable.; The analysis of diffusion (part II) represented a significant tension of “brick-and-mortar” models of SC permeability, specifically addressing the roles played by lateral and transbilayer transport in the lipid phase, as well as permeability of the corneocyte phase. Solution of the governing equations by finite differences and relaxation led to quantitative understanding of the relative contributions of lipid (intercellular) and corneocyte (transcellular) pathways. For practical application, methods were developed to estimate partition and diffusion coefficients characterizing the lipid and corneocyte phases for the (very common) circumstance where experimental data on these input parameters may not be available. By matching the model to experimental data on SC permeability, new insights were obtained into the transbilayer mass transfer coefficient k_trans, a key (and poorly understood) parameter characterizing the rate of transport between lipid bilayers.; The overall conclusions were that: (1) the tortuosity τ _2D of the lipid pathway is 12.42 and 4.47, for the respective cases of partially hydrated (unswollen) and fully hydrated (swollen) SC seen in 2-D cross section; (2) these figures translate into respective values for τ_3D of 9.32 and 3.51 in three dimensions; (3) transbilayer transport is a key step in percutaneous permeation whether or not transcellular transport is dominant; (4) overall, k_trans decreases strongly with increasing permeant molecular weight, and weakly with increasing octanol-water partition coefficient (lipophilicity); (5) values of k_trans deduced from SC permeability data using our diffusion model are roughly consistent with limited available data on this parameter from liposome release experiments.