Abstract

We present a multiscale approach to the modeling and simulation of human skin with an emphasis on dermal drug delivery. We focus on the top-layer of the skin, the stratum corneum, which is modeled at three distinct resolutions covering macroscopic, mesoscopic and microscopic levels. At the macroscale the stratum corneum is represented as a two-phase composite model of impermeable corneocyte cells embedded in a permeable lipid matrix. We calculate the permeability of a test compound as a function of cell thickness and show how this may be influenced by changes in local humidity. We find that increasing humidity leads to an increase in diffusion normal to the skin surface, but a decrease in overall permeability due to the increase in path length. At the mesoscale we zoom in on the extracellular space at a resolution of about 1 nm and model a mixture of lipids in confinement using an assembly of coarse-grained particles. The self-assembled morphology is predicted as a function of the composition of the lipid phase, by varying the relative amount of ceramides, free fatty acids, and cholesterol. Mixtures of ceramide type 2 and palmitic acid are found to readily separate into lamellae. After phase separation we study diffusion of test probes, where increased diffusivity correlates with drug molecules with increased lipophilicity (log P). At the microscale we focus on the ceramide lipid multilayer. We simulate the molecular dynamics of a TeCd quantum dot inside a ceramide bilayer at constant temperature and pressure. The presence of a nanoparticle has the effect of decreasing the lipid chain radius of gyration and minor alterations in the hydrogen bonding pattern, stabilizing the layer.

Keywords: Finite element method, lipid membranes, multiscale modeling, quantum dot, skin, stratum corneum