Thermal in vivo skin electroporation pore development and charged macromolecule transdermal delivery: A numerical study of the influence of chemically enhanced lower lipid phase transition temperatures

Electroporation is an approach used to enhance transdermal transport of large molecules in which the skin is exposed to a series of electric pulses. Electroporation temporarily destabilizes the structure of the outer skin layer, the stratum corneum, by creating microscopic pores through which agents, which ordinarily are unable to pass into the skin, are able to pass through this outer barrier. Long duration electroporation pulses can cause localized temperature rises which result in thermotropic phase transitions within the lipid bilayer matrix of the stratum corneum. Chemical agents applied to the skin can reduce the lipid phase transition temperatures. This paper studies the benefits of the combination of the chemical enhancer, terpene d-limonene with low voltage electroporation pulses in order to further aid in electroporation pore development resulting from fluidization of the lipid structures within the stratum corneum. A transient finite volume model is developed in which the thermal and electrical behavior associated with electroporation of in vivo human skin is analyzed and lipid phase transition is represented by a melting process. The Nernst–Planck model is used to represent the electrophoretic-assisted transport of large charged molecules through the skin. The results show that the lower lipid phase transition temperatures associated with the topical application of chemical enhancers to the skin allow for increased solute delivery and solute penetration of the skin reaching radial locations much further than in the untreated case. Solute transport solutions of both cases exhibit local accumulation of concentrations below the stratum corneum – epidermis interface which exceed concentration values initially contained within the applicator gel.