A propagating heat wave model of skin electroporation.

The main barrier to transdermal drug delivery in human skin is the stratum corneum. Pulsed electric fields (PEFs) of sufficient amplitude can create new aqueous pathways across this barrier and enhance drug delivery through the skin. Here, we describe a model of pore formation between adjacent corneocytes that predicts the following sequence of events: (1) the PEF rapidly charges the stratum corneum near the electrode until the transepidermal potential difference is large enough to drive water into a small region of the stratum corneum, creating new aqueous pathways. (2) PEFs then drive a high current density through this newly created electropore to generate Joule heating that warms the pore perimeter. (3) This temperature rise at the perimeter increases the probability of further electroporation there as the local sphingolipids reach their phase transition temperature. (4) This heat-generated wave of further electroporation propagates outward until the surface area of the pore becomes so large that the reduced current density no longer generates sufficient heat to reach the phase transition temperature of the sphingolipids. (5) Cooling and partial recovery occurs after the field pulse. This process yields large, high permeability regions in the stratum corneum at which molecules can more readily cross this skin barrier. We present a model for this process that predicts that the initial radius of the first aqueous pathway is approximately 5nm for a transdermal voltage of 60V at room temperature.

Local and transient structural changes in stratum corneum at high electric fields: contribution of Joule heating.

Electroporation of skin is accompanied by local heating, such that thermally induced structural changes of the stratum corneum (SC) accompany the field effect. Comparing on the time scale, the local changes in structure, temperature and conductance of the SC, during and after the pulse, it is seen that Joule heating also facilitates the subsequent molecular transport. It is found that the transport of medium-sized, ionic molecules occurs through localized transport regions (LTR). The size of a LTR increases with the pulse length, whereas the density of the LTRs increases with increasing voltage, for instance at U(SC=)80 V, the LTR cover approximately 0.02--1% of the surface area. The state of low resistance within the LTR is long-lived. During high voltage application, the center of the LTR is heated above the phase transition temperature of the SC lipids (70 degrees C) and the heat front propagates outwards. Inside the SC, the pulse causes aggregates of small-sized vesicles. At a higher temperature, the aggregate formation and their disappearance are delayed. Multiple pulses with the applied voltage of U(appl)=80 V induce the formation of long-lasting vesicle aggregates with a diameter of slashed circle=1--30 microm, covering 0.05--0.5% of the total sample area. The electric energy dissipated within the LTR during high voltage application is apparently sufficient to raise the temperature well above the phase transition temperature of the lipids of the SC, accounting for the conformational changes from the multi-lamella to the vesicular structures.