A propagating heat wave model of skin electroporation

Abstract

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 5 nm for a transdermal voltage of 60 V at room temperature.

Transdermal transport pathway creation: Electroporation pulse order

“…The SC altered electrical conductivity and transport coefficients that are associated with lipid phase transitions of Eqs. (8) and (9) are updated at each time step. The specific heat of the SC lipids during phase transition are updated at each time step in using the values listed in Table 1 of Ref.…”

“…amplitude, duration, number and frequency). The expert opinions in the field are in general agreement that there are different responses according to two primary pulsing regimes: (i) that short duration-high intensity pulses result in an altered SC that is perforated with nano-to micrometer-sized aqueous ''pores'', and (ii) that long duration medium intensity pulses result in regions of increased permeability within the SC that are relatively large (up to hundreds of lm) but that occur at a much lower density (number of pathways per SC surface area) than the high voltage (HV)-created pathways [3][4][5][6][7][8][9][10][11][12][13][14][15].…”

“…These LTRs are formed within the sites of the so-called stratum corneum ''defects'' [4] which have a higher electrical conductivity than the surrounding SC so that under the application of the low voltage (LV) electric pulses, the current density within these defects is high. The development of the LTR is believed to be associated with resistive (Joule) heating which has been documented under certain experimental pulse conditions to cause localized temperature rises of over 60°C [3,6,9,10,[18][19][20][21].…”

Perspectives on Transdermal Electroporation

“…, 0.3–1.0 V per bilayer [ 28 ]. Electroporation is a non-thermal process at the level of the cell membrane [ 39 ]. When a membrane is subject to electroporation, water is forced into the lipid environment because of the large difference in dielectric constant ( 87, 2).…”

“…When a membrane is subject to electroporation, water is forced into the lipid environment because of the large difference in dielectric constant ( 87, 2). As soon as an electropore is formed, the water inside the pore becomes polarized, stabilizing the pore in the process [ 39 ].…”