Non-linearity of molecular transport through human skin due to electric stimulus.

The multilamellar bilayer system of the skin's stratum corneum (SC) provides the main barrier to transdermal transport of ions and charged molecules. Electrically driven transport of charged species at low trans-SC voltages (U(SC)<5 V) occurs predominantly via pre-existing aqueous pathways. In contrast, high voltage, (HV; U(SC)>50 V) has been hypothesized to involve electroporation within the SC's multilamellar bilayer membranes, creating new aqueous pathways that contribute to a rapid, large increase in transport. Thus, it might be expected that HV-pulses would always increase subsequent iontophoresis. Here we show, however, that for some charged molecules the opposite occurs, because the low skin resistance due to new aqueous pathways leads to an actual decrease in U(SC) for the same applied current, and the transport of some, highly charged molecules has a highly nonlinear dependence on U(SC).

Perturbation of human skin due to application of high voltage.

Electroporation is believed to be the effect that greatly enhances the transport of water-soluble molecules across the stratum corneum (SC) by application of short high voltage pulses. However, electroporation was originally a phenomenon investigated at the level of cell and model membranes, which is only partially comparable to the complicated structure of the stratum corneum. Here, we show, that electroporation is accompanied by other effects, which may be primarily involved in creation of new pathways and altering existing pathways, respectively. Experimental evidence shows that the dramatic increase in skin permeability is due to synergistic effect of electric field and heating by high local current density. Heating starts at small spots, not related to a visible skin structure and results in a propagating heat front. The phase transition of the SC lipids plays a major role in skin permeability during the pulse. The permeability after a high voltage pulse correlates well with the surface area showing a permanent low electrical resistance after pulsing. The main transport of water-soluble molecules is facilitated by the electric field due to the electrophoretic driving force in conjunction with the high permeability due to the breakdown of the multilamellar system of the SC lipids.

Overcoming electrically induced artifacts in penetration studies with fluorescent tracers.

The use of model molecules in transdermal transport studies reveals transport behavior while providing an economical setup by detection of readily measured quantities such as fluorescence, radioactivity or absorbance of low-cost substances. Water soluble fluorescent tracers such as calcein have been repeatedly used as model molecules in transdermal transport studies. However, if electrically enhanced calcein transport across the human skin barrier is measured, artifacts due to interaction between calcein and electrode byproducts influence the result. Here, we describe an experimental setup which avoids known artifacts and makes calcein or other fluorescent tracers a suitable model for transdermal transport studies.