Theoretical analysis of localized heating in human skin subjected to high voltage pulses

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Abstract

Electroporation, the increase in the permeability of bilayer lipid membranes by the application of high voltage pulses, has the potential to serve as a mechanism for transdermal drug delivery. However, the associated current flow through the skin will increase the skin temperature and might affect nearby epidermal cells, lipid structure or even transported therapeutic molecules. Here, thermal conduction and thermal convection models are used to provide upper and lower bounds on the local temperature rise, as well as the thermal damage, during electroporation from exponential voltage pulses (70 V maximum) with a 1 ms and a 10 ms pulse time constant. The peak temperature rise predicted by the conduction model ranges from 19 °C for a 1 ms time constant pulse to 70 °C for the 10 ms time constant pulse. The convection (mass transport) model predicts a 18 °C peak rise for 1 ms time constant pulses and a 51 °C peak rise for a 10 ms time constant pulse. The convection model compares more favorably with previous experimental studies and companion observations of the local temperature rise during electroporation. Therefore, it is expected that skin electroporation can be employed at a level which is able to transport molecules transdermally without causing significant thermal damage to the tissue.

Introduction

Controlled, transdermal delivery of therapeutic agents is potentially of major clinical importance. This process requires an increase in skin permeability such that a sufficient amount of drug may be transported in a controlled fashion. Electroporation, which can increase the permeability of bilayer lipid membranes in the stratum corneum (SC) using high voltage pulses, has potential as a mechanism for transdermal drug delivery.

Despite the number of studies that investigate the application of electroporation to transdermal drug delivery [1], [2], [3], [4], very little attention has been given to the thermal effects that may be caused by these high voltage pulses. A voltage pulse causes an associated current flow through the skin, which due to its finite electrical resistance, will increase the local skin temperature through electrical dissipation (Joule heating). This local temperature rise may affect: (1) the barrier function of the skin if the temperature rise causes a phase change in the SC lipids and/or a denaturization of SC proteins; (2) the local morphology of the skin structure if the heating causes water to vaporize; and (3) the therapeutic molecules destined for transdermal drug delivery. Further, if nearby epidermal tissues experience a prolonged temperature rise beyond a threshold, damage may result. It is the purpose of the present theoretical study to model and investigate the magnitude of the temperature rise within skin during electroporation and to assess the potential thermally mediated effects.

Section snippets

Materials and methods

The skin's barrier function is mainly afforded by the stratum corneum (SC), a multi-lamella structure within the first ∼20 μm of the skin surface. This structure exhibits a very high electrical resistance and an extremely low permeability to transport. Thus, an electric field applied across skin will concentrate mainly within the SC. Depending on the pulse duration, an electric “breakdown” is likely to occur if the voltage across the SC is about 50–100 V. During this breakdown, the resistance

Results and discussion

Fig. 3 summarizes the simulation results for both the conduction and the convection models. The top panel shows the peak temperature rise resulting from an exponential pulse, τpulse=1 ms, for thermal conduction alone (solid line) and thermal convection (dashed line—fluid velocity of 1 m/s, dashed–dotted line—fluid velocity of 5 m/s). This peak temperature rise is taken at the center of the LDR (z=0, r=0) where the temperature is greatest at any given time. In the case of conduction alone, the

Conclusion

Tissue electroporation holds promise as a mechanism for transdermal drug delivery. Of the many studies performed to date, very little attention has been given to the thermal effects that may be induced by these high voltage pulses. In this study, we have performed analytical and computer modeling of the temperature rise in the stratum corneum (SC) during electroporation. Current flowing through aqueous pathways created by electroporation dissipates electrical energy into heat energy. It is the

Acknowledgements

Supported by NIH Grant ARH4921 and Whitaker Foundation grant RR10963. The authors would like to thank Dr. Timothy Vaughan for his insight, comments and assistance.

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    Present address: Faculty of Chemistry/PCIII, University of Bielefeld, D-33615 Bielefeld, Germany, Tel.: +49-521-106-6261.

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