| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Biophys J, February 1998, p. 679-680, Vol. 74, No. 2
Biophysics Department, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
The skin is an effective barrier against toxic
chemicals and pathogens. Its uppermost layer, the stratum corneum, is
composed of layers of corneocytes and lipid multilayers and is
impermeable to most water soluble substances. It also constitutes a
formidable obstacle to transdermal delivery of drugs and genetic
materials. The transdermal route, if available, provides an
alternative, convenient, and noninvasive pathway for local and systemic
delivery, especially with regard to timed release and the avoidance of
degradation or metabolism in the gastrointestinal tract or liver. The
stratum corneum is crossed by many appendages such as hair follicles
and sweat glands. The lining of these appendageal ducts, consisting of
two layers of epithelial cells, is much less resistant than the stratum
corneum to drug transport.
Many biophysical approaches have been made to facilitate the transport
of selected chemicals across the skin barrier. The most well known
method is iontophoresis. In this approach, a low DC voltage (normally
<5 V) is applied across the skin. Charged molecules to be delivered
are placed under an appropriate electrode and are driven through the
skin barrier by electrophoresis and electroosmosis (Oh et al., 1993 About 20 years ago, reversible electroporation of biological membranes
was recognized as a means to deliver materials into living cells (Chang
et al., 1992 A paradox is realized that, if electroporation occurs when a potential
of 1 V is applied across a cell membrane, the membranes of the
epithelial cell layers lining the skin appendages are porated as soon
as the low iontophoretic voltage (>4 V) is applied to the skin. The
molecular transport by iontophoresis should then be considered as the
consequence of electroporation of the epithelial layers of the skin
appendages. This alternative interpretation is complicated by the fact
that the potential drop along narrow hair follicles or sweat glands
must also be taken into account in calculating the net potential drop
across the epithelial cell layers at different depths from the skin
surface. Furthermore, the response and resealing times of the membrane
to the applied electric field are unknown, adding to the difficulty in
modeling the low field electroporation if a pulse or AC voltage is
applied in the traditional iontophoretic setting (Gallo et al., 1997 This problem is now considered in detail by Chizmadzhev et al. (1997) The analyses and the experimental support given in this paper provide
us with a broad picture of what happens when a low electric voltage is
applied to the skin with appendages. The initial event, characterized
by the charging of the skin capacitor and the subsequent poration of
the appendages lining, is clearly depicted. It bridges the gap between
the theories of iontophoresis and electroporation. This work paves the
ground for the future development of combined high and low voltage
protocols designed to enhance the transdermal transport, which will
play an increasingly important role in drug and gene delivery.
ARTICLE
;
Cullander, 1992). The transport passage is believed to be mainly
through the appendages. The electrical impedance spectra of the skin
are well characterized, and the transport by iontophoresis has been
analyzed by macroscopic theory (Edwards and Langer, 1994).
). This method is based on the resilience of the cell
membrane to reseal after a temporary electric breakdown. Dielectric
breakdown of a lipid bilayer and a cell membrane is reached at a
transmembrane potential of about 0.5 and 1 V, respectively (Abidor et
al., 1979; Benz et al., 1979; Neumann et al., 1982; Zimmermann, 1986;
Tsong, 1987; Stenger et al., 1991). Because of the low electric
conductivity across the membrane, as compared with those of the
cytoplasm and the external media, the major potential drop across the
cell is concentrated across the plasma membrane "poles" facing the
electric field direction. This leads to the electroporation of the
membrane, whereas the rest of the cell experiences a much lower
potential gradient. The same advantage applies to the electroporation
of the skin barrier in which the major potential drop develops across
the highly resistive stratum corneum, the target for electroporation. This was recognized recently, and the technique has been applied, although sometimes in an irreversible sense, to permeabilize the skin
for drug delivery purposes (Prausnitz et al., 1993; Vanbever et al.,
1994). For short term permeabilization of the skin, a pulse of 20-40 V
across some 70-100 lipid bilayers in the stratum corneum (about
250-500 mV/bilayer) is sufficient (Pliquett et al., 1995; Gallo et
al., 1997). To achieve a prolonged electrical permeabilization of the
stratum corneum, a pulse voltage exceeding a threshold of about 75 V (1 V/bilayer), is required (Prausnitz et al., 1993; Vanbever et al., 1994;
Gallo et al., 1997). This threshold agrees with that measured for the
electrical breakdown of lipid bilayers and cell membranes (Edwards et
al., 1995; Chizmadzhev et al., 1995).
).
in this issue. They present a simple geometric model for the appendages
with its equivalent circuit. After an elegant classical analysis, they
derived the potential along the appendageal tube at given times after
the initiation of the pulse and the development of electropores
manifesting as the decrease of electric resistance. The calculation,
using realistic parameters for skin tissues, matches well with the
steady state and time-resolved measurements of the current-voltage
characteristics reported previously and in this paper. Furthermore,
with increasing applied voltages, electroporation of the stratum
corneum occurs and becomes the major transport pathway in place of the
appendageal route. The reconciliation of the two electroporation
pathways is shown as closely matched theoretical and experimental
curves spanning a wide voltage range.
| |
FOOTNOTES |
|---|
Received for publication 19 September 1997 and in final form 4 November 1997.
Address reprint requests to Dr. S.W. Hui, Membrane Biophysics Laboratory, Roswell Park Cancer Institute, Buffalo, NY 14263. Tel.: 716-845-8595; Fax: 716-845-8683; E-mail: roswhui{at}acsu.buffalo.edu.
| |
REFERENCES |
|---|
Biophys J, February 1998, p. 679-680, Vol. 74, No. 2
© 1998 by the Biophysical Society 0006-3495/98/02/679/02 $2.00
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
