Skin electroporation is an approach used to enhance the transdermal transport of large molecules in which the skin is exposed to a series of electric pulses, resulting in the structural alteration of the stratum corneum. This article suggests the use of passive transdermal transport models in combination with models depicting the electrically induced structural alterations in order to advance the modeling development of transport associated with skin electroporation. A review of the major physical phenomena observed in skin electroporation transport experiments is provided. A compendium of representative models is made available through a review of the current understanding of the two fields: (1) porous media descriptions of nondestructive transdermal transport and (2) modeling electroporation related structural changes within the skin. To show the applicability and potential of merging transdermal transport modeling with skin electroporation modeling, an example model is developed that combines a brick and mortar style skin representation with a thermodynamic based model of skin electroporation.

1.
Bouwstra
,
J. A.
,
Honeywell-Nguyen
,
P. L.
,
Gooris
,
G. S.
, and
Ponec
,
M.
, 2003, “
Structure of the Skin Barrier and Its Modulation by Vesicular Formulations
,”
Prog. Lipid Res.
0163-7827,
42
(
1
), pp.
1
36
.
2.
Madison
,
K. C.
, 2003, “
Barrier Function of the Skin: “La Raison d’Être” of the Epidermis
,”
J. Invest. Dermatol.
0022-202X,
121
(
2
), pp.
231
241
.
3.
Denet
,
A. R.
,
Vanbever
,
R.
, and
Préat
,
V.
, 2004, “
Skin Electroporation for Transdermal and Topical Delivery
,”
Adv. Drug Delivery Rev.
0169-409X,
56
(
5
), pp.
659
674
.
4.
Regnier
,
V.
,
De Morre
,
N.
,
Jadoul
,
A.
, and
Préat
,
V.
, 1999, “
Mechanisms of a Phosphorothioate Oligonucleotide Delivery by Skin Electroporation
,”
Int. J. Pharm.
0378-5173,
184
(
2
), pp.
147
156
.
5.
Pliquett
,
U. F.
, and
Gusbeth
,
C. A.
, 2000, “
Perturbation of Human Skin Due to Application of High Voltage
,”
Bioelectrochemistry
1567-5394,
51
(
1
), pp.
41
51
.
6.
Pliquett
,
U.
,
Zewert
,
T. E.
,
Chen
,
T.
,
Langer
,
R.
, and
Weaver
,
J. C.
, 1996, “
Imaging of Fluorescent Molecule and Small Ion Transport Through Human Stratum Corneum During High Voltage Pulsing: Localized Transport Regions Are Involved
,”
Biophys. Chem.
0301-4622,
58
(
1–2
), pp.
185
204
.
7.
Prausnitz
,
M. R.
, 1996, “
Do High Voltage Pulses Cause Changes in Skin Structure?
,”
J. Controlled Release
0168-3659,
40
(
3
), pp.
321
326
.
8.
Vanbever
,
R.
, and
Preat
,
V.
, 1999, “
In Vivo Efficacy and Safety of Skin Electroporation
,”
Adv. Drug Delivery Rev.
0169-409X,
35
(
1
), pp.
77
88
.
9.
Pliquett
,
U.
,
Langer
,
R.
, and
Weaver
,
J. C.
, 1995, “
Changes in the Passive Electrical Properties of Human Stratum Corneum Due to Electroporation
,”
Biochim. Biophys. Acta
0006-3002,
1239
(
2
), pp.
111
121
.
10.
Krassowska
,
K.
, and
Filev
,
P.
, 2007, “
Modeling Electroporation in a Single Cell
,”
Biophys. J.
0006-3495,
92
(
2
), pp.
404
417
.
11.
Smith
,
K. C.
,
Neu
,
J. C.
, and
Krassowska
,
W.
, 2004, “
Model of Creation and Evolution of Stable Electropores for DNA Delivery
,”
Biophys. J.
0006-3495,
86
(
5
), pp.
2813
2826
.
12.
Stewart
,
D. A.
,
Gowrishankar
,
T. R.
, and
Weaver
,
J. C.
, 2004, “
Transport Lattice Approach to Describing Cell Electroporation: Use of a Local Asymptotic Model
,”
IEEE Trans. Plasma Sci.
0093-3813,
32
(
4
), pp.
1696
1708
.
13.
Satkauskas
,
S.
,
Andre
,
F.
,
Bureau
,
M. F.
,
Scherman
,
D.
,
Miklavcic
,
D.
, and
Mir
,
L. M.
, 2005, “
Electrophoretic Component of Electric Pulses Determines the Efficacy of In Vivo DNA Electrotransfer
,”
Hum. Gene Ther.
1043-0342,
16
(
10
), pp.
1194
1201
.
14.
Pliquett
,
U. F.
,
Vanbever
,
R.
,
Preat
,
V.
, and
Weaver
,
J. C.
, 1998, “
Local Transport Regions (LTRs) in Human Stratum Corneum Due to Long and Short ‘High Voltage’ Pulses
,”
Bioelectrochem. Bioenerg.
0302-4598,
47
(
1
), pp.
151
161
.
15.
Pliquett
,
U.
,
Gallo
,
S.
,
Hui
,
S. W.
,
Gusbeth
,
C.
, and
Neumann
,
E.
, 2005, “
Local and Transient Changes in Stratum Corneum at High Electric Fields: Contribution of Joule Heating
,”
Bioelectrochemistry
1567-5394,
67
(
1
), pp.
37
46
.
16.
Vanbever
,
R.
,
Pliquett
,
U. F.
,
Preat
,
V.
, and
Weaver
,
J. C.
, 1999, “
Comparison of the Effects of Short, High-Voltage and Long, Medium-Voltage Pulses on Skin Electrical and Transport Properties
,”
J. Controlled Release
0168-3659,
60
(
1
), pp.
35
47
.
17.
Golden
,
G. M.
,
Guzek
,
D. B.
,
Kennedy
,
A. H.
,
Mckie
,
J. E.
, and
Potts
,
R. O.
, 1987, “
Stratum Corneum Lipid Phase-Transitions and Water Barrier Properties
,”
Biochemistry
0006-2960,
26
(
8
), pp.
2382
2388
.
18.
Potts
,
R. O.
, and
Francoeur
,
M. L.
, 1990, “
Lipid Biophysics of Water Loss Through the Skin
,”
Proc. Natl. Acad. Sci. U.S.A.
0027-8424,
87
(
10
), pp.
3871
3873
.
19.
Al-Saidan
,
S. M.
,
Barry
,
B. W.
, and
Williams
,
A. C.
, 1998, “
Differential Scanning Calorimetry of Human and Animal Stratum Corneum Membranes
,”
Int. J. Pharm.
0378-5173,
168
(
1
), pp.
17
22
.
20.
Cornwell
,
P. A.
,
Barry
,
B. W.
,
Bouwstra
,
J. A.
, and
Gooris
,
G. S.
, 1996, “
Modes of Action of Terpene Penetration Enhancers in Human Skin Differential Scanning Calorimetry, Small-Angle X-Ray Diffraction and Enhancer Uptake Studies
,”
Int. J. Pharm.
0378-5173,
127
(
1
), pp.
9
26
.
21.
Tanojo
,
H.
,
Bouwstra
,
J. A.
,
Junginger
,
H. E.
, and
Bodde
,
H. E.
, 1999, “
Thermal Analysis Studies on Human Skin and Skin Barrier Modulation by Fatty Acids and Propylene Glycol
,”
J. Therm Anal. Calorim.
1418-2874,
57
(
1
), pp.
313
322
.
22.
Silva
,
C. L.
,
Nunes
,
S. C. C.
,
Eusebio
,
M. E. S.
,
Pais
,
A. A. C. C.
, and
Sousa
,
J. J. S.
, 2006, “
Study of Human Stratum Corneum and Extracted Lipids by Thermomicroscopy and DSC
,”
Chem. Phys. Lipids
0009-3084,
140
(
1–2
), pp.
36
47
.
23.
Silva
,
C. L.
,
Nunes
,
S. C. C.
,
Eusebio
,
M. E. S.
,
Sousa
,
J. J. S.
, and
Pais
,
A. A. C. C.
, 2006, “
Thermal Behaviour of Human Stratum Corneum—A Differential Scanning Calorimetry Study at High Scanning Rates
,”
Skin Pharmacol. Physiol.
,
19
(
3
), pp.
132
139
.
24.
White
,
S. H.
,
Mirejovsky
,
D.
, and
King
,
G. I.
, 1988, “
Structure of Lamellar Lipid Domains and Corneocyte Envelopes of Murine Stratum Corneum. An X-Ray-Diffraction Study
,”
Biochemistry
0006-2960,
27
(
10
), pp.
3725
3732
.
25.
Pliquett
,
U.
, and
Gusbeth
,
C.
, 2004, “
Surface Area Involved in Transdermal Transport of Charged Species Due to Skin Electroporation
,”
Bioelectrochemistry
1567-5394,
65
(
1
), pp.
27
32
.
26.
Pliquett
,
U.
,
Gusbeth
,
C.
, and
Nuccitelli
,
R.
, 2008, “
A Propagating Heat Wave Model of Skin Electroporation
,”
J. Theor. Biol.
0022-5193,
251
(
2
), pp.
195
201
.
27.
Higuchi
,
W. I.
,
Li
,
K. S.
,
Abdel-Halim
,
G.
,
Honggang
,
Z.
, and
Yang
,
S.
, 1999, “
Mechanistic Aspects of Iontophoresis in Human Epidermal Membrane
,”
J. Controlled Release
0168-3659,
62
(
1–2
), pp.
13
23
.
28.
Li
,
S. K.
,
Higuchi
,
I.
,
Kochambilli
,
R. P.
, and
Zhu
,
H.
, 2004, “
Mechanistic Studies of Flux Variability of Neutral and Ionic Permeants During Constant Current dc Iontophoresis With Human Epidermal Membrane
,”
Int. J. Pharm.
0378-5173,
273
(
1–2
), pp.
9
22
.
29.
Michaels
,
A. S.
,
Chandraskeran
,
S. K.
, and
Shaw
,
J. E.
, 1975, “
Drug Permeation Through Human Skin: Theory and In Vitro Experimental Measurement
,”
AIChE J.
0001-1541,
21
(
5
), pp.
985
996
.
30.
Johnson
,
M. E.
,
Blankschtein
,
D.
, and
Langer
,
R.
, 1997, “
Evaluation of Solute Permeation Through the Stratum Corneum: Lateral Bilayer Diffusion as the Primary Mechanism
,”
J. Pharm. Sci.
0022-3549,
86
(
10
), pp.
1162
1172
.
31.
Wang
,
T.
,
Kasting
,
G. B.
, and
Nitsche
,
J. M.
, 2006, “
A Multiphase Microscopic Diffusion Model for Stratum Corneum Permeability. I. Formulation, Solution, and Illustrative Results for Representative Compounds
,”
J. Pharm. Sci.
0022-3549,
95
(
3
), pp.
620
648
.
32.
Frasch
,
H. F.
, and
Barbero
,
A. M.
, 2003, “
Steady-State Flux and Lag Time in the Stratum Corneum Lipid Pathway: Results From Finite Element Models
,”
J. Pharm. Sci.
0022-3549,
92
(
11
), pp.
2196
2207
.
33.
Barbero
,
A. M.
, and
Frasch
,
H. F.
, 2005, “
Modeling of Diffusion With Partitioning In Stratum Corneum Using a Finite Element Model
,”
Ann. Biomed. Eng.
0090-6964,
33
(
9
), pp.
1281
1292
.
34.
Kushner
,
J.
,
Deen
,
W.
,
Blankschtein
,
D.
, and
Langer
,
R.
, 2007, “
First-Principles, Structure-Based Transdermal Transport Model to Evaluate Lipid Partition and Diffusion Coefficients of Hydrophobic Permeants Solely From Stratum Corneum Permeation Experiments
,”
J. Pharm. Sci.
0022-3549,
96
(
12
), pp.
3236
3251
.
35.
Mitragotri
,
S.
, 2002, “
A Theoretical Analysis of Permeation of Small Hydrophobic Solutes Across the Stratum Corneum Based on Scaled Particle Theory
,”
J. Pharm. Sci.
0022-3549,
91
(
3
), pp.
744
752
.
36.
Lian
,
G.
,
Chen
,
L.
, and
Han
,
L.
, 2008, “
An Evaluation of Mathematical Models for Predicting Skin Permeability
,”
J. Pharm. Sci.
0022-3549,
97
(
1
), pp.
584
598
.
37.
Mitragotri
,
S.
, 2003, “
Modeling Skin Permeability to Hydrophilic and Hydrophobic Solutes Based on Four Permeation Pathways
,”
J. Controlled Release
0168-3659,
86
(
1
), pp.
69
92
.
38.
Kushner
,
J.
,
Blankschtein
,
D.
, and
Langer
,
R.
, 2007, “
Evaluation of the Porosity, the Tortuosity, and the Hindrance Factor for the Transdermal Delivery of Hydrophyllic Permeants in the Context of the Aqueous Pore Pathway Hypothesis Using Dual-Radiolabeled Permeability Experiments
,”
J. Pharm. Sci.
0022-3549,
96
(
12
), pp.
3263
3282
.
39.
Tezel
,
A.
,
Sens
,
A.
, and
Mitragotri
,
S.
, 2003, “
Description of Transdermal Transport of Hydrophilic Solutes During Low-Frequency Sonophoresis Based on a Modified Porous Pathway Model
,”
J. Pharm. Sci.
0022-3549,
92
(
2
), pp.
381
393
.
40.
Li
,
S. K.
,
Ghanem
,
A. H.
,
Teng
,
C. L.
,
Hardee
,
G. E.
, and
Higuchi
,
W. I.
, 2001, “
Iontophoretic Transport of Ogligonucleotides Across Human Epidermal Membrane: A Study of the Nernst-Plank Model
,”
J. Pharm. Sci.
0022-3549,
90
(
7
), pp.
915
931
.
41.
Deen
,
W. M.
, 1987, “
Hindered Transport of Large Molecules in Liquid-Filled Pores
,”
AIChE J.
0001-1541,
33
(
9
), pp.
1409
1425
.
42.
Chizmadzhev
,
Y. A.
,
Indenbom
,
A. V.
,
Kuzmin
,
P. I.
,
Galichenko
,
S. V.
,
Weaver
,
J. C.
, and
Potts
,
R. O.
, 1998, “
Electrical Properties of Skin at Moderate Voltages: Contribution of Appendageal Macropores
,”
Biophys. J.
0006-3495,
74
(
2
), pp.
843
856
.
43.
Pavselj
,
N.
,
Bregar
,
Z.
,
Cukjati
,
D.
,
Batiuskaite
,
D.
,
Mir
,
L. M.
, and
Miklavcic
,
D.
, 2005, “
The Course of Tissue Permeabilization Studied on a Mathematical Model of a Subcutaneous Tumor in Small Animals
,”
IEEE Trans. Biomed. Eng.
0018-9294,
52
(
8
), pp.
1373
1381
.
44.
Pavšelj
,
N.
,
Préat
,
V.
, and
Miklavčič
,
D.
, 2007, “
A Numerical Model of Skin Electropermeabilization Based on In Vivo Experiments
,”
Ann. Biomed. Eng.
0090-6964,
35
(
12
), pp.
2138
2144
.
45.
Becker
,
S. M.
, and
Kuznetsov
,
A. V.
, 2008, “
Thermal In Vivo Skin Electroporation Pore Development and Charged Macromolecule Trans-Dermal Delivery: A Numerical Study of the Influence of Chemically Enhanced Lower Lipid Phase Transition Temperatures
,”
Int. J. Heat Mass Transfer
0017-9310,
51
(
7–8
), pp.
2060
2074
.
46.
Becker
,
S. M.
, and
Kuznetsov
,
A. V.
, 2007, “
Thermally Induced Pore Growth Associated With In Vivo Skin Electroporation: A Numerical Model of Lipid Phase Transition Influence
,”
ASME J. Biomech. Eng.
0148-0731,
129
(
5
), pp.
712
721
.
47.
Ozisik
,
M. N.
, 1993,
Heat Conduction
,
Wiley
,
New York
.
48.
Pennes
,
H. H.
, 1948, “
Analysis of Tissue and Arterial Blood Temperatures in the Resting Forearm
,”
J. Appl. Physiol.
0021-8987,
1
, pp.
93
122
.
49.
Craane-van Hinsberg
,
W. H. M.
,
Verhoef
,
J. C.
,
Junginger
,
H. E.
, and
Bodde
,
H. E.
, 1995, “
Thermoelectrical Analysis of the Human Skin Barrier
,”
Thermochim. Acta
0040-6031,
248
, pp.
303
318
.
50.
Cussler
,
E.
,
Hughes
,
S.
,
Ward
,
W.
, and
Aris
,
R.
, 1988, “
Barrier Membranes
,”
J. Membr. Sci.
0376-7388,
38
(
2
), pp.
161
174
.
51.
Lange-Lieckfeldt
,
R.
, and
Lee
,
G.
, 1992, “
Use of a Model Lipid Matrix to Demonstrate the Dependence of the Stratum-Corneum Barrier Properties on Its Internal Geometry
,”
J. Controlled Release
0168-3659,
20
(
3
), pp.
183
194
.
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