Comparison of five dermal substitutes in full-thickness skin wound healing in a porcine model

Department of Plastic Surgery, Hôpital Nord, Chemin des Bourrely, 13915 Marseille, France.
Burns: journal of the International Society for Burn Injuries (Impact Factor: 1.88). 05/2012; 38(6):820-9. DOI: 10.1016/j.burns.2012.02.008
Source: PubMed

ABSTRACT

The wound healing attributes of five acellular dermal skin substitutes were compared, in a two-step procedure, in a porcine model. Ten pigs were included in this experimental and randomized study. During the first step, dermal substitutes (Integra(®), ProDerm(®), Renoskin(®), Matriderm(®) 2mm and Hyalomatrix(®) PA) were implanted into full-thickness skin wounds and the epidermis was reconstructed during a second step procedure at day 21 using autologous split-thickness skin graft or cultured epithelial autograft. Seven pigs were followed-up for 2 months and 3 pigs for 6 months. Dermal substitute incorporation, epidermal graft takes, wound contraction and Vancouver scale were assessed, and histological study of the wounds was performed. Results showed significant differences between groups in dermis incorporation and in early wound contraction, but there was no difference in wound contraction and in Vancouver scale after 2 and 6 months of healing. We conclude there was no long-term difference of scar qualities in our study between the different artificial dermis. More, there was no difference between artificial dermis and the control group. This study makes us ask questions about the benefit of artificial dermis used in a two-step procedure.

Full-text

Available from: Serge Mordon, Jun 11, 2015
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model
Ce
´
cile
Philandrianos
a,
*
,
Lucile
Andrac-Meyer
b
,
Serge
Mordon
c
,
Jean-Marc
Feuerstein
d
,
Florence
Sabatier
e
,
Julie
Veran
f
,
Guy
Magalon
f
,
Dominique
Casanova
f
a
Department
of
Plastic
Surgery,
Ho
ˆ
pital
Nord,
Chemin
des
Bourrely,
13915
Marseille,
France
b
Department
of
Pathological
Anatomy,
Ho
ˆ
pital
Nord,
Chemin
des
Bourrely,
13915
Marseille,
France
c
INSERM,
U
703,
Univ
Lille
Nord
de
France,
Lille
University
Hospital,
Loos,
France
d
Laboratory
of
Animal
Experimentation,
Faculty
of
Medicine
La
Timone,
Marseille,
France
e
Laboratoire
de
culture
et
the
´
rapie
cellulaire
CIC
BT
510,
Centre
Hospitalier
Universitaire
la
Conception,
Marseille,
France
f
Department
of
Plastic
Surgery,
Ho
ˆ
pital
de
la
Conception,
13005
Marseille,
France
1.
Introduction
In
full-thickness
skin
wound
healing,
dermal
reconstruction
is
fundamental
to
optimize
the
functional
and
esthetic
outcome.
Usually,
full-thickness
skin
graft
or
flaps
are
used
to
recon-
struct
the
dermis.
When
the
full-thickness
skin
wound
is
large,
like
in
burn
patients,
the
dermis
cannot
be
recon-
structed
by
classical
plastic
surgery
techniques
but
it
can
be
reconstructed
by
allograft
skin
[1].
An
alternative
is
the
use
of
artificial
dermal
substitutes
[2].
Dermal
substitutes
are
scaffolds
composed
of
extracellular
matrix
components:
collagen
and
glycosaminoglycan
or
hyaluronic
acid.
Their
composition
and
their
thickness
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
30
September
2011
Received
in
revised
form
14
January
2012
Accepted
4
February
2012
Keywords:
Artificial
dermis
Dermal
substitute
Skin
wound
healing
Porcine
model
a
b
s
t
r
a
c
t
The
wound
healing
attributes
of
five
acellular
dermal
skin
substitutes
were
compared,
in
a
two-step
procedure,
in
a
porcine
model.
Ten
pigs
were
included
in
this
experimental
and
randomized
study.
During
the
first
step,
dermal
substitutes
(Integra
1
,
ProDerm
1
,
Reno-
skin
1
,
Matriderm
1
2
mm
and
Hyalomatrix
1
PA)
were
implanted
into
full-thickness
skin
wounds
and
the
epidermis
was
reconstructed
during
a
second
step
procedure
at
day
21
using
autologous
split-thickness
skin
graft
or
cultured
epithelial
autograft.
Seven
pigs
were
followed-up
for
2
months
and
3
pigs
for
6
months.
Dermal
substitute
incorporation,
epidermal
graft
takes,
wound
contraction
and
Vancouver
scale
were
assessed,
and
histo-
logical
study
of
the
wounds
was
performed.
Results
showed
significant
differences
between
groups
in
dermis
incorporation
and
in
early
wound
contraction,
but
there
was
no
difference
in
wound
contraction
and
in
Van-
couver
scale
after
2
and
6
months
of
healing.
We
conclude
there
was
no
long-term
difference
of
scar
qualities
in
our
study
between
the
different
artificial
dermis.
More,
there
was
no
difference
between
artificial
dermis
and
the
control
group.
This
study
makes
us
ask
questions
about
the
benefit
of
artificial
dermis
used
in
a
two-step
procedure.
#
2012
Elsevier
Ltd
and
ISBI.
All
rights
reserved.
*
Corresponding
author
at:
Service
de
Chirurgie
Plastique
et
maxillo-facicale,
Department
of
Plastic
Surgery,
Hoˆ
pital
Nord,
Chemin
des
Bourrely,
13915
Marseille
Cedex
20,
France.
Tel.:
+33
491
968
690;
fax:
+33
491
964
350.
E-mail
addresses:
Cecile.philandrianos@ap-hm.fr,
cecphil@gmail.com
(C.
Philandrianos).
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Available
online
at
www.sciencedirect.com
journal
homepage:
www.elsevier.com/locate/burns
0305-4179/$36.00
#
2012
Elsevier
Ltd
and
ISBI.
All
rights
reserved.
doi:10.1016/j.burns.2012.02.008
Page 1
(1–2
mm)
are
variable.
Some
of
them
can
be
coupled
to
a
silicone
film.
Usually,
the
dermal
substitutes
are
covered
by
an
autolo-
gous
split-thickness
skin
graft
in
a
two-step
procedure
performed
21
days
after
dermal
substitute
grafting
[3].
This
delay
is
necessary
to
obtain
neovascularization
and
incorpo-
ration
of
the
matrix.
When
the
scaffold
is
vascularized,
it
is
able
to
provide
blood
supply
to
the
skin
graft.
Some
dermal
substitutes
like
Matriderm
1
1
mm
can
be
used
in
a
one-step
procedure:
the
dermal
substitute
is
immediately
covered
by
an
autologous
ski n
graft
[4].
In
this
case,
autograft
survival
is
not
altered
by
simultaneous
application
of
the
dermal
matrix
because
the
dermal
substitute
is
thin
(1
mm)
and
the
wound
can
feed
the
graft
through
the
matrix.
The
main
interest
lies
in
the
one
step
procedure;
its
disadvantage
is
the
thinness
of
the
recon-
str ucted
skin.
Dermal
substitutes
have
been
developed
for
30
years
[5].
Integra
1
dermal
regeneration
template
(Integra
LifeSciences
Services,
USA)
has
been
for
many
years
the
only
dermal
substitute
commercialized,
but
recently
several
new
artificial
dermis
have
been
developed
[6].
Unfortunately,
no
study
exists
that
compares
the
different
substitutes
in
skin
wound
healing,
except
in
a
mouse
model
[7]
and
in
a
rat
model
[8].
However,
data
provided
into
the
literature
[9–11]
are
not
sufficient
to
compare
these
different
substitutes.
The
reference
model
in
skin
wound
healing
studies
is
the
pig
model
[12–14].
This
model
is
used
by
most
teams
studying
artificial
dermis
[15–17].
The
interest
of
this
model
is
that
it
can
be
used
to
treat
large
wounds,
with
size
similar
to
human
beings.
That
is
why
we
conducted
an
experimental
randomized
study
in
a
porcine
model,
which
aimed
to
compare
the
wound
healing
attributes
of
five
artificial
acellular
dermal
skin
substitutes
(Integra
1
,
ProDerm
1
,
Renoskin
1
,
Matriderm
1
2
mm
1
and
Hyalomatrix
1
PA),
in
a
two-step
procedure.
Different
dermal
substitutes
were
implanted
into
full-thick-
ness
skin
wounds
during
the
first
step,
and
after
21
days,
the
epidermis
were
reconstructed
using
autologous
split-thick-
ness
skin
graft
or
cultured
keratinocytes.
2.
Materials
and
methods
2.1.
Animal
models
Ten
female
Large-White
(Yorkshire)
pigs,
weighing
approxi-
mately
20–25
kg
each,
were
studied
and
kept
under
standard
conditions
in
the
animal
care
unit
in
Marseille
‘‘Timone
Medical
University’’.
The
protocol
was
approved
by
the
experimental
ethic
committee.
2.2.
Anesthesia
The
pigs
were
sedated
by
intramuscular
injection
with
ketamine
10
mg/kg,
stressnil
and
1
mg/kg
atropine.
Complete
anesthesia
was
induced
with
an
intravenous
perfusion
of
propofol.
The
animals
were
incubated
and
artificial
respira-
tion
was
applied.
During
the
surgery,
analgesia
was
provided
by
intramuscular
injections
of
morphine.
2.3.
Artificial
dermis
preparation
Five
acellular
artificial
dermis
were
chosen
to
be
compared;
all
of
them
had
to
be
used
in
a
two-step
procedure:
-
Integra
1
dermal
regeneration
template
(Integra
LifeSciences
Services,
USA)
is
a
2.1
mm
thick
bi-laminar
skin
substitute
composed
of
a
layer
of
bovine
tendon
collagen
type
I
matrix
and
shark
chondroı
¨
tine-6-sulfate
and
a
silicone
layer
that
acts
as
a
temporary
pseudo-epidermis
[3],
-
Renoskin
1
(Symate
`
se,
France)
is
a
2
mm
thick
bi-laminar
skin
substitute
composed
of
a
bovine
collagen
matrix
type
1
and
a
strengthened
silicone
film
[16,18],
-
Matriderm
1
2
mm
(Skin
&
Health
Care,
Germany)
is
a
2
mm
thick
lyophilized
single-laminar
matrix
of
bovine
collagen
type
1,
3,
5
with
elastin
[4],
-
ProDerm
1
(Laboratoire
Gene
´
vrier,
France)
is
a
2
mm
thick
equine
collagen
matrix
type
1,
chitosan
and
chondroitin
sulfates
[17,19],
-
Hyalomatrix
1
(Fidia
Advanced
Biopolymers,
Italy)
is
a
2
mm
thick
esterified
hyaluronic
acid
fiber
matrix
beneath
a
silicone
membrane
[20,21].
Prior
to
use,
Renoskin
1
,
ProDerm
1
,
Matriderm
1
were
rehydrated
in
physiological
saline
solution
for
a
few
minutes
and
Integra
1
was
rinsed
with
physiological
serum
for
a
few
minutes.
2.4.
Wound
healing
and
dermal
reconstruction
On
day
0,
each
pig
was
anesthetized
and
placed
in
a
ventral
recumbent
position.
The
surgical
site
was
cleaned
with
betadine
1
and
the
animals
were
administered
a
prophylactic
antibiotic
(amoxicillin).
Twelve
16
cm
2
full-thickness
excision
wounds
were
performed
on
the
dorsum
of
each
animal.
The
borders
of
each
4
cm
4
cm
paraspinal
defect
were
marked
with
a
tattooing
device.
Each
wound
was
either
immediately
implanted
with
one
of
the
five
acellular
dermal
substitutes
(previously
cut
to
the
size
of
the
wounds
with
scissors)
or
assigned
to
the
control
group
with
no
dermal
substitute
using
a
randomization
scheme
to
avoid
site
bias.
Matrices
were
held
in
place
with
skin
staples.
Wounds
were
primarily
dressed
with
Adaptic
1
,
and
were
covered
with
compresses.
The
dorsum
of
the
animal
was
secured
with
elastic
tape.
Every
week,
the
animals
were
anesthetized
to
change
the
dressing
and
to
perform
a
gross
wound
observation,
including
digital
photographies.
The
silicone
films
were
removed
when
complete
detachment
of
the
pseudo-epidermis
was
noted.
Artificial
dermis
integration
gross
observations
were
recorded
at
day
14.
2.5.
Epidermal
reconstruction
21
days
after
surgery,
each
pig
was
anesthetized
again,
placed
in
a
ventral
recumbent
position
and
the
surgical
site
was
cleaned
with
betadine
1
.
All
wounds
(including
the
control
wounds)
were
prepared
for
application
of
epidermal
autograft
by
excising,
with
a
surgical
blade,
any
epithelia
from
the
wound
periphery.
Hemostasis
was
obtained
through
cauterization.
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x2
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 2
2.5.1.
Autologous
thin
skin
graft
(for
7
pigs)
Split-thickness
skin
grafts
(0.2
mm
thick)
were
taken
with
a
dermatome
from
the
lateral–thoracic
region.
The
skin
was
perforated
with
a
surgical
blade
in
4
pigs
(pigs
1,
2,
3
and
5),
and
was
meshed
by
a
ratio
of
1:2
in
3
pigs
(pigs
7,
9
and
10),
grafted
onto
the
wounds,
and
held
in
place
with
surgical
staples.
2.5.2.
Cultured
epithelial
autograft
(for
pigs
4,
6
and
8)
The
cultured
epithelial
autograft
was
prepared
as
described
by
Rheinwald
and
Green
[22].
At
day
0,
split-thickness
skin
samples
were
taken
from
the
excised
skin.
The
epidermis
was
mechanically
separated
from
the
dermis
after
incubation
with
Dispase
(2.4
UI/ml,
Roche,
Ref.
10295825)
at
4
8C
for
18
h.
The
epidermis
was
disaggregated
in
a
0.05%
trypsine–0.01%
ethylenediaminetetraacetic
solution
(Gibco,
Ref.
25300)
at
37
8C
for
15
min.
The
keratinocyte
suspension
was
filtered
and
supplemented
with
20%
fetal
calf
serum
and
growth
substances.
Approximately
4
10
6
keratinocytes
were
inocu-
lated
in
75-cm
2
cell
culture
flask
and
maintained
in
culture
at
37
8C,
5%
CO
2
for
18–21
days
until
confluence
of
keratinocytes
and
stratification
into
a
several
layers
thick
cultured
epider-
mis.
Incubation
at
37
8C
with
Dispase
II
during
15
min
allowed
gentle
detachment
of
the
epidermal
sheets
from
the
culture
flasks.
They
were
then
attached
by
ligating
clips
to
calcium
alginate
gauze
(Algosteryl
1
5
cm
5
cm),
backing
with
their
basal
surfaces
away
from
the
gauze.
Cultured
epithelial
autografts
associated
to
gauze
bilayers
were
bathed
in
sterile
phosphate
buffered
saline
to
remove
residual
dispase.
The
basal
layer
of
the
cultured
epithelial
autograft
associated
to
gauze
grafts
was
placed
on
the
wound
bed
of
the
3
pigs.
The
gauze
backing
was
secured
to
the
wound
with
surgical
staples.
Gross
observations
of
epidermal
graft
taken
were
recorded
at
day
28.
2.6.
Clinical
evaluation
Seven
pigs
were
under
observation
for
60
days
and
three
pigs
for
6
months.
The
surface
of
the
wounds
at
day
21,
day
60
(for
all
pigs)
and
6
months
(for
pigs
7,
9
and
10)
have
been
measured
and
each
wound
was
assessed
for
contraction.
Surfaces
were
followed
by
tracing
the
wound
edges
and
the
tattooed
grid
on
computer
(Autocad
software)
with
digital
pictures.
Wound
contraction
(or
expansion)
was
measured
by
computer
planimetry,
expressed
as
percentage
of
reduction
(or
expansion)
of
original
wound
area
(16
cm
2
).
The
surface
of
the
incorporated
matrix
at
day
14
and
the
surface
of
the
taken
skin
graft
at
day
28
have
been
measured.
A
score
was
used
to
assess
dermal
incorporation
and
epidermal
graft
take:
-
Score
0:
0%
taken
-
Score
1:
<50%
taken
-
Score
2:
50%
taken
-
Score
3:
100%
taken
Functional
and
esthetic
outcome
was
assessed
using
the
Vancouver
scale
(height,
pliability,
vascularization
and
pig-
mentation
of
scars)
at
day
60
and
6
months.
2.7.
Histological
wound
evaluation
4
mm
biopsies
were
performed
on
each
wound,
in
the
middle
part
of
the
wound,
at
day
21,
day
60
and
for
3
pigs,
at
6
months.
Each
biopsy
was
fixed
in
10%
formalin,
embedded
in
paraffin,
section
(5
mm),
and
stained
with
hematoxylin
and
eosin.
Histological
aspects
of
the
dermis
and
epidermis
were
assessed
by
an
independent
pathologist
unaware
of
the
applied
wound
healing
strategy.
2.8.
Statistical
analysis
The
statistical
analysis
was
performed
with
SAS
Version
9.1.
An
analysis
of
variance
(parametric
approach),
or
a
Kruskal–
Wallis
(non
parametric
approach)
tests
were
used
to
detect
a
treatment
effect.
They
were
followed
by
appropriate
multiple
comparisons
tests
in
case
of
significant
global
effect:
-
Parametric
approach:
Dunn
test–Dunnett
test
in
case
of
control
group.
-
Non
parametric
approach:
Kruskal–Wallis
with
Bonferroni
adjustment.
3.
Results
3.1.
Gross
wound
observations
(Fig.
1)
3.1.1.
Artificial
dermis
integration
(Table
1)
We
observed
significant
differences
in
dermis
incorporation
between
some
groups:
integration
of
Integra
1
was
signifi-
cantly
less
than
integration
of
Hyalomatrix
1
(
p
=
0.022)
and
Matriderm
1
(
p
=
0.020).
We
also
observed
complete
lysis
of
the
substitute
in
6
wounds
treated
with
Integra
1
,
5
wounds
treated
with
Renoskin
1
and
2
wounds
treated
with
ProDerm
1
.
Conversely,
complete
lysis
was
never
observed
on
wounds
treated
with
Hyalomatrix
1
and
Matriderm
1
.
Table
1
Dermis
incorporation
at
day
14.
Dermal
substitute
Wound
dermis
incorporation
(score
0–1–2–3)
Mean
score
Pig
1
Pig
2
Pig
3
Pig
4
Pig
5
Pig
6
Pig
7
Pig
8
Pig
9
Pig
10
Integra
1
3
2
1
3
0
0
0
0
0
0
3
3
3
3
2
3
3
3
3
3
1.90
Renoskin
1
0
0
1
3
0
3
0
0
2
1
3
3
3
3
3
3
3
3
3
3
2.00
Matriderm
1
2
2
3
2
2
3
2
0
3
3
3
3
3
3
3
3
3
3
3
3
2.60
ProDerm
1
2
3
3
0
0
1
2
0
2
3
3
3
3
3
3
3
3
3
3
3
2.30
Hyalomatrix
PA
1
3
3
0
3
3
0
3
3
3
3
2
3
3
3
3
3
3
3
3
3
2.65
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x
3
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No.
of
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Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 3
3.1.2.
Epidermal
graft
integration
(Table
2)
-
Split-thickness
skin
graft
integration
We
did
not
observe
differences
in
skin
graft
integration
between
artificial
dermis
groups.
There
was
also
no
difference
between
artificial
dermis
groups
and
the
control
group.
-
Cultured
epithelial
autograft
We
did
not
observe
epidermalisation
of
the
wounds
at
day
28
in
our
study.
We
suppose
there
was
a
lysis
of
the
cultured
epithelium
in
all
wounds
whatever
the
dermal
substitute
used.
3.1.3.
Surfaces
of
the
wounds
(Fig.
2)
At
day
0,
surfaces
of
every
wound
were
about
16
cm
2
.
At
day
21
mean
surfaces
were
between
10.4
cm
2
for
control
group
(standard
error
of
the
mean
was
0.63
cm
2
)
and
12
cm
2
for
Hyalomatrix
1
and
Integra
1
groups
(standard
error
of
the
means
were
0.89
cm
2
and
0.64
cm
2
).
At
day
60,
mean
surfaces
were
between
8.8
cm
2
for
Proderm
1
group
(standard
error
of
the
mean
was
0.45
cm
2
)
Fig.
1
Gross
aspect
of
one
wound
of
each
group
from
the
pig
#7
at
day
0,
day
21
(before
skin
grafting),
day
28,
2
months
and
6
months.
Day
0:
implantation
of
the
scaffold,
day
21:
we
observe
contraction
of
the
wounds
and
peripherical
epidermization
of
the
wounds,
day
28:
we
observe
skin
graft
take,
two
months:
we
observe
contraction
of
the
scars,
six
months:
we
observe
expansion
of
the
scars.
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x4
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 4
and
9.4
cm
2
for
control
group
(standard
error
of
the
mean
was
0.53
cm
2
).
At
6
months,
mean
surfaces
were
between
20
cm
2
for
Hyalomatrix
1
group
(standard
error
of
the
mean
was
0.65
cm
2
)
and
23.5
cm
2
for
control
group
(standard
error
of
the
mean
was
0.9
cm
2
).
3.1.4.
Scar
contraction
or
expansion
(Fig.
3)
-
Day
21
At
day
21,
we
observed
contraction
of
all
wounds.
Wound
contraction
percentages
were
significantly
different
(less
contraction)
from
the
control
group
for
wounds
treated
with
Integra
1
(25%
of
contraction,
standard
error
of
the
mean
was
4%,
p
=
0.038),
Hyalomatrix
1
(24%
of
contraction,
standard
error
of
the
mean
was
5.6%,
p
=
0.032)
and
Matriderm
1
(28%
of
contraction,
standard
error
of
the
mean
was
3.4%,
p
=
0.048).
At
the
opposite
there
was
no
difference
between
ProDerm
1
(29%
of
contraction,
standard
error
of
the
mean
was
4.8%),
Renoskin
1
(34%
of
contraction,
standard
error
of
the
mean
was
3.51%)
and
Control
(35%
of
contraction,
standard
error
of
the
mean
was
4%).
-
Day
60
At
day
60,
we
also
observed
contraction
of
all
wounds.
Percentages
retraction
range
from
41.4%
(standard
error
of
the
mean
was
3.3%)
to
44.7%
(standard
error
of
the
mean
was
2.8%)
of
contraction.
We
did
not
observe
differences
in
wound
contraction
between
artificial
dermis
groups
at
2
months
of
healing.
Also,
there
was
no
difference
between
artificial
dermis
groups
and
control
group.
-
Six
months
Three
pigs
were
followed
for
6
months
(pigs
7,
9
and
10).
There
was
no
contraction
but
expansion
of
the
scars.
We
observed
growth
of
the
scars
in
all
groups.
There
was
no
significant
difference
between
groups.
3.1.5.
Vancouver
scale
All
scars
were
supple,
with
a
normal
height
and
a
normal
pigmentation.
The
only
differences
between
scars
were
about
the
color.
Scars
were
pink
when
skin
graft
take
was
good,
and
red
when
skin
graft
did
not
take.
There
was
no
significant
difference
on
Vancouver
scale
at
2
months
and
6
months
between
the
groups.
3.2.
Histological
observations
(Fig.
4)
3.2.1.
Day
21
In
all
cases,
the
scars,
observed
under
microscope,
were
composed
of
richly
vascularized
granulation
tissue
(measured
5
mm
thick
for
all
groups)
and
there
was
no
epidermis.
We
observed
differences
between
groups
about
resorption
of
the
scaffolds:
some
scaffolds
were
intact,
some
were
fragmented
and
some
were
totally
resorbed.
-
Wounds
treated
with
Integra
1
The
matrices
were
intact
in
most
of
the
wounds.
In
the
others,
the
matrices
were
partially
fragmented.
Mean
thickness
of
the
scaffolds
was
1.2
mm.
-
Wounds
treated
with
Renoskin
1
Wounds
treated
with
Renoskin
1
showed
complete
resorption
of
the
collagen
scaffolds
at
day
21
in
all
wounds.
Mean
thickness
of
the
scaffold
was
0
mm.
Table
2
Epidermal
take
at
day
28.
Dermal
substitute
Split-thickness
skin
graft
take
(score
0–1–2–3)
Mean
score
Pig
1
Pig
2
Pig
3
Pig
5
Pig
7
Pig
9
Pig
10
Integra
1
2
0
0
3
3
2
1
1
2
3
2
3
3
3
2.000
Renoskin
1
0
1
0
1
0
2
1
1
3
3
2
0
2
3
1.357
Matriderm
1
3
2
0
1
2
2
2
1
1
3
3
0
3
3
1.857
ProDerm
1
0
0
0
3
2
2
2
1
3
3
1
2
3
2
1.714
Hyalomatrix
PA
1
1
0
2
0
2
0
1
3
2
0
0
0
2
0
0.928
Control
1
3
0
3
0
2
1
1
3
3
1
1
3
2
1.714
Fig.
2
Mean
surfaces
of
the
wounds
(cm
2
)
at
day
0,
day
60
and
6
months.
Error
bars
are
the
standard
error
of
the
means.
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x
5
JBUR-3704;
No.
of
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Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 5
-
Wounds
treated
with
Matriderm
1
The
matrices
were
partially
fragmented.
Mean
thickness
of
the
scaffold
was
0.8
mm.
-
Wounds
treated
with
ProDerm
1
In
all
wounds,
the
matrices
were
totally
fragmented.
Mean
thickness
of
the
scaffolds
was
2.9
mm.
-
Wounds
treated
with
Hyalomatrix
1
The
matrices
were
intact
in
all
wounds.
The
mean
thickness
of
the
scaffold
was
4.9
mm.
-
Control
wounds
Granulation
tissue
had
formed
in
the
full
thickness
of
the
wounds.
3.2.2.
Day
60
An
epidermis
was
present
in
all
wounds
whatever
the
artificial
dermis
used.
Skin
basement
membranes
had
two
different
aspects:
a
papillary
basement
membrane
was
observed
in
wounds
that
had
incorporated
skin
graft;
conversely,
an
immature
linear
basement
membrane,
was
observed
in
wounds
where
skin
grafts
or
cultured
keratinocytes
grafts
has
failed.
But
there
was
no
difference
between
groups.
For
each
group,
the
reconstructed
dermis
had
a
histological
appearance
similar
to
control
group
at
2
months.
In
all
wounds,
the
scaffolds
were
either
totally
resorbed
or
totally
fragmented
and
partially
resorbed.
-
Wounds
treated
with
Integra
1
Wounds
showed
complete
resorption
of
the
collagen
scaffolds
in
most
of
the
wounds.
In
2
wounds,
the
matrices
were
incompletely
degraded.
-
Wounds
treated
with
Renoskin
1
Wounds
showed
complete
degradation
of
the
collagen
scaffolds
in
all
wounds.
-
Wounds
treated
with
Matriderm
1
The
scaffolds
were
totally
resorbed
in
all
wounds.
-
Wounds
treated
with
ProDerm
1
Resorption
of
the
scaffolds
was
not
complete.
The
scaffolds
were
fragmented.
-
Wounds
treated
with
Hyalomatrix
1
The
scaffolds
were
fragmented
in
all
wounds.
3.2.3.
Six
months
There
was
no
difference
of
histological
aspect
of
the
scars
between
groups
after
6
months
of
healing.
All
scaffolds
were
resorbed.
In
all
cases,
the
epidermis
and
dermis
was
reconstructed
with
a
papillary
basal
membrane
(Fig.
4).
4.
Discussion
Many
artificial
dermis
are
commercially
available,
each
claim-
ing
better
than
the
competitors.
However,
there
are
few
studies
comparing
the
effects
of
artificial
dermis.
Schneider
et
al.
in
2009
[8]
made
a
comparison
between
Integra
1
and
Matriderm
1
in
a
two-steps
procedure
in
a
rat
model.
They
did
not
observe
any
significant
differences.
Trunog
in
2005
[7],
reported
a
comparison
between
some
synthetic
dermal
substitutes
and
some
human
skin-derived
products
in
mice
model.
Several
studies
assessed
wound
healing
using
artificial
dermis
in
porcine
model
[4,15,23,24,25,26].
Sometimes
studies
Fig.
3
Scar
contraction
or
expansion.
We
observe
contraction
of
all
wounds
at
21
and
60
days
and
then
expansion
of
the
wounds
at
6
months.
There
was
no
difference
between
groups
at
2
months
and
6
months.
Error
bars
are
the
standard
error
of
the
means.
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x6
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 6
aim
to
highlight
the
benefit
of
an
artificial
dermis
over
a
simple
skin
graft
[25].
Sometimes
properties
of
a
new
artificial
dermis
are
compared
to
substitute
reference
(Integra
1
).
For
example,
Druecke
et
al.
in
2004
[16]
made
a
comparison
between
Integra
1
,
a
polyethyleneglycer ol
terephthalate–
polybutylene
terephthalate
scaffold
and
a
collagen
scaffold
prepared
by
Symatese,
Biomateriaux
(Lyon,
France)
in
a
pig
model,
in
a
one-step
procedure.
They
studied
graft
take,
contraction,
cosmetic
appearance
and
histological
charac-
teristics
(scar
tissue
quality,
scaffold
angiogenesis)
during
6
weeks.
In
some
studies,
modalities
of
artificial
dermis
epithelialization
such
as
keratinocyte
seeding,
cultured
epithelial
autograft,
split
skin
graft
thickness
are
evaluated
[23,24,26].
Fig.
4
Histological
aspect
of
the
scaffold
and
of
one
wound
of
each
group
at
day
21,
day
60
and
6
months.
At
day
21:
Integra
W
-treated
wound:
granulation
tissue
is
formed
through
the
scaffold,
the
matrix
is
not
fragmented;
Renoskin
W
-
treated
wound:
the
matrix
is
degraded,
very
few
fragments
of
the
scaffold
are
founded
in
giant
cells;
Matriderm
W
-treated
wound:
the
scaffold
is
partially
fragmented;
ProDerm
W
-treated
wound:
the
scaffold
is
fragmented
and
a
clear
host
response
reaction
is
evidenced
by
giant
cells
surrounding
scaffold
fragments;
Hyalomatrix
W
-treated
wound:
the
hyaluronic
acid
fibers
are
intact;
Control
wound:
granulation
tissue.
At
day
60:
An
epidermis
was
present
in
all
wounds.
In
the
Hyalomatrix
wound
image,
we
can
see
that
basement
membrane
can
be
papillary
or
linear
At
6
months:
Epidermis
and
dermis
are
reconstructed
in
all
cases.
There
is
no
difference
between
wounds.
Scars
are
very
close
to
normal
pig
skin.
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x
7
JBUR-3704;
No.
of
Pages
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Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 7
However,
there
are
no
studies
where
many
commercial
artificial
derma
are
compared
in
a
two-step
procedure.
To
the
best
of
our
knowledge,
our
study
is
the
first
in
which
the
effects
of
many
dermal
substitutes
are
compared
in
a
standardized
pig
model.
Despite
the
increasing
use
of
artificial
dermis
in
a
single
session
[4,27],
and
in
particular
Matriderm
1
1
mm,
we
chose
to
compare,
artificial
dermis
applied
in
two
operating
steps
because
they
are
the
most
frequently
used
to
date.
Since
there
is
no
comparative
study
on
artificial
dermis
used
in
two
steps,
it
seemed
preferable
to
start
the
study
with
those
first.
In
this
study,
we
observed
significant
differences
concern-
ing
the
integration
of
artificial
dermis,
with
a
better
rate
of
integration
for
Hyalomatrix
1
and
Matriderm
1
.
There
was
no
difference
concerning
autologous
epidermal
graft
integration
and
conversely
to
Orgill
et
al.
[28],
we
did
not
obtain
evidence
of
keratinocytes
engraftment
in
all
groups
as
Melendez
et
al.
[29]
in
their
study.
We
observed
significant
differences
for
early
wounds
retraction
(21
days)
between
some
groups,
but
there
was
no
difference
in
long-term
wound
retraction
(day
60
and
6
months).
There
was
also
no
long-term
difference
of
functional
and
esthetic
outcome
assessed
with
Vancouver
scale.
In
our
histological
study,
we
observed
differences
between
groups
in
resorption
of
the
matrices.
The
scaffolds
tested
had
different
kinetics
of
resorption:
Renoskin
1
had
the
fastest
resorption,
then
ProDerm
1
,
then
Matriderm
1
,
then
Integra
1
and
then
Hyalomatrix
1
had
the
slowest.
But,
there
was
no
difference
of
dermal
and
epidermal
architecture
on
the
2
months
and
the
6
months
biopsies
between
groups.
So
this
study
demonstrates
that,
in
spite
of
differences
of
dermis
integration,
dermis
resorption
and
early
wound
contrac-
tion,
there
was
no
significant
difference
of
long-term
macro-
scopic
and
microscopic
scar
qualities
between
artificial
dermis
groups
and
between
artificial
dermis
group
and
control
group.
Our
first
conclusion
is
that
in
this
study,
long
term
scar
quality
of
a
wound
treated
with
artificial
dermis
and
skin
graft
is
as
good
as
a
skin
graft
alone.
These
results
make
us
ask
questions
about
our
experimental
model,
about
our
methods,
and
about
the
usefulness
of
the
artificial
dermis
tested.
Is
our
experimental
model
a
good
model?
The
reference
model
in
skin
wound
healing
studies
is
the
pig
model
[18–20].
This
model
is
used
by
most
teams
studying
artificial
dermis
[15–17,23–26,28].
But
pigs
are
not
the
only
animals
that
can
be
used
to
study
artificial
dermis:
mouse
[7]
and
rat
[8]
can
also
be
used.
The
interest
of
pig
model
is
that
it
can
be
used
to
treat
large
wounds,
with
size
similar
to
human
beings.
That’s
why
we
choose
this
model.
However
pigs
are
large
animals,
which
can
make
their
handling
a
challenge.
So,
the
number
of
animals
is
limited.
Another
limitation
of
this
model
is
related
to
the
rapid
healing
of
pigs
when
compared
to
humans.
Indeed,
pigs
heal
wounds
faster
and
tend
to
retract
more
significantly.
Thus
we
chose
to
make
larger
wounds
in
comparison
to
some
previous
studies
[16,23].
A
size
of
16
cm
2
(4
cm
4
cm)
allowed
us
both
to
limit
the
number
of
animals,
and
to
reduce
spontaneous
epitheli-
alization.
Like
most
of
the
studies
[15,17,24,25,28,30,31],
we
used
Yorkshire
pigs
weighing
about
20–25
kg.
At
this
weight,
pigs
are
considered
immature.
Immature
pigs
heal
faster
and
tend
to
contract
more
significantly
than
mature
pigs.
In
our
study,
pigs
were
immature
at
the
beginning
and
became
mature
at
the
end
of
the
study
(after
6
months
of
follow
up).
They
have
grown
during
the
study,
that
is
why
the
scars
were
bigger
at
6
months.
First
we
observed
a
contraction
of
the
wounds,
and
then
we
observed
an
expansion.
Was
our
protocol
good?
Among
the
artificial
derma
we
compared,
some
were
supposed,
in
human
beings,
to
be
covered
with
a
skin
graft
at
21
days
(Integra
1
[32],
Renoskin
1
).
Others
could
be
grafted
either
21
days
or
earlier
(in
particular:
Matriderm
1
[8]
and
Hyalomatrix
1
[26,33]).
For
our
study,
we
chose
to
perform
the
second
surgical
procedure
at
21
days
for
all
groups
to
have
a
standardized
procedure
in
order
to
avoid
bias
in
the
evalua-
tion.
But
we
know
that
pigs
heal
wounds
faster
than
human.
To
observe
difference
between
control
group
and
artificial
dermis
groups
it
should
be
probably
better
to
perform
the
second
surgical
procedure
at
14
days.
This
should
be
done
in
another
future
study.
To
study
scar
contraction
in
pigs,
Druecke
et
al.
[16]
and
Lamme
et
al.
[25]
made
3
cm
3
cm
wounds,
Reid
et
al.
[30]
performed
4
cm
4
cm
wounds,
Myers
et
al.
[26]
performed
5
cm
5
cm
wounds,
Braye
et
al.
[17]
performed
10
cm
10
cm
wounds.
Li
performed
2.5
cm
2.5
cm
wounds
and
Truong
[7]
2
cm
2
cm
wounds
in
mice.
To
be
able
to
compare
5
artificial
dermis
on
each
pig,
we
used
4
cm
4
cm
wounds.
It
is
possible
that
if
we
had
performed
bigger
wounds
we
would
be
able
to
observe
a
significant
difference
of
wound
retraction
at
2
months,
if
there
was
one.
Also,
maybe
if
we
had
included
more
pigs
we
would
be
able
to
find
a
difference.
Maybe
we
did
not
find
it
because
of
the
statistical
power
of
our
study.
But
at
6
months,
instead
of
having
a
retraction
of
the
scars,
we
observed
an
expansion.
There
was
also
no
difference
between
groups,
but
the
group
with
the
better
expansion
was
the
control
group.
We
conclude
that
artificial
dermis,
as
delayed
skin
graft,
allowed
expansion
of
scars
with
growth.
What
about
the
usefulness
of
the
artificial
dermis
tested?
In
this
study,
we
were
not
able
to
light
a
long-term
difference
between
the
5
artificial
dermis
tested.
Despite
all
arguments
described
upper
(young
pigs,
small
wounds),
our
results
demonstrated
that
long
term
results
of
full
thickness
skin
wound
healing
using
epidermal
graft
after
3
weeks
of
spontaneous
healing
was
as
good
as
using
each
of
the
5
artificial
dermis
in
two-step
procedure.
Our
findings
corrobo-
rate
a
recent
study
in
a
porcine
model
that
suggested
that
good
skin
graft
take
was
more
important
than
neodermis
formation
for
wound
contraction
[30].
Regarding
our
results,
we
think
that
limitation
of
long-term
scar
retraction
and
esthetic
outcome
are
not
arguments
for
using
artificial
dermis
in
2-
step
procedure.
We
obtain
same
long-term
results
with
spontaneous
healing
and
delayed
skin
graft.
5.
Conclusion
Create
an
artificial
skin
is
a
challenge
in
plastic
surgery.
It
is
also
a
commercial
challenge
for
the
laboratories.
No
effect
was
b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x8
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 8
seen
in
this
pre-clinical
model,
and
these
results
question
whether
artificial
dermis
has
beneficial
effects
in
patients;
this
must
be
tested
in
humans.
Conflict
of
interest
statement
None
of
the
authors
have
conflict
of
interest
regarding
the
commercial
skin
constructs.
Acknowledgments
The
authors
wish
to
thank
Pascal
Servell
for
his
careful
review
of
the
English
language
of
this
manuscript.
The
authors
would
like
to
thank
Patricia
Stellman
and
Laurent
Giraudo
for
technical
assistance
in
the
production
of
cultured
epidermal
sheets
and
Marie-Noelle
Lavaut
for
assistance
in
histological
analyses.
The
authors
would
also
like
to
thank
Addmedica,
Medical
Z,
Genevrier,
Skin
&
Health
Care
Laboratories,
for
their
financial
support,
Perouse
for
giving
them
the
matrix
(Reno-
skin
1
)
for
the
study.
r
e
f
e
r
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c
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9
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 9
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b
u
r
n
s
x
x
x
(
2
0
1
2
)
x
x
x
x
x
x10
JBUR-3704;
No.
of
Pages
10
Please
cite
this
article
in
press
as:
Philandrianos
C,
et
al.
Comparison
of
five
dermal
substitutes
in
full-thickness
skin
wound
healing
in
a
porcine
model.
Burns
(2012),
doi:10.1016/j.burns.2012.02.008
Page 10
  • Source
    • "No long-term difference of scar quality between the different substitutes and the control group was seen. The authors therefore question the benefit of a two-step procedure [71]. Nevertheless, we clearly see a role for a two-step procedure making use of the bilayered version of Integra in treating extensively burned patients. "
    Full-text · Article · Feb 2016 · International Journal of Burns and Trauma
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    • "All of these techniques have encouraged the initiation and development of dermal substitutes or equivalents (Rennekampff et al., 1996; Yannas, 1998). In recent decades, numerous dermal substitutes have been developed to repair various skin defects, and have been applied in clinical practice (Banyard et al., 2015; Philandrianos et al., 2012). The available evidence indicates that the use of dermal substitutes in this setting results in high-quality healing with improved skin elasticity, and reduced scar contracture (Jiong et al., 2010; Sasidaran et al., 2008; Yim et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: The advent of dermal substitutes provides a revolutionary strategy for the repair and reconstruction of deep skin defects. Dermal substitutes form a regenerative template that provides the porous structure and mechanical support necessary to guide cell migration, deposition of the extracellular matrix (ECM) and angiogenesis. Commercially available dermal substitutes, particularly collagen-based dermal scaffolds, are widely used in clinical practice. However, the poor mechanical properties of collagen-based dermal scaffolds compromise their biological effects, as well as the repair outcomes. Here, we describe a bilayer dermal substitute prepared by integrating a hybrid dermal scaffold with a polyurethane (PU) membrane to obtain a PU membrane/knitted mesh-reinforced collagen-chitosan bilayer dermal substitute (PU-PLGAm/CCS). The morphology of PU-PLGAm/CCS was investigated and, to characterize the effects of PU-PLGAm/CCS on tissue regeneration, dermal substitutes were transplanted to repair full-thickness skin wounds in Sprague-Dawley rats using a two-step surgical procedure. These results were then compared with those obtained using the PELNAC™ Artificial Dermis. In the weeks after the first operation, wound changes were analysed based on macroscopic observations, and tissue specimens were harvested for histology, immunohistochemistry, immunofluorescence real-time quantitative PCR, and Western blotting analysis. Following the second operation (i.e., transplantation of split-thickness skin grafts), the repair outcomes were investigated based on the mechanical strength and ECM expression. PU-PLGAm/CCS significantly inhibited wound contracture, promoted angiogenesis, and facilitated the ordered arrangement of neotissue, such that the repair outcomes were improved in the PU-PLGAm/CCS group compared with the PELNAC™ group. In conclusion, the favourable microstructure and structural stability of dermal substitutes facilitated tissue regeneration. PU-PLGAm/CCS achieved a balance between porous structure, biocompatibility and mechanical properties for dermal regeneration by integrating the advantages of biological and synthetic biomaterials, which demonstrates its potential for skin tissue engineering.
    Full-text · Article · Dec 2015 · Journal of the Mechanical Behavior of Biomedical Materials
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    • "Dermal substitutes including AlloDerm (LifeCell Corp., Branchburg, N.J.), Integra (Integra Life Science Corp., Plainsboro, N.J.) and Pelnac (Gunze Ltd., Ayabe, Japan) in combination with a split thickness skin graft have been used for the treatment of GCMN [28,29] . However, the results achieved with skin substitutes did not provide superior form and function compared with other conventional methods [26] and the Inactivation of Human Skin Using High Hydrostatic Pressurization long-term efficacy of these substitutes is still controversial [3,30,31]. Skin inactivated by HHP at 200 MPa in our method can retain its native quality comparable to that of autologous dermis , and inactivated nevus in combination with autologous cultured epidermis should be a breakthrough therapy in the treatment of GCMN. The skin inactivated after HHP at 200 MPa has cellar debris that is usually washed out in the process of preparation of decellularized tissue because this debris can cause host rejection or an immunological response [32]. "
    [Show abstract] [Hide abstract] ABSTRACT: We have reported that high-hydrostatic-pressure (HHP) technology is safe and useful for producing various kinds of decellularized tissue. However, the preparation of decellularized or inactivated skin using HHP has not been reported. The objective of this study was thus to prepare inactivated skin from human skin using HHP, and to explore the appropriate conditions of pressurization to inactivate skin that can be used for skin reconstruction. Human skin samples of 8 mm in diameter were packed in bags filled with normal saline solution (NSS) or distilled water (DW), and then pressurized at 0, 100, 150, 200 and 1000 MPa for 10 minutes. The viability of skin after HHP was evaluated using WST-8 assay. Outgrowth cells from pressurized skin and the viability of pressurized skin after cultivation for 14 days were also evaluated. The pressurized skin was subjected to histological evaluation using hematoxylin and eosin staining, scanning electron microscopy (SEM), immunohistochemical staining of type IV collagen for the basement membrane of epidermis and capillaries, and immunohistochemical staining of von Willebrand factor (vWF) for capillaries. Then, human cultured epidermis (CE) was applied on the pressurized skin and implanted into the subcutis of nude mice; specimens were subsequently obtained 14 days after implantation. Skin samples pressurized at more than 200 MPa were inactivated in both NSS and DW. The basement membrane and capillaries remained intact in all groups according to histological and immunohistological evaluations, and collagen fibers showed no apparent damage by SEM. CE took on skin pressurized at 150 and 200 MPa after implantation, whereas it did not take on skin pressurized at 1000 MPa. These results indicate that human skin could be inactivated after pressurization at more than 200 MPa, but skin pressurized at 1000 MPa had some damage to the dermis that prevented the taking of CE. Therefore, pressurization at 200 MPa is optimal for preparing inactivated skin that can be used for skin reconstruction.
    Full-text · Article · Aug 2015 · PLoS ONE
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