Wound Care
Hypertrophic scar
formation following burns and trauma: new approaches to treatment
Hypertrophic scar formation is a major clinical problem in developing and industrialised injuries, and surgical procedures can give rise to exuberant scarring that results in permanent functional loss and the stigma of disfigurement. Shahram Aarabi, Michael T. Longaker and Geoffrey C. Gurtner examine the process of hypertrophic scar formation, the results of current treatments, and areas likely to lead to significant advances in the field.
Annually, over 1 million
people require treatment for
burns in the United States[1],
2 million are injured in
motor vehicle accidents[2],
and over 34 million related
surgical procedures are
performed[3]. Although the
incidence of hypertrophic
scarring following these
types of injuries is not
known, it is a common
outcome that creates a
problem of enormous
magnitude. Treatment of
these cases is estimated to
cost at least US$4 billion per
annum in the US alone[4].
The incidence of burns and
traumatic injuries is even
greater in the developing
world[5].
Evolution of patient care
Advances over the past 60
years have allowed us to
extend the lives of patients
whose injuries would previously
have been invariably
fatal. Fire disasters such as
those at the Rialto concert
hall (1930)[6] and the
Cocoanut Grove nightclub
(1942)[7] led to the development
of new treatments,
such as fluid resuscitation, to
prevent death in the early
stages following burn injury.
World War II led to the
development of critical care
medicine[8], further
improving the ability to keep
those with traumatic injuries
alive until surgical management
of their wounds was
possible. Antibiotics and
aggressive surgical debridement
have also contributed
to the survival of the great
majority of burn and trauma
patients. However, despite
advances in life-saving technology,
progress to prevent
the late functional and
aesthetic sequelae of hypertrophic
scar formation has
been slow[9].
Efforts to limit scar formation
in burn and trauma
patients have relied largely
on immediate skin replacement[
10] with human splitthickness
allografts or
dermal analogs such as
Integra. Although these
measures provide excellent
barriers against infection
and mechanical trauma, the
long-term improvement in
appearance has been
modest[11,12]. After healing
has occurred, massage, pressure
therapies, steroids, and
silicone dressings are
frequently used to manage
the massive scar burden in
these patients[13]. Many of
these treatments predate
modern medicine and their
benefits remain unclear[11].
As stated in a major review
on burns and scarring, even
with state-of-the-art care,
“hypertrophic scarring
remains a terrible clinical
problem”[11].
One barometer of the
futility of these attempts at
scar modulation is the
interest in total facial transplantation.
This procedure
has been suggested as a
measure of last resort for
patients with severe facial
disfigurement due to scar
formation[14,15]. However,
facial transplantation has
sparked controversy due to
the severe antigenicity of
allograft skin used and side
effects of the antirejection
medications required. It is a
testament to the
intractability of this
problem that such desperate
measures are currently being
considered. When full facial
transplantation is eventually
performed, it is likely
that the recipient will be a
patient with facial burns
and the resulting functional
deficits and stigmata of
hypertrophic scar formation.
Pathophysiology
Clinical experience suggests
that hypertrophic scarring is
an aberrant form of the
normal processes of wound
healing[16]. However, the
etiology of the overexuberant
fibrosis is unknown.
Hypertrophic scarring
should be distinguished
from keloid formation, the
other
major form of excessive
scarring seen in
humans. There is stronger
evidence for genetic predisposition
in keloid formation
than in hypertrophic scarring,
although both occur
more frequently in certain
groups (e.g., people of
African and Asian descent).
Keloids are characterised by
overgrowth of fibrosis
beyond the boundaries of
the original injury, while
hypertrophic scars do not
extend beyond the original
wound margins. Keloids and
hypertrophic scars can also
be differentiated by established
histopathological
criteria, which include differences in collagen
density and orientation,
vascularity, and other
factors[17,18].
The pathophysiology of
hypertrophic scar formation
involves a constitutively
active proliferative phase of
wound healing[16]. Scar tissue
has a unique structural
makeup that is highly
vascular, with inflammatory
cells and fibroblasts
contributing to an abundant
and disorganised
matrix structure[16]. The net
result is that the original
skin defect is replaced by a
nonfunctional mass of
tissue. Beyond these observations,
investigations into
the pathophysiology of the
disease have been limited by
the absence of a practical
animal model and have
relied upon the use of
human pathological specimens[
19–21]. These studies are
problematic in that such
specimens represent the
terminal stages of the scarring
process and may not
contain the initiating
factors that originally led to
the development of the
disease. The few animal
models that have been used
include the rabbit ear[22] and
the red Duroc pig[23]. While
they have given us some
insight into the genetics
and pathogenesis of cutaneous
fibrosis[24,25], it is
unclear how closely the
process of hypertrophic
scarring in these models
resembles that seen in
humans. Specifically, it is
unknown whether the same
factors that initiate hypertrophic
scarring in these
species are involved in
human disease. Further,
studies using these species
have been limited by a
paucity of molecular
reagents available for rabbits
and pigs. For the aforementioned
reasons, these observational
studies have not
resulted in notable therapeutic
advances.
Foetal wound healing has
been proposed as a vehicle
to study skin regeneration.
Early foetal wound healing
is characterised by the
complete absence of scar
formation[26]. The developing
foetus transitions to a
scarring phenotype during
the third trimester of gestation[
27]. During the scarless
phase of development, both
low fibroblast activity and a
decreased inflammatory
response to injury are
observed[27]. Experiments
have shown that local
factors in wounded skin,
rather than systemic or
maternal factors, are responsible
for this transition from
scarless to scarred
healing[28–31]. However, it is
unclear which local factors
in the wound initiate scar
formation and which are
secondary to the scarring
process. Thus it has been
difficult to separate cause
from effect using the foetal
wound model.
In both adult and foetal
healing, the local wound
environment interacts with
the cellular components of
wound healing and vice
versa. The local wound
environment consists of
noncellular influences such
as matrix components,
oxygen tension, and
mechanical forces. The
interplay between cellular
(“seed”) and noncellular
(“soil”) components is
complex, with constant
feedback between the two
during the healing process
(Figure 2). Many therapies
for hypertrophic scar formation
may underestimate this
complexity by focusing on a
single component of this
relationship. Tables 1 and 2
provide a review of the
multitude of established
and experimental therapies
and their proposed mechanisms
of action. To date,
none of these approaches
have achieved wide clinical
adoption[11].
It is unclear whether
changes in the seed or soil
are responsible for the
phenomenon of hypertrophic
scar formation.
When compared to foetal
wound healing, adult
wound healing is a response
to injury that sacrifices the
regeneration of original
tissue for a rapid matrix
plug, or scar, that protects
the organism from infection
and trauma[16]. This response
is evolutionarily conserved
and allows the adult
organism to survive despite
the harsh extrauterine environment.
However, the
possibility exists that regenerative
capacity can be
restored in adults, and that
wound healing could
proceed with a recapitulation
of the original skin
architecture rather than
with the patching characteristic
of scar formation. In
the next section we will
consider existing and
proposed therapies for
hypertrophic scar formation
using this framework.
Therapeutic approaches:
targeting inflammatory
mediators
The inflammatory response is
a normal component of the
wound healing process, serving both as an immunological
barrier from infection
and as a stimulus for
fibrosis to close the site of
injury. Observations from
human pathological specimens
and from healing foetal wounds suggest that a
robust inflammatory
response may underlie the
excessive fibrosis seen in
hypertrophic scar formation[
16,18]. Mast cells,
macrophages, and lymphocytes
have all been implicated
in this process[16,18]. For
example, mast cells have
been shown to directly regulate
stromal cell activity in
vitro[32] as well as to be
strongly associated with the
induction of fibrosis in
vivo[33]. Mechanical activity,
age-specific changes, and
delayed epithelialisation
have all been implicated as
inciting factors for this
intense inflammatory
response.
While the phenomenology
of the myriad
cytokines involved in
wound healing is vast, the
discussion of some key regulators
of the scarring process
is unavoidable. Following cutaneous injury, endothelial
damage and platelet
aggregation occur resulting
in the secretion of cytokines
including the transforming
growth factor (TGF)-ß
family, platelet-derived
growth factors (PDGF), and
epidermal growth factors
(EGF)[11,16]. These cytokines
stimulate fibroblast proliferation
and matrix secretion,
and induce leukocyte
recruitment. Leukocytes, in
turn, reinforce fibroblast
activity, fight infection, and
increase vascular permeability
and ingrowth. They
do this acting through the
TGF-ß family, fibroblast
growth factors (FGF),
vascular endothelial growth
factors (VEGF), and other
factors[11,16]. Prostaglandins[34]
and SMAD activation[35] also
increase inflammatory cell
proliferation and impair
matrix breakdown[36].
Increased levels of TGF-ß1
and ß2 as well as decreased
levels of TGF-ß3 have been
associated with hypertrophic
scarring through inflammatory cell stimulation, fibroblast
proliferation, adhesion, matrix
production, and contraction[37,38].
Consistent with these observations,
anti-inflammatory agents (cytokine
inhibitors, corticosteroids, interferon
a and ß, and methotrexate) have been
used with some success to reduce scar
formation[11,39]. Novel antifibrotic
agents are also in development to
target specific mediators of the scarring
process[40,41].
Increased vascular density, extensive microvascular obstruction, and
malformed vessels[25,42] have also been
observed in hypertrophic scars. These
structural changes may account for
the persistent high inflammatory cell
density observed in hypertrophic
scars. Conversely, persistent inflammation
could itself contribute to
increased vascularity through positive
feedback loops. Although the presence
of a robust inflammatory
response during scar formation has
been described, many questions
remain unanswered. Specifically, what
distinguishes physiological or
“normal” inflammation from the
pathological inflammation that
occurs during hypertrophic scar
formation? What signals act to initiate
or stop this excessive inflammatory
process in scar formation? Until these
issues are clarified it will be difficult to
ascertain what causal roles inflammatory
pathways have in initiating
hypertrophic scar formation.
Therapeutic approaches: targeting
epithelial–mesenchymal interactions
Epithelial cells have important roles
in normal skin physiology, which
include acting as stem cell niches and
participating in complex signaling
pathways to regulate mesenchymal
cell function. The net results of these
functions are the constant renewal of
skin layers and the regulation of
matrix deposition and remodeling.
Cell-based skin substitutes take advantage
of the regenerative nature of skin
and are clinically used to cover
wounds, but their utility in subsequent
scar formation remains
unknown. Epidermal stem cells are
thought to act in concert with
mesenchymal cells in the dermal
papillae, functioning to recruit new
cells to sites of skin regeneration[43,44].
However, large traumatic skin defects
(such as those following burn injuries)
destroy the resident epidermal stem
cell population and cannot be spontaneously
regenerated.
Efforts to isolate and purify
epidermal stem cells in order to prepare
them for ex vivo expansion and subsequent
transplantation require the identification
of surface markers specific to
these cells[45,46]. Elucidation of these
markers has been challenging, but
work is progressing [43] and will hopefully
soon yield methods to easily
obtain pure populations of cells with
high proliferative potential.
In addition to their regenerative
function, epithelial cells act to modulate mesenchymal cell proliferation
and activity in normal skin and during
wound healing and scar formation[47].
In healing wounds, epithelial cells
promote fibrosis and scarring through
multiple pathways including SMAD,
phosphoinositide-3 kinase (PI3K), TGFß,
and connective tissue growth factor
(CTGF)[48–51]. Epithelial cells stimulate
fibroblasts during hypertrophic scar
formation and fibroblasts themselves
undergo intrinsic changes during the
process of scarring[52–54]. Subsequently,
fibroblasts remain in an activated state,
participating in cytokine autocrine
loops that maintain fibrosis[52–56].
Hypertrophic scar fibroblasts also have
fundamentally altered profiles of
cellular apoptosis, matrix production,
and matrix degradation[52–56]. It is
unclear whether these altered, profibrotic
properties are due to genetic
predisposition or secondary to unique
conditions present in the wound environment.
Therapeutic approaches: targeting
the physical environment
Following injury, the wound is a
complex and mechanically unique
environment[57,58] with multiple levels
of interaction between cells and the
surrounding milieu. Fibroblasts and keratinocytes respond to the density
and orientation of collagen and other
matrix components[59–61]. As a result, cells near the wound
margin proliferate while
those further away from the
edge of the wound are less
active[62,63]. At the same
time, these cells are actively
producing and remodeling
the surrounding matrix. It
is this delicate balance that
is responsible for a rapid
and healthy response to
injury and, when disturbed,
leads to aberrant wound
healing.
Many cells are known to
be mechanoresponsive[64,65].
It has recently become clear
that cells in the skin are also
able to respond to their
mechanical environment[
66–68]. Specifically, cell
surface molecules such as
the integrin family are activated
by mechanical forces,
leading to increased fibroblast
survival as well as to the
remodeling of deposited
collagen and fibrin[66,69].
While the intracellular
signaling involved in this
process is complex and
incompletely understood,
transcriptional regulators
such as AKT and focal adhesion
kinase (FAK) have been
found to be essential
elements[66,69,70]. Keratinocyte
proliferation and migration
are similarly regulated by
mechanical stress[67,71].
Following tissue injury,
mechanotransduction may
serve a biological function
to signal the presence of a
tissue defect. Cells experience
the highest levels of
mechanical stress on the
edge of a monolayer[72] and,
in the same way, the wound
margin experiences high
levels of mechanical
stress[73]. These stresses may
have evolved to stimulate
components of wound
healing and initiate repair.
Differences in exogenous
forces may act to change
cellular activation in the
wound healing milieu and,
when overactivated, lead to
hypertrophic scar formation[
74]. Clinically, we see
that these expectations hold
true. Skin subjected to high
levels of stress (secondary to
trauma or joint movement)
usually demonstrates robust
hypertrophic scar formation[
27,75].
Oxygen tension is
another component of the
physical environment that
may be important for scar
formation. Changes in
levels of the transcription
factor hypoxia-inducible
factor (HIF)-1a during
foetal skin development are
thought to be partly
responsible for the transition
from scarless to scarred
healing[76,77]. Varying levels
of HIF-1a in turn result in
changes in a number of
downstream proteins
including TGF-ß3 and
VEGF[76,78]. Changes in
hypoxia signaling pathways
contribute to the maturation
of foetal skin and the
development of a scarring
phenotype following
wounding[77,78]. Changes in
oxygen tension and
increases in reactive oxygen
species have also been
shown to mediate early scar
formation in tissues such as
the lung and heart[79,80].
However, the observation
that scars are normally
highly vascular is at odds
with the theory that
hypoxia increases scar
formation, and further
work is needed to definitely
establish this relationship.
What is clear is that the
wound environment is a
powerful modulator of scar
formation and could potentially
be manipulated for
therapeutic effect.
Conclusion
The complex interplay
between cell influx into the
wound bed, environmental
factors in the surrounding
skin, and various cytokine
mediators makes the task of
manipulating the wound
environment to promote
regeneration appear
daunting. Presently, most
therapies consist of a single
cell type or cytokine being
added to the healing wound
in the hopes that this will
result in perfect healing. As
we have described, monotherapy is unlikely to
be effective. However, it is
equally improbable that the
entire web of factors that
promote tissue regeneration
can be incorporated into a
single therapeutic strategy.
It is likely that the development
of more effective therapeutics
will require an
incorporation of known
environmental factors along
with cellular components to
promote healing. A comprehensive
strategy taking into
account both the cellular
(seed) and environmental
(soil) contributions to
hypertrophic scar formation
will have the highest likelihood
of therapeutic success
against this currently incurable
condition.
The authors
Shahram Aarabi, Michael
T. Longaker, and Geoffrey C.
Gurtner are with the
Department of Surgery,
Stanford University School
of Medicine, Stanford,
California, United States of
America.
References
A full list of references are
available with the online
version of this article:
“Hypertrophic Scar
Formation Following Burns
and Trauma: New
Approaches to Treatment” –
4 September 2007 – PLoS
Medicine – http://medicine.plosjournals.org
Aarabi S, Longaker MT,
Gurtner GC (2007)
Hypertrophic Scar Formation
Following Burns and
Trauma: New Approaches to
Treatment. PLoS Med 4(9):
e234 doi:10.1371/journal.
pmed.0040234
