CONTINUING

MEDICAL EDUCATION

Cutaneous scarring: Pathophysiology, molecular

mechanisms, and scar reduction therapeutics
Part I. The molecular basis of scar formation
Christos Profyris, MA, BM, BCh (Oxon), MRCS (Eng),a Christos Tziotzios, MA, MB, BChir (Cantab),
MRCP (UK),b and Isabel Do Vale, MB, BCh (Wits)c
London and Cambridge, United Kingdom; and Parktown, South Africa

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Learning Objectives
After completing this learning activity, participants should be able to
describe the 3 pathological stages of cutaneous scarring and delineate
the differences between embryonic regenerative healing and adult scarinduced healing.
Date of release: January 2012
Expiration date: January 2015
2011 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2011.05.055

Cutaneous scarring is often the epicenter of patient-related concerns, and the question Will there be a
scar? is one that is all too familiar to the everyday clinician. In approaching this topic, we have reviewed
the pathology, the embryology, and the molecular biology of cutaneous scarring. ( J Am Acad Dermatol
2012;66:1-10.)
Key words: cutaneous scar; early growth response protein-1; homeobox13; interleukins; mechanisms of
scarring; platelet-derived growth factor; transforming growth factorebeta; Wnt pathway.

2 Profyris, Tziotzios, and Do Vale

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JANUARY 2012

d Embryonic cutaneous wounds in the first

People with exaggerated skin scarring may face
substantial physical and psychosocial consethird of gestation heal without a scar
quences.1 In this first installment of a two-part
Disruption of cutaneous epithelial continuity recontinuing medical education series, we aim to
sults
in a characteristic pathophysiologic response.
explore the pathophysiology underlying cutaneous
This
response
has been traditionally subcategorized
scarring and the molecular mechanisms governing
into
the
three
phases of normal wound healing.
scar formation. Understanding the biology of scarThese
phases
are
the inflammatory, proliferative,
ring will allow for a better
and remodeling phases (Fig
understanding of the scien1). Wound healing, however,
CAPSULE
SUMMARY
tific basis of scar-reduction
is a dynamic process, and at
strategies. The latter shall be
After
cutaneous
injury,
the
any point in time, processes
discussed in Part II of this
pathophysiology
of
wound
healing
is
occurring in one phase overseries.
characterized by an inflammatory phase
lap with those occurring in
(days 1-3), a proliferative phase (days
another.2
METHODOLOGY
4-21), and a remodeling phase (day 21 to
In preparing this work, we
year 1).
Inflammatory phase
used PubMed to perform litMammalian cutaneous wounds during
(days 1-3)
erature searches on scarthe first third of gestation do not scar,
After the disruption of eprelated research. Key terms
because healing occurs via tissue
ithelial integrity, the immediused in the search were
regenerative pathways.
ate priority is hemostasis.
scarring, wound healing,
This is achieved by activation
Scarring is a healing process that has
prevention, and treatof the extrinsic clotting pathbeen selected for during evolution
ment. Review articles were
way. Ultimately, this results
because it tackles pathogens quickly,
used as an initial source of
in formation of a fibrin hewalls off foreign bodies, and seals off an
information and, where relemostatic plug, which is furinjured area from the environment.
vant, information from prither solidified by the arrival
mary research papers was
Transforming growth factorebeta
of platelets from the local
obtained.
(TGFb) is pivotal in scar-mediated
microcirculation.2
healing.
Once the danger of exsanThe expression of TGFb1 and TGFb2
PATHOPHYSIOLOGY
guination subsides, the next
enhances scarring, and the expression of
OF THE CUTANEOUS
priority is the removal of dead
TGFb3 reduces scarring.
SCAR
tissue and the prevention of
Key points
infection. Inflammatory cells
The proinflammatory cytokines
d The inflammatory phase
are crucial to this process. For
interleukin-6 (IL-6) and IL-8 augment
of wound healing aims
the first 5 days, neutrophils
scarring, but the antiinflammatory
to contain the injury and
enter the fibrin-rich zone of
cytokine IL-10 has the opposite effects
prevent infection
injury. Through their actions
on the scarring response.
d The proliferative phase is
of phagocytosis and protease
Homeobox b13, the Wnt signaling
characterized by granusecretion, neutrophils kill lopathway, early growth response proteinlation tissuecomposed
cal bacteria and help degrade
1, and platelet-derived growth factor all
of macrophages, fibrodead tissue. On the third day
propagate a robust fibroblast response
blasts, and epithelial
after injury, macrophages
in the healing wound, leading to
tissue
also enter the injury zone. In
increased scarring.
d The remodeling phase
addition to phagocytosing
is the lengthy process
pathogens and tissue debris,
of extracellar matrix rethese cells secrete a multitude
organization around the site of injury
of growth factors, chemokines, and cytokines. These
d

From the Department of Plastic and Burns,a Chelsea and Westminster Hospital, London; Addenbrookes Hospital,b Cambridge
University Hospitals NHS Foundation Trust, Cambridge, United
Kingdom; and the Department of Plastic and Reconstructive
Surgery,c Charlotte Maxeke Johannesburg Academic Hospital,
Parktown, South Africa.

Reprint requests: Christos Tziotzios, MA, MB, BChir (Cantab), MRCP

(UK), Addenbrookes Hospital, Cambridge University Hospitals
NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ,
Cambridge, United Kingdom. E-mail: ct287@cantab.net.
0190-9622/$36.00

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VOLUME 66, NUMBER 1

Profyris, Tziotzios, and Do Vale 3

Abbreviations used:
EGR-1:
IL:
PDGF:
TGFb:

early growth response protein-1

interleukins
platelet-derived growth factor
transforming growth factor beta CI

signaling molecules are vital for the coordination of

downstream events occurring during the proliferative
phase.2
Proliferative phase (days 4-21)
Granulation tissuecomposed of macrophages,
fibroblasts, and endothelial cellsis the hallmark of
the proliferative phase. This tissue replaces the fibrin
hemostatic plug set up during the inflammatory
phase. Macrophages, via the secretion of plateletderived growth factor (PDGF) and transforming
growth factorebeta 1 (TGFb1), induce fibroblasts
to proliferate and lay down type III collagen. This
provides a structural framework for endothelial cells
to proliferate and lay down new vessels by the
process of angiogenesis.2
Reepithelialization is essential for the reestablishment of tissue integrity. Keratinocytes adjacent to the
wound edge and in hair follicles undergo dedifferentiation and reorganize their adhesion molecules.
This loosens their connections to both the basement
membrane and to each other, and subsequently
allows them to migrate across the wound surface
and close the skin defect.2
Remodeling phase (day 21 to year 1)
During the remodeling phase, formation of granulation tissue ceases through apoptosis of the responsible cells. This process is important, because its
aberration leads to hypertrophic scarring and keloids.2
With maturation of the wound, the composition of
the extracellular matrix undergoes change. The type
III collagen deposited during the proliferative phase
is slowly degraded and replaced with stronger type I
collagen. This type of collagen is oriented as small
parallel bundles, which differs drastically from the
basket-weave orientation of collagen present in
normal dermis.2
Towards the later stages of healing, the wound
undergoes a contractile response through the action
of myofibroblasts. By virtue of their multiple attachment points to collagen, these actin-rich cells contract and reduce the surface area of the scar.2
Macroscopic considerations
The immediate macroscopic appearance of the
wound after injury is that of a skin defect with a

Fig 1. Histologic view of the wound healing process. (A)

Inflammatory phase of wound healing (day 1). (B) Early
proliferative phase of wound healing (day 5). (C) Late
proliferative phase of wound healing with early remodeling (day 14). C, Clot; D, dermis; E, epidermis; ES,
eschar; F, fatty tissue; G, granulation tissue; G/S, late
granulation tissue/early scar tissue; HE, hyperproliferative
epithelium; HF, hair follicle; M, muscle; RE, regenerating
epithelium. (Adapted from Schafer and Werner9 and
reprinted with permission from the Annual Review of
Cell and Developmental Biology, vol 23, 2007 by
Annual Reviews [http://www.annualreviews.org].)

glistening surface attributed to the fibrin exudate. A

few days later, eschara collection of dead tissuereplaces this defect. In the coming weeks, a
red and indurated cutaneous scar forms. The scar
remodels in the year that follows to become soft
and slightly lighter in color than the surrounding
skin.3,4
The abnormal architecture of collagen that
results following the remodeling phase is the
cause of the visible cutaneous scar. Within the

J AM ACAD DERMATOL

4 Profyris, Tziotzios, and Do Vale

abnormal collagenous network, there is a notable

absence of hair follicles, sebaceous glands, and
sweat glands. The extent to which this abnormal
dermal phenotype arises depends on the depth of
injury; deeper cutaneous injuries give rise to more
scar tissue.5

JANUARY 2012

MOLECULAR BIOLOGY OF WOUND

HEALING
Key points
d

Embryonic regenerative healing

Cutaneous wounds made during the first third of
gestation in mammals heal via tissue regeneration.
This type of healing uses reactivation of the developmental pathways that originally gave rise to the
tissue. Ultimately, the original tissue constituents are
replaced and healing occurs without scar formation.6 Consequently, this prompts the question,
Why should there be a scar-mediated healing
response?
In evolutionary terms, most wounds encountered by animals were the result of postcombat
trauma or falls. Consequently, the common wounds
faced by mammals were bites, blows, contusions,
and degloving injuries. These injuries involved
widespread areas of tissue and were frequently
contaminated with bacteria and foreign bodies. In
such a scenario, evolutionary pressure favored a
healing response that would control infection, wall
off foreign bodies, and seal off the injured area
from the environment. The inflammatory and proliferative phases witnessed in normal adult wound
healing are remnants of this evolutionary selection.
The multitude of leukocytes in the inflammatory
phase helps prevent systemic infection, and the
fibroblast activity during the proliferative phase
walls off foreign bodies and reestablishes tissue
integrity. In stark contrast to the scar-forming healing response, regenerative healingas witnessed in
early embryos and in liver regenerationhas a
notable absence of fibroblast or inflammatory cell
activity. In an evolutionary context, this attribute of
regenerative healing would have been negatively
selected for, because animals would face a high risk
of septicemia and death.7
Wound healing today is likely to take place at an
injury site that has been debrided, sterilized, and
approximated with the use of suture material. As a
result, the coarse and dirty wounds encountered
throughout evolution are less of a commonality and
the abundance of inflammatory cells and fibroblasts
seen in scar-mediated healing are less of a necessity.
In fact, in such controlled conditions for wound
healing, a regenerative response would provide the
advantage of a superior cosmetic result and would
avoid the potential for aberrant scarring as seen in
hypertrophic scars and keloids.7

TGFb1 and TGFb2 expression leads to increased scarring, whereas expression of

TGFb3 reduces scarring
Proinflammatory cytokines interleukin-6
(IL-6) and IL-8 enhance scarring, whereas
the antiinflammatory cytokine IL-10 decreases the amount of scar tissue
Homeobox b13, the Wnt signaling pathway,
early growth response-1, and plateletderived growth factor all favor fibroplasia

The mammalian cutaneous wound is enriched

with a multitude of extracellular matrix proteins,
growth factors, and cytokines not normally present
in intact skin.8 Because the literature on molecules
proposed to have a role in wound healing is vast,
the following account will concentrate on molecules that are noted to have a significant influence
on tissue scarring.9,10 Preference was given to
molecules with robust research evidence. Key
molecules in the wound healing machinery and
their pathologic significance are summarized in
Table I.
Transforming growth factorebeta
Signaling. TGFb is crucial in the regulation of
wound scarring. The three isoforms, TGFb1e3,
exert their effects by binding to dimeric TGFb
receptor complexes. Upon activation, this receptor
complex phosphorylates SMAD2 and SMAD3 proteins, which subsequently form dimers with
SMAD4. In its dimeric form, this SMAD aggregation is able to translocate into the nucleus and
function as a transcription factor (Fig 2). TGFs
b1 and b2 activate the receptor complex and
thereby downstream signaling, whereas TGFb3 is
a receptor antagonist and thereby blocks signal
transduction.9,10
Expression. Expression studies have strongly
implicated TGFbs in scarring, because TGFbs and
their receptors are expressed prominently in adult
scar forming wounds. Conversely, in nonscarring
fetal wounds, their expression is only transient.11 In
addition, fibroblasts from both hypertrophic scars
and keloids consistently overexpress proteins involved in TGFb signal transduction.12-16
Animal studies
Genetically engineered animal models have provided invaluable information about the involvement
of TGFb signaling in cutaneous wound healing.
Knock-out mouse animal models for TGFb1 have

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VOLUME 66, NUMBER 1

Table I. Key molecules in the wound healing

machinery and their pathologic significance
Molecule

TGFb1
and TGFb2

TGFb3
IL-6 and IL-8

IL-10

Homeobox13

Wnt signaling
pathway

PDGF

Osteopontin

EGRe1

Function

Key in the proliferative phase of

wound healing; promote signaling
via SMAD and Wntedependent
pathways to enhance scarring
Receptor antagonist; reduces scarring
Proinflammatory cytokines expressed
immediately after cutaneous injury;
recruit and activate inflammatory
cells, thereby promoting scarring
Antiinflammatory cytokine that
reduces scarring; it inhibits the
infiltration of neutrophils and
macrophages towards the wound
site and dampens the expression of
proinflammatory cytokines
Transcription factor; absent from the
scar-free healing wounds of
foetuses; favors fibroplasia
Aberrant transduction has been
implicated as causative factor of
aggressive fibromatosis;
hypertrophic scars and keloids
display excessive signaling via the
Wnt pathway
Secreted by macrophages during the
proliferative phase of wound
healing and induces fibroblasts to
produce type III collagen and
exocytose osteopontin;
overexpressed in hypertrophic
scars and keloids
Extracellular glycoprotein that
enhances fibroplasia; connects
integrins on cell surfaces to
collagen within the extracellular
matrix and promotes cell adhesion
and cellular migration; abolition of
osteopontin reduces the trafficking
of both inflammatory cells and
fibroblasts and also leads to a larger
number of these cells dying by
apoptosis
A zinc-finger transcription factor; upregulates the expression of TGFb1
and PDGF, mediators of enhanced
fibroplasia

EGR-1, Early growth response protein-1; IL, interleukin; PDGF,

platelet-derived growth factor; TGFb, transforming growth
factorebeta.

revealed a characteristic defect in healing during the

proliferative phase: at 10 days after incisional injury,
histologic analysis of the wounds reveals reduced
granulation tissue bulk and collagen deposition.17

Fig 2. The transforming growth factorebeta signaling

pathway (see text for details).

Conversely, in a transgenic mouse model where

TGFb1 was overexpressed in keratinocytes, type I
collagen expression was significantly up-regulated
and scar tissue bulk increased.18
The downstream mediators of TGFb signaling
have also been the subject of intense investigation.
Because SMAD3 is an important molecule in TGFb
signaling, SMAD3 knock-out mice have been created
to decipher its role in wound healing. These studies
show that animals deficient for SMAD3 have enhanced cutaneous healing with reduced deposition
of scar tissue.19
Recent research indicates that the scar-inducing
signal transduction mechanism of TGFb1 is mediated
via the Wnt pathway (Fig 3). The application of
exogenous TGFb1a scar induceron the wounds
of b-catenin conditional knock-out mice results in
minimal scarring.20 In addition, the constitutive expression of an active form of b-catenin in SMAD3
knock-out mice results in scarring not normally seen
in the animals with SMAD3 deficiency alone.20 These
data imply that TGFb1 induces SMAD3 to transcribe
proteins that activate the Wnt pathway to induce
scarring.

6 Profyris, Tziotzios, and Do Vale

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JANUARY 2012

b2 promote signaling via SMAD and Wnt-dependent

pathways to enhance scarring. Conversely, TGFb3
prevents signaling via these pathways and leads to
scar reduction. Deciphering the role of TGFb
signaling in wound healing has provided fruitful
avenues for therapeutic intervention.

Fig 3. The Wnt signaling pathway. Binding of Wnt to the

seven-transmembrane domain receptor fizzled leads to the
activation of dishevelled (Dsh). Once activated, Dsh
blocks the ubiquinating complex of axin, glycogen synthase kinase 3 (GSK3), and adenomatous polyposis coli
(APC). This leads to reduced ubiquination and thereby
proteosomal degradation of b-catenin. b-catenin is now
able to transclocate into the nucleus and induce transcription through its association with the T-cell factor (TCF) and
lymphoid enhancer factor (LEF) transcription factors.

Transforming growth factorebeta modulation studies. Studies using strategies to alter the
concentration of TGFbs during healing have revealed that the adult scar-forming mechanism can
be altered. The application of neutralizing antibodies
to TGFs b1 and b2 in incisional rat wounds results in a
significant reduction of extracellular matrix deposition and, by extension, subsequent scarring.21
Importantly, the enhanced availability of TGFb3 in
the healing environmentvia the application of
recombinant TGFb3results in scar tissue reduction
and a subepidermal collagen architecture that resembles that of normal skin (Fig 4).22
Summary
The studies above underpin the pivotal role of
TGFb signaling in scar-mediated healing. TGFs b1 and

Inflammatory response modulators

Proinflammatory
cytokines. Regenerative
healing has a notable absence of inflammatory
cell activity. Consequently, mediators of the inflammatory response have been a focus of investigation
in studies aiming to curtail scarring.7 Both
interleukin-6 (IL-6) and IL-8 are expressed immediately after cutaneous injury and continue to be
expressed at elevated levels for several days. These
cytokines act to recruit and activate inflammatory
cells. In stark contrast to adult wounds, there is only
transient expression of these interleukins in fetal
scar-free healing wounds.23,24 Collectively, these
expression studies suggest that scar tissue deposition may be reduced by dampening the proinflammatory cytokine profile of healing wounds.
Importantly, the administration of IL-6 to fetal
healing wounds results in scarring that would not
normally occur.24
Antiinflammatory cytokines. IL-10 is an antiinflammatory cytokine. It inhibits the infiltration of
neutrophils and macrophages toward the wound site
and dampens the expression of proinflammatory
cytokines. The importance of IL-10 as a scar modulator can be seen in IL-10 knock-out mouse embryos.
Cutaneous injury to these knock-out animals results
in adult-like scar-mediated healing, which is not
observed in wild-type embryonic counterparts.25
The antiscarring role of IL-10 has been exploited in
a recent clinical trial.
Inflammatory
response
transcription
factors. The modulation of the inflammatory response transcription factors in cutaneous injury
models has also produced promising data. Knockout mouse models for the PU.1 transcription factor
lack macrophages and functional neutrophils.
Incisional wounds in neonates with this genetic
background revealed normal healing with absence
of any obvious scarring.26 This adds weight to the
hypothesis that the inflammatory response in wound
healing is a remnant of evolution and in many
instances counterproductive to the healing of incisional wounds.
Fibroplasia
The molecular biology behind fibroblast proliferation and collagen deposition is central to the
study of wound healing. Consequently, several

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Profyris, Tziotzios, and Do Vale 7

Fig 4. The application of transforming growth factorebeta 3 (TGFb3) to wound surfaces

stimulates scar-free healing. (A) Macroscopic and microscopic views of a placebo-treated
wound. There is a visible scar with an abnormally organized dermis. (B) Macroscopic and
microscopic views of a recombinant TGFb3-treated wound. In comparison to the placebotreated wound, scarring is not visible and the dermal architecture in the wound matches the
surrounding uninjured dermis. (Adapted from Ferguson and OKane7 with permission from the
authors and the Royal Society.)

transcription factors and growth factors have

been implicated for the control of these two
processes.
Homeobox b13. The homeobox (hox) b13 transcription factor is notably absent from the scar-free
healing wounds of fetuses. Conversely, in adults,
hoxb13 expression is consistently high.27
Consequently, in an attempt to recreate this fetal
parameter in adult healing wounds, hoxb13 knockout animals were engineered. In these animals,
healing is strongly enhanced with increased wound
tensile strength and reduced scarring (Fig 5).
Structural analysis of the healed wounds in these
animals revealed collagen architecture that resembles that of uninjured dermis. This implies that
switching off hoxb13 is an important trigger to
activating regenerative healing.28
Wnt signaling pathway
Aberrant transduction via the Wnt signaling pathway has been implicated as a causative factor of
aggressive fibromatosis; a connective tissue disorder
leading to multiple subcutaneous nodulesdesmoid tumorsand an excessive scar-forming healing response.29 Hypertrophic scars and keloids, in
individuals without this disorder, also display excessive signaling via the Wnt pathway (Fig 3).30 The
incidence of hypertrophic scars and keloids is higher

in certain body areas, and regional variation in the

activation of this pathway would be a reasonable
speculationone that has not been addressed in the
scientific literature.
In aggressive fibromatosis, there is a mutation of
the b-catenin gene, which leads to stabilization of
the catenin protein product and thereby continuous
activation of the Wnt signaling pathway. Transgenic
mice that constitutively express this mutant form of
b-catenin develop a phenotype similar to aggressive fibromatosis. In addition, experimental cutaneous injury in these animals gives rise to excessive
scarring reminiscent of keloids and hypertrophic
scars.31
In order to further assess the outcome of manipulating b-catenin levels during wound healing, a
conditional knock-out mouse was engineered. In
this animal model, the b-catenin gene could be
specifically deleted at the site of experimental injury.
In comparison, wild-type mice, animals with the
conditional deletion of b-catenin, display much
smaller wounds and have fewer fibroblasts in their
granulation tissue.20
Early growth response protein-1. Early
growth response protein 1 (EGR-1) is a member
of the zinc-finger transcription factor group. Upon
cutaneous injury, its concentration within fibroblasts rises acutely.32 In mouse embryos that have

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8 Profyris, Tziotzios, and Do Vale

JANUARY 2012

Fig 5. Homeobox13 (Hoxb13) knock-out (KO) incisional wounds show enhanced healing.
Full-thickness hematoxylineeosin-stained sections from wild-type (WT) (A) and Hoxb13 KO
(B) skin harvested 7 days after wounding. The wounded areas, outlined in black, indicate less
deposition of scar tissue in Hoxb13 KO animals. Full-thickness Masson trichromeestained
sections of the dermis, emphasizing collagen structure, in wounded and uninjured skin of both
Hoxb13 KO mice and WT animals. Hoxb13 KO mice wounds (D9) displayed a basket weave
collagen architecture similar to uninjured skin (D). In WT animals, collagen architecture took
the form of small parallel bundles (C9) that differed from uninjured skin (C). (Adapted from
Mack et al28 with permission.)

been modified to overexpress EGR-1, excisional

wounds result in enhanced collagen deposition
and wound contraction. Because EGR-1 upregulates the expression of TGFb1 and PDGF, these
growth factors are the likely mediators of this
response.33
Platelet-derived growth factor. PDGF exists in
several isoforms, and signals via the activation of
dimeric transmembrane tyrosine kinase receptors.
Within cutaneous wounds, it is a strong inducer of
fibroblast-mediated collagen deposition, and it has
been observed that both PDGF and its receptor are
markedly overexpressed in hypertrophic scars and
keloids.34,35 Importantly, recent studies have shown
that PDGF secreted by macrophages during the
proliferative phase of wound healing induces fibroblasts to produce and exocytose osteopontin.36
Osteopontin is an extracellular glycoprotein that
connects integrins on cell surfaces to collagen within

the extracellular matrix. This acts to promote cell

adhesion and enhance cellular migration. In addition, via integrin-mediated intracellular signaling,
osteopontin provides an important antiapoptotic
signal via the nuclear factor kB group of transcription
factors.37 Importantly, the application of osteopontin
antisense oligonucleotides in mouse incisional
wounds results in accelerated healing with reduced
granulation tissue and scarring.36 These results suggest that the abolition of osteopontin from the
wound environment reduces the trafficking of both
inflammatory cells and fibroblasts and also leads to a
larger number of these cells dying by apoptosis.

CONCLUSION
An increased understanding of the molecular
mechanisms governing regenerative cutaneous healing would be expected to dispel the age-old notion
that scarring is an inevitable consequence of injury or

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Profyris, Tziotzios, and Do Vale 9

VOLUME 66, NUMBER 1

surgery. Numerous approaches have been taken to

successfully manipulate the adult scar-forming
wound environment in the context of dermatologic
surgery with the aim to recreate a scar-free healing
environment. So, Will there be a scar? Part II will
discuss the evidence-base of the available scar
reduction modalities and attempt to answer this
question.

17.

18.

19.
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