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Journal of the Chinese Medical Association xx (2017) 1e8
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Review Article

Wound healing
Peng-Hui Wang a,b,c,d,*, Ben-Shian Huang a,b,c, Huann-Cheng Horng a,b,e, Chang-Ching Yeh a,b,c,
Yi-Jen Chen a,b,c
a
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
b
Department of Obstetric and Gynecology, National Yang-Ming University, Taipei, Taiwan, ROC
c
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
d
Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
e
Institute of BioMedical Informatics, National Yang-Ming University, Taipei, Taiwan, ROC
Received October 6, 2017; accepted October 6, 2017

Abstract

Wound healing is an important physiological process to maintain the integrity of skin after trauma, either by accident or by intent procedure.
The normal wound healing involves three successive but overlapping phases, including hemostasis/inflammatory phase, proliferative phase, and
remodeling phase. Aberration of wound healing, such as excessive wound healing (hypertrophic scar and keloid) or chronic wound (ulcer)
impairs the normal physical function. A large number of sophisticated experimental studies have provided insights into wound healing. This
article highlights the information after 2010, and the main text includes (i) wound healing; (ii) wound healing in fetus and adult; (iii) pros-
taglandins and wound healing; (iv) the pathogenesis of excessive wound healing; (v) the epidemiology of excessive wound healing; (vi) in vitro
and in vivo studies for excessive wound healing; (vii) stem cell therapy for excessive wound healing; and (viii) the prevention strategy for
excessive wound healing.
Copyright © 2017, the Chinese Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Pathophysiology; Wound healing

1. Introduction factors (chemokines) and growth factors (GFs) to form the

Wound healing is an important but complicated process in
human or animal, containing a multifaceted process governed
by sequential yet overlapping phases, including hemostasis/
inflammation phase, proliferation phase, and remodeling
phase.1 After an injury to skin, the exposed sub-endothelium,
collagen and tissue factor will activate platelet aggregation,
which results in degranulation and releasing chemotactic
Conflicts of interest: The authors declare that they have no conflicts of interest
related to the subject matter or materials discussed in this article.
* Corresponding author. Dr. Peng-Hui Wang, Department of Obstetric and
Gynecology, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road,
Taipei 112, Taiwan, ROC.
E-mail addresses: phwang@vghtpe.gov.tw, phwang@ym.edu.tw,
pongpongwang@gmail.com (P.-H. Wang).
clot, and all above-mentioned procedures will achieve suc-
cessful hemostasis.2 Neutrophils, the first cells to appear at the
injury site, cleanse debris and bacteria to provide a good
environment for wound healing. In the following, macro-
phages accumulate and facilitate phagocytosis of bacteria and
damage tissue.3 The hemostasis and inflammatory phase often
takes 72 h to finish.
The following proliferative phase is characterized with an
accumulation of lots of cells and profuse connective tissue.
The wound encompasses fibroblasts, keratinocytes, and
endothelial cells. Extracellular matrix (ECM), including pro-
teoglycans, hyaluronic acid, collagen, and elastin forms a
granulation tissue to replace the original formation of clot.4
Many kinds of cytokines and GFs participate this phase,
such as transforming growth factor-b family (TGF-b,
including TGF-b1, TGF-b2, and TGF-b3), interleukin (IL)

https://doi.org/10.1016/j.jcma.2017.11.002
1726-4901/Copyright © 2017, the Chinese Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Wang P-H, et al., Wound healing, Journal of the Chinese Medical Association (2017), https://doi.org/10.1016/
j.jcma.2017.11.002
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2 P.-H. Wang et al. / Journal of the Chinese Medical Association xx (2017) 1e8
family and angiogenesis factors (i.e., vascular epidermal
growth factor). This phase continues days and weeks.4
The last step of wound healing is a remodeling phase,
which needs a precise balance between apoptosis of existing
cells and production of new cells. Gradual degradation of
profuse ECM and the immature type III collagen and forma-
tion of mature type I collagen are critical in this phase, which
continues a few months and years. Any aberration in this
phase may lead to excessive wound healing or chronic
wound.5,6
Since a better understanding of the mechanism of wound
healing can be presumed from the increased number of in vitro or
in vivo experiments and a better treatment algorithm to maintain
a regulated and orchestrated inflammatory response will be
developed,7,8 the following is an update of wound healing.
2. Wound healing in the fetus and adult
It is evident that the ability to repair wounds without
excessive wound healing is age-dependent.9 The more
advanced age is and the higher possibility of excessive wound
healing occurs. Fetal wound healing is characterized by
regeneration of normal dermal architecture, which includes
restoration of neurovasculature and dermal appendages.9
Wound healing in the fetal skin involves a distinct GF pro-
file, a lower inflammatory response with an anti-inflammatory
cytokine profile, lower biomechanical stress, an ECM rich in
hyaluronic acid and type III collagen, and a potential role for
stem cells.6,8e11 Compared with fetal skin, adult has a higher
risk of scar formation.
There are at least four mechanisms to show the difference
of wound healing between fetal skin and adult's skin.10 The
early stage of adult healing is characterized by an inflamma-
tory reaction with migration of neutrophils and macrophages
but inflammation is not apparent in fetus. Studies show that
fewer of the inflammatory cells are found in the fetal wound
than those in the adult wound.10
Studies found that several cytokines, including IL-6 and IL-
8, are elevated significantly in adult healing process compared
with those in fetal healing process.8e11 By contrast, while IL-
10 is higher in fetal healing than that in adult healing. TGF-b1
and TGF-b2 concentrations are higher in the adult wound,
while TGF-b3 is lower in the adult wound.
The content of ECM is significantly different between the
fetal and adult wounds. Fibroblasts produce ECM at a higher
rate in the fetal wound, and the ratio of type III to type I
collagen is higher in the fetal wound. The amount of hyal-
uronic acid in the ECM is also high in the fetal wound but low
in the adult wound.
Myofibroblasts are only found in the adult wound. When
mechanical tension of the adult wound increases, myofibro-
blasts become more apparent in the adult wound. By contrast,
no or very few myofibroblasts can be found in the fetal
wound.8 Therefore, further studies of the fundamental mech-
anisms of fetal wound healing will identify the potential
remedies to minimize scar formation.
Please cite this article in press as: Wang P-H, et al., Wound healing, Journal of the Chinese Medical Association (2017), https://doi.org/10.1016/
j.jcma.2017.11.002
3. Prostaglandins and their inhibitors on wound healing
Prostaglandins (PGs) are lipid compounds that participate
in a variety of physiologic and pathologic processes. Prosta-
glandin synthesis is dependent on three enzymatic conversions
beginning with the conversion of membrane-derived phos-
pholipids to arachidonic acid by phospholipase.4 Among them,
PGE2 is a major mediator for inflammation,12 and also in-
volves various kinds of diseases, such as rheumatoid arthritis
and osteoarthritis. The cyclooxygenase (COX) pathway is
essential for the conversion of arachidonic acid into PGH2, a
precursor of various biologically active mediators including
thromboxane A2, PGE2 and prostacyclin. Two types of COXs
have been identified, including (i) COX-1 (house keeping
gene) has been expressed constitutively in various tissues,
including stomach, and (ii) COX-2 (induction gene) has been
induced by cytokines, growth factors, tumor promoters, and
other agents.4,13 COX-2-derived PGE2 and nitric oxide syn-
thase (NOS)-derived NO is upregulated by pro-inflammatory
mediators such as tumor necrosis factor (TNF)-a, lipopoly-
saccharide, and IL-1b. This induced inflammatory response
triggers further damage to adjacent cells and tissues around the
wound site, thus delaying the wound healing process. Prosta-
glandin E2 regulates fibroblasts in an autocrine pattern,
including inhibition of fibroblast proliferation, migration,
myofibroblast differentiation and collagen synthesis.4 As the
aforementioned role of pro-fibrotic effect, overexpressed TGF-
b1 is found in fibrotic tissues and widely involved in fibroblast
functions. Nitric oxide is a highly reactive radical that is
generated by the activation of iNOS and contributes to various
biological processes including inflammation.14 Nitric oxide is
thought to be a main disruptive factor in the wound healing
process. Excessive generation of COX-2-derived PGE2 is a
crucial physiological factor accelerating inflammation. Pros-
taglandin E2 is related to keratinocyte proliferation, angio-
genesis and mediation of the inflammatory response. There are
four receptors for PGE2, including EP1, EP2, EP3 and EP4.
PGE2 through EP2 and EP4, known as coupling to G-proteins,
increases intracellular cAMP formation.15,16
Newly synthesized PGE2 simply diffused and actively
extruded by the multidrug resistance 4 from the cells. Subse-
quently, EP receptor is activated followed by pericellular
PGE2 is cleared via re-uptake of PGE2 by PG transporter and
then rapidly metabolized by cytosolic enzyme named nico-
tinamide adenine dinucleotide (NAD)þ-dependent 15-
hydroxyprostaglandin dehydrogenase.17 This enzyme is
expressed ubiquitously in mammalian tissues and responsible
for biologic inactivation of PGE2 to 15-keto PGs.4
Prostaglandin E2 has been also known as an important
mediator for bone formation, gastric ulcer healing, and dermal
wound healing. The level of PGE2 is positively correlated with
wound healing rate. The release of PGE2 from skin tissue after
toxic stimuli produces local edema and hyperalgesia. Prosta-
glandin E2 elevation using 15-hydroxy PGDH inhibitor would
be valuable for the management disease that required elevated
PGE2, like wound healing, contributing to the clinical use of
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P.-H. Wang et al. / Journal of the Chinese Medical Association xx (2017) 1e8
PGE2 in the management of gastric ulcer in spite of high price
and low efficacy.18
Conventionally, aspirin, and non-steroidal anti-inflamma-
tory drugs (NSAIDs) or their selective COX-2 inhibitors,
having been known as analgesic, antipyretic and anti-
inflammatory effects, are reported to inhibit PGE2 produc-
tion and act as effective pain-killers, and they are often pre-
scribed and used postoperatively for pain control.19e23
However, the impact of aspirin and NSAIDs on wound heal-
ing is highly controversial, since the scientific literature sug-
gests that inhibition of COX by aspirin or other NSAIDs, may
be deleterious to normal wound repair processes and result in
healing inhibition.24 Aspirin involves the first step of wound
healing e hemostasis/inflammation phase directly.19 Aspirin
can not only affect thrombotic activity of platelet activation
(hemostasis) but also inhibit several potential pro-
inflammatory effects (inflammation), which include platelet
release of matrix metalloproteinases (MMPs), elastases,
release of P selectin, and hence recruitment and activation of
monocytes, monocyte and neutrophil adhesion to the endo-
thelium, further release of chemoattractants for inflammatory
cells such as monocyte chemoattractant protein 1, and release
of pro-inflammatory cytokines, such as IL1 b, IL-6, and IL-
8.19,25 Antagonizing EP2, not EP4, might abrogate the effect
of PGE2 on TGF-b1-induced Smad pathway activation, un-
balanced expression of MMPs/TIMP-1, and collagen synthe-
sis.26 Zhao et al. demonstrated that TGF-b1 decreased the
endogenous expression of COX-2 and PGE2 in dermal fibro-
blasts, and exogenous PGE2 could reverse TGF-b1-induced
collagen over-expression mediated by cAMP.27
The balance between these pro-inflammatory and inflam-
matory pathways is very important. The benefits of acute in-
flammatory response occur on early wound cellular functions,
such as removing debris, and responding to pathogens in acute
wound but chronic activation and prolonged production of
these pro-inflammatory factors are likely to lead to continuous
tissue destruction, inhibition of wound repair and pathological
or excessive wound healing.
4. The pathogenesis of excessive wound healing
Excessive wound healing is caused by skin injury, which
includes trauma, inset bite, burns, surgery, vaccinations, skin
piercing, acne, and infections.2,3 After an injury to skin, the
inflammatory process begins to initiate wound healing.
Although the pathogenesis of excessive wound healing is not
fully elucidated, clinical experience suggests that excessive
wound healing is an aberrant form of wound healing, which
may occur as a result of dysregulation in one of the three
phases of wound healing, and is characterized by continuously
localized inflammation.2,3 Excessive wound healing often in-
volves an exaggerated function of fibroblasts and excess
accumulation of ECM during wound healing.28 Two forms of
excessive wound healing are reported, including keloid and
hypertrophic scar. Dr. Ogawa defined “keloid” as strongly
inflamed pathological process, and “hypertrophic scar” is a
much more weakly inflamed pathological process, because
Please cite this article in press as: Wang P-H, et al., Wound healing, Journal of the Chinese Medical Association (2017), https://doi.org/10.1016/
j.jcma.2017.11.002
3
both can be considered as successive stages of the same
fibroproliferative skin disorders, with differing degrees of
inflammation that might be affected by genetic predisposition
(also shown below in Section 5 the epidemiology of excessive
scarring).29,30 All excessive wound healings include initial
purulent inflammatory process, upregulated fibroblast func-
tion, and excessive ECM deposition.31
Hypertrophic scar does not overgrowing over the original
wound boundaries and generally fades as well as flattens to the
surrounding skin level, although it may be raised above the
normal skin level, and contracture or more raised or larger
than normal wound healing might occur. Hypertrophic scar is
often self-limited and sometimes can regress with time.
The histological features of keloid are whorls and nodules
of thick, hyalinized collagen bundles, known as keloidal
collagen, and tongue-like projections of scar tissue that
advance underneath the surrounding normal epidermis.28
Representing an abnormally vigorous scarring formation
extending beyond the edges of the original wound, and
causing symptoms of pruritus and hyperesthesia, keloid scar is
often more of a cosmetic concern than a health on.28 Keloid
scar does not regress and tends to recur after excision.
Keloid scar contains disorganized type I collagen and type
III collagen. Hypertrophic scar consists of mainly type III
collagen arranged parallel with skin surface.28 Elastic content
was significantly different between normal and abnormal
wound healings.31 Keloid scars contain more elastin content in
deep dermal layer than hypertrophic scar and normal skin.31 In
the superficial dermis, elastin content was 51% and 37%
higher in normal skin compared to hypertrophic scars or ke-
loids.31 Moreover, the significant decrease of fibrilin-1 is also
noted throughout the dermis in both scar types, indicating the
distortion of the composition of microfibrils.31
Excessive collagen synthesis and abnormal collagen turn-
over, caused by dysregulation of matrix degrading enzymes
contributes to excessive wound healing.32,33 Tissue inhibitors
of metalloproteinases (TIMPs) can inhibit MMPs by either
binding to the zinc-binding domain of active MMPs or by
binding to the inactive proMMP zymogen, thereby slowing the
process of activation.33 The MMP and TIMP proteins work in
combination to regulate the synthesis and degradation of ECM
at wound sites, and an imbalance of MMP and TIMP results in
abnormal wound healing. These factors, including TGF-b and
PG will be reviewed in the in vitro and in vivo models
subsequently.
5. The epidemiology of excessive wound healing
Although excessive wound healing is seen in all ethnicities,
the prevalence of keloid scars varies among different pop-
ulations. Evidence shows the importance of genetic factors in
excessive scarring and keloid scars are more common in
African-Americans and Asians, especially in dark-skinned
individuals.34 The familiar heritability and prevalence in
twins also support the concept of the genetic predisposition to
excessive scarring. Many local factors are believed to increase
the chance of excessive scarring, including high skin tension,
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4 P.-H. Wang et al. / Journal of the Chinese Medical Association xx (2017) 1e8
hypoxia, endocrine dysfunction, fatty acid, autoimmune, and
genetic hypothesis.2,3 Cross-sectional analysis of BioBank
Japan clinical data enrolling 200,000 patients with 47 common
diseases found that individuals with a family history of keloid
exhibited a higher odds ratio than those without a family
history, highlighting the strong impact of host genetic factor
on disease onset.35 Genome-wide association study suggested
that some are an autosomal recessive inheritance pattern; some
are an autosomal dominant inheritance mode with incomplete
clinical penetrance and variable expression.36 Nakashima and
colleagues found that significant associations of keloid with
four single nucleotide polymorphism loci in three chromo-
somal regions: 1q41, 3q22.3e23 and 15q21.3 and among
these, the most significance was observed at rs873549 (odds
ratio [OR], 1.77) on chromosome 1.36 Association of
rs8032158 located in neural precursor cell expressed devel-
opmentally downregulated protein 4 (NEDD4) on chromo-
some 15 yielded OR of 1.51.36,37 The possible mechanism of
NEDD4 involves keloid formation, including (i) NEDD4
affected subcellular localization and protein stability of p27
which was implied its critical role in contact inhibition; (ii)
NEDD4 induced accumulation of b-catenin in the cytoplasm
and activated the T-cell factor/b-catenin transcriptional activ-
ity; (iii) NEDD4 upregulated expressions of fibronectin and
type 1 collagen and contributed to the excessive accumulation
of extracellular matrix.37 One study focused on Chinese Han
population and the results showed plasminogen activator
inhibitor-1 promoter polymorphism -675 4G/5G and plasma
plasminogen activator inhibitor levels are associated with
keloid risk, supporting the importance of hereditary factor
responsible for keloid formation.38 To date, there are several
studies having reported polymorphisms that may be associated
with keloids in many above-mentioned genes, such as TGF-b
with known functions relevant to fibrosis; however, epigenetic
modification (environmental factor) has been shown to be an
important regulator during the dysfunction of wound repair
process.39 Recent epidemiologic studies showed that some of
medical illnesses, such as hypertension (endothelial cell
dysfunction) are also associated with excessive scar formation,
since many medical illnesses are also tendency to hereditary
penetrance for the development of hypertrophic scar and
keloid formation, supporting the evidence of important role of
genetic and epigenetic characteristics on the scar formation.40
However, due to limitations of genetic studies on keloid
scarring, there is still a long way to clarify the genetic role on
the keloid formation.
6. The in vitro and in vivo studies for excessive wound
healing
In response to TGF-b1, fibroblasts differentiate into myo-
fibroblasts to contract wound and help to remodel ECM.41,42
TGF-b1-induced myofibroblasts expression is mediated via
Smad3 activation by the TGF-b1 receptor complex, resulting
in Smad2/3 complex combination with Smad4 and trans-
location into the nucleus. Smad3 binding to Smad binding
elements in the promoter region regulates a-smooth muscle
Please cite this article in press as: Wang P-H, et al., Wound healing, Journal of the Chinese Medical Association (2017), https://doi.org/10.1016/
j.jcma.2017.11.002
actin (SMA) transcription to promote deposition of ECM
proteins, such as collagen I and III.42
There are different rolls for TGF-b1 and TGF-b3 on cell
migration and progression in the in vitro medial edge epithelial
(MEE) cell model.41 TGF-b1 induces cell cycle arrest in G1
phase in 98% of cultured cells, and TGF-b3 ceases progres-
sion in 79% of cells. But it is interesting, the two isoforms
cause cell arrest commonly through the p15ink4b, a D-cyclin
dependent kinase inhibitor.43 However, TGF-b1, instead of
TGF-b3, plays a major role in activation of the p15ink4b gene
to induce cell arrest via multiple Smad4 binding sites in the
latter's promoter.43 In the same study, TGF-b3 was more
effective in inducing MEE cell migration and this effect could
be accentuated by adding p15ink4b to TGF-b3, but not to
TGF-b1. Both TGF-b1 and TGF-b3 are capable to induce
apoptosis, and augmented by adding p15ink4b. Finally, Ior-
danskaia and Nawshad suggested that early cell cycle arrest by
TGF-b1 might be a condition for TGF-b3 mediated migration,
but the overlapping roles of the two isoforms in abnormal
wound healing demand further studies.43
Downregulated TGF-b1, TGF-b1 type 1 receptor and TGF-
b1 type 2 receptor expression inhibits fibroblast proliferation,
contraction, and collagen production.4 The TGF-b1/Smad
pathway is a promising target for the modulation of the scar-
ring response.4 Persistent TGF-b1/Smad signaling caused
proliferation of fibroblasts and excessive production of type I
collagen and fibronectin, resulting in hypertrophic scarring,
even when the wound has healed.41,42 Lin and colleagues have
demonstrated that TGF-b1 increased the collagen content,
procollagen I, and TIMP-1 production, but slightly decreased
MMP-3 production of pulp cells through activin receptor-like
kinase-5/Smad2/3 and MEK/ERK signaling.44 Aoki and col-
leagues using small interfering RNA (siRNA) to target TIMP1
also successfully increased degradation of collagen type I and
further increased degradation of their thick collage bundles.45
Inhibition of TGF-b1 expression by siRNA and oxymatrine
(Chinese herb extracts) resulted in an attenuation of TGF-b1
mediated phosphorylation of the kinase p38 and ERK1/2, and
decreased phosphorylation of Smad2, Smad3, and Smad4 in
keloid derived fibroblasts.46 Targeting fibroblast TGF-b type I
receptor showed the decreased fibroblast production of ECM
as well as scar tissue formation in rabbit model.46
In recent studies, Smad7 expression was induced by asiat-
icoside and TNF-a-stimulated protein 6 (TSG-6) released
from mesenchymal stem cells (MSCs), and the upregulated
Smad7 altered hypertrophic scar fibroblast proliferation and
collagen production, resulting in fibrosis inhibition.6,47 Venous
ulcer keratinocytes possess under-phosphorylated Smad2 and
this attenuation in Smad2 activation was not correlated with
increased inhibitory signal of Smad7.48 MSCs might accel-
erate wound healing by reducing deleterious tissue inflam-
mation, inducing angiogenesis in the wound bed, and reducing
scarring following the repair process.49 MSC-released TSG-6
was identified to improve wound healing by limiting inflam-
mation, fibrosis and macrophage activation.49 Reduced wound
scarring was correlated with reduced TGF-b1/TGF-b3 ratio
from wound lysates.1
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P.-H. Wang et al. / Journal of the Chinese Medical Association xx (2017) 1e8
In the process of hypertrophic scar, keratinocytes are
excessively differentiated and produce fibrotic factors to
stimulate fibroblasts, such as vascular endothelial GF,
epidermal GF, connective tissue GF and TGF-b.1e3 In recent
studies, keratinocytes were excessively differentiated and
produced TGF-b1, TGF-b2, insulin growth factor-1, epidermal
GF, vascular endothelial GF and connective tissue GF, thus
leading to fibroblast hyperproliferation and collagen produc-
tion. Inhibiting keratinocyte function by Notch signaling
blockade, for example, a g-secretase inhibitor (DAPT) could
inhibit fibroblast hyperproliferation.50
In addition to the canonical TGF-b signaling pathway,
TGF-b also activates several non-Smad signaling pathways,
including members of the mitogen-activated protein kinase
(MAPK) family, protein kinases A and C (PKA and PKC), or
phosphatidylinositol-3 kinase (PI3K).51 Carthy and colleagues
reported that tamoxifen inhibited TGF-b-mediated activation
of cultured human primary fibroblasts via non-Smad signaling
through ERK1/2 MAP-kinase and downstream AP-1 tran-
scription factor FRA2.52 Interestingly, in the same study,
tamoxifen exerted its effect in the fibroblasts independently of
the estrogen receptor (ER).52 Furthermore, Kim et al.
demonstrated that the effect of tamoxifen was dependent on its
action as an ER-a agonist in renal fibroblasts. It is known that
active ER can bind to Smad3 and inhibit its activity.53 Thus,
the different tissue/organ distribution and function of tamox-
ifen in anti-fibrotic treatment demand further exploration,
since using tamoxifen might prevent keloids or hypertrophic
scar after burns or surgery.54,55
MicroRNAs (miRNAs) act in post-transcriptional regula-
tion of gene expression and involve in the regulation of skin
fibrosis, including TGF-b signaling, fibroblast proliferation
and differentiation, ECM deposition, and epithelial-to-
mesenchymal transition (EMT).56e59 Growing evidences
revealed different expression profiles of miRNAs between
hyperplastic scar and normal skin and the altered miRNAs
expression in abnormal scarring might be associated with
TGF-b signaling.56 Li et al. reported that downregulated miR-
200b was shown in hypertrophic scarring and miR-200b
regulated cell proliferation and apoptosis of human hypertro-
phic scar fibroblasts by altering the TGF-b1/a-SMA signaling,
fibronectin expression, and type I and III collagen synthesis.60
Further study revealed that decorin reduced fibrosis and
induced regeneration in many tissues; decorin expression was
significantly downregulated in hypertrophic scar and normal
deep dermal fibroblasts.32 MicroRNA-181b involved in the
different expression of decorin in skin and wound healing and
TGF-b1 stimulation increased miR-181b level in hypertrophic
scar and deep dermis.61 Blocking miR-181b reversed TGF-b1-
induced decorin downregulation and myofibroblast differen-
tiation in hypertrophic scar fibroblasts.61 The expression of
miR-21 and miR-200b might participate in hypertrophic scar
formation by TGF-b/miR-21/Smad7 and TGF-b/miR-200b/
Zeb1 pathways.62 Studies also found that upregulation of miR-
29b possessed anti-fibrotic effect in cardiac and renal fibro-
blasts via suppressing the activation of TGF-b/smad3
signaling pathway.63 Furthermore, overexpression of miR-29b
Please cite this article in press as: Wang P-H, et al., Wound healing, Journal of the Chinese Medical Association (2017), https://doi.org/10.1016/
j.jcma.2017.11.002
5
decreased type I collagen expression in skin fibroblasts
in vitro.64 Overexpression of miR-29b markedly reduced the
expression levels of COL1A1 and a-SMA, and inhibited
myofibroblast-like cell proliferation and induced apoptosis.65
Chau et al. have found that the miR-29 family involves in
hypertrophic scar through regulating the translation of ECM
mRNAs.66
These data were further corroborated by a study using
intravenous recombinant decorin, a natural inhibitor of TGF-b.
Adult mice treated with recombinant decorin between days 3
and 14 post wounding showed 50% smaller scars.32 This
reduction of scar volume (and length) was associated with
decreased immunostaining for TGF-b1 and TGF-b2, but not
TGF-b3.67 Together, these studies suggest that the develop-
ment of a scar may be related to the relative expression and
ratio of TGF-b3 to TGF-b1 and TGF-b2.
7. Stem cell therapy
Recently, stem cell-based therapies have been used for
skin-regenerative and anti-fibrotic properties and have been
shown to be efficacious in experimental and human dis-
ease.68e74 Human amniotic membrane (HAM) is the inner-
most layer of the fetal membrane and is derived from the
epiblast as early as 8 days after fertilization and before
gastrulation.69,75 HAM is a special tissue with anti-
inflammatory and anti-fibrotic properties.76 Amniotic mem-
brane can be collected during pregnancy and holds great po-
tential for therapeutic use because it is an abundant source of
progenitor cells from cells shed from the fetus.77 At least two
kinds of stem cells can be isolated from the amniotic mem-
brane: amniotic epithelial cells (AECs) and amniotic mesen-
chymal cells (AMCs).76e78 Both stem cell types are capable of
self-renewal and differentiate into multiple cell lineages. Pri-
mary human AECs take the following advantages when they
are considered most attractive for cellular therapies, including
(i) AECs are plentiful and obtained without invasive and
expensive procedures from term placenta, compared with adult
tissue-derived stem cells; (ii) there are no tumor induction and
ethical constraints of AECs, compared with embryonic stem
cells; (iii) AECs still possess the ability to be differentiate
toward the adipogenic, osteogenic, chondrogenic, skeletal
myogenic, neurogenic lineage hepatic and pancreatic lineages.
All support the use of AECs as a new anti-fibrotic treatment
strategy, such as an attenuation of wound inflammation and a
reprograming of resident cells to favor tissue regeneration and
inhibit fibrosis. Paracrine signaling is considered one of the
main underlying mechanisms behind the therapeutic effects of
stem cells.78
8. The prevention strategy
The first step toward treatment of excessive wound healing
is early recognition and institution of therapy after surgery or
trauma. Meticulous tissue handling, suturing, and wound
management with efforts to prevent infection are mandatory.79
Sun protection to reduce scar hyperpigmentation is essential.
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6 P.-H. Wang et al. / Journal of the Chinese Medical Association xx (2017) 1e8
Patients who are at increased risk of excessive wound healing
benefit from preventive techniques, which include silicone gel
sheeting or ointments, hypoallergenic microporous tape, and
concurrent intralesional steroid injection.80,81 Silicone gel
sheeting is widely used for hypertrophic scar treatment and the
only remedy with high evidence. Silicone gel sheeting has a
20-plus-year history with several randomized controlled trials
that support its safe and effective use.82,83 Proposed mecha-
nisms of action for scar reduction include improved hydration
and occlusion, increased temperature and change in scar me-
chanical tension.
In conclusion, most in vitro data derived from fibroblasts
cultured from abnormal wound lesions only represent the
terminal stage of this disease and in vivo animal models might
not present a real condition in humans. The current review
only provides a basic understanding of pathogenesis about the
wound healing. More studies focusing on human wound
healing are welcome.
Acknowledgments
This work was supported by grants from the Ministry of
Science and Technology (MOST 106-2314-B-075-061-MY3)
and the Taipei Veterans General Hospital (Grant V106C-129
and V106D23-001-MY2-1), Taipei, Taiwan.
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j.jcma.2017.11.002