Effect of astaxanthin on cutaneous wound healing

Abstract

Wound healing consists of a complex series of convoluted processes which involve renewal of the skin after injury. ROS are involved in all phases of wound healing. A balance between oxidative and antioxidative forces is necessary for a favorable healing outcome. Astaxanthin, a member of the xanthophyll group, is considered a powerful antioxidant. In this study, we investigated the effect of topical astaxanthin on cutaneous wound healing. Full-thickness dermal wounds were created in 36 healthy female mice, which were divided into a control group and a group receiving 78.9 µM topical astaxanthin treatment twice daily for 15 days. Astaxanthin-treated wounds showed noticeable contraction by day 3 of treatment and complete wound closure by day 9, whereas the wounds of control mice revealed only partial epithelialization and still carried scabs. Wound healing biological markers including Col1A1 and bFGF were significantly increased in the astaxanthin-treated group since day 1. Interestingly, the oxidative stress marker iNOS showed a significantly lower expression in the study. The results indicate that astaxanthin is an effective compound for accelerating wound healing.

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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CCID.S142795
Effect of astaxanthin on cutaneous wound healing
Jitlada Meephansan1
Atiya Rungjang1
Werayut Yingmema2
Raksawan Deenonpoe3
Saranyoo Ponnikorn3
1Division of Dermatology, Chulabhorn
International College of Medicine,
Thammasat University, Pathum Thani,
Thailand; 2Laboratory Animal Centers,
Thammasat University, Pathum Thani,
Thailand; 3Chulabhorn International
College of Medicine, Thammasat
University, Pathum Thani, Thailand
Abstract: Wound healing consists of a complex series of convoluted processes which involve
renewal of the skin after injury. ROS are involved in all phases of wound healing. A balance
between oxidative and antioxidative forces is necessary for a favorable healing outcome. Astax-
anthin, a member of the xanthophyll group, is considered a powerful antioxidant. In this study,
we investigated the effect of topical astaxanthin on cutaneous wound healing. Full-thickness
dermal wounds were created in 36 healthy female mice, which were divided into a control
group and a group receiving 78.9 µM topical astaxanthin treatment twice daily for 15 days.
Astaxanthin-treated wounds showed noticeable contraction by day 3 of treatment and complete
wound closure by day 9, whereas the wounds of control mice revealed only partial epithelializa-
tion and still carried scabs. Wound healing biological markers including Col1A1 and bFGF were
significantly increased in the astaxanthin-treated group since day 1. Interestingly, the oxidative
stress marker iNOS showed a significantly lower expression in the study. The results indicate
that astaxanthin is an effective compound for accelerating wound healing.
Keywords: astaxanthin, wound healing, reactive oxygen species, antioxidant
Introduction
Wound healing or repair is a complex and crucial process of response to injury. To
accomplish this, coordination of multiple cells and components is necessary. The heal-
ing process is composed of three overlapping phases: inflammation, proliferation, and
remodeling.1 In the coagulation and inflammatory phase, cutaneous injury affecting
primarily the epithelial and endothelial compartments results in a coagulation cas-
cade forming a blood clot and release of pro-inflammatory mediators. The blood clot
within the vessel lumen provides hemostasis, and the clot within the injury site acts
as a provisional matrix for cell migration, promoting formation of fresh extracellular
matrix (ECM), a reservoir for cytokines and growth factors. Inflammatory white cell
functions include debridement of necrotic material and bacteria, and production of
critical cytokines. Twenty-four to forty-eight hours after injury, monocytes replace
neutrophils and differentiate into tissue macrophages which phagocytose and kill
bacteria, scavenge tissue debris, and release several growth factors. The growth factors
stimulate migration and proliferation of fibroblasts, endothelial cells, and keratino-
cytes, and production and modulation of ECM, constituting the proliferation/migration
phase resulting in reepithelialization and angiogenesis. The remodeling phase begins
5–7 days after injury to break down excess macromolecules. Cells within the wound
are returned to a stable phenotype and ECM material is altered.
Correspondence: Jitlada Meephansan
Division of Dermatology, Chulabhorn
International College of Medicine,
Thammasat University, Rangsit Campus,
99 Moo 18 Phahonyothin Road,
Klongluang, Pathum Thani, 12120,
Thailand
Tel +66 2564 4444 ext 1535
Email kae_mdcu@yahoo.com
Journal name: Clinical, Cosmetic and Investigational Dermatology
Article Designation: ORIGINAL RESEARCH
Year: 2017
Volume: 10
Running head verso: Meephansan et al
Running head recto: Astaxanthin and wound healing
DOI: http://dx.doi.org/10.2147/CCID.S142795
This article was published in the following Dove Press journal:
Clinical, Cosmetic and Investigational Dermatology
13 July 2017
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ROS are involved in all phases of wound healing. ROS are
small chemically reactive molecules of oxygen such as oxygen-
free radicals. They strongly react with multiple molecular com-
ponents such as nucleic acids, proteins, lipids, and other small
inorganic molecules. ROS may alter the function or ir reversibly
destroy the target molecule through their cascading reactions.
On the other hand, low concentrations of ROS play a role in
initiating signaling during the proliferative phase, including
homeostasis,2,3 formation of granulation tissue, reepithelializa-
tion, and angiogenesis.4 The physiological level of ROS, such
as hydrogen peroxide at the wound site, increases after injury
and gradually declines. Prolonged generation or large amounts
of ROS, called oxidative stress, can cause chronic inflamma-
tion by initiating the NF-kB/Rel pathway,4 which is believed
to be the major cause of chronic unhealed wounds. The nega-
tive effects of oxidative stress can be restrained by antioxidant
enzyme systems and dietary antioxidants such as carotenoids.5
The carotenoid structure has a common chemical feature con-
taining a long-conjugated double-bond polyene chain, which
has an ability to quench or scavenge ROS.6 Several kinds of
antioxidants are proposed to regulate the oxidation–reduction
balance, and studies of the effects of various antioxidants on
wound healing have reported accelerated healing outcomes.7,8
Astaxanthin, a member of the xanthophyll group, is a
red-orange carotenoid. Its antioxidative effect has been shown
to exceed those of pro-vitamin A and vitamin E,9 and it is
considered one of the most powerful antioxidants. The inter-
est in antioxidant activity of astaxanthin in the pharmaceutical
industry, aquaculture, and nutritional health is expanding. It
has been used as a highly effective antioxidant in various health
conditions.10 In dermatology, clinical studies suggest that oral
supplementation and topical treatment of an astaxanthin extract
from Haematococcus pluvialis improves the skin condition
and provides protective effects mediated by balanced oxidative
actions. A balance between oxidative and antioxidative forces is
needed for favorable wound healing. Among studies on various
health-promoting effects of astaxanthin, very few studies on
wound healing have been reported. In this study, we investigated
the effect of topical astaxanthin on cutaneous wound healing
in animal models, serving as a preliminary study for the use
of astaxanthin in accelerating wound healing. We evaluated
wound contraction area and histopathology, and determined the
mRNA levels of iNOS, Col1A1, and bFGF at the wound area.
Materials
Drugs
The astaxanthin material, composed of 78.9 µM of astax-
anthin extracted from H. pluvialis, was supplied by China
Jiangsu International Economic and Technical Cooperation
Group, Ltd. The vehicle was palm oil.
Animals
The animal protocol (no 015/2558) was approved by the
Institutional Animal Care and Use Committee of Thammasat
University, which is accredited by the National Research
Council of Thailand. All animals were housed at the Labo-
ratory Animal Center of Thammasat University according
to guidelines for the care and use of laboratory animals,
National Research Council 2011. Young female BALB/c
mice (8 weeks old) were procured from the National Labo-
ratory Animal Center, Thailand. A total of 36 mice were
randomly assigned to an astaxanthin-treated group and a
control group. During the experiments, the animals were
housed under strict hygiene standards and controlled envi-
ronmental conditions (12-hour light/dark cycle, temperature
approximately 23°C). Standard laboratory food and water
were provided ad libitum.
Animal experiments
Anesthesia and surgical procedure
Mice were anesthetized with 1.5% isoflurane in 100% oxy-
gen at a 0.9 L/minute flow after induction with 5% isoflurane
using a single circuit anesthesia system. Mice were posi-
tioned in ventral recumbency. Hair on the dorsal surface of
the skin was removed with a razor, the skin was aseptically
prepped with 70% alcohol gauze sponges, and a sterile
drape positioned. All wounding procedures were performed
under sterile conditions by one surgeon. The dorsal skin was
picked up and a punch hole extending through the panniculus
carnosus was made using a 4-mm sterile disposable biopsy
punch. Two full-thickness wounds were created at designated
locations. The wounds were left open with no dressing. Each
wound site was digitally photographed and tissues were
collected. Tissues at wound sites were collected for reverse
transcription polymerase chain reaction (RT-PCR) on days
1, 3, 6, 9, 12, and 15 using a disposable biopsy punch (6 mm
in diameter).
Tissues for histopathology were collected from treat-
ment and control groups by elliptical excision on day 3 and
7 post-wounding.
Post-operative and wound care
The wounds were treated topically twice daily with astaxanthin
extract in the treatment group and vehicle in control group
(0.025 mL/wound). A digital image of each wound with a
scale was recorded daily until complete closure. For the wound

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Astaxanthin and wound healing
contraction study, a template containing a 10-mm diameter cir-
cular window was used to standardize the size of each wound.
Outcome measures
Wound contraction
Digital photographs were taken on the day of surgery and
every day from then on. Time to wound closure was defined
as the time point at which the wound bed was filled with new
tissue. Wound area was analyzed by tracing the wound margin
with a fine-resolution computer mouse and calculating the
pixel area using Adobe Illustrator CS6 software, run on an
Intel® Core™ i7-2600K CPU. All tracing was performed by
the same computer graphics professional, without knowledge
of treatment conditions. Wound contraction was calculated
as the percentage decrease in original wound area. Complete
closure was considered when the wound area disappeared,
and became grossly equal to zero.
RT-PCR
Collected tissue samples were stored fresh frozen at -80°C
until use. The RNeasy Mini Kit (Qiagen NV, Venlo, the
Netherlands) was used for extraction and purification of total
RNA from tissues, following the manufacturer’s protocol.
A260/280 ratios of the samples were used to evaluate the
RNA quantity and quality. cDNA synthesis was performed
using the ImProm-II™ Reverse Transcription System (Pro-
mega Corporation, Fitchburg, WI, USA) following the manu-
facturer’s protocol. Expression of the wound healing markers
Col1A1 (Mm00801666_g1), bFGF (Mm00438930_m1),
and iNOS (qMmuCIP0035502) was analyzed using real-
time PCR following the manufacturer’s protocol from iTaq
Universal Probes Supermix (Bio-Rad Laboratories Inc.,
Hercules, CA, USA). The relative ratio of gene expression
for each gene was determined by standard exponential curves
using the CFX 96 TouchTM PCR Detection System (Bio-
Rad Laboratories Inc.). The internal control gene (B2M,
Hs00985689_m1; Thermo Fisher Scientific, Waltham, MA,
USA) was used to normalize target gene expression.
Histopathological evaluation
Histologic evaluation was performed using visible light
microscopy. The samples were fixed in 10% buffered for-
malin. After fixation, sections perpendicular to the anterior–
posterior axis of the wound were dehydrated with graded
ethanol and embedded in paraffin. Hematoxylin and eosin,
and Masson’s trichrome stains were used on sections of
paraffin-embedded tissue. Images were captured at 4× and
10× magnification with a Leica DM3000 LED microscope
under the same exposure. Reepithelialization, granulation
tissue formation, angiogenesis, and inflammatory cell infil-
tration were evaluated.
Statistical analysis
Results were recorded as mean±SD. The Student’s t-test and
Mann–Whitney test were performed to analyze differences
between data obtained from different experimental groups.
A P-value of less than 0.05 was considered significant.
Results
Wound contraction
The astaxanthin extract applied topically on the wounds
showed significant acceleration of wound closure which
was clearly visible at day 3 of the experiment (Figure 1). On
day 9 after wounding, the astaxanthin-treated wounds had
already lost their eschars and appeared fully epithelialized,
whereas the wounds of control mice showed only partial
epithelialization and still carried scabs. Complete wound
closure in the control group was observed only by day 11. The
mean original wound area in the astaxanthin-treated group
was larger than that in the control group, at 14.69 mm2 and
12.42 mm2, respectively. In addition, on day 1 post-injury,
wound area in the astaxanthin-treated group significantly
decreased to 10.33 mm2 (28.15% reduction of the original
wound area), whereas the control group showed an 18.12%
reduction, to 10.23 mm2. On day 7 after wounding, closure
of the wounds in the astaxanthin-treated group was more
pronounced than that in the control group, at 90% (1.27 mm2)
Day 0
Control
A
staxanthin
Day 3 Day 5 Day 7 Day 9 Day 11
Figure 1 Images of wound contraction in astaxanthin and control groups from day 0 to day 11.

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Meephansan et al
and 82.35% (2.17 mm2), respectively (Figure 2). No mice
were excluded from the study and no wounds showed signs of
infection. At the end of the experiment, mice in both groups
showed complete wound closure without visible scars or
chronic wounds.
The data indicated that wound closure in astaxanthin-treated
mice was significantly accelerated compared with vehicle-
treated mice. A significant difference between the two groups
was observed beginning at day 1 and continued until complete
wound closure in the astaxanthin-treated group at day 10.
Histology
At day 3, almost complete reepithelialization was observed in
the astaxanthin-treated group but poor reepithelialization was
seen in the control group. In the control group, stellate and
spindle fibroblasts were scattered in the granulation tissue with
a moderate to high degree of edema, whereas collagen bundles
with a mild degree of edema were observed in the astaxanthin-
treated group. In addition, a few capillary vessels were present
in the wound area which were poorly arranged in the control
group, but were well arranged in the astaxanthin-treated group.
Mononuclear cells, which were marginated in the vessels and
scattered in perivascular and dermis regions, were markedly
decreased in the astaxanthin-treated group compared to the
control group. At day 7, complete reepithelialization and a well-
elongated epidermis with keratinization was observed in mice
treated with astaxanthin. The degree of infiltrated inflammatory
cells was minimal in both groups. Well-formed granulation tis-
sue, fibroblasts oriented parallel to the skin surface, and abundant
organization of collagen were observed in the astaxanthin-
treated group. Treatment with astaxanthin significantly promoted
the wound healing process in mice (Figure 3).
Day
*
*
*
**
*
***
0123 45678910 11 12 13 14 15
–120.00
–100.00
–80.00
–60.00
Change of baseline (%)
–40.00
–20.00
0.00
Astaxanthin
Control
Figure 2 Wound area contraction in astaxanthin and control groups from day 0 to day 15.
Notes: Error bars indicate standard deviations. *P<0.05.
Day 3 Day 7
A
staxanthin
Control
AB
CD
Figure 3 Skin wound sections from the astaxanthin-treated group and the control group at day 3 and day 7 stained with hematoxylin and eosin.
Notes: (A, B) Control; (C, D) astaxanthin-treated group; (A, C) and (B, D) represent day 3 and day 7 of the experiment, respectively.

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Astaxanthin and wound healing
Wound healing markers and oxidative
stress markers
The mRNA expression of tissue-specific wound healing bio-
markers and oxidative stress biomarkers including Col1A1,
bFGF, and iNOS were determined using real-time PCR.
Dynamic gene expression profiles in astaxanthin-treated
mice and the control group were compared on days 1–15
(Figure 4). During the healing process, expression of Col1A1
and bFGF in the astaxanthin-treated group was higher than
that in the control group, throughout the healing period. The
expression of collagen1 mRNA in both groups was mark-
edly increased and reached a maximum on day 6 post-injury.
bFGF mRNA expression in both groups decreased during the
first 3 days post-injury, and then gradually increased until
day 15 in both groups. iNOS was selected as an oxidative
stress marker, for monitoring ROS during the wound heal-
ing process. Real-time PCR analysis revealed a decrease
in expression of iNOS in astaxanthin-treated mice from
day 3 onward, until the end of the experiment. In summary,
astaxanthin treatment caused a significant increase in expres-
sion of wound healing biomarkers Col1A1 and bFGF, but a
significant decrease in expression of oxidative stress (ROS)
biomarker iNOS (Figure 4).
Discussion
Significant accelerated healing effects of astaxanthin were
observed on the first day after injury, during the inflammatory
phase. This effect could be mediated either by suppression of
the inflammation level or by acceleration of the inflammatory
phase. Minimal inflammation is known to contribute to better
wound healing. Astaxanthin may suppress this unfavorable
condition through various mechanisms. First, this effect could
be facilitated by balancing oxidative stress. While the produc-
tion of ROS in the early phase is significantly higher than
normal in order to defend against invading microorganisms
and transmit intercellular signals supporting the process of
inflammation,11,12 astaxanthin may be quenching and scav-
enging excessive ROS and RNS, which is consistent with
our result which showed significantly decreased expression
of iNOS, an oxidative stress marker, in the astaxanthin-
treated group. As a result, activation of the NF-kB pathway
may be prevented, leading to reduced pro-inflammatory
gene transcription and pro-inflammatory cytokine produc-
tion.13,14 Second, astaxanthin may have an inhibitory effect
on the expression of adhesion molecules. The main source of
ROS during inflammation is NADPH oxidase in the plasma
membrane of neutrophils and macrophages. It was found
that traditional antioxidants suppress expression of adhesion
molecules (ICAM-1, VCAM-1, E-selectin) and chemokines
(IL-8) during inflammation.15,16 Astaxanthin may also inhibit
expression of these molecules, leading to inhibition of inflam-
matory cell infiltration. ROS production in mitochondria was
found to be involved in inflammatory signaling pathways,16
and the protective effects of astaxanthin may protect against
Col1A1
bFGF
iNOS
Relative Col1A1
mRNA expression
Relative iNOS mRNA expression
Relative bFGF mRNA expression
Astaxanthin
Control
Astaxanthin
Control
Astaxanthin
Control
0
100
200
300
00
10
20
30
40
50
60
70
80
100
50
150
250
350
200
300
400
500
600
**
*
Day 1 Day 3 Day 6 Day 9 Day 12 Day 15 Day 1 Day 3 Day 6 Day 9 Day 12 Day 15
Day 1 Day 3 Day 6 Day 9 Day 12 Day 15
A B
C
Figure 4 The mRNA expression of tissue-specic wound healing biomarkers.
Notes: Gene expression of wound healing and oxidative stress markers were analyzed using real-time polymerase chain reaction analysis of astaxanthin-treated mice and
control mice, represented by the orange and the blue line, respectively. The (A–C) show the expression of Col1A1, bFGF, and iNOS, respectively. The asterisk represents
a signicant difference in expression (P<0.05) on the indicated day. Error bars indicate standard deviations.

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Meephansan et al
these intracellular oxidative molecules as well.5 In addition,
its anticomplement activity may also be involved in the sup-
pression of inflammation.17
The results during the proliferative and remodeling
phases also indicate the significant potential of astaxanthin
to reduce wound size throughout the closure process. This
correlates with the increased expression of bFGF due to
astaxanthin in our study. bFGF plays a significant role in
granulation tissue formation, reepithelialization, matrix
formation, and remodeling,18 which are the major events
during proliferative and remodeling phases. In vitro studies
have demonstrated that bFGF regulates the synthesis and
deposition of various EMC components, increases kerati-
nocyte motility during reepithelialization,19 promotes the
migration of fibroblasts, and stimulates them to produce
collagenase. The increased expression of bFGF mRNA
in the astaxanthin-treated group during the early phase of
wound healing may contribute to a significant acceleration
of wound closure.
As mentioned previously, a low concentration of ROS
is needed to initiate a normal repair process. Astaxanthin
was shown to preserve that physiological function by redox
regulation. For example, in host defense mechanisms,
astaxanthin suppresses ROS and inflammatory cell infiltra-
tion. At the same time, it improves the capacity and ability
of leukocytes to destroy pathogens.20 In angiogenesis, ROS
signals regulate formation of new blood vessels. Astaxanthin
may enhance the effect of ROS in activating physiological
angiogenesis, and regulate ROS at an appropriate level,
which is not harmful to endothelial cells.21 Additionally, it
may also inhibit pathological angiogenesis in vascularized
tumors by suppressing angiogenesis via the JAK2/STAT3
signaling pathway.22
Collagen is an essential component of the proliferative and
remodeling phase, as it provides strength to the wound.23,24 In
the early process of granulation tissue formation, fibroblasts
produce collagen type 3, which is later substituted with a
stronger type 1 collagen during the maturation phase. Our
data showed a significantly higher expression of Col1A1 on
day 6 after injury in the astaxanthin-treated group, compared
to the control group. This is consistent with a study on vocal
fold wound healing,25 which found that astaxanthin upregu-
lates Col1A1 expression. Wound contraction is another
important mechanism in the process of wound closure, espe-
cially in rodents.26 Astaxanthin probably accelerates wound
contraction during the proliferative and maturation phase
by enhancing the function of myofibroblasts, the cells that
are differentiated from tissue fibroblasts, which play a key
role in this process. Their smooth muscle features produce
contractile forces between the wound edges and ECM. They
also produce collagen matrix to form scar tissue, and release
cytokines and growth factors contributing to the increasing
rate of wound healing.27
However, in later stages, the myo-
fibroblasts are removed from the normally healed wound; a
persistent accumulation possibly results in hypertrophic scar
or keloid.28 In our study, there was no visible scar observed
at the end of the study in both groups. While increasing the
contraction of the wound, astaxanthin may also reduce the
chance of fibrosis by inducing apoptosis of the myofibroblast
and/or suppressing TGF-β.29,30
Conclusion
Topical treatment with astaxanthin extract appears to acceler-
ate wound healing in full-thickness dermal wounds in mice.
Future studies are likely to employ astaxanthin as a novel
redox-based strategy to treat wounds in humans.
Acknowledgment
The authors gratefully acknowledge the financial support
provided by Chulabhorn International College of Medicine,
Thammasat University, contract no 11/2558.
Disclosure
The authors report no conflicts of interest in this work.
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