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ORIGINAL RESEARCH
Efficacy Evaluation of a Topical Hyaluronic Acid
Serum in Facial Photoaging
Zoe Diana Draelos .Isabel Diaz .Jin Namkoong .Joanna Wu .
Thomas Boyd
Received: March 29, 2021 / Accepted: June 10, 2021
ÓThe Author(s) 2021
ABSTRACT
Introduction: Hyaluronic acid (HA) acts as a
biologic humectant, thus retaining water in the
skin, making HA useful as a topical moisturizing
ingredient. The goal of the research was to
evaluate the ability of a HA facial serum to
deliver skin benefits.
Methods: Forty females 30–65 years of age with
Fitzpatrick skin types I–VI who exhibited pho-
toaging used the HA facial serum twice daily
with sunscreen. The dermatologist investigator
evaluated smoothness, plumping, hydration,
fine lines/wrinkles, and global appearance issues
on a 5-point ordinal scale. The subjects assessed
product tolerability in terms of stinging, itch-
ing, and burning. Corneometry was under-
taken, with assessments performed at baseline,
immediately after application, and at weeks 2,
4, and 6. Facial swabbing and photography were
performed at the same intervals on a subset of
15 subjects.
Results: The HA serum demonstrated excellent
tolerability and produced an increase in skin
hydration (as measured by corneometry)
immediately after application of 134%
(p\0.001), with a sustained increase of 55%
(p\0.001) at week 6. At week 6, there was also
improvement (pB0.001) in all evaluated attri-
butes: smoothness (64%), plumping (60%),
hydration (63%), fine lines (31%), wrinkles
(14%), and overall global assessment (43%).
Facial swabbing confirmed an increase in topi-
cal HA at week 6 (p= 0.04), accounting for the
enhanced skin appearance, but there was no
statistically significant increase in IL-1a, indi-
cating no product irritation.
Conclusion: Topical HA in a serum formulation
provides excellent skin hydration, as demon-
strated through clinical, photographic, chemi-
cal, and instrumental assessments.
Keywords: Moisturizer; Facial aging;
Humectant; Corneometry; Transepidermal
water loss
Z. D. Draelos (&)
Dermatology Consulting Services, PLLC, High
Point, NC, USA
e-mail: zdraelos@northstate.net
I. Diaz
Dermal Clinical Research, Colgate-Palmolive,
Piscataway, NJ, USA
J. Namkoong J. Wu T. Boyd
Early Research, Colgate-Palmolive, Piscataway, NJ,
USA
Dermatol Ther (Heidelb)
https://doi.org/10.1007/s13555-021-00566-0
Key Summary Points
Topical hyaluronic acid in a serum
formulation can increase skin hydration
by 55%, as measured by corneometry.
Topical hyaluronic acid skin hydration is
visualized as improved skin plumping,
smoothness, and overall skin appearance.
Topical hyaluronic acid possesses an
excellent skin tolerability profile.
Topical hyaluronic acid is suitable for all
Fitzpatrick skin types.
DIGITAL FEATURES
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including a summary slide, to facilitate under-
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for this article go to https://doi.org/10.6084/
m9.figshare.14748876.
INTRODUCTION
Improvement in overall facial skin appearance
is most rapidly achieved through enhanced
moisturization. Moisturization occurs by
increasing the water content of the epidermis,
thereby improving skin texture and reducing
the appearance of fine lines and superficial
wrinkles. The skin naturally achieves hydration
through dermal glycosaminoglycans (GAGs)
such as hyaluronic acid [1]. Hyaluronic acid
(HA), also known as hyaluronan, is a linear
carbohydrate polysaccharide found in all living
organisms [2]. It is a highly hydrophobic sub-
stance [3]. The human body contains 15 g of
HA, with one-third residing in the skin [1]. HA
is multifunctional in the skin, modulating cel-
lular immunity, regulating epidermal cell
interactions, residing in extracellular matrix
molecules, and absorbing high amounts of
water [4]. Six liters of water can be absorbed by
1 g of HA [5].
HA can penetrate into the stratum corneum
if it is of the correct size [6]. Raman
microimaging and other techniques are able to
monitor the penetration of HAs of different
molecular weights [7]. HA with a low molecular
weight of 20–300 kDa passes through the stra-
tum corneum, while high molecular weight
(1000–1400 kDa) HA is largely impermeable [1].
This points to the importance of selecting HA of
the proper molecular weight in effective skin
formulations.
The ability to manufacture large quantities
of HA from bacterial fermentation has led to
enhanced-efficacy moisturizers that are able to
mimic the natural moisturization process of the
skin. The objective of this study was to evaluate
the ability of a facial serum to deliver skin
benefits by promoting skin plumpness and
hydration while minimizing fine lines/wrinkles
and improving the overall global assessment of
facial appearance. The clinical study was addi-
tionally supported by in vitro work to deter-
mine if the HA serum product could increase
hyaluronan expression.
METHODS
In Vivo Clinical
Forty females 30–65 years of age with Fitzpatrick
skin types I–VI who were diagnosed by the
dermatologist investigator as possessing poor
skin plumpness and hydration along with
photoaging were enrolled in this single-site
study to evaluate the efficacy of a facial serum.
This study was conducted in compliance with
the Helsinki Declaration of 1964 and its later
amendments. The study was approved by the
Allendale Institutional Review Board (AIRB),
Old Lyme, CT). Informed consent for partici-
pation and for photograph and article publica-
tion was received from all participants.
Following this, and after meeting all inclusion
criteria and none of the exclusion criteria
(Table 1), subjects with a lack of skin hydration
and plumping and with global photoaging were
enrolled. Subjects were asked to wash their face
at the research center. They were provided with
a headband to pull hair off their face and a black
Dermatol Ther (Heidelb)
neck drape to conceal their clothing. All visible
facial jewelry was removed and the subjects
were instructed to close their eyes and mouth.
These procedures were undertaken to anon-
ymize the photographs.
Table 1 Inclusion and exclusion criteria
Inclusion criteria:
1. Subjects must be diagnosed by the investigator as possessing poor skin plumpness and hydration along with
photoaging.
2. Subjects must be female, 30–65 years of age, Fitzpatrick skin types I–VI, with no known medical conditions that, in
the investigator’s opinion, may interfere with study participation.
3. Women of childbearing potential must be willing to use a form of birth control during the study. For the purpose of
this study, the following are considered acceptable methods of birth control: oral contraceptives, Norplant, Depo-
Provera, double barrier methods (e.g., condom and spermicide), and abstinence. No new methods of birth control
should be started during the study.
4. Subjects must be able to read, understand and provide written informed consent.
5. Individuals must agree to continue to use all regular brands of cosmetics, makeup remover, and the assigned test
materials for the duration of the study. Individuals must refrain from using any new products other than the assigned
test materials.
6. Willingness not to use any moisturizer, cleanser, and/or sunscreen on the face other than the provided study product
and sunscreen along with their normally used facial cleanser.
7. Subjects must agree to avoid excessive sun exposure and the use of artificial tanning methods.
8. Subjects must agree to arrive at their study visits with a clean face and without any products (lotions, creams, makeup,
etc.) applied to their face.
Exclusion criteria:
9. Any dermatological disorder that, in the investigator’s opinion, may interfere with the accurate evaluation of the
subject’s face.
10. Subjects who have demonstrated a previous hypersensitivity reaction to any of the ingredients of the study products.
11. Concurrent therapy with any medication, either topical or oral, that might interfere with the study.
12. Subjects who have used a topical retinoid or other cosmeceutical preparation within 2 weeks of study enrollment, to
include kojic acid, vitamin C, licorice extracts, alpha hydroxy acids, etc.
13. Subjects who are unwilling to discontinue use of all other facial moisturizers.
14. Subjects who are unwilling to leave their current oral and/or topical product medications unchanged for the duration
of the study.
15. Subjects who use an indoor tanning booth.
16. Subjects who are pregnant, breastfeeding, or planning a pregnancy.
17. Subjects with clinically significant unstable medical disorders.
18. Subjects who are unwilling or unable to comply with the requirements of the protocol.
19. Individuals who are participating in any other research study.
Dermatol Ther (Heidelb)
Subjects were provided with the study facial
serum (PCA Skin Hyaluronic Acid Boosting
Serum, Colgate-Palmolive Co., Piscataway, NJ
and PCA Skin, Scottsdale, AZ) for twice-daily use
and a sunscreen (Neutrogena Clear Face Broad
Spectrum SPF 55, Johnson & Johnson, Skillman,
NJ) for use as needed during the study. The use
of facial sunscreen was required by the IRB and
it was used by all subjects, as documented in the
subject diaries. Subjects used their own self-se-
lected cleanser and cosmetics, but these prod-
ucts were stable for 30 days prior to study entry
and throughout the study. A compliance diary
was provided to record the use of the study
serum.
The dermatologist investigator evaluated
smoothness, plumping, hydration, fine lines/
wrinkles, and global appearance issues. The
following 5-point ordinal scale was used:
0 = none, 1 = minimal, 2 = mild, 3 = moderate,
4 = severe. Subjects assessed product tolerability
in terms of stinging, itching, and burning. The
following 5-point ordinal scale was used:
0 = none, 1 = minimal, 2 = mild, 3 = moderate,
4 = severe. Corneometry (Dermalab Combo Pin
Probe, Cortex Technologies, Hadsund, Den-
mark) of the left cheek was conducted for all
subjects in triplicate after they had acclimated
to the study environment for 20–30 min.
VISIA CR4.3 (Canfield Scientific, Parsippany,
NJ) photography of the front, right, and left face
with visible light was conducted for a subset of
15 subjects. The faces of these 15 subjects were
then swabbed on the right cheek for HA levels
after photos had been captured at each study
visit so as not to interfere with images. Swabs
were collected on clean skin, as each subject was
asked to wash their face with their self-selected
cleanser at the research center prior to all study
assessments during their afternoon study visits
(the last product application was completed in
the morning of the study visit at weeks 2, 4, and
6). The swabbing technique is often used to
collect skin surface microbiome samples.
HydraFlock (25-3606-H, Puritan Medical Prod-
ucts Company LLC, Guiford, ME) was first
wetted by dipping it into sterile phosphate-
buffered saline (PBS). A skin surface sample was
collected by covering a surface area of 2 inches
by 2 inches with a swab while rotating and
moving the swab. Swabs collected throughout
the study were stored at – 80 °C until process-
ing. Each swab was soaked and shaken in 1 mL
of PBS with protease inhibitor cocktails for 1 h
at room temperature. Freezing/thawing of the
extracts to/from – 80 °C was limited to three
times within 2 weeks which did not impact the
ELISA results. The resulting extracts were used
in interleukin-1a (IL-1a, SLA50, Human IL-1
Alpha/IL-1F1 Quantikine ELISA Kit, R&D Sys-
tems Minneapolis, MN), hyaluronan (DHYAL0,
Hyaluronan Quantikine ELISA Kit, R&D Sys-
tems, Minneapolis, MN), and filaggrin (CSB-
EL008712HU, Cusabio, Houston, TX) enzyme-
linked immunosorbent assays (ELISAs) accord-
ing to the manufacturer’s protocols.
During the baseline visit only, all subjects
applied the study product and sat for 10–15 min
at the end of their study visit after all assess-
ments were completed. Investigator assess-
ments were completed for immediate plumping
and hydration. Postapplication corneometry of
the left cheek was conducted for all subjects in
triplicate. Subjects returned for the same
assessments at weeks 2, 4, and 6.
In Vitro
Full-thickness human skin equivalents from
MatTek (EpiDermFT, EFT-400, Ashland, MA)
were used to evaluate whether the study HA
serum product could increase hyaluronan
expression. After equilibration overnight after
receiving EFT-400, 10 lL of the product were
applied on top of the skin equivalents for fur-
ther incubation at 37 °C with 5% CO
2
. Tripli-
cates were used for untreated samples and
duplicates for the serum-treated samples. After
24 h of treatment, the medium was collected for
IL-1a release. Tissues were rinsed with PBS three
times and collected for HA expression. The
epidermis and the dermis were separated from
tissues for protein extraction using a TissueLyser
II (85300, Qiagen, Carlsbad, CA) and RIPA lysis
buffer (R0278, Sigma-Aldrich, St. Louis, MO).
The protein concentration was determined
using a Micro BCA Protein Assay Kit (23235,
Thermo Scientific, Waltham, MA) according to
the manufacturer’s protocol. IL-1a release and
Dermatol Ther (Heidelb)
hyaluronan expression were determined using
ELISAs (SLA50, DHYAL0, R&D Systems)
according to the manufacturer’s protocols. For
the hyaluronan ELISA, protein lysates were
diluted 1000-fold (epidermis) and 10,000-fold
(dermis) and normalized to the protein
concentration.
Levels of HA and other active ingredients in
the PCA Skin Hyaluronic Acid Boosting Serum
are kept proprietary. The serum contains HA as
well as HA Pro Complex containing disodium
acetyl glucosamine phosphate, hydrolyzed
yeast extract, polyglucuronic acid, and sodium
carrageenan.
RESULTS
In Vivo Clinical
40/40 subjects with Fitzpatrick skin types I–VI
(35 Caucasians, 5 African Americans) success-
fully completed the 6-week study. Subjects aged
38–60 years were enrolled, with 8 on hormonal
contraception and 32 postmenopausal. Statisti-
cal significance was defined as pB0.05. Ordinal
five-point nonparametric subject and investi-
gator questionnaire data were evaluated as the
change from baseline and percent change in an
intragroup analysis using a Wilcoxon signed
rank test. Numeric corneometry data repre-
senting the average of three facial measure-
ments were assessed using a Student t-test and
reported as the average for each visit and as the
percent change from baseline.
The subjects noted no statistically significant
stinging, itching, or burning immediately after
product application or at any time during the
6-week study. The investigator assessed hydra-
tion and plumping visually immediately after
product application. There was a statistically
significant (p\0.001) 30% improvement in
plumping and a 31% improvement in skin
hydration. This improvement continued into
week 2 with statistically significant (pB0.003)
improvements in smoothness (29%), plumping
(35%), hydration (35%), fine lines (9%), and
overall global assessment (19%). Cumulative
improvement was seen at week 4, with statisti-
cally significant (p\0.001) improvements in
smoothness (49%), plumping (48%), hydration
(46%), fine lines (21%), and overall global
assessment (33%). The study concluded at week
6 with continued improvement (p\0.001) in
all attributes: smoothness (64%), plumping
(60%), hydration (63%), fine lines (31%),
Fig. 1 Investigator assessments. Percent improvements from baseline immediately after application and at week 2, week 4,
and week 6 are shown. Note the cumulative improvement over time with continued use of the product
Dermatol Ther (Heidelb)
Fig. 2 Before treatment (afront of face, bright of face,
cleft of face) and after 6 weeks of treatment (dfront of
face, eright of face, fleft of face) of Fitzpatrick type II
skin. This Caucasian female photographically demon-
strated increased light reflection from the face (seen as
facial shine) after treatment. This increased light reflection
is due to smoothing of the skin surface and a reduction in
fine facial lines
Fig. 3 Before treatment (afront of face, bright of face,
cleft of face) and after 6 weeks of treatment (dfront of
face, eright of face, fleft of face) of Fitzpatrick type V
skin. This African-American female demonstrated
increased light reflection from the face, especially from
the medial cheeks, improving overall skin tone
Dermatol Ther (Heidelb)
wrinkles (14%), and overall global assessment
(43%) (Fig. 1). Before and after photographs of
representative subjects are presented in Figs. 2
and 3.
The investigator noted that the improve-
ment was probably due to the enhanced water-
holding capacity of the topically applied HA,
which was effective for all Fitzpatrick skin types
regardless of the degree of photodamage.
Immediately after application, there was a 134%
increase in skin water content (p\0.001) as
measured by corneometry. This is possible due
to the water-holding effect of the HA when
present on the skin surface. After 2 weeks of
application, a 15% increase (p= 0.025) was
seen; there was a further improvement in water
content of 29% at 4 weeks (p\0.001) and of
55% at 6 weeks (p\0.001).
Facial swabs taken at baseline and weeks 2, 4,
and 6 were analyzed. Posttreatment swabs col-
lected at weeks 2, 4, and 6 were compared to
baseline swabs (control, prior to serum treat-
ment). IL-1a was measured to determine if the
HA serum produced any irritation. Baseline
swabs (before serum application) were used as a
control. There was no statistically significant
increase in IL-1a, indicating that there was no
irritation (data not shown). Filaggrin, which is
broken down into natural moisturizing factor
(NMF), was also measured. There was no statis-
tically significant change in filaggrin, indicating
that the HA serum helped maintain NMF (data
not shown). An examination of the HA present
on the skin surface was conducted. There was a
statistically significant increase in HA. The
change from baseline p-values was p= 0.02 at
week 2, p= 0.04 at week 4, and p= 0.04 at week
6 (Fig. 4).
One problem with HA-containing products
is stickiness due the humectant properties of
HA, which draws water from the atmosphere,
which means that the serum does not dry down
on the skin. The subjects were asked to assess
product stickiness at week 6. Minimal stickiness
was noted by the subjects. Subjects reported no
application concerns.
In Vitro
After 24 h of treatment with serum, the full-
thickness skin equivalents were rinsed with PBS.
The epidermis and the dermis of the full-thick-
ness skin equivalents were separated by pulling,
which was followed by protein extraction.
Samples were analyzed for the presence of
hyaluronan by ELISA. More hyaluronan was
present in the dermis compared to the epider-
mis, which is consistent with the literature.
Serum-treated samples were compared to the
untreated samples (control). While no differ-
ences in the epidermis were observed between
the untreated and serum-treated samples, there
was an increase in the hyaluronan in the dermis
from serum-treated samples. Based on this
finding, the increase in dermal hyaluronan is
from the boosting effects of the HA serum, not
residual hyaluronan from the study product,
since there was no difference between the
untreated and serum-treated epidermis (Fig. 5).
The paired t-test was used as the method of
statistical analysis.
Fig. 4 In vivo clinical hyaluronic acid analysis based on
skin surface swabs. Skin surface swabs were collected and
extracted using PBS with protease inhibitor cocktails. HA
concentrations were analyzed by ELISA for all four time
points (baseline, 2 weeks, 4 weeks, and 6 weeks). Average
HA concentrations from 40 subjects are shown, and
statistical tests were performed for weeks 2, 4, and 6 using
the baseline for comparison. The increases in HA from the
skin at weeks 2, 4, and 6 are shown
Dermatol Ther (Heidelb)
DISCUSSION
HA is a valuable ingredient to improve facial
appearance in women with poor skin plump-
ness, decreased skin hydration, and photoaging
[8]. It has been used both topically and orally
for appearance improvement [9]. HA is multi-
functional, even possessing a role in immune
modulation in disease [10] and as a postproce-
dure treatment in facial resurfacing [11].
Changes occur in HA with aging such that a HA-
based moisturizer might improve facial appear-
ance through topical application [12].
The current formulation contains hydro-
lyzed 50 kDa HA and 10–1000 kDa sodium
hyaluronate. This size of the HA allowed it to
penetrate into and through the stratum cor-
neum [4]. These humectant ingredients
produced an immediate increase in the water-
holding capacity of the skin, as demonstrated
by the investigator assessments and corneome-
try 15 min postapplication. The film-forming
capabilities of the HA formulation created a
smoothed skin surface with excellent humec-
tant properties, producing appearance
improvement. In addition, the improvement
was cumulative, with increasing results over the
6 weeks of study product application as con-
tinued hydration occurred.
HA increased significantly after 2 weeks of
product application, with slight continued
increases observed through weeks 4 and 6
(Fig. 5). These results indicate there was a sig-
nificant amount of HA deposited on the skin
from the study serum, which may account for
the cumulative improvement observed over
Epidermis Dermis
Average StDev Average StDev
Untreated 8.39 6.12 205.29 35.76
Serum 7.62 5.31 306.93 94.12
0
5
10
15
20
Untreated Serum
Epidermis
g HA per mg protein
0
100
200
300
400
500
Untreated Serum
Dermis
g HA per mg protein
Fig. 5 In vitro hyaluronic acid analysis using EpiDermFT.
EpiDermFT was treated with Hyaluronic Acid Boosting
Serum (Serum) or left untreated (Untreated) for compar-
ison. Proteins for the epidermis and the dermis were
separately extracted using the RIPA lysis buffer with
protease inhibitor cocktails, and ELISAs were run to
evaluate the HA concentrations in these tissue samples.
The HA ELISA results were normalized to the total
protein concentrations in the same samples and are
represented as the HA concentration per mg protein.
The epidermis results and the dermis results are shown
separately. Increased dermal hyaluronan was detected in
these samples. The increase in dermal hyaluronan was from
the boosting effects of the Hyaluronic Acid Boosting
Serum (HABS)
Dermatol Ther (Heidelb)
time. This research supported the clinical find-
ings of increased skin hydration by document-
ing the increase in HA through skin swabbing.
This increased skin hydration resulted in the
investigator observing facial appearance
improvement. This type of improvement was
probably not due to the sunscreen used for
photoprotection during the study, as it did not
possess humectant properties.
However, there are some limitations of this
study. While skin punch biopsies can defini-
tively assess the modulation of HA in the skin
after serum application, skin punch biopsies are
invasive and may produce facial scarring in
volunteers. In order to assess clinical subjects
noninvasively, we utilized skin surface swab-
bing as well as in vitro assessment. Even though
we were able to demonstrate modulation of HA,
these changes were not assessed via biopsy.
Since clinical assessments demonstrated chan-
ges in plumpness and hydration, it is likely that
biomarkers related to increased skin hydration,
as seen in the HA ELISA from skin surface
swabbing. Another limitation of this study is
the lack of a placebo to compare with the serum
product. It might have been possible to com-
pare the serum to placebo, but there are no true
moisturizer placebos. Therefore, the serum was
compared to baseline or no treatment instead.
Finally, this study did not consider the possible
preventative activity of HA in photoaging.
CONCLUSIONS
Skin hydration is one of the major concerns for
skin health. Among ingredients that improve
skin hydration, HA stands out with its ability to
retain moisturization. With an appropriately
selected HA based on efficacy, this well-formu-
lated HA serum can visually improve skin
plumping and mechanistically improve skin
hydration by 55% as measured by corneometry
due to an increase in dermal hyaluronan in all
Fitzpatrick skin types.
ACKNOWLEDGEMENTS
Disclosures. Zoe Diana Draelos, MD,
received an educational grant from Colgate
Palmolive to conduct this research. Isabel Diaz,
BA, is an employee of Colgate-Palmolive Com-
pany. Colgate-Palmolive Company (Piscataway,
NJ, USA). Jin Namkoong, PhD, is an employee
of Colgate-Palmolive Company. Colgate-Pal-
molive Company (Piscataway, NJ, USA). Joanna
Wu, PhD, is an employee of Colgate-Palmolive
Company. Colgate-Palmolive Company (Pis-
cataway, NJ, USA). Thomas Boyd, PhD, is an
employee of Colgate-Palmolive Company. Col-
gate-Palmolive Company (Piscataway, NJ, USA).
Medical Writing and Editorial Assis-
tance. Editorial assistance was provided by
Giorgiana Giancola, PhD; Scientific Affairs,
Colgate-Palmolive Company, Piscataway, NJ.
Compliance with Ethics Guidelines. This
study was conducted in compliance with the
Helsinki Declaration of 1964 and its later
amendments. The study was approved by the
Allendale Institutional Review Board (AIRB),
Old Lyme, CT). Informed consent for partici-
pation, photograph and article publication was
received from all participants.
Data Availability. The datasets generated
during and/or analyzed during the current
study are available from the corresponding
author on reasonable request.
Authors’ Contribution. Zoe Diana Draelos,
MD, Isabel Diaz, BA, Jin Namkoong, PhD,
Joanna Wu, PhD, and Thomas Boyd, PhD all
contributed to the conduct of the scientific
research detailed in this manuscript and the
writing of the manuscript.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given heir
approval for this version to be published.
Dermatol Ther (Heidelb)
Funding. This research and the journal’s
rapid service fee were funded by Colgate-Pal-
molive Company.
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommer-
cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,
distribution and reproduction in any medium
or format, as long as you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons licence, and
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included in the article’s Creative Commons
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regulation or exceeds the permitted use, you
will need to obtain permission directly from the
copyright holder. To view a copy of this licence,
visit http://creativecommons.org/licenses/by-
nc/4.0/.
REFERENCES
1. Bukhari SNA, Roswandi NL, Waqas M, Habib H,
Hussain F, Khan S, Sohail M, Ramli NA, Thu HE,
Hussain Z. Hyaluronic acid, a promising skin reju-
venating biomedicine: a review of recent updates
and pre-clinical and clinical investigations on cos-
metic and nutricosmetic effects. Int J Biol Macro-
mol. 2018;120(Pt B):1682–95.
2. Essendoubi M, Gobinet C, Reynaud R, Angiboust JF,
Manfait M, Piot O. Human skin penetration of
hyaluronic acid of different molecular weights as
probed by Raman spectroscopy. Skin Res Technol.
2016;22(1):55–62.
3. Trookman NS, Rizer RL, Ford R, Ho E, Gotz V.
Immediate and longer-term clinical benefits of a
topical treatment for facial lines and wrinkles. J Cin
Aesthet Dermatol. 2009;2(3):38–43.
4. Stern R, Maibach HI. Hyaluronan in skin: aspects of
aging and its pharmacologic modulation. Clin
Dermatol. 2008;26:106–22.
5. Jegasothy SM, Zabolotniaia V, Bielfedt A. Efficacy of
a new topical nano-hyaluroinc acid in humans.
J Clin Aesthet Dermatolog. 2014;7(3):27–9.
6. Pavicic T, Gauglitz GG, Lersch P, Schwach-Abdel-
laoui K, Malle B, Korting HC, Farwick M. Efficacy of
cream-based novel formulations of hyaluronic acid
of different molecular weights in anti-wrinkle
treatment. J Drugs Dermatol. 2011;10(9):990–1000.
7. Lubart R, Yariv I, Fixler D, Lipovsky A. Topical
hyaluronic acid facial cream with new micronized
molecule technology effectively penetrates and
improves facial skin quality: results from in-vitro,
ex-vivo, and in-vivo (open-label) studies. J Clin
Aesthet Dermatol. 2019;12(10):39–44.
8. Papakonstantinou E, Roth M, Karakiulakis G. Hya-
luronic acid, a key molecule in skin aging. Dermato-
Endocrinol. 2012;4:253–8.
9. Oe M, Sakai S, Yoshida H, Okado N, Kaneda H,
Masuda Y, Urushibata O. Oral hyaluronan relieves
wrinkles: a double-blinded, placebo-controlled
study over 12-week period. Clin Cosmet Investig
Dermatol. 2017;10:267–73.
10. Nobel PW, Liang J, Jiang D. Hyaluronan as an
immune regulator in human disease. Physiol Rev.
2011;2011(91):221–64.
11. Kim DS, et al. Synergistic effects of using novel
home-use-660- and 850 nm light emitting diode
mask in combination with hyaluronic acid
ampoule on photoaged Asian skin. J Cosmet Der-
matol. 2020;19:2606–15.
12. Longas MO, Russell CS, He HY. Evidence for struc-
tural changes in dermatan sulfate and hyaluronic
acid with aging. Carbohydr Res. 1987;159:127–36.
Dermatol Ther (Heidelb)
