ArticlePDF Available

Hyaluronic Acid, a Promising Skin Rejuvenating Biomedicine: A Review of Recent Updates and Pre-clinical and Clinical Investigations on Cosmetic and Nutricosmetic Effects

Authors:

Abstract and Figures

Hyaluronic acid (HA) plays multifaceted role in regulating the various biological processes such as skin repairmen, diagnosis of cancer, wound healing, tissue regeneration, anti-inflammatory, and immunomodulation. Owing to its remarkable biomedical and tissue regeneration potential, HA has been numerously employed as one of the imperative components of the cosmetic and nutricosmetic products. The present review aims to summarize and critically appraise recent developments and clinical investigations on cosmetic and nutricosmetic efficacy of HA for skin rejuvenation. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, intra-dermal filler injections, dermal fillers, facial fillers, autologous fat gels, lotion, serum, and implants, etc.) exhibit remarkable anti-wrinkle, anti-nasolabial fold, anti-aging, space-filling, and face rejuvenating properties. This has been achieved via soft tissue augmentation, improved skin hydration, collagen and elastin stimulation, and face volume restoration. HA, alone or in combination with lidocaine and other co-agents, showed promising efficacy in skin tightness and elasticity, face rejuvenation, improving aesthetic scores, reducing the wrinkle scars, longevity, and tear trough rejuvenation. Our critical analysis evidenced that application/administration of HA exhibits outstanding nutricosmetic efficacy and thus is warranted to be used as a prime component of cosmetic products.
Content may be subject to copyright.
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules
journal homepage: www.elsevier.com
Review
Hyaluronic acid, a promising skin rejuvenating biomedicine: A review of recent
updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic
effects
Syed Nasir Abbas Bukharia, Nur Liyana Roswandib, Muhammad Waqasc, Haroon Habibc, Fahad Hussaind,
Shahzeb Khane, Muhammad Sohailf, Nor Amlizan Ramlib, Hnin Ei Thug, Zahid Hussainb,
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia
bDepartment of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Selangor, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
cJohar Institute of Professional Studies Lahore, Nabi Bux, Main Ferozpur Road, Punjab, Pakistan
dInstitute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Raiwind Road, 55150 Lahore, Pakistan
eDepartment of Pharmacy, University of Malakand, Dir Lower, Chakdara, KPK, Pakistan
fDepartment of Pharmacy, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
gDepartment of Pharmacology and Dental Therapeutics, Faculty of Dentistry, Lincoln University College, Jalan Stadium, SS 7/15, Kelana Jaya, 47301 Petaling Jaya, Selangor,
Malaysia
ARTICLE INFO
Article history:
Received 22 July 2018
Received in revised form 4 September 2018
Accepted 28 September 2018
Available online xxx
Keywords:
Hyaluronic acid
Face rejuvenation
Anti-wrinkle
Anti-aging, nasolabial folds, dermal filler
Nutricosmetic
ABSTRACT
Hyaluronic acid (HA) plays multifaceted role in regulating the various biological processes such as skin re-
pairmen, diagnosis of cancer, wound healing, tissue regeneration, anti-inflammatory, and immunomodulation.
Owing to its remarkable biomedical and tissue regeneration potential, HA has been numerously employed
as one of the imperative components of the cosmetic and nutricosmetic products. The present review aims
to summarize and critically appraise recent developments and clinical investigations on cosmetic and nutri-
cosmetic efficacy of HA for skin rejuvenation. A thorough analysis of the literature revealed that HA based
formulations (i.e., gels, creams, intra-dermal filler injections, dermal fillers, facial fillers, autologous fat gels,
lotion, serum, and implants, etc.) exhibit remarkable anti-wrinkle, anti-nasolabial fold, anti-aging, space-fill-
ing, and face rejuvenating properties. This has been achieved via soft tissue augmentation, improved skin
hydration, collagen and elastin stimulation, and face volume restoration. HA, alone or in combination with
lidocaine and other co-agents, showed promising efficacy in skin tightness and elasticity, face rejuvenation,
improving aesthetic scores, reducing the wrinkle scars, longevity, and tear trough rejuvenation. Our critical
analysis evidenced that application/administration of HA exhibits outstanding nutricosmetic efficacy and thus
is warranted to be used as a prime component of cosmetic products.
© 2018.
1. Introduction
Hyaluronic acid (HA) (molecular formula C28H44N2O23) is a
non-sulfated glycosaminoglycan that is composed of repeating poly-
meric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine
linked via glycoside bond in the arrangement of alternating β-(1 4)
and β-(1 3) bonds (Fig. 1) [1]. The stability of HA structure confides
in the stereochemistry of the disaccharides. Due to the natural abun-
dance (animals and human bodies) of this biopolymer, its biodegrad-
ability, and biocompatibility appeals for its versatile uses as prognos-
tic molecules and for treatment of a wide range of human and animal
diseases. The structure of hyaluronic acid exhibits remarkable ability
to hold/trap approximately 1000 times its weight of water. In human
synovial fluid, the average molecular weight of HA is 3
Corresponding author.
Email address: zahid3224@puncakalam.uitm.edu.my (Z. Hussain)
4 million Daltons. It may consist of 10,000 or more disaccharides re-
peating units in length in ~4 million Da molecular weight of HA [2].
HA has been utilized in various forms such as hydrogel, der-
mal filler, intradermal injection, scaffolds, creams, films, foams, and
gels for treatment of different types of diseases. HA has shown wide
range of pharmacological activities including anti-inflammatory [3],
wound healing and tissue regenerating [4], immunomodulatory [5],
anticancer and anti-proliferative [6], anti-diabetic [7], anti-aging [8],
skin repairing [9], and cosmetic properties [10]. HA plays multifac-
eted role in regulating various the biological processes and maintain-
ing homeostasis in the body.
HA has been found at the periphery and at interfaces of collagen
and elastin fibers where it facilitates holding collagen and elastin in
a proper configuration. In the aged skin, these connections with HA
are particularly absent, which may contribute to the disorganization
of collagen and elastin fibers might leads to the presence of skin fine
line, wrinkle and nasolabial folds. HA has become one of the most
crucial ingredients in the cosmetic as well as nutricosmetic products.
https://doi.org/10.1016/j.ijbiomac.2018.09.188
0141-8130/ © 2018.
UNCORRECTED PROOF
2 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Fig. 1. Chemical structure of hyaluronic acid.
Fig. 2. Summary of cosmetic and nutricosmetic effects of HA.
Almost all products having moisturizing, skin protective, and anti-ag-
ing properties consists of HA. It has been acknowledged for its ability
to replenish moisture in the skin. The water holding ability of HA re-
sults in softer, smoother, and radiant skin. The hydration of the skin
also leads to slow down the wrinkle formation and improves deep fine
lines and already developed wrinkles which generally appear with age.
The skin hydration and antioxidant effects of HA also promote cell
regeneration and stimulate production of collagen due to its nutricos-
metic effects. There are various products of HA being used as der-
mal filler for cosmetic procedure. HA is non-toxic and non-sensitiz-
ing, therefore it is safely used for all types of skin with no risk of al-
lergic reactions. This naturally-occurring biomolecule has commonly
been used to inject into the dermis (as dermal filler) to restore skin
volume and minimize the appearance of wrinkles as well as nasolabial
folds. They are specifically injected into skin folds, deep wrinkles to
lift and reshape the face due to its unique characteristics that mimic
the natural materials found in our cells. Many studies been done to
compare their effectiveness and safety as well as tolerability to the pa-
tients. Moreover, some researchers developed a new HA filler with the
combination of other material such as lidocaine and carbon dioxide.
There is also a combination of administration of HA filler with devices
like radiofrequency and non-ablative infrared.
Plenteous researches have investigated the cosmetic and nutricos-
metic effects of HA for skin rejuvenation. However, there was lack-
ing of critical appraisal of different formulations of HA for a partic-
ular type of skin defect and validation on safety and biocompatibil-
ity of HA based biomedicines for skin rejuvenation. The aim of the
present review is to summarize and critically appraise recent develop
ments in cosmetic and nutricosmetic efficacy of HA based formula-
tions including moisturizing effects, skin hydration, skin smoothening
and rejuvenating, and skin regeneration efficacy. A thorough analy-
sis of the literature revealed that HA based formulations (i.e., gels,
creams, intra-dermal filler injections, dermal fillers, facial fillers, au-
tologous fat gels, lotion, serum, and implants, etc.) have shown re-
markable efficacy to treat a wide range of skin defects such as wrin-
kles, nasolabial folds, and skin aging. This has been achieved via soft
tissue augmentation, improved skin hydration level, collagen stimu-
lation, and face rejuvenation. The safety, tolerability, and efficacy of
HA (as intra-dermal or facial filler injection) have also been well-doc-
umented for treatment of various types of skin problems. HA, alone
or in combination with lidocaine and other agents, produce promising
cosmeceutical and nutricosmetic effects such as anti-aging, skin tight-
ness and elasticity, face rejuvenation and improved aesthetic scores,
reduced wrinkle scars, longevity of rejuvenating effects, and tear
trough rejuvenation. The current critical appraisal and comparative
analysis of various formulations of HA will enable scientists and re-
searchers to understand pharmaceutical significance and therapeutic
and clinical efficacy of HA-based formulations for skin rejuvenation.
2. Biomedical and pharmaceutical implications of HA
HA exhibits versatile algorithm of biomedical and pharmaceuti-
cal applications. HA in the form of hydrogel, scaffolds, films, creams,
foams, and gels has shown wide ranges of pharmacological activities
including anti-inflammatory [3], wound healing and tissue regenerat-
ing [4], immunomodulatory [5], anticancer and anti-proliferative [6],
anti-diabetic [7], anti-aging [8], skin repairing [9], and cosmetic prop-
erties [10].
HA based hydrogels are also capable of rejuvenating injured car-
diac tissues in myocardial infraction [11]. The temporal effect of HA
hydrogels on left ventricle (LV) remodeling, infarct thinning and ex-
pansion, and infarct stiffness has been investigated in a porcine in-
farct model. HA based hydrogel treatment led to reduced LV volumes,
increased wall thickness, and enhanced ejection fraction, when com-
pared to the control groups [11]. HA has also been used in the preven-
tion of urinary tract infections in fertile women. HA is an essential part
of bladder surface glycosaminoglycans and encloses the urothelium
which may help to prevent urinary tract infections. Breakage to this
part has been hypothesized as a causal factor for the progression of re-
current urinary tract infections (RUTIs) [12]. In this study, 28 women
who were diagnosed with RUTI, were underwent treatment with in-
tra-vesicular instillations of chondroitin sulfate (CS) and HA. The ef-
fectiveness of treatment was evaluated in terms of symptom improve-
ment, reduction of number of episodes of urinary tract infection, and
quality of life. The evidence showed that patients treated with CS and
HA combined therapy showed remarkable improvement in quality of
life and reduction in RUTI episodes [12]. The efficacy of combina-
tion therapy with CS and HA has been validated by many researchers
[1315].
HA has also been used as a cosmeceutical to treat wide ranges of
skin problems including wrinkles, nasolabial folds, anti-aging, skin
augmentation, skin hydration, and collagen stimulator. Due to its
strong water-binding potential, HA has been utilized as active ingre-
dient in a large range of cosmetic formulations. HA used to help the
skin to hold and maintain elasticity, turgor and moisture. A study
was conducted on 76 female subjects (3060 years age) having clin-
ical signs of peri-ocular wrinkles. They were administrated with HA
cream formulation to the wrinkled area two time a day for 60 days
[16]. A vehicle control cream was applied around the other eye. The
skin hydration and elasticity ware measured as evaluation parameters.
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 3
Table 1
A summary of clinical significance of HA for treatment of wrinkles: human clinical studies.
Cosmetic
effect
HA
formulation Application
Experimental model/study
design Study parameters Key findings Ref.
Anti-
wrinkle
effect
Cream 0.1%
(w/w) (50,
130, 300, 800
and
2000 kDa,
respectively)
Twice daily at periocular
wrinkles for 60 days
76 female aged between
30 and 60 years with clinical
signs of periocular wrinkles
Skin hydration, skin
elasticity, wrinkle depth
1. Significant improvement in
skin hydration level.
2. Remarkable improvement in
skin elasticity.
3. Significant reduction of wrinkle
depth due to better penetration
abilities of low molecular
weight (LMW) HA.
[28]
Topical
(lotion,
serum, and
cream)
8 weeks of treatment using a
DermaTOP, Corneometer,
Cutometer and a Chroma Meter
in the periorbital region
33 women with an average
age of 45.2
Skin hydration, skin
elasticity, skin roughness,
wrinkle depth
1. Significant improvement in
moisturizing effect of the prod-
uct range.
2. Significantly improved of the
skin elasticity.
3. Remarkable improved in skin
roughness.
[29]
Cream 3 month trial of the product for
daily use.
20 patients assigned in four
groups each with a different
anti-wrinkle cream
containing HA (Balea,
Nivea, Lancôme, Chanel)
Wrinkle reduction, skin
tightness and elasticity.
1. Significant reduction in the
depth of perioral and orbital
wrinkles in all groups
2. All groups achieved remarkable
increase in skin tightness.
3. Minimal significant changes in
skin-elasticity could only be
seen in individual groups.
[30]
Gel
intradermal
injection
Treated with either SGP-HA or
LGP-HA for 2 weeks.
20 patients aged range
4965 years with moderate-
to-severe wrinkles.
Product safety and
effectiveness
1. Indication of aesthetic improve-
ment by Global Aesthetic Im-
provement Scale (GAIS).
2. Both SGP-HA and LGP-HA
were found to be safe and effec-
tive for the correction of perio-
ral wrinkles and folds with no
serious adverse event occurred.
[31]
Injection 6 months treatment of different
types of HA E fillers.
The efficacy, patient
satisfaction, and safety of
new range of hyaluronic
acid fillers (HA E) in
perioral enhancement.
1. Significant improvement in
wrinkle assessment scale and
lip fullness.
2. The products were indicated
safe and well tolerated.
3. Perioral enhancement with HA
E fillers led to sustained effects
and high subjects' satisfaction.
[32]
UNCORRECTED PROOF
4 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Table 1 (Continued)
Cosmetic
effect
HA
formulation Application
Experimental model/study
design Study parameters Key findings Ref.
Injectable
filler
6 months treatment of different
types of HA E filler.
The efficacy, patient
satisfaction, and safety of
the HA E filler range in
periorbital rejuvenation
1. HA E Touch effective for peri-
orbital lines; HA E Classic and
HA E Deep for the treatment of
tear troughs.
2. Clinical improvement in wrin-
kle severity and aesthetic out-
come of all treatments.
3. Treatments were safe and well-
tolerated with high level of pa-
tients' satisfaction.
[33]
Injectable
filler
6 months treatment with five
different fillers from the same
range (HA (E))
77 participants with a mean
age of 54.5
The efficacy, patient
satisfaction, and safety of
the HA E filler range in
full-face rejuvenation.
1. Participants were satisfied with
the durability of result.
2. Product was indicated effective
and safe.
[34]
Injection
filler
6 months treatment using BoNT-
A and 5 HA fillers
Subject satisfaction,
efficacy, and safety of
BoNT-A and HA fillers
for full-facial aesthetic
rejuvenation.
1. Full-face aesthetic outcome
gives high satisfaction level of
the patients.
2. Significant aesthetic improve-
ment and product safety.
[35]
Implants
injection
Facial wrinkles and scars 1. HA is the most promising ma-
terial for soft tissue augmenta-
tion.
2. The efficacy of HA is compara-
ble to collagen.
[36]
Injectable gel 48 weeks follow-up 80 subjects Wrinkle correction 1. Significant improvement in the
effectiveness for wrinkle cor-
rection after repeat treatment.
2. Remarkable improvement in
NLF severity score.
[37]
Dermal fillers Injection of finer viscosity
follow up with thicker viscosity
of HA. 0.5 mL Restylane and
0.5 mL Perlane were used per
side, evaluate to 20 weeks
21 patients with mild to
moderate tear trough
deformities
Wrinkles severity
improvement
1. Clinically apparent improve-
ment in wrinkle severity with
the combination of two HA
fillers with different viscosities.
2. Significant improvement in aes-
thetic scores with high patient
satisfaction.
[38]
A remarkable improvement in skin hydration and elasticity were ob-
served in patients treated with HA based cream compared to the pa-
tients treated with placebo. The roughness index also showed a sig-
nificant improvement in HA treated group after 60 days of treatment
compared to the placebo group [16]. Several other researchers have
also highlighted the significance of HA based formulation in the skin
repairmen [1719].
HA has also been extensively used as a targeting ligand for tar-
geted drug delivery systems [2022]. HA based modifications of nan-
odelivery system enhance their penetrability across the biological
membranes and improve the targeting efficiency and drug accumula-
tion at target sites [2022]. According to a recent review, HA based
modifications improved tumor-specific delivery of anticancer agents,
maximized anticancer efficacy, and mitigated tumor progression [6].
HA-based conjugation or surface modulation of anticancer drugs-en-
capsulated nanocarriers have shown promising efficacy against vari-
ous types of carcinomas of liver, breast, colorectal, pancreatic, lung,
skin, ovarian, cervical, head and neck and gastric. The success of this
emerging platform is assessed in achieving the rapid internalization
of anticancer payloads into the tumor cells, impeding cancer cells di
vision and proliferation, induction of cancer-specific apoptosis and
prevention of metastasis (tumor progression) [6].
3. Cosmetic and nutricosmetic efficacy of HA
Many researchers have investigated the cosmetic and nutricos-
metic efficacies of HA based formulations for skin rejuvenation. Evi-
dence based meta-analysis revealed that HA exhibits remarkable cos-
metic and nutricosmetic efficacies in rectifying various skin defects
such as wrinkles, nasolabial folds, and skin aging. To investigate cos-
metic and nutricosmetic effects, HA has been utilized in various forms
(i.e., gels, creams, intra-dermal filler injections, dermal fillers, facial
fillers, autologous fat gels, lotion, serum, and implants, etc.). The cos-
metic and nutricosmetic effects of HA have been associated with their
ability to induce soft tissue augmentation, improve skin hydration, col-
lagen stimulation, and face rejuvenation (Fig. 2).
3.1. Anti-wrinkle efficacy of HA
A wrinkle is a fold, ridge or crease in the skin, also known as a
rhytide. The appearance of wrinkles is one of the typical signs of ag
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 5
Table 2
A summary of clinical significance of hyaluronic acid for treatment of nasolabial folds: human clinical studies.
Cosmetic
effect
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Nasolabial
folds
Gel dermal
filler
Hyaluronic acid gel implantation on one
side of the face and hyaluronic acid gel
followed by one of the nonablative
laser/RF/IPL therapies on the
contralateral side of the face.
33 patients with
prominent nasolabial
folds
Wrinkle severity,
aesthetic scores
1. The use of hyaluronic acid gel
implantation alone and
hyaluronic acid gel with laser/
RF/IPL treatment have the same
efficacy and safe.
2. No statistically significant dif-
ferences between wrinkle sever-
ity and global aesthetic scores.
[39]
Gel dermal
filler
One of three types of smooth-gel HA
dermal filler (in one NLF) and cross-
linked bovine collagen (in the other
NLF) and were evaluated for
24 weeks.
439 subjects with
moderate or severe
nasolabial folds.
Longer lasting
correction of NLF
1. Significant improvement with
long lasting effect with HA der-
mal fillers.
2. Majority of subjects preferred
HA dermal filler over bovine
collagen.
[40]
Gel dermal
filler
Nonanimal stabilized hyaluronic acid
gel (Perlane) and bovine collagen
(Zyplast) on contralateral sides of the
face for 6 months.
68 patients with
prominent nasolabial
folds
Effectiveness
comparison.
1. Significant greater improvement
of Perlane in cosmetic correction
compared to Zyplast.
2. Perlane is superior to Zyplast in
wrinkle severity and aesthetic
scores.
3. Long-term safety and long-last-
ing improvement with Perlane.
[41]
Gel dermal
filler
Hyaluronic acid gel and bovine
collagen on contralateral sides of the
face and evaluated up to 6 months after
baseline.
138 patients with
prominent nasolabial
folds.
Efficacy and safety
comparison.
1. HA gel was suggested to be
more effective in maintaining
cosmetic correction.
2. HA gel was superior in the im-
provement of wrinkle severity
and aesthetic scores.
[42]
Dermal
filler
Further treatment with HA filler
incorporating lidocaine
3566 patients had
previously received
facial fillers.
Skin comfort,
improved aesthetic
result.
1. Significant improvement of aes-
thetic result with HA filler incor-
porating lidocaine.
2. Patients provided with more
comfortable injection experi-
ence.
[43]
Facial filler Hyaluronic acid facial filler containing
pre-incorporated lidocaine (Juvederm
ULTRA 3) and the established
hyaluronic acid facial filler Restylane-
Perlane randomly applied to the right or
left naso-labial fold
Split-face, single blind
study with 126
individuals
Skin comfort and
ease of injection.
1. Total of 95% individual indi-
cated more comfortable with
Juvederm ULTRA 3 injection.
2. Remarkable greater ease in in-
jection with Juverderm ULTRA
3 than Restylane-Perlane.
[44]
Injectable
gel dermal
filler
Lidocaine filler in one NLF and the
filler without lidocaine in the other NLF
Procedural pain. 1. Significant improvement NLF
severity comparable for both
products.
2. Procedural pain reduction with
dermal filler formulated with li-
docaine
[45]
UNCORRECTED PROOF
6 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Table 2 (Continued)
Cosmetic
effect
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Dermal gel
filler
Non-animal-derived hyaluronic acid
based filler formulated with lidocaine
(Prevelle SILK) was injected in one
NLF, and without lidocaine (Captique)
was injected in the contralateral NLF
Patient-blinded,
prospective, randomized,
split-face design trial
with 45 patients with
NLFs.
Pain evaluation at
the injection site
1. Significant reduced in pain asso-
ciated with addition of lidocaine
to HA filler.
2. No significant difference in out-
come after 2 weeks for both
products.
[46]
Dermal gel
filler
Injected into the deep layer of the
dermis and/or subcutis of the NLF for
6 months.
Multicenter, randomized,
patient and evaluator-
blind, matched pairs, and
active-controlled design
clinical study with 66
subjects with moderate
or severe wrinkle
severity.
Efficacy and safety
of both products.
1. Both fillers were well tolerated
and adverse reactions were mild
and transient in most cases.
2. Remarkable equivalent efficacy
and safety of both products.
[47]
Dermal
filler
HA IDF plus containing lidocaine was
injected to one side of NLF, and HA
IDF without lidocaine was injected to
the other side.
62 subjects Injection site pain 1. Significant greater improvement
in reduced pain with HA IDF
plus compared to HA IDF.
2. No significant different in wrin-
kle correction and safety with
both treatments.
[48]
Injection
filler
24 mg/mL hyaluronic acid with pre-
incorporated lidocaine or without
lidocaine and were followed-up for up
to 76 weeks.
60 patients with
moderate-severe bilateral
nasolabial folds
Longevity of HA
fillers.
1. No significant effect on product
longevity with addition of 0.3%
lidocaine.
2. Significant improvement in HA
gel with pre-incorporated lido-
caine for physician assessment
of injection pain.
[49]
Dermal
fillers
Injection of Neuramis or Perlane-L in
the left or right side of the face for
24 weeks.
Randomized,
multicenter, double-
blind, intraindividual
trial for 58 patients with
moderate to severe
nasolabial folds
Pain reduction,
wrinkle severity and
aesthetic scale
1. Significant improvement effi-
cacy in Wrinkle Severity Rating
Scale and comparable aesthetic
outcome with Neuramis.
2. No significant difference in pain
reduction of both products.
[50]
Dermal
filler
Randomized injections with
monophasic HA or biphasic HA on the
left or right side of the face and
evaluated up to 52 weeks.
72 Korean subjects with
moderate to severe NLFs
Efficacy and safety
of monophasic HA
filler and biphasic
HA filler.
1. No significant difference in the
efficacy between monophasic
HA and biphasic HA filler.
2. Monophasic HA filler had lower
elasticity and higher viscosity
than biphasic HA filler.
[51]
Dermal
filler
Each subject was injected with
Mesoglow® in one NLF and IAL
System® in the other for 12 weeks.
40 subjects with visible
nasolabial folds (NLFs)
Efficacy and safety
of two non-cross-
linked HA fillers.
1. Mesoglow® and IAL System®
were found to be equally effec-
tive in correction of NLFs.
2. No serious systemic adverse
events occurred with both treat-
ments.
[52]
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 7
Table 2 (Continued)
Cosmetic
effect
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Gel dermal
filler
6 months treatment. 88 subjects with
moderate to severe NLF
Efficacy and safety
of products.
1. Significant improvement in
wrinkle severity.
2. No significant difference in ef-
ficacy with Restylane and Bio-
Hyalux.
[53]
Fillers Injection of Emervel Classic or
Restylane on their left or right side with
6 months follow up treatment.
Split-face, randomized
and evaluator-blinded
comparison study.
Efficacy and safety
of dermal filler
1. Significant improvement in
wrinkle severity with Restylane
and Emervel Classic are similar
2. Emerval Classic offer better tol-
erability compared to Restylane.
[54]
Filler Injected with PP-501-B in one NLF and
with Restylane Perlane (Q-med) in the
contralateral NLF for 24 months.
81 patients Long-term efficacy,
durability and safety
of PP-501-B
1. Significant decreased in wrinkle
severity score.
2. No severe complication after
treatment of both products.
[55]
Gel dermal
filler
Juverdem ULTRA in NLF and
Restylane in the other NLF.
104 subjects Product safety and
effectiveness
1. Significant improvement in NLF
severity with Juverderm and
Restylane.
2. Juverdem more preferable with
fewer severe response.
[56]
Dermal
filler
A single injection of Belotero® Basic
and Restylane® in a split-face design in
4 weeks.
20 subjects with
bilateral, symmetrical
NLF
Effectiveness
comparison.
1. Belotero® Basic is significantly
greater improvement compared
to Restylane®.
2. Excellent tolerability of both
treatments.
[57]
Injections 6 months evaluation 40 female patients Cosmetic correction 1. Significant greater cosmetic re-
sult with HA plus carbon diox-
ide.
2. Remarkable improvement in
wrinkle severity.
[58]
Fillers Retreatment of one nasolabial fold at
4.5 months and the contralateral fold at
9 months
75 patients with
moderate to severe
nasolabial folds
Skin wrinkle
severity
1. Significant improvement in
wrinkle severity.
2. High patient satisfaction level.
[59]
Dermal
filler
36 months follow-up 52 subjects Skin wrinkle
severity
1. Significant improvement in
wrinkle severity.
2. Remarkable improvement of
NLFs correction.
[60]
5 subjects were treated with HA filler
alone, the other five subjects were
treated with intradermal RF prior to HA
filler, follow up to 1224 weeks
10 female volunteers
with mild to severe
NLFs
Wrinkle severity 1. Significant greater improvement
in wrinkle severity with the
combination treatment.
2. RF treatment prior to HA filler
provide synergistic and long-
lasting effect.
[61]
UNCORRECTED PROOF
8 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Table 2 (Continued)
Cosmetic
effect
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Gel HA filler on both NLFs and with a
nonablative IR device on the
experimental side of the face for
2 months.
12 patients Correction of facial
wrinkles and folds.
1. No significant difference of both
HA gel alone and HA gel with
nonablative IR device treatment.
2. Effectiveness in wrinkle remains
the same.
[62]
Injection
filler
Direct excision of the NLF followed by
advancement of the nasolabial fat
compartment into the nasolabial crease.
Excised tissue samples were injected
with HA fillers (Restylane, Perlane, or
layered Restylane/Perlane), sectioned,
and treated with histological stains.
Patients with deep NLF Surgical correction
of a prominent
nasolabial fold
(NLF) technique
and the histology
and localization of
injected hyaluronic
acid (HA) fillers.
1. The surgical was a success for
treatment patients with deep
NLF.
2. Regardless of HA product ap-
plied, the localization appeared
similar in the lower reticular der-
mis and subcutis which near the
site of injection emphasized the
importance of proper placement
of HA fillers during soft tissue
augmentation.
[63]
Dermal
filler
PCL-based dermal filler in one of their
NLFs, and a NASHA-based dermal
filler on the contralateral side for
12 months
40 subjects Safety, efficacy, and
duration of cosmetic
correction.
1. Remarkable prove of safety of
both products.
2. Significant greater improvement
in wrinkle severity of PCL-
based dermal filler than
NASHA-based dermal filer.
[64]
Gel Treatments of HA or fat in both NLFs
for 12 months.
62 patients NLF correction 1. Significant improvement of both
HA and fat in NLFs.
2. Similar in safe and efficacious in
both products.
[65]
Gel 24 weeks follow-up 150 patients NLF correction 1. Remarkable safe for the correc-
tion of facial wrinkles in patients
with skin of color.
2. Only mild to moderate adverse
effect upon injection.
[66]
ing processes [23]. Different causes which can enhance wrinkle for-
mation include, habitual sleeping positions, loss of body mass, pro-
longed immersion in water, habitual facial expressions, aging, sun
damage, smoking, and poor hydration. Wrinkles referred to the fine
lines that appear on the skin, may become deep crevices or furrows
in some people. Wrinkles are typically appeared around the eyes,
mouth, forehead, hands, and neck. Aging is one of the primary fac-
tors which contribute to wrinkle formation as the skin loses its elas-
ticity and fat contents, decrease collagen and elastin that causes skin
thinner and less smooth appearance. Another undeniable fact is the
morphological alterations which appear on the skin with ages as oc-
curred in all other tissues and organs of the body. These morpho-
logic changes associated with chronologically aged skin result in cu-
taneous laxity and fine wrinkling on the face. The progression loss
of thickness in aging skin begins with a thinning of the epidermis
and flattening of the dermoepidermal junction. Atrophy mainly oc-
curs in the dermis as a consequence of these age-related morpholog-
ical alterations in the skin [24]. With age, total number of fibroblasts
and eosinophil also decreases [24]. The cutaneous tensile strength de-
creases as there is continuous reduction of elastic fibers and changes
in collagen components [25]. Moreover, diminished dermal microvas-
culature and reduced sebaceous gland activity tenders to worse dry-
ness of the skin [26]. The atrophy in subcutaneous tissues (fat, mus-
cles, and bones) creates further prominence of skin folds with the
overlying skin hanged from points of deep attachments. A clear grav
itational line which represent the influence of atrophy and gravity on
aged skin appear between the ages of 40 and 50 years, commonly oc-
cur through the face and neck [27]. Many researches have demon-
strated the promising anti-wrinkle potential of HA based formulations
(cream, gels, and injection).
Evidence-based analysis revealed that the anti-wrinkle efficacy of
HA is molecular weight dependent which is expected to be due to dif-
ferences in percutaneous absorption of different molecular weight HA
across the stratum corneum [28]. Authors have conducted a clinical
trial involving 76 female aged between 30 and 60 years having peri-
ocular wrinkles. These patients were applied with 0.1% (w/w) cream
formulation containing different molecular weights of HA (50, 130,
300, 800, 2000 kDa) twice daily for a period of 60 days. They ob-
served greater improvements in the skin hydration level, skin elas-
ticity, and reduction in peri-ocular wrinkles in women applied with
cream formulation containing low molecular weight HA [28]. In view
of molecular weight dependent percutaneous absorption, researchers
have tested ultra-small sized HA (nano-HA) containing topical for-
mulations (lotion, serum, and cream) [29]. In this clinical trial, 33
women with an average age of 45.2 years having periorbital wrinkles
were treated for eight weeks. The measurements were performed in
the periorbital regions by investigating the three-dimensional struc-
ture using a DermaTOP for wrinkles, Corneometer for skin hydra-
tion, Cutometer for skin elasticity and Chroma Meter for erythema
intensity. Standardized images were taken and evaluated by six se
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 9
Table 3
A summary of clinical significance of hyaluronic acid as anti-aging biomedicine: human clinical studies.
Cosmetic
effect
HA
formulation Application
Experimental model/study
design Study parameters Key findings Ref.
Anti-
aging
efficacy
Injection
filler
HA is injected in the subgaleal glide plane
between the brows at the mid procerus level
between the supratrochlear vascular arcades.
Rejuvenation of
upper face.
1. HA filler proved to be satisfy-
ing if proper patient selection
and procedure are done.
[82]
Injection of
HA gel
Patients with bilateral volume loss of the
cheeks.
A multi-center, six-month,
open-label study
Subject
satisfaction,
efficacy, and
safety
1. Significant aesthetic improve-
ment in the cheeks.
2. The aesthetic outcome showed
high satisfaction level.
[72]
Injection Voluma injected into the midface, follow up
to 18 months.
102 patients (93 females,
nine males; mean age:
51.27 years)
Facial volume
restored, long
lasting effect.
1. Significant improvement in
aesthetic scores with Voluma.
2. Remarkable improvement of
facial volume and long-lasting
effect.
[73]
Tear trough
deformity
filler
0.48 ml per eye 151 patients, female (86%),
and middle-aged (mean age
48 years old).
Tear trough
rejuvenation.
1. Significant cosmetic improve-
ment in the treatment of tear
trough rejuvenation.
2. High level of patients' satisfac-
tion as well as tolerability of
the treatment.
[74]
Injection 0.1ml was injected at each pass, follow up to
12 months.
25 patients with tears
troughs
Correct tear
trough deformity
1. Significant improvement in
the treatment of tear trough
deformity with HA gel filler.
2. Clinically effective and have
high subject satisfaction.
[75]
HA gel as
tear trough
filler
Mean volume of 0.59 ml per eye follow up to
5.1 months.
100 patients, female (87%),
white (89%), and middle-
aged (mean
age = 47.8 years)
Tear trough
rejuvenation
1. Significantly effective in the
treatment of tear trough reju-
venation.
2. High level of patient tolerabil-
ity and satisfaction
[76]
Injection Application on one side of nasojugal groove 10 Korean women. A
prospective randomized
split face clinical controlled
study.
Volume
correction and
skin tone of
nasojugal
groove.
3. Highly patients' satisfaction
with minimal tissue trauma.
4. Restylane Vital® injector al-
lows exact placement of
hyaluronic and offer more pre-
dictable results.
[77]
Injection Two treatment with native HA at an interval
of 14 days
20 patients with distinct to
substantial signs of facial
skin aging.
Skin elasticity
and turgor.
1. Significant improvement in
skin elasticity and turgor.
2. Remarkable method for exten-
sive superficial treatment of
skin.
[78]
UNCORRECTED PROOF
10 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Table 3 (Continued)
Cosmetic
effect
HA
formulation Application
Experimental model/study
design Study parameters Key findings Ref.
Intradermal
injection
Received 2 treatments with natural HA 20 adults with flaccid facial
skin
Skin elasticity
and turgor
1. The mean elasticity values sig-
nificantly increased 90 days
later.
2. There is an improvement in
the mean turgor values with no
significant adverse events.
[79]
Aqueous
injection
6 to 8 ml of HA in 24weeks. 10 women were no laser
and HA fillers for 6 months.
Skin anti-aging. 1. Significant reduction of appar-
ent aging face.
[80]
O/W
Cream
0.1%
Twice daily for 60 days 12 female aged between
30 and 60 years
Skin elasticity
and hydration.
1. Reduced formation of intercel-
lular tight junction in aged and
photodamaged skin.
2. Remarkable reduction of wrin-
kles.
[81]
lected and trained rate for reduction of visible wrinkles, skin color uni-
formity and pigmentation. Results revealed a significant improvement
in fines of skin in 2 weeks and improved skin elasticity in 28 weeks
of treatment. The swift anti-wrinkle and skin rejuvenating effects of
nano-HA containing topical formulations were expected to be due to
superior percutaneous absorption of ultra-small HA molecules [29].
Anti-wrinkle efficacy of HA based topical cream formulation has
also been investigated by other researchers [30]. Daily application of
HA incorporated cream causes significant reduction in depth of wrin-
kles and improves skin elasticity and tightness. In this study, authors
have tested four topical cream formulations (Balea, Nivea, Lancome,
Chanel) containing HA on 20 women with periorbital wrinkles for
3 months. After treatment period, they observed significant improve-
ment in skin elasticity and tightness by 1330%, significant reduction
in wrinkle depth by 1020%, and improved hydration level in all treat-
ment patients [30].
Besides topical application, the safety, tolerability, patient satis-
faction, and efficacy of intradermal injection of HA (as fillers, gels,
implants) in treating the facial wrinkles and skin rejuvenation have
also been validated by many researchers [3137]. Patients were as-
sessed using Global Aesthetic Improvement Scale (GAIS). There were
no serious adverse effects appeared in most of the patients; however,
some patient showed mild sings of bruising, swelling, and tender-
ness which were resolved within seven days [3133]. The tolerabil-
ity and efficacy of injectable HA filler has also been validated for full
face rejuvenation [34]. In this study, 77 human subjects with average
age of 54.5 years were for treated for 6 months. At the end of treat-
ment period, 92.1% subjects showed significant improvement in wrin-
kle depths; however, remaining participant showed complete satisfac-
tion. There were no serious side effects reported during or after the
end of the study. Full-face rejuvenation using HA proved to be ef-
fective, safe in participants with multiple indications [34]. The safety
and efficacy of injectable HA filler has also been tested after com-
bined with botulinum toxin Type A (BoNT-A) for full facial rejuve-
nation to reduce wrinkles [35]. In this multicenter, open-label clini-
cal study, authors have tested five different HA fillers and BoNT-A
to treat up to 13 facial zones. Resulting evidences showed that 96.5%
subjects showed high level of satisfaction within 3weeks of treatment
and treatment was well-tolerated [35]. The anti-wrinkle and anti-scar
ability of HA based injectable filler has also been compared with
many other commonly utilized injectable implants such as injectable
bovine collagen (Zyderm and Zyplast), gelatin matrix (Fibrel), and
synthetic implants polytetrafluoroethylene (Gore-tex) for face rejuve
nation [36]. Results revealed that HA based injectable filler showed
the most promising efficacy for soft tissue augmentation which was
equivalent to collagen [36]. These results were also validated by other
researchers [37].
Combination of two HA fillers with different viscosities provide
safe and effective mean of skin rejuvenation of the periorbital-cheek
complex [38]. In this clinical trial, 21 patients with mild to moder-
ate tear trough deformities were treated with concomitant injection
of two dermal fillers (Restylane® and Perlane®). The result showed
a statistically significant improvement in modified Wrinkle Severity
Rating Scale scores at 20 weeks. Patients' self-reported overall mean
improvement was 2.23, indicating moderate (26% to 50%) to good
(51% to 75%) improvement. Overall, the combination filler procedure
proves to produce clinically apparent improvement with high degree
of patient satisfaction [38]. The therapeutic significance of hyaluronic
acid formulations for the treatment of wrinkles including are shown in
Table 1.
The molecular evidences revealed that skin rejuvenation and
anti-wrinkle effects produced by the application/administration of HA
is due to its ability to stimulate collagen synthesis via induction of fi-
broblasts in the dermis. The increased production of collagen makes
skin smoother, reduce wrinkles, and improve skin elasticity and
longevity.
3.2. HA based treatment of nasolabial folds
HA based dermal fillers have also shown promising ability to treat
nasolabial folds. Nasolabial folds are the deep wrinkles or lines that
form from the bottom of nose to the corners of the mouth. The appear-
ance of the nasolabial folds are usually seen in the facial features as
smile linesor laugh lines. It makes the distinctive look between
the cheek and the upper lip. Literally, every person may develop with
a slight trace of laugh lines. As a person ages, the fold becomes ac-
cessible. All wrinkles are a result of a combination of factors. One of
the factors is the weakening of facial muscles as person's ages. It may
also be due to the loss of foundation underneath mid-face known as
the base of the face.
Common causes of nasolabial folds are aging, sun damage and
smoking. When skin exposed to the skin regularly, ultraviolet (UV)
rays may cause breakdown of collagen and elastin fibers that support
structure integrity of the skin. Smoking can also lead to mouth wrin-
kles and hasten the process of aging by the chemicals contain in to-
bacco cigarettes by 20%. Significant weight gain or loss and the side
sleeping habit also contribute in the presence of more pronounced na
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 11
Table 4
A summary of other aesthetic improvements, cosmetic and nutricosmetic effects of HA.
Cosmetic
effects
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Soft tissue
augmentation
Gel
intradermal
injection.
Apply on wrinkles and folds,
and for lip augmentation and/
or recontouring with 8 months
follow-up.
158 patients Safety and efficacy of HA
gel
1. Remarkable improvement of
dermal implantation in augmen-
tation therapy.
2. No major evidence of side ef-
fect developed along the treat-
ment.
[83]
Skin
augmentation
Gel 21 days treatment. 115 subjects Cosmetic effect, mid-face
volume enhancement.
1. Significant improvement in the
cosmetic effect with
Juvéderm® VOLUMA® with
Lidocaine.
2. High level of subjects' satisfac-
tion and tolerability for face
volume enhancement.
[84]
Skin
augmentation
Gel Injection of in one or more of
three facial subregions: (the
zygomatic malar region, the
anteromedial cheek and
nasolabial folds)
60 adults aged
4065 years with bilateral
moderate to severe
volume loss or contour
deficiency for 6 months.
Face volume enhancement
and contouring
1. Significant improvement in aes-
thetic scores HA gel treatment.
2. Remarkable improved in vol-
ume loss and contour defi-
ciency.
[85]
Soft tissue
augmentation
Injection Retrospective review
144,000 patients
(injection) 262,000
patients (gel)
Safety profile of non-
animal stabilized
hyaluronic acid gel
1. The incidence of hypersensitiv-
ity appears to be declining after
the introduction of a more puri-
fied hyaluronic acid raw mater-
ial.
[86]
Face
rejuvenation
Injection Wrinkles and volume. 1. The use of different HAs for
each area offers real possibili-
ties to rejuvenate the skin with-
out downtime.
2. Longevity of the correction de-
pends on treated areas, HA
used, and on the individual.
[87]
Skin hydration Injection Pilot study 6 middle-aged male
subjects.
Corneometer, TEWL,
cutometer, measures of
patient satisfaction, and the
global aesthetic
improvement scale (GAIS)
1. There is significant improve-
ment in the aesthetic score.
2. The patient satisfaction level
greatly increases with the out-
comes of treatment in terms of
the enhancement of moisture,
elasticity, and brightness.
[88]
Collagen
stimulator
Dermal
filler
injection
Filler injected into forearm
skin and skin biopsy
specimens taken 4 and
13 weeks later.
11 healthy volunteers
(mean age, 74 years) with
photodamaged forearm
skin.
De novo synthesis of
collagen
1. Remarkable increase in colla-
gen deposition around the filler.
2. There is an activation of dermal
fibroblast demonstrated by me-
chanically stretched appearance
around the injected skin.
[89]
UNCORRECTED PROOF
12 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
Table 4 (Continued)
Cosmetic
effects
HA
formulation Application
Experimental model/
study design Study parameters Key findings Ref.
Collagen
stimulator
Dermal
filler
injection
Filler injected intradermally
and skin biopsy specimens
taken 1, 3, and 6 months
60 females were
randomized who
received a 0.5 mL
injection of HA gel
De novo synthesis of
collagen
1. Significant increase in collagen
synthesis.
2. Expression of procollagen,
MMP and TIMP1 were also in-
creased in subjects received HA
dermal filler injection.
[90]
Space filling
properties
Dermal
filler
injection
Intradermal injection and
evaluation were performed at
15 days and 618months later
32 patients (aged
1332 years) with
congenital or acquired
facial malformations
Space-filling, collagen and
elastin synthesis
1. Greater space filling efficacy of
HA dermal filler was observed
in all patients.
2. Significant improvement in col-
lagen and elastin synthesis.
[93]
solabial folds. Recent treatment of nasolabial folds is the use of
skin-tightening treatment that includes fractional radiofrequency de-
vice, ultrasound, and fractional laser. Other than that, plastic surgery
that involves facelift, cheek implants and nasolabial excision reduce
the appearance of nasolabial folds and even other signs of aging.
Many researches have investigated the anti-nasolabial fold efficacy
of HA dermal fillers, alone or in combination with other cosmetic
procedures. The anti-nasolabial fold efficacy of HA based gel dermal
filler alone is comparative with HA gel implantation in combination
with nonablative laser/RF/IPL therapy [39]. In this clinical trial, 33 pa-
tients with prominent nasolabial folds were applied with HA gel im-
plantation on one side and HA gel implantation in combination with
nonablative laser/RF/IPL therapy on the contralateral side of the face.
Results demonstrated significant improvement in wrinkles depth and
anti-nasolabial fold depth and the efficacy was comparable on both
sides of the faces of all patients [39].
The anti-nasolabial fold efficacy of dermal fillers containing
non-animal originated HA showed better anti-nasolabial and
anti-wrinkle efficacy compared to bovine collagen [40]. In this study,
439 subjects with moderate-to-severe nasolabial folds were enrolled.
Resulting evidences and patients rating revealed that non-animal sta-
bilized hyaluronic acid gel (Perlane) was found to be more effective
and tolerable in maintaining the cosmetic correction compared to the
bovine collagen (Zyplast) [40]. These results were in agreement with
another clinical trial involving 68 patients with prominent nasolabial
folds [41]. Result demonstrated that Perlane was found to be supe-
rior and efficacious in cosmetic corrections, reducing wrinkle severity,
and longevity compared to Zyplast [41]. The efficacy of non-animal
sourced HA (Restylane) compared to bovine collagen (Zyplast) has
also been explored by Narins et al. [42]. In this randomized, placebo
controlled trial, 138 patients were randomized to treat with Restylane
on one side of the face and Zyplast on contralateral side of the face. It
is also found that Zyplast were non-superior compared to Restylane.
A high improvement was shown in effectiveness for maintaining cos-
metic correction and wrinkle severity with the treatment of Restylane
[42].
The quality of dermal HA filler has been improved to provide
more comfortable injection by incorporating lidocaine (HAL) for the
treatment of nasolabial folds [43]. Patients reported to experience less
pain during the procedure and obtain a better aesthetic result com-
pared to previous dermal filler. In this clinical trial, 3566 patients,
485 injectors across 16 countries participated. For comparative analy-
sis, all the patients were recruited because they had previously re-
ceived facial fillers. Hence, they received the new hyaluronic acid
filler incorporating lidocaine (HAL). The comfort and aesthetic re-
sults obtained with HAL following the treatment of nasolabial folds
were evaluated by the injector and the patients. It was reported that
the patients experiencing less pain during the procedure compared to
previous dermal fillers. There is significant improvement in the aes-
thetic result and more comfortable injection experience for most of
the patients with HAL than the previous dermal fillers [43]. The ef-
ficacy and tolerability of HAL dermal filler compared to HA dermal
filler (Restylane-Perlane) has also been validated in another split-face,
single blind study by involving 126 individuals [44]. Both products
were randomly assigned to the right or left nasolabial fold and tol-
erability and anti-nasolabial fold efficacy was assessed. Injectors in-
dicated that 92% of Juvederm ULTRA 3 injections were easily ad-
ministered with higher patient compliance compared to 21% of Resty-
lane-Perlane. Majority of individuals had preferred Juvederm ULTRA
3 which provides more comfortable and gentle experience during the
procedure [44]. Nevertheless, Juverderm injectable gel with lidocaine
(JUV + L) and commercially available Juvederm injectable gel with-
out lidocaine (JUV) showed equivalent safety and efficacy in reduc-
ing severity of nasolabial folds; however, it was found that dermal
filler formulated lidocaine is more effective in reducing procedural
pain during correction of facial wrinkles and nasolabial folds com-
pared to the filler without lidocaine [45]. These results were also in
agreement with another study in which safety, efficacy, and effec-
tiveness of HA based dermal filler formulated with lidocaine (Prev-
elle SILK) was compared with another dermal filler with same com-
position but without lidocaine (Captique) [46]. The safety, efficacy,
and patient compliance were evaluated two weeks after dermal pro-
cedure in 45 human subjects. Results revealed that there was signif-
icant difference in safety and efficacy of both products in reducing
severity of nasolabial folds; however, procedural pain was remarkably
decreased in case Prevelle SILK compared to HA filler without lido-
caine [46]. Similarly, a multicenter, randomized, patient and evalua-
tor-blind, matched pairs, and active-controlled design clinical study to
compare the efficacy and safety of PP-501-A-Lidocaine dermal filler
with Restylane-Lidocaine® when injected into deep layer of the der-
mis and/or subcutis of the NLF was also conducted [47]. In this clini-
cal trial, 66 subjects with moderate-to-severe wrinkle severity were in-
volved. It was observed that PP-501-A-Lidocaine has the similar effi-
cacy and safety after 6months of follow-up compared to Restylane-Li-
docaine®. Both fillers were well tolerated and adverse reactions were
mild and transient in most cases [47].
One of the common problems to patients undergoing soft tissue
augmentation is the pain at the injection-site. With the invention of li-
docaine incorporated HA gel/matrix dermal filler, patient compliance
to nasolabial folds related cosmetic procedures has been optimized
[48]. A split-face study was conducted to compare procedural pain,
efficacy, and safety of HA intradermal filler (IDF) containing lido
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 13
caine with HA IDF without lidocaine in the correction of nasolabial
folds (NLFs). Lidocaine incorporated HA IDF was injected to one side
of NLF and HA IDF without lidocaine was injected to the other side
in 62 subjects [48]. Upon follow-up visit, it was observed that the two
fillers were not significantly different in safety profile or wrinkle cor-
rection; however, injection-related pain had been significantly reduced
with lidocaine-incorporated HA IDF compared with HA IDF without
lidocaine [48].
Besides improvement of patient compliance achieved after the in-
clusion of lidocaine in HA IDF, its effect on longevity of anti-na-
solabial folds efficacy of dermal filler has also been investigated due
to limited data available on this aspect [49]. In this clinical study, 60
human subjects with moderate-to-severe bilateral nasolabial folds re-
ceived 24 mg/ml HA with pre-incorporated lidocaine or same product
without lidocaine. The patients were followed up for up to 76 weeks.
Upon patient follow-up, investigators observed that although there
was significant improvement in injection-related pain at injection site;
however, inclusion of 0.3% w/w lidocaine had no effect on filler
longevity even after long-term follow-up. Researchers further sug-
gested than despite full treatment, small volume required for
touch-upshowed longevity along with high level of patient satisfac-
tion [49].
In an attempt to manipulate release behaviour and physicochem-
ical characteristics of intradermal filler, two different types of IDF
have been designed; 1) monophasic, and 2) biphasic. Although, liter-
ature has suggested comparable efficacy and durability of both types
of IDF; however, monophasic IDF are more cohesive due to ho-
mogeneous sizes of microspheres. A randomized, multicenter, dou-
ble-blind, intra-individual trial was conducted to evaluate the effect
of inclusion of lidocaine on the safety, efficacy, and durability of
monophasic and biphasic IDF [50]. In this clinical trial, 58 patients
with moderate-to-severe NLFs were treated with lidocaine-contain-
ing monophasic HA IDF (Neuramis Deep Lidocaine) on left side
of the face and a lidocaine-containing biphasic HA IDF (Restylane
Perlane-L) on right side of the face. Results revealed a significantly
greater improvement in wrinkle severity and comparable aesthetic out-
come with Neuramis Deep Lidocaine compared with Restylane Per-
lane-L. There was no significant difference in pain reduction between
Neuramis and Perlane-L in the management of NLFs [50].
Rheological property is one of the primitive physicochemical char-
acteristics of pharmaceutical formulations which affect the behaviour,
efficacy, and safety of formulations. In a randomized clinical trial in-
volving 72 Korean subjects with moderate to severe NLFs, rheologi-
cal characteristics and clinical efficacies of monophasic HA IDF and
biphasic HA IDF were compared [51]. Patients received intradermal
injections with monophasic HA or biphasic HA on the left or right
side of the face and were evaluated at 2, 10, 18, 26 and 52 weeks. The
results reported that monophasic HA filler had lower elasticity and
higher viscosity than biphasic HA filler. Both treatments were well
tolerated and no significantly difference in efficacy with only mild
and transient adverse reactions [51]. The safety, efficacy, and toler-
ability of other HA based IDF have also been investigated by other
researchers [5257] and the major findings have been summarized in
Table 3.
Durability and longevity of IDF is vital for soft tissue augmenta-
tion. Among various techniques to improve durability and longevity
of HA IDF to maintain anti-nasolabial folds effects, the clinical effi-
cacy of a combined therapy with HA IDF and subcutaneous injection
of carbon dioxide was evaluated compared to HA IDF without car-
bon dioxide injection for cosmetic correction [58]. Results revealed
that combination of subcutaneous injection of carbon dioxide with
HA filler significantly improved cosmetic corrections compared to
IDF without carbon dioxide. Carbon dioxide has the ability to improve
quality and elasticity of the dermis and increases the oxygen release to
the tissue via enhancing Bohr's effect [58].
Non-animal-stabilized hyaluronic acid (NASHA) fillers are com-
monly used for cosmetic procedure; however unfortunately, their ef-
fects on the longevity of different retreatment procedures have yet
to be discovered. A multicenter, randomized, evaluator-blinded study
was conducted by involving 75 patients with moderate-to-severe
NLFs to investigate the efficacy and perseverance of NASHA 100,000
gel particles/ml filler for two different retreatment schedule. With one
retreatment, the filler persisted up to 18 months along with signifi-
cant efficacy improvement [59]. On the other hand, 18-month small
gel-particle HA persistence study continues to establish improvement
of nasolabial folds up to 36 months after second retreatment [60].
There were 52 subjects involved in this study and the skin wrinkle
severity is being measured. They found that, there was a significant
improvement in wrinkle severity with remarkable improvement of
NLFs correction [60].
Although HA IDF have shown significant promise and have been
extensively used for skin rejuvenation, but their longevity is not estab-
lished yet. To deal with this problem, some researchers investigated
the effect of combination therapy of intradermal radiofrequency and
HA filler on mild-to-severe NLFs [61]. Results revealed that combi-
nation treatment may provide synergistic and long-lasting effects for
cosmetic correction of NLFs [61]. In contrast, another study was con-
ducted to evaluate the efficacy of combined treatment using a nonabla-
tive infrared (IR) device and HA filler. Results revealed an equivalent
efficacy of combined therapy with HA filler alone with no significant
differences between wrinkle severities [62].
One study has been carried out to illustrate a technique for sur-
gical correction a prominent nasolabial fold and use the excised fold
to determine the histology and localization of injected hyaluronic
acid (HA) fillers [63]. The excised tissue sample from the surgi-
cal correction by direct excision of the NLF were injected with HA
fillers (Restylane, Perlane or layered Restylane/Perlane), sectioned
and treated with histological stains. It was appeared that HA localized
primarily in lower reticular dermis and subcutis of the excised NLF re-
gardless of the HA product employed. Direct excision of the NLF with
advancement of the nasolabial fat compartment is a successful treat-
ment for patients with deep NLF. The injection of HA into the excised
tissue near the site of injection shows the importance of proper place-
ment of HA fillers during soft tissue augmentation. [63].
Nevertheless; NASHA-based dermal filler have been exclusively
used for soft tissue augmentation; however, their efficacy was com-
pared with bio-stimulatory polycaprolactone (PCL)-based dermal
filler [64]. In this clinical trail, 40 subjects with mild-to-moderate
NLFs were treated with NASHA-based dermal filler one side and
PCL-based dermal filler on the contralateral side for a period of
12 months. At the end of treatment period, clinical observations re-
vealed equivalent safety and tolerability of both products; however,
a significantly greater improvement in wrinkle severity was achieved
with PCL-based dermal filler compared with NASHA-based dermal
filer [64]. The efficacy, durability, and safety of HA gel dermal filler
has also been compared with autologous fat gel for cosmetic correc-
tion of NLFs [65]. This clinical trial involved 62 human subjects who
were treated for 12 months. The result showed comparable efficacy of
both products in treatment of NLFs and equivalent safety and tolera-
bility in all patients [65]. The therapeutic significance of HA formula-
tions for the treatment of nasolabial has been summarized in Table 2.
UNCORRECTED PROOF
14 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
3.3. Anti-aging properties of HA
Aging is a natural process which declines/weakens biological func-
tions and ability to adapt to the metabolic stresses. It is a progressive
physiological change in an organism that leads to senescence or old
age. As the age increases, tendons, blood vessels and skin lose its elas-
ticity. This is due to the formation of cross-links between or within the
molecules of collagen that alter the structure and shape of the enzyme
molecules thus unable to carry out their functions in the cells.
Symptoms of aging include hearing loss [67], loss of muscle mass
and mobility and impaired loss of vision. Aging causes skin to develop
wrinkles especially at the sun-exposed areas, mainly at the face. The
color of hair turns to grey [68] and cause hair loss rapidly. The reduc-
tion of skin elasticity makes skin become thin and more fragile with
age and the fatty tissue underneath the skin decreases concurrently.
The reduction in the production of natural oils causes skin to get dry,
crackled, and thin.
In view of the importance of youthfulness in the life of every per-
son, many scientists have discovered different anti-aging modalities.
Anti-aging is one of the most beneficial elements in cosmetic applica-
tion. A number of products including, diets and exercises, drugs and
supplements are claimed to have anti-aging properties. Common an-
tioxidants such as vitamin A, C, and E and coenzyme Q10 consumed
to fight the release of free radicals called reactive oxygen species that
contributes to aging process. But, there is little evidence shows the ef-
ficacy of the products instead many studies indicate that antioxidants
do not slow the process of aging otherwise only slightly increase in
the longevity [6971]. Other treatments include laser therapy, wrin-
kle injections, peptide formulation and anti-aging sunscreens believed
to delay aging process. In addition of these treatments, eating healthy
food, having regular physical activity and avoid stress also promote in
maintaining the youthful looking of aged person.
Among the various common signs and symptoms, facial volume
loss is one of characteristic symptoms of aging process. The natural
aging process and your genetics are the major causes of facial vol-
ume loss. However, certain medications, weight loss, stress and other
lifestyle factors may contribute to exacerbated facial volume loss. Fa-
cial volume loss may appear as hollow temples, sunken-in eye sockets,
flattened cheeks, or loose sagging skin around the jawline also known
as jowls.
Numerous researchers have demonstrated that subcutaneous injec-
tion of HA E Volume gel improved the facial volume which is an im-
portant part of facial rejuvenation. A multicenter, six-month, open-la-
bel study was conducted with the application of HA E in the cheeks at
baseline in patients with bilateral volume loss of the cheeks. After six
months, a significant improvement (an optimal correction of 65.8%)
has been achieved with high patient satisfaction of about 92.1% [72].
Similarly, another clinical trial involving 102 patients (93 females and
9 males) with the average age of 51.27 years received Voluma, a
HA based sub-dermal facial filler injected into the midface [73]. Re-
sults revealed a significant improvement in maintaining increased fa-
cial volume for up to 18-month post-treatment with HA sub-dermal
filler [73].
Despite facial volume loss, tear trough deformity is also one of
the most common symptoms of aging process due to the volume loss
and muscular hyperactivity. HA gel also acts as a tear trough defor-
mity filler for patients for cosmetic improvement in periorbital reju-
venation. A clinical trial was conducted involving 151 patients with
a total of 302 eyes which were administered with mean volume of
0.48 ml of semi-cross-linked HA gel per eye preperiosteally to achieve
correction of tear trough deformity [74]. Most of the patients showed
great satisfaction and tolerability with the treatment after experiencing
remarkable improvement in the cosmetic effect with minimal compli-
cations [74]. Similarly, another group of researchers have also inves-
tigated the efficacy of periorbital filling with HA injection into prepe-
riosteal tissues [75]. In this study, 25 human subjects were injected
with 0.1 ml periorbital filling with HA at each preperiosteal tissues,
follow up to 12 months. After 12 months, they measure the correct tear
trough deformity in each patient. They found a significant improve-
ment in the treatment of tear trough deformity with HA gel filler with
clinically effective and have high subject satisfaction [75].
Despite injection of HA in periorbital tissues, the anti-aging effect
of HA gel as tear trough filler have also been investigated [76]. In this
clinical trial, 100 patients were recruited and were applied with mean
volume of 0.59 ml of gel on each eye and followed up to 5.1 months.
The resulting findings showed a significantly higher effectiveness of
HA gel in the tear trough rejuvenation with high level of patient toler-
ability and satisfaction [76].
HA filler can also be used for reducing the nasojugal sulcus; how-
ever, it is associated with common adverse reactions such as irreg-
ular lumpiness and overcorrection. To overcome this, a prospective
randomized split face controlled study was conducted to evaluate the
effect of administering Restylane Vital® with its specialized injec-
tor on volume correction and skin tone of nasojugal groove [77]. The
study enrolled 10 Korean women and randomly injected a stabilized
HA-based gel of NAHSA injector, Restylane Vital®, Q-med on one
side of nasojugal groove with the other side as control. The outcome
duration of overall effect varied among the patients. The correction of
the nasojugal groove with a Restylane Vital® injector provides a high
degree of satisfaction to the patients with minimal tissue trauma and
more specific injection site. It also has lower incidence of adverse re-
action compared to more commonly used techniques. HA filler intra-
dermal injection with special injector indicates to be safe and effective
method for correction of nasojugal groove [77].
Skin elasticity, moisture and turgor are the best parameters to mea-
sure the effects of treatment with native HA. It has been shown that
native HA has the positive effects in improving skin elasticity and tur-
gor [78]. With regards to treatment of elastotic skin with native HA,
one study using the product based on natural hyaluronic acid (Ial-Sys-
tem) was assessed whether it is able to restore elasticity and tur-
gor to the skin. Two treatments with native HA were given to 20 pa-
tients with distinct to substantial signs of the facial skin with mean
age of 52 years old. The applications at an interval of 14 days found
that there was significant improvement in the turgor and elasticity. Ap-
proximately 95% physicians and patients each judged the treatment
results as very good or good [79].
To create more youthful appearance, the requirements of aesthetic
treatments toward volume replacement were needed in multiple ar-
eas. One study shows positive effect of using multi-syringes of HA in
the degree of perceived age reduction. Ten women with the criteria of
6 months for no laser and HA fillers or 1 year for no semi-permanent
fillers, were treated with 6 to 8 ml of HA Multi-syringe injection of
HA that has been applied to the aging face resulted in a reduction of
apparent age from 6.1 to 9 years after several weeks [80]. This shows
that full-face correction with HA is a promising remedy for anti-aging
effects.
Besides the action of HA as dermal filler, in order to treat skin
aging related problems, topical formulation of HA was introduced to
treat aged skin in the parameters of skin roughness. An eight-week
placebo controlled study with an oil-in-water cream containing 0.1%
Na-salt of the HA derivatives were demonstrated to compare the ef
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 15
fects of different low molecular weight HA molecules. Twelve female
volunteers with age of 3060 years were applied with topical cream
twice daily for 60 days. It was reported that the better permeation of
low molecular weight of HA has significantly reduced skin roughness
as well as wrinkles. Although there was different penetration ability
on variation molecular weight, the strong moisturizing properties of
HA is undeniable [81]. Thus, by strengthening its penetration abilities
based on decreasing molecular size, the effects of anti-aging and skin
functioning could be achieved and improved. A summary of anti-ag-
ing potential of HA based formulations is appended in Table 3.
4. Other aesthetic improvements and cosmetic effects of HA
Besides anti-wrinkle, anti-aging, and anti-nasolabial folds, HA has
also shown remarkable potential in soft tissue augmentation, skin
augmentation, face rejuvenation, skin hydration, skin radiant, and as
collagen stimulator. Duranti et al. [83] conducted a clinical trial in-
volving 158 patients who were treated with facial intradermal im-
plant of HA gel for face and lip augmentation/or recontouring. Re-
sults demonstrated a marked improvement and soft tissue augmenta-
tion after 8 months. Face rejuvenating potential (mid face augmenta-
tion) of HA-based injectable gel (Juvéderm® VOLUMA® with Li-
docaine) has also been investigated by Philipp-Dormston et al. [84].
This prospective, observational, single-arm, open-label post-market-
ing study enrolled 115 healthy subjects. Results suggested that
Juvéderm® VOLUMA® with Lidocaine was well accepted by all sub-
jects and evaluators. HA based dermal filler has shown remarkable
potential for treating facial volume loss and contour deficiency [85].
In this open label study, sixty adults (aged 4060 years) with bilateral
moderate-to-severe volume loss or contour deficiency were enrolled.
At six months post-treatment, a significant improvement in FVLS (Fa-
cial Volume Loss Scale) scores and GAIS (Global Aesthetic Improve-
ment Scale) was observed. These results were also in agreement with
findings of other researchers [86,87]. Skin hydration is one of the
prime factors that influence the skin health. The potential relationship
between HA and skin hydration has been investigated by Seok et al.
[88]. In this pilot study, six middle-aged male subjects were enrolled
who were injected with 0.020 mL of HA filler at each injection point
with a total of 100 points (2 mL of HA filler was injected to entire face
at every treatment session) using an automatic intradermal injector.
A total of three sessions were conducted for each subject in 2 weeks
interval. Efficacy of HA filler was evaluated in terms of transepider-
mal water loss (TEWL), hydration level (corneometer), patient satis-
faction, and the GAIS. Results demonstrated a considerable improve-
ment in skin hydration and gradual decrease in TEWL at each treat-
ment session. The satisfaction level of all patients was measured at
very much improvedor much improvedaccording to GAIS scale.
These results evidenced that HA dermal filler is a promising treatment
to enhance skin hydration, brightness, and skin elasticity [88].
Another attractive feature associated with intradermal injection of
HA filler is collagen production [89]. Collagen is the major struc-
tural protein of dermal extracellular matrix. To evaluate the efficacy
of HA dermal filler injection on collagen biosynthesis, Wang et al.
[89] conducted a clinical trial by enrolling eleven healthy subjects (av-
erage aged 74 years) with photodamaged forearm skin. The HA der-
mal filler was injected into forearm of each subject and nutricosmetic
efficacy was evaluated in terms of de novo synthesis of collagen us-
ing immunohistochemical analysis, quantitative polymerase chain re-
action, and electron microscopy. Results revealed that the subjects in-
jected with HA cross-linked dermal filler showed greater increase in
collagen deposition around the filler compared to control groups (in-
jected with normal saline). Fibroblasts in filler-injected skin demon-
strated a mechanically stretched appearance and a biosynthetic phe-
notype. Resulting evidences validated that the intradermal injection
of cross-linked HA stimulate collagen synthesis and partially restore
dermal extracellular matrix components that are lost in photodamaged
skin [89]. These results were also validated by another research group
[90]. They conducted a clinical trial involving sixty female subjects
who received dermal injection of 0.5 mL of HA gel and the skin biopsy
samples were collected at 1, 3, and 6 months. The efficacy of col-
lagen synthesis was evaluated in terms of protein and gene expres-
sion of procollagen, matrix metalloproteinases (MMP) and MMP tis-
sue inhibitors (TIMP1) using ELISA and qPCR, respectively. A con-
siderable improvement in collagen synthesis, procollagen expression,
and increased levels of MMP and TIMP1 were evident at 1 month of
post-receiving intradermal injection of HA gel [90]. A greater poten-
tial of HA based formulations to enhanced collagen synthesis to repair
skin defects had also been validated by other researchers [91,92].
Besides improving skin hydration, restoring lost facial volume,
collagen de novo synthesis stimulation, HA fillers have also shown
greater space-filling properties in patients presented with congenital
or acquired facial malformations [93]. In this study, three different
commercially available HA fillers (15 mg/mL, 17.5 mg/mL, 20 mg/
mL) were injected in 32 patients (aged 1332 years) with congenital
or acquired facial malformations and a total of 46 sessions were con-
ducted. Clinical assessment was performed by patients and plastic sur-
geon, 15 days after injections and 618 months later. Post-treatment
evaluation revealed a remarkable space-filling efficacy of HA filler,
while having greater potential of enhancing skin elasticity and softness
of scaring tissues. This observational study evidenced that intrader-
mal injection of cross-linked HA stimulates production of several ex-
tra-cellular matrix components, including dermal collagen and elastin
[93].
Mid-face volume deficit (MVD) is one of the most common signs
of aging. Few et al. [94] conducted a clinical trial in which they en-
rolled 235 subjects with moderate-to-severe age-related MVD. All pa-
tients received Juvéderm Voluma XC for voluminizing their MVD.
At quarterly follow-up visits for 2 years, patients rated treatment out-
comes on the GAIS, overall satisfaction with facial appearance, satis-
faction with midfacial regions, achievement of treatment goal, Look
and Feel of the Midface (LAFM), and Self-Perception of Age (SPA).
Juvéderm Voluma XC for age-related MVD is effective and well-tol-
erated from the patient perspective, with results lasting up to 2 years
[94]. The remarkable potential of HA dermal filler to correct age-re-
lated MVD has also been evidenced by other researchers [9597]. In
an attempt to elevate the supporting facial features, Bertucci et al.
[98] conducted a 24-weeks open-label study in which they recruited
40 adults (aged 18 to 65) with bilateral moderate to substantial MVD
or contour deficiency. They tested cosmetic efficacy of HA dermal
filler with 0.3% lidocaine. They evidenced that MVD and contour
deficiency is well-accepted treatment to repair skin defects and to
restore MVD. These results were also in agreement with other re-
searchers [99]. Besides restoring face contour deficiency, HA filler
have also been attempted to restore lip contour and perioral area,
thereby reducing age-related changes in lips [100]. In this study, the
short-term aesthetic impact of HA dermal filler (Juvéderm® VOL-
BELLA®) with lidocaine was tested on 62 subjects for enhancement
or correction of age-related asymmetry of the lips using a patient-cen-
tric approach. A patient satisfaction scale was at 83.6% immediately
after injection at first visit which rated as Extremely Satisfied, Very
Satisfied or Satisfied. In terms of improvement in the lips. The pa
UNCORRECTED PROOF
16 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
tient satisfaction level was increased to 94.1% and 93.0% of subjects
with/without top-up treatment at follow-up, respectively [100]. These
results were also in accordance with other study [101]. A summary of
aesthetic improvements with HA dermal filler is presented in Table 4.
5. Summary
A thorough analysis of the literature revealed that HA exhibits re-
markable cosmetic and nutricosmetic efficacy in treating the various
skin defects such as wrinkles, nasolabial folds, and skin aging. HA has
been utilized in various forms (i.e., gels, creams, intra-dermal filler in-
jection, dermal filler, lotion, serum, and implants). The cosmetic and
nutricosmetic effects of HA have been associated with their ability
to stimulate collagen synthesis via induction of fibroblasts, improve
skin hydration, and soft tissue augmentation. The anti-wrinkle efficacy
of topically applied HA is molecular weight dependent which might
be associated with differences in percutaneous absorption of differ-
ent molecular weight HA across the stratum corneum. HA based der-
mal fillers have also shown promising ability to treat nasolabial folds.
Many researches have investigated the anti-nasolabial fold efficacy of
HA dermal fillers, alone or in combination with other cosmetic modal-
ities such as non-ablative laser/RF/IPL therapy, lidocaine, and carbon
dioxide. Comparative analysis of various anti-nasolabial folds formu-
lations revealed that the anti-nasolabial fold efficacy of dermal fillers
containing non-animal sourced HA showed better anti-wrinkle effi-
cacy compared to bovine collagen. Nevertheless; NASHA-based der-
mal filler have been exclusively used for soft tissue augmentation;
however, their efficacy was found to be significantly lower compared
with bio-stimulatory polycaprolactone (PCL)-based dermal filler. One
of the common problems to patients undergoing soft tissue augmen-
tation is the pain at injection site. However, inclusion of lidocaine in
HA dermal fillers significantly improve patient compliance and reduce
severity of pain at injection site associated with intradermal injection.
Though, inclusion of lidocaine with HA filler reduces injection re-
lated pain; however, it does not affect longevity, clinical efficacy, and
durability of HA based dermal fillers. Moreover, many studies have
also highlighted the clinical significance of HA based formulations
(intradermal injection or topical application) to restore facial volume
in periorbital tissues, face rejuvenation, lip contour, treatment of tear
trough, treatment of mid-face volume deficit, nasojugal sulcus, restore
moisture and turgor, and skin elasticity. These evidence based find-
ings validated that application/administration of HA is a promising
biomedicine and pharmacotherapy for the treatment of various skin re-
lated defects and slow down various physiological changes related to
aging process. Having promising cosmetic and nutricosmetic efficacy,
acceptable safety profile, biocompatibility, non-toxicity, and greater
patient compliance, HA based formulations are warranted to be used
for treatment of various skin defects and as anti-aging modality.
Acknowledgement
The authors would like to acknowledge Institute of Research
Management & Innovation (IRMI), Universiti Teknologi MARA
(UiTM) for providing LESTARI grant (600-IRMI/DANA 5/3/
LESTARI (0007/2016)) and support in writing this review article.
Declaration of interest
The authors report no declaration of interest in the present work.
References
[1] J.R. Fraser, T.C. Laurent, U.B. Laurent, Hyaluronan: its nature, distribution,
functions and turnover, J. Intern. Med. 242 (1997) 27–33.
[2] R.D. Price, M.G. Berry, H.A. Navsaria, Hyaluronic acid: the scientific and clin-
ical evidence, J. Plast. Reconstr. Aesthet. Surg. 60 (2007) 1110–1119.
[3] L.H. Chen, J.F. Xue, Z.Y. Zheng, M. Shuhaidi, H.E. Thu, Z. Hussain,
Hyaluronic acid, an efficient biomacromolecule for treatment of inflammatory
skin and joint diseases: a review of recent developments and critical appraisal
of preclinical and clinical investigations, Int. J. Biol. Macromol. 116 (2018)
572–584.
[4] Z. Hussain, H.E. Thu, H. Katas, S.N.A. Bukhari, Hyaluronic acid-based bioma-
terials: a versatile and smart approach to tissue regeneration and treating trau-
matic, surgical, and chronic wounds, Polym. Rev. 57 (2017) 594–630.
[5] B. Fiszer-Szafarz, M. Rommain, C. Brossard, P. Smets, Hyaluronic acid-de-
grading enzymes in rat alveolar macrophages and in alveolar fluid: stimulation
of enzyme activity after oral treatment with the immunomodulator RU 41740,
Biol. Cell. 63 (1988) 355–360.
[6] M.H. Safdar, Z. Hussain, M.A.S. Abourehab, H. Hasan, S. Afzal, H.E. Thu,
New developments and clinical transition of hyaluronic acid-based nanothera-
peutics for treatment of cancer: reversing multidrug resistance, tumour-specific
targetability and improved anticancer efficacy, Artif. Cells Nanomed. Biotech-
nol. (2017) 1–14, https://doi.org/10.1080/21691401.2017.1397001.
[7] N.I. Ievdokimova, Hyaluronic acid, receptor CD44, and their role in diabetic
complications, Ukr. Biokhim. Zh. 80 (2008) 5–44.
[8] E. Papakonstantinou, M. Roth, G. Karakiulakis, Hyaluronic acid: a key mole-
cule in skin aging, Dermatoendocrinol. 4 (2012) 253–258.
[9] V.A. Narurkar, S.G. Fabi, V.W. Bucay, R. Tedaldi, J.B. Downie, J.A. Zeichner,
K. Butterwick, A. Taub, K. Kadoya, E.T. Makino, R.C. Mehta, V.L. Vega, Re-
juvenating hydrator: restoring epidermal hyaluronic acid homeostasis with
instant benefits, J. Drugs Dermatol. 15 (2016) S24–S37.
[10] T. Pavicic, G.G. Gauglitz, P. Lersch, K. Schwach-Abdellaoui, B. Malle, H.C.
Korting, M. Farwick, Efficacy of cream-based novel formulations of hyaluronic
acid of different molecular weights in anti-wrinkle treatment, J. Drugs Derma-
tol. 9 (2011) 990–1000.
[11] S.M. Dorsey, J.R. McGarvey, H. Wang, A. Nikou, L. Arama, K.J. Koomals-
ingh, N. Kondo, J.H. Gorman, J.J. Pilla, R.C. Gorman, J.F. Wenk, J.A. Burdick,
MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit
ventricular remodeling after myocardial infarction, Biomaterials 69 (2015)
65–75.
[12] J.I. Tornero Ruiz, G. Martínez Gómez, J.F. Escudero Bregante, G.A. Gómez
Gómez, Recurrent urinary tract infections: prevention of recurrence with intrav-
esical instillations of chondroitin sulfate and hyaluronic acid, Arch. Esp. Urol.
70 (2017) 288–293.
[13] O. Ciani, E. Arendsen, M. Romancik, R. Lunik, E. Costantini, M. Di Biase, G.
Morgia, E. Fragalà, T. Roman, M. Bernat, G. Guazzoni, R. Tarricone, M.
Lazzeri, Intravesical administration of combined hyaluronic acid (HA) and
chondroitin sulfate (CS) for the treatment of female recurrent urinary tract in-
fections: a European multicentre nested case-control study, BMJ Open
6 (2016), e009669.
[14] M. Cervigni, M. Sommariva, R. Tenaglia, D. Porru, E. Ostardo, A. Giammò, S.
Trevisan, V. Frangione, O. Ciani, R. Tarricone, G.L. Pappagallo, A random-
ized, open-label, multicenter study of the efficacy and safety of intravesical
hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women
with bladder pain syndrome/interstitial cystitis, Neurourol. Urodyn. 36 (2017)
1178–1186.
[15] D. Porru, F. Leva, A. Parmigiani, D. Barletta, D. Choussos, B. Gardella, M.D.
Daccò, R.E. Nappi, M. Allegri, C. Tinelli, C.M. Bianchi, A. Spinillo, B.
Rovereto, Impact of intravesical hyaluronic acid and chondroitin sulfate on
bladder pain syndrome/interstitial cystitis, Int. Urogynecol. J. 23 (2012)
1193–1199.
[16] T. Pavicic, G.G. Gauglitz, P. Lersch, K. Schwach-Abdellaoui, B. Malle, H.C.
Korting, M. Farwick, Efficacy of cream-based novel formulations of hyaluronic
acid of different molecular weights in anti-wrinkle treatment, J. Drugs Derma-
tol. 10 (2011) 990–1000.
[17] F. Brandt, B. Bassichis, M. Bassichis, C. O'Connell, X. Lin, Safety and effec-
tiveness of small and large gel-particle hyaluronic acid in the correction of peri-
oral wrinkles, J. Drugs Dermatol. 10 (2011) 982–987.
[18] B. Rzany, H. Cartier, P. Kestermont, P. Trevidic, G. Sattler, N. Kerrouche, J.C.
Dhuin, Correction of tear troughs and periorbital lines with a range of cus-
tomized hyaluronic acid fillers, J. Drugs Dermatol. 11 (2012) S27–S34.
[19] B. Rzany, H. Cartier, P. Kestemont, P. Trevidic, G. Sattler, N. Kerrouche, J.C.
Dhuin, Y.M. Ma, Full-face Rejuvenation Using a Range of Hyaluronic Acid
Fillers: Efficacy, Safety, and Patient Satisfaction Over 6 Months Dermatologic
Surgery, 38, 20121153–1161.
[20] M. Pandey, H. Choudhury, T.A.P. Gunasegaran, S.S. Nathan, S. Md, B.
Gorain, M. Tripathy, Z. Hussain, Hyaluronic acid-modified betamethasone en-
capsulated polymeric nanoparticles: fabrication, characterisation, in vitro re
UNCORRECTED PROOF
International Journal of Biological Macromolecules xxx (2018) xxx-xxx 17
lease kinetics, and dermal targeting, Drug Deliv. Transl. Res. (2018) https://doi.
org/10.1007/s13346-018-0480-1.
[21] F. Zhuo, M.A.S. Abourehab, Z. Hussain, Hyaluronic acid decorated
tacrolimus-loaded nanoparticles: efficient approach to maximize dermal target-
ing and anti-dermatitis efficacy, Carbohydr. Polym. 197 (2018) 478–489.
[22] J. Dong, L. Tao, M.A.S. Abourehab, Z. Hussain, Design and development of
novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and
alendronate: fabrication, characterization, and cellular and molecular evidences
of enhanced bone regeneration, Int. J. Biol. Macromol. 116 (2018) 1268–1281.
[23] F.W. Danby, Nutrition and aging skin: sugar and glycation, Clin. Dermatol. 4
(28) (JulAug 2010) 409–411.
[24] M.S. Zimbler, M.S. Kokoska, J.R. Thomas, Anatomy and pathophysiology of
facial aging, Facial Plast. Surg. Clin. North Am. 9 (2) (2001 May) 179–187,
(vii).
[25] D.J. Prockop, K.I. Kivirikko, L. Tuderman, N.A. Guzman, The biosynthesis of
collagen and its disorders (second of two parts), N. Engl. J. Med. 301 (2) (1979
Jul 12) 77–85.
[26] J. Bhawan, W. Andersen, J. Lee, R. Labadie, G. Solares, Photoaging versus in-
trinsic aging: a morphologic assessment of facial skin, J. Cutan. Pathol. 22 (2)
(1995 Apr) 154–159.
[27] T.D. Rees, S.J. Aston, C.H. Thorne, Blepharoplasty and facialplasty, in: J. Mc-
Carthy (Ed.), Plastic Surgery, WB Saunders, Philadelphia, PA, 1990, pp.
2320–2414.
[28] T. Pavicic, G.G. Gauglitz, P. Lersch, K. Schwach-Abdellaoui, B. Malle, H.C.
Korting, M. Farwick, Efficacy of cream-based novel formulations of hyaluronic
acid of different molecular weights in anti-wrinkle treatment, J. Drugs Derma-
tol. 10 (9) (01 Sep 2011) 990–1000.
[29] S. Manjula Jegasothy, Valentina Zabolotniaia, Stephan Bielfeldt, Efficacy of a
new topical nano-hyaluronic acid in humans, J. Clin. Aesthet. Dermatol. 7 (3)
(2014 Mar) 27–29.
[30] J. Poetschke, H. Schwaiger, S. Steckmeier, T. Ruzicka, G.G. Gauglitz,
Anti-wrinkle creams with hyaluronic acid: how effective are they?, MMW
Fortschr. Med. 158 (Suppl. 4) (2016 May 25) 1–6.
[31] F. Brandt, B. Bassichis, M. Bassichis, C. O'Connell, X. Lin, Safety and effec-
tiveness of small and large gel-particle hyaluronic acid in the correction of peri-
oral wrinkles, J. Drugs Dermatol. 10 (9) (2011 Sep) 982–987.
[32] H. Cartier, P. Trevidic, B. Rzany, G. Sattler, P. Kestemont, N. Kerrouche, J.C.
Dhuin, Perioral rejuvenation with a range of customized hyaluronic acid fillers:
efficacy and safety over six months with a specific focus on the lips, J. Drugs
Dermatol. 11 (1 Suppl) (2012 Jan) s17–s26.
[33] B. Rzany, H. Cartier, P. Kestermont, P. Trevidic, G. Sattler, N. Kerrouche, J.C.
Dhuin, Correction of tear troughs and periorbital lines with a range of cus-
tomized hyaluronic acid fillers, J. Drugs Dermatol. 11 (1 Suppl) (2012 Jan)
s27–s34.
[34] Berthold Rzany, Hugues Cartier, Philippe Kestemont, Patrick Trevidic, Gerhard
Sattler, Nabil Kerrouche, Jean-Charles Dhuin, May Y. Ma, Full-face rejuvena-
tion using a range of hyaluronic acid fillers: efficacy, safety, and patient satis-
faction over 6 months, Dermatol. Surg. 38 (7 Pt 2) (2012 Jul) 1153–1161.
[35] Beatriz Molina, Michel David, Ravi Jain, Moisés Amselem, Ricardo Ruiz-Ro-
driguez, May Y. Ma, Nabil Kerrouche, Sotirios P. Georgantopoulos, Thierry
Radeau, Dominique Boineau, Patient satisfaction and efficacy of full-facial re-
juvenation using a combination of botulinum toxin type A and hyaluronic acid
filler, Dermatol. Surg. 41 (Suppl. 1) (2015 Dec) S325–S332.
[36] M. Streit, C.U. Brand, L.R. Braathen, Soft tissue augmentation for treatment of
wrinkles and scars of the face, Ther. Umsch. 56 (4) (1999 Apr) 212–218.
[37] Stacy R. Smith, Derek Jones, Jane A. Thomas, Diane K. Murphy, Frederick C.
Beddingfiel dIII, Duration of wrinkle correction following repeat treatment
with Juvéderm hyaluronic acid fillers, Arch. Dermatol. Res. 302 (10) (Decem-
ber 2010) 757–762.
[38] R. Tung, A.M. Ruiz de Luzuriaga, K. Park, M. Sato, M. Dubina, M. Alam,
Brighter eyes: combined upper cheek and tear trough augmentation: a system-
atic approach utilizing two complementary hyaluronic acid fillers, J. Drugs
Dermatol. 11 (9) (2012) 1094–1097.
[39] M.P. Goldman, T.S. Alster, R. Weiss, A randomized trial to determine the in-
fluence of laser therapy, monopolar radiofrequency treatment, and intense
pulsed light therapy administered immediately after hyaluronic acid gel implan-
tation, Dermatol. Surg. 33 (5) (2007 May) 535–542.
[40] L.S. Baumann, A.T. Shamban, M.P. Lupo, G.D. Monheit, J.A. Thomas, D.K.
Murphy, P.S. Walker, JUVEDERM vs. ZYPLAST Nasolabial Fold Study
Group, Comparison of smooth-gel hyaluronic acid dermal fillers with
cross-linked bovine collagen: a multicenter, double-masked, randomized,
within-subject study, Dermatol. Surg. 33 (Suppl. 2) (2007 Dec) S128–S135.
[41] C. Lindqvist, S. Tveten, B.E. Bondevik, D. Fagrell, A randomized, evalua-
tor-blind, multicenter comparison of the efficacy and tolerability of Perlane ver-
sus Zyplast in the correction of nasolabial folds, Plast. Reconstr. Surg. 115 (1)
(2005 Jan) 282–289.
[42] R.S. Narins, F. Brandt, J. Leyden, Z.P. Lorenc, M. Rubin, S. Smith, A random-
ized, double-blind, multicenter comparison of the efficacy and tolerability of
Restylane versus Zyplast for the correction of nasolabial folds, Dermatol. Surg.
29 (6) (2003 Jun) 588–595.
[43] G. Wahl, European evaluation of a new hyaluronic acid filler incorporating li-
docaine, J. Cosmet. Dermatol. 7 (4) (2008 Dec) 298–303.
[44] P.M. Levy, K. De Boulle, H. Raspaldo, A split-face comparison of a new
hyaluronic acid facial filler containing pre-incorporated lidocaine versus a stan-
dard hyaluronic acid facial filler in the treatment of naso-labial folds, J. Cos-
met. Laser Ther. 11 (3) (2009 Sep) 169–173.
[45] S.H. Weinkle, D.E. Bank, C.M. Boyd, M.H. Gold, J.A. Thomas, D.K. Murphy,
A multi-center, double-blind, randomized controlled study of the safety and ef-
fectiveness of Juvéderm injectable gel with and without lidocaine, J. Cosmet.
Dermatol. 8 (3) (2009 Sep) 205–210.
[46] G.D. Monheit, R.M. Campbell, H. Neugent, C.P. Nelson, C.L. Prather, N.
Bachtell, D. Eng, L. Holmdahl, Reduced pain with use of proprietary
hyaluronic acid with lidocaine for correction of nasolabial folds: a pa-
tient-blinded, prospective, randomized controlled trial, Dermatol. Surg. 36 (1)
(2010) 94–101.
[47] Choi WJ1, Han SW1, Kim JE1, Kim HW2, Kim MB3, Kang H4, The efficacy
and safety of lidocaine-containing hyaluronic acid dermal filler for treatment of
nasolabial folds: a multicenter, randomized clinical study, Aesthet. Plast. Surg.
39 (6) (2015 Dec) 953–962.
[48] Lee JH1, Kim SH2, Park ES3, The efficacy and safety of HA IDF plus (with li-
docaine) versus HA IDF (without lidocaine) in nasolabial folds injection: a ran-
domized, multicenter, double-blind, split-face study, Aesthet. Plast. Surg. 41
(2) (2017 Apr) 422–428.
[49] H. Raspaldo, K. De Boulle, P.M. Levy, Longevity of effects of hyaluronic acid
plus lidocaine facial filler, J. Cosmet. Dermatol. 9 (1) (2010 Mar) 11–15.
[50] H.J. Joo, Y.J. Woo, J.E. Kim, B.J. Kim, H. Kang, A randomized clinical trial to
evaluate the efficacy and safety of lidocaine-containing monophasic hyaluronic
acid filler for nasolabial folds, Plast. Reconstr. Surg. 137 (3) (2016 Mar)
799–808.
[51] H.J. Kwon, E.J. Ko, S.Y. Choi, E.J. Choi, Y.J. Jang, B.J. Kim, Y.W. Lee, The
efficacy and safety of a monophasic hyaluronic acid filler in the correction of
nasolabial folds: a randomized, multicenter, single blinded, split-face study, J.
Cosmet. Dermatol. (2017 Sep 14) https://doi.org/10.1111/jocd.12380.
[52] J.Y. Ahn, S.H. Lee, K.Y. Park, C.K. Hong, H.J. Song, M.Y. Park, Y.S. Choi,
S.J. Seo, Clinical comparison of two hyaluronic acid-derived fillers in the treat-
ment of nasolabial folds: Mesoglow® and IAL system®, Int. J. Dermatol. 51
(5) (2012 May) 601–608.
[53] Y. Wu, N. Sun, Y. Xu, H. Liu, S. Zhong, L. Chen, D. Li, Clinical comparison
between two hyaluronic acid-derived fillers in the treatment of nasolabial folds
in Chinese subjects: BioHyalux versus Restylane, Arch. Dermatol. Res. 308 (3)
(2016 Apr) 145–151.
[54] B. Rzany, C. Bayerl, I. Bodokh, D. Boineau, T. Dirschka, C. Queille-Roussel,
M. Sebastian, B. Sommer, M. Poncet, M. Guennoun, M. Podda, Efficacy and
safety of a new hyaluronic acid dermal filler in the treatment of moderate na-
solabial folds: 6-month interim results of a randomized, evaluator-blinded, in-
tra-individual comparison study, J. Cosmet. Laser Ther. 13 (3) (2011 Jun)
107–112.
[55] T.K. Noh, H.R. Moon, J.S. Yu, S.E. Chang, I.J. Moon, S.Y. Choi, W.J. Oh,
C.H. Won, B.J. Kim, Y.W. Lee, Effects of highly concentrated hyaluronic acid
filler on nasolabial fold correction: a 24-month extension study, J. Dermatolog.
Treat. 27 (6) (2016 Nov) 510–514.
[56] Y. Wu, J. Xu, Y. Jia, D.K. Murphy, Safety and effectiveness of hyaluronic acid
injectable gel in correcting moderate nasolabial folds in Chinese subjects, J.
Drugs Dermatol. 15 (1) (2016 Jan) 70–76.
[57] W. Prager, V. Steinkraus, A prospective, rater-blind, randomized comparison of
the effectiveness and tolerability of Belotero ® Basic versus Restylane ® for
correction of nasolabial folds, Eur. J. Dermatol. 20 (6) (2010 NovDec)
748–752.
[58] G. Nisi, R. Cuomo, C. Brandi, L. Grimaldi, A. Sisti, C. D'Aniello, Carbon diox-
ide therapy and hyaluronic acid for cosmetic correction of the nasolabial folds,
J. Cosmet. Dermatol. 15 (2) (2016 Jun) 169–175.
[59] Narins RS1, S.H. Dayan, F.S. Brandt, E.K. Baldwin, Persistence and improve-
ment of nasolabial fold correction with nonanimal-stabilized hyaluronic acid
100,000 gelparticles/mL filler on two retreatment schedules: results up to
18 months on two retreatment schedules, Dermatol. Surg. 34 (Suppl. 1) (2008
Jun) S2–S8, https://doi.org/10.1111/j.1524-4725.2008.34236.x, (discussion S8).
[60] R.S. Narins, F.S. Brandt, S.H. Dayan, C.S. Hornfeldt, Persistence of nasolabial
fold correction with a hyaluronic acid dermal filler with retreatment: results of
an 18-month extension study, Dermatol. Surg. 37 (5) (2011 May) 644–650.
[61] S.Y. Choi, Y.H. Lee, H. Kim, H.J. Koh, S.Y. Park, W.S. Park, I.H. Bae, K.Y.
Park, B.J. Kim, A combination trial of intradermal radiofrequency and
hyaluronic acid filler for the treatment of nasolabial fold wrinkles: a pilot study,
J. Cosmet. Laser Ther. 16 (1) (2014 Jan) 37–42.
[62] K.Y. Park, M.K. Park, K. Li, S.J. Seo, C.K. Hong, Combined treatment with a
nonablative infrared device and hyaluronic acid filler does not have enhanced
efficacy in treating nasolabial fold wrinkles, Dermatol. Surg. 37 (12) (2011
Dec) 1770–1775.
UNCORRECTED PROOF
18 International Journal of Biological Macromolecules xxx (2018) xxx-xxx
[63] Greco TM1, R. Elenitsas, Localization and histological characterization of in-
jected hyaluronic acid in excised nasolabial fold tissue, J. Drugs Dermatol. 9
(4) (2010 Apr) 399–404.
[64] H. Galadari, D. van Abel, K. Al Nuami, F. Al Faresi, I. Galadari, A random-
ized, prospective, blinded, split-face, single-center study comparing polycapro-
lactone to hyaluronic acid for treatment of nasolabial folds, J. Cosmet. Derma-
tol. 14 (1) (2015 Mar) 27–32.
[65] X. Hu, Z. Xue, H. Qi, B. Chen, Comparative study of autologous fat vs
hyaluronic acid in correction of the nasolabial folds, J. Cosmet. Dermatol. 16
(4) (2017 Dec) e1–e8.
[66] S.C. Taylor, C.M. Burgess, V.D. Callender, Safety of nonanimal stabilized
hyaluronic acid dermal fillers in patients with skin of color: a randomized, eval-
uator-blinded comparative trial, Dermatol. Surg. 35 (Suppl. 2) (2009 Oct)
1653–1660.
[67] L.P. Fried, C.M. Tangen, J. Walston, A.B. Newman, C. Hirsch, J. Gottdiener,
T. Seeman, R. Tracy, W.J. Kop, G. Burke, McBurnie MA, Cardiovascular
Health Study Collaborative Research Group, Frailty in older adults: evidence
for a phenotype, J. Gerontol. A Biol. Sci. Med. Sci. 56 (3) (2001 Mar)
M146–M156.
[68] D. Pandhi, D. Khanna, Premature graying of hair, Indian J. Dermatol. Venereol.
Leprol. 79 (5) (2013 SepOct) 641–653.
[69] M.L. Heidrick, L.C. Hendricks, D.E. Cook, Effect of dietary 2-mercaptoethanol
on the life span, immune system, tumor incidence and lipid peroxidation dam-
age in spleen lymphocytes of aging BC3F1 mice, Mech. Ageing Dev. 27 (3)
(1984 Oct 31) 341–358.
[70] J.O. Holloszy, Longevity of exercising male rats: effect of an antioxidant sup-
plemented diet, Mech. Ageing Dev. 100 (3) (1998 Feb 16) 211–219.
[71] K. Saito, H. Yoshioka, R.G. Cutler, A spin trap, N-tert-butyl-alpha-phenylni-
trone extends the life span of mice, Biosci. Biotechnol. Biochem. 62 (4) (1998
Apr) 792–794.
[72] P. Kestemont, H. Cartier, P. Trevidic, B. Rzany, G. Sattler, N. Kerrouche, J.C.
Dhuin, Sustained efficacy and high patient satisfaction after cheek enhancement
with a new hyaluronic acid dermal filler, J. Drugs Dermatol. 11 (1 Suppl) (2012
Jan) s9–16.
[73] H. Raspaldo, Volumizing effect of a new hyaluronic acid sub-dermal facial
filler: a retrospective analysis based on 102 cases, J. Cosmet. Laser Ther. 10 (3)
(2008 Sep) 134–142.
[74] M. Berguiga, O. Galatoire, et al., Orbit 36 (1) (2017 Feb) 22–26.
[75] G.A. Viana, M.H. Osaki, A.J. Cariello, R.W. Damasceno, T.H. Osaki, Treat-
ment of the tear trough deformity with hyaluronic acid, Aesthet. Surg. J. 31 (2)
(2011 Feb) 225–231.
[76] A.M. Morley, R. Malhotra, Use of hyaluronic acid filler for tear-trough rejuve-
nation as an alternative to lower eyelid surgery, Ophthalmic Plast. Reconstr.
Surg. 27 (2) (2011 MarApr) 69–73.
[77] H.K. Lim, D.H. Suh, S.J. Lee, M.K. Shin, Rejuvenation effects of hyaluronic
acid injection on nasojugal groove: prospective randomized split face clinical
controlled study, J. Cosmet. Laser Ther. 16 (1) (2014 Jan) 32–36.
[78] L. Wiest, M. Kerscher, Native hyaluronic acid in dermatologyresults of an ex-
pert meeting, J. Dtsch. Dermatol. Ges. 6 (3) (2008 Mar) 176–180.
[79] A. Di Pietro, G. Di Sante, Recovery of skin elasticity and turgor by intradermal
injections of hyaluronic acid (Ial-System) by the cross-linked technique, G.
Ital. Dermatol. Venereol. 136 (2001) 187–194.
[80] A.F. Taub, D. Sarnoff, M. Gold, C. Jacob, Effect of multisyringe hyaluronic
acid facial rejuvenation on perceived age, Dermatol. Surg. 36 (3) (2010 Mar)
322–328.
[81] M. Farwick, P. Lersch, G. Strutz, Low molecular weight hyaluronic acid: its
effects on epidermal gene expression & skin ageing, SOFW J. 134 (2008) 11.
[82] S. Nanda, S. Bansal, Upper face rejuvenation using botulinum toxin and
hyaluronic acid fillers, Indian J. Dermatol. Venereol. Leprol. 79 (1) (2013
JanFeb) 32–40.
[83] Duranti F1, G. Salti, B. Bovani, M. Calandra, M.L. Rosati, Injectable
hyaluronic acid gel for soft tissue augmentation. A clinical and histological
study, Dermatol. Surg. 24 (12) (1998 Dec) 1317–1325.
[84] W.G. Philipp-Dormston, D. Eccleston, K. De Boulle, S. Hilton, H. van den
Elzen, M. Nathan, A prospective, observational study of the volumizing effect
of open-label aesthetic use of Juvéderm® VOLUMA® with lidocaine in
mid-face area, J. Cosmet. Laser Ther. 16 (4) (2014 Aug) 171–179.
[85] A. Alessandrini, P. Fino, N. Giordan, V. Amorosi, N. Scuderi, Evaluation of a
new hyaluronic acid dermal filler for volume restoration, J. Cosmet. Laser
Ther. 17 (6) (2015) 335–342.
[86] P.M. Friedman, E.A. Mafong, A.N. Kauvar, R.G. Geronemus, Safety data of
injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation,
Dermatol. Surg. 28 (6) (2002 Jun) 491–494.
[87] P. Andre, New trends in face rejuvenation by hyaluronic acid injections, J. Cos-
met. Dermatol. 7 (4) (2008 Dec) 251–258.
[88] J. Seok, J.Y. Hong, S.Y. Choi, K.Y. Park, B.J. Kim, A potential relationship be-
tween skin hydration and stamp-type microneedle intradermal hyaluronic acid
injection in middle-aged male face, J. Cosmet. Dermatol. 15 (4) (2016 Dec)
578–582.
[89] F. Wang, L.A. Garza, S. Kang, J. Varani, J.S. Orringer, G.J. Fisher, J.J.
Voorhees, In vivo stimulation of de novo collagen production caused by
cross-linked hyaluronic acid dermal filler injections in photodamaged human
skin, Arch. Dermatol. 143 (2) (2007 Feb) 155–163.
[90] V. Turlier, A. Delalleau, C. Casas, A. Rouquier, P. Bianchi, S. Alvarez, G.
Josse, A. Briant, S. Dahan, C. Saint-Martory, J. Theunis, A. Bensafi-Benaouda,
A. Degouy, A.M. Schmitt, D. Redoulès, Association between collagen produc-
tion and mechanical stretching in dermal extracellular matrix: in vivo effect of
cross-linked hyaluronic acid filler. A randomised, placebo-controlled study, J.
Dermatol. Sci. 69 (3) (2013 Mar) 187–194.
[91] S. Paliwal, S. Fagien, X. Sun, T. Holt, T. Kim, C.K. Hee, D. Van Epps, D.J.
Messina, Skin extracellular matrix stimulation following injection of a
hyaluronic acid-based dermal filler in a rat model, Plast. Reconstr. Surg. 134
(6) (2014 Dec) 1224–1233.
[92] F. Wang, L.A. Garza, S. Kang, J. Varani, J.S. Orringer, G.J. Fisher, J.J.
Voorhees, In vivo stimulation of de novo collagen production caused by
cross-linked hyaluronic acid dermal filler injections in photodamaged human
skin, Arch. Dermatol. 143 (2) (2007 Feb) 155–163.
[93] G. Franchi, C. Neiva-Vaz, A. Picard, M.P. Vazquez, Facial injections of
hyaluronic acid-based fillers for malformations. Preliminary study regarding
scar tissue improvement and cosmetic betterment, Ann. Chir. Plast. Esthet. 63
(3) (2018 Jun) 197–204.
[94] J. Few, S.E. Cox, D. Paradkar-Mitragotri, D.K. Murphy, A multicenter, sin-
gle-blind randomized, controlled study of a volumizing hyaluronic acid filler
for midface volume deficit: patient-reported outcomes at 2 years, Aesthet. Surg.
J. 35 (5) (2015 Jul) 589–599.
[95] L. Baumann, R.S. Narins, K. Beer, A. Swift, K.J. Butterwick, J. Few, A.
Drinkwater, D.K. Murphy, Volumizing hyaluronic acid filler for midface vol-
ume deficit: results after repeat treatment, Dermatol. Surg. 41 (Suppl. 1) (2015
Dec) S284–S292.
[96] D.A. Glaser, J.M. Kenkel, D. Paradkar-Mitragotri, D.K. Murphy, L. Romag-
nano, A. Drinkwater, Duration of effect by injection volume and facial subre-
gion for a volumizing hyaluronic acid filler in treating midface volume deficit,
Dermatol. Surg. 41 (8) (2015 Aug) 942–949.
[97] D. Jones, D.K. Murphy, Volumizing hyaluronic acid filler for midface volume
deficit: 2-year results from a pivotal single-blind randomized controlled study,
Dermatol. Surg. 39 (11) (2013 Nov) 1602–1612.
[98] V. Bertucci, X. Lin, R.A. Axford-Gatley, M.J. Theisen, A. Swift, Safety and ef-
fectiveness of large gel particle hyaluronic acid with lidocaine for correction of
midface volume loss, Dermatol. Surg. 39 (11) (2013 Nov) 1621–1629.
[99] R.A. Weiss, A. Moradi, Bank D, J. Few, J. Joseph, J. Dover, X. Lin, A.
Nogueira, J. Mashburn, Effectiveness and safety of large gel particle hyaluronic
acid with lidocaine for correction of midface volume deficit or contour defi-
ciency, Dermatol. Surg. 42 (6) (2016 Jun) 699–709.
[100] W.G. Philipp-Dormston, S. Hilton, M. Nathan, A prospective, open-label, mul-
ticenter, observational, postmarket study of the use of a 15 mg/mL hyaluronic
acid dermal filler in the lips, J. Cosmet. Dermatol. 13 (2) (2014 Jun) 125–134.
[101] P. Sharma, S. Sharma, Comparative study of a new dermal filler Uma Je-
unesse® and Juvéderm®, J. Cosmet. Dermatol. 10 (2) (2011 Jun) 118–125.
... Meanwhile, elastin, the key protein located in the elastic fibers of connective tissue, is significant for its unique elastic recoil properties (Bravo et al., 2016). Hyaluronic acid (HA), also called hyaluronan, contributes to maintaining the appropriate form of collagen and elastin, water-holding capability related to various physiological activities including skin moisturizing, regeneration, and consequently, anti-aging properties (Bukhari et al., 2018;Ding et al., 2018). As mentioned above, dermal enzymes indirectly activated by external stimulus destruct collagen, elastin, and HA, causing premature skin aging represented by wrinkle, freckles, saggy and chappy skin or dermatopathy like rubeosis, asteatosis (Peres et al., 2011). ...
... HA is a glycosaminoglycan in ECM, vital for various physiological activities including anti-inflammatory, anticancer, and anti-diabetic as well as cosmetic properties like skin moisturizing via its water-retentive capacity. Hyaluronidase is responsible for the breakdown of HA, leading to skin dehydration, wrinkle formation, and eventually skin aging (Bravo et al., 2016;Bukhari et al., 2018). Tyrosinase plays a key role in melanin synthesis, and contributes to hyperpigmentation and skin aging, through a series of oxidative polymerization following DOPA and DOPA quinone (Pak et al., 2016). ...
Article
Marine resources have various biological activities and their constituents are more novel than those of land organisms. Several biologically active constituents have been found in marine organisms. Recently, many studies have reported that marine animals (MAs) can be used as functional ingredients in functional foods or nutraceutical due to their health benefits. However, no studies have extensively investigated the cosmeceutical activities of MAs extracts. Here, 70% ethanol extracts of 38 MAs were investigated for their activities of whitening and anti-aging properties for use as materials in novel cosmeceuticals. Anti-aging activities were determined by skin aging-related enzyme activities (anti-collagenase, anti-elastase, anti-hyaluronidase) and whitening activities (anti-tyrosinase, anti-3,4-dihydroxyl-L-phenylalanine [DOPA] oxidation) evaluated by colorimetric method. Among the 38 MAs, we found that Urechis unicinctus and Petrosia corticata extracts showed the strongest inhibitory effects against tyrosinase and DOPA oxidation, respectively. Our results additionally showed that Protankyra bidentata extract might provide a major source of anti-hyaluronidase and anti-elastase; meanwhile, anti-collagenase effects were similar in most MAs. Overall, these results suggest that extracts of marine animals have potential as a tyrosinase, collagenase, elastase, and hyaluronidase inhibitors. Taken together, MA resources could be considered as a novel cosmeceutical agent to be applied in cosmetic industry.
... Due to its ubiquitous expression in the human body, its peculiar biological and physicochemical features, and its high safety profile, HA has been widely used for various medical applications [86] apart from GSM. It is employed in dermatology for the formulation of skincare and wound-healing products [87]. In ophthalmology, it is applied both in surgery and as ophthalmic solution for the relief of dry eye [82,88]. ...
Article
Full-text available
Genitourinary syndrome of menopause (GSM) is a chronic condition affecting a large number of women, with a major impact on their urogenital health and sexual function. It occurs at midlife because estrogen levels decline with menopause enhancing aging-related changes of the functional anatomy of the urogenital system. Unfortunately, GSM may occur early in the lifespan of women or be exacerbated following anticancer treatments, such as chemotherapy, ionizing radiation, or surgical removal of reproductive organs. Symptoms of GSM are often under-reported by women, under-estimated and under-diagnosed by health care providers (HCPs), and subsequently under-treated, despite their profound negative impact on the quality of life. The mainstay of vaginal treatments is local estrogen therapy (LET) ensuring an effective management of moderate to severe symptomatic GSM. However, LET is generally contraindicated in women with a history of hormone receptor positive cancer, due to the fear of increased recurrence or possible interference with endocrine adjuvant therapies. Among non-hormonal treatments, hyaluronic acid-based moisturizers have shown promising clinical results both in healthy women and in cancer patients or survivors. Its strong water-binding properties provide lubricating and moisturizing effects, which contribute to maintaining a proper level of hydration and viscoelasticity in several body parts, including the urinary tract and genital tissues. Hyaluronic acid-based moisturizers are effective, safe, and well tolerated; therefore, they may represent a valid option for the early management of GSM-associated symptoms in every woman with a history of cancer who is unable or unwilling to undergo hormone-based therapies. Hence, the aim of this review was to provide an overview of GSM etiology and treatment in women with natural or iatrogenic menopause, with a focus on the use of hyaluronic acid as a prophylactic treatment in the context of an integrated management protocol for cancer patients.
... HA chains of up to 4 MDa were generated by HAS2 while chains of less than 300 kDa were synthesized by HAS3 [40]. The use of HA in skin care formulas to increase tissue hydration and reduce wrinkles has been extensively studied [41][42][43] and is also reported to enhance delivery for drugs and cosmetics [44][45][46]. Additionally, we found a significant increase in elastin fibers after topical application of the test products on human skin explants. ...
Article
Full-text available
Skin aging is a biological process leading to visible skin alterations. The mechanism of action, clinical efficacy and tolerance of a novel anti-wrinkle technology were evaluated in two skin care products formulated for different skin types. Two single-arm monocentric, open-label observational clinical studies, which were 56 days long, evaluated a cream-gel (n = 30) and a cream (n = 33) on the face and neck. Morphometric analyses of five types of wrinkles were performed at 0, 7, 28 and 56 days. Structural changes in extracellular matrix (ECM) including collagen, elastin and hyaluronic acid (HA) were visualized and quantified by histochemical imaging after daily treatment of skin explants for 6 days. Protein and gene expression related to barrier and hydration were analyzed using ELISA and qRT-PCR, respectively, in a reconstituted human skin model treated daily for 48 h. A decrease in wrinkle dimensions was found in the majority of parameters after 28 days of treatment. Collagen, elastin, HA, procollagen type I, hyaluronan synthases, HAS2 and HAS3 were all stimulated. Based on significant and consistent changes in our investigations, we conclude that the underlying mechanism of action of the novel anti-wrinkle technology could be the remodeling of dermal ECM, and both the test formulations were efficacious and well tolerated.
... When hydrated, HA has the capability of increasing its initial solid volume thousand-fold [47]. For this reason, it has become a primary component in several skincare and cosmetology products as a hydrating agent [48,49]. HA is a primary component of the extracellular matrices (ECM) surrounding connective tissues and exhibits inherent biocompatibility, biodegradability, and mucoadhesive capabilities [45,[50][51][52]. ...
Article
Full-text available
Extensive research is currently being conducted into novel ocular drug delivery systems (ODDS) that are capable of surpassing the limitations associated with conventional intraocular anterior and posterior segment treatments. Nanoformulations, including those synthesised from the natural, hydrophilic glycosaminoglycan, hyaluronic acid (HA), have gained significant traction due to their enhanced intraocular permeation, longer retention times, high physiological stability, and inherent biocompatibility, and biodegradability. However, conventional nanoformulation preparation methods often require large volumes of organic solvent, chemical cross-linkers, and surfactants, which can pose significant toxicity risks. We present a comprehensive, critical review of the use of HA in the field of ophthalmology and ocular drug delivery, with a discussion of the physicochemical and biological properties of HA that render it a suita-ble excipient for drug delivery to both the anterior and posterior segments of the eye. The pivotal focus of this review is a discussion of the formation of HA-based nanoparticles via poly-electrolyte complexation, a mild method of preparation driven primarily by electrostatic interaction between opposing polyelectrolytes. To the best of our knowledge, despite the growing number of publications centred around the development of HA-based polyelectrolyte complexes (HA-PECs) for ocular drug delivery, no review articles have been published in this area. This review aims to bridge the identified gap in the literature by (1) reviewing recent advances in the area of HA-PECs for anterior and posterior ODD, (2) describing the mechanism and thermodynamics of polyelectrolyte complexation, and (3) critically evaluating the intrinsic and extrinsic formulation parameters that must be considered when designing HA-PECs for ocular application.
... This compound exhibits high biocompatibility and biodegradability due to its ubiquitous distribution in the human body and plays an important role in cell division, differentiation and migration [66]. In addition, it is associated with angiogenesis [67], would healing [68], skin rejuvenation [69] and injury tissue regeneration [70,71], and it can be employed in drug delivery [72]. However, beneficial biological functions depend directly on its molecular weight, where high molecular weight HAs (>5 MDa) may induce anti-angiogenic and immunosuppressive events and low molecular weight HAs (6-20 kDa) can trigger pro-inflammatory processes and angiogenesis and often induce the gene expression of heat-shock proteins. ...
Article
One of the limitations in organ, tissue or cellular transplantations is graft rejection. To minimize or prevent this, recipients must make use of immunosuppressive drugs (IS) throughout their entire lives. However, its continuous use generally causes several side effects. Although some IS dose reductions and withdrawal strategies have been employed, many patients do not adapt to these protocols and must return to conventional IS use. Therefore, many studies have been carried out to offer treatments that may avoid IS administration in the long term. A promising strategy is cellular microencapsulation. The possibility of microencapsulating cells originates from the opportunity to use biomaterials that mimic the extracellular matrix. This matrix acts as a support for cell adhesion and the syntheses of new extracellular matrix self-components followed by cell growth and survival. Furthermore, by involving the cells in a polymeric matrix, the matrix acts as an immunoprotective barrier, protecting cells against the recipient's immune system while still allowing essential cell survival molecules to diffuse bilaterally through the polymer matrix pores. In addition, this matrix can be associated with IS, thus diminishing systemic side effects. In this context, this review will address the natural biomaterials currently in use and their importance in cell therapy.
Article
Hydrogels are widely used in biomedical field such as wound healing, tissue adhesive and tissue regeneration. Hydrogels with customized functions to meet the requirements of personalized medicine have increasingly become the frontier of clinical translation in the future. However, selecting appropriate functional materials and design strategies to optimize the biological performance of hydrogels are still challenging. It requires the integration of the network structure and physical properties of hydrogels with their functions and biological performances. The situation will be more complicate when hydrogels serve as a platform on which cooperate and communicate with biological systems. In this review, the principles in affording functions of hydrogels systems are outlined, with focus on the relation between the basic properties of hydrogels and biological functions. Their benefit and limitation from design strategies are summarized, and the prospects of advanced applications such as cellular scaffolds and immune therapy are discussed. These principles and understanding will facilitate to improve the therapeutic performance of hydrogels and further advance the robust design and implementation of such functional biomaterials.
Article
The utilization of cosmetics is not a recent practice. In ancient times, kohl was used by women to darken their eyelids, also, milk is used during bathing to get soften and whiten skin. Cosmetics have a huge market all over the world, and a business of billion dollars per annum. An extensive variety of ingredients involves polymers, minerals, chemicals, and also other materials like preservatives, color, pH stabilizers, emulsifiers, and thickeners to convey anticipated characteristics to the cosmetics products. Over the past years, biopolymeric materials have gained a lot of attraction in the global cosmetics industry because of their price, durability, and adaptability. Consumer awareness concerning the harmful influence of synthetic polymers on the atmosphere guides the path for biopolymer development from natural sources. Cosmetic polymers are utilized for the nanoparticle’s preparation for the fragrance’s delivery. Also, nanoparticles have been loaded with dermal permeation enhancers to enhance their bioactivities on the skin. Natural polymers in cosmetic formulations are of specific significance due to their eco-friendly, safe, and biocompatible characteristics. These formulations are appropriate for a number of applications such as hair, skincare, and make-up as they are highly attractive and marketable to consumers. In this review, the applications of biopolymers such as starch, chitosan, cellulose, collagen, keratin, Polyhydroxyalkanoates (PHA), etc., in cosmetic and cosmetic packaging are discussed.
Chapter
Aging is a unique phenomenon for living organisms. Though aging is a natural process that occurs with time, it is complex and fascinating. Birth and death are facets of life and aging decides how these two events of life are distanced in terms of time, also called lifespan. Since times immemorial, humans are inclined to delay aging either for physical appearance or for extensive survival or because of some of the unique lifestyle practices which have lifespan-extending benefits. Extensive research in the area of exploring antiaging drugs has led to greater insights into the mechanism of action of aging as well. In this chapter, we summarize the journey so far and the milestones achieved toward research on antiaging drugs, their targets, and cross-talks at the molecular level. This chapter aims to give an overview of the status of drugs, biochemical entities being explored, and the presence of the antiaging components in the foods.
Article
Full-text available
Hyaluronic acid (HA) plays multifaceted role in regulating various biological processes and maintaining homeostasis into the body. Plenteous researches have evidenced biomedical implications of HA in the skin repairmen, diagnosis of cancer, wound healing, tissue regeneration, anti-inflammatory, and immunomodulation. The present review aims to summarize and critically appraise recent developments and efficacy of HA for treatment of inflammatory skin and joint diseases. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, autologous grafts, thin sheets, soaked gauzes, gauze pads, tinctures, injections, etc.) have shown remarkable efficacy in treating a wide range of inflammatory skin diseases. The safety, tolerability, and efficacy of HA (as intra-articular injection) have also been well-documented for treatment of various types of joint disease including knee osteoarthritic, joint osteoarthritis, canine osteoarthritis, and meniscal swelling. Intra-articular injection of HA produces significant reduction in the joint pain, synovial inflammation, and articular swelling. A remarkable improvement in chondrocyte density, territorial matrix appearance, reconstitution of superficial amorphous layer of the cartilage, collagen remodelling, and regeneration of meniscus have also been evidenced in the patients treated with HA. Conclusively, the application/administration of HA is a promising pharmacotherapy for treatment of inflammatory skin and joint diseases.
Article
Full-text available
Atopic dermatitis (AD) is a chronically relapsing eczematous skin disease characterised by frequent episodes of rashes, severe flares, and inflammation. Till date, there is no absolute therapy for the treatment of AD; however, topical corticosteroids (TCs) are the majorly prescribed class of drugs for the management of AD in both adults and children. Though, topical route is most preferable; however, a limited penetration of therapeutics across the startum cornum (SC) is one of the major challenges for scientists. Therefore, the present study was attempted to fabricate a moderate-potency TC, betamethasone valerate (BMV), in the form of chitosan nanoparticles (CS-NPs) for optimum dermal targeting and improved penetration across the SC. To further improve the targeting efficiency of BMV and to potentiate its therapeutic efficacy, the fabricated BMV-CS-NPs were coated with hyaluronic acid (HA). The prepared NPs were characterised for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, loading capacity, crystallinity, thermal behaviour, morphology, in vitro release kinetics, drug permeation across the SC, and percentage of drug retained into various skin layers. Results showed that optimised HA-BMV-CS-NPs exhibited optimum physicochemical characteristics including finest particle size (<300 ± 28 nm), higher zeta potential (+58 ± 8 mV), and high entrapment efficiency (86 ± 5.6%) and loading capacity (34 ± 7.2%). The in vitro release study revealed that HA-BMV-CS-NPs displayed Fickian-diffusion type mechanism of release in simulated skin surface (pH 5.5). Drug permeation efficiency of BMV was comparatively higher in case of BMV-CS-NPs; however, the amount of drug retained into the epidermis and the dermis was comparatively higher in case of HA-BMV-CS-NPs, compared to BMV-CS-NPs. Conclusively, we anticipate that HA-BMV-CS-NPs could be a promising nanodelivery system for efficient dermal targeting of BMV and improved anti-AD efficacy.
Article
Full-text available
This review aims to overview and critically analyses recent developments in achieving tumor- specific delivery of anticancer agents, maximizing anticancer efficacy, and mitigating tumor progression and off-target effects. Stemming from critical needs to develop target-specific delivery vehicles in cancer therapy, various hyaluronic acid (HA)-conjugated nanomedicines have been fabricated owing to their biocompatibility, safety, tumor-specific targetability of drugs and genes, and proficient interaction with cluster-determinant-44 (CD44) receptors over-expressed on the surface of tumor cells. HA-based conjugation or surface modulation of anticancer drugs encapsulated nanocarriers have shown promising efficacy against the various types of carcinomas of liver, breast, colorectal, pancreatic, lung, skin, ovarian, cervical, head and neck, and gastric. The success of this emerging platform is assessed in achieving the rapid internalization of anticancer payloads into the tumor cells, impeding cancer cells division and proliferation, induction of cancer-specific apoptosis, and prevention of metastasis (tumor progression). The present review extends detailed insight into the engineering of HA-based nanomedicines, characterization, utilization for the diagnosis or treatment of CD44 over-expressing cancer subtypes, and emphasizing the transition of nanomedicines to clinical cancer therapy.
Article
Full-text available
Wound healing is a multipart and dynamic process of replacing devitalized and damaged cellular structures and tissue layers. Numerous conventional wound dressings are employed for the management of wounds but there is a lack of absolute and versatile choice. An ideal wound healing modality should provide a moist environment, offer protection from secondary infections, eliminate wound exudate, and stimulate tissue regeneration. Hyaluronic acid (HA) has been known to promote angiogenesis, granulation tissue formation, remodeling of extracellular matrix (ECM), and wound healing. Accumulation and turnover of ECM is a hallmark of tissue injury, repair, and remodeling in wound healing. HA is a major component of ECM and plays an important role in regulating tissue injury, accelerating tissue repair, and controlling disease outcomes. A wide range of in vitro, in vivo, and clinical studies have demonstrated the wound healing efficacy of HA-based biomaterials not only in the treatment of wound in the tympanic membrane, skin, and articular cartilage but also in tracheal and corneal wound healing. Recent progress and improved therapeutic efficacy achieved through partial modification and formation of HA-based biomaterials, including HA-scaffolds, sponge-like hydrogels, anti-adhesive sheets, cultured dermal substitutes, thin membranes, and dermal matrix grafts, have been discussed. The current review summarizes the evidence for the therapeutic effectiveness of HA-based biomaterials in the treatment of traumatic, surgical, and chronic wounds and tissue regeneration.
Article
Background: The different rheological properties of hyaluronic acid (HA) filler reflect their specific manufacturing processes and resultant physicochemical characteristics. However, there are few researches about the relationship between product differences and clinical outcome when HA fillers are used for nasolabial folds (NLFs). Aims: This study sought to compare the rheological properties, efficacy and safety of a monophasic HA filler, and a well-studied biphasic HA filler, in the treatment of NLFs. Patients/methods: A total of 72 Korean subjects with moderate to severe NLFs were randomized to receive injections with monophasic HA or biphasic HA on the left or right side of the face. Efficacy was evaluated by the change in the Wrinkle Severity Rating Scale (WSRS) at 2, 10, 18, 26, and 52 weeks. Safety was assessed on the basis of all abnormal reactions during the clinical test period. To compare the rheological characteristics of two cross-linked HA fillers, viscoelastic analysis was performed. Results: At week 26, the mean WSRS was 2.26±0.56 for the monophasic HA side and 2.24±0.54 for the biphasic HA side. Both treatments were well tolerated. The adverse reactions were mild and transient. Monophasic HA filler had lower elasticity and higher viscosity than biphasic HA filler. Conclusion: Despite a number of different rheological properties, monophasic HA is noninferior to biphasic HA in the treatment of moderate to severe NLFs for 52 weeks. Therefore, monophasic HA provides an alternative option for NLFs correction.
Article
Background: Anti-wrinkle creams containing hyaluronic- acid are often advertised as an efficacious option for the treatment of wrinkles and have even been presented as an option equal to some medical procedures in this regard. Evidence from conclusive and systematic research supporting those claims, however, is widely lacking. Objectives: During this trial we examined whether the daily use of anti-wrinkle creams containing hyaluronic- acid has an influence on the depth of wrinkles as well as skin tightness and elasticity. Methods: We split up 20 patients into four groups, each of which were assigned an anti-wrinkle cream containing hyaluronic acid for daily use. Four different creams within different price ranges were chosen (Balea, Nivea, Lancôme, Chanel). Before and after the 3 month trial, wrinkle depth was assessed using the PRIMOSpico (GFMesstechnik, Teltow, Germany) and skin-tightness and elasticity were evaluated using the Cutometer MP580 (Courage+Khazaka, Cologne, Germany). Additionally, after the trial, questionnaire data on patient satisfaction with their individual product was collected. Results: The depth of perioral and orbital wrinkles decreased significantly in all groups, with depth reduction ranging between 10% and 20%. Skin-tightness increased significantly in all groups, rising by 13 to 30%. Minimal significant changes in skin-elasticity could only be shown in individual groups. Conclusions: The regular use of hyaluronic-acid containing anti-wrinkle creams for over 3 months showed clear and positive effects on wrinkle-depth and skintightness. Due to the design of the study, however, no clear indication on the efficacy of hyaluronic acid could be shown.
Article
Objective: The aim of our study is to demonstrate that intravesical administration of the association chondroitin sulfate (CS) and hyaluronic acid (HA), according to our treatment schedule, is a benefit for women with recurrent urinary tract infections (RUTI), not only from a clinical point of view, but also reducing recurrences. Methods: This is a study of 28 women diagnosed with RUTI, with a positive culture, and compatible symptoms;frethey underwent treatment according to the protocol of intravesical instillations of the combination CS 2%-1 gr + HA 1.6%-800 mg. To evaluate the effectiveness of the treatment, symptoms improvement, reduction of the number of episodes of urinary tract infection and quality of life were considered. Results: In our series, we can observe an improvement of the quality of life assessed by PG-I, 66% after 12 months. It was seen that 55.6% of the patient's urine cultures became negative, while 44.4% had episodes of urinary infection, but with lower baseline symptoms intensity. Discussion: Patients included in the protocol of instillation improved significantly their quality of life; in addition, to a considerable extent new urinary infections were not presented, being milder when they presented.
Article
Objective: In the article, comparison of the hyaluronic acid (HA) and autologous fat is conducted to evaluate the effectiveness and safety in correction of the nasolabial folds (NLFs). Methods: From November 2012 to December 2015, a single-blinded, randomized study was conducted. Sixty-two patients were included in the study, and 57 of them completed the whole procedure. The patients were randomly allocated to receive the treatments of HA or fat in both NLFs. The Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale (GAIS) were used for assessment. Efficacy was assessed using two parameters: evaluation of final improvement by blinded evaluator and patient-self using photographs. The effectiveness endpoint was improvement of scores at 1, 3, 6, 9, and 12 months from baseline. The adverse events (AEs) were recorded. Results: In the blinded evaluator scores for NLF in accordance with WSRS, there were no significant differences between the two methods within 9 months. A statistically significant difference between the lipoinjection and HA groups was found at 12-month follow-up period. Subjects' self-assessment was similar to the results seen for the evaluator scores. The difference of AEs between the HA and fat group was obvious in the early stage of recovery. In the later stage, the AEs of the HA and fat group were similar. Conclusions: Both HA gel and autologous fat provide augmentation of NLFs. The magnitude and duration of NLF correction appear to be similarly effective and safe within a period.