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Received: 28 August 2021    Revised: 27 November 2021    Accepted: 14 December 2021

DOI: 10.1111/jocd.14710

ORIGINAL ARTICLE

The selection of hyaluronic acid when treating with the

nasolabial fold: A meta-­analysis

Tong Peng MD1,2 | Wei-­Jin Hong MD, PhD2 | Jun-­Ren Fang MD1,2 |

Sheng-­Kang Luo MD, PhD2,1

1
The Second School of Clinical Medicine,
Southern Medical University, 253 Industry
Avenue, Guangzhou City, Guangdong
Province, People's Republic of China
2
Department of Plastic and
Reconstructive Surgery, Guangdong
Second Provincial General Hospital,
Guangzhou City, China
Correspondence
Sheng-­Kang Luo, Department of Plastic
and Reconstructive Surgery, Guangdong
Second Provincial General Hospital, 466
Middle Xin Gang Road, Guangzhou City,
Guangdong Province 510317, China.
Email: luoshk@gd2h.org.cn
Abstract
Background: Hyaluronic acid (HA) gel is a widely used dermal filler for the correction
of facial volume loss. The relationship between the characteristics of HA and clinical
efficacy remains unclear. The aim of this systematic review and meta-­analysis was to
compare the efficacy and safety of monophasic and biphasic HA in the treatment of
nasolabial folds (NLFs).
Methods: Studies were identified by searching the electronic databases PubMed,
Embase, and Web of Science from inception to May 2021. Randomized controlled
trials (RCTs) were selected according to the inclusion criteria. Outcomes included the
Wrinkle Severity Rating Scale (WSRS) score, Global Aesthetic Improvement Scale
score, and incidence of adverse events.
Results: A total of 1190 patients from 14 RCTs were included in the meta-­analysis.
The mean WSRS score improvement in the biphasic HA group was much lower than
that in the monophasic HA group (MD = 0.18, 95% CI: 0.16–­0.20, p < 0.00001). The
subject satisfaction percentage was significantly higher for monophasic than biphasic
HA (RR = 1.95, 95% CI: 1.09–­3.48, p = 0.02). There was no significant difference in
the adverse event rate between the monophasic and biphasic HA groups (RR = 0.96,
95% CI: 0.75–­1.24, p = 0.77).
Conclusions: Regardless of whether improvement in NLFs or patient satisfaction is
considered, monophasic HA is better than biphasic HA. Regarding the adverse event
rate, there is no difference between monophasic and biphasic HA.

KEYWORDS
cosmetic, hyaluronic acid, nasolabial fold

1  |  I NTRO D U C TI O N
Since Karl Meyer found a previously unknown substance from
the vitreous of crows’ eyes in 1934, hyaluronic acid (HA) has en-
tered into public eyes as a dermal filler.1 However, it was not until
December of 2003 that Restylane was approved by the FDA for
treating moderate-­to-­severe facial wrinkles and folds. To date, HA
has become the most popular dermal filler. 2 Owing to different
manufacturing technologies, there are differences in the attributes
of various HA products, such as the type of cross-­linker used, the
degree of cross-­linking, and the total HA concentration, these fea-
tures contribute to the rheology and cohesivity of HA and thus in-
fluence clinical efficacy.3 Monophasic HA consists of large and small
HA particles, while biphasic HA consists of selectively uniformly

Tong Peng and Wei-­Jin Hong contributed equally to the article and should be considered co-­f irst authors.

This article has not been presented at any meeting or conference.

J Cosmet Dermatol. 2022;21:571–579. wileyonlinelibrary.com/journal/jocd© 2021 Wiley Periodicals LLC     571 |

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572      PENG et al.
sized particles of cross-­linked HA mixed with non–­cross-­linked HA.
Both biphasic HA and monophasic HA are widely used in products
on the market, and plastic surgeons select the proper form of HA
for different injection sites.4 Many studies have been conducted to
investigate the differences between monophasic and biphasic HA
in cosmetic efficacy in the treatment of nasolabial folds (NLFs), but
credible conclusions have not been drawn yet. Therefore, we per-
formed this systematic review and meta-­analysis to explore the ef-
ficacy and safety of monophasic HA versus biphasic HA in treating
NLFs to provide a robust evidence for clinicians.
2  |  M E TH O D S
2.1  |  Search Strategy
This systematic review and meta-­analysis was conducted in accord-
ance with the “Preferred Reporting Item for Systematic reviews
and Meta-­Analyses (PRISMA)” guidelines and already registered in
PROSPERO with the register ID CRD42021264431. Studies were
identified through a digital search of PubMed, Embase, and Web of
Science using the terms “hyaluronic acid” AND “nasolabial fold” from
inception to May 2021. In addition, further articles were obtained by
reviewing relevant citations of the identified articles. The detailed
search process is shown in Figure 1.
2.2  |  Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) patients with bilateral
moderate-­to-­severe NLFs; (2) treatment with HA; (3) comparison of
monophasic HA with biphasic HA in a split-­face study; (4) evalua-
tion of efficacy, cosmetic outcome, or adverse events as outcomes;
(5) randomized controlled trials (RCTs); (6) published in English. Any
studies that did not provide original data, such as case reports, re-
views, letters, and commentaries, were excluded, as well as studies
in which data were duplicated or overlapped.
2.3  |  Data extraction
In our study, two reviewers independently extracted data using a
standard data extraction form. Any disagreement was resolved by
discussion until a consensus was reached or by consulting a third
reviewer. The following data were extracted: author, publication
date, patient characteristics, sample size, HA brand, and indexes of
F I G U R E 1  Searching flow chart
PENG et al.
efficacy and safety. When necessary, attempts were made to ask
authors for original data.
2.4  |  Quality assessment
Two reviewers independently assessed the quality of the RCTs using
the Cochrane Collaboration tool, which includes criteria such as ran-
domization, allocation concealment, blinding, withdrawals, and drop-
outs. The assessment of the included studies is shown in Figure 2 and 3.
2.5  |  Statistical analysis
Statistical analysis was performed using RevMan 5.3 provided by the
Cochrane Collaboration. For continuous data, the mean difference
(MD) and 95% confidence interval (CI) were used for assessment.
For binary data, the relative risk (RR) and 95% CI were calculated.
Heterogeneity among studies was assessed using the chi-­square and
2 2
I tests. When I  < 50%, a fixed-­effects model was used; otherwise,
a random-­effects model was used. In the presence of heterogeneity,
subgroup analysis was performed to explore the source. A two-­t ailed
p value of less than 0.05 was considered statistically significant.
2.6  |  Role of the funding source
The funding source played no role in the study design, data collec-
tion, data analysis, data interpretation, or writing of the report. The
corresponding author had full access to all the data in the study and
had final responsibility for the decision to submit the manuscript for
publication.
3  |   R E S U LT S
3.1  |  Search Results
A total of 1034 studies comparing monophasic HA and biphasic HA
were identified from the databases. Among them, 636 were ex-
cluded based on the title and abstract, 269 studies were excluded
F I G U R E 2  Risk of bias graph: review
authors’ judgements about each risk of
bias item presented as percentages across
all included studies
|
      573
due to duplication, and 14 studies met the final inclusion criteria
following a careful reading of the full manuscript. Therefore, the
systematic review and meta-­analysis was performed on the basis of
14 studies, all of which were RCTs. A total of 1190 patients were in-
cluded. The characteristics of the patient cohort and the 14 included
studies are shown in Table 1.
3.2  |  Description of included studies
Kaufman-­Janette et al.5 conducted a 15-­month, controlled, rand-
omized, double-­blind, within-­subject (split-­face) clinical trial compar-
ing Teosyal RHA4 and Restylane Perlane.
Dai et al.6 conducted a split-­face, randomized, evaluator-­and
subject-­blinded, multicenter trial comparing Princess Volume and
Restylane.
Rzany et al.7 conducted an 18-­month, evaluator-­and subject-­
blinded, split-­face study comparing Emervel Classic and Restylane.
Kwon et al.8 conducted a randomized, multicenter, single-­blind,
split-­face study comparing Elravie Deep and Restylane.
Joo et al.9 conducted a randomized, multicenter, double-­blind,
intraindividual trial comparing Neuramis Deep and Restylane.
Ascher et al.10 conducted an evaluator-­and subject-­
blinded,
split-­face study comparing Emervel and Restylane Perlane.
Suh et al.11 conducted a multicenter, randomized, double-­blind
clinical study comparing Dermalax Implant Plus and Restylane.
Zhou et al.12 conducted a double-­blind, randomized study com-
paring Matrifill and Restylane.
Rhee et al.13 conducted a randomized, evaluator-­blinded, split-­
face study comparing Elravie and Restylane.
Nast et al.14 conducted a prospective, randomized, double-­
blind, actively controlled clinical pilot study comparing Teosyal and
Restylane Perlane.
Qiao et al.15 conducted a randomized, patient-­and evaluator-­
blinded study comparing Dermalax and Restylane.
Prager et al.16 conducted a prospective, split-­face, randomized,
comparative study using the Merz severity scale.
Goodman et al.17 conducted a multicenter, prospective, ran-
domized, controlled, single-­blind, within-­subject study comparing
Juvéderm ULTRA PLUS and Restylane Perlane using the NLF sever-
ity scale.
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574      PENG et al.

In our meta-­
analysis, the forms of monophasic HA included
Teosyal RHA4, Princess Volume, Emervel Classic, Elravie and Elravie
Deep, Neuramis Deep, Dermalax and Dermalax Implant Plus,
Matrifill, and Juvéderm ULTRA PLUS, while the forms of biphasic
HA included only Restylane and Restylane Perlane.

3.3  |  Meta-­Analysis

Considering the limitations of the Wrinkle Severity Rating Scale

(WSRS) and Global Aesthetic Improvement Scale (GAIS), we strictly
selected the indexes of blind estimators and subjects at week 24
to represent objective improvement and subjective satisfaction. The
indicators included the blind estimator mean WSRS score improve-
ment, blind estimator responder rate, blind estimator mean GAIS
score, subject GAIS 1-­point rate, subject satisfaction percentage,
and adverse event rate.

3.3.1  |  Blind Estimator Mean WSRS Score

Improvement at Week 24

Eight studies with a total of 408 subjects were included in the mean

WSRS score improvement meta-­
analysis. All WSRS scores were
evaluated by blind estimators at week 24 following the touch-­up
injection. There was limited heterogeneity among these studies
(v2  = 10.87, df =6, p  = 0.09, I2  = 45%), and a fixed-­effects model
was adopted. The mean WSRS score improvement in the biphasic
HA group was much lower than that in the monophasic HA group
(MD =0.18, 95% CI: 0.16–­0.20, p < 0.00001). When we divided these
studies into two subgroups, Restylane and Restylane Perlane, we
found that the heterogeneity mainly originated from the Restylane
Perlane group (v2 = 8.90, df =2, p = 0.01, I2 = 78%) (Figure 4).

3.3.2  |  Blind estimator responder rate at week 24

The responder rate represents the proportion of subjects whose

WSRS score reduction has reached 1 point or above. Eight stud-
ies with a total of 635 subjects were included in the responder rate
meta-­analysis. All WSRS scores were evaluated by blind estimators
at week 24 following the touch-­up injection. There was limited het-
erogeneity among these studies (v2 = 6.25, df =6, p = 0.40, I2 = 4%),
and a fixed-­effects model was adopted. The responder rate in the
monophasic HA group was higher than that in the biphasic HA group
(RR =1.65, 95% CI: 1.18–­2.33, p = 0.004) (Figure 5).
F I G U R E 3  Risk of bias summary: review authors’ judgements
about each risk of bias item for each included study

3.3.3  |  Blind estimator mean GAIS score at week 24

Pak et al.18 conducted a randomized, multicenter, double-­ Three studies with a total of 277 subjects were included in the mean
masked, matched-­pairs, active-­controlled trial comparing Neuramis GAIS score meta-­analysis. All mean GAIS scores were evaluated
and Restylane. by blind estimators at week 24 following the touch-­up injection.
PENG et al. |
      575

TA B L E 1  Characteristics of included studies

Publication Sample Female Blind

Number Author year size proportion Mean age Outcome indicator method

1 Joely 2019 88 81 (92.0%) 57.4 ± 9.3 WSRS, GAIS, AE Double blind

2 Xia 2019 120 116 (96.67%) 43 WSRS, GAIS, AE Double blind
3 Berthold 2010 52 51 (98.1%) 50.6 ± 10.1 WSRS, AE Double blind
4 Hyun 2017 72 70 (97.2%) 48.3 WSRS, GAIS, AE Double blind
5 Hong 2015 60 53 (88.33%) 47.62 ± 7.64 WSRS, GAIS, AE Double blind
6 Benjamin 2016 68 61 (89.7%) 52.7 ± 8.7 WSRS, AE Double blind
7 Joon 2017 60 58 (96.67%) 46.02 ± 7.21 WSRS, GAIS, AE Double blind
8 Shuang 2017 49 48 (98.0%) 47.8 WSRS, GAIS, AE Double blind
9 Do 2014 68 62 (91.2%) 49.03 WSRS, GAIS, AE Double blind
10 Alexander 2011 60 52 (86.7%) 54.8 ± 8.8 WSRS, GAIS, AE Double blind
11 Qiao 2019 324 321 (99.1%) 46 WSRS, AE Double blind
12 Welf 2012 20 19 (95%) 45.8 MSS, AE Double blind
13 Greg 2011 80 76 (95%) 47.5 NLFSS, AE Single blind
14 Changsik 2015 69 68 (98.55%) 48.96 ± 8.90 WSRS, GAIS, AE Double blind

F I G U R E 4  Forest plot for WSRS score improvement of blind estimator in monophasic HA versus biphasic HA

Heterogeneity existed among these studies (v2  = 8.34, df =2,
p  = 0.02, I2  = 76%), and a random-­effects model was adopted.
There was no significant difference between the monophasic HA
group and the biphasic HA group (MD =0.01, 95% CI: −0.21 to 0.32,
p = 0.82) (Figure 6).
All GAIS scores were evaluated by subjects at week 24 following the
touch-­up injection. There was no heterogeneity among these stud-
ies (v2 = 0.06, df =2, p = 0.02, I2 = 0%), and a fixed-­effects model
was adopted. There was no significant difference in the subject GAIS
1-­point rate between the monophasic HA group and the biphasic HA
group (RR =1.18, 95% CI: 0.93–­3.80, p = 0.08) (Figure 7).

3.3.4  |  Subject GAIS 1-­Point Rate at Week 24

The GAIS 1-­point rate refers to the proportion of subjects in whom
the GAIS score reached 1 point or above. Three studies with a total
of 171 subjects were included in the GAIS 1-­point rate meta-­analysis.
3.3.5  |  Subject Satisfaction Percentage at Week 24
Three studies with a total of 168 subjects were included in the
satisfaction percentage meta-­
a nalysis. All satisfaction indexes
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576      PENG et al.

F I G U R E 5  Forest plot for WSRS response rate of blind estimator in monophasic HA versus biphasic HA

F I G U R E 6  Forest plot for GAIS score of blind estimator in monophasic HA versus biphasic HA

F I G U R E 7  Forest plot for GAIS response rate of subject in monophasic HA versus biphasic HA

F I G U R E 8  Forest plot for satisfaction rate of subject in monophasic HA versus biphasic HA

were evaluated by subjects. There was no heterogeneity among was significantly higher in the monophasic HA group than in
these studies (v 2  = 0.31, df  =2, p  = 0.86, I2  = 0%), and a fixed-­ the biphasic HA group (RR =1.95, 95% CI: 1.09–­3 .48, p  = 0.02)
effects model was adopted. The subject satisfaction percentage (Figure 8).
PENG et al. |
      577

F I G U R E 9  Forest plot for total adverse event rate in monophasic HA versus biphasic HA

injecting biphasic HA. The same result was found for the responder
TA B L E 2  Individual adverse event rate of monophasic HA vs
rate. However, we found that the heterogeneity mainly originated
biphasic HA and p-­value
from the Restylane Perlane subgroup. The only difference between
Monophasic Biphasic Restylane and Restylane Perlane is the particle size; Restylane par-
Adverse events HA HA p-­value
ticles are approximately 250 µm in size, while Perlane particles are
Swelling 0.28 0.242 0.55 approximately 550 µm in size. 20 The larger the HA particle is the
Nodule 0.1 0.07 0.28 better the effect of augmentation. Therefore, we consider that for
Angiotelectasis 0.013 0.007 0.65 biphasic HA, the particle size can also influence the outcome of
Edema 0.207 0.212 0.88 filler injection. 21 However, the forms of biphasic HA included were
Bruise 0.338 0.323 0.71 all Restylane family products, which diminishes the reliability of ap-
Prutitus 0.234 0.209 0.52 plying this conclusion to other forms of biphasic HA. Regarding the

Tenderness 0.28 0.242 0.48

3.3.6  |  Adverse Events
All studies reported any adverse events encountered during the trial.
Nine studies with a total of 745  subjects were included in the ad-
verse event rate meta-­analysis. There was no heterogeneity among
these studies (v2 = 5.72, df =8, p = 0.68, I2 = 0%), and a fixed-­effects
model was adopted. There was no significant difference in the inci-
dence of adverse events between the monophasic HA group and the
biphasic HA group (RR =0.96, 95% CI: 0.75–­1.24, p = 0.77) (Figure 9).
We summarized individual adverse event and found no significance
either. All adverse events rate between monophasic HA and biphasic
HA and p value was showed in Table 2.
4  |   D I S C U S S I O N
The WSRS was first proposed by Day et al.19 in 2004 for evaluat-
ing the severity of NLFs. The GAIS is also widely used in the cos-
metic field. Considering the inherent subjectivity of these scales,
we selected multiple outcome indicators for analysis. For blinded
estimators, the reduction of the WSRS score achieved by inject-
ing monophasic HA was significantly superior to that achieved by
GAIS score according to the blind estimators, there was little differ-
ence between monophasic and biphasic HA. According to the sub-
jects, monophasic HA was considered to improve NLFs better than
biphasic HA, and the subjects were more satisfied with monophasic
HA. Therefore, when addressing NLFs in a clinical setting, mono-
phasic HA is a better choice. There was no significant difference in
the adverse event rate between monophasic and biphasic HA, which
indicates that they are the same in terms of safety issues.
With the short half-­life of natural HA, a cross-­linker is used
to bind the HA polymer chains to each other and thereby extend
the persistence of HA. 22 Biphasic HA is a mixture of “liquid” non–­
cross-­linked HA and “gel” cross-­linked HA 23 particles with a uniform
cross-­linked HA particle size. In contrast, monophasic HA contains
particles of an array of sizes owing to its particular manufacturing
procedure. Numerous studies have been conducted to explore the
physical, chemical, and biological differences between biphasic and
monophasic HA. An in vitro MRI study revealed that biphasic fillers
showed shortened T2 signals,4 indicating that biphasic fillers were
more viscous than monophasic fillers. Histological examination has
shown that when injected into the dermis, biphasic HA tends to con-
centrate in the lower portion of the dermis in clumps or beads, while
monophasic HA is dispersed throughout the dermis in large clumps
in channels, pushing against and stretching the collagen fibers.
There are many factors affecting the formation of NLFs. For
example, maxillofacial bone retrusion, 24 repeated facial muscle
 |
578      PENG et al.
constriction, 24 and tissue discrepancies on either side of the NLF25
all play an important role in NLF deepening. As a minimally inva-
sive technique, HA augmentation is very popular in the cosmetic
field. 26 Compared with normal wrinkles, such as crow's feet, NLFs
seem much more complex; therefore, multilayer filler augmentation
27
is needed for the treatment of NLFs.
Our analysis shows that regardless of the degree of NLF sever-
ity improvement or the subject satisfaction percentage, monopha-
sic HA was superior to biphasic HA. One possible reason could be
that the non-­cross-­linked fraction of biphasic HA responds quickly
after injection, retaining the cross-­linked fraction surrounded by the
hyaluronidase. For monophasic HA, hyaluronidase can only affect
the outermost surface of the aliquot, thereby taking longer to de-
27
grade. After 6 months, there was a difference in the remainder of
monophasic and biphasic HA, resulting in a difference in efficacy.
Additionally, monophasic HA is suitable for use in tissue augmenta-
tion due to its swelling attributes.
This meta-­a nalysis compared monophasic and biphasic HA in
treating NLFs. With all the RCTs included being designed rigor-
ously and of high quality in recent 10 years, as assessed using the
Cochrane Collaboration tool, the results greatly support the su-
periority of monophasic HA over biphasic HA, which is in accor-
dance with the findings of previous meta-­a nalyses. 28 However,
are still conflicting results in terms of the adverse event rate be-
tween our study and previous studies. Huang et al. 28 reported
that the adverse event rate was significantly lower in patients
treated with monophasic HA than in those treated with biphasic
HA. However, in our meta-­a nalysis, we found that there was no
difference in the adverse event rate between these two products
of different categories, which is reasonable 29 because complica-
tions are often directly related to the injection technique applied
by the clinician. 30
According to the website, Restylane is the first HA product ap-
proved by FDA, making it a standard control group for clinical trial
when new HA was ready to put on the market. There is a few studies
using other forms of biphasic HA as comparison, however, which was
excluded for quality problem. To this, the forms of biphasic HA in
the included studies were mostly Restylane family products in our
study. This problem, to a certain extent, reduces the applicability of
our results to other forms of biphasic HA. But considering Restylane
and its family products are one of the most widely used biphasic HA,
it is practical and valuable to regard Restylane as a representative.
Meanwhile, more high-­quality studies are needed to verify this con-
clusion consequently.
5  |  CO N C LU S I O N S
Regardless of whether improvement in NLFs or patient satisfaction
is considered, monophasic HA is better than biphasic HA. Regarding
the adverse event rate, there is no difference between monophasic
and biphasic HA. Thus, monophasic HA is a better choice for treat-
ing NLFs.
AU T H O R C O N T R I B U T I O N S
Dr. Tong Peng is a plastic surgeon who designed the study, extracted
the data, performed the data analysis, and prepared the manuscript.
Dr. Wei-­Jin Hong is a plastic surgeon who reviewed the manuscript
and was involved in the study design. Dr. Jun-­Ren Fang is a plastic
surgeon who helped extracting the data. Prof. Sheng-­Kang Luo con-
ceived the research idea, supervised this project, critically reviewed
the manuscript, and was responsible for the study. All authors have
seen and approved the manuscript.
E T H I C A L S TAT E M E N T
The authors confirm that the ethical policies of the journal, as noted
on the journal's author guidelines page, have been adhered to. No
ethics approval was required as this is a review article with no origi-
nal research data.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on re-
quest from the corresponding author. The data are not publicly avail-
able due to privacy or ethical restrictions.
ORCID
Sheng-­Kang Luo  https://orcid.org/0000-0002-5123-1656
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How to cite this article: Peng T, Hong W-­J, Fang J-­R , Luo S-­K .
The selection of hyaluronic acid when treating with the
nasolabial fold: A meta-­analysis. J Cosmet Dermatol.
2022;21:571–­579. doi:10.1111/jocd.14710