|

Received: 6 October 2021    Accepted: 9 November 2021

DOI: 10.1111/jocd.14632

ORIGINAL ARTICLE

Monophasic versus biphasic hyaluronic acid filler for correcting

nasolabial folds: a systematic review and meta-­analysis

Abdullah A. Ghaddaf1,2 | Yara E. Aljefri1,2 | Fahad A. Alharbi1,2 | Rahaf K. Sharif1,2 |

Wejdan A. Alnahdi1,2 | Rasha Baaqeel MD, FRCSC3

1
College of Medicine, King Saud bin
Abdulaziz University for Health Sciences,
Jeddah, Saudi Arabia
2
King Abdullah International Medical
Research Center, Jeddah, Saudi Arabia
3
Department of Surgery/Plastic section,
King Abdulaziz Medical City, Jeddah,
Saudi Arabia
Correspondence
Abdullah A. Ghaddaf, College of Medicine,
King Saud bin Abdulaziz University for
Health Sciences, Jeddah, Saudi Arabia.
Email: abdullahg.official@gmail.com
Funding information
None.
Abstract
Background: Hyaluronic acid (HA) fillers are the most popular dermal fillers for wrin-
kle correction and facial rejuvenation. Recently, there has been an interest toward
classifying HA fillers based on the cross-­linking properties into monophasic (MHA)
and biphasic (BHA) fillers. We aimed to compare the efficacy and safety outcomes
between MHA and BHA fillers for the correction of nasolabial folds (NLFs).
Methods: We searched Medline, Embase, and CENTRAL for randomized controlled
trials (RCTs) that compared MHA filler to BHA filler for individuals with moderate-­to-­
severe bilateral NLFs. We sought to evaluate the following outcomes: Wrinkle severity
rating scale (WSRS), pain on visual analog scale (VAS), global aesthetic improvement
scale (GAIS), and adverse events. The standardized mean difference (SMD) was used
to represent continuous outcomes while risk ratio (RR) was used to represent dichoto-
mous outcomes.
Results: A total of 11 RCTs that enrolled 935 participants deemed eligible. MHA filler
revealed a significant improvement in the overall WSRS score and GAIS score com-
pared to BHA filler (SMD = −0.38, 95% CI −0.49 to −0.27 and SMD = 0.34, 95% CI
0.24–­0.45, respectively). No significant difference was noted between MHA and BHA
fillers in terms of pain score or adverse events (SMD = −0.39, 95% CI −0.81–­0.03 and
RR = 1.00, 95% CI 0.89–­1.12, respectively).
Conclusions: MHA filler showed discernable cosmetic results and comparable effec-
tive and tolerability to BHA filler.

KEYWORDS
biphasic hyaluronic acid, filler, hyaluronic acid, monophasic hyaluronic acid, nasolabial folds

1  |  I NTRO D U C TI O N human skin. HA-­based dermal fillers are characterized by ease of

Nasolabial folds (NLFs) start to lose the fat and collagen fibers filling
as an early skin sign of aging process.1–­4 Facial rejuvenation and na-
solabial folds correction are the most commonly consulted cosmetic
procedures.5 Since their introduction in 1990s, hyaluronic acid (HA)
fillers heralded a shift in aesthetics and became the most popular
dermal fillers for facial tissue augmentation.6 Hyaluronic acid is a
naturally occurring polysaccharide and normal component of the
administration, resistance to deformation after application, biocom-
patibility, high water-­binding capacity, and reversibility with hyaluro-
nidase. Thus, they provide more favorable cosmetic properties over
non-­HA fillers.7–­10
HA fillers are readily metabolized in vivo with a half-­
life of
less than 2 days.6 Therefore, the intermolecular bonds between
HA-­derived dermal fillers are stabilized by chemical cross-­linking
chemical agents, such as 1,4-­butanediol diglycidyl ether (BDDE),

J Cosmet Dermatol. 2022;21:627–635. wileyonlinelibrary.com/journal/jocd© 2021 Wiley Periodicals LLC     627 |

 |
628      GHADDAF et al.
to enhance their stability and durability.11,12 The cross-­linked HA
fillers are further subdivided into two categories: monophasic HA
fillers (MHA) and biphasic HA fillers (BHA). MHA fillers are based
on a homogenous and cohesive cross-­linked mixture of HA, mak-
ing them perfect to fill small spaces between collagen and elastin
fibrils. On the other hand, BHA fillers are based on a heterogenous
mixture of cross-­linked and non-­cross-­linked HA particles, making
them more elastic and easily customized to obtain the appropriate
particle size.13 Recently, many randomized controlled trials (RCTs)
have been introduced to the literature comparing MHA and BHA fill-
ers. Some RCTs showed better cosmetic outcomes in favor of MHA,
whereas others showed no discernable difference.14–­17 To the best
of our knowledge, no previous systematic review and meta-­analysis
compared the cosmetic and safety outcomes between MHA and
BHA fillers.
This systematic review aimed to compare the cosmetic and
safety outcomes for individuals undergoing NLF correction through
MHA or BHA fillers with respect to Wrinkle severity rating scale
(WSRS), pain on visual analog scale (VAS), global aesthetic improve-
ment scale (GAIS), and adverse events.
2  |  M E TH O D S
This systematic review and meta-­
analysis were performed ac-
cording to a pre-­
specified protocol registered with PROSPERO
(CRD42021260845) and reported in the light of the Preferred
Reporting Items for Systematic Reviews and Meta-­
Analysis
(PRISMA) checklist.18
2.1  |  Eligibility criteria
Participants: healthy individuals with visibly moderate-­to-­severe bi-
lateral NLFs defined as ≥3 points on WSRS scale; intervention: MHA
filler injection; comparison: BHA filler injection; outcomes: WSRS
score, pain on VAS scale within 30 min after HA filler injection, GAIS
score, and adverse effects.
2.2  |  Search strategy
The systematic search was performed on Medline, Embase,
Cochrane Central Register of Controlled Trials (CENTRAL) from
database inception to June 14, 2021 with no restriction on date
or language. The complete search strategy is provided in the
Appendix S1. We also sought ongoing or recently completed tri-
als by searching the following trial registries: ClinicalTrials.gov,
UMIN Clinical Trials Registry, Australian New Zealand Clinical
Trials Registry ISRCTN registry, and MetaRegister of Controlled
Trials. We further screened the reference lists of the included
RCTs for potentially relevant RCTs missed during the systematic
search.
2.3  |  Study selection and data extraction
Two reviewers performed titles and abstracts' eligibility screening:
full-­text assessment and data extraction from eligible trials indepen-
dently and in duplicate. Any disagreement was settled by consensus
or by discussion with a third reviewer.
2.4  |  Meta-­analysis
We performed the meta-­analysis through RevMan (Review Manger)
version 5.3 (Cochrane Collaboration) and using the random-­effects
model. We used 95% as a confidence level and p <0.05 as a thresh-
old. We assessed the statistical heterogeneity using I2 and the p of
the Chi-­squared test for heterogeneity. The continuous outcomes
WSRS, GAIS, and pain of VAS were represented as standardized
mean difference (SMD) and pooled using the inverse variance
weighting method. The dichotomous outcome adverse event rate
was represented as risk ratio (RR) and pooled using the inverse
variance weighting method. We performed a subgroup analysis
for WSRS and GAIS according to the following follow-­up periods:
2 weeks; 2 months; 4 months; and 6 months.
2.5  |  Risk of bias assessment
Two reviewers performed the risk of bias assessment for the in-
cluded RCTs using the Revised Cochrane Risk of Bias Assessment
Tool independently and in duplicate.19 We sought to assess the po-
tential for publication bias by visual inspection of the funnel plot
with SMD/RR and standard error. An evidence of publication bias
was considered present when the funnel plot is not symmetrical.
3  |  R E S U LT S
Figure 1 shows the flowchart and study inclusion in this review.
The literature search yielded 1410 articles, of which 308 dupli-
cates were excluded. A total of 1102 articles were excluded after
title and abstract screening, leaving 28 articles for full-­text assess-
ment. Ultimately, 13 articles representing 11 RCTs were deemed
eligible.14–­17,20–­28
3.1  |  Trial characteristics
A total of 935 participants were included in this review. Of them, 216
(23.10%) participants received MHA filler bilaterally, 216 (23.10%)
participants received BHA filler bilaterally, and 719 (76.90%) re-
ceived MHA filler in one NLF and BHA filler in the contralateral NLF
(split face). The mean age of the participants in the included RCTs
ranged from 46 to 54.8 years. Most of the participants who received
HA filler injections were female (95.29%) (Table 1).
GHADDAF et al.
F I G U R E 1  Study flow diagram
3.2  |  Risk of bias assessment
Of the 11 RCTs, six had an overall low risk of bias, three had some
concerns, and two had high risk of bias. Of the three RCTs that had
some concerns, the source of bias was selection of the reported re-
sults in two RCTs and an issue with randomization in one RCT. Of the
two RCTs that had high risk of bias, the source of bias was selection
of the reported results (Figures 2 and 3).
|
      629
3.3  |  Wrinkle severity rating scale
All included RCTs reported on WSRS score (n  = 935).14–­17,20–­28
However, Buntrock et al. (n = 20) could not be included in the analysis
due to the insufficient provided information.14 Overall, MHA filler
showed a significantly better WSRS score compared to BHA filler
(SMD = −0.38, 95% CI −0.49 to −0.27, p < 0.01; I2 = 51%) (Figure 4).
Similarly, the subgroup analysis revealed a significantly better WSRS
 |
630      GHADDAF et al.

TA B L E 1  Characteristics of the included studies

WSRS score WSRS score, pain of WSRS score, pain of VAS

Measured WSRS score and and pain of VAS VAS score, GAIS score, score, GAIS score, and
outcomes adverse events score and adverse events adverse events

Mean age (years) Biphasic HA filler 52.7 52 48.04 47.62

Monophasic HA filler 52.7 52 48.04 47.62
Gender Female 61 18 81 53
Male 7 2 10 7
Number of Biphasic HA filler 30 20 (split face) 91 (split face) 60 (split face)
participants Monophasic HA filler 29 20 (split face) 91 (split face) 60 (split face)
Total 59 20 91 60
Filler brand Biphasic HA filler Restylane Perlane Restylane® Restylane LYFT® Restylane
Sub-­Q Perlane-­Lidocaine
Monophasic HA filler Emervel Deep Belotero Sardenya shape Neuramis Deep Lidocaine
Intense
Study, year Ascher Buntrock Chung 202123 Joo 201622
2011/201720,28 201314

F I G U R E 2  Risk of bias graph

score in favor of MHA filler at 2 weeks (SMD = −0.51, 95% CI −0.85
to −0.17, p < 0.01), 2 months (SMD = −0.42, 95% CI −0.59 to −0.25,
p < 0.01), 4 months (SMD = −0.52, 95% CI −0.85 to −0.19, p < 0.01),
and 6 months (SMD = −0.28, 95% CI −0.46 to −0.10, p < 0.01). The
funnel plot was symmetrical, and no evidence of publication bias
was noted (Figure S1A). Buntrock et al. showed that MHA filler was
confers a significant improvement in WSRS score compared to BHA
filler at 2 weeks (−51% reduction from baseline value versus −38%),
6 months (−26% versus −20%), and 12 months (−29% versus −18%).14
p < 0.01), 4 months (SMD = 0.36, 95% CI 0.12–­0.59, p < 0.01), and
6 months (SMD = 0.43, 95% CI 0.16–­0.70, p < 0.01). The funnel plot
for publication bias was symmetrical, and no evidence of publica-
tion bias was noted (Figure S1B). Nast et al. showed a significant
improvement in GAIS score from baseline for participants who re-
ceived MHA filler compared to those who received BHA filler at
4 weeks (−2.15 versus −2.40, p = 0.03) and 28 weeks (−1.87 versus
−2.22, p < 0.01).

3.5  |  Pain on visual analog scale

3.4  |  Global aesthetic improvement scale
Five RCTs provide data on GAIS score (n = 587).9,21–­23,27 However,
Nast et al. (n = 60) could not be included in the analysis due to the
different follow-­up time points provided by their study.9 Overall,
GAIS score was significantly better in MHA filler compared to BHA
filler (SMD = 0.34, 95% CI 0.24–­0.45, p < 0.01; I2 = 30%) (Figure 5).
Likewise, the subgroup analysis showed a discernable improvement
in GAIS score in favor of MHA filler at 2 weeks (SMD = 0.28, 95%
CI 0.09–­0.47, p < 0.01), 2 months (SMD = 0.32, 95% CI 0.09–­0.55,
Data on pain on VAS scale within 30 min after HA filler injection
were reported by five RCTs (n  = 295).14,21–­23,26 No significant dif-
ference was found between MHA and BHA fillers in terms of pain
on VAS scale (SMD = −0.39, 95% CI −0.81–­0.03, p = 0.07; I2 = 84%)
(Figure 6). The funnel plot for publication bias was symmetrical, and
no evidence of publication bias was noted (Figure S1C). Since the
statistical heterogeneity was significant (I2 = 84%), we performed a
sensitivity analysis by removing the source of heterogeneity to de-
termine the stability of our findings. Similarly, the sensitivity analysis
GHADDAF et al. |
      631

WSRS score, pain WSRS score, WSRS score, pain of WSRS score
of VAS score, and WSRS score and GAIS score, and WSRS score and VAS score, GAIS score, and adverse
adverse events GAIS score adverse events WSRS score adverse events and adverse events events

48.3 54.8 46 49.03 50.8 46.02 48

48.3 54.8 45.36 49.03 50.8 46 47.7
70 52 311 62 77 58 48
2 8 10 6 4 2 1
72 (split face) 60 (split face) 162 68 (split face) 81 split face) 52 (split face) 24
72 (split face) 60 (split face) 162 68 (split face) 81 split face) 52 (split face) 25
72 60 324 68 81 52 48
Restylane® Restylane Restylane® Restylane® Restylane Restylane® Sub-­Q Restylane
Perlane®
Elravie® Teosyal 27G DermalaxTM Elravie® Emervel Dermalax implant plus Matrifill
Deep Lines DEEP
Kwon 201726 Nast 20119 Qiao 202027 Rhee 201416 Rzany Suh 201721 Zhou 201617
2011/201724,25

showed no significant difference between the two groups in terms

of pain on VAS scale (SMD = −0.07, 95% CI −0.29–­0.16, p = 0.56;
I2 = 29%) (Figure S1D).

3.6  |  Adverse events

Data on adverse events were reported by nine articles represent-

17,20–­22,24–­26
ing nine RCTs (n = 696). No discernable difference was
found between MHA and BHA fillers in terms of adverse events
(RR  =  1.00, 95% CI 0.89–­1.12, p  = 0.96; I2  =  21%) (Figure  7). The
funnel plot for publication bias was symmetrical, and no evidence of
publication bias was noted (Figure S1E).

4  |  D I S C U S S I O N

This systematic review and meta-­analysis of 11 RCTs, representing

935 participants compared MHA filler and BHA filler injection for
the cosmetic correction of moderate-­to-­severe NLFs. The pooled
estimate showed a significant improvement in the overall WSRS
score and GAIS score in favor of MHA filler. Similarly, the subgroup
analysis showed a discernable improvement favoring MHA filler at
2 weeks, 2 months, 4 months, and 6 months. Both groups showed
similar pain scores and adverse event profile.
Wrinkle severity rating scale is a photograph-­based tool used
to determine the degree of facial wrinkles by assessing the length
and the apparent depth of facial folds. 29 Wrinkle severity rating
scale showed high validity and reliability standards in 2004, and
since then, it became the most commonly used tool to assess the
severity of NLF wrinkles in clinical trials. 30 MHA filler was found
F I G U R E 3  Risk of bias summary to be associated with better WSRS score consistently among all
 |
632      GHADDAF et al.

F I G U R E 4  Forest plot for WSRS score

F I G U R E 5  Forest plot for GAIS score

GHADDAF et al.
F I G U R E 6  Forest plot for pain on VAS score
F I G U R E 7  Forest plot for adverse events
the included RCTs at the different follow-­up time points. Kwon
et al. were the only exception, showing that BHA filler was slightly
better than MHA filler at 6 months follow-­up (2.24 versus 2.26). 26
Among the studies that showed better WSRS score in favor of MHA
filler, some showed significantly discernable findings while others
did not. We believe that it could be attributed, in part, to the use
of different filler brands for MHA filler. Interestingly, the RCTs
that showed non-­significant improvement in WSRS score follow-
ing MHA filler injection used the following filler brands for MHA
filler: Emervel (HA concentration: 20 mg/mL, lidocaine concentra-
tion: without lidocaine, cross-­linking agent: BDDE) or Elravie (HA
concentration: 23 mg/mL, lidocaine concentration: 0.3% lidocaine,
cross-­linking agent: BDDE).16,20,24–­26,28 However, no difference was
noted among the included RCTs with regard to the injection tech-
nique. Furthermore, HA gel particles have been thought to influ-
ence WSRS score following HA injection. Nikolis et al. showed that
large-­particle size HA filler injection confers a significantly better
WSRS score compared to small-­particle size.31 Conversely, other
trials revealed no difference between small-­and large-­particle size
32–­35
HA fillers. This contrast has been attributed to the use of a
different injection technique. Nikolis et al. injected small-­and large-­
particle size HA fillers into the periosteum, while the other studies
injected at the level of the mid-­dermis, deep dermis, or subcutane-
ous region. The use of the anesthetic agent lidocaine as an adjuvant
to HA fillers has also been thought to influence the improvement
in WSRS score after the injection. Suh et al. showed that HA filler
with a pre-­incorporated lidocaine is associated with a significant
improvement in WSRS score compared to HA filler without con-
21
taining lidocaine. However, a recent systematic review of RCTs
demonstrated similar WSRS score following HA filler injection with
or without lidocaine for NLF correction. 36
|
      633
Global aesthetic improvement scale is a photograph-­based tool
used to determine the overall improvement in NLF following the
administration of the cosmetic intervention as compared to the
patient's photograph before at baseline. Unlike WSRS, which es-
timates the absolute degree for the severity of NLFs after the cos-
metic intervention, GAIS reflects the overall improvement in the
NLFs cosmetic parameters after receiving the cosmetic implant rel-
ative to the pre-­intervention state. 29 All the included RCTs report-
ing GAIS revealed a significant improvement in favor of MHA filler
except Suh et al., which showed a non-­significant improvement at
all the follow-­up time points. 21 Moreover, GAIS does not seem to
be influenced by the gel particle size or the use of lidocaine. Nikolis
et al. displayed that GAIS response rate (defined as ≥ “improved”
from baseline) was achieved by 100% of the participants who re-
ceived small-­particle size or large-­particle size HA filler at 2 weeks
and by ≥95% at 4 weeks of receiving the intervention. 31 Likewise, Li
et al. revealed ≥80% improvement in GAIS in both groups over the
6 months post-­HA filler injection. However, the rate of improve-
ment in GAIS started to fall after 6 months and reached up to 22%
at 12 months.35 Furthermore, trials comparing HA filler injection
with or without lidocaine showed similar rate of improvement in
GAIS between the two groups. 37,38
Injection site pain is the main complain after receiving the dermal
fillers. Therefore, the efforts have been pursued to overcome this
issue by giving the patients topical or local anesthetics before inject-
ing the filler implants or by incorporating the anesthetic agents within
the dermal fillers.39 Two of the included RCTs in our review compared
MHA filler with lidocaine to BHA filler without lidocaine.21,26 Suh
et al. showed a significant reduction in pain within 30 min after HA
filler injection in MHA filler with lidocaine, while Kwon et al. displayed
a non-­significant reduction. We hypothesize that the use of local
634     |
anesthetic agents (lidocaine 2.5% and prilocaine 2.5%) 1  h prior to
the injection has influenced the significance of their findings. This hy-
pothesis is supported by many trails showing a significant reduction
in procedural pain with lidocaine-­containing HA fillers compared to
HA fillers without lidocaine.40,41 Similarly, a recent systematic review
demonstrated a significant reduction in the 30-­min injection site pain
with lidocaine-­containing HA fillers.36 Lidocaine incorporation with
HA fillers has also been linked with less injection-­associated bruising
and swelling by inhibiting the activation of eosinophils after the injec-
22,42
tion. However, Raspaldo et al. found no evidence of NLFs asym-
metry in patients who received HA fillers with or without lidocaine at
long-­term follow-­up (76 weeks), indicating that lidocaine incorpora-
tion does not increase the longevity of HA fillers.43
To the best of our knowledge, this is the first systematic review
and meta-­analysis that compared the efficacy and safety of the two
cross-­linked fillers MHA and BHA fillers. Our review provided a rela-
tively large sample size obtained from high level of evidence RCTs. The
findings of these RCTs were consistent with a low rate of heteroge-
neity, except pain on VAS scale, conferring the optimal evidence for a
meta-­analysis. Our review determined the efficacy of HA fillers using
the most reliable tools for the assessment of wrinkle severity of NLFs.
We acknowledge that our review has several limitations. First, we
were not able to determine the influence of the different HA filler
brands on the findings of our review, owing to the various filler brands
used in the included RCTs. Second, although MHA filler demonstrated
satisfactory cosmetic results, we could not determine the optimal
dose of HA filler as HA concentration varied among the different filler
brands (from 16 mg/mL to 25.5 mg/mL). Finally, some of the included
RCTs injected the HA fillers into mid-­dermis, while others injected
into the deep dermis and the surface layer of subcutaneous region.
However, the optimal injection of HA fillers is yet to be delineated.
5  |  CO N C LU S I O N S
This systematic review and meta-­analysis showed that both MHA and
BHA fillers are effective for the correction of moderate-­to-­severe
NLFs. MHA filler displayed a significant improvement in WSRS score
and GAIS score compared to BHA filler. This significant improvement
was reflected in the subgroup analysis, showing satisfactory cosmetic
results at 2 weeks, 2 months, 4 months, and 6 months. Both fillers
showed similar procedural pain scores and adverse event profile. This
demonstrates that MHA filler has similar efficacy and tolerability as
BHA filler. Further RCTs are warranted to determine the optimal con-
centration and injection technique for MHA filler.
C O N FL I C T O F I N T E R E S T
The authors declare that they have no conflict of interest.
AU T H O R C O N T R I B U T I O N S
A.A.G contributed to the research idea, design of the study, data
extraction, statistical analysis/interpretation, risk of bias assess-
ment, and writing/editing of the final manuscript. Y.E.A and F.A.A
GHADDAF et al.
contributed to the design of the study, data extraction, statistical
analysis, and interpretation, and editing of the final manuscript.
R.K.S. and W.A.A. contributed to the data extraction, statistical
analysis/interpretation, risk of bias assessment, and editing of the
final manuscript. R.B contributed to the statistical analysis/interpre-
tation and editing of the final manuscript. All the authors have read
and approved the final manuscript.
E T H I C A L A P P R OVA L
Not required.
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 from
the corresponding author upon reasonable request.
REFERENCES
1. Burgess CM, editor. Cosmetic Dermatology. Springer-­Verlag Berlin
Heidelberg. ISBN 9783540273332. Retrieved 20 February 2015.
2005:106.
2. M. Smith A, Ferris T, K. Nahar V, Sharma M. Non-­traditional and
non-­invasive approaches in facial rejuvenation: a brief review.
Cosmetics. 2020;7(1):10. doi:10.3390/cosme​tics7​010010
3. Cohen JL, Dayan SH, Brandt FS, et al. Systematic review of clin-
ical trials of small-­ and large-­gel-­ particle hyaluronic acid inject-
able fillers for aesthetic soft tissue augmentation. Dermatol Surg.
2013;39(2):205-­231.
4. Prager W, Wissmueller E, Havermann I, et al. A prospective,
split-­
f ace, randomized, comparative study of safety and 12-­
month longevity of three formulations of hyaluronic acid der-
mal filler for treatment of nasolabial folds. Dermatol Surg.
2012;38(7):1143-­1150.
5. American Society for Aesthetic Plastic Surgery. American Society
of Aesthetic Plastic Surgery Practice Survey 2008 [PDF file].
[Accessed September 25, 2021] Available from: http://www.surge​
ry.org/sites/​defau​lt/files/​2008s​t ats.pdf
6. Brandt FS, Cazzaniga A. Hyaluronic acid gel fillers in the manage-
ment of facial aging. Clin Interv Aging. 2008;3(1):153.
7. Bentkover SH. The biology of facial fillers. Facial Plast Surg.
2009;25:73-­85.
8. Baumann LS, Shamban AT, Lupo MP, et al. Comparison of smooth-­
gel hyaluronic acid dermal fillers with cross-­linked bovine collagen:
a multicenter, double-­masked, randomized, within-­subject study.
Dermatol Surg. 2007;33(Suppl 2):S128-­S135.
9. Nast A, Reytan N, Hartmann V, et al. Efficacy and durability of two
hyaluronic acid-­based fillers in the correction of nasolabial folds:
results of a prospective, randomized, double-­blind, actively con-
trolled clinical pilot study. Dermatol Surg. 2011;37:768-­775.
10. Narins RS, Brandt FS, Lorenc ZP, et al. A randomized, multicenter
study of the safety and efficacy of Dermicol-­P35 and non-­animal-­
stabilized hyaluronic acid gel for the correction of nasolabial folds.
Dermatol Surg. 2007;33(Suppl 2):S213-­S221; discussion S221.
11. Gold MH. Use of hyaluronic acid fillers for the treatment of the
aging face. Clin Interv Aging. 2007;2(3):369.
12. Ballin AC, Cazzaniga A, Brandt FS. Long-­
term efficacy, safety
and durability of Juvéderm® XC. Clin Cosmet Investig Dermatol.
2013;6:183.
13. da Costa A, Biccigo DG, de Souza Weimann ET, et al. Durability
of three different types of hyaluronic acid fillers in skin: are
there differences among biphasic, monophasic monodensi-
fied, and monophasic polydensified products? Aesthetic Surg J.
2017;37(5):573-­581.
GHADDAF et al.
14. Buntrock H, Reuther T, Prager W, Kerscher M. Efficacy, safety,
and patient satisfaction of a monophasic cohesive polydensi-
fied matrix versus a biphasic nonanimal stabilized hyaluronic
acid filler after single injection in nasolabial folds. Dermatol Surg.
2013;39(7):1097-­1105.
15. Nast A, Reytan N, Hartmann V, et al. Efficacy and durability of two
hyaluronic acid-­based fillers in the correction of nasolabial folds:
results of a prospective, randomized, double-­blind, actively con-
trolled clinical pilot study. Dermatol Surg. 2011;37(6):768-­775.
16. Rhee DY, Won CH, Chang SE, et al. Efficacy and safety of a new
monophasic hyaluronic acid filler in the correction of nasola-
bial folds: a randomized, evaluator-­ blinded, split-­
face study. J
Dermatolog Treat. 2014;25(5):448-­452.
17. Zhou SB, Xie Y, Chiang CA, Liu K, Li QF. A randomized clinical trial
of comparing monophasic monodensified and biphasic nonanimal
stabilized hyaluronic acid dermal fillers in treatment of Asian naso-
labial folds. Dermatol Surg. 2016;42(9):1061-­1068.
18. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-­analyses of studies that
evaluate health care interventions: explanation and elaboration. J
Clin Epidemiol. 2009;62(10):e1-­e34.
19. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for as-
sessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
20. Ascher B, Bayerl C, Kestemont P, Rzany B, Edwartz C, Podda M. A
12-­month follow-­up, randomized comparison of effectiveness and
safety of two hyaluronic acid fillers for treatment of severe nasola-
bial folds. Dermatol Surg. 2017;43(3):389.
21. Suh JH, Oh CT, Im SI, Lim JS, Kim BJ, Lee JH. A multicenter, ran-
domized, double-­blind clinical study to evaluate the efficacy and
safety of a new monophasic hyaluronic acid filler with lidocaine
0.3% in the correction of nasolabial fold. J Cosmet Dermatol.
2017;16(3):327-­332.
22. Joo HJ, Woo YJ, Kim JE, Kim BJ, Kang H. A randomized clinical trial
to evaluate the efficacy and safety of lidocaine-­containing mono-
phasic hyaluronic acid filler for nasolabial folds. Plast Reconstr Surg.
2016;137(3):799-­8 08.
23. Chung C, Lee JH. A single-­center, randomized, double-­blind clinical
trial to compare the efficacy and safety of a new monophasic hy-
aluronic acid filler and biphasic filler in correcting nasolabial fold.
Aesthetic Plast Surg. 2021;13:1-­7.
24. Rzany B, Bayerl C, Bodokh I, et al. An 18-­month follow-­up, random-
ized comparison of effectiveness and safety of two hyaluronic acid
fillers for treatment of moderate nasolabial folds. Dermatol Surg.
2017;43(1):58-­65.
25. Rzany B, Bayerl C, Bodokh I, et al. Efficacy and safety of a new
hyaluronic acid dermal filler in the treatment of moderate naso-
labial folds: 6-­month interim results of a randomized, evaluator-­
blinded, intra-­ individual comparison study. J Cosmet Laser Ther.
2011;13(3):107-­112.
26. Kwon HJ, Ko EJ, Choi SY, et al. The efficacy and safety of a mono-
phasic hyaluronic acid filler in the correction of nasolabial folds: a
randomized, multicenter, single blinded, split-­face study. J Cosmet
Dermatol. 2018;17(4):584-­589.
27. Qiao J, Li F, Jin HZ, et al. The efficacy and safety of DermalaxTM
DEEP in the correction of moderate to severe nasolabial folds: a
multicenter, randomized, double-­blind clinical study. J Dermatolog
Treat. 2021;32(5):548-­555.
28. Ascher B, Bayerl C, Brun P, et al. Efficacy and safety of a new
hyaluronic acid dermal filler in the treatment of severe nasola-
bial lines–­6-­month interim results of a randomized, evaluator-­
blinded, intra-­ individual comparison study. J Cosmet Dermatol.
2011;10(2):94-­98.
29. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A ran-
domized, double-­blind, multicenter comparison of the efficacy and
tolerability of Restylane versus Zyplast for the correction of naso-
labial folds. Dermatol Surg. 2003;29(6):588-­595.
|
      635
3 0. Day DJ, Littler CM, Swift RW, Gottlieb S. The wrinkle severity rat-
ing scale. Am J Clin Dermatol. 2004;5(1):49-­52.
31. Nikolis A, Enright KM, Öhrlund Å, Winlöf P, Cotofana S. A ran-
domized, split-­ face, double-­ blind, comparative study of the
safety and efficacy of small-­ and large-­
particle hyaluronic acid
fillers for the treatment of nasolabial folds. J Cosmet Dermatol.
2021;20(5):1450-­1458.
32. Dover JS, Rubin MG, Bhatia AC. Review of the efficacy, durability,
and safety data of two nonanimal stabilized hyaluronic acid fillers
from a prospective, randomized, comparative, multicenter study.
Dermatol Surg. 2009;35:322-­331.
33. Taylor SC, Burgess CM, Callender VD. Safety of nonanimal stabi-
lized hyaluronic acid dermal fillers in patients with skin of color:
a randomized, evaluator-­blinded comparative trial. Dermatol Surg.
2009;35:1653-­1660.
3 4. Taylor SC, Burgess CM, Callender VD. Efficacy of variable-­particle
hyaluronic acid dermal fillers in patients with skin of color: a ran-
domized, evaluator-­ blinded comparative trial. Dermatol Surg.
2010;36:741-­749.
35. Li D, Sun J, Wu S. A multi-­center comparative efficacy and safety
study of two different hyaluronic acid fillers for treatment of
nasolabial folds in a Chinese population. J Cosmet Dermatol.
2019;18(3):755-­761.
36. Wang C, Luan S, Panayi AC, Xin M, Mi B, Luan J. Effectiveness and
safety of hyaluronic acid gel with lidocaine for the treatment of
nasolabial folds: a systematic review and meta-­analysis. Aesthetic
Plast Surg. 2018;42(4):1104-­1110.
37. Moreno-­Moraga J, Isarría MJ, Muñoz E, Cruz I, Pérez G, Cornejo P.
The evaluation of hyaluronic acid, with and without lidocaine, in the
filling of nasolabial folds as measured by ultrastructural changes
and pain management. J Drugs Dermatol. 2013;12(3):e46-­e52.
38. Weiss R, Bank D, Brandt F. Randomized, double-­blind, split-­face
study of small-­ gel-­
particle hyaluronic acid with and without li-
docaine during correction of nasolabial folds. Dermatol Surg.
2010;36:750-­759.
39. Matarasso SL, Carruthers JD, Jewell ML. Consensus recommenda-
tions for soft-­tissue augmentation with nonanimal stabilized hyal-
uronic acid (Restylane). Plast Reconstr Surg. 2006;117(3):3S-­4S.
4 0. Weinkle SH, Bank DE, Boyd CM, Gold MH, Thomas JA, Murphy
DK. A multi-­center, double-­blind, randomized controlled study of
the safety and effectiveness of Juvéderm® injectable gel with and
without lidocaine. J Cosmet Dermatol. 2009;8(3):205-­210.
41. Lupo MP, Swetman G, Waller W. The effect of lidocaine when
mixed with large gel particle hyaluronic acid filler tolerability and
longevity: a six-­month trial. J Drugs Dermatol. 2010;9(9):1097-­1100.
42. Okada S, Hagan JB, Kato M, et al. Lidocaine and its analogues in-
hibit IL-­5-­mediated survival and activation of human eosinophils. J
Immunol. 1998;160(8):4010-­4 017.
43. Raspaldo H, De Boulle K, Levy PM. Longevity of effects of hy-
aluronic acid plus lidocaine facial filler. J Cosmet Dermatol.
2010;9(1):11-­15.
S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found in the online
version of the article at the publisher’s website.
How to cite this article: Ghaddaf AA, Aljefri YE, Alharbi FA,
Sharif RK, Alnahdi WA, Baaqeel R. Monophasic versus
biphasic hyaluronic acid filler for correcting nasolabial folds: a
systematic review and meta-­analysis. J Cosmet Dermatol.
2022;21:627–­635. doi:10.1111/jocd.14632