COSMETIC
Long-Term Follow-Up of Longevity andDiffusion Pattern of Hyaluronic Acid in
Nasolabial Fold Correction throughHigh-Frequency UltrasoundJu Qiao, M.D.
Qian-Nan Jia, M.S.
Hong-Zhong Jin, M.D.
Feng Li, M.D.
Chun-Xia He, M.D.
Jun Yang, M.D.
Ya-Gang Zuo, M.D.
Lan-Qin Fu, M.D.
Beijing and Tianjin, People’s Republicof China

Background: Injectable hyaluronic acid fillers have been widely applied in theclinical treatment of facial wrinkles. However, further information and clinicalevidence concerning dermal changes and hyaluronic acid filler longevity after
injection and diffusion pattern are limited.
Methods: The authors evaluated the longevity and diffusion pattern of two hyaluronic acid fillers generated by different cross-linking technologies used in thetreatment of nasolabial folds using high-frequency ultrasound. Forty-one subjects
were treated with Restylane 2 and the remaining 41 were treated with Dermalax DEEP. Wrinkle severity rating scale score and high-frequency ultrasoundevaluation of nasolabial folds were performed before and after the injection of
hyaluronic acid filler. The ultrasound images were acquired and analyzed to determine dermal thickness and the shape and distribution of hyaluronic acid filler.
Results: At 2 and 24 weeks from baseline, increased dermal thickness induced byhyaluronic acid filler treatment was not significantly different between groups.
At 48 weeks after injection, increased dermal thicknesses of the Restylane 2group (0.14 ± 0.12 mm) were much lower than those of the Dermalax DEEP
group (0.20 ± 0.13 mm). Ultrasound examination revealed that hyaluronic acidmaterials form well-demarcated and hypoechogenic areas. Restylane 2 tended
to form a more diffuse pattern, with multiple smaller bubbles, whereas Dermalax DEEP developed into a more localized configuration, with larger clumps.
Conclusions: This study is the first long-term assessment of nasolabial fold correction that reveals the performance of different hyaluronic acid materials invivo and validates high-frequency ultrasound as a simple and rapid modality. Hyaluronic acid fillers generated by different cross-linking technologies display differential diffusion patterns in skin tissues. (Plast. Reconstr. Surg. 144: 189e, 2019.)
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

S

kin aging is associated with intrinsic, hormonal, and environmental factors in addition to chronic ultraviolet radiation. The

From the Department of Dermatology, Peking Union Medical College Hospital, and the Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking
Union Medical College.
Received for publication May 16, 2018; accepted January
31, 2019.
Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0(CCBY-NC-ND), where it is permissible to download andshare the work provided it is properly cited. The work cannot
be changed in any way or used commercially without permission from the journal.
DOI: 10.1097/PRS.0000000000005848

mechanical and morphologic appearance of theskin hinges largely on the connective tissue components, including collagen, fibroblasts, and elastic fibers. Accompanying the aging of skin, thedermal extracellular matrix is rearranged into a
type of more sparsely interlinked collagen networkwith reduced connective tissue components.1
Disclosure: ACROSS Co., Ltd provided investigational and reference devices, the cost of patients’physical examination and follow-up. All authors except Jun Yang received payment for participation in
the study from ACROSS Co., Ltd. The company had
no role in the design and conduct of the study, datacollection and analysis, preparation and approval ofthe manuscript, or the decision to submit the manuscript for publication.

www.PRSJournal.com

189ePlastic and Reconstructive Surgery • August 2019
As an endogenous glycosaminoglycan, hyaluronic acid is an essential component of the skinand connective tissues. With high affinity forwater, hyaluronic acid polymers play a critical rolein mediating the hydration and flexibility of theskin. Recent study suggested that hyaluronic acidcould promote fibroblast proliferation and collagen synthesis.2 Accordingly, skin aging is naturally accompanied by hyaluronic acid reduction,
which could accelerate the dehydration, loss ofelasticity, and wrinkling of the skin.3 In the pastfew decades, injectable hyaluronic acid fillers
have been widely applied in the treatment offacial wrinkles.4 Indeed, the cosmetic outcome isstrongly associated with the longevity and distribution of hyaluronic acid products in skin tissues.5
However, there are limited details and clinical evidence regarding postinjection dermal changes in
addition to the longevity6 and diffusion pattern ofhyaluronic acid filler over time.
High-frequency ultrasound is a noninvasive
soft-tissue imaging technology that can detectvarious echogenicities because of different tissue
densities.7 With the ability to acquire high-resolution images and visualize changes of the skin andsubcutaneous tissues, ultrasonographic evaluation
is well applied in the assessment of the efficacy
of injectable dermal fillers.8 Our current study is
aimed at evaluating the longevity and diffusion of
two hyaluronic acid fillers, Restylane 2 and Dermalax DEEP, generated by different hyaluronic
acid cross-linking technologies in the treatmentof nasolabial folds, and also to assess the effectiveness of high-frequency ultrasound.

PATIENTS AND METHODSThis study was designed to be randomized andpatient and evaluator blinded, and the protocol
was approved by the institutional review board.
The ultrasonographic examinations were all performed at Peking Union Medical College Hospital (Beijing, People’s Republic of China). A totalof 84 subjects were enrolled in this study, all withwritten informed consent. For the inclusion criteria of the enrollment, subjects were healthy, with
(1) age ranging from 25 to 65 years, (2) moderate
to severe nasolabial folds, and (3) a Wrinkle Severity Rating Scale score of 3 or 4 (Table 1). Subjects
with one of the following were excluded from thestudy: (1) history of allergy or hypersensitivity tofiller materials, including hyaluronic acid andstreptococcal protein; (2) dermatologic disease,including active infection or unhealed wound on
the face; (3) the use of topical corticosteroid or

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Table 1. Wrinkle Severity Rating Scale for Nasolabial
Folds
Grade
1
2
3
4
5

Severity
Absent: no visible NLFs; continuous skin line
Mild: shallow but visible NLFs with a slightindentation
Moderate: moderately deep NLFs; visible atnormal appearance but not when stretched
Severe: very long and deep NLFs; <2-mm visible NLFs when stretched; prominent facial
features
Extreme: extremely deep and long NLFs; 2- to
4-mm V-shaped folds when stretched; detrimental to facial appearance

NLFs, nasolabial folds.

retinoic acid at the nasolabial folds within 4 weeks;(4) history of facial botulinum toxin injection,laser resurfacing, face-lift procedures, tissue augmentation, or chemical peels within 6 months; (5)facial cosmetic surgery or hyaluronic acid injection
within 12 months before inclusion; (6) history of
bleeding disorder or use of aspirin, nonsteroidal
antiinflammatory drugs, warfarin, or other drugs
that can prolong the coagulation time; (7) historyof vitiligo or psoriasis; (8) systemic disease; (9)infectious disease including syphilis and acquired
immune deficiency syndrome; (10) pregnancy orbreast feeding; or (11) history of drug or alcoholabuse.
At the beginning, the enrolled subjects wererandomly separated into two groups: (1) 42
subjects treated with Restylane 2 (Q-MED AB,
Uppsala, Sweden) using a 30-gauge needle; and(2) 42 subjects treated with Dermalax DEEP
(ACROSS Co., Seoul, Republic of Korea) using
a 27-gauge needle. Dermalax DEEP had not yet
been registered in China at the beginning of thestudy. A topical 5% lidocaine cream was applied
to each side of nasolabial folds 1 hour before each
injection. Hyaluronic acid filler was injected into
each subject at the nasolabial folds by the same
experienced dermatologist. The volume of hyaluronic acid filler that was injected into each sideof the nasolabial folds ranged from 0.5 to 1 ml at
a concentration of 20 mg/ml.
Wrinkle Severity Rating Scale scores of all
subjects were evaluated (Table 1) by well-trained
investigators before inclusion and at 2, 8, 16, 24,
36, and 48 weeks after injection. Photographs ofnasolabial folds of all subjects were taken before
injection and at 2, 8, 16, 24, 36, and 48 weeks after
injection, and with shutting the mouth and withthe same posture under constant environmental
conditions by the same investigator and equipment. For ultrasound analysis, high-frequency
ultrasound evaluation (3XSKIN; MEDA, Tianjin,

Volume 144, Number 2 • Diffusion Pattern In Vivo on UltrasoundPeople’s Republic of China) of nasolabial folds
was performed at the 20 MHz before injection andat 2, 24, and 48 weeks after injection by the sameinvestigator. The probe was placed perpendicular
to the nasolabial folds with the subject in the lying
position. The ultrasound images of each side ofnasolabial folds were acquired and reviewed todetermine the dermal thickness and the shapeand distribution of hyaluronic acid filler. All data
were analyzed by repeated measures analysis ofvariance using SAS 9.3 (SAS Institute, Inc., Cary,N.C.), and a value of p < 0.05 was considered to bestatistically significant.

RESULTS
From October of 2016 to March of 2018, 82
of 84 enrolled subjects successfully completed
the study. Forty-one subjects were treated with
Restylane 2, whereas the other 41 subjects weretreated with Dermalax DEEP. The mean age of thesubjects was 44.99 years (range, 26 to 60 years).
The mean age of patients in the Dermalax DEEP

group was 45.14 years (range, 26 to 60 years). The
mean age of patients in the Restylane 2 groupwas 44.83 years (range, 28 to 60 years). In the
Restylane 2 group, 21 subjects were defined as having a Wrinkle Severity Rating Scale grade of 3 and
20 were grade 4; in the Dermalax DEEP group, 24
subjects were defined as having a Wrinkle Severity Rating Scale grade of 3 and 17 were grade 4.
For hyaluronic acid injection, the average volume
into each side of nasolabial folds was 0.76 ml of
Restylane 2 and 0.68 ml of Dermalax DEEP. The
two groups did not display any significant differences in the Wrinkle Severity Rating Scale grade
and hyaluronic acid volumes.
As expected, the skin exhibited a three-layer
structure by analysis with high-frequency ultrasound (Fig. 1, above, left). Interestingly, the epidermis presented as a bright hyperechogenic linewith a mean thickness of 0.15 mm, and the dermis
appeared to be a homogenous hypoechogenic
band with a hyperechogenic area beneath it. Two
weeks after treatment, the dermis was obviously
noted to be thicker, with less echogenicity (Fig. 1,

Fig. 1. Human skin was revealed as a three-layer structure by means high-frequency ultrasound imaging. (Above, left) Before
treatment, the dermis appeared as a homogenous hypoechogenic band with a hyperechogenic area beneath it and the epidermis as a bright hyperechogenic line. The dermis displayed increased in thickness with lower echogenicity, (above, right)
two weeks, (below, left) 24 weeks, and (below, right) 48 weeks after treatment. Hyaluronic acid materials presented as welldemarcated, homogeneous, hypoechogenic, or nonechogenic areas (black arrow).

191e

Plastic and Reconstructive Surgery • August 2019
above, right). Meanwhile, the results of Wrinkle
Severity Rating Scale also revealed decreasesof three grades in 22 subjects, two grades in 50
subjects, and one grade in 10 subjects 2 weeks
after injection (Fig. 2). The data regarding dermal thickness are summarized and presented in
Figure 3.
The dermal thickness of all subjects before
treatment was 1.45 ± 0.16 mm (minimum,
1.03 mm; maximum, 1.84 mm). Impressively,
significant elevations of dermal thickness wereobserved in all subjects after hyaluronic acid injection (Fig. 1, above, right, and below, left and right).
The increase in dermal thickness from baseline
was determined to be 40.29 percent at 2 weeks,
21.34 percent at 24 weeks, and 11.74 percent at 48
weeks after injection (Fig. 3, left). However, a dramatic reduction of dermal thickness was observed
at 48 weeks after injection compared with that at
24 weeks. Repeated measures analysis of varianceshowed significant differences (p < 0.001) in all
subjects at 2, 24, and 48 weeks after injection, anddemonstrated a time effect in the increased dermal thickness.
At 2 and 24 weeks after injection, the increased
dermal thicknesses were 0.57 ± 0.20 and 0.27 ±0.18 mm in the Restylane 2 group and 0.59 ± 0.15
and 0.34 ± 0.14 mm in the Dermalax DEEP group,
respectively (Fig. 3, right). Both Restylane 2 andDermalax DEEP injection resulted in satisfactory
cosmetic outcomes in nasolabial fold correction
within 24 weeks after injection. At 48 weeks after
injection, however, increased dermal thickness in
the Restylane 2 group (0.14 ± 0.12 mm) was muchless than that of the Dermalax DEEP group (0.20± 0.13 mm). Variation between groups was demonstrated to be statistically significant (p < 0.01),
with a linear trend of time between groups (p <0.05). These findings indicate that relative to Dermalax DEEP, Restylane 2 may be more prone to be
diffused or degraded and displays much shorter
longevity in vivo. Compared with 2 weeks after
treatment, the average Wrinkle Severity Rating
Scale scores of the Dermalax DEEP and Restylane
2 groups increased 0 and 0.107 at 24 weeks and0.293 and 0.327 at 48 weeks, respectively. There
was no significant difference on Wrinkle Severity
Rating Scale scores at 24 and 48 weeks between
the two groups. However, given that the Wrinkle
Severity Rating Scale scores are not sufficiently
detailed, the possibility of clinically significant differences may not be excluded.

Fig. 2. Clinical representative images (above, left) before and (above, right) 2 weeks, (below, left) 24 weeks, and (below, right)
48 weeks after hyaluronic acid injection.

192e

Volume 144, Number 2 • Diffusion Pattern In Vivo on UltrasoundFig. 3. The thickness (mean ± SE) of dermis was measured using high-frequency ultrasound. (Left) The dermis displayed significantly increased thickness at 2, 24, and 48 weeks after hyaluronic acid injection. (Right) The dermal thickness of the two groups
showed similar changes at 2 and 24 weeks. At 48 weeks after injection, the dermal thickness of the Dermalax DEEP group increased
compared with the Restylane 2 group (repeated measures analysis of variance).

Because of different echogenicities and distinct boundaries along with the surrounding
tissues, hyaluronic acid materials of both the
Restylane 2 and Dermalax DEEP groups could be
detected and visualized using ultrasound.9 In fact,hyaluronic acid materials were found to localizein the subcutaneous tissues and present as welldemarcated, homogeneous, hypoechogenic andnonechogenic areas (Fig. 1, above, right). Images
obtained at 2, 24, and 48 weeks after injection
clearly demonstrated the diffusion and distribution patterns of hyaluronic acid materials overtime (Fig. 4). The results revealed that Dermalax DEEP developed into a localized configuration and broke up into hypoechogenic clumps
with slightly degraded sizes over time. However,Restylane 2 tended to spread more widely andform a more diffuse pattern, with multiple smaller
bubbles in the skin tissues compared with Dermalax DEEP.

DISCUSSION
Because it is a safe and natural substance,with a reversible procedure, hyaluronic acid filler
injection is currently a widely used approach forfacial wrinkle correction.10 However, hyaluronic
acid usually exhibits a short lifespan, as the material is rapidly degraded in skin tissues.11 Therefore, the longevity of hyaluronic acid products
in skin tissues is considered the key factor that
impacts cosmetic outcome. An increasing numberof methods are applied to determine the longevity

of hyaluronic acid fillers in vivo, including histology, cytochemistry, magnetic resonance imaging,electron microscopy, and high-frequency ultrasound.12 High-frequency ultrasound is a noninvasive approach for visualizing hyaluronic acid fillers
and dermal modifications that can be performed
without skin biopsies. Moreover, dermal changes
over a long-term period can be monitored andquantified by the use of high-frequency ultrasound, in the event of cyst or granuloma inducedby hyaluronic acid filler treatment. Furthermore,compared with magnetic resonance imaging,high-frequency ultrasound can display dynamics
of hyaluronic acid diffusion beneath the skin surface, and is much more easy to perform.
The Wrinkle Severity Rating Scale is a validated five-point reference scale for classifying
facial wrinkles, and it is widely used in a growing number of investigational studies. Thus, theWrinkle Severity Rating Scale for nasolabial folds
enables valid assessment and represents a clinically meaningful change in nasolabial fold severity. In the current study, the results of Wrinkle
Severity Rating Scale scores confirmed satisfactory
cosmetic outcomes in nasolabial fold correction
and were also consistent with our observations by
ultrasound examination.
Our high-frequency ultrasound examination
data revealed that the skin displayed a threelayer structure, which is in accordance with previous study.13 Normally, the epidermis presented
as a bright hyperechogenic line and the dermis
appeared as a homogenous hypoechogenic band

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Plastic and Reconstructive Surgery • August 2019

Fig. 4. Hyaluronic acid distribution in vivo was visualized by high-frequency ultrasound (black arrow). Representative highfrequency ultrasound images revealed that Restylane 2 tended to spread more widely and form a more diffuse pattern, withmultiple smaller bubbles (above, left, 2 weeks; above, right, 24 weeks after injection); and Dermalax DEEP developed into a
more localized configuration and broke up into hypoechogenic clumps, with slightly degraded sizes (below, left, 2 weeks;
below, right, 24 weeks after injection).

with a hyperechogenic area beneath it. After injection, the dermis became much thicker, with lower
echogenicity in all subjects. It has been consideredthat hyaluronic acid fillers improve the aesthetic
appearance by means of filling space.3 It is perfectly confirmed by our ultrasound examination,
which identified injected hyaluronic acid materials as well-demarcated, homogeneous, hypoechogenic or nonechogenic areas in skin tissues. The
hydration effect and the induction of collagensynthesis14 by hyaluronic acid materials are also
hypothesized to contribute to maintenance ofcosmetic benefits. It is worth noticing that dermal thickness at 48 weeks after injection showed
an obvious reduction in comparison with that at
24 weeks after injection, suggesting that injectedhyaluronic acid fillers might be diffused, reabsorbed, degraded, or fragmented in skin tissues.
The longevities of two different hyaluronic
acid fillers were determined in our current study.
At 2 or 24 weeks after injection, the increased dermal thickness induced by Restylane 2 injection was
not significantly different compared to Dermalax

194eDEEP, indicating that both hyaluronic acid fillers
provided satisfactory cosmetic outcomes in nasolabial fold correction. However, the increased
dermal thickness at 48 weeks after injection was
significantly different between the two groups,
suggesting that, relative to Restylane 2, DermalaxDEEP is not easy to diffuse or be degraded andhas greater longevity in vivo.
By high-frequency ultrasound, we also evaluated the differences of diffusion patterns between
Restylane 2 and Dermalax DEEP in vivo. Our data
revealed that Restylane 2 tended to form a morediffuse pattern, with multiple smaller bubbles,
whereas Dermalax DEEP developed into a more
localized configuration, with larger clumps. These
results are consistent with our clinical experience
with hyaluronic acid filler injection. Restylane 2
is relatively smooth for correcting facial wrinkles
and has better performance in superficial wrinkle correction. In contrast, Dermalax DEEP has
a more powerful and long-lasting effect of physical volume occupation, and thus is more suitablefor deep wrinkle improvement and facial contour

Volume 144, Number 2 • Diffusion Pattern In Vivo on Ultrasoundcorrection. In addition, Restylane 2 is much easierfor injection and molding of fillers compared withDermalax DEEP. In clinical practice, the selectionof hyaluronic acid filler products usually depends
on individual specific requirements. Our current
study might provide more helpful clues for theselection and clinical application of hyaluronic
acid products in padding treatment.
In consideration of the hyaluronic acid clumps
on the ultrasound images, we observed palpable
but invisible nodules in the nasolabial folds fromboth groups. There were four reports of palpablenodules from Dermalax DEEP, with three nodules regressing within 1 month and the other one
remaining for 9 months. In the Restylane 2 group,
one nodule was reported regressing in 1 week andanother one remained for 6 months. In addition,
high-frequency ultrasound could also be used in
the clinical application for the differentiation ofpotential confused occurrences, including nodules, granulomas, or other adverse reactions.
The cross-linking technology and percentages
have major influences on the longevity and diffusion pattern of hyaluronic acid fillers in vivo.15
Restylane 2 and Dermalax DEEP are both derived
from nonanimal hyaluronic acid substances thatare synthesized by Streptococcus species biologicalfermentation. The enhanced stability of hyaluronic acid could be generated when the hyaluronic acid molecules are cross-linked by meansof 1,4-butanediol diglycidyl ether.16 Comparedwith Restylane 2, Dermalax DEEP has a greater
cross-linking percentage and a larger particle
size because of different 1,4-butanediol diglycidyl ether bonding technology. These differential properties result in variations of rheologic
characteristics and thus clinical performance in
Restylane 2 and Dermalax DEEP.17
The present study has some limitations. First,
we could not confirm that the hyaluronic acidproduct was injected at the same depth in all
subjects. However, we have three ways of reducing interference through the (1) resistance ofinjection, (2) outline of the needle, and (3) elevation of the skin. Moreover, during preexperiment study, we evaluated the depth of injection
through high-frequency ultrasound immediately
after injection, which revealed that all of thehyaluronic acid materials were in the middle andlower dermis. Second, the needles used and theaverage volume injected in the two groups weredifferent. The hyaluronic acid volume injected
into each side of nasolabial folds was scaled from
0.5 to 1 ml. The specific volume depended on
satisfactory cosmetic outcomes in each subject.

Third, we did not include a more powerful product with a longer lasting effect or a softer andless robust product in this study. In addition, further studies are required to illustrate the utilityof high-frequency ultrasound in the differentiation of potential confused occurrences, including
nodules, granulomas, or other adverse reactions.

CONCLUSIONSThe current study is the first long-term assessment of nasolabial fold correction, which visualized hyaluronic acid material and its subsequent
performance in vivo, and also validated high-frequency ultrasound as a simple and rapid modality
for follow-up assessment. This large series illustrates our clinical and ultrasonographic observations with respect to the dermal changes andhyaluronic acid filler longevity and diffusion pattern, which complement previous studies. Injectable hyaluronic acid fillers generated by different
cross-linking technologies displayed differential
diffusion patterns in the skin tissues. This study
would be of great assistance for the selection andclinical application of hyaluronic acid products in
padding treatment.
Hong-Zhong Jin, M.D.
No. 1, Shuaifuyuan
Dongcheng District
Beijing, People’s Republic of China
jinhongzhong@263.net

ACKNOWLEDGMENT

This study was supported by the Chinese Academyof Medical Sciences Initiative for Innovative Medicine(2017-I2M-B&R-01).
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