Clinical, Cosmetic and Investigational Dermatology

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Efficacy and tolerance of an injectable medical

device containing stable hybrid cooperative
complexes of high- and low-molecular-weight
hyaluronic acid: a monocentric 16 weeks open-
label evaluation

Adele Sparavigna & Beatrice Tenconi

To cite this article: Adele Sparavigna & Beatrice Tenconi (2016) Efficacy and tolerance of an
injectable medical device containing stable hybrid cooperative complexes of high- and low-
molecular-weight hyaluronic acid: a monocentric 16 weeks open-label evaluation, Clinical,
Cosmetic and Investigational Dermatology, , 297-305, DOI: 10.2147/CCID.S114450

To link to this article: https://doi.org/10.2147/CCID.S114450

© 2016 Sparavigna and Tenconi. This work Published online: 26 Sep 2016.
is published and licensed by Dove Medical
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Open Access Full Text Article ORIGINAL RESEARCH

Efficacy and tolerance of an injectable medical

device containing stable hybrid cooperative
complexes of high- and low-molecular-weight
hyaluronic acid: a monocentric 16 weeks
open-label evaluation
This article was published in the following Dove Press journal:
Clinical, Cosmetic and Investigational Dermatology
26 September 2016
Number of times this article has been viewed

Adele Sparavigna Background: An injectable medical device containing stable hybrid cooperative complexes of
Beatrice Tenconi high- and low-molecular-weight hyaluronic acid (HA) has been developed with characteristics
suited for a global improvement of facial esthetics.
DermIng srl, Clinical Research and
Bioengineering Institute, Monza, Objective: To evaluate the HA product performance in improving some key facial esthetic
MB, Italy features. The study employed clinical scales, subjective evaluations, and facial skin objective
measurements.
Methods: A single Italian site treated 64 female subjects aged 38–60 years, with injections at
five predetermined points, on each side of the face, with a 4-week time lapse between the first and
the second product administration. Subjects were evaluated after 4, 8, 12, and 16 weeks, using
validated clinical scales, subjective evaluation, and objective quantitative outcome measures.
Assessment of esthetic results included photographic documentation.
Results: Both the clinical and subjective assessments, and the majority of objective instrumental
parameters indicated an improvement throughout the study and were already significant at week
4 or 8 and were still significant at week 16 (3 months after the second treatment). Minor and
temporary local skin reactions were observed in 23% of subjects at the site of the injections,
and the global judgment on tolerability was good or excellent, both in the investigators’ opinion
and volunteers’ self-evaluation.
Conclusion: Both subjective and objective improvement of the facial parameters was consistent
with the bio-remodeling purpose, and persistent and still statistically significant at the end of the
study. The tolerability and safety profile of the product were judged good or excellent both by
investigators and volunteers. This study supports the claim for bio-remodeling of these stable
hybrid cooperative complexes of low- and high-molecular-weight HA.
Keywords: hyaluronic acid, bio-remodeling, facial rejuvenation, hybrid cooperative complexes

Introduction
Bio-revitalization is an esthetic medicine technique for improving skin characteristics,
Correspondence: Adele Sparavigna by intra-dermal injection of hyaluronic acid (HA)-containing compounds, leading to
DermIng srl, Clinical Research and
Bioengineering Institute, Viale Cesare
human fibroblast modulation.1
Battisti 38, Monza, MB, Italy The improved understanding of the structural changes involved in face aging has
Tel +39 039 329 666
Fax +39 039 232 9448
shifted the focus of treatment from just concentrating on isolated problem areas to
Email adele.sparavigna@derming.com multiple facial areas, for a global revitalizing and rejuvenation effect.2

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Sparavigna and Tenconi Dovepress

It is well known that society places great deal of impor- the name Profhilo. The composition of each syringe, accord-
tance on beauty, and cultural factors inevitably influence our ing to the International Nomenclature, was made of H-HA
perception of attractiveness, but several lines of research (1,100–1,400 kDa) and L-HA (80–100 kDa) 32 mg each
indicate that, besides social and cultural factors, there may in 2 mL of buffered sodium chloride physiologic solution.
be biologic correlates of attractiveness.3,4 The list of materials employed in the study, including
Evenly colored, smooth, elastic skin is viewed as attrac- those for the objective/instrumental assessments, is displayed
tive and healthy.5 Studies have demonstrated that skin surface in Table 1.
topography and skin coloration affect the perception of facial
age, health, and attractiveness in both men and women.5,6 Subjects selection and study design
One of the primary skin aging processes, resulting in loss This evaluation was a monocentric, open-label, not-con-
of skin elasticity and turgidity, consists of decreased fibro- trolled, exploratory study, which aims to assess the global
blasts activity with reduction in the biosynthesis of dermal bio-remodeling effect on the facial frame of healthy female
extracellular matrix components and HA.7,8 volunteers of hybrid complexes of L-HA and H-HA injected
HA is a polysaccharide capable of maintaining the correct in five predetermined different areas bilaterally on the face.
moisturization of tissues and inducing optimal conditions for The study center was the DermIng srl, a single member
the proliferation of dermal cells.9 company, Clinical Research and Bioengineering Institute,
The product studied (Profhilo® produced and distributed Monza, Italy.
by IBSA Farmaceutici Italia Srl, Lodi, Italy) is a medical The study involved 64 female subjects, aged 30–60 years,
device containing a blend of high- and low-molecular-weight who gave written informed consent for the use of their photo-
HA (H-HA and L-HA) packed in prefilled glass disposable graphs in this study and for the study procedures, including
syringes for local injections. the specific requests for keeping the same habits on food,
This product contains a highly purified sodium salt of HA, exercise, make-up, cosmetics, and detergent, and avoiding
obtained without any chemical modification through a patented ultraviolet exposure without a total block cream.
technology based on stable hybrid cooperative complexes of Exclusion criteria were (as per protocol): pregnancy,
H-HA L-HA (NAHYCO™ technology). The concentration lactation, not being in menopause without adequate contra-
of HA is 3.2%, with 32 mg of H-HA and 32 mg of L-HA, in ception or not willing to perform the pregnancy test sched-
2 mL of buffered sodium chloride physiologic solution. uled in the protocol, performing skin treatments of esthetic
The simultaneous presence in a single injection solution
of different HA molecular weights (high and low) enables
Table 1 Materials and instruments employed in the study
the integration of endogenous HA levels with balanced con-
Materials Model/producer/country
centrations of stabilized HA hybrid complexes.
Profhilo®: 2.25 mL non-pyrogenic IBSA Farmaceutici Italia srl, Italy
L-HA, which binds to specific receptors, stimulates
prefilled syringe, containing 2 mL of
fibroblasts and keratinocyte proliferation, providing nourish- 3.2% hyaluronic acid (HA) for intra-
ment and deep hydration to the aged skin. The technology, dermal use (32 mg H-HA + 32 mg
rheological, and biological proprieties have been described L-HA dissolved in 2 mL of saline-
buffered sodium chloride)
by D’Agostino et al.10 On the other hand, H-HA, owing to
Camera 3D Vectra H1, Canfield, USA
its high capacity to bind water molecules and interact with Corneometer CM825, Courage-Khazaka, Köln,
collagen and proteoglycans, exerts a dermal scaffold action. Germany
The aim of the study was to explore the clinical efficacy MoistureMeterD Delfin Technologies, Kuopio,
Finland
and tolerability of the product using a prospective design and, Primos compact portable GFMesstechnik, Teltow,
besides the standardized clinical judgment of investigators11,12 Germany
and the volunteers self-evaluation, some well-regarded quan- Optical colorimetry Chroma meter CR-200 Minolta,
Japan
titative outcome measures.13–16
Silicon liquid Optosil – Heraeus Kulzer,
Germany
Materials Catalyst Universal Activator – Optosil® –
The injectable medical device evaluated in this study is based Xantopren®, Germany
FotoFinderDermoscope TeachScreen, Germany
on NAHYCO technology and produced following the proce-
Dermal Torque Meter Dia-Stron Ltd, UK
dure described in patent application WO2011EP65633. This Abbreviations: 3D, three-dimensional; HA, hyaluronic acid; H-HA, high-
product is distributed by IBSA Farmaceutici Italia Srl with molecular-weight HA; L-HA, low-molecular-weight HA.

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Dovepress An open study with hyaluronic acid injections for facial frame bio-remodeling

c­ orrection (biomaterials implant, face lifting, Botox injection, After a clinical and instrumental assessment, they were
laser, chemical peeling) in the 12 months prior to the study treated bilaterally with the first injection treatment on the
start, having performed permanent filler, having an anamnesis predetermined face points.
for sensitivity to the test product or its ingredients, having in All the instrumental evaluations, at baseline and during
the opinion of the investigator an expected lack of adhesion the following visits, were carried out mono-laterally, accord-
to study procedure, participating in a similar study within ing to a randomization list, which assigned each subject to
the previous 3 months, being affected with dermatologi- the evaluation of the right or the left side of the face.
cal diseases of the face, as well as scars of malformations, Four weeks after the baseline visit, clinical and instrumental
being affected with general significant diseases (diabetes, assessments and the second round of bilateral injections were
endocrine, hepatic, renal, cardiac, pulmonary disorders, performed. The next assessments were scheduled at 8 weeks
cancer, neurological or psychological diseases, inflammatory/ (T8W), 12 weeks (T12W), and 16 weeks (T16W) from the
immunosuppressive disease, drug allergy), and undergoing baseline. At week eight, a global tolerance evaluation of the
some pharmacological treatments (anti-inflammatory, anti- product was carried out by the investigators and volunteers,
histaminic, topic and systemic corticosteroids, narcotics, using a five-point ordinal scale. From week 8–16, a self-assess-
antidepressants, immunosuppressive drugs, and any drug able ment questionnaire on efficacy was filled by the volunteers.
to influence results in the investigator’s opinion).
Outcome measures
Ethical and regulatory aspects Efficacy
A final version of the study protocol and appendices was The efficacy outcome measures were both clinical and
submitted to the Local Ethic Committee at DermIng srl; instrumental. All instrumental evaluations were carried out
on December 5, 2014, the study obtained the approval; an mono-laterally for each subject, on the right or left side,
amendment to the protocol on minor study procedure modi- according to a randomization list.
fication was approved on April 30, 2015. Clinical assessments employed three rating scales: The
This study was performed in agreement with the Dec- first was the Wrinkle Severity Rating Scale (WSRS),10 a
laration of Helsinki. Before the screening, all subjects gave validated categorical five-point rating scale assessing face
written informed consent. wrinkles, ranging from 1 (absent) to 5 (very severe). The
second scale was the Facial Volume Loss Scale (FVLS),11
Injection technique a well-regarded categorical five-point more global scale on
The product, a medical device class III, is provided in pre- folds and creases, as well as volume loss in the different
filled syringes of 2 mL. The product was administered bilat- facial zones. The third one, Beagley and Gibson Scale, a four-
erally in 0.2 mL bolus with the 29-G needle provided with point categorical one, evaluating the skin surface microrelief
the product injected in the deep dermis. The injections were regularity grade, was applied by clinicians on the pictures
performed in the following five predetermined points of each acquired by the FotoFinderDermoscope (TeachScreen, Bad
subject’s face, in the malar and sub-malar areas: zygomatic Birnbach, Germany), ranging from grade 1 (same depth of
protuberance, nostril’s angle, inferior margin of the tragus, lip primary and secondary lines) to 4 (deep primary lines distor-
marionette lines, and mandibular angle. These points were the tion and loss of secondary lines).
same described by Laurino et al.17 This injection technique From week 8, volunteers were asked to fill a self-evalu-
focuses the action of the study treatment, where the skin ation questionnaire, both on efficacy (superficial and deep
appears loose and with a loss of turgor and tone, concentrating wrinkles, skin suppleness, skin smoothness, skin brightness,
a defined volume of the compound in the malar and sub-malar skin hydration, skin lifting, face silhouette) and global toler-
region. Moreover, this results in fewer injection points and ance (bad, poor, medium, good, excellent).
less possibility of side effects. The injection treatment was Instrumental, noninvasive evaluations employed were:
performed at baseline (T0) and after 4 weeks (T4W). optical colorimetry (Chroma meter CR-200 Minolta, Osaka,
Japan), electrical capacitance of the skin (indicative of skin
Assessments surface hydration) (Corneometer CM825, Courage-Khazaka,
After the detailed explanation of the study procedures and Köln, Germany), tissue dielectric constant of superficial and
the signature of the informed consent form, the subjects were deep skin layers (another measure of hydration taken with
checked for inclusion and exclusion criteria, and, if eligible the MoistureMeterD (Delfin Technologies, Kuopio, Finland),
for the study, enrolled. measuring skin layer up to 5 mm deep), torsiometry (measures

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299
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Sparavigna and Tenconi Dovepress

of skin plasto-elasticity: immediate and maximum extensi- Efficacy results

bility, viscoelasticity, immediate elastic recovery) (Dermal Results from clinical assessments were significant (P<0.05,
Torque Meter, Dia-Stron Ltd, Andover, UK), profilometry after testing for multiplicity) from week 4 for the skin surface
(replicas of nasolabial folds and marionette lines obtained with microrelief: −16.1% at T4W, −19.4% at T8W, 16.1% at T12W,
silicone rubber coupled with the Primos software elaboration), and −12.9% at T16W (Figure 1), corresponding to a reduction
and photographic documentation (three-dimensional [3D] of the clinical score (visual evaluation on FotoFinderDermo-
pictures taken with Vectra H1, Canfield, Parsippany, NJ, USA). scope acquired images) of at least 1 grade, respectively, on
Moreover, face volume instrumental analysis was carried 52%, 58%, 55%, and 39% of included subjects compared
out on the 3D pictures taken at baseline, week 8, and week 16. to the baseline.
Specifically, the Vectra analysis module overlays the images The results were also significant from week 8 for the rat-
taken at two different time points and automatically calculates ing in the FVLS of “cheek volume loss” and in the WSRS rat-
the volume differences through a color distance map. ing of “wrinkle severity”. FVLS showed a reduction of 21.2%
at T8W, 24.2% at T12W, and 18.2% at T16W (Figure 2),
Safety corresponding to a reduction of the clinical score of at least
The assessment of safety was based on the frequency of 1 grade, respectively, on 62%, 70%, and 55% of volunteers
adverse events and the evaluation of local tolerability. compared to the baseline. WSRS showed a decrease of 11.8%
Adverse events were defined in the protocol according to at T8W, 14.7% at T12W, and 14.7% at T16W (Figure 3),
Good Clinical Practice and treated accordingly. corresponding to a decrease of the clinical score of at least
1 grade, respectively, on 35%, 45%, and 46% of included
Statistical methodology subjects compared to the baseline.
The population to be analyzed were all subjects who com- Results from instrumental assessments were statistically
pleted the study according to the protocol. significant on the majority of parameters: starting from
The statistical analysis of clinical data was to be carried week 4 for the superficial skin hydration and from week 8
out with nonparametric test while the instrumental data were for the skin deep layers hydration; the effect size was more
planned to be analyzed with analysis of variance for repeated pronounced on the skin electrical capacitance (indicative of
measure or with nonparametric tests in case of non-normality skin surface hydration) (Figure 4).
of data distribution, as proved by the K­ olmogorov–Smirnov Regarding skin profilometry, image analysis of nasola-
test. Alpha level was set to 0.05. bial folds/marionette lines skin replicas found a statistically
significant reduction (P<0.05) on the following parameters:
Results average roughness, wrinkles total high, and wrinkles’ maxi-
A total of 64 white female volunteers, age range 38–60 years mum depth. The percentage of reduction from baseline at
(mean 53±5.20 years), were enrolled. Slightly more than half week 16 reached 9.7%, 8.2%, and 9.6%, respectively, indicat-
of the volunteers (35 of 64, 55%) had had a previous esthetic ing a long-lasting effect of the microinjections.
treatment for the face in 2013 or the first month of 2014, The evaluation of the principal torsiometric parameters
mostly for a bio-revitalization purpose. The present study Ue (immediate extensibility), Uf (final extensibility), Uv
began on March 11, 2015, more than a year after the last (viscoelasticity), and Ur (immediate elastic recovery) showed
esthetic treatment was performed on some of the volunteers. at week 16 a statistically (P<0.05) significant decrease of Uf
After having agreed to participate in the study and signed and Uv, with a reduction of 10% and 17.1%, respectively.
the informed consent, the volunteers were evaluated both The improvement in the other two parameters (Ue and Ur)
clinically and with the instrument devices, and received the did not reach statistical significance.
first expected injections of HA and, the second, after 4 weeks. No significant differences were observed in the optical
Not all subjects were fully compliant with the procedures. colorimetry parameters.
Four volunteers withdrew due to “personal reasons” after Face volume analysis highlighted an increase of volume
the second microinjection session and were excluded from versus T0 of 0.549 cm3 at T8W and of 0.0476 cm3 at T16W
the analysis. Another four subjects did not come to the last (Figure 5), corresponding to an increase of at least 0.2 cm3,
visit, again due to personal reasons, but were included in respectively, on the 73% and 65% of the analyzed subjects
the analysis, using the week 12 assessment data as the final. compared to the baseline.
No major protocol violations were recorded, and there were Results of the efficacy volunteers’ self-evaluation showed
no missing data. an increase in positive assessments throughout the weeks,

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Dovepress An open study with hyaluronic acid injections for facial frame bio-remodeling

Surface microrelief
(Fotofinderdemoscope images)

T0 (baseline)
T4W (4 weeks after the first injection procedure)
T8W (8 weeks after the first injection procedure)
4
T12W (12 weeks after the first injection procedure)
T16W (16 weeks after the first injection procedure)
3.1
Visual score (mean value)

2.7
3 2.6 2.6
2.5

2 * * *
–19.4% *
–16.1% –16.1%
–12.9%

Figure 1 Reduction in the surface microrelief throughout the study.

Note: *P<0.05 vs T0.

Facial volume
(FVLS reference photographic scale)

T0 (baseline)
T4W (4 weeks after the first injection procedure)

5 T8W (8 weeks after the first injection procedure)

T12W (12 weeks after the first injection procedure)
T16W (16 weeks after the first injection procedure)

4 3.3
3.1
Visual score (mean value)

2.6 2.7
2.5
3

2
*
* –24.2% *
–6.1% –21.2%
1 –18.2%

Figure 2 Reduction in the FVLS “cheek volume loss” throughout the study.
Note: *P<0.05 vs T0.
Abbreviation: FVLS, facial volume loss scale.

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Wrinkles severity grade

(WSRS reference photographic scale)

T0 (baseline)
T4W (4 weeks after the first injection procedure)

5 T8W (8 weeks after the first injection procedure)

T12W (12 weeks after the first injection procedure)
T16W (16 weeks after the first injection procedure)
3.4
4 3.2
3.0
Visual score (mean value)

2.9 2.9

2
* * *
–5.9% –11.8% –14.7% –14.7%

Figure 3 Reduction in the WSRS “wrinkle severity” throughout the study.

Note: *P<0.05 vs T0.
Abbreviation: WSRS, wrinkle severity rating scale.

Instrumental evaluation
skin electrical capacitance (skin surface hydration)

80

70 60.56 62.39

58.02
60 52.49
AU (mean value)

50 44.84

40
*
*
39.1% *
35.1%
30 * 29.4%
17.1%

20

10

0
T0 (baseline) T4W (4 weeks T8W (8 weeks T12W (12 weeks T16W (16 weeks
after the first after the first after the first after the first
injection injection injection injection
procedure) procedure) procedure) procedure)

Figure 4 Variation from baseline in the skin electrical capacitance.

Note: *P<0.05 vs T0.
Abbreviation: AU, arbitrary unit.

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Instrumental evaluation
3D face volume image analysis

1.0

0.8
Volume increase (cm3)

0.6

0.549
0.476
0.4

0.2

0.0
∆ T8W (8 weeks after the ∆ T16W (16 weeks after the
first injection procedure) first injection procedure)
versus T0 (baseline) versus T0 (baseline)

Figure 5 Three-dimensional face volume analysis: increase of volume (cm3) T0 versus T8W and T16W versus T0.

starting from week 8. Results from week 16 are displayed treating multiple facial areas.1,2 The technique employed
in Figure 6, with bar plots indicating the percentages on the in this study is performed by deep intra-dermal injection
different items of the questionnaire. of HA; the product under investigation contains 32 mg of
H-HA and 32 mg of L-HA in a 2 mL syringe. The results
Safety results of this explorative prospective study, evaluating the clini-
Regarding tolerability and safety, after the first and the second cal efficacy and tolerability of this class III device, clearly
treatment, nine volunteers (14%) reported the appearance supports the bio-remodeling and rejuvenation claim of the
of light bruises on the injection points, while another five hybrid cooperative complexes.
subjects (7.8%) reported light edema at the injection points. All subjective clinical outcomes and the majority of objec-
Both light bruises and light edema were reported to disappear tive instrumental ones have indicated a rapid and statistically
between 3 and 10 days after the injections. significant improvement in the face attractiveness parameters.
After the first session, one subject referred a light pinch- In particular, starting 4 weeks after the first microinjection,
ing sensation at the injection points, which were reported to volumetric effect and tightening effect, as measured by the
disappear after 2 weeks. Facial Volume Loss Surface score and confirmed by the 3D
Four weeks after the second treatment session, the face volume analysis and by the Skin Surface Microrelief
investigators judged the product tolerance as good (30%) evaluation, were significant and maintained until the end of
or excellent (70%), while the subjects’ self-assessment of the study. From week 8, a filler, anti-wrinkles, plumping,
tolerability was good (48%) or excellent (52%). and moisturizing activity become statistically significant, as
measured by the reduction of WSRS score, profilometric,
Discussion torsiometric, and skin electrical capacitance parameters.
The perception of facial age, health, and attractiveness These instrumental and clinical findings are also con-
has been demonstrated to be influenced by skin surface firmed by the photographic documentation (Figures 7 and 8).
­topography and appearance, and the aim of the bio-revi- A minor percentage of volunteers (23%) showed mild and
talization procedures is indeed to improve the global face, temporary local reactions (light bruises and light edema) to

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2% 0% 0% 0%
4% 4% 4% 4%

14% 18% 21%

30% 38% 28%

34%
48%

43%
55% 50%

45%
45%
46% 48%
32%

13% 29%
25%
16% 19%
18%
14% 12%
14%
5% 5% 4% 7%
2% 2% 2%
Reduction of Reduction of Lifting Improvement Improvement Improvement Improvement Reshaping of
deep wrinkles superficial effect of skin of skin of skin of skin face silhouette
wrinkles firmness smoothness brightness hydration
Absent Light Medium Marked Very marked

Figure 6 Stacked bar plots of self-assessed efficacy by volunteers at week 16.

A B

Figure 7 Subject 11 (49 years old): (A) T0 Baseline and (B) T8W 8 weeks after the first injection procedure.

the procedures, expected events imputable to the injections, subjective assessments and majority of the objective ones,
and “nonspecific skin reactivity” in subjects unknown to indicating full face effects, consistent with the claim of bio-
have allergy and/or cosmetic intolerances. The final product remodeling effect.
tolerance was judged good or excellent in all subjects, both The main limitation of the study was the not-controlled
by the investigators and the volunteers. nature of the trial, but this fact could be compensated by
The points of strength for the present study were the the presence of objective instrumental efficacy outcome
rapid and persistent statistical significant effect in all the measures and consistency of results across all assessments.

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A B

Figure 8 Subject 19 (39 years old): (A) T0 Baseline and (B) T8W 8 weeks after the first injection procedure.

Disclosure 9. Redbord KP, Busso M, Hanke CW. Soft-tissue augmentation with

hyaluronic acid and calcium hydroxyl apatite fillers. Dermatol Ther.
The study was supported by IBSA Farmaceutici Italia srl, 2011;24(1):71–81.
the company that distributes the product used in the trial. 10. D’Agostino A, Stevellato A, Busico T, et al. In vitro analysis of the
effects on wound healing of high- and low-molecular weight chains of
The authors report no other conflicts of interest in this work. hyaluronan and their hybrid H-HA/L-HA complexes. BMC Cell Biol.
2015;16(1):19.
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