Katsantonis Ioannis MD PhD; Tampouratzi Eleftheria MD; Talaiporou Kyriakos Bsc Msc;*

This article was published by Zartaux Medical Aesthetics

ABSTRACT

Background: Nasolabial wrinkles or folds (NF) treatment outcome has been widely considered as a strong criterion to estimate overall esthetic results, of different type Hyaluronic Acid (HA) injectable fillers which have been gradually undergone a lot of modifications, classified as monophasic or biphasic ones. Monophasic fillers would be further divided to monodensified or polydensified. The purpose of the present split face study concerned clinical efficacy, result duration and overall skin reaction of two different hyaluronic acid injectable fillers for nasolabial wrinkles: facial right NF were treated with monophasic, polydensified HA filler, while the left ones were treated by a scientifically modified monophasic monodensified counterpart.
Methods: Fifteen (15) facial aesthetic patients (mean age 52, 47 ± 9,39) consented to participate in the study. Injection technique and injected HA quantity was always the same. The outcome was estimated by both Wrinkle Severity Rating Scale (WSRS) and GAIS – ANOVA statistical methods. Besides, the assessment of post-treatment naturalness feeling was calculated with FACE-Q questionnaire. Base line photos were taken in standardized settings. The follow-up visits were concluded in 1st, 6th and 12th months respectively.
Results: Both HA injectables have been shown to offer similar effectiveness concerning aesthetic outcome and result duration, by interpretation of WSRS and GAIS findings. However, by using the FACE questionnaire, results were decisive about the subjective feeling or naturalness, in favor of the monodensified HA products (p<0.05).
Conclusion: All subjects have reported that although there was not any obvious sign of skin irregularity in both injected wrinkles, after a big smile (mouth wide open), they expressed the feeling of intracutaneous tension in the right NF, while there was not at all such a feeling in the left one (treated with the monodensified molecule). Although, some limitations would exist regarding the subjectivity of the answers, the unanimous patient’s choice for the monodensified product, as more compatible to natural feeling, offers a reasonable argument to support strongly the implementation of the studied modified HA injectable product in every day common aesthetic clinical practice.

INTRODUCTION

Injectable Hyaluronic Acid (HA) fillers are a type of temporary dermal fillers, which have predominated all over the aesthetic medicine, as the main non-surgical anti-wrinkle intervention [1]. These fillers have been proven quite effective to inverse facial sagging by restoring the volume loss and by filling the sunken areas, caused by deep (linear) wrinkles [2].
The most prominent and esthetically striking skin deficits of that type are the nasolabial wrinkles or folds (NF), which represent an undoubtedly eye catching sign of aging.
Therefore, NF treatment outcome, has been widely considered as a strong criterion to estimate both efficacy and durability of different type HA injectable fillers [3].

Although more youthful appearance is the main target, natural looking results are also constantly demanded by aesthetic patients [4]. On that purpose, HA fillers have been gradually undergone a lot of modifications to optimize durability along with naturalness [5].

To further analyze, HA fillers have been cross-linked with intermolecular bonds, permitting the product stability by delayed degrading of the injected material into the dermal tissue [6].

However, the price of HA longevity acquired by cross-linking, is the endotoxins increase [7]. Hence, trying to minimize the cross-linking molecules quantity, different techniques have been developed to optimize the HA filler tissue behavior [8].

According to these techniques, HA fillers could be classified as monophasic or biphasic ones (8). Monophasic fillers are consisted of a rather homogeneous mixture of different molecular weight HA, while heterogeneous biphasic HA contain cross-linked particles dispersed in a flaccid vehicle [9].

Monophasic fillers probably perform better tissue results and would be further divided to monodensified (cross-linking after homogenous mixing) or polydensified (cross-linking at early separate stages, before the eventual filler production) [10].

Since the forementioned structural differences have been noted to interfere seriously in the aesthetic outcome, concerning both duration and natural appearance, close clinical observation of various monodensified HA fillers behavior on treating NF, would reasonably be a reliable criterion to overall estimate their apparent esthetic effectiveness.

MATERIALS AND METHODS

A) Patients

Fifteen (15) females (aesthetic) patients were eligible to take part voluntarily in the study. They all consented after given detailed information about the split face observation method as scheduled.
Subjects age ranked from 40 to 70 (mean age 52,4 Std (+-) 2,42).

No previous surgery or permanent fillers injections were reported (excluding criteria, along with any filler injection less than two years ago).
The under-treatment NF were of similar age-related course, and severity of grade 4 according to the Wrinkle Severity Rating Scale [11].

The skin phototype was II - III (Fitzpatrick).
All of them underwent the filler injections as described following, in section C.

B) Nasolabial folds improvement

The outcome was estimated by both WSRS and Global Aesthetic Improvement Scale (GAIS), methods [11, 12]. The technique was kept always the same (retrograde linear deposition with the same filler quantity into both wrinkles of each one subject).

Base line photos were taken in standardized settings with a high-resolution camera, while each one esthetic patient, was asked to keep the same non-moving expression (smiling etc.)

C) HA molecule comparison

In all cases facial right NF were treated with the established technology HA filler consisted of monophasic, polydensified molecules, while the left ones were treated by the under-investigation HA filler with molecular basis made up by monophasic monodensified ultrafine multi-spheres, according to the innovative S.C.E.D.I.S.™ method, as depicted below in Figure 1.

Figure 1
HA fillers used for the right NF treatment originated the established monophasic type of line production, whilst their injectable counterparts for the left NF elevation resulted by modified HA linearized chains according to the science method S.C.E.D.I.S.™.

D) Duration of the result

Subjects were photographed before, immediately after, one month after and 12 months after HA injections. According to both clinical aspect and estimation by photography comparison, the wrinkle depth was given the corresponding values, following the referred methodology [13].

E) Statistical Analysis

Statistical Analysis was performed by using Friedman’s ANOVA followed by post-hoc Wilcoxon Signed Ranks, with Bonferroni adjustment and Mann-Whitney U, according to widely established methods [14], whilst the FACE-Q scale and checklists, in order to estimate the subjects feeling of naturalness, was carried out by the methodology shown in Table 1 [15].

Table 1. Content of the FACE-Q Scales and Checklists

RESULTS

In Figure 2, the most typical cosmetic outcomes are presented, confirming that “a picture paints a thousand words”. Performed statistical analysis corroborated this, as shown in Table 2a, 2b, 2c. (MP: Monophasic Polydensified, MM: Monophasic Monodensified).

Figure 2

Figure 2. Random cases citation, clearly depicting a noticeable and time sustained cosmetic result, in both NFs, indifferently of the HA type used.

Table 2a. The overall reduction of WSRS after filler application

Table 2b. The reduction of WSRS after filler application on the right side.

Table 2c. The reduction of WSRS after filler application on left side.

Table 2a, 2b, 2c. There is a statistically significant difference between the measurements of the Baseline and every following measurement, independently of whether the sample is tested as a whole, or each side is tested separately (p<0,001 for a=0,05). However, both sides behaved in an almost identical manner. This means that there was a significant improvement in the WSRS score. The mean score appeared to be reduced from the 4.40 baseline score by 1.77 units when measured at the end of the first month, while getting reduced all the way to a mean score of 2.50 by the end of the final measurement 12 months later (p<0,001 for a=0,0083). The results are depicted in the diagrams above.

In addition to this, the statistics according to GAIS score, demonstrated a similar cosmetic response, one more time for both sides (p>0.05), remaining optimal over the course of one year (p=0.3). The above results are shown in Table 3, and furthermore are clearly depicted in Table 2a, 2b, 2c.: It is more than obvious that both NF responded adequately to the tested HA filler types. And this esthetic amelioration, lasted for at least 12 months.

Table 3. Descriptive Statistics for GAIS scores

By this method, it was tested whether the sample both as whole and each of the slides individually had a significant improvement on the GAIS scale and how well this was maintained over the course of 12 months. Friedman’s ANOVA failed to reject the null hypothesis for the sample as a whole (n = 30) suggesting that the improvement that has been recorded on the Baseline measurement remained similar over the course of one year (p=.300 for a=.05)

Table 4. BAR CHART

Cumulative Frequency Bar Chart for the FACE-Q variable presenting the stacked frequencies of the medians of each category for the two sides. The x axis presents the two sides. The categories presented in the y axis are: 2, somewhat dissatisfied (blue block); 3, somewhat satisfied (green block); 4, very satisfied (yellow block). The subcategories are a result of the median function used to calculate the FACE-Q variable from the 10 items and occur between two categories: 2.5, (red block); 3.5, (orange block). The overall conclusion strongly supports the subjects feeling of naturalness after NF filling with monophasic monodensified HA product.

Following the FACE-Q questionary, as analyzed earlier, a bar chart was drawn (Table 4), demonstrating that MM HA fillers outweighs strongly the MP ones, taking in account esthetic patients feeling of naturalness. A statistical significance came out and it is clearly shown in Figure 4. It has been shown that the left side injected, offered a more “comfort feeling” than the right one (p<0.01).

Figure 4.
The patient’s satisfaction evaluated with FACE-Q after filler application on the left and right side comparatively.

Line Chart representing the number of cases for each side in each category of the FACE-Q variable. The “x” axis presents the number of cases and the “y” axis presents the values taken by the FACE-Q variable. A statistical significance was evident between the two groups when the measurements of the twelfth month were compared (p=0.01). That leads us to the conclusion that patients perceived a noticeable difference concerning natural feeling between the two sides of their face.

DISCUSSION

In the present study, both HA injectables have been shown to offer similar effectiveness concerning aesthetic outcome and result duration as well.
This was clearly depicted by the photos taken during the follow-up observation (1 month – 6 months – 12 months), and was demonstrated statistically by WSRS and Scale – GAIS methods (p>0.05).
This was somehow expected, since it has been repeatedly reported that similar concentrations of HA products lead to similar injectable results, concerning the wrinkle depth elevation, no matter their biphasic or monophasic composition. In line with this, it seems that, in our hands, the durability of the result is not seriously affected by those composition differences [5].
So, herewith it was confirmed that mono- or polydensified nature of the investigated monophasic HA products, had few things to do with aesthetic result and durability.
The main factor for optimized outcome seems to be the physician’s technique, along with injected quantity.
Same quantity, under the same injector led to almost same results, as expected [16 ,17].
However, dealing with aesthetic practice, we should seriously take in account the overall degree of every single participant satisfaction. This was approached by using the FACE questionnaire [15].
Regarding this, results were decisive about the subjective feeling or naturalness, in favor of the monodensified HA products (p<0.05).
Meanwhile, all patients were intensively satisfied in comparison to their base line appearance (p<0.001).
All subjects have reported that although there was not any obvious sign of skin irregularity in both injected wrinkles, after a big smile (mouth wide open), they expressed the feeling of intracutaneous tension in the right NF, while there was not at all such a feeling in the left one (treated with the monodensified molecule).
In addition, they alike affirmed their preference, when time would come, to repeat the cosmetic HA injections procedure by the left side used injectable product.
Although, some limitations would exist regarding the subjectivity of the answers, the unanimous patients choice for the monodensified product, as more compatible to natural feeling, offers a reasonable argument to support strongly the implementation of the studied modified HA injectable product in every day common aesthetic clinical practice.
These fillers seem to surpass the common HA injectables in aesthetic patients feeling of naturalness, while simultaneously they have been shown to fulfill all the demanded criteria for optimum cosmetic results.

ACKNOWLEDGMENT

This study was totally supported by Sandine Zartaux Holding Ltd., by providing all injectable materials. Authors are expressing their gratitude about this.

*Corresponding authors:

Katsantonis Ioannis MD PhD; Devoli 10 Str., 16121 Athens Greece Email: johnkatsadonis@hotmail.com

Tampouratzi Eleftheria MD; Deligiorgi 15 Str., 18553 Piraeus Greece Email: elefteria_tab@yahoo.gr

Talaiporou Kyriakos Bsc Msc; Pentelis 8 str., 12243 Athens Greece Email: kyriakostalaiporou@gmail.com

REFERENCES

[1] Keen M. A. Hyaluronic Acid in Dermatology. SKINmed, 15(6):441-448, 2017

[2] Pereira H., Sousa D. A., Cunha A., Andrade R., Espregueira-Mendes J., Oliveira J. M. & Reis R. L., Hyaluronic Acid. Part of the Advances in Experimental Medicine and Biology book series. AEMB, (vol 1059): 137-153, 2018

[3] Benjamin Ascher, Christiane Bayerl, Philippe Kestemont, Berthold Rzany, Carolina Edwartz, Maurizio Podda, A. 12-Month Follow-up, Randomized Comparison of Effectiveness and Safety of Two Hyaluronic Acid Fillers for Treatment of Severe Nasolabial Folds. Dermatol Surg, 43(3): 389–395, 2017

[4] Wolfgang G Philipp-Dormston, Bernd Schuster, Maurizio Podda, Perceived naturalness of facial expression after hyaluronic acid filler injection in nasolabial folds and lower face, J Cosmet Dermatol. 2020 Jul;19(7):1600-1606.

[5] Adilson da Costa, Danilo Guerreiro Zeolo Biccigo, Ellem Tatiani de Souza Weimann, Larissa Mondadori Mercadante, Paulo Roberto Grimaldi Oliveira, Stefânia Bazanelli Prebianchi, Beatrice Martinez Zugaib Abdalla, Durability of Three Different Types of Hyaluronic Acid Fillers in Skin: Are There Differences Among Biphasic, Monophasic Monodensified, and Monophasic Polydensified Products? Aesthetic Surg Jour, 37, (5): 573–581, 2016

[6] Xiao Zheng Shu, Yanchun Liu, Fabio S Palumbo, Yi Luo, Glenn D Prestwich, In situ crosslinkable hyaluronan hydrogels for tissue engineering. Biomaterials, 25(7-8):1339-48, 2004

[7] David Stocks, Hema Sundaram, Jason Michaels, Manzer J Durrani, Mitchell S Wortzman, Diane B Nelson, Rheological evaluation of the physical properties of hyaluronic acid dermal fillers. J Drugs Dermatol, 10(9):974-80, 2011

[8] Berthold Rzany, Christiane Bayerl, Isaac Bodokh, Dominique Boineau, Thomas Dirschka, Catherine Queille-Roussel, Michael Sebastian, Boris Sommer, Carolina Edwartz, Maurizio Podda, An 18-Month Follow-up, Randomized Comparison of Effectiveness and Safety of Two Hyaluronic Acid Fillers for Treatment of Moderate Nasolabial Folds. Dermatol Surg. 2017, 43(1):58-65, 2017

[9] Timothy Corcoran Flynn, Didier Sarazin, Alain Bezzola, Cyrus Terrani, Patrick Micheels, Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol Surg, 37(5):637-43, 2011

[10] J Åke Öhrlund, Katarina L M Edsman, The Myth of the "Biphasic" Hyaluronic Acid Filler. Dermatol Surg, 41 (Suppl 1: S358-64), 2015

[11] Do Young Rhee, Chong Hyun Won, Sung Eun Chang, Tai Kyung Noh, Myoung Shin Kim, Beom Joon Kim, Gyeong Hun Park, Jee Soo An, Mi Woo Lee, Jee Ho Choi, Kee Chan Moon, Sung Hoon Lim, Efficacy and safety of a new monophasic hyaluronic acid filler in the correction of nasolabial folds: a randomized, evaluator-blinded, split-face study. J Dermatolog Treat, 25(5):448-52, 2014

[12] Daisy Kopera, Michael Palatin, Rolf Bartsch, Katrin Bartsch, Maria O'Rourke, Sonja Höller, Renate R Baumgartner, Martin Prinz, An open-label uncontrolled, multicenter study for the evaluation of the efficacy and safety of the dermal filler Princess VOLUME in the treatment of nasolabial folds, Biomed Res Int. 2015:195328.

[13] Wolfgang G Philipp-Dormston, Cindy Wong, Bernd Schuster, Markus K Larsson, Maurizio Podda, Evaluating Perceived Naturalness of Facial Expression After Fillers to the Nasolabial Folds and Lower Face With Standardized Video and Photography. Dermatol Surg, 44(6):826-832, 2018

[14] Ton J. Cleophas, Aeilko H. Zwinderman, Paired Continuous Data (Paired T-Test, Wilcoxon Signed Rank Test, 10 Patients), SPSS for Starters and 2nd Levelers pp 7–10, 2016

[15] Andrea L Pusic, Anne F Klassen, Amie M Scott, Stefan J Cano, Development and psychometric evaluation of the FACE-Q satisfaction with appearance scale: a new patient-reported outcome instrument for facial aesthetics patients. Clin Plast Surg, 40(2):249-60, 2013

[16] Richard G Glogau, Michael A C Kane, Effect of injection techniques on the rate of local adverse events in patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg, 34 (Suppl 1:S105-9), 2008

[17] Maya Vedamurthy, Amar Vedamurthy, Dermal Fillers: Tips to Achieve Successful Outcomes. J Cutan Aesthet Surg, 1(2):64–67, 2008