Comparative Clinical Study For The Efficacy And Safety Of Two Different Hyaluronic Acid-based Fillers With Tri-Hyal Versus Vycross Technology: A Long-term Prospective Randomized Clinical Trial Part 2
Jun 27, 2023
3.4 | Remanence and aesthetic benefits confirmed by the Global Aesthetic Improvement Scale (GAIS)
The investigator and subject satisfaction rates were assessed by the seven levels Global Aesthetic Improvement Scale (GAIS) score (from +3 for very much improved to −3 for very much worse). The overall impression of the expert investigators (iGAIS) was correlated to the score from the subjects themselves (sGAIS) for each treated area and at each time point. As shown in Figure 6, the evolution curves for ART FILLER® Volume and Juvéderm® Voluma overlaid confirming the similar efficacy of the fillers on volume restoration. Furthermore, the GAIS assessment performed by the investigators (Figure 6 left panels) conformed to the score recorded by the subjects (Figure 6 right panels). Interestingly, although no difference was observed between the 2 fillers for midface, jawline, and temple; the proportion of subjects feeling an aesthetic improvement at D540 was higher than the proportion of investigators (Table 1). This data support that the investigator's opinion on GAIS was reliable.
Glycoside of cistanche can also increase the activity of SOD in heart and liver tissues, and significantly reduce the content of lipofuscin and MDA in each tissue, effectively scavenging various reactive oxygen radicals (OH-, H₂O₂, etc.) and protecting against DNA damage caused by OH-radicals. Cistanche phenylethanoid glycosides have a strong scavenging ability of free radicals, a higher reducing ability than vitamin C, improve the activity of SOD in sperm suspension, reduce the content of MDA, and have a certain protective effect on sperm membrane function. Cistanche polysaccharides can enhance the activity of SOD and GSH-Px in erythrocytes and lung tissues of experimentally senescent mice caused by D-galactose, as well as reduce the content of MDA and collagen in lung and plasma, and increase the content of elastin, have a good scavenging effect on DPPH, prolong the time of hypoxia in senescent mice, improve the activity of SOD in serum, and delay the physiological degeneration of lung in experimentally senescent mice With cellular morphological degeneration, experiments have shown that Cistanche has the good antioxidant ability and has the potential to be a drug to prevent and treat skin aging diseases. At the same time, echinacoside in Cistanche has a significant ability to scavenge DPPH free radicals and has the ability to scavenge reactive oxygen species and prevent free radical-induced collagen degradation, and also has a good repair effect on thymine free radical anion damage.
Click On Cistanche Tubulosa
【For more info:george.deng@wecistanche.com / WhatApp:86 13632399501】
3.5 | Assessment of skin characteristics by high-frequency ultrasound
To further characterize the long-term morphological effects of filler injections, the dermal density and thickness were assessed at each visit for a selected number of subjects per zone (Figure 7). For the midface area (Figure 8A), the available data showed no significant effect on skin thickness for both fillers. However, a significant increase in skin density was observed only with ART FILLER® volume at D90 and D180. For the jawline (Figure 8B), no significant effect on skin thickness for both fillers was measured, but both products induced a significant increase in skin density that was observed until D540. Interestingly, this increase in skin density was more relevant with ART FILLER® Volume than with the reference product. For the temple area (Figure 8C), only a tendency to increase skin density was observed for both fillers. Similarly, a tendency to increase the chin skin density was measured for each time point and was significant for D90 only (Figure 8D).
3.6 | Analysis of the side effects induced by the fillers
Most of the reported reactions were slight pain during injection, erythema just after injection, or irregularities at palpation (Table 2). All detected events were expected and routinely seen with HA-based fillers. Most of these events disappeared at D21 and no serious adverse events have been reported during the study for both fillers. However, there is an important but not statistically significant difference in the tolerability of the two products in favor of ART FILLER® Volume. As shown in Table 2, the total number of adverse events tended to be higher by 30% for the reference product compared with ART FILLER® Volume.
3.7 | Ex vivo characterization of fillers-induced skin inflammation
To understand the differences between the slight and moderate side effects observed during the clinical phase, we analyzed the potential inflammation induced by the fillers on human skin explants. Using the skin micro-dialysis technic, we measured the levels of Interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-α), and histamine after the injection of saline solution, ART FILLER® Volume, or the reference product. Injection of fillers, such as hyaluronic acid, has been shown to induce local mechanical stress induced by the needle but also by tissue deformation due to volume augmentation.17 This mechanical stress is translated by biochemical, metabolic, and secretory profile modifications of the surrounding cells.17 Here, we found that injection by the reference item induced a rapid release of IL-8 that remained significant until 12 h post-injection and disappeared after 24 h (Figure 9A, B). This increase of IL-8 secretion was not observed either in control or for ART FILLER® Volume. Similarly, histamine secretion was rapidly increased by the injection of both products (Figure 9E, F). However, this secretion was significantly higher with the reference item at 1 and 6 h post-injection compared with ART FILLER® Volume. Finally, none of the tested fillers induced an effect on TNF-α release (Figure 9C, D).
4 | DISCUSSION
This study brought evidence for the non-inferiority of ART FILLER® Volume versus the reference Juvéderm® Voluma regarding volume restoration for the midface, jawline, and temple. Moreover, a satisfactory result was observed for all the studied area (including the chin) injected with ART FILLER® Volume. Three weeks post-injection, a significant improvement of the chin was observed for 80% of the subjects, 90% for the jawline, 93% for the midface, and 100% for the temple. The positive evolution was still observed 18 months postinjection (55% for midface, 53% for jawline, 62% for temple, and 73% for chin), and no significant difference between products was observed. Interestingly, these results were obtained without any touch-up injection during the whole study.
The success rates after injection observed in this study were similar to those reported previously.18,19 However, we noticed a faster decrease in the success rate for the midface when compared with previous studies using the same reference product Juvéderm Voluma (76% of success rate at 6 months versus 86% in Baumann, L. et al. and Jones, D. et al.18,20 studies and 96% in Jung, J.M. et al.19 studies, then 55% after 18 months versus 72% in Baumann, L. et al.18). Similarly, the satisfaction of the subjects was slightly higher on other published article, (71% of subjects that rated themselves as improved on the GAIS scale after 6 months versus 97% published by Baumann, L. et al. and Jones, D. et al.18,20 studies, and 50% after 18 months versus 71% published by Baumann, L. et al.18). These differences in the long-term efficacy may be related to the injected volume of filler and the possibility of touch-up injections during the studies. Here, 1.2 ml maximum was injected in the midface whereas an average of 6.6 ml was injected in Baumann, L. et al.18 6.65 ml in Jones, D. et al.20, and 6.68 ml in Few, J., et al.21 studies.
It has been demonstrated that an increase in dermis density and/or thickness is associated with an improvement in skin quality and smoothing of dermal depressions.22,23 The ability of the skin to reflect ultrasound echogenic signals comes principally from the dermis network of collagen and elastin fibers. Assessment of these parameters by high-frequency ultrasound revealed that the observed volume restoration was mainly due to an increase in dermis density. Interestingly, the dermis thickness has not been increased in any of the assessed areas despite a significant restoration of volume. We hypothesize that the absence of modification in skin thickness was due to the deep injections of the fillers. Indeed, these injections were far from the dermis layer and thus, the observed volume restorations could result from the interactions of the fillers with the hypodermis fat layer. Recently, a published article by Nadra et al.24 supports this hypothesis that the human adipocyte life cycle is influenced by highly cross-linked HA. The authors have demonstrated that in addition to their filler properties, HA-based fillers are excellent carriers of adipocyte cells to reconstruct and maintain the dimensions of volume loss.24 However, given that the echogenicity of the hypodermis is very low, our selected method of investigation did not allow us to measure these effects on the subcutaneous fat layer. Furthermore, the assessments remained exploratory and were performed on a small panel of subjects only. Still, the observations suggested that injection of ART FILLER® Volume or the reference product tended to increase the density of the skin (whatever the studied area) and that this effect persists over time. The possible reason for the higher effect of the ART FILLER® Volume may be due to Tri-Hyal Technology, which provides a good viscosity to the ART FILLER® Volume thanks to free HA within the composition.
Hyaluronic acid is the most used soft-tissue filler for facial volumizing treatment due to its favorable outcomes and safety profile. In this study, the injections were well tolerated, causing a few numbers of expected side effects such as erythema, hematoma, or spontaneous pain. The intensity of these reactions varied from light to moderate, beginning soon after application and promptly disappearing within a few days. The reported side effects were those typically expected following HA filler injection.25,26 As previously hypothesized by Micheels P, some rare inflammatory episodes due to allergic responses could explain such acute reactions.27 In addition, mechanical stress has been also described as the increase in pressure occasioned by the injection that causes the filler to flow naturally toward areas that deform easily such as the hypodermis, leading to a local modification of the biochemical, metabolic, and secretory profile of the surrounding cells. In this study, we observed a slight difference in the safety level of the two products in favor of ART FILLER® Volume (31% more events with the reference product). This hypothesis was explored using ex vivo human skin explants. A higher potential of the reference product, Juvéderm® Voluma to promote the secretion of IL-8 (a cytokine secreted by epithelial cells), and histamine (a factor secreted by macrophages) was observed. These data suggested a better tolerability and safety of ART FILLER® Volume regarding the acute inflammation induction compared with the Juvéderm® Voluma which could explain the safety clinical results. However, many variables can influence inflammation, including the filler properties, the application technique, the site of the injection, and the individual sensibility. Even if the 2 fillers were compared by contralateral injections and with similar treatment procedures, further exploration is needed to conclude the superiority of ART FILLER® Volume on Juvéderm® Voluma on acute inflammation. More recently, a direct effect of the COVID vaccination or infection has been demonstrated on the inflammatory reactions post-injection by HA-fillers. 28
5 | CONCLUSION
In conclusion, this study validated the efficacy and safety of the injectable hyaluronic acid-based filler, based on Tri-Hyal technology versus Vycross technology with a sustained efficacy for at least 18 months for the midface, temple, jawline, and chin. The evaluation methods used in this study confirmed its non-inferiority to the CEmarked comparator for all injected areas, except for the chin where the evaluations were non-comparative. Taken together, the methodology and observations brought a reliable approach for the long-term assessment of HA fillers.
AUTHOR CONTRIBUTIONS
All authors made substantial contributions to the acquisition of data, drafting and revising the manuscript for important intellectual content, approved the final version, and agreed to be accountable for all aspects of the work. Further, FF and KN conducted the study design, management, and data analysis. FB, PG, HD, FL, LB, and PK were all study investigators. FB, FF, PG, HD, FL, LB, KN, and PK made a substantial contribution to the interpretation of the data.
ACKNOWLEDGEMENT
A special thanks to Hanane Issa and Shannel Curic for their remarkable help in monitoring and data recovery. The authors deeply thank Sophie Mac, Jean-Marie Sainthillier, Marie-José Moschetti, Ana De Lemos, Luc Sentier, Elizabetta Izzo, and Berengere Boucly for their dynamic support from the concept to the execution of the study.
CONFLICT OF INTEREST
FF and KN are employees of FILMED Laboratories. There is no conflict of interest for any other authors.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
1. Gilbert E, Hui A, Waldorf HA. The basic science of dermal fillers: past and present part I: background and mechanisms of action. J Drugs Dermatol. 2012;11(9):1059-1068.
2. Narins RS, Bowman PH. Injectable skin fillers. Clin Plast Surg. 2005;32(2):151-162.
3. Cowman MK, Matsuoka S. Experimental approaches to hyaluronan structure. Carbohydr Res. 2005;340(5):791-809. 4. Bukhari SNA, Roswandi NL, Waqas M, et al. Hyaluronic acid, a promising skin rejuvenating biomedicine: a review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects. Int J Biol Macromol. 2018;120(Pt B):1682-1695.
5. De Boulle K, Glogau R, Kono T, et al. A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. Dermatol Surg. 2013;39(12):1758-1766.
6. Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83(7):317-325.
7. Cohen JL, Dayan SH, Brandt FS, et al. A systematic review of clinical trials of small- and large-gel-particle hyaluronic acid injectable fillers for aesthetic soft tissue augmentation. Dermatol Surg. 2013;39(2):205-231.
8. Brandt F, Bank D, Cross SL, Weiss R. A lidocaine-containing formulation of large-gel particle hyaluronic acid alleviates pain. Dermatol Surg. 2010;36(Suppl 3):1876-1885.
9. 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.
10. Philipp-Dormston WG, Eccleston D, de Boulle K, Hilton S, van den Elzen H, Nathan M. A prospective, observational study of the volumizing effect of open-label aesthetic use of Juvederm(R) VOLUMA(R) with lidocaine in the mid-face area. J Cosmet Laser Ther. 2014;16(4):171-179.
11. Li D, Wang X, Wu Y, et al. A randomized, controlled, multicenter study of Juvederm Voluma for enhancement of malar volume in Chinese subjects. Plast Reconstr Surg. 2017;139(6):1250e-1259e.
12. Kopera D, Palatin M, Bartsch R, et al. 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;2015:195328.
13. Carruthers J, Jones D, Hardas B, et al. Development and validation of a Photonumeric scale for evaluation of the volume deficit of the Temple. Dermatol Surg. 2016;42(Suppl 1):S203-S210.
14. Lorenc ZP, Bank D, Kane M, Lin X, Smith S. Validation of a four-point photographic scale for the assessment of midface volume loss and/ or contour deficiency. Plast Reconstr Surg. 2012;130(6):1330-1336.
15. Narins RS, Carruthers J, Flynn TC, et al. Validated assessment scales for the lower face. Dermatol Surg. 2012;38(2):333-342.
16. Sykes JM, Carruthers A, Hardas B, et al. Development and validation of a Photonumeric scale for assessment of Chin retrusion. Dermatol Surg. 2016;42(Suppl 1):S211-S218.
17. Turlier V, Delalleau A, Casas C, et al. Association between collagen production and mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic acid filler. A randomized, placebo-controlled study. J Dermatol Sci. 2013;69(3):187-194.
18. Baumann L, Narins RS, Beer K, et al. Volumizing hyaluronic acid filler for midface volume deficit: results after repeat treatment. Dermatol Surg. 2015;41(Suppl 1):S284-S292.
19. Jung JM, Lee WS, Kim HT, et al. A multi-center, randomized, double-blinded, comparative study of two hyaluronic acid fillers for temporary restoration of mid-face volume in Asians. J Cosmet Dermatol. 2020;19(7):1619-1626.
20. Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume deficit: 2-year results from a pivotal single-blind randomized controlled study. Dermatol Surg. 2013;39(11):1602-1612.
21. Few J, Cox SE, Paradkar-Mitragotri D, Murphy DK. A multicenter, single-blind randomized, controlled study of a volumizing hyaluronic acid filler for midface volume deficit: patient-reported outcomes at 2 years. Aesthet Surg J. 2015;35(5):589-599.
22. Gniadecka M, Jemec GB. Quantitative evaluation of chronological aging and photoaging in vivo: studies on skin echogenicity and thickness. Br J Dermatol. 1998;139(5):815-821.
23. Kohn JC, Goh AS, Lin JL, Goldberg RA. Dynamic high-resolution ultrasound in vivo imaging of hyaluronic acid filler injection. Dermatol Surg. 2013;39(11):1630-1636.
24. Nadra K, André M, Marchaud E, et al. A hyaluronic acid-based filler reduces lipolysis in human mature adipocytes and maintains adherence and lipid accumulation of long-term differentiated human preadipocytes. J Cosmet Dermatol. 2021;20(5):1474-1482.
25. Goodman GJ, Liew S, Callan P, Hart S. Facial aesthetic injections in clinical practice: pretreatment and posttreatment consensus recommendations to minimize adverse outcomes. Australas J Dermatol. 2020;61(3):217-225.
26. Ortiz AE, Ahluwalia J, Song SS, Avram MM. Analysis of U.S. Food and Drug Administration data on soft-tissue filler complications. Dermatol Surg. 2020;46(7):958-961.
27. Micheels P. Human anti-hyaluronic acid antibodies: is it possible? Dermatol Surg. 2001;27(2):185-191.
28. Munavalli GG, Guthridge R, Knutsen-Larson S, Brodsky A, Matthew E, Landau M. COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment. Arch Dermatol Res. 2022;314(1):1-15.
【For more info:george.deng@wecistanche.com / WhatApp:86 13632399501】
