Long-term Safety and Effectiveness of Cold-Crosslinked Hyaluronic Acid Fillers: Multicenter, Randomized, Controlled, Double-Blind Study.

Background: Within the last few years, hyaluronic acid (HA) fillers and radiofrequency (RF) devices have shown significant promise for skin rejuvenation. But the effects of HA only lasted for a relatively short duration. Therefore, we tried a new combination therapy of intradermal RF and HA filler. Objective: To evaluate the clinical efficacy of combination therapy of intradermal RF and HA filler for nasolabial fold (NLF) wrinkle reduction. Materials and methods: Ten Korean female volunteers with mild to severe NLFs were enrolled. In the control group, five subjects were treated with HA filler alone. In the experimental group, the other five subjects were treated with intradermal RF prior to HA filler. Efficacy was evaluated based on the change on the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS) from baseline. Results: At 12 and 24 weeks after treatment, the experimental group showed significantly greater improvement in mean WSRS score compared to the control group. And two (40%) of the five patients in the experimental group achieved ‘very much improved’ and two (40%) showed ‘much improved’ at 12 weeks after treatment. Conclusions: Intradermal RF treatment prior to HA filler injection may provide synergistic and long-lasting effects for the reduction of NLF wrinkles.

Hyaluronic acid fillers are known to be effective for correction of nasolabial folds. Recently, a novel biphasic hyaluronic acid filler incorporating lidocaine, DIVAVIVA medium has been introduced. We compared the efficacy and safety between DIVAVIVA medium and Restylane Perlane Lidocaine for moderate to severe nasolabial folds. This was a multicenter, randomized, evaluator/subject-blind, active-controlled, split-face study. A study 1 evaluated the efficacy and safety until 24weeks. Extension study, study 2, included subjects who wanted to enroll and evaluated the efficacy and safety until 52weeks. The Wrinkle Severity Rating Scale (WSRS) score, Global Aesthetic Improvement Scale, and Visual Analogue Scale measuring pain were evaluated. All adverse events were monitored. The mean change of WSRS at week 24 was -0.61±0.54 in DIVAVIVA medium group and -0.59±0.49 in Restylane Perlane Lidocaine group. The difference between two groups was 0.08, which was lower than noninferior limit. In study 2, the mean change of WSRS score at week 52 from baseline was -0.01±0.62 in DIVAVIVA group, 0.06±0.57 in Restylane Perlane Lidocaine group. The primary and secondary efficacy outcomes were also achieved in study 1 and 2. There was no significant difference in the incidence of adverse events between the two groups. DIVAVIVA medium has comparable efficacy and safety with Restylane Perlane Lidocaine for correction of moderate to severe nasolabial folds.

This pilot study compared a monophasic hyaluronic acid dermal filler with a biphasic filler for the correction of nasolabial folds. Participant- and assessor-blinded, randomized clinical trial involving participants with moderate to severe nasolabial folds. Split-face design comparing a monophase hyaluronic acid (HA) filler (mono-HA) with a biphasic HA filler (bi-HA). Injection with touch-up after 1 month. Wrinkle improvement was measured before and after injection and after 1, 2, 4, and 7 months, using the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale as outcome criteria. An optional treatment was offered at the end of the study, with participants allowed to choose one of the products. Evaluation of efficacy and safety of both products. Both products showed immediate, good results after injection and touch-up and demonstrated good durability over time. Participant preference for optional treatment at the end of the study favoured mono-HA. Both products were well tolerated, without serious adverse events. The effect after injection of mono-HA and bi-HA is generally comparable, although there was a trend in favor of mono-HA. Materials and funding for this study were provided by Teoxane, Geneva, Switzerland.

In the article, comparison of the hyaluronic acid (HA) and autologous fat is conducted to evaluate the effectiveness and safety in correction of the nasolabial folds (NLFs). From November 2012 to December 2015, a single-blinded, randomized study was conducted. Sixty-two patients were included in the study, and 57 of them completed the whole procedure. The patients were randomly allocated to receive the treatments of HA or fat in both NLFs. The Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale (GAIS) were used for assessment. Efficacy was assessed using two parameters: evaluation of final improvement by blinded evaluator and patient-self using photographs. The effectiveness endpoint was improvement of scores at 1, 3, 6, 9, and 12 months from baseline. The adverse events (AEs) were recorded. In the blinded evaluator scores for NLF in accordance with WSRS, there were no significant differences between the two methods within 9 months. A statistically significant difference between the lipoinjection and HA groups was found at 12-month follow-up period. Subjects' self-assessment was similar to the results seen for the evaluator scores. The difference of AEs between the HA and fat group was obvious in the early stage of recovery. In the later stage, the AEs of the HA and fat group were similar. Both HA gel and autologous fat provide augmentation of NLFs. The magnitude and duration of NLF correction appear to be similarly effective and safe within a period.

PurposeCannulas are increasingly used for injecting hyaluronic acid fillers, as they are thought to improve patient comfort safety and treatment tolerability. This study aimed to demonstrate the non-inferiority of a Resilient Hyaluronic Acid 4 (RHA 4) filler injected with a cannula versus a needle for the treatment of moderate to severe nasolabial folds (NLF).Patients and MethodsA total of 50 subjects were included in a randomized, evaluator-blinded, split-face trial. The NLF were injected with RHA 4 using a cannula on one side of the face and using a needle on the other side on Day 0. A touch-up could be performed 4 weeks later. The subjects were followed up for 12 weeks after the last injection, ie, injection on Day 0 or touch-up. Efficacy was evaluated using a Wrinkle Severity Rating Scale (WSRS), the Global Aesthetic Improvement Scale (GAIS), and patient-reported outcomes. Safety assessments included the injection-site pain, common treatment reactions (CTRs), and adverse events (AEs).ResultsTwelve weeks after the last injection, the efficacy of the cannula treatment was found to be non-inferior to that of the needle treatment, based on the WSRS score improvements. The other study endpoints showed the equivalent efficacy and safety of the two methods. No serious or unexpected AEs were reported.ConclusionRHA 4 may be effectively and safely injected into the NLF using a cannula or a needle, provided it is administrated by a trained practitioner.

The use of injectable hyaluronic acid-based gel is well established in aesthetic facial procedures especially on the nasolabial fold (NLF). To compare the efficacy and safety of PP-501-A-Lidocaine dermal filler with RestylaneLidocaine(®) when administered to the NLF. Sixty-six subjects seeking correction of NLFs, with moderate or severe wrinkle severity, were recruited for this multicenter, randomized, patient and evaluator-blind, matched pairs, and active-controlled design clinical study. PP-501-A-Lidocaine and RestylaneLidocaine(®) were injected into the deep layer of the dermis and/or subcutis of the NLF. The first validity evaluation variable was the average wrinkle severity rating scale (WSRS), as scored by independent blinded evaluators at week 24. The second validity evaluation variable including the global aesthetic improvement scale (GAIS), the WSRS, and adverse event reporting at weeks 8, 16, and 24 were also performed. The mean improvement in the WSRS from baseline was 1.58 ± 0.68 for the PP-501-A-Lidocaine and 1.51 ± 0.66 for the RestylaneLidocaine(®) at week 24. The average value at week 8 after the final application was 1.62 ± 0.78 and 1.60 ± 0.75 in parts subject to PP-501-A-Lidocaine and RestylaneLidocaine(®), respectively, and 1.58 ± 0.70 and 1.57 ± 0.68 at week 16, respectively. Both improvement and duration of the treatment effect were similar between the two groups. GAIS data rated by the treating investigator and participants showed no statistically significant differences. Both fillers were well tolerated and adverse reactions were mild and transient in most cases. PP-501-A-Lidocaine showed an equivalent efficacy and safety observed after 6 months of follow-up compared to RestylaneLidocaine(®). This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266.

Thread lifting is a minimally invasive procedure using absorbable sutures like polydioxanone (PDO) to provide immediate lifting and stimulate collagen for long-term skin rejuvenation. This prospective study evaluates the safety and efficacy of Croquis® Barbed Cutting PDO threads, featuring a unique 3D bi-directional barb design, in enhancing facial lifting outcomes. Thirty participants with Wrinkle Severity Rating Scale (WSRS) scores of 3 or 4 underwent midfacial lifting using 3D bi-directional barbed PDO threads (Croquis®, Samyang Holdings Corporation, Korea) between June 2023 and February 2024. Outcomes were assessed at 1, 3, and 6 months using 3D imaging (LifeViz®, Quantificare, France). Efficacy was evaluated by both investigators and patients using the WSRS and the Global Aesthetic Improvement Scale (GAIS). A generalized estimating equation (GEE) model was used to identify associations between covariates and outcomes. Thirty female patients (mean age, 58.0 ± 5.6 years) were included. WSRS scores significantly decreased over time, from 2.33 ± 0.12 at 1 month to 1.47 ± 0.09 at 6 months (p < 0.001), indicating sustained wrinkle reduction. Investigator-assessed GAIS also improved significantly at 6 months compared with 1 and 3 months (p < 0.01), while patient-assessed GAIS showed a gradual improvement, reaching significance between 3 and 6 months (p = 0.010). Multivariable analysis confirmed that time and thread number were significant predictors of WSRS and investigator GAIS improvement, whereas age, BMI, and comorbidities had no effect. No major complications occurred, and only minor, self-limiting adverse events such as bruising were observed. 3D bi-directional PDO threads demonstrated safety and efficacy for midfacial rejuvenation, producing sustained wrinkle reduction and investigator-rated aesthetic improvement at 6 months. While a paired comparison with other thread types would have provided stronger evidence, ethical and technical limitations precluded direct contralateral-thread trials. These prospective data nonetheless contribute objective evidence to a field largely informed by retrospective or anecdotal reports. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Various rejuvenation surgeries, including hyaluronic acid (HA) fillers, aim to address mid-face volume loss. However, literature on the comparative efficacy and safety of different HA fillers for the zygomatic area remains limited. This systematic review and network meta-analysis (NMA), adhering to NMA PRISMA 2020 and Cochrane guidelines. Searches were conducted on different bases. Eligible studies included patients with mid-face volume loss undergoing HA interventions. The primary outcome was the Global Aesthetic Improvement Scale (GAIS) at different time points and the incidence of adverse events. Among 1742 articles, six randomized controlled trials (RCTs) met the inclusion criteria with a total of 579 patients. The studies evaluated Giselleligne, VYC-20, Neuramis Lidocaine and ART-Filler. Results showed that Giselleligne demonstrated superior safety compared to VYC-20, ART-Filler and Neuramis-Lidocaine (Risk Ratios (RR) = 0.27, 95% Confidence interval (CI) [0.14; 0.54]), (RR = 0.36, 95% CI [0.17; 0.75], & RR = 0.22, 95% CI [0.07; 0.67]) respectively However, there were no significant differences in the Global Aesthetic Improvement Scale Assessment (GAIS) scores between HA fillers at 1, 3, and 6months. While no significant differences were observed in efficacy among HA fillers, Giselleligne emerged as a potentially safer option for the cheeks volume restoration. The study emphasizes the need for further well-designed RCTs to explore the long-term safety and durability of HA fillers. These findings contribute valuable insights for clinicians and patients in making evidence-based decisions regarding mid-face rejuvenation options.

Hyaluronic acid (HA) fillers are frequently used for the correction of facial soft tissue defects. To compare the efficacy and safety of a novel HA filler, HA(E) (Emervel Deep), with those of HA(P) (Restylane Perlane) in the treatment of severe nasolabial folds (NLF). A split-face, randomized and evaluator-blinded comparison study. Subjects were randomized to receive injection of HA(E) or HA(P) on their left or right NLF. Efficacy was evaluated based on the change in Wrinkle Severity Rating Scale (WSRS) from baseline. Local tolerability was assessed based on subject diary during the first 3 weeks after injection. Adverse events were also evaluated. At both weeks 12 and 24, the mean improvement in WSRS from baseline was significantly greater for HA(E) than for HA(P) (1.58±0.89 vs. 1.33±0.82 at week 24; P=0.002). Similar volume of both products was injected at baseline and touch-up. Both fillers were well tolerated, with similar worst score distribution and mean score for erythema, edema/swelling, bruising, and pruritus. Significantly less severe pain/tenderness was reported with HA(E) than with HA(P) (P<0.05). The new HA filler HA(E) provides better efficacy and similar local tolerability compared with HA(P) 6 months after the treatment of severe NLF.

BackgroundHyaluronic acid dermal fillers are used for multiple indications, including wrinkle correction and restoration of volume/fullness.ObjectivesThe aim of this study was to compare the efficacy and safety of 2 hyaluronic acid products for correcting moderate to severe nasolabial folds (NLFs).MethodsA prospective, randomized, double-blind, split-face study was undertaken. The subjects’ left and right NLFs were randomly allocated for treatment with DKL23 or Juvéderm Volift. Follow-up was conducted at 1, 3, 6, and 9 months. The changes from baseline on the Wrinkle Severity Rating Scale and the Global Aesthetics Improvement Scale were evaluated. Posttreatment adverse events (AEs) were recorded.ResultsForty-eight women (median age, 57.0 years) with Type I to VI skin were enrolled. Both treatments showed statistically significant improvement (P < .0001) in NLFs according to the Wrinkle Severity Rating Scale score from baseline to each of the time points assessed. The improvement in NLFs was maintained until the end of the study (9 months). Furthermore, the change from baseline to each of the time points assessed was similar between DKL23 and Juvéderm Volift. Investigator- and subject-rated Global Aesthetics Improvement Scale scores showed similar rates of improvement (indicated by the sum of responses of improved, much improved, or very much improved) between the 2 products. The AEs reported in the study were in line with previous and expected experience after injection of hyaluronic acid dermal fillers. The types of AEs, their rates, intensity, and duration were comparable between the 2 products.ConclusionsDKL23 improved NLF severity from baseline and for up to 9 months, and the results were comparable to the improvement shown by Juvéderm Volift. Treatment was safe and well tolerated.Level of Evidence: 2

Basis: Hyaluronic acid-based temporary dermal filler are used in the treatment of facial folds and wrinkles. Objectives: Evaluate the effectiveness and safety of Rennova®, a hyaluronic acid-based filler used in nasolabial folds. Methods: An open label, single-center, phase IV, prospective, observational clinical study, with duration of 360 days, totaling 11 visits. The study included 30 female volunteers, between 30 and 60 years of age, presenting nasolabial folds classified as 3 and 4 according to the Wrinkle Severity Rating Scale and skin phototypes I to V, according to the classification of Fitzpatrick. The effectiveness was subjectively evaluated using the wrinkle severity scale and the Global Aesthetic Improvement Scale and objectively analyzed suing photographs and biopsies. The volunteers gave their opinions about the procedure and results in a questionnaire. The safety was evaluated by observing adverse events; pain, discomfort and local sensitivity; tolerability and biopsies. Results: In the beginning of the study, 76% of the volunteers presented moderate wrinkles and 24% severity. At the end, 8% presented severe, 56% moderate and 36% mild wrinkles. The adverse events with positive causal nexus were: local erythema/edema, ecchymosis, hematoma and local pain. They presented mild to moderate intensity, short to medium duration. Conclusions: In relation to the wrinkle severity rating scale and global aesthetic improvement scale, the results were satisfactory (p<0.05). The adverse events with positive causal nexus were temporary and the biopsy did not show any inflammatory process, which demonstrates the product safety.

Lateral orbital hollowing is a subtle yet influential contributor of periorbital ageing. It results from attenuation of subcutaneous fat, atrophy of the lateral orbital fat pad, and descent of the orbicularis oculi muscle, creating a concavity that contributes to a fatigued and aged appearance. To evaluate the efficacy and safety of supraperiosteal hyaluronic acid (HA) filler injection for lateral orbital hollowing, with outcomes assessed at the longest available follow-up (6mo) by both patients and physicians using the Global Aesthetic Improvement Scale (GAIS). A single-centre prospective case series enrolled 48 consecutive patients (40 women, 8 men; mean age 46.2±5.8y) between July and November 2025, treated with cross-linked HA. All injections were performed by a single experienced aesthetic physician using a 30-gauge blunt cannula introduced through a lateral entry point 1.5cm from the canthus, delivering 0.5 to 0.8mL per side in the supraperiosteal plane. Standardised photographs were obtained at baseline and at follow-up visits (earliest 1mo; longest 6mo). GAIS ratings were completed by 2 independent physicians and by patients; patient satisfaction was additionally summarised as the proportion rating outcomes as good/very good/exceptional versus slight/none. Follow-up was completed in 48/48. The shortest photographic interval presented was 1 month and the longest follow-up was 6 months. At 6 months, physician GAIS was 4.4±0.5 and patient GAIS was 4.5±0.6. On patient GAIS, 43/48 (89.6%) rated the outcome as "very good" or "exceptional," while 5/48 (10.4%) rated "good"; no patients rated "slight" or "none" (0% dissatisfied). Adverse events were minor and self-limited: bruising in 13/48 (27.1%) and oedema in 14/48 (29.2%); each resolved within 1 week. No serious complications occurred. Supraperiosteal HA placement for lateral orbital hollowing restored the lateral contour with high satisfaction and minimal downtime through 6 months. Presenting clinical photographs in a single composite figure enables a clear baseline-to-follow-up comparison. Longer-term follow-up beyond 6 months is needed to better define durability and late events in this region. Level IV.

Repeat treatments of nonpermanent dermal fillers are used in the long-term treatment of wrinkles and folds and to volumize. OBJECTIVE To determine the safety and effectiveness of a nonanimal-sourced hyaluronic acid (HA) (which uses a cohesive polydensified matrix (CPM) technology [CPMHA]) for the treatment of nasolabial folds (NLFs) during an 18-month open-label extension trial. Ninety-five of 118 subjects continued with this optional open-label extension of a split-face, double-blind trial. All subjects received CPMHA in both NLFs at 24 weeks after treatment in this study and were assessed at weeks 32, 48, 72, and 96. Touch-ups were allowed for optimal correction. Safety was assessed according to reported adverse events (AEs) and serum antibody measurement. At all four post-week 24 time points, the severity of the NLFs showed a decrease from baseline on the Wrinkle Severity Rating Scale. The effects persisted in the majority (∼80%) of subjects without repeat treatment for at least one interval of 48 weeks. The study filler was well tolerated, with only one related AE (injection site bruising) reported. Little potential for immunogenic reactions was identified. This CPMHA is a well-tolerated and effective treatment for at least 48 weeks in the majority of subjects for the correction of moderate to severe NLFs with repeat injections given over an 18-month period.

Facial aging results from intrinsic and extrinsic factors causing soft tissue volume loss, skin laxity, and wrinkles; minimally invasive fillers combining calcium hydroxyapatite (CaHA) and hyaluronic acid (HA) may mitigate these changes. This pilot study explored the feasibility, safety, and preliminary efficacy of a hyper-diluted 1:1 CaHA-HA combination in nine patients (30–65 years) with mild-to-moderate facial volume loss and laxity. Injections were delivered to affected areas using blunt-tip cannulas and fine needles. Clinical outcomes were measured with the Merz Aesthetic Scale (MAS), Wrinkle Severity Rating Scale (WSRS), and Global Aesthetic Improvement Scale (GAIS), while adverse events and patient satisfaction were recorded. MAS showed notable improvements in upper cheek fullness, lower cheek fullness, and jawline contour (+0.94, +0.94, and +0.89, respectively), and WSRS nasolabial fold severity decreased from 3.28 ± 0.18 to 2.50 ± 0.00 (p &lt; 0.0001) with large effect sizes (Cohen’s d &gt; 5.0). All patients rated themselves “very improved” on GAIS; no adverse events were reported, and satisfaction was high. These preliminary findings suggest that hyper-diluted CaHA–HA may be a safe and promising minimally invasive approach for facial rejuvenation, although confirmation in larger, controlled studies with longer follow-up is required.

Sagging and loss of elasticity of the facial skin and tissues leads to jowling and an aged appearance. Jowling is a common reason for aesthetic surgical consultations. Prospective open-label study of the JOLT (jowl lifting) technique using hyaluronic acid (HA) fillers in healthy women 40-65 years of age with Fitzpatrick skin phototypes II-IV (n = 8). To be eligible, patients had jowling grade 2-3 on the jowl appearance scale as assessed by both the physician and patient. Treatment was administered at the baseline visit and consisted of an average of 6 mL of HA filler, 3 mL per side. Efficacy was assessed at baseline, week 4, and week 12. Assessment measures included the jawline rating scale (JRS) and a five-point global aesthetic improvement scale performed by two independent observers. Success was defined as an improvement of 1-2 grades on JRS. The mean JRS was improved from 2.75 at baseline to 1.53 at 90 days, which was considered a significant improvement. Mean global aesthetic improvement scale scores at 90 days were 1.44 ± 0.66 (range 1-3), indicating a "very much improved" appearance compared with baseline on both investigator and subject ratings. The procedure was well tolerated by all patients. Injection-related side effects (bruising and localized swelling) resolved spontaneously within 1 week of treatment. No other adverse events were reported. The JOLT technique effectively uses HA fillers to lift and tighten the lower face/neck and camouflage the remaining jowl, diminishing marionette lines, defining the mandibular border, and improving jowl sagging.