Abstract
Background
Lip augmentation has become increasingly accepted and popular. However, there are still a few approved lip fillers that are versatile, biocompatible, suitable for lip enhancement, and backed by large-scale clinical trials.
Objectives
To assess the safety and effectiveness of Janlane LIPs (Shanghai Qisheng Biopharmaceutical Co., Ltd, Shanghai, China), a new hyaluronic acid filler for lip augmentation.
Methods
This prospective, multicenter, randomized, controlled study randomized subjects to the treatment group or the concurrent no-treatment control group that received delayed treatment. The level of Lip Fullness Grading Scale (LFS) was evaluated by the blinded evaluator, and the Global Aesthetic Improvement Scale (GAIS) was evaluated by the blinded evaluator and the subjects at pre-injection and after injection. Adverse reactions were recorded. Statistical analysis of subject satisfaction was performed.
Results
A total of 176 subjects were enrolled. The scores of LFS after injection were higher than those before injection; the degree of GAIS evaluated by the evaluator and subjects improved significantly. Local redness, swelling, etc. occurred after injection, most of which resolved within 1 week. The patient satisfaction was high and statistically significant.
Conclusions
Janlane LIPs showed long-term aesthetic improvement and safety for lip augmentation, high patient satisfaction, and are worthy of clinical promotion.
Level of Evidence: 2 (Therapeutic)
Lip augmentation has gained increasing acceptance in aesthetic medicine, as full lips are widely associated with youth and attractiveness.1-3 Hyaluronic acid (HA) has emerged as a leading soft tissue filler for lip enhancement due to its biocompatibility, naturala esthetic outcomes, and reversible effects.4-6 With HA-based fillers now widely adopted for their ability to volumize and refine lip contour.7-10 However, large-scale clinical studies evaluating HA for lip augmentation remain scarce, and few HA fillers are specifically approved for this indication globally. The lips' unique biomechanical and sensory requirements—demanding specialized formulations to ensure optimal texture, flexibility, and tactility—further limit suitable products. Notably, prior to this study, no China-manufactured HA filler had been approved for lip augmentation in the Chinese market, highlighting both the unmet clinical need and the novelty of our investigation. To address this gap, we conducted a prospective, multicenter, randomized, controlled, evaluator-blinded clinical trial (May 2019–June 2022) assessing a modified sodium hyaluronate gel (trade name: Janlane LIPs, Shanghai Qisheng Biopharmaceutical Co., Ltd, Shanghai, China) for lip augmentation, evaluating its safety, efficacy, and the aesthetic preferences of the Chinese population. Our findings aim to advance standardized protocols and inform future research in this evolving field.
METHODS
Study Design
This is a prospective, multicenter, randomized, no-treatment-controlled study (ChiCTR2100054328) of the safety and effectiveness of injectable hyaluronate gel for lip augmentation. The study was conducted at 5 well-known clinical trial-qualified hospitals in China from May 2019 to June 2022. Approval was obtained from each hospital ethics committee. Informed consent was submitted by all subjects when they were enrolled. A total of 176 subjects were randomly assigned to the treatment group and the control group at a ratio of 3:1. One month (30 days) after the initial injection treatment, the subjects and the treating researcher will decide together whether a second modification treatment is needed. Subjects randomly assigned to the treatment group began receiving treatment in the first month after enrollment. They then entered a 1-month treatment period and a 12-month follow-up period (at Months 1, 3, 6, 9, and 12 after injection). Subjects randomly assigned to the control group did not receive injection treatment during the control period (3 months). They then entered a 1-month treatment period and a 9-month follow-up period (at Months 1, 3, 6, and 9 after injection) (Figure 1). The primary efficacy endpoint was evaluated by 2 specialized plastic surgeons or dermatologists who were not involved in the injection, trained to a uniform standard, and if the evaluations were inconsistent, evaluated by a third plastic surgeon or dermatologist with the same training. They objectively evaluated the primary efficacy endpoint based on standardized photographs without knowing the patient's grouping.
Figure 1.
Trial flowchart.
Study Subjects
The inclusion criteria included normal Chinese adults, aged 18 to 60 years, Lip Fullness Grading Scale (LFS) score of 1, 2, or 3, and signed informed consent. Exclusion criteria included previous treatment with other fillers in the lips, permanent fillers, abnormal traces (tattoos, piercings), color, masses, scars, etc. on the lip surface, abnormal coagulation function, pregnant or lactating women, subjects with scar constitution, subjects with severe organic diseases, subjects with allergic diseases, and subjects with psychological abnormalities or mental illness.
Injection Procedure
Each sub-center specifies an injection doctor, and the injection doctors in all centers were trained in uniform injection methods. The injection procedure depends on the subject's lip base and the desired lip shape, while ensuring that at least one grade of fullness can be improved. The first step was to inject along the edge of the vermilion border with a sharp needle. The injection was in the subcutaneous layer. The second step is injected at the dry-wet junction or the skin-mucosal junction at the lower margin of the upper lip and/or the upper margin of the lower lip. The third step is to inject the bead of the upper lip and the spine of the middle. The lip bead injection could also use 2 to 3 parallel lines or a fan-shaped injection method to emphasize the “Cupid” bow shape. The fourth step was the shaping injection of the 2 bumps of the lower lip. The serial injection method could be used to overcorrect and modify the lower lip protrusions to form a more natural central depression of the lower lip (Figure 2). In addition, the suggestions to understand a relatively safe injection area, reduce the risk of injection. The position of the upper labial artery in region ① (midline area) is more superficial, region ② is more likely to encounter thicker vessels, and region ③ is a safer area (Figure 3). The single-point injection did not exceed 0.1 mL.
Figure 2.
Protocol used for injection sites.
Figure 3.
Injection are administered at the attention site and the safety site.
Products Utilized
Each patient received Janlane Lips injection, which is China's first and currently the only China-manufactured HA dermal filler approved specifically for lip augmentation. Janlane Lips is a soft HA-based filler with a high dynamic viscosity of 632,500 mPa and a low elastic modulus of ∼150,000 mPa, not only does it have strong anti-displacement ability, but it is also easier to retain the natural and lively facial expressions. Each 1.1 mL of the filler contains 20 mg HA. Janlane Lips is manufactured with the low-temperature secondary cross-linking process to yield a higher viscosity gel with greater lift capacity and improved response durability. Therefore, Janlane Lips is indicated for lip augmentation.
Clinical Outcome Measures
Efficacy Evaluation
The Primary efficacy endpoint was the response rates for the LFS score (a change of ≥1 in the LFS score from baseline) at Month 3 after injection, as evaluated by the third-party blinded evaluator.11
The secondary efficacy endpoints included (1) response rates for the LFS score (a change of ≥1 in the LFS score from baseline) at Months 1, 3, 6, 9, and 12 (treatment group only) after injection evaluated by the blinded evaluator; (2) aesthetic improvement from baseline based on the Global Aesthetic Improvement Scale (GAIS) score at 1, 3, 6, 9, and 12 (treatment group only) months after injection evaluated by blinded evaluator and subject; (3) participants' satisfaction with the appearance of their lips at Months 1, 3, 6, 9, and 12 (treatment group only).12
Safety Evaluation
Injection site reactions were recorded in subject diaries post-treatment. Safety assessments (vital signs, blood tests) occurred at 1 and 6 months after the final injection. An independent evaluator assessed early-onset adverse events (AEs) (edema, erythema, bruising) on Days 0, 1, 3, 7, and 14. Pain/tenderness and pruritus intensity were reported by subjects, graded 0-3 (none to severe). The evaluator also checked if the product feel was as expected (uniform density without lumpiness). Post-Day 14 AEs were monitored by physicians.
Statistical Methods
Statistical analysis was performed using SAS 9.4 or higher version statistical analysis software. In descriptive analysis, group comparison, categorical variables were analyzed by χ2 test or Fisher's exact probability method. Continuous variables, if the data were normally distributed and the residual variance was homogeneous, analysis of variance was used; otherwise, the Wilcoxon rank sum test or Kruskal–Wallis test was used. The efficacy rate of lip augmentation evaluated by the researcher and the main endpoint between groups were compared by Cochran-Mantel-Haenszel χ2, considering the center effect. The treatment group was compared with the control group. And the difference between the treatment group and control group, and its 95% CI was calculated. The Kappa coefficient was used to evaluate the consistency between the researcher's evaluation and the subject's evaluation. LFS and GAIS group comparison was performed by the Wilcoxon rank sum test. All statistical tests were performed by 2-sided test; P < .05 was considered statistically significant.
RESULTS
Subject Characteristics
A total of 176 subjects were enrolled, 18 dropped out, and 158 completed. There were 133 subjects in the treatment group and 43 subjects in the control group: Full analysis set (FAS), 164 cases; per-protocol set (PPS), 156 cases; safety analysis set (SAS), 166 cases. Subject demographics and baseline characteristics were similar between groups (Table 1). The PPS analysis included only subjects who strictly adhered to the study protocol, completed all scheduled visits, and had no major protocol deviations. The FAS analysis was performed according to the intention-to-treat principle, incorporating data from all randomized subjects (regardless of treatment completion or protocol violations), with conservative methods (such as last observation carried forward) typically employed to handle missing data. The SAS included all subjects receiving ≥1 treatment dose, analyzed for safety regardless of protocol compliance or treatment completion, following actual treatment received.
Table 1.
Subject Demographics and Baseline Characteristics (FAS Analysis)
| Treatment group (n = 127) | Control group (n = 37) | Total (n = 164) | P value | |
|---|---|---|---|---|
| Sex | ||||
| Male | 4 (3.1%) | 0 | 4 (2.4%) | NS |
| Female | 123 (96.9%) | 37 (100%) | 160 (97.6%) | |
| Age | ||||
| Mean (standard deviation) | 33.7 (9.00) | 32.8 (9.40) | 33.5 (9.07) | NS |
| Median | 32.4 | 31.2 | 32.1 | |
| Minimum, maximum | 20, 59 | 20, 59 | 20, 59 | |
| Lip Fullness Grading Scale (LFS) | ||||
| Number (missing) | 127(0) | 37(0) | 164(0) | NS |
| Mean (standard deviation) | 2.46 (0.53) | 2.46 (0.61) | 2.46 (0.55) | |
| Median | 2.0 | 3.0 | 2.0 | |
| Minimum, maximum | 1, 3 | 1, 3 | 1, 3 | |
| Whether to supplement injection | ||||
| No | 114 (89.8) | 35 (94.6) | 149 (90.9) | NS |
| Yes | 12 (9.4) | 1 (2.7) | 13 (7.9) | |
| Missing | 1 (0.8) | 1 (2.7) | 2 (1.2) |
FAS, full analysis set.
Clinical Efficacy
Primary Efficacy Endpoint
FAS analysis results showed that the response rate (lip fullness increased by ≥1 grade) at 3 months after injection evaluated by the third-party blinded evaluator assessment was 92.1% in the treatment group and 29.7% in the control group at 3 months during the control period. There was a statistically significant difference between the treatment group and the control group (P < .0001) (Table 2).
Table 2.
Third-party Blinded Evaluator of Lip Augmentation Efficacy at 3 Months After Injection (Missing Values as Ineffective) (FAS Analysis)
| Treatment group (n = 127) n (%) |
No-treatment period control group (n = 37) n (%) |
|
|---|---|---|
| Ineffective | 10 (7.9) | 26 (70.3) |
| Effective | 117 (92.1) | 11 (29.7) |
| P value | <.0001 | |
| Effective difference (CI) | 0.6240 (0.47, 0.78) |
FAS, full analysis set.
These findings were consistently supported in the PPS, with the response rate being 93.3% in the treatment group and 30.6% in the control group (Table 3).
Table 3.
Third-party Blinded Evaluator of Lip Augmentation Efficacy at 3 Months After Injection (Missing Values as Ineffective) (PPS Analysis)
| Treatment group (n = 120) n (%) |
No-treatment period control group (n = 36) n (%) |
|
|---|---|---|
| Ineffective | 8 (6.7) | 25 (69.4) |
| Effective | 112 (93.3) | 11 (30.6) |
| P value | <.0001 | |
| Effective difference (CI) | 0.6278 (0.47, 0.78) |
PPS, per protocol set.
Secondary Efficacy Endpoints
Response rate of lip augmentation based on LFS evaluated by the blinded evaluator. FAS analysis showed that the response rates at 1 and 3 months after injection in the treatment group were 97.6% and 94.5%, respectively, and the response rates at 1 and 3 months during the no-treatment period in the control group were both 0%. There was a statistically significant difference between the treatment group and the control group (P < .0001). The response rates at 1, 3, 6, 9, and 12 months after injection in the treatment group were 97.6%, 94.5%, 78.7%, 70.9%, and 57.5%, respectively, and the response rates at 1, 3, 6, and 9 months after delayed treatment in the control group were 91.9%, 94.6%, 89.2%, and 59.5%, respectively. The combined response rates of the treatment group and the control group at 1, 3, 6, 9, and 12 months (treatment group only) after injection were 96.3%, 94.5%, 81.1%, 68.3%, and 57.5% (treatment group only), respectively (Figure 4).
Figure 4.
Response rate (a change of ≥1 in the LFS score from baseline) of lip augmentation evaluated by the blinded evaluator (FAS analysis). *P < .05. ns, not significant. FAS, full analysis set; LFS, Lip Fullness Grading Scale.
PPS and FAS results were consistent.
Lip Fullness Based on Lip Fullness Grading Scale Evaluated by the Blinded Evaluator
FAS analysis showed that the average score of lip fullness assessed by the blinded evaluator was 3.80 and 3.70 at 1 and 3 months after injection in the treatment group, and 2.46 and 2.50 at 1 and 3 months in the control group during the no-treatment period, which was statistically significant compared with the control group (P < .0001). The average score of lip fullness were 3.80, 3.70, 3.54, 3.39, and 3.14 at 1, 3, 6, 9, and 12 months after injection in the treatment group, and 3.77, 3.77, 3.64, and 3.22 at 1, 3, 6, and 9 months after delayed treatment in the control group, respectively, which were statistically significant compared with before injection (P < .05) (Figure 5). The average score of lip fullness for all subjects was 3.79, 3.72, 3.56, 3.35, and 3.14 (treatment group only) at 1, 3, 6, 9, and 12 months (treatment group only) after injection, respectively, which were significantly higher than before injection (2.46) (P < .05). These findings were consistently supported in the PPS.
Figure 5.
Lip fullness evaluated by the blinded evaluator (FAS analysis). Quantitative statistics of LFS scores at 1, 3, 6, 9, and 12 months after injection treatment (treatment group only) compared with before injection treatment. *P < .05, **P < .01, ***P < .001, and ****P < .0001. ns, not significant. FAS, full analysis set; LFS, Lip Fullness Grading Scale.
Aesthetic Improvement From Baseline Based on the GAIS
Aesthetic Improvement Evaluated by the Blinded Evaluator
FAS analysis showed that the average score of aesthetic improvement was 1.98 and 1.89 at 1 and 3 months after injection in the treatment group, and 0.00 at both 1 and 3 months in the control group during the no-treatment period, which was statistically significant compared with the control group (P < .0001). The average score of aesthetic improvement were 1.99, 1.89, 1.73, 1.54, and 1.34 (treatment group only) at 1, 3, 6, 9, and 12 months (treatment group only) after injection in the combined treatment and control groups.
The satisfaction (improved and markedly improved) of aesthetic improvement from baseline based on the GAIS were 99.2% and 97.6% at 1 and 3 months after injection in the treatment group, and 0% at 1 and 3 months in the control group during the no-treatment period, which was statistically significant compared with the control group (P < .0001). The satisfaction (improved and markedly improved) of aesthetic improvement were 99.2%, 97.6%, 92.9%, 88.9%, and 83.5% at 1, 3, 6, 9, and 12 months after injection in the treatment group, and 97.3%, 94.6%, 97.3%, and 81.0% at 1, 3, 6, and 9 months after delayed treatment in the control group, respectively. The satisfaction (improved and markedly improved) of aesthetic improvement was 98.8%, 96.9%, 93.9%, 87.2%, and 83.5% (treatment group only) at 1, 3, 6, 9, and 12 months (treatment group only) after injection in the combined treatment and control groups. PPS results were consistent with FAS results.
Aesthetic Improvement Evaluated by the Subject
FAS analysis showed that the average score of aesthetic improvement was 1.98 and 1.82 at 1 and 3 months after injection in the treatment group, and both were 0.00 in the control group during the no-treatment period, which was statistically significant compared with the control group (P < .0001). The average score of aesthetic improvement were 1.98, 1.84, 1.63, 1.36, and 1.14 (treatment group only) at 1, 3, 6, 9, and 12 months (treatment group only) after injection in the combined treatment and control groups (Figure 6).
Figure 6.
The average score of aesthetic improvement based on GAIS (FAS analysis). FAS, full analysis set; GAIS, Global Aesthetic Improvement Scale.
The satisfaction (improved and markedly improved) of aesthetic improvement was 98.5% and 96.1% at 1 and 3 months after injection in the treatment group, and both were 0.00 in the control group during the no-treatment period, which was statistically significant compared with the control group (P < .0001). The satisfaction (improved and markedly improved) of aesthetic improvement were 98.5%, 96.1%, 89.0%, 80.3%, and 70.0% at 1, 3, 6, 9, and 12 months after injection in the treatment group, and 97.3%, 94.6%, 91.9%, and 70.2% at 1, 3, 6, and 9 months after delayed treatment in the control group, respectively. The satisfaction (improved and markedly improved) of aesthetic improvement were 98.1%, 95.7%, 89.6%, 78.1%, and 70.0% (treatment group only) at 1, 3, 6, 9, and 12 months (treatment group only) after injection in the combined treatment and control groups (Figure 7). These findings were consistently supported in the PPS.
Figure 7.
Overall lip aesthetic improvement satisfaction assessment based on GAIS (FAS analysis). FAS, full analysis set; GAIS, Global Aesthetic Improvement Scale.
Consistency of Evaluator and Subject Assessment
The consistency analysis of satisfaction with overall aesthetic improvement between evaluator and subject showed that FAS and PPS had Kappa coefficients of 0.7158 and 0.7114, respectively, indicating good consistency. Figures 8–11 show representative photographs of the treatment effect.
Figure 8.
First example: before-and-after treatment photographs of a 27-year-old female patient’ lip at (A, D, G) baseline, (B, E, H) Month 3, and (C, F, I) Month 12.
Figure 11.
Fourth example: A–D shows before-and-after treatment photographs of a 28-year-old female patient's lip at (A) baseline, (B) Month 3, (C) Month 6, and (D) Month 12. E–H shows before-and-after treatment photographs of a 36-year-old female patient's lip at (E) baseline, (F) Month 3, (G) Month 6, and (H) Month 12. I–L shows before-and-after treatment photographs of a 29-year-old female patient's lip at (I) baseline, (J) Month 3, (K) Month 6, and (L) Month 12. M–P shows before-and-after treatment photographs of a 30-year-old female patient's lip at (M) baseline, (N) Month 3, (O) Month 6, and (P) Month 12.
Figure 9.
Second example: before-and-after treatment photographs of a 28-year-old female patient’ lip at (A, D, G) baseline, (B, E, H) Month 3, and (C, F, I) Month 12.
Figure 10.
Third example: before-and-after treatment photographs of a 29-year-old female patient’ lip at (A, D, G) baseline, (B, E, H) Month 3, and (C, F, I) Month 12.
Safety Evaluation Indicators
A total of 2 AEs related to the test device occurred during the trial, with an incidence rate of 1.2%, of which 1 case had mild lip itching 12 days after injection, no measures were taken, and it healed after more than 20 days; the other case was a delayed treatment subject in the control group, who had mild fever 3 months after injection of the test device, and healed after symptomatic treatment for 1 day, and then had mild blisters on the upper lip 1 week later, no measures were taken, and healed after 1 month.
DISCUSSION
We used a prospective, large sample, multicenter, randomized, controlled, long-term follow-up, blind evaluation study, and strictly followed the procedures, which can provide some reference for the later use of HA for lip injection. Comparing with the no-treatment control group for lip augmentation, the primary endpoint was met, with 92.1% of the treatment group improving by ≥1 point on the LFS at Month 3 (P < .0001 vs control group). In terms of secondary efficacy indicators, they have the same results; therefore, the efficacy of the treatment group was better than that of the control group. All subjects who received lip injection with HA gel (combined treatment group and delayed treatment control group) had significantly higher lip fullness scores than before injection. Although there were differences in the response rates between the 2 groups at the same follow-up time point, the response rates in both groups remained higher throughout the entire follow-up period compared with those before treatment (with statistically significant differences). Moreover, at 12 months after treatment, there were still 57.5% responders and an 83.5% satisfaction rate. In our opinion, this supports the above-mentioned hypothesis that high dynamic viscosity and low elastic modulus fillers support volume enhancement without distortion of the natural motion of this highly dynamic facial area. This high level of satisfaction was maintained over time.
With the improvement of living standards and the awakening of self-appearance requirements, more and more people begin to pay attention to lip aesthetics, and HA gel, as a filler that has been active in the medical beauty market for many years, is especially loved by most people.13-15 According to our preliminary analysis of subject questionnaires, most Chinese people do not pursue thick lips excessively, but prefer petal lips with obvious lip beads, pursuing naturalness without exaggeration, most of them can accept the pain degree and recovery time during injection, and can achieve natural touch after 7 days. We also observed that the improvement of lip shape has a significant effect on improving the overall proportion of the face, such as visually shortening the philtrum, reducing the nose size, adjusting the proportion of 3 courts and 5 eyes, changing the lip shape and thus changing the facial expression, etc., most people reported no significant change in lip color after injection, and lip wrinkles significantly reduced after injection. This provides a reference for our later communication with beauty seekers and injection.
The safety evaluation confirmed that modified HA gel for lip augmentation was safe and well-tolerated, with adverse reactions consistent with typical HA filler injections, like injection site pain, swelling, and bruising. Proper needle positioning is critical—superficial plane misplacement poses risks. Studies indicate that in ∼80% of cases, the upper and lower lip arteries lie deep (beneath the orbicularis oris muscle and mucosa).16,17 Thus, avoiding deep injection is essential. Post-injection mucosal abrasion or excessive massage may cause pigment deposition. Bruising should be treated with immediate ice, followed by warm compresses after 24 h, along with postoperative sun protection.18 Overcorrection can distort lip shape (eg, sagging lip beads elongating the philtrum or drooping corners), often requiring surgical revision.19,20 Allergic reactions are rare but should be managed promptly with hyaluronidase, glucocorticoids, or 5-fluorouracil if needed.
Limitations
This study enrolled both male and female participants to better reflect the gender distribution in the target population, enhancing the generalizability of our findings. However, a notable limitation is that all clinical trial sites were located in China, which may introduce inherent population bias due to regional variations. As previously demonstrated by Heidekrueger et al, country of residence, ethnicity, and occupation play key roles in shaping individual preferences for lip morphology—potentially leading to discrepancies between patient and physician aesthetic ideals.21 These findings provide valuable insights into Chinese population preferences for lip augmentation across regions, informing culturally tailored product development and contributing to the understanding of cross-cultural aesthetic variations. While this randomized, self-controlled trial (with a 3-month delayed treatment in the control group) did not include comparator products, limiting direct comparative efficacy assessments, the rigorous investigator-blinded design ensured robust evaluation of the HA filler's safety and efficacy for lip augmentation while safeguarding participant rights. Future studies will incorporate head-to-head product comparisons. AE monitoring had several limitations: although early local reactions were documented by independent assessors, subjective symptoms (eg, pain/pruritus) relied on patient reporting, potentially introducing recall bias; post-14-day events were only tracked by treating physicians without independent verification; and while no severe AEs (eg, vascular embolism, hypersensitivity) occurred, proactive prevention remains crucial—future protocols may integrate ultrasound for enhanced vascular mapping. Additionally, discontinuation of 3D volumetric analysis due to device inconsistencies resulted in a lack of objective measurement tools. Subsequent aesthetic research will employ advanced measurement technologies and artificial intelligence to enable standardized, unbiased evaluations.22,23
CONCLUSIONS
Based on the above results, Janlane LIPs has good efficacy and safety for lip filling, can effectively increase lip tissue volume, correct lip tissue atrophy, and the effect can last for more than 12 months after initial injection combined with supplemental injection.
Acknowledgments
Drs T Wang and Huang contributed equally to this work as co-first authors.
Disclosures
The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding
This work was funded by the Fujian Medical University Union Hospital, Fujian Medical University Union Hospital Key Discipline Fund (Grant number: 0218002).
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