Efficacy and Safety of Picosecond Laser Combined With Sodium Hyaluronate for Melasma

Abstract

Background:

Melasma is a common hyperpigmentation disorder that presents a significant therapeutic challenge. This study aims to evaluate the efficacy and safety of a novel combination approach using a picosecond laser followed by microinjections of a sodium hyaluronate composite solution for the treatment of mixed-type melasma.

Methods:

In this retrospective study, 30 female patients with mixed-type melasma received 3 treatment sessions. Each session consisted of a fractional picosecond laser treatment followed by the administration of a non–cross-linked sodium hyaluronate composite solution. Efficacy was primarily assessed by the change in the Melasma Area and Severity Index score from baseline to 4 weeks posttreatment, as evaluated by an independent blinded investigator. Secondary endpoints included Physician’s Global Assessment and patient satisfaction.

Results:

The combination therapy resulted in a statistically significant reduction in the mean Melasma Area and Severity Index score, from a baseline of 18.30 ± 7.85 to 8.20 ± 3.50 posttreatment (P < 0.05). Physician assessments showed marked or moderate improvement in 70% of patients, and the overall patient satisfaction rate was high (86.7%). The treatment was well tolerated with only mild, transient side effects and no serious adverse events reported.

Conclusions:

The combination of a picosecond laser with a sodium hyaluronate composite solution demonstrated significant short-term efficacy at 4 weeks posttreatment with an acceptable safety profile, offering a promising approach for its clinical management.

Takeaways

Question: Do novel combination therapies improve efficacy, safety, and prevention of relapse in patients with melasma, given the limited effectiveness of current treatments?

Findings: In our prospective study of 30 women, 3 sessions combining a picosecond laser with a sodium hyaluronate solution significantly reduced melasma severity scores. The therapy was well tolerated, with high patient satisfaction.

Meaning: This combination therapy may represent an effective and safe option for the clinical management of melasma.

INTRODUCTION

Melasma is a chronic, acquired disorder of skin pigmentation that develops gradually and often persists once established. It manifests as light- to dark-brown macules and patches with irregular margins, typically arranged in a symmetrical pattern, and is most observed on the face, including the cheeks, forehead, and chin. The condition predominantly affects women of reproductive age, with a reported prevalence of up to 30% in Asian populations.¹ Based on the depth of pigment deposition, it is clinically classified into epidermal, dermal, and mixed types.² The mixed type is characterized by pigment deposition in both the epidermis and the dermis. Melasma remains a significant clinical challenge due to its recalcitrant nature and high recurrence rate.³

The pathogenesis of melasma is complex, involving genetic predisposition, ultraviolet (UV) radiation exposure, hormonal fluctuations, and psychological stress.⁴ Consequently, many therapeutic options are available for melasma treatment currently, including oral and topical agents,^5,6 energy-based devices,⁷ and chemical peels.⁸ Among these, energy-based devices are established as primary modalities in the management of melasma.⁹ However, monotherapy often yields insufficient efficacy and carries a notable risk of adverse effects, such as postinflammatory hyperpigmentation (PIH).^10–13

This study investigates a novel combination therapy that begins with a fractional picosecond laser to create epidermal microchannels, thereby enhancing the transdermal delivery of a therapeutic solution.¹⁴ Following laser treatment, a non–cross-linked sodium hyaluronate composite solution was applied through microneedling. The solution is composed of non–cross-linked hyaluronic acid, L-carnosine, amino acids, and vitamin B2, and is specifically formulated to counteract the photoaging and oxidative stress that are commonly associated with melasma. Furthermore, the solution also aims to restore cutaneous hydration, improve the skin’s barrier function, and facilitate melanin clearance. Therefore, the primary objective of this retrospective analysis was to evaluate the clinical efficacy and safety of a combination therapy using a picosecond laser followed by a sodium hyaluronate composite solution for the treatment of melasma.

MATERIAL AND METHOD

Study Design and Patients

This was a retrospective single-center chart review that analyzed data collected from August 2022 to January 2023. All patients provided written informed consent for the procedure and for the subsequent anonymized use of their clinical data and photographs for research and publication. All study-related treatments were provided free of charge.

Eligible patients were adult women or men, aged 18–60 years, with a clinical diagnosis of mixed-type melasma confirmed by Wood lamp examination and clinical observation, and with no known allergies to the study medications. Participants included in the analysis were required to have discontinued all topical treatments for at least 6 months before the initial treatment. Exclusion criteria included pregnancy or lactation, a history of photosensitivity, significant systemic diseases, severe hepatic or renal insufficiency, employment at the clinic or its affiliates, and any other conditions deemed unsuitable for the study by the investigator.

Treatment Procedure

Before each session, the patient’s facial skin was thoroughly cleansed. A topical anesthetic (compound lidocaine 5% cream, Tongfang Pharmaceutical) was applied 30 minutes before treatment to mitigate discomfort during laser therapy. A picosecond neodymium-doped yttrium aluminum garnet laser (PicoWay, Candela, Wayland, MA) equipped with a fractional handpiece was then used to deliver a single pass across the entire face. The parameters were standardized at a 10-Hz frequency, with the fluence titrated within a narrow range of 0.7–0.9 J/cm² to achieve a consistent clinical endpoint of mild, uniform erythema in all patients.¹⁵ The procedure continued until mild, uniform erythema was observed.

Two weeks following the initial laser treatment, the non–cross-linked sodium hyaluronate composite solution (Taihuo Paopao, Imeik Technology Development Co., Ltd.) was administered via an automatic intradermal injector. The device injected 0.05 mL of the non–cross-linked sodium hyaluronate composite solution at each injection point, with a total volume of 5 mL. The fractional picosecond laser induces controlled microinjuries in the dermis, known as laser-induced optical breakdown, which initiates the physiological cascade of skin regeneration and dermal remodeling.¹⁶ The rationale for the 2-week interval was to coincide with the peak of the proliferative phase of wound healing.¹⁷ Administering the non–cross-linked sodium hyaluronate composite solution at this time interval was intended to optimize tissue repair and modulate the dermal microenvironment.

The complete treatment cycle was repeated every 4 weeks for a total of 3 consecutive sessions. As part of their posttreatment care, all participants were instructed to use moisturizers and were counseled on strict photoprotection, which included daily application of a broad-spectrum sunscreen as well as avoidance of known triggers such as high-heat environments and strenuous exercise.

Efficacy and Safety Assessments

Clinical evaluations and photographic documentation were performed at baseline and 4 weeks after the final treatment session. To mitigate potential bias, the Melasma Area and Severity Index (MASI) was evaluated by a single, independent, board-certified dermatologist who was not involved in patient treatment. The evaluator was not affiliated with the product manufacturer or any of the authors’ institutions. The assessment was conducted retrospectively using standardized, high-resolution clinical photographs taken at baseline and at the 4-week follow-up. Blinding was achieved by presenting the “before” and “after” images for each patient in a randomized, unpaired fashion. The investigator was unaware of the temporal sequence of the photographs and was asked to score the MASI for each image independently. The pre- and posttreatment scores were then compared to calculate the mean reduction and statistical change.

The primary efficacy endpoint was the change in the MASI score from baseline. To ensure consistency and avoid bias, the same blinded investigator was invited to evaluate the MASI score at each visit. The MASI system assesses melasma severity based on its distribution across 4 facial regions (forehead 30%, right malar 30%, left malar 30%, and chin 10%) and 3 key parameters: area (A) of involvement, darkness (D), and homogeneity (H) of the hyperpigmentation.¹⁸ A higher score indicates a more severe degree of melasma.

The secondary endpoint was the Physician’s Global Assessment (PGA) score, where the treating physician rated the overall percentage of pigment clearance by comparing clinical photographs to baseline. The PGA was a 7-point scale defined as follows: 0 corresponded to complete clearance (100%) or near-complete clearance with minimal residual pigmentation; 1 indicated excellent clearance (≥90%); 2 indicated marked improvement (75%–89%); 3 indicated moderate improvement (50%–74%); 4 indicated mild improvement (25%–49%); 5 indicated no improvement (<25%); and 6 indicated worse than baseline.

Patient satisfaction was evaluated using a 4-point scale: “very satisfied” corresponded to improvement greater than 75%; “satisfied” indicated improvement between 50% and 75%; “fair” indicated improvement between 25% and 49%; and “unsatisfied” indicated improvement less than 25%. The overall satisfaction rate was subsequently calculated as the percentage of patients who reported “very satisfied” or “satisfied.” Adverse events were monitored and recorded throughout the study. In addition, patient-reported tolerability of the procedural discomfort and pain was also assessed and documented.

Statistical Analysis

Statistical analysis was performed using SPSS Statistics software (Version 26, IBM). MASI scores were presented as mean ± SD. A paired-samples t test was used to compare mean MASI scores between baseline and the posttreatment follow-up. Categorical data, including the PGA scores and patient satisfaction, were presented as frequencies (n) and corresponding percentages (%). A 2-sided P value of less than 0.05 was considered statistically significant.

RESULT

A total of 30 female patients with mixed-type melasma were enrolled in this study. The mean patient age was 32.4 ± 4.7 years, and all participants had Fitzpatrick skin types III or IV. Regarding previous treatments, 76.7% (n = 23) of patients had previously used topical agents, and 26.7% (n = 8) had received chemical peels. Other reported interventions included mesotherapy injections (n = 4, 13.3%) and traditional Chinese medicine formulations (n = 1, 3.3%).

The MASI score decreased from a baseline of 18.30 ± 7.85 to 8.20 ± 3.50 at the follow-up after the final treatment session (P < 0.05), with a mean reduction of 55.2%. Figure 1 represents the MASI score change of each patient, indicating that the combination therapy was universally effective in reducing melasma severity. Representative photographs illustrating clinical improvement and red area feature analysis are shown in Figures 2 and 3.

Fig. 1.

Individual changes in MASI scores for 30 patients at baseline (circles) and 2 weeks posttreatment (triangles).

Fig. 2.

Clinical photographs and corresponding red area feature maps of a 35-year-old woman at baseline (A–D) and 4 weeks posttreatment (E–H).

Fig. 3.

Clinical photographs and corresponding red area feature maps of a 29-year-old woman at baseline (A–D) and 4 weeks posttreatment (E–H).

The overall clinical improvement after 3 treatment sessions was evaluated by the treating physician using the PGA scale. The majority of patients were assessed as having either “marked improvement” (n = 11, 36.7%) or “moderate improvement” (n = 10, 33.3%). Notably, 4 (13.33%) patients reported near-complete clearance with minimal residual pigmentation, indicating a clearance of more than 90%. None of the patients were assessed as worse than the baseline (Fig. 4). Patient-reported satisfaction was high, with 86.67% (n = 26) of participants reporting satisfaction with the treatment outcome (Fig. 5). No patients reported being “unsatisfied.”

Fig. 4.

PGA scores evaluating clinical improvement after 3 treatment sessions.

Fig. 5.

Patient-reported satisfaction outcomes at 4 weeks posttreatment.

The treatment was well tolerated. The overall side effects were mild, and the pain was tolerable. Twenty-seven (90%) patients experienced a mild burning and pain sensation during both the picosecond laser and the non–cross-linked sodium hyaluronate composite solution treatment, which resolved within an hour. No serious side effects, including blister, edema, PIH, infection, or scarring, were observed.

DISCUSSION

The management of melasma presents a persistent clinical challenge due to its complex pathogenesis and high recurrence rate. Despite the development of various treatment approaches, current monotherapies often show limited effectiveness. Network meta-analyses further indicate that the combination therapies are currently preferable, offering better efficacy and a lower recurrence rate.¹¹

In this context, our study investigated a novel combination therapy combining a picosecond neodymium-doped yttrium aluminum garnet laser with the mesotherapy injection of a non–cross-linked sodium hyaluronate composite solution. The results demonstrate clinically and statistically significant improvement, evidenced by a 55.2% mean reduction in MASI scores, high PGA ratings, and patient satisfaction (86.7%).

This efficacy compares favorably with existing literature on picosecond laser monotherapy. Previous studies evaluating 1064-nm picosecond lasers alone at 4 weeks posttreatment have reported the MASI reductions ranging from approximately 29.6% to 40.1%.^19,20 The superior improvement observed in our cohort suggests that the addition of the non–cross-linked sodium hyaluronate composite solution provides a significant synergistic benefit.

Furthermore, the efficacy of our combination approach is competitive with other reported combination therapies. Published studies combining a picosecond laser with topical tranexamic acid have reported a 41.9% hemi-MASI reduction.¹⁹ Another study combining a Q-switched laser with oral tranexamic acid for mixed-type melasma reported a 41.1% modified melasma area and severity index reduction.²¹ The results of this study are well aligned with these findings.

The effect observed in the study can be attributed to a synergistic mechanism. This dual approach not only addresses the existing hyperpigmentation but also corrects the compromised skin barrier function and chronic inflammation.²² The initial laser therapy induces fragmentation of melanin granules, which can then be efficiently cleared by the immune system. Subsequently, the non–cross-linked sodium hyaluronate composite solution modulates the dermal microenvironment, mitigates side effects of laser therapy, and prevents melasma relapse. The composite solution contains both high- and low-molecular-weight sodium hyaluronate, which is fundamental for repairing the skin barrier, stabilizing the cellular microenvironment, and downregulating this inflammatory cascade. Furthermore, L-carnosine in the solution provides potent, multitargeted biochemical benefits. As oxidative stress is a well-established trigger for melanogenesis,²³ carnosine effectively neutralizes this pathway by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses.²⁴

The pathogenesis of melasma also involves increased vascularity and expression of vascular endothelial growth factor.²⁵ Although the primary targets of our combination therapy were pigment elimination and barrier repair, it is hypothesized that the hyaluronic acid and L-carnosine of the composite solution may offer an indirect beneficial effect on the vascular microenvironment via their known anti-inflammatory and microenvironment-modulating properties.^26,27

In terms of safety, the treatment was well tolerated. The observed side effects were mild and transient. Aggressive laser settings or ablative modalities are associated with a risk of PIH, a complication particularly prevalent in individuals with Fitzpatrick skin types III and IV. The absence of PIH in our cohort is noteworthy and may be attributed to the nonablative approach combined with the anti-inflammatory properties of the composite solution.

There are several limitations in our study. First, as a retrospective study, the sample size was determined by the number of available patient records rather than an a priori power calculation; thus, the statistical findings should be interpreted with caution. Second, although our findings suggest superiority compared with historical controls, the single-arm design is a significant limitation. Third, the study lacked systematic data collection on potential confounding triggers, preventing assessment of their potential impact on treatment outcomes. Finally, the 4-week posttreatment endpoint was selected to evaluate the acute therapeutic response and safety profile. However, this timeframe corresponds to the proliferative phase of wound healing rather than the maturation phase and is therefore insufficient to assess long-term efficacy or recurrence rates.

In conclusion, the combination of a fractional picosecond laser and a sodium hyaluronate composite solution demonstrates significant short-term efficacy at 4 weeks posttreatment and an acceptable safety profile for treating mixed-type melasma. Given the study’s limitations, these promising results should be validated in larger scale, prospective, randomized controlled trials with long-term follow-ups.

DISCLOSURES

Muyan Zou, Ming Sun, Yating Yang, and Tong Liu are employees of Imeik Technology Development Co., Ltd., the manufacturer of the products used in this study. The other authors have no financial interest to declare in relation to the content of this article.