Laser-assisted delivery of vitamin c or vitamin c plus growth factors in the treatment of chloasma in women: a systematic review and meta-analysis

Hui Huang, Mingxia Liu, Huan Liu, Hui Wan, Fang Wu*

Department of Dermatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China


The use of lasers can be an effective approach for treating chloasma in women via the delivery of vitamin C and growth factors. This meta-analysis aimed to assess laser-assisted drug delivery (LADD) vs. traditional techniques for women’s skin disorders such as chloasma. According to the “Preferred Reporting Items for Systematic Reviews and Meta-Analysis” (PRISMA) guidelines, we searched the PubMed, ScienceDirect, Google Scholar, Springer, and Wiley online digital libraries. Articles published between 2000 and August 5, 2021, were included in this meta-analysis. A random-effects model was used to determine the pooled risk ratio (RR) with a 95% confidence interval (CI). This meta-analysis included a total of 16 studies. No significant heterogeneity values were observed. A subgroup analysis showed that patients receiving vitamin C plus growth factors had decreased the average wrinkle depth (AD) rates that were more significant than for the patients who received vitamin C alone. Moreover, patients in the treatment group showed greater reductions in the “Melasma Area and Severity Index” (MASI) score than in the control group. This meta-analysis suggested that the laser-assisted delivery of vitamin C plus growth factors should be widely used for certain skin diseases. Future studies need to conduct more trials with large populations using cosmeceutical or other growth factors.

Key words: laser-assisted delivery, melasma, risk ratio, skin disorders, systematic review

*Corresponding Author: Fang Wu, Department of Dermatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China. E-mail: [email protected]

Received: 28 February 2022; Accepted: 31 May 2022; Published: 3 August 2022

DOI: 10.15586/qas.v14i3.1082

© 2022 Codon Publications
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (


Lasers have several applications in the biomedical field, particularly in dermatology. Lasers, as photogenic devices, act as a therapy modality to treat skin disorders. For the last two decades, lasers have shown significant advances in facilitating skin resurfacing and rejuvenation (Lin et al., 2014). Fractional lasers promote enhanced drug delivery through the skin. Customized delivery (LADD) has improved the therapeutic consequences for many medical indications. LADD, as an effective technique, increases the dermal uptake of topically used agents. Several studies have been published on LADD techniques, but little is known about their implementation in dermatological practice (Wenande et al., 2020).

Melasma, as a common hyperpigmentary disease, affects severely childbearing women. More than 30% of these women are affected by this disease. Melasma has adverse impacts on individual quality of life. An asymptomatic “light to dark brown hyperpigmentation” with irregular borders and symmetrical disposition represents the clinical pattern (Passeron and Picardo, 2018). Melasma is also known as chloasma (e.g., mass of pregnancy). Chloasma has been well defined in the literature as follows: “It is a required hypomelanosis of sun-exposed areas that occurs during pregnancy and can affect 50–70% of pregnant women” (Bolanča et al., 2008). Furthermore, the literature states that chloasma typically appears on the cheeks, forehead, and face. Chloasma can occur spontaneously but primarily results from taking oral contraceptives or pregnancy (Wang et al., 2014).

Although fruits, vegetables, and cereals can be chemically contaminated (Cheng et al., 2022; He et al., 2021; Hu et al., 2021; Ma et al., 2022; Rahman et al., 2019; Sapkota et al.; Sharmin and Ahmed, 2021; Tang et al., 2020; Yang et al., 2022), they are important sources of vita-mins such as vitamin C, vitamin A, vitamin B1, vitamin B2, and vitamin B6 (Ma et al., 2021; Sharma et al., 2020; Wang et al., 2021). Recently, several publications have specified the use of LADD with vitamins to treat skin disorders. Vitamin C or vitamin C plus growth factors GFs was the predominant focus of a small-sample study conducted by Machado et al. (Machado et al., 2021b). The individuals in the group that was treated with vitamin C and GFs showed significantly reduced skin roughness compared to those treated with vitamin C alone. Moreover, Mann–Whitney tests were conducted to compare the performances of two groups in studies (Machado et al., 2021a; Machado et al., 2021b). While these studies indicated satisfactory results, the interquartile range (IQR) and median results of the two studies varied. In comparison, another study by Oresajo et al. confirmed that vitamin C and ferulic acid protected skin from sunscreen effects (Oresajo et al., 2008). As no consensus has been reached among the findings of published studies, the authors of this study conducted a meta-analysis to determine the overall importance of LADD for vitamin C, “cosmeceutical growth factors,” and skin disorders.

Material and Methods


This systematic review and meta-analysis were performed according to the updated PRISMA guidelines (Page et al., 2021) and recommendations of the Cochrane Collaboration (Higgins, 2011).

Search strategy and selection of studies

The PubMed, ScienceDirect, Springer, Google Scholar, and Wiley online digital libraries were searched for literature that were published between 2000 and August 5, 2021. We also performed a cross-reference search for eligible articles to identify those studies that were missed by a computerized search. A combination of search keywords and MeSH terms was used with the help of Boolean operators described as follows:

“Laser-Assisted Delivery,” OR “Laser-assisted drug delivery,” AND “Vitamins,” OR “Vitamin C,” OR “Growth Factors.”

Two colleagues, who are also researchers (e.g., HH and ML), independently assessed the titles and abstracts of the studies using the same inclusion criteria. We resolved any disagreements regarding the inclusion of studies with the consensus of a third researcher (e.g., HL).

Study eligibility and inclusion criteria

The eligibility of the study was evaluated based on the study design approach, participants, comparators, interventions, and outcomes according to the PRISMA guidelines. The participants and interventions were defined as female patients with chloasma disease who received laser treatment with vitamin C. The comparators were defined as those patients who were treated with vitamin C or vitamin C plus GFs for Crohn’s disease. There were no restrictions regarding the study design, as both randomized controlled and nonrandomized controlled studies were included in this meta-analysis. The exclusion and inclusion criteria were as follows:

We included studies meeting the following inclusion criteria: (1) all patients who were treated with vitamin C, other vitamins or growth factors; (2) studies mentioning the mandatory use of laser-assisted delivery (LADD) approaches; (3) two study groups, RC (receiving vitamin C) and CGFs (cosmeceutical-containing growth factors) or ROV (receiving other vitamins); and (4) studies published in English.

We did not consider the studies that met the following exclusion criteria: (1) studies on diseases other than melasma or chloasma; (2) seminar reviews, case reports, letters, and reviews; and (3) experiments on animals.

Data extraction

This study involved five researchers. Three researchers (e.g., HH, ML, and HL) independently screened the records that were identified from the database searches. They reviewed the included studies and extracted information at the trial level. The fourth researcher addressed the different opinions among the three researchers regarding data extraction from the studies. Two researchers (e.g., HW and FW) assessed the full-text studies, and another researcher (e.g., HL) repeated this process to provide arbitration with respect to the results. Data extracted from the eligible studies included the study ID (Authors and year), country of the first author, population, LADD model and type, vitamin, growth factors, statistical method, and P-value.

Quality assessment

The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the studies included in this meta-analysis(Margulis et al., 2014). Two researchers (e.g., HH and ML) examined the quality assessments of the included studies by using the NOS selection, comparability, and exposure categories. Each study was rated based on the three broad perspectives mentioned above. A prospective and cross-sectional study was rated with a maximum of nine stars. A study that received six stars was considered to be of high quality. We resolved any disagreements between the two researchers with the consensus of the third researcher (e.g., HL).

Statistical analysis

We used Review Manager (RevMan) v.5.3.1 to perform the meta-analysis. The Cochran–

Mantel–Haenszel test was used to calculate the pooled estimation (risk ratio) from the categorical variables. The risk ratio (RR) is widely used to determine confidence intervals for unknown populations. The authors determined the RR of individuals receiving vitamin C and vita-min C plus GFs. Similarly, the RR was calculated in this meta-analysis by comparing the LADD and conventional techniques. Forest plots represent the results with 95% confidence intervals (CI 95%).

The I2 test was used to measure the homogeneity assumption that revealed the percentage of total variation across studies. The level of heterogeneity was considered to be acceptable if the I2 value was <50% when a fixed-effects model was used. For the random-effects model, the heterogeneity was considered to be elevated when the I2 value was >50%, and publication bias was visually addressed by using a funnel plot derived from Egger’s test.


Study selection

The literature search resulted in the identification of 1095 studies from five popular databases. Of these, 35 records were removed due to duplications, ineligibility, or other reasons. After screening a total of 1060 records, 997 articles were removed as they did not meet the inclusion criteria. Of the 63 potentially articles eligible for the full-text review, we were not able to retrieve 2 papers. A full-text analysis of the remaining 61 studies was performed at the screening stage. Of these studies, 45 were excluded from this meta-analysis. Of these 45 studies, 21 discussed lasers related to other topics, 16 were out of scope, and 8 did not provide the data used in this meta-analysis. Consequently, 16 studies (n = 1095) were selected for use in this meta-analysis (Figure 1).

Study characteristics

Table 1 contains the baseline characteristics of the included studies. As seen in Table 1, two studies were published in each country, which included the UK, USA, Korea, Taiwan, and Philippines. Of the remaining six studies, one was published in each country, which included Japan, Egypt, Turkey, Iran, Brazil, and China. Of the 712 participants who contributed to the included studies, melasma and chloasma were common diseases studied in the included articles. Fractional, CO2, Q-switched (Nd:YAG), and (Er:YAG) lasers were used to deliver agents in these studies. Three studies did not specify the vitamins used (Ooe et al., 2013; Qu et al., 2021; Robati and Asadi, 2017). At the same time, vitamin C remained the dominant type of vitamin used in the majority of studies. Two studies mentioned the use of cosmeceuticals (GFs) (Machado et al., 2021a; Machado et al., 2021b), and one study mentioned basic fibroflast growth factors bFGFs(Waibel et al., 2016). A study revealed the growth factors that were released from microneedling procedures. In the included studies, t-tests were predominantly used as the statistical method (Ustuner et al., 2017).

Skin disorder control

Three studies with 331 patients (e.g., 136 events in Group A and 254 events in Group B) were used for skin disorder control meta-analysis (Machado et al., 2021a; Machado et al., 2021b; Rattanawiwatpong et al., 2020). Skin roughness (Rgh) or SEr and average wrinkle depth improvements were two necessary outcome measures used in these studies. Baseline skin roughness scores were used to calculate the skin disorder improvements. The patients in the two groups (e.g., A and B) were treated with vita-min C and vitamin C plus GFs, respectively, for different numbers of weeks. We used data on the overall effects on skin roughness to perform the meta-analysis. Figures 2 and 3 show the publication results that were used in this meta-analysis. We took the reduced skin roughness values from the included articles. Three studies using RC and R-CGFs (pooled RR and 95% Cl: 1.50 [1.16–1.96], I2 = 0.00%) indicated high levels of disorder control by using vitamin C plus GCFs. However, we can measure skin improvements from the perspective of treatment duration, which can further clarify the effects on patients receiving vitamin C plus growth factors.

A total of eight studies qualified for inclusion in the meta-analysis on LADD of vitamin C and vitamin C plus growth factor GFs. (Alvin et al., 2011; Badawi and Osman, 2018; Choi et al., 2015; Handog et al., 2009; Kim et al., 2020; Lima et al., 2017; Qu et al., 2021; Ustuner et al., 2017). The Melasma area and severity index (MASI) values were used for the control and experimental groups. Pigmentation changes are mainly measured using the MASI scores. Hence, we used the MASI scores at baseline and the end of treatment. Severe hyperpigmentation was associated with higher MASI scores, which reached as high as 48 (Badawi and Osman, 2018). As shown in Figure 3, significant decreases were observed in five studies compared to three studies. The heterogeneity among the included studies was calculated as I2 = 0.00, which indicated no publication bias. The random-effects model was applied to pool data regarding melasma reduction (RR 1.49 95% CI 1.23, 3.65 P = 0.69). Furthermore, we justify our results in this meta-analysis from the recent literature, as shown in Table 1.

Figure 1. Process selection of papers based on PRISMA.

Table 1. Study characteristics.

Study ID Country Population (characteristics) LADD model and type Vitamin Growth factors Statistical method
Machado et al. (Machado et al., 2021b) UK N = 132, age (19–62) years, requiring scar treatment fractional ablative lasers (AFLXs) C cosmeceutical Mann-Whitney test
Machado et al. (Machado et al., 2021a) UK N = 149, age (43–70) years, fractional ablative lasers (AFLXs) C cosmeceutical Mann-Whitney test
Ooe et al. (Ooe et al., 2013) Japan Age ≥ 20 years and wrinkle score ≥2 YAG laser and other three methods Not specified bombined vitamins t-test, Tukey’s test, and Wilcoxon signed-rank sum test
Hsiao et al. (Hsiao et al., 2016) Taiwan N = 8 CO2 Laser Two vitamin C not specified one-way ANOVA
Choi and Song (Choi et al., 2015) Korea N = 93 with 440 AK lesions,
age >18 years
ablative fractional laser-assisted not specified not specified Pearson’s chi-squared test
(Waibel et al.(Waibel et al., 2016) USA N = 15, ages between 30 and 55 years fractional ablative CO2 laser C, E, and Ferulic acid basic fibroblast (bFGF) t-test
Kim et al. (Kim et al., 2020) Korea N =18, ages between 26 and 53 years Q-switched 1064-nm Nd: YAG
C, E, and Ferulic acid not specified t-test
Badawi & Osman (Badawi and Osman, 2018) Egypt N = 30, bilateral melasma (Er: YAG) laser C, E, and Ferulic acid not specified t-test
Kauvar (Kauvar, 2012) USA N = 27 with photo-types (II–V) Q-switched Nd: YAG laser C not specified Mann–Whitney test and t-test
Ustuner et al. (Ustuner et al., 2017) Turkey N = 16, with recalcitrant dermal QS-Nd: YAG laser C growth factors released by
micro-needling procedure
Wilcoxon Signed-Rank
Lee et al. (Lee et al., 2003) Taiwan Not specified (Er: YAG) laser C not specified t-test
Robati & Asadi (Robati and Asadi, 2017) Iran N = 40, ages between 34 and
62 years, and facial rhytides.
ablative fractional lasers (CO2 and (Er: YAG) lasers not specified not specified Mann–Whitney U and Wilcoxon signed-rank tests
Alvin et al. (Alvin et al., 2011) Philippines N = 50 model not specified C mulberry extract oil Mann–Whitney test
Handog et al. (Handog et al., 2009) Philippines N = 56, melasma not specified A, C, and E oralprocyanidin t-test
Lima et al. (Lima et al., 2017) Brazil N = 6, ages between 34 and 46, melasma not specified C hepatocyte growth factor t or Wilcoxon test
Qu et al. (Qu et al., 2021) China N = 90, ages between 24 and
49 years, and melasma
fractional CO2 laser not specified tranexamic acid Kolmogorov-Smirnov and ANOVA tests

Figure 2. Forest plot of disorder control.

Figure 3. Funnel plot of disorder control.

The data listed in Table 1 indicate that LASER-assisted drug delivery has improved chloasma in women. When the MASI scores of the included studies are compared with the corresponding data from existing studies, it can be verified that the LASER-assisted drug delivery of vitamin C and growth factors decreased the complexities in chloasma.

Heterogeneity test

Two meta-analyses were conducted in this study. The first meta-analysis was performed to assess two study groups, namely, a group that received vitamin C and a group that received vitamin C plus growth factors. In the second meta-analysis, a comparison of two study groups (e.g., control group vs. experimental group) was performed. The heterogeneity I2 values in the two meta-analyses remained at 0, which suggested no heterogeneity among the included studies.

Publication bias

The diagnostic accuracy of a test is mainly affected by the publication bias in a meta-analysis. A narrower 95% confidence interval was indicative of a high accuracy of a trial. Funnel plots (Figures 4 and 5) were used to evaluate the publication bias (Simmonds, 2015).


In this study, two meta-analyses were performed to assess the performance of LADD for vitamin C and vita-min C plus growth factors and to determine how LADD effectively treats melasma or chloasma skin disorders in women.

In the first meta-analysis, three studies qualified for the subgroup analysis of individuals receiving vitamin C and vitamin C plus GFs. For this case, cosmeceutical GFs were used in three studies. This meta-analysis indicated that a combination of vitamin C plus CGFs assisted by LADD yielded better results than vitamin C alone (Figure 2). The subgroup analysis showed decreased skin disorder severities (e.g., melasma or chloasma) in both groups (e.g., A and B), but LADD with vitamin C plus CGFs significantly decreased wrinkles and skin roughness. This was achieved by analyzing the Rgh or SEr values after using vitamin C and C plus GFs. The baseline values, as shown in Figure 2, were different in the three studies.

Figure 4. Forest plot of a comparison between two techniques using MASI score.

Figure 5. Funnel plot of a comparison between two techniques.

Second, eight studies qualified for the subgroup analysis of LADD (control vs. experimental groups) used for treating melasma or chloasma disorders (Figure 3). The results of the meta-analysis indicated significant treatment differences in the patients of the two groups. A significant reduction in MASI scores was observed in the experimental group compared to the control. The MASI scores significantly decreased in five studies, while they remained either unchanged or were slightly lower in three studies. These results might be due to variations in treatment periods and the agents used in the studies. For example, one study reported that microneedling sessions continued for 30 days (Lima et al., 2017), while in another study, patients were treated with a combination of anti-oxidant serum for 2 weeks (Kim et al., 2020).

An earlier meta-analysis discussed the microneedling technique when used for topical therapies in melasma disorder (Bailey et al., 2021). Furthermore, a study was performed to observe the safety and efficacy of acupuncture for chloasma (Liang et al., 2017). This is the first meta-analysis conducted to evaluate LADD for vitamin C and growth factors. Moreover, this meta-analysis first showed that the LADD technique decreased wrinkles in patients of both the two groups.

This meta-analysis has several strengths. Primarily, studies were conducted in different regions that involved different age groups. The I2 values in both meta-analyses remained at 0.00, which indicated no heterogeneity. There was no publication bias in the present meta-analyses.

Our study has two main limitations. The results of two meta-analyses need to be interpreted with caution. First, the number of studies and individuals in these meta-analyses was relatively small. Second, different types of laser devices were used, and their influence varied over various platforms.


Numerous LADD trials have been conducted to treat certain skin disorders (e.g., melasma or chloasma) with vitamin C and vitamin C plus growth factors. Overall, the LADD technique is more effective than traditional techniques in treating these skin disorders. In summary, this meta-analysis suggests evaluating more growth factors in a large population in future studies.

Conflict of Interests

The authors declare that they have no conflicts of interest.


This research is supported by the mechanism of the malignant skin tumor AHR-MERTK-PD-L1 axis and HPV16 E7 through TGFβ-downregulated MIR-34B-5P. The grant numbers of the first and second funders are WX21M01 and WX21A12, respectively.


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