Application of fractional carbon dioxide laser monotherapy in keloids: A meta‐analysis

There is no evidence‐based guidance on the use of fractional CO2 laser in the excision of scars.


| INTRODUC TI ON
A keloid is a pathological scar manifesting as a lump that extends beyond the scope of the original injury.It protrudes from the surface of the skin and has continuous growth, poor elasticity, and hard texture, may be accompanied by itching or pain, and has a high recurrence rate after treatment. 1,2An epidemiological analysis revealed that keloids commonly occur in individuals aged 10-30 years, the difference in time of onset between men and women was not statistically significant, and most patients had a family history of scars. 3Keloids not only affect aesthetics, but may also affect local function in severe cases.
They may even affect growth and development in adolescents, and they are not conducive to the patient's mental health. 4Common treatments include injections of glucocorticoids and 5-fluorouracil, laser therapy, surgical treatment, radiation therapy, topical silicone preparations, and compression therapy.However, the high recurrence rate always complicates clinical treatment. 5,6ser therapy is one of the most studied treatment methods in recent years, and it was used for the treatment of keloids as early as 1984. 7At present, the lasers used in clinical scar treatment can be classified as non-ablative lasers and exfoliative lasers according to treatment principles. 8Exfoliative lasers such as the fractional CO 2 laser can produce microscopic thermal damage bands on the skin to promote fibroblast and collagen remodeling, thereby improving the appearance of the skin. 9After the fractional laser beam penetrates the epidermis, drugs can diffuse from the epidermis into the dermis, promoting the transdermal absorption of topical drugs such as glucocorticoids.This also eliminates the pain of drug injection and reduces the risk of pigmentation. 10The fractional CO 2 laser has been clinically studied for keloid treatment.However, to date, there are no published data supporting the efficacy and safety of fractional CO 2 laser in the treatment of keloids.This meta-analysis included studies reporting fractional CO 2 laser treatment of keloids, with the aim of summarizing its efficacy and safety in the treatment of keloids and to guide clinical management.

| Literature inclusion and exclusion criteria
We included English-language studies reporting fractional CO 2 laser for the treatment of keloids.We excluded duplicate published studies, incomplete studies, those with incomplete data or unavailability of data, animal experiments, reviews, and systematic reviews.

| Search strategy
In this meta-analysis, we searched the PubMed, Embase, and Cochrane databases from their years of inception to April 2023.

| Literature screening and data extraction
Two researchers conducted separate literature searches, data screening, and data retrieval.Any problems or disputes were resolved in consultation with a third party.The main study components included author, date of publication, country of origin, trial design, sample size, patient sex, patient age, duration of disease, the Vancouver Scar Scale (VSS), and the Patient Scars Assessment Scale (PSAS).

| Literature quality assessment
Two independent researchers used the methodological index for non-randomized studies (MINORS) 11 to evaluate the quality of evidence for each study.There are 12 items, each with a mean score of 0-2, for a total of 24 points.The studies are categorized by score as "moderate quality" (9-16) and "high quality" (17-24).The metaanalysis was performed in accordance with the relevant items in the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. 12

| Data synthesis and statistical analysis
All data were processed using the statistical software STATA (v. 15.1; StataCorp LLC, College Station, TX, USA). 12Differences between continuous variables were evaluated using the weighted mean difference (WMD).I 2 was used to evaluate between-study heterogeneity.If the test for heterogeneity revealed p > 0.1 and I 2 < 50%, homogeneity between studies was indicated and the studies were analyzed together using a fixed-effects model; if p < 0.1 and I 2 > 50%, significant heterogeneity was indicated; if there was a difference, the source of the difference was identified using sensitivity analysis.If the differences were still large, the randomeffects model was used or the results of the combined study were discarded in favor of descriptive analysis.Publication bias was analyzed using funnel plots.

| Literature search results
A total of 58 articles were collected for this study.After excluding duplicate studies, 21 articles remained.After reading the titles and abstracts, a total of 16 articles were selected.Ultimately, six studies were integrated into the meta-analysis (Figure 1).

| Baseline characteristics and quality assessment of the included studies
In total, we included six non-RCT studies in this meta-analysis, and all were prospective in design.The sample sizes ranged from All MINOR scores, used for quality assessment, were greater than 16 (Table 1).

VSS parameters
The pooled results showed that the three

Total VSS
Three studies reported the total VSS after fractional CO 2 laser treatment for keloids.Because of significant heterogeneity (I 2 = 84.9%,p = 0.001), a random-effects model was used for the meta-analysis.The combined analysis revealed that the fractional CO 2 laser treatment significantly improved total VSS values (WMD = −4.01,95% CI: −6.22 to −1.79, p = 0.000) (Figure 3).F I G U R E 2 Changes in VSS parameters after fractional CO 2 laser treatment for keloids.

PSAS
Two studies reported the PSAS after fractional CO 2 laser treatment for keloids.Because of the significant heterogeneity (I 2 = 76.6%, p = 0.039), a random-effects model was used for the meta-analysis.

| Sensitivity analysis
A sensitivity analysis was conducted to remove studies that were excluded, and a full analysis was conducted on the remainder.After the meta-analysis, we found that the meta-analysis did not have a significant effect on the results of the meta-analysis, indicating that the results of the meta-analysis were stable and credible.

| Publication bias
The funnel plot constructed for this meta-analysis is displayed in Figure 6.It is largely symmetrical, indicating that no significant publication bias was found in the meta-analysis.

| DISCUSS ION
Scars are believed to result from a series of processes such as excessive accumulation or reduced degradation of substrates such as collagen during wound healing, leading to changes in the appearance and histopathological features of skin.Keloids result from excessive scarring caused by different factors during wound healing. 19They protrude from the normal skin, and not only is there severe itching, neuropathic pain, infection, and purulence, but also dysfunction and aesthetic damage of the affected area, resulting in increased anxiety and reduced quality of life. 20,21Keloids usually continue to grow for years, tend not to resolve over time, and have tumor-like characteristics, resulting in a high recurrence rate. 22,235][26] Because of its low efficiency and high recurrence 95% CI: −1.17 to −0.63) were significantly improved after fractional CO 2 laser treatment for keloids, although vascularity did not significantly change.However, there was significant heterogeneity (I 2 = 98.0%, p = 0.000) in the analysis of vascularity, challenging the confidence in this aspect of our results.Only two such articles were included in the study, and further research is required to verify this finding.Notably, we also analyzed total VSS, finding that total VSS after fractional CO 2 laser treatment for keloids was significantly higher than before treatment.This shows that fractional CO 2 laser treatment is effective in improving skin scarring.
In addition to objective performance, the patient's subjective feelings require attention.Our pooled results showed that the PSAS after fractional CO 2 laser treatment for keloids was significantly higher than before treatment.This shows that the treatment can achieve patient satisfaction, further supporting the effectiveness of fractional CO 2 laser in the treatment of keloids.The fractional CO 2 laser can inhibit fibroblast proliferation, stimulate the production of basic fibroblast growth factor, inhibit the expression of TGF-β1, promote normal wound healing and collagen remodeling, and improve the clinical symptoms of keloids. 16 terms of safety, our previous study found that fractional CO 2 laser surgery was significantly effective in the treatment of scars (95% CI: 1%-11%, 5%, 0% CI: 0% 2%, 11% CI: 4%-21%) and microvascular dilation (0%-6%, 0%-4%).This result suggests that, apart from a high incidence of pain, other side effects were infrequent.
The incidence of side effects was within acceptable levels and the treatment was safe.
Although the summary results of this study show that fractional CO 2 laser monotherapy can effectively treat keloids, and more studies have revealed that fractional CO 2 laser combined therapy can significantly improve the efficacy of the treatment of keloids.Tawaranurak et al. 24 discovered that the combination of fractional CO 2 laser treatment and topical triamcinolone resulted in a more significant reduction in scar volume compared to using topical triamcinolone alone for treating keloids (86.5% vs. 59.1%, p-value = 0.016).In addition, Sabry et al. s study revealed that fractional CO 2 laser combined with 5-fluorouracil or verapamil hydrochloride can significantly reduce VSS.However, laser-assisted 5-FU delivery tended to show a higher extent of improvement in scar characteristics than laser-assisted verapamil hydrochloride delivery, without significance. 25The latest study also found that fractional CO 2 laser combined with radiotherapy is a Changes in PSAS after fractional CO 2 laser treatment for keloids.
new comprehensive therapy composed of ablative lasers and radiotherapy for keloids with excellent clinical efficacy, low recurrence rate and no serious adverse effects. 26Therefore, future studies will focus on exploring the efficacy and safety of fractional CO 2 laser combined with keloids.If conditions permit, meta-analysis can be carried out to compare the efficacy of fractional CO 2 laser combined with different drugs.
This meta-analysis has several limitations.First, we included only a small number of studies, and our conclusions must be verified by the inclusion of new studies in the future.Second, there was significant heterogeneity in some analyses, possibly due to individual patient differences.However, we were unable to perform subgroup analyses, as the available studies had no detailed descriptions of individual patient characteristics.

| CON CLUS ION
Fractional CO 2 laser is effective in the treatment of keloids and can effectively improve the height, pigmentation, and pliability of scars, and patients are satisfied with this treatment.Further studies of combination therapy should be conducted.

F I G U R E 5
Incidence of adverse events after fractional CO 2 laser treatment for keloids.F I G U R E 6 Funnel plot for evaluating the publication bias of this meta-analysis.0 The search strategies were as follows: (keloid[Title/Abstract]) OR (keloids[Title/Abstract]) AND (CO 2 fractional laser[Title/ Abstract]) OR (carbon dioxide fractional laser[Title/Abstract]) OR (fractional carbon dioxide laser[Title/Abstract]) OR (fractional CO 2 laser[Title/Abstract]) OR (CO 2 laser[Title/Abstract]) OR (carbon dioxide laser[Title/Abstract]) OR (CO 2 fractional lasers[Title/ Abstract]) OR (carbon dioxide fractional lasers[Title/Abstract]) OR (fractional carbon dioxide lasers[Title/Abstract]) OR (fractional CO 2 lasers[Title/Abstract]) OR (CO 2 lasers[Title/Abstract]) OR (carbon dioxide lasers[Title/Abstract]).
10 to 45, totaling 155 patients.The six studies included in this meta-analysis used VSS and PSAS to assess scar severity.Studies by Srivastava and Sabry et al. reported changes in VSS parameters (including height, pigmentation, vascular density, and flexibility) before and after treatment.Additionally, Sabry, Alhamzawi, and El-Azhary reported changes in total VSS before and after treatment, while Soliman and Wang et al. used PSAS to assess scar severity before and after treatment.Three studies were conducted in Asia, including India, Iraq, and China, and four studies were conducted in Africa (Egypt).The patient ages ranged from 24.5 to 32.7 years.

TA B L E 1
Baseline characteristics and quality assessment of the included studies.

F I G U R E 3
Changes in VSS parameters after fractional CO 2 laser treatment for keloids.rates, the conventional CO 2 laser has been supplanted by the fractional CO 2 laser.In this meta-analysis, we collected six reports, including 155 patients, analyzing their reported VSS and PSAS scores and side effects.The pooled results showed that the three VSS parameters including height (WMD = −1.10,95% CI: −1.46 to −0.74), pigmentation (WMD = −0.61,95% CI: −1.00 to −0.21), and pliability (WMD = −0.90, pseudo 95% confidence limits