How effective is Vitamin C for gingival depigmentation? a scoping review

How effective is Vitamin C for gingival depigmentation? a scoping review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review How effective is Vitamin C for gingival depigmentation? a scoping review Aditi Chopra, Shubhankar Mehrotra, Malvika Shyamkumar, Shravya Marcherla, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7803852/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: Excessive gingival pigmentation can be treated by surgically removing the pigmented gingival tissue with a scalpel, bur, LASER, electrocautery, cryotherapy, chemical peeling, and masking with free gingival grafts. Recently, Vitamin C in gel, powder, or liquid has been used alone or as an adjunct to micro-needling or a scalpel. This paper aims to critically appraise current evidence on the role of Vitamin C in gingival depigmentation. Material and Method: The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis for Scoping Review (PRISMA-Scoping Review). Studies using ‘vitamin C’ in any form, via any application method, frequency, duration, and dosage for gingival depigmentation were compared to the scalpel, LASER, bur abrasion, or cryotherapy, including. Results: Out of 119, 103 articles were excluded, and 16 articles were taken up for full-text screening. Of 16, 12 articles were included in the review. The results showed that vitamin C can be used along with scalpel depigmentation or as a stand-alone therapy (as mesotherapy or topical application). Vitamin C effectively reduced gingival pigmentation; however, with no statistical difference between the scalpel and Vitamin C application. No studies have compared the efficacy of Vitamin C to Cryotherapy. Microneedling of the gingiva followed by vitamin C application was also done. The recurrence rate of pigmentation following Vitamin C mesotherapy application was 32.59% after three months, compared to 32.87% with the scalpel. Vitamin C mesotherapy also revealed a significant reduction in VAS scores for itching and pain, and better patient acceptance than scalpel depigmentation. Conclusion: Vitamin C application with microneedle or mesotherapy is a promising atraumatic alternative to a scalpel for gingival depigmentation. Clinical Pharmacology Dentistry Gingival depigmentation Gingiva Melanin Vitamin C Pigmentation Aesthetics Mucogingival surgery periodontal plastic surgery Figures Figure 1 Figure 2 Introduction Gingiva is physiologically pigmented due to the deposition of melanin pigments by the melanocytes in the gingival tissues (Dummett, 1946 ). However, increased melanin pigmentation may occur in some individuals due to certain local and systemic conditions and syndromes such as smoking, use of certain medications, unintended implantation of amalgam restoration, Addison's disease, Albright's syndrome, Acromegaly, etc. (Rotbeh et al., 2022 ; Alhajj and Alhajj, 2020 ). According to a recent meta-analysis, 20.8% of the population suffers from physiologic/pathologic oral hyperpigmentation, corresponding to one out of five people. Studies have noted that men were more likely to be affected by the increased pigmentation than women (Rotbeh et al., 2022 ). Smokers or those exposed to second-hand smoke are also more likely to be affected. Those drinking hot drinks and dark-skinned individuals show an increased prevalence of gingival pigmentation (Alhajj and Alhajj, 2020 ; Scully and Bagan, 2004 ). Approximately 30–98% of Asians are estimated to suffer from hyperpigmented gingiva with diffuse deep purplish discoloration or irregularly shaped patches, striae, or strands (Javali et al., 2011 ). Patients often seek depigmentation procedures as a result of excessive gingival pigmentation, which compromises the aesthetics of the gingiva. There are various methods available for removing pigmented gingival tissue surgically through scalpel de-epithelialization, bur abrasion, laser depigmentation, electrosurgical subtraction, cryotherapy, chemical peeling, and masking with free gingival grafts or acellular dermal matrices (Parwani and Parwani, 2013; Alhabashneh et al., 2018 ; Suragimath et al., 2016 ). Compared to all these techniques, soft tissue lasers have become increasingly popular due to improved patient satisfaction, improved aesthetic outcomes, shorter operating times, and decreased bleeding (Muruppel et al., 2020 ; Jagannathan et al., 2020 ). Carbon dioxide, Erbium-doped yttrium-aluminium-garnet (Er: YAG), neodymium-doped yttrium aluminum garnet (Nd: YAG), erbium, chromium: yttrium-scandium-gallium-garnet (Er, Cr: YSGG), and diode are some of the common LASERS used for gingival depigmentation. Among these, diode lasers tend to have the longest depigmentation duration, especially in non-smoker patients (Altayeb et al., 2021 ). For gingival pigmentation, a diode laser operating at 980 nm wavelength or an erbium-YAG laser at 2940 nm, with a power range of 2–4 watts, can be used in a sweeping motion in continuous wave mode over the pigmented area to ablate the melanin-rich epithelium. Recently, Gul et al. conducted a systematic review comparing the efficacy of various treatment modalities to treat gingival pigmentation. They concluded that laser-assisted depigmentation is equal to, or even better than, scalpel depigmentation regarding pigmentation outcomes and recurrence. The precise mechanism of repigmentation is not yet fully understood. However, the migration theory suggests that active melanocytes from the adjacent pigmented tissues may migrate to the treated areas, potentially leading to a failure in the process. It would seem that reports of repigmentation are somewhat limited in number and variety. A study by Ginwalla et al. found that 50% of patients showed repigmentation after depigmentation with the bur abrasion technique within 24 to 56 days. Pal et al. also noted repigmentation in 19% of patients following gingival depigmentation by surgical bur. Nevertheless, lasers have shown superior results in terms of patient acceptance, pain relief, and satisfaction when compared with surgical blades (Gul et al., 2019 ). A recent systematic review by Ahmed et al (2023), including eight studies, reported superior characteristics and treatment outcomes for diode lasers as compared to Erbium lasers. The time before pigmentation recurrence was longer for the diode laser compared to the Erbium laser. Inchingolo et al. ( 2024 ) also conducted a systematic review and evaluated the efficacy of the diode laser for the treatment of gingival pigmentation compared to the conventional scalpel technique and found that the diode laser provides better results in terms of intraoperative bleeding and perception of pain for the patient. However, there were no differences in depigmentation and wound healing intensity (Jnaid et al., 2021). Additionally, studies have shown that diode lasers have a lower recurrence rate, but this finding has not yet been confirmed by long-term clinical evidence (Muharib and Almasoud, 2020; Alasmari, 2018 ). Furthermore, several studies have demonstrated that both laser electrocautery and scalpels are associated with being technically demanding, time-consuming, and increasing anxiety and discomfort in patients [Patil et al.,2015; Kumar et al., 2013 ; Bergamaschi et al., 1993 ; Kathariya and Pradeep, 2011 ; Lagdive et al., 2009; Bakutra et al., 2017 ]. Laser treatment has been reported to delay wound healing when compared to scalpel-based depigmentation, especially at sites with thin gingival biotypes and narrow inter-papillary spaces (Kathariya and Pradeep, 2011 ; Lagdive et al., 2009; Bakutra et al., 2017 ). As a result, many authors promote the use of cryogens for gingival depigmentation; however, clinically, it is difficult to control the depth of penetration of cryogens into the gingival tissues, which limits their use. When applied, several cryogens have been shown to cause tissue damage and stinging or burning sensations (Kumar et al., 2013 ; Bergamaschi et al., 1993 ; Kathariya and Pradeep, 2011 ). Accordingly, the need for exploring non-invasive alternatives to gingival hyperpigmentation is often perceived. There is an emerging use of vitamin C for gingival depigmentation and aesthetic procedures (Sanadi and Deshmukh, 2020 ; Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; Shimada et al., 2009 ; Lerner and Fitzpatrick, 1950 ; Yussif et al., 2017 ). Topical application of Vitamin C in gel, powder, or liquid forms, either alone or as an adjunct to micro-needling or scalpel, over the pigmented gingival epithelium is being used (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; Shimada et al., 2009 ). Vitamin C inhibits the activity of the tyrosinase enzyme by interacting with the copper (Cu) ions at the tyrosinase active site. This in turn reduces the melanin formation, which is responsible for converting the amino acid dehydroyphylalanine (DOPA) to dopaquinone. The inhibition of Dopaquinone prevents the formation of melanin pigments (Lerner and Fitzpatrick, 1950 ; Yussif et al., 2017 ) (Fig. 1 ). Vitamin C also has an epigenetic suppressive action on cells and controls melanocyte activity (Gustafson et al., 2015 ). Vitamin C can even affect the intercellular junctions between melanocytes and keratinocytes and affect the HMB-45 receptor, which controls the activity of melanocytes in the suprabasal layers of the epithelium (Yussif et al., 2017 ). Although vitamin C has shown promising results for the depigmentation of the skin, few clinical studies have been conducted to explore its role in gingival depigmentation. To our knowledge, no review has critically appraised the existing evidence on the role of Vitamin C as an adjunct for gingival depigmentation. With the use of Vitamin C as a new method of gingival depigmentation gaining popularity, many professionals are unaware of the various types, modes of application, and current evidence on its effectiveness and long-term prognosis. Hence, this scoping review aims to critically appraise the existing literature and provide a comprehensive review of the current methods and efficacy of Vitamin C for gingival depigmentation. Methodology The review is based on the guidelines for the scoping review by the Preferred Reporting Items for Systematic Review and Meta-analysis for Scoping Review (PRISMA-Scoping Review) checklist (Tricco et al., 2018 ). The objectives of the review were: To assess the current evidence regarding the efficacy and mechanism of action of Vitamin C in gingival depigmentation To determine the most effective method of applying Vitamin C for reducing gingival pigmentation To review current evidence regarding patient-reported outcome measures, adverse events, and recurrence following Vitamin C depigmentation compared to other treatment methods for gingival depigmentation. The eligibility criteria are described using the Participant-Intervention-Comparison-Outcome-Study Design (PICOS) framework as follows: Types of Participants (P): Participants over the age of 18 (males and females) who have increased gingival pigmentation due to heavy melanin deposition. Studies on hospitalized patients, physically or mentally handicapped patients, and patients with terminal or serious illnesses were excluded. Intervention (I): Studies where vitamin C was used in any form, via any application method, frequency, duration, and dosage for gingival depigmentation. Comparator group (C): Studies where gingival depigmentation was done by any of the following: scalpel, laser, electrocautery, cryogen, bur abrasion, or LASER. Outcomes (O): Studies assessing the effect of Vitamin C on the reduction in intensity, area of pigmented gingiva; patients' perception of aesthetics, nature of wound healing, and postoperative complications (Table 2 ) Types of studies (S): Observational, case-control, cohort, clinical trials, and qualitative studies utilizing questionnaires and surveys to assess patient-related outcomes were included. All preclinical, in vitro, animal, case reports, and case series studies were also included. However, all editorials, book reviews, literature reviews, and letters to the editor were excluded from this review. Search strategy, information sources, and keywords : The following electronic databases: MEDLINE (PubMed), Scopus, EBSCO (dentistry and open science access), Cochrane database, Web of Sciences, and ClinicalTrial.org. Were searched on 14th December 2022, and updated on 15th August 2023. The following keywords and MeSH terms were utilized for data collection: (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation). The PubMed search string was adapted to the other database. Articles written in any language were included. The search results were transferred into the ‘Mendeley reference manager (version 1.19.4)’ and duplicates were removed. The comparator group was not added in the search string, as it would exclude studies where only Vitamin C was used without any other intervention. The details of the search strings in the individual database are provided in Table 1 . Table 1 Search Strategy for different databases for including articles for the title and abstract screening. S/No Database Search string used No of articles PubMed (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation) 14 Scopus (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation) 6 Embase (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation) 14 Web of Science (vitamin C OR ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva OR melanin OR pigment OR depigmentation) 77 Cochrane Database (clinical trials) (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation) 7 Clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT03719274?cond=%28Vitamin+C+OR+Ascorbic+acid%29+AND+%28gingival+OR+gingiva+OR+keratinized+gingiva+OR+pigmented+gingiva%29+AND+%28melanin+OR+pigment*+OR+depigmentation%29&draw=2&rank=1 1 Total Search 119 Data charting and the Selection of studies process The results from the data search were transferred into the Mendeley reference manager (version 1.19.4), and the duplicates were removed. After removing the duplicates, all articles were copied into the Microsoft Excel spreadsheet for screening. During the review process, authors from both teams (S.M. & S.H.) and (M.S. & A.C.) screened titles and abstracts for eligibility. All articles where Vitamin C was either used alone or compared to any other intervention for depigmentation of gingival tissues were included. The following articles were excluded: articles where Vitamin C was used for any periodontal surgical procedure other than depigmentation of gingival tissues; articles where Vitamin C was used as a supplement to treat vitamin C deficiency or for treating any periodontal disease; articles where Vitamin C was used for the removal of pigmented tissues in any other part of the body except gingival tissues. Any discrepancies during the initial screening were resolved by involving the other reviewer (MM), who was not involved in the initial screening phase. Following the selection of titles and abstracts by both teams, full-text screening was conducted. The full-text screening was conducted by two independent reviewers (S.M. & S.H.) following the eligibility criteria. At the full-text stage, discrepancies were resolved through mutual discussion and consultation with another reviewer (A.C.). Citations of the final included articles were copied into another Microsoft Excel 2013 version, and data were extracted independently by all authors. Data Items and Synthesis of Results The following data items were extracted from each study: bibliographic and study details i.e. author details, funding, organization, aims and objectives of the study, type of study; participants’ detail i.e. number, age, gender, socioeconomic status, income, study settings (community/ hospital/ university/private clinic); contextual information; exposure details i.e. type and mode of Vitamin C used in the study along with the outcome details of each study. A preliminary data extraction form for all the data extracted from each study is given in Table 2 . In case of missing data, the reviewers tried to obtain it by contacting the corresponding authors. Table 2 Preliminary data extraction/ coding form S/No. Sections Required information 1 Bibliographic details First author, corresponding author email; Year of publication; Funding information Language of the paper; Site of study (country) 2 Study details Aim and Objectives of the Study Methodology of the study (study design, sampling, sample size (in each group if applicable), Type of analysis, duration of the study, the follow-up, drop-outs); blinding method; allocation concealment 4 Population characteristics Age (mean + SD) or age range; Gender (male to female); Nature of study population (healthy or diseased population); Type of gingival pigmentation; presence or absence of any other disease reported in the patient (gingivitis/ periodontitis/ others). 5 Exposure details Nature of Vitamin (gel/ liquid/ powder); Type or form of Vitamin C (name of vitamin C analog), Dosage (mg or %), frequency (once or twice), mode of application of Vitamin C (topical/ injection); Ease of use; Duration of surgery (mins) 6. Comparator group Gingival depigmentation using a scalpel, laser, electrocautery, or cryogen. 7 Outcome Gingival pigmentation score before and after, as measured by any method or index (Dummet-Gupta Oral Pigmentation Index (DOPI), Hanioka’s Melanin Index, Spectrophotometric analysis, inhibition of tyrosinase activity and melanin composition, Kumar’s gingival pigmentation index, and qualitative assessment of histological and immunohistochemical outcomes. Pain, itching, and discomfort score by any method or index (Visual Analog Score and Patient Satisfaction Surveys) Presurgical, surgical, and post-surgical requirements and complications before and after depigmentation Adjuncts used with Vitamin C (Laser, surgical blade, micro-needling) Time required for the procedure Patient-reported post-operative outcomes The results from each study and its characteristics of included studies are reported in Table 3 , and a description of the factors is provided as a narrative synthesis below as follows: Table 3 Characteristics of included studies Author/ Year/ Country of origin/ study design Age Male/Female ratio Sample Size Smokers/Non-smokers Comorbidities Mode of Application of Vitamin C Study Groups and sample size in each Group Outcome/Parameters assessed Follow-up period The index used for the assessment of gingival pigmentation Study Outcome Limitations/ Adverse events Shimada et al. ( 2009 ) Japan Prospective Clinical Split-mouth Trial 25–57 years (mean age: 37.2 years) 22 males; 51 females 73 subjects 38 smokers, 10 former smokers, and 25 non-smokers Topical Ascorbic Acid- glucoside Gel (10%) Test: Topical Vitamin C gel Control: Placebo gel Changes in luminescence (L*) In vitro assessment of inhibition of tyrosinase and melanin concentration 12 weeks Spectro -photometric analysis (L*) The luminescence values changed significantly from 54.47 at baseline to 57.04 at 12 weeks in the test group (p < 0.05) No direct assessment of changes in pigmentation indices. Short-term follow-up Sheel et al. (2015) India Case Report 18 years Female patient Non-smoker Ascorbic acid ampoules applied topically (10%/250mg/ml) Test group: Surgical scalpel along with topical applications of Vitamin C Visual Analog Scores (VAS) Patient satisfaction using a three-point scale.38 9 months Dummet-Gupta’s Oral Pigmentation Index (DOPI) 39 Subjective decrease in pigmentation and absence of recurrence at 9 months. Reduction of VAS score from 1.8 intraoperatively to 1.5 10 days postoperatively. High patient satisfaction score of 3 Quantitative reduction in DOPI and recurrence rate not specified. Yussif et al. ( 2017 ) Egypt Animal-model Study 15 Adult male goats Non-smokers Intraepidermal injection (mesotherapy) using L-Ascorbic acid Group I: Saline (5) Group II: 0.1ml Vit C (5) Group III: 0.3ml Vitamin C (5) Immunohistochemical changes: antibodies against human melanoma black (HMB-45) and E-Cadherin - Histological evidence revealed a marked reduction in melanin pigment and an increase in the number of cells with the perinuclear haloing in both groups II and III as compared to Group I. No quantitative assessment of histologic changes. No follow-up. Yussif et al. ( 2019 ) Egypt Prospective Clinical Parallel-arm Study 30 study participants Age > 18 years Non-smokers Intraepidermal injection (mesotherapy) using L-Ascorbic acid Test: Non-surgical Vitamin C injections (15) Control: Scalpel depigmentation (15) Changes in two pigmentation indices Visual Analog Score (VAS) for pain and itching. Patient Satisfaction 9 months Hanioka’s Melanin Index 40 Kumar’s Gingival pigmentation index (GPI) 15 A significant difference in GPI in favor of the control group over the test group at 1 month. Significant reduction in VAS scores (from 5 at baseline to 0 on the 7th day) for itching and pain on the 2nd day (p = 0.0001), 3rd (p = 0.0001), and 7th day (p = 0.0015) when compared to scalpel depigmentation Not reported El-Mofty et al. (2021) Egypt Prospective Parallel-arm Clinical Study 18–40 years, with a mean age of 27.3 2 males and 8 females in both study groups 20 subjects Non-smokers Intraepidermal injection (mesotherapy) using L-Ascorbic acid and Topical Ascorbic Acid- glucoside Gel (10%) Group I: Vitamin C Mesotherapy (10) Group II: Topical Vitamin C (10) Changes in DOPI Satisfaction questionnaire modified from McGill Pain Questionnaire Digital Melanin Area Fraction Analysis 6 months DOPI Median DOPI changed significantly from 2 at baseline to 1 at 6 months (p < 0.001) in Group I Median DOPI remained 1 at 6 months for Group II (p = 0.223) Both groups revealed a significant reduction in melanin area fraction at 6 months when compared to the baseline (p = 0.005 and p = 0.012, respectively) Statistically significant differences between study groups at baseline may confound statistical analysis. Mostafa et al. (2022) Egypt Case Report 25 year Female Patient Non-smoker 1000mg/ml Ascorbic Acid powder-saline slurry applied after micro-needling - Reduction of 2 pigmentation indices Qualitative assessment of pain, healing, and re-pigmentation 6 months DOPI and Hanioka’s Melanin Index 39 Reduction of DOPI from 3 to 0 and Melanin Index score from 2 to 0. Light brown solitary re-pigmentation at 6 months Short-term follow-up with a limited sample size. No histologic evaluation Chaudhary et al. (2022) India Prospective Parallel-arm Clinical Trial 18–40 years 60% (18) were females and 40% (12) were males 30 subjects Exclusion of chronic smokers (criteria unspecified) Intraepidermal injection (mesotherapy) using L-Ascorbic acid Group I: Scalpel depigmentation (15) Group II: Vitamin C mesotherapy (15) Changes in pigmentation and repigmentation were assessed by graphical estimation. VAS for pain Verbal scale for itching 3 months DOPI The non-significant difference in reduction of pigmentation area at 1 month (32.27 with the control group and 37.07 with the test group, p = 0.932) Non-significant influence on re-pigmentation (p = 0.903) Significant reduction in VAS scores with the test group over the control group (0.73 and 3.33, respectively, p = 0.001) Non-quantitative classification of periodontal phenotypes Maxillary sextants are compared with mandibular sextants, which may confound study results due to differences in area, phenotype, and intensity. Dawar et al. ( 2022 ) India Case series > 18 years 5 patients Non-smokers Intraepidermal injection (mesotherapy) using L-Ascorbic acid Intraepidermal injection (mesotherapy) using L-Ascorbic acid No control group Change in gingival luminescence (L*) Pigmented surface area (PSA) Melanocyte count VAS score for pain Patient satisfaction survey 3 months DOPI GPI 15 Significant reduction in the median GPI (p = 0.05), DOPI (p = 0.04), pigmented surface area (PSA) (p = 0.04), and L* (p = 0.04) at 1-month follow-up Between the 1st and 3rd months, a marked improvement in the only change in gingival luminescence was noted (p = 0.04). Reduction in median melanocyte count from 102 to 52 at 3 months. Three out of five patients gave a high satisfaction score of 4 (scale of 0–4), and 2 gave a score of 3 at the 3-month follow-up. Median VAS pain score of 3 on the day of the procedure No consideration of gingival biotype. Short-term follow-up. Esmat et al., ( 2023 ) Randomized, parallel double-blinded clinical trial Egypt 18 and 40 years 26 Patients 5.4% males and 84.6% females Non-smokers Intra-mucosal injection of vitamin C (L-Ascorbic acid 1000 mg/5 ml) Group 1: Intra-mucosal injection of vitamin C (L-Ascorbic acid 1000 mg/5 ml) Group 2: Diode laser (980 nm, 1.5 W, continuous wave mode) Clinical evaluation of pigmentation intensity and distribution was performed preoperatively and at 1, 2, and 3 months postoperatively. Dummett-Gupta Oral Pigmentation Index (DOPI), and Gingival Pigmentation Index (GPI). Pain intensity and patients’ satisfaction were checked using VAS and questionnaires. Dummett-Gupta Oral Pigmentation Index (DOPI), and Gingival Pigmentation Index (GPI). Pigmentation scores decreased significantly between pre-operative visits and different follow-up visits for both treatment modalities (p < 0.0001*). When compared to the vitamin C mesotherapy group, the laser group demonstrated significantly lower gingival pigmentation scores (p < 0.0001*). Both treatment modalities were equally satisfying for the patients. Longer follow-up periods are required to assess the recurrence rate. Sandhu et al., 2023 Case series India Two male patients aged 22 and 25 years Non-smokers Topical application of Enshine Cream 15 g) along scalpel depigmentation Case 1: Vitamin C + scalpel depigmentation Case 2: scalpel depigmentation Dummett Oral Pigmentation Index (DOPI). Dummett Oral Pigmentation Index (DOPI). Improved healing and positive effects of vitamin C in the healing phase of the gingival tissues following scalpel depigmentation No quantitative data were reported for the DOPI score for both cases, and no long-term follow-up was conducted. Mostafa et al. ( 2023 ) Case Series: prospective Riyadh, KSA 16 patients 17–35 years old; 8 women and 8 men Non-smokers Ascorbic acid powder (1000 mg) and a Dermapen (a pen-like instrument with a handle and 12–24 needles arranged in rows moving at a speed of 700 cycles/min. Microneedling technique using the Dermapen with needles of 1.5 mm depth followed by topical Vitamin C powder (1000 mg/ml) mixed with saline was applied for 10 minutes and repeated after two weeks. Hedin melanin index and Dummett Oral Pigmentation Index (DOPI) at baseline and follow-up at one month Hedin melanin index and Dummett Oral Pigmentation Index (DOPI) Generally, healing was normal and satisfactory, and all patients achieved excellent aesthetic results with a reduction in both indices. Seven out of the 16 patients showed complete depigmentation of the gingiva, while nine patients displayed a reduction in their indices. The analysis using paired T-tests demonstrated a statistically significant reduction in the post-treatment DOPI score, with a mean difference of 1.8 ± 0.7 (95% CI: 0.17–1.49). Similarly, the HMI score was also lower post-treatment, with a mean difference of 3.1 ± 0.7 (95% CI: 2.74–3.50). The discomfort was experienced in most cases. Meenakshi and Subasree, 2024 India Randomized clinical trial 16 participants Mandible sites Mean age: 26.7 ± 5.67 years. 50% (n = 8), and 50% women (n = 8). Non-smokers Dermapen (Dr. Pen, Las Vegas, NV) device and topical ascorbic acid powder (1,000 mg/mL) mixed with saline were applied over the gingiva for 10 minutes. three treatment sessions of microneedling, spaced out by 10 days Case group: Microneedling with Vitamin C 1000 mg/ml) mixed with saline was applied for 10 minutes (three times) Control group: surgical depigmentation with a scalpel Dummett-Gupta Oral Pigmentation Index (DOPI) and early wound healing index by Maria et al (2018) At baseline, one month, and three months follow-up. Dummett-Gupta Oral Pigmentation Index (DOPI) and early wound healing index by Maria et al (2018) DOPI scores at baseline: 2.65 ± 0.16 and 2.61 ± 0.17 in the scalpel and microneedling with Vitamin C. The mean DOPI score at the end of the third month was 1.67 ± 0.39 and 0.87 ± 0.17 in the surgical and MN with ascorbic acid groups, respectively. The healing index exhibited a statistically significant difference between the treated groups (p < 0.04), both at baseline and after one week. The healing index scores did not show a statistically significant difference within the same group in the surgical technique group at baseline and on the seventh day. Patients treated with conventional surgical techniques showed incomplete healing and ulceration on the first and seventh days after the procedure when compared to the microneedling technique with ascorbic acid. Nature, type, mode, dosage, and frequency of application of Vitamin C Efficacy of Vitamin C in reducing gingival melanin pigmentation compared to other depigmentation procedures Effect of Vitamin C on the gingival tissues Recurrence of pigmentation after Vitamin C depigmentation compared to other conventional treatments. Vitamin-C Depigmentation and Patient-reported Outcomes The patient-reported outcomes and the presence of any side effects were noted. The quantitative data in terms of mean and standard deviation, standard mean difference, gingival pigmentation score, pain score, and aesthetic score were noted. Qualitative data, if present, about the procedure and pain score, were noted. The critical appraisal of included studies was assessed for their risk of bias using the Joanna Briggs Institute (JBI) scale. The risk of bias analysis was scored according to JBI risk of bias analysis and scored as follows: Studies with scores 0–4 were considered to have a high risk of bias; 5–7 were considered to have a moderate risk of bias, and more than equal to 8 were considered to have a low risk of bias. Results Characteristics of the individual studies A total of 119 articles were obtained from all databases (Fig. 2 ). After removing duplicates, 103 articles were eligible for titles and abstracts. Following title and abstract screening, 16 articles were included, out of which 4 articles were removed as they did not pertain to our particular focus question. Thus, a total of 12 studies were eligible for the review (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; Shimada et al., 2009 ; Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ; Mostafa et al., 2023 ; Meenakshi and Subasree, 2024). Out of the 12 research articles, five were case reports/ case series (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; Dawar et al., 2022 ; Mostafa et al., 2023 ; Sandhu et al., 2023 ; ), one was an animal-model study (goat model) (Yussif et al., 2017 ); five were clinical trials (Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Esmat et al., 2023 ; Meenakshi and Subasree, 2024); one was a hybrid study with cell-culture assessment as well as clinical evaluations on human patients (Shimada et al., 2009 ). Six studies were conducted in Egypt (Mostafa and Alotaibi, 2022 ; Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Esmat et al., 2023 ; Mostafa et al., 2023 ), five in India (Sheel et al.,2015; Chaudhary et al., 2023 ; Dawar et al., 2022 ; Sandhu et al., 2023 ; Meenakshi and Subasree, 2024), and one in Japan (Shimada et al., 2009 ). The sample size ranged from 20–73 subjects (Shimada et al., 2009 ; El-Mofty et al, 2021 ). One study included both smokers and non-smokers, whereas four studies excluded smokers at the eligibility check (Shimada et al., 2009 ; Yussif et al.,2019; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ). The subjects included in two case-report studies were self-reported non-smokers (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ). The mean age of the samples from all the studies ranged from 27.2 years to 37.2 years (Shimada et al., 2009 ; Yussif et al.,2019) (Fig. 2 ). The detailed characteristics of the demographic data from the included studies are also mentioned in Table 2 . One case report showed high risk of bias (Sandhu et al., 2023 ); four studies depicted a moderate risk of bias (Mostafa and Alotaibi, 2022 ; Sheel et al, 2015 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ); whereas seven studies had a low risk of bias (Shimada et al., 2009 ; Tricco et al., 2018 ; Yussif et al., 2017 ; Yussif et al., 2019 ; Dawar et al., 2022 ; Esmat et al., 2023 , Mostafa et al. 2023 ; Meenakshi and Subasree, 2024) (Supplementary Table 1 to Table 3 ). Type of gingival pigmentation and method used for analysis All studies carried out depigmentation for the removal of physiologic melanin pigments. The depigmentation was done for maxillary and mandibular anterior regions only (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; Shimada et al., 2009 ; Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ; Meenakshi and Subasree, 2024). The classification and evaluation of changes in pigmentation were assessed using ‘Dummet-Gupta’s Oral Pigmentation Index (DOPI) (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ; El-Mofty et al., 2021 ; Dawar et al., 2022 ; Esmat et al., 2023 ; Sandhu et al., 2023 ; Mostafa et al., 2023 ; Meenakshi and Subasree, 2024); Hanioka’s melanin index (Mostafa et al., 2023 ; Mostafa and Alotaibi, 2022 ; Yussif et al., 2019 ); Spectrophotometric analysis (Shimada et al., 2009 , Dawar et al., 2022 ); inhibition of tyrosinase activity and melanin composition (Shimada et al., 2009 ); Kumar’s gingival pigmentation index (Yussif et al., 2019 ; Dawar et al., 2022 ; Esmat et al., 2023 ); early wound healing score by Marini et al. ( 2018 ) (Meenakshi and Subasree, 2024), and qualitative assessment of histological and immunohistochemical outcomes (Yussif et al., 2017 ; El-Mofty et al., 2021 ). Five studies reported patient-reported outcomes in terms of pain, discomfort, or itching using the visual analog scale (VAS) (Sheel et al., 2015 ; Yussif et al., 2019 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ; Esmat et al., 2023 ); and the McGill pain and patient satisfaction questionnaire (El-Mofty et al., 2021 ; Esmat et al., 2023 ). Results of Individual Sources of Evidence and Synthesis of Results Mode, dosage, and frequency of application of Vitamin C Studies tested the efficacy of Vitamin C as an adjunct to scalpel depigmentation (Sheel et al., 2015 ) and as a stand-alone therapy (Mostafa and Alotaibi, 2022 ; Shimada et al., 2009 ; Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ). Two studies compared the efficacy of Vitamin C to Scalpel depigmentation (Yussif et al., 2019 ; Chaudhary et al., 2023 ), and one study compared two modes of application of Vitamin C (mesotherapy and topical) (El-Mofty et al., 2021 ); two case series compared the role of Vitamin C to Scalpel (Sandhu et al., 2023 ); one RCT compared the role of Vitamin C to LASER (diode LASER) (Esmat et al., 2023 ). One animal study compared different concentrations of Vitamin C as mesotherapy (Yussif et al., 2017 ). One clinical study compared the topical application of Vitamin C to a placebo gel (Shimada et al., 2009 ). The mode of application of vitamin C included: topical application of ascorbic acid powder-saline slurry (Mostafa and Alotaibi, 2022 ; Mostafa et al., 2023 ); cotton roll-assisted topical application of vitamin C capsule contents (Sheel et al., 2015 ); topical application of a vitamin-C derivative gel composed of 10% ascorbic acid 2-glucoside (Shimada et al., 2009 ; El-Mofty et al., 2021 ) and intraepidermal injections (oral mesotherapy) of L-ascorbic acid (Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ; Esmat et al., 2023 ). L-ascorbic acid and ascorbic acid 2-glucosides were two derivatives of Vitamin C that were employed for depigmentation procedures (Boo 2022 ; Yokota and Yahagi, 2022 ). Different doses of vitamin C (ascorbic acid) were used such as 1000mg/ml (Mostafa and Alotaibi, 2022 ; Mostafa et al., 2023 ); 10% ascorbic acid (Sheel et al., 2015 ); 10% ascorbic acid-glucoside gel (Shimada et al., 2009 ) and 1-2ml of 1mg/5mL L-ascorbic acid (ampoules) equivalent to 200-300mg vitamin C concentration as 0.1 ml for each point with 2–3 mm apart, once a week for four to five weeks (Yussif et al., 2017 , Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ). One study also compared the effect of 0.1ml and 0.3ml of vitamin C mesotherapy (Yussif et al., 2017 ). Another study applied Vitamin C using an alternate approach and carried out micro-needling for 30–40 seconds per tooth, followed by a topical application for 10 minutes, twice at an interval of two weeks (Mostafa and Alotaibi, 2022 ; Mostafa et al., 2023 ). When used as an adjunct to scalpel depigmentation, topical Vitamin C was applied to surgically treated sites at weekly intervals for a month, followed by monthly intervals for 9 months (Sheel et al., 2015 ). In two prospective clinical trials, topical gel application once daily after brushing at night, for 12 weeks, was also tested (Shimada et al., 2009 ; El-Mofty et al., 2021 ). The intraepidermal injections of Vitamin C were done using different protocols. In three studies that carried out non-surgical Vitamin C mesotherapy, the agent was delivered using 30-gauge syringes/insulin syringes either once a week for a maximum duration of 4 weeks (Yussif et al., 2017 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ) or thrice at intervals of one week (El-Mofty et al., 2021 ). Table 3 describes the characteristics of the included studies. Efficacy of Vitamin C in reducing gingival melanin pigmentation compared to other depigmentation procedures. Vitamin C was found to be effective in reducing gingival pigmentation in all of the included studies. Mesotherapy (intra-epithelial injection) was the most employed technique for Vitamin C depigmentation (Yussif et al., 2017 ; Yussif et al., 2019 ; El-Mofty et al., 2021 ; Dawar et al., 2022 ). A study by El-Mofty et al ( 2021 ) compared the efficacy of mesotherapy versus topical depigmentation and found that intra-epidermal injection has better reduction at 6 months (p < 0.001) (El-Mofty et al., 2021 ). The DOPI value of two at baseline reduced to one at six months for epidermal injection; however, for topical application, the DOPI remained unchanged at six months (p = 0.223). Both groups revealed a significant reduction in melanin area fraction at six months when compared to the baseline (p = 0.005 and p = 0.012, respectively), with an insignificant inter-group difference (p = 0.082). At one week and six months, there was a significant improvement in patient-reported cosmetic changes for group I (p = 0.001 and p < 0.001, respectively). Shimada et al. evaluated the effect of the topical application of Vitamin C compared to the placebo gel and found a significant change in luminescence value, which changed from 54.47 at baseline to 57.04 at 12 weeks in the vitamin C group (p < 0.05). After nine months, the pigmentation has decreased subjectively, and there has been no recurrence. There was a decrease in VAS score from 1.8 intraoperatively to 1.5 at 10 days after surgery. In addition, a high patient satisfaction score of three was recorded (Shimada et al., 2009 ). Another study by Yussif et al. compared Vitamin C mesotherapy with scalpel depigmentation and revealed a significantly improved reduction in Kumar’s Gingival pigmentation index for the scalpel group after one month (p = 0.003). At the end of nine months, the results of the scalpel and vitamin C groups were comparable when measured using Hanioka's Melanin Index and Kumar's Gingival pigmentation. The itching sensation score (from 5 at baseline to 0 on the 7th day postoperatively) and pain score (on the 2nd, 3rd, and 7th day postoperatively) reduced significantly compared to scalpel depigmentation, which then became non-significant at the 9th month (p = 0.46) (Yussif et al., 2019 ). Chaudhary et al. assessed the effect of Vitamin C mesotherapy compared to scalpel and found no difference in the reduction of pigmentation area at one month (32.27 for the control group and 37.07 for the Vitamin C group, p = 0.932). No significant influence on repigmentation was noted (p = 0.903). A significantly favorable reduction in VAS scores with the Vitamin C group over the control group was also observed (0.73 and 3.33, respectively, p = 0.001) (Chaudhary et al., 2023 ). A case series using oral Vitamin C mesotherapy revealed a significant reduction in gingival pigmentation as evident by median gingival pigmentation index (p = 0.05), DOPI (p = 0.04), pigmented surface area (PSA) (p = 0.04), and change in luminescence(p = 0.04) at 1-month follow-up. When comparing one- and three-month follow-ups, only luminescence showed a marked improvement (p = 0.04). Another study showed that micro-needling with adjunct topical administration of Vitamin C resulted in excellent aesthetic outcomes after two applications at the end of one month. They observed that DOPI and melanin index scores of 3 and 2, respectively, reduced to 0 after two applications (Dawar et al., 2022 ). Topical application after scalpel depigmentation produced a significant improvement in DOPI (Sandhu et al., 2023 ). In 2023, Mostafa et al ( 2023 ) also reported a significant reduction in melanin pigmentation upon the use of micro-needling with topical application of Vitamin C (twice application after two weeks). A statistically significant lower DOPI score posttreatment (mean difference 1.8 ± 0.7, 95% confidence interval (CI): 0.17–1.49, p ≤ 0.001) at the end of one month. Seven out of the 16 patients showed complete depigmentation of the gingiva, while nine patients displayed a reduction in their indices (Mostafa et al., 2023 ). A randomized clinical trial compared the efficacy of vitamin C mesotherapy to diode LASER and found that the pigmentation decreased significantly between pre-operative visits and at three-month follow-up visits for both the Vitamin C and LASER group (p < 0.0001*). However, the laser was found to have better results and lower gingival pigmentation scores compared to Vitamin C at the follow-up visits (p < 0.0001*) (Esmat et al., 2023 ). Effect of Vitamin C on the gingival tissues As evidenced by in-vitro and histopathological studies, Vitamin C was found to induce biochemical and histological changes in the gingiva (Shimada et al., 2009 ; Yussif et al., 2017 ). A Vitamin C derivative gel composed of 10% ascorbic acid 2-glucoside resulted in a proportional, marked inhibition in the tyrosinase activity (p < 0.01), along with a significant decrease of 48% in the melanin composition (p < 0.05) in mouse melanoma cells when compared to placebo (Shimada et al., 2009 ). Similarly, another study on goats revealed a definite qualitative histologic reduction in melanin, causing perinuclear vacuolating and disruption of the intercellular contact between melanocytes and keratinocytes (Yussif et al., 2017 ). The study reported that the depigmenting effect was enhanced with a higher dose of Vitamin C. The test groups also revealed a strong HMB-45 antibody reaction with low levels of residual melanin granules concerning basal and suprabasal epithelial layers. Another study comparing Vitamin C as mesotherapy, and topical form reported a significant reduction in histologic melanin area fraction at six months when compared to the baseline for both modalities (p = 0.005 and p = 0.012 respectively) (El-Mofty et al., 2021 ). However, the inter-group difference at six months was non-significant. (p = 0.082). A case-series study assessing melanocyte-histopathologic count after Vitamin C mesotherapy showed a reduction in median values from 102 at baseline to 52 at three months (Dawar et al., 2022 ). Recurrence of pigmentation after Vitamin C depigmentation The recurrence rate of pigmentation following Vitamin C application was measured both quantitatively and qualitatively. Based on the quantitative data it was found that a recurrence of 32.59% was observed after three months of Vitamin-C mesotherapy compared to 32.87% in the scalpel group (p = 0.903) (Chaudhary et al., 2023 ). Based on qualitative data, multiple studies reported the occurrence of re-pigmentation (Mostafa and Alotaibi, 2022 ; Sheel et al., 2015 ). Light brown solitary pigmented areas were observed at six months follow-up with micro-needling-assisted Vitamin C depigmentation (Mostafa and Alotaibi, 2022 ). However, when used as a topical adjunct to scalpel depigmentation, no recurrence was observed up to a follow-up of nine months (Sheel et al., 2015 ). A prospective clinical trial using topical vitamin C gel revealed no recurrence at 12 weeks (Shimada et al., 2009 ). Intramucosal injections of Vitamin C revealed no recurrence at nine months which was comparable to scalpel depigmentation (Yussif et al., 2019 ). There are no studies comparing recurrence rates between different modalities of Vitamin C or comparing Vitamin C and LASER/cryotherapy-assisted depigmentation. Vitamin-C depigmentation and patient-reported outcomes Five studies evaluated pain and satisfaction following Vitamin C depigmentation, out of which four utilized the visual analog score (VAS) (Sheel et al., 2015 ; Yussif et al., 2017 ; Yussif et al., 2019 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ). Simultaneously, two studies quantitatively evaluated patient satisfaction (El-Mofty et al., 2021 ; Dawar et al., 2022 ). The topical application of vitamin C on the scalpel depigmentation site exhibited a VAS score of 1.8 on the day of the procedure and 1.5 after 10 days (Sheel et al., 2015 ). Vitamin C mesotherapy revealed a significant reduction in VAS scores for itching and pain compared to scalpel depigmentation, thus rendering it comparatively atraumatic (Yussif et al., 2019 ). Similarly, scalpel depigmentation depicted a significantly higher mean VAS score when compared to Vitamin C mesotherapy after 24 hours of the procedure (p = 0.001) (Chaudhary et al., 2023 ). A case series of five patients who received Vitamin C mesotherapy revealed a median pain score of three on the day of the procedure (Dawar et al., 2022 ). The study comparing Vitamin C mesotherapy and topical application reported that 100% of the patients in both study groups experienced no pain on the day of the surgery, as well as one week after the procedure (El-Mofty et al., 2021 ). The study evaluating the micro-needling approach only mentioned a qualitative reduction in pain and discomfort after the third postoperative day (Mostafa and Alotaibi, 2022 ). In terms of patient satisfaction, a comparison between mesotherapy and topical Vitamin C showed significant differences in favor of the former in terms of patient-reported cosmetic change at one week and 6 months (p = 0.001 and p < 0.001, respectively) (El-Mofty et al., 2021 ). 100% of the patients in the topical application group were unsatisfied with the treatment outcome compared to 40% in the mesotherapy group (p = 0.011) (El-Mofty et al., 2021 ). In the case series using Vitamin C mesotherapy, three out of five patients gave a high satisfaction score of four, and two patients gave a score of three at the three-month follow-up (Dawar et al., 2022 ). Multiple studies have corroborated that pain, itching, and discomfort are prominently reduced using Vitamin C, regardless of the mode of application (Yussif et al., 2019 ; El-Mofty et al., 2021 ; Chaudhary et al., 2023 ; Dawar et al., 2022 ). Even intraepidermal injections of Vitamin C have shown excellent patient acceptance when contrasted with scalpel depigmentation (Yussif et al., 2019 ; Chaudhary et al., 2023 ). Esmat et al ( 2023 ) compared the patient satisfaction score and pain score using a questionnaire and VAS between patients treated with LASER and Vitamin C mesotherapy for depigmentation. The authors found A statistically significant difference (P = 0.005) in immediate postoperative pain scores between the two groups, favoring the LASER group. However, no significant differences in pain scores on the 1st and 7th postoperative days were detected between the two groups. No difference was seen in the patient's satisfaction and acceptance of the treatment method between the two groups as assessed by the questionnaire for assessing the aesthetic/cosmetic appearance after three months, fulfilment of expectation, and willingness to repeat the procedure (Esmat et al., 2023 ). Discussion and summary of evidence The aim of this review is to provide an evaluation of the effectiveness of vitamin C in the management of gingival pigmentation. Vitamin C is known for its anti-inflammatory, antioxidant, and wound-healing properties, which have led to its common use in dermatology and cosmetics for depigmentation and skin lightening. It is also being considered for use in the management of gingival hyperpigmentation. It is noted that studies have compared both topical and mesotherapy for vitamin C application to reduce the melanin pigments in the gingiva. It has been observed that microneedling with a dermapen can create pinpoint holes in the gingival epithelium, with a depth of up to 0.2 to 1 mm. Subsequently, vitamin C is applied to the affected area and left for approximately 10 to 20 minutes, during which the vitamin C is permitted to enter the epithelium. Vitamin C can be injected into the gingiva via microneedles or applied directly, with the latter being less effective. It can be used as an atraumatic method of reducing heavy physiologic melanin deposits in the gingiva. It would seem that the most effective results in reducing clinical pigmentation can be achieved by repeating the application of vitamin C, either via intradermal injection or micro-needling, with a gap of 10–15 days between each application. Studies have indicated that vitamin C may be an effective approach to reducing gingival pigmentation, and it may offer a less invasive alternative to other methods such as scalpel, bur, and electrocautery (Hanioka et al., 2005 ; Miot et al., 2012 ). It is thought that the use of vitamin C with microneedling may help to improve patient acceptance and ease of procedure compared to surgical de-epithelization. Additionally, the anti-inflammatory and antioxidant properties of vitamin C may help to accelerate wound healing and reduce post-operative inflammation and pain following de-epithelization of gingiva with a scalpel/bur. Vitamin C depigmentation is an effective treatment for young adults with special needs, including those with mental retardation and developmental anomalies. It is important to note, however, that a mesotherapy technique involving multiple injections may be unacceptable and uncomfortable for some patients, particularly those with a needle phobia. Furthermore, the necessity for multiple visits for vitamin C mesotherapy presents a significant challenge in terms of patient compliance. However, we must highlight some of the limitations of the current evidence. There is insufficient evidence that quantitatively evaluates the recurrence rate and efficacy of vitamin C depigmentation in the long term. It is crucial to acknowledge that one study evaluated the impact of vitamin C on smokers, which could potentially bias the results due to the detrimental effects of smoking on gingival tissues. Future studies must therefore compare the effect of re-pigmentation following vitamin C application in smokers versus non-smokers. We could find no studies comparing the role of vitamin C with laser depigmentation. Furthermore, it is essential to determine whether vitamin C can be used as a monotherapy or if it should always be used in conjunction with scalpels or lasers, as no studies have done so. The limited number of studies that evaluated the effect of topical vitamin C preparations demonstrated unequivocally that a reduction in oral pigmentation indices was observed even after topical application for one week (Shimada et al., 2009 ; El-Mofty et al., 2021 ). One case report evaluated the effect of topical vitamin C as an adjunct to scalpel depigmentation and found a reduction in pigmentation that did not recur over a nine-month follow-up period (Sheel et al., 2015 ). A clinical trial is required to validate the suggestion that its efficacy will extend over a longer period, given the absence of a control group and the fact that the results were observed only in one patient (Sheel et al., 2015 ). Furthermore, no studies have considered the biotype/phenotype of the gingiva when assessing the role of vitamin C as an adjunct to gingival depigmentation. The maxillary gingiva is thicker than the mandibular region, so the depth of penetration of vitamin C will vary among patients. The gingiva ranges from 0.2 mm to 3 mm in thickness/phenotype. Furthermore, a quantitative assessment of wound healing following vitamin C depigmentation, along with a comparison with existing treatment modalities, must be conducted. Furthermore, the application of vitamin C to treat pathologic gingival pigmentation represents another potential research area. However, future studies should assess the long-term effect of using different modes of application of Vitamin C for gingival depigmentation and compare its effectiveness and recurrence rate compared to other depigmentation procedures. Conclusion Vitamin C application either topically or via microneedling is a good treatment option for managing gingival pigmentation, with mesotherapy (intra-epithelial injection) being the most effective outcome. Vitamin C application for gingival pigmentation is a less invasive alternative to other methods such as scalpel, bur, and electrocautery. Vitamin C with micro-needling has better patient acceptance and ease of procedure compared to scalpel de-epithelization. Vitamin C has shown good anti-inflammatory and antioxidant properties that help accelerate wound healing and reduce post-operative inflammation and pain. Declarations Compliance with Ethical Standards Conflict of Interest: Author Shubhankar Mehrotra declares that she has no conflict of interest. Author Malvika Shyam Kumar R declares that she has no conflict of interest. Author Shravya M declares that she has no conflict of interest. Author Aditi Chopra declares that she has no conflict of interest. Author Marwa Madi declares that she has no potential conflict of interest. Funding: No funding for this review Ethical approval: not applicable. Informed consent: not applicable. No AI or generative AI writing tools were used. Data will be available upon request via email to the corresponding author. Author contribution: Conceptualization : SM, MS, AC; Methodology: SM , MS, SHM, AC; Development or design of methodology; creation of models: Software : MS, AC; Validation : MS, SM, AC, MM; Formal analysis : MS, SM, AC; Investigation : MS, AC, SM, SHM; Resources : MS, AC, SM; Data Curation : MS, AC, SM, SHM; Writing: Original Draft : MS, AC, SM, SHM, MM, Writing: Review & Editing : MS, AC, SM, SHM Visualization : AC Supervision : AC; Project administration : AC; Funding acquisition : AC; " all authors approved the final version to be published-" References Alasmari DS (2018) An insight into gingival depigmentation techniques: The pros and cons. Int J health Sci 12(5):84–89 Alhabashneh R, Darawi O, Khader YS, Ashour L (2018) Gingival depigmentation using Er: YAG laser and scalpel technique: A six-month prospective clinical study. 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Case reports in dentistry, 2022, 3655543. https://doi.org/10.1155/2022/3655543 Mostafa D, Sr A, Alaizari N, AlOtaibi M, Ahmed Aldosari S, Al-Anazi NR, Alsughayer JS, AlFayir RM, AlHarthi HS, M., AlAnazi H, M. Gingival depigmentation using microneedling technique with topical vitamin c: a prospective case series. Cureus, 15(2), e35345., Almasoud AA (2023) (2020). Different surgical techniques for gingival depigmentation and their outcomes; a literature review. International Journal of Medical Dentistry, 24:607–611 Muruppel AM, Pai BSJ, Bhat S, Parker S, Lynch E (2020) Laser-Assisted Depigmentation: An Introspection of the Science, Techniques, and Perceptions. Dentistry J 8(3):88. https://doi.org/10.3390/dj8030088 Pal TK, Kapoor KK, Parel CC, Mukharjee K (1994) Gingival melanin pigmentation: A study on its removal for esthetics. J Indian Soc Periodontology 3:52–54 P SM, S S Comparative Assessment of Gingival Depigmentation Using Scalpel Versus Microneedling With Ascorbic Acid: A Randomized Controlled Trial. Cureus, 16(4), e58285., Parwani S, Parwani R (2024) (2013). Achieving better esthetics by gingival de-pigmentation: report of three cases with a review of the literature. The Journal of the Michigan Dental Association, 95(2), 52–78 Rotbeh A, Kazeminia M, Kalantari M, Rajati F (2022) Global prevalence of oral pigmentation and its related factors: a systematic review and meta-analysis. J stomatology oral maxillofacial Surg 123(5):e411–e424. https://doi.org/10.1016/j.jormas.2022.01.009 Sanadi RM, Deshmukh RS (2020) The effect of Vitamin C on melanin pigmentation - A systematic review. J oral maxillofacial pathology: JOMFP 24(2):374–382. https://doi.org/10.4103/jomfp.JOMFP_207_20 Sandhu A, Jyoti D, Sharma H, Phull T, Khurana NS, Tiwana JK (2023) Efficacy of Topical Vitamin C Application on Healing After Gingival Depigmentation by Scalpel: A Case Series. Cureus 15(11):e48417. https://doi.org/10.7759/cureus.48417 Scully C, Bagan JV (2004) Adverse drug reactions in the orofacial region. Critical reviews in oral biology and medicine. official publication Am Association Oral Biologists 15(4):221–239. https://doi.org/10.1177/154411130401500405 Sheel V, Purwar P, Dixit J, Rai P (2015) Ancillary role of vitamin C in pink aesthetics. BMJ case reports 2015. bcr2014208559. https://doi.org/10.1136/bcr-2014-208559 Shimada Y, Tai H, Tanaka A, Ikezawa-Suzuki I, Takagi K, Yoshida Y, Yoshie H (2009) Effects of ascorbic acid on gingival melanin pigmentation in vitro and in vivo. J Periodontol 80(2):317–323. https://doi.org/10.1902/jop.2009.080409 Suragimath G, Lohana MH, Varma S (2016) A Split Mouth Randomized Clinical Comparative Study to Evaluate the Efficacy of Gingival Depigmentation Procedure Using Conventional Scalpel Technique or Diode Laser. J lasers Med Sci 7(4):227–232. https://doi.org/10.15171/jlms.2016.40 Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, Moher D, Peters MDJ, Horsley T, Weeks L, Hempel S, Akl EA, Chang C, McGowan J, Stewart L, Hartling L, Aldcroft A, Wilson MG, Garritty C, Lewin S, Straus SE (2018) PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med 169(7):467–473. https://doi.org/10.7326/M18-0850 Yokota M, Yahagi S (2022) Evaluation of the anti-wrinkle effect of a lipophilic pro-vitamin C derivative, tetra-isopalmitoyl ascorbic acid. J Cosmet Dermatol 21(8):3503–3514. https://doi.org/10.1111/jocd.14604 Yussif NM, Korany NS, Abbass MM (2017) Evidence of the Effect of Intraepidermic Vitamin C Injection on Melanocytes and Keratinocytes in Gingival Tissues: In Vivo Study. Dentistry 7(3):1000417 Yussif NM, Rahman AR, El-Barbary A (2019) Minimally invasive non-surgical locally injected vitamin C versus the conventional surgical depigmentation in treatment of gingival hyperpigmentation of the anterior esthetic zone: A prospective comparative study. Clin Nutr Exp 24:54–65 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7803852","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":526269777,"identity":"04302b80-544e-4c87-8190-bf997ddfae74","order_by":0,"name":"Aditi Chopra","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYFCCxAaGBAYQAoIPQMzGwMB4gIGBGZ+WxgaYFsYZEC0MBLQkMDYwQLUw80DF8Grhb09uf/CAwS6PX7r34WfbHLs8PunmBwcYKqwTG3BokTjzEOSw5GLJOceNpXO3JRezyRwzOMBwJh2nFoYbYL8cSNxwI40BqIU5sU0iweAAY9thnFrkkbQw/7bcVg/Ukv7hAOM/3FoMkLSwSTNuOwzUkgO0pQG3FkOgX2YkGCQnzpxzjM2yd9vxxDaZMwUHEo6lG+PSInc8/cHHHxV2if3Sbcw3fm6rTpw/u33jgw811rI4vQ9xHhBLwDggRgJe5cgqURmjYBSMglEwCiAAANNvY6UK1FWcAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, Pin: 576104","correspondingAuthor":true,"prefix":"","firstName":"Aditi","middleName":"","lastName":"Chopra","suffix":""},{"id":526273179,"identity":"052af984-b0fc-4903-8513-2aeec6c59744","order_by":1,"name":"Shubhankar Mehrotra","email":"","orcid":"","institution":"Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, Pin: 576104","correspondingAuthor":false,"prefix":"","firstName":"Shubhankar","middleName":"","lastName":"Mehrotra","suffix":""},{"id":526273180,"identity":"5d05c507-d3a1-4530-8b4a-a527621549e6","order_by":2,"name":"Malvika Shyamkumar","email":"","orcid":"","institution":"Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, Pin: 576104","correspondingAuthor":false,"prefix":"","firstName":"Malvika","middleName":"","lastName":"Shyamkumar","suffix":""},{"id":526273181,"identity":"3a8c279e-29a9-472b-b9ef-ce855bb5dfa4","order_by":3,"name":"Shravya Marcherla","email":"","orcid":"","institution":"Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, Pin: 576104","correspondingAuthor":false,"prefix":"","firstName":"Shravya","middleName":"","lastName":"Marcherla","suffix":""},{"id":526273183,"identity":"94518acc-45f3-4a3e-b59f-4bc9656109e1","order_by":4,"name":"Marwa Khalil","email":"","orcid":"","institution":"Department of Oral Medicine, Periodontology, Oral Diagnosis and Oral Radiology, Faculty of Dentistry, Alexandria University, Champolion St. Azarita, Alexandria, 21521, Egypt","correspondingAuthor":false,"prefix":"","firstName":"Marwa","middleName":"","lastName":"Khalil","suffix":""}],"badges":[],"createdAt":"2025-10-08 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14:46:09","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":414439,"visible":true,"origin":"","legend":"","description":"","filename":"FINALMANUSCRIPTVITCNOV2024withouttrackchanges.docx","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/c45b630d560eac676e24b076.docx"},{"id":93341155,"identity":"dcc6af80-aa9b-47f4-9614-33ff72bf1bb2","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs7803852.json","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/c7f6f044c49b2a39cbd72f13.json"},{"id":93341160,"identity":"1843d378-2ef0-445a-baee-9426248188dd","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":160615,"visible":true,"origin":"","legend":"","description":"","filename":"rs78038520enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/aa975daab849bf4939ac8925.xml"},{"id":93341159,"identity":"5fb64144-4ecd-49a6-872c-9179d2acf4cf","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":145058,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/3b1bff03f43bd86c36371b5c.png"},{"id":93341163,"identity":"138fc689-da19-4259-944c-a7c10b8c857e","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32814,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/d888ca96bb1affba8e2dd47c.png"},{"id":93343035,"identity":"7bb39863-f9ec-42a2-93a7-806a1fb7ea95","added_by":"auto","created_at":"2025-10-12 14:46:09","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157750,"visible":true,"origin":"","legend":"","description":"","filename":"rs78038520structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/b85b065b2a5f7244c959de49.xml"},{"id":93341161,"identity":"01344f2d-3a03-4ed3-be5e-eb200d2db8e7","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":168043,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/7d53428c5844e6dabd908032.html"},{"id":93341158,"identity":"fbdcac76-eec8-4d4d-a76c-5e33749031e8","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":685026,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of explaining how Vitamin C can be used for gingival pigmentation: 1) Continuous exposure to sunlight and high stress levels (increase cortisol) activates melanocytes in the gingival tissues and increases the levels of melanocyte-stimulating hormones. 2) Melanocyte-stimulating hormone stimulates melanocytes to produce keratinocytes to form melanosomes to form melanin pigment. 3) The process of melanin formation takes place in the melanosomes. The Tyrosine kinase enzymes in the melanosome convert dehroxyphenyalanine (DOPA) into dopaquinone. Dopaquinone gets oxidized into Eumelanin and Pheomelanin. Vitamin C can bind to the Copper ions (Cu2+) in the tyrosine enzyme and inhibit the conversion of DOPA to Dopaquinone. This inhibits the process of melanin formation.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/05f845122fc53c163538d6d2.jpeg"},{"id":93341157,"identity":"22800973-b820-42af-a506-7918a925a7da","added_by":"auto","created_at":"2025-10-12 14:38:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48283,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/5b9e9d162541c9079c9a2cfe.png"},{"id":93343865,"identity":"a862b345-7657-40e6-bfc9-d8e11b90b5c0","added_by":"auto","created_at":"2025-10-12 14:54:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2288722,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7803852/v1/c654176c-cbf3-423c-ad7e-aef1e3692365.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eHow effective is Vitamin C for gingival depigmentation? a scoping review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGingiva is physiologically pigmented due to the deposition of melanin pigments by the melanocytes in the gingival tissues (Dummett, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1946\u003c/span\u003e). However, increased melanin pigmentation may occur in some individuals due to certain local and systemic conditions and syndromes such as smoking, use of certain medications, unintended implantation of amalgam restoration, Addison's disease, Albright's syndrome, Acromegaly, etc. (Rotbeh et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Alhajj and Alhajj, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). According to a recent meta-analysis, 20.8% of the population suffers from physiologic/pathologic oral hyperpigmentation, corresponding to one out of five people. Studies have noted that men were more likely to be affected by the increased pigmentation than women (Rotbeh et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Smokers or those exposed to second-hand smoke are also more likely to be affected. Those drinking hot drinks and dark-skinned individuals show an increased prevalence of gingival pigmentation (Alhajj and Alhajj, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Scully and Bagan, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Approximately 30\u0026ndash;98% of Asians are estimated to suffer from hyperpigmented gingiva with diffuse deep purplish discoloration or irregularly shaped patches, striae, or strands (Javali et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatients often seek depigmentation procedures as a result of excessive gingival pigmentation, which compromises the aesthetics of the gingiva. There are various methods available for removing pigmented gingival tissue surgically through scalpel de-epithelialization, bur abrasion, laser depigmentation, electrosurgical subtraction, cryotherapy, chemical peeling, and masking with free gingival grafts or acellular dermal matrices (Parwani and Parwani, 2013; Alhabashneh et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Suragimath et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Compared to all these techniques, soft tissue lasers have become increasingly popular due to improved patient satisfaction, improved aesthetic outcomes, shorter operating times, and decreased bleeding (Muruppel et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Jagannathan et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Carbon dioxide, Erbium-doped yttrium-aluminium-garnet (Er: YAG), neodymium-doped yttrium aluminum garnet (Nd: YAG), erbium, chromium: yttrium-scandium-gallium-garnet (Er, Cr: YSGG), and diode are some of the common LASERS used for gingival depigmentation. Among these, diode lasers tend to have the longest depigmentation duration, especially in non-smoker patients (Altayeb et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). For gingival pigmentation, a diode laser operating at 980 nm wavelength or an erbium-YAG laser at 2940 nm, with a power range of 2\u0026ndash;4 watts, can be used in a sweeping motion in continuous wave mode over the pigmented area to ablate the melanin-rich epithelium.\u003c/p\u003e\u003cp\u003eRecently, Gul et al. conducted a systematic review comparing the efficacy of various treatment modalities to treat gingival pigmentation. They concluded that laser-assisted depigmentation is equal to, or even better than, scalpel depigmentation regarding pigmentation outcomes and recurrence. The precise mechanism of repigmentation is not yet fully understood. However, the migration theory suggests that active melanocytes from the adjacent pigmented tissues may migrate to the treated areas, potentially leading to a failure in the process. It would seem that reports of repigmentation are somewhat limited in number and variety. A study by Ginwalla et al. found that 50% of patients showed repigmentation after depigmentation with the bur abrasion technique within 24 to 56 days. Pal et al. also noted repigmentation in 19% of patients following gingival depigmentation by surgical bur. Nevertheless, lasers have shown superior results in terms of patient acceptance, pain relief, and satisfaction when compared with surgical blades (Gul et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). A recent systematic review by Ahmed et al (2023), including eight studies, reported superior characteristics and treatment outcomes for diode lasers as compared to Erbium lasers. The time before pigmentation recurrence was longer for the diode laser compared to the Erbium laser. Inchingolo et al. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) also conducted a systematic review and evaluated the efficacy of the diode laser for the treatment of gingival pigmentation compared to the conventional scalpel technique and found that the diode laser provides better results in terms of intraoperative bleeding and perception of pain for the patient. However, there were no differences in depigmentation and wound healing intensity (Jnaid et al., 2021). Additionally, studies have shown that diode lasers have a lower recurrence rate, but this finding has not yet been confirmed by long-term clinical evidence (Muharib and Almasoud, 2020; Alasmari, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Furthermore, several studies have demonstrated that both laser electrocautery and scalpels are associated with being technically demanding, time-consuming, and increasing anxiety and discomfort in patients [Patil et al.,2015; Kumar et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bergamaschi et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Kathariya and Pradeep, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lagdive et al., 2009; Bakutra et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2017\u003c/span\u003e]. Laser treatment has been reported to delay wound healing when compared to scalpel-based depigmentation, especially at sites with thin gingival biotypes and narrow inter-papillary spaces (Kathariya and Pradeep, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lagdive et al., 2009; Bakutra et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). As a result, many authors promote the use of cryogens for gingival depigmentation; however, clinically, it is difficult to control the depth of penetration of cryogens into the gingival tissues, which limits their use. When applied, several cryogens have been shown to cause tissue damage and stinging or burning sensations (Kumar et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bergamaschi et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Kathariya and Pradeep, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Accordingly, the need for exploring non-invasive alternatives to gingival hyperpigmentation is often perceived.\u003c/p\u003e\u003cp\u003eThere is an emerging use of vitamin C for gingival depigmentation and aesthetic procedures (Sanadi and Deshmukh, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Lerner and Fitzpatrick, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1950\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Topical application of Vitamin C in gel, powder, or liquid forms, either alone or as an adjunct to micro-needling or scalpel, over the pigmented gingival epithelium is being used (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Vitamin C inhibits the activity of the tyrosinase enzyme by interacting with the copper (Cu) ions at the tyrosinase active site. This in turn reduces the melanin formation, which is responsible for converting the amino acid dehydroyphylalanine (DOPA) to dopaquinone. The inhibition of Dopaquinone prevents the formation of melanin pigments (Lerner and Fitzpatrick, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1950\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Vitamin C also has an epigenetic suppressive action on cells and controls melanocyte activity (Gustafson et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Vitamin C can even affect the intercellular junctions between melanocytes and keratinocytes and affect the HMB-45 receptor, which controls the activity of melanocytes in the suprabasal layers of the epithelium (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Although vitamin C has shown promising results for the depigmentation of the skin, few clinical studies have been conducted to explore its role in gingival depigmentation. To our knowledge, no review has critically appraised the existing evidence on the role of Vitamin C as an adjunct for gingival depigmentation. With the use of Vitamin C as a new method of gingival depigmentation gaining popularity, many professionals are unaware of the various types, modes of application, and current evidence on its effectiveness and long-term prognosis. Hence, this scoping review aims to critically appraise the existing literature and provide a comprehensive review of the current methods and efficacy of Vitamin C for gingival depigmentation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eThe review is based on the guidelines for the scoping review by the Preferred Reporting Items for Systematic Review and Meta-analysis for Scoping Review (PRISMA-Scoping Review) checklist (Tricco et al., \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e). The objectives of the review were:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eTo assess the current evidence regarding the efficacy and mechanism of action of Vitamin C in gingival depigmentation\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eTo determine the most effective method of applying Vitamin C for reducing gingival pigmentation\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eTo review current evidence regarding patient-reported outcome measures, adverse events, and recurrence following Vitamin C depigmentation compared to other treatment methods for gingival depigmentation.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe eligibility criteria are described using the Participant-Intervention-Comparison-Outcome-Study Design (PICOS) framework as follows:\u003c/p\u003e\n\u003cp\u003eTypes of Participants (P): Participants over the age of 18 (males and females) who have increased gingival pigmentation due to heavy melanin deposition. Studies on hospitalized patients, physically or mentally handicapped patients, and patients with terminal or serious illnesses were excluded.\u003c/p\u003e\n\u003cp\u003eIntervention (I): Studies where vitamin C was used in any form, via any application method, frequency, duration, and dosage for gingival depigmentation.\u003c/p\u003e\n\u003cp\u003eComparator group (C): Studies where gingival depigmentation was done by any of the following: scalpel, laser, electrocautery, cryogen, bur abrasion, or LASER.\u003c/p\u003e\n\u003cp\u003eOutcomes (O): Studies assessing the effect of Vitamin C on the reduction in intensity, area of pigmented gingiva; patients' perception of aesthetics, nature of wound healing, and postoperative complications (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e)\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003eTypes of studies (S): Observational, case-control, cohort, clinical trials, and qualitative studies utilizing questionnaires and surveys to assess patient-related outcomes were included. All preclinical, in vitro, animal, case reports, and case series studies were also included. However, all editorials, book reviews, literature reviews, and letters to the editor were excluded from this review.\u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cem\u003eSearch strategy, information sources, and keywords\u003c/em\u003e: The following electronic databases: MEDLINE (PubMed), Scopus, EBSCO (dentistry and open science access), Cochrane database, Web of Sciences, and ClinicalTrial.org. Were searched on 14th December 2022, and updated on 15th August 2023. The following keywords and MeSH terms were utilized for data collection: (Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation). The PubMed search string was adapted to the other database. Articles written in any language were included. The search results were transferred into the \u0026lsquo;Mendeley reference manager (version 1.19.4)\u0026rsquo; and duplicates were removed. The comparator group was not added in the search string, as it would exclude studies where only Vitamin C was used without any other intervention. The details of the search strings in the individual database are provided in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSearch Strategy for different databases for including articles for the title and abstract screening.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eS/No\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDatabase\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSearch string used\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo of articles\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePubMed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eScopus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEmbase\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeb of Science\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(vitamin C OR ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva OR melanin OR pigment OR depigmentation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e77\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCochrane Database (clinical trials)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(Vitamin C OR Ascorbic acid) AND (gingival OR gingiva OR keratinized gingiva OR pigmented gingiva) AND (melanin OR pigment* OR depigmentation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinicaltrials.gov\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT03719274?cond=%28Vitamin+C+OR+Ascorbic+acid%29+AND+%28gingival+OR+gingiva+OR+keratinized+gingiva+OR+pigmented+gingiva%29+AND+%28melanin+OR+pigment*+OR+depigmentation%29\u0026amp;draw=2\u0026amp;rank=1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal Search\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e119\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eData charting and the Selection of studies process\u003c/h2\u003e\n\u003cp\u003eThe results from the data search were transferred into the Mendeley reference manager (version 1.19.4), and the duplicates were removed. After removing the duplicates, all articles were copied into the Microsoft Excel spreadsheet for screening. During the review process, authors from both teams (S.M. \u0026amp; S.H.) and (M.S. \u0026amp; A.C.) screened titles and abstracts for eligibility. All articles where Vitamin C was either used alone or compared to any other intervention for depigmentation of gingival tissues were included. The following articles were excluded: articles where Vitamin C was used for any periodontal surgical procedure other than depigmentation of gingival tissues; articles where Vitamin C was used as a supplement to treat vitamin C deficiency or for treating any periodontal disease; articles where Vitamin C was used for the removal of pigmented tissues in any other part of the body except gingival tissues. Any discrepancies during the initial screening were resolved by involving the other reviewer (MM), who was not involved in the initial screening phase. Following the selection of titles and abstracts by both teams, full-text screening was conducted. The full-text screening was conducted by two independent reviewers (S.M. \u0026amp; S.H.) following the eligibility criteria. At the full-text stage, discrepancies were resolved through mutual discussion and consultation with another reviewer (A.C.). Citations of the final included articles were copied into another Microsoft Excel 2013 version, and data were extracted independently by all authors.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eData Items and Synthesis of Results\u003c/h3\u003e\n\u003cp\u003eThe following data items were extracted from each study: bibliographic and study details i.e. author details, funding, organization, aims and objectives of the study, type of study; participants\u0026rsquo; detail i.e. number, age, gender, socioeconomic status, income, study settings (community/ hospital/ university/private clinic); contextual information; exposure details i.e. type and mode of Vitamin C used in the study along with the outcome details of each study. A preliminary data extraction form for all the data extracted from each study is given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. In case of missing data, the reviewers tried to obtain it by contacting the corresponding authors.\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePreliminary data extraction/ coding form\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eS/No.\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSections\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRequired information\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBibliographic details\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFirst author, corresponding author email; Year of publication; Funding information\u003c/p\u003e\n\u003cp\u003eLanguage of the paper; Site of study (country)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStudy details\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAim and Objectives of the Study\u003c/p\u003e\n\u003cp\u003eMethodology of the study (study\u0026nbsp;design,\u0026nbsp;sampling,\u0026nbsp;sample size (in each group if applicable),\u0026nbsp;Type of analysis, duration of the study, the follow-up, drop-outs); blinding method; allocation concealment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePopulation characteristics\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (mean\u0026thinsp;+\u0026thinsp;SD) or age range; Gender (male to female); Nature of study population (healthy or diseased population); Type of gingival pigmentation; presence or absence of any other disease reported in the patient (gingivitis/ periodontitis/ others).\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExposure\u0026nbsp;details\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNature of Vitamin (gel/ liquid/ powder); Type or form of Vitamin C (name of vitamin C analog), Dosage (mg or %), frequency (once or twice), mode of application of Vitamin C (topical/ injection); Ease of use; Duration of surgery (mins)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComparator group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGingival depigmentation using a scalpel, laser, electrocautery, or cryogen.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGingival pigmentation score before and after, as measured by any method or index (Dummet-Gupta Oral Pigmentation Index (DOPI), Hanioka\u0026rsquo;s Melanin Index, Spectrophotometric analysis, inhibition of tyrosinase activity and melanin composition, Kumar\u0026rsquo;s gingival pigmentation index, and qualitative assessment of histological and immunohistochemical outcomes.\u003c/p\u003e\n\u003cp\u003ePain, itching, and discomfort score by any method or index (Visual Analog Score and Patient Satisfaction Surveys)\u003c/p\u003e\n\u003cp\u003ePresurgical, surgical, and post-surgical requirements and complications before and after depigmentation\u003c/p\u003e\n\u003cp\u003eAdjuncts used with Vitamin C (Laser, surgical blade, micro-needling)\u003c/p\u003e\n\u003cp\u003eTime required for the procedure\u003c/p\u003e\n\u003cp\u003ePatient-reported post-operative outcomes\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe results from each study and its characteristics of included studies are reported in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, and a description of the factors is provided as a narrative synthesis below as follows:\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of included studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr style=\"height: 123px;\"\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eAuthor/ Year/\u003c/p\u003e\n\u003cp\u003eCountry of origin/\u003c/p\u003e\n\u003cp\u003estudy design\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003cp\u003eMale/Female ratio\u003c/p\u003e\n\u003cp\u003eSample Size\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eSmokers/Non-smokers\u003c/p\u003e\n\u003cp\u003eComorbidities\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eMode of Application of Vitamin C\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eStudy Groups and sample size in each Group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eOutcome/Parameters assessed\u003c/p\u003e\n\u003cp\u003eFollow-up period\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eThe index used for the assessment of gingival pigmentation\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eStudy Outcome\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eLimitations/ Adverse events\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 126px;\"\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eShimada et al. (\u003cspan class=\"CitationRef\"\u003e2009\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eJapan\u003c/p\u003e\n\u003cp\u003eProspective Clinical Split-mouth Trial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003e25\u0026ndash;57 years (mean age: 37.2 years)\u003c/p\u003e\n\u003cp\u003e22 males; 51 females\u003c/p\u003e\n\u003cp\u003e73 subjects\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003e38 smokers, 10 former smokers, and 25 non-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eTopical Ascorbic Acid- glucoside Gel (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eTest: Topical Vitamin C gel\u003c/p\u003e\n\u003cp\u003eControl: Placebo gel\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eChanges in luminescence (L*)\u003c/p\u003e\n\u003cp\u003eIn vitro assessment of inhibition of tyrosinase and melanin concentration\u003c/p\u003e\n\u003cp\u003e12 weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eSpectro\u003c/p\u003e\n\u003cp\u003e-photometric analysis (L*)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eThe luminescence values changed significantly from 54.47 at baseline to 57.04 at 12 weeks in the test group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 126px;\" align=\"left\"\u003e\n\u003cp\u003eNo direct assessment of changes in pigmentation indices.\u003c/p\u003e\n\u003cp\u003eShort-term follow-up\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 190px;\"\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eSheel et al.\u003c/p\u003e\n\u003cp\u003e(2015)\u003c/p\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003cp\u003eCase Report\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003e18 years\u003c/p\u003e\n\u003cp\u003eFemale patient\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eAscorbic acid ampoules applied topically (10%/250mg/ml)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eTest group: Surgical scalpel along with topical applications of Vitamin C\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eVisual Analog Scores (VAS)\u003c/p\u003e\n\u003cp\u003ePatient satisfaction using a three-point scale.38\u003c/p\u003e\n\u003cp\u003e9 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eDummet-Gupta\u0026rsquo;s Oral Pigmentation Index (DOPI) 39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eSubjective decrease in pigmentation and absence of recurrence at 9 months.\u003c/p\u003e\n\u003cp\u003eReduction of VAS score from 1.8 intraoperatively to 1.5 10 days postoperatively.\u003c/p\u003e\n\u003cp\u003eHigh patient satisfaction score of 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 190px;\" align=\"left\"\u003e\n\u003cp\u003eQuantitative reduction in DOPI and recurrence rate not specified.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 155px;\"\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eYussif et al. (\u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003cp\u003eAnimal-model Study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003e15 Adult male goats\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eGroup I: Saline (5)\u003c/p\u003e\n\u003cp\u003eGroup II: 0.1ml Vit C (5)\u003c/p\u003e\n\u003cp\u003eGroup III: 0.3ml Vitamin C (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eImmunohistochemical changes: antibodies against human melanoma black (HMB-45) and E-Cadherin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eHistological evidence revealed a marked reduction in melanin pigment and an increase in the number of cells with the perinuclear haloing in both groups II and III as compared to Group I.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 155px;\" align=\"left\"\u003e\n\u003cp\u003eNo quantitative assessment of histologic changes.\u003c/p\u003e\n\u003cp\u003eNo follow-up.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 246px;\"\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eYussif et al. (\u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003cp\u003eProspective Clinical Parallel-arm Study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003e30 study participants\u003c/p\u003e\n\u003cp\u003eAge\u0026thinsp;\u0026gt;\u0026thinsp;18 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eTest: Non-surgical Vitamin C injections (15)\u003c/p\u003e\n\u003cp\u003eControl: Scalpel depigmentation (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eChanges in two pigmentation indices\u003c/p\u003e\n\u003cp\u003eVisual Analog Score (VAS) for pain and itching.\u003c/p\u003e\n\u003cp\u003ePatient Satisfaction\u003c/p\u003e\n\u003cp\u003e9 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eHanioka\u0026rsquo;s Melanin Index 40\u003c/p\u003e\n\u003cp\u003eKumar\u0026rsquo;s Gingival pigmentation index (GPI) 15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eA significant difference in GPI in favor of the control group over the test group at 1 month.\u003c/p\u003e\n\u003cp\u003eSignificant reduction in VAS scores (from 5 at baseline to 0 on the 7th day) for itching and pain on the 2nd day (p\u0026thinsp;=\u0026thinsp;0.0001), 3rd (p\u0026thinsp;=\u0026thinsp;0.0001), and 7th day (p\u0026thinsp;=\u0026thinsp;0.0015) when compared to scalpel depigmentation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 246px;\" align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 270px;\"\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eEl-Mofty et al.\u003c/p\u003e\n\u003cp\u003e(2021)\u003c/p\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003cp\u003eProspective Parallel-arm Clinical Study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003e18\u0026ndash;40 years, with a mean age of 27.3\u003c/p\u003e\n\u003cp\u003e2 males and 8 females in both study groups\u003c/p\u003e\n\u003cp\u003e20 subjects\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid and\u003c/p\u003e\n\u003cp\u003eTopical Ascorbic Acid- glucoside Gel (10%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eGroup I: Vitamin C Mesotherapy (10)\u003c/p\u003e\n\u003cp\u003eGroup II: Topical Vitamin C (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eChanges in DOPI\u003c/p\u003e\n\u003cp\u003eSatisfaction questionnaire modified from McGill Pain Questionnaire\u003c/p\u003e\n\u003cp\u003eDigital Melanin Area Fraction Analysis\u003c/p\u003e\n\u003cp\u003e6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eDOPI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eMedian DOPI changed significantly from 2 at baseline to 1 at 6 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in Group I\u003c/p\u003e\n\u003cp\u003eMedian DOPI remained 1 at 6 months for Group II (p\u0026thinsp;=\u0026thinsp;0.223)\u003c/p\u003e\n\u003cp\u003eBoth groups revealed a significant reduction in melanin area fraction at 6 months when compared to the baseline (p\u0026thinsp;=\u0026thinsp;0.005 and p\u0026thinsp;=\u0026thinsp;0.012, respectively)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 270px;\" align=\"left\"\u003e\n\u003cp\u003eStatistically significant differences between study groups at baseline may confound statistical analysis.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 123px;\"\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eMostafa et al.\u003c/p\u003e\n\u003cp\u003e(2022)\u003c/p\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003cp\u003eCase Report\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003e25 year\u003c/p\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003ePatient\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003e1000mg/ml Ascorbic Acid powder-saline slurry applied after micro-needling\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eReduction of 2 pigmentation indices\u003c/p\u003e\n\u003cp\u003eQualitative assessment of pain, healing, and re-pigmentation\u003c/p\u003e\n\u003cp\u003e6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eDOPI and Hanioka\u0026rsquo;s Melanin Index 39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eReduction of DOPI from 3 to 0 and Melanin Index score from 2 to 0. Light brown solitary re-pigmentation at 6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 123px;\" align=\"left\"\u003e\n\u003cp\u003eShort-term follow-up with a limited sample size.\u003c/p\u003e\n\u003cp\u003eNo histologic evaluation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 297px;\"\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eChaudhary et al.\u003c/p\u003e\n\u003cp\u003e(2022)\u003c/p\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003cp\u003eProspective Parallel-arm Clinical Trial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003e18\u0026ndash;40 years\u003c/p\u003e\n\u003cp\u003e60% (18) were females and 40% (12) were males\u003c/p\u003e\n\u003cp\u003e30 subjects\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eExclusion of chronic smokers (criteria unspecified)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eGroup I: Scalpel depigmentation (15)\u003c/p\u003e\n\u003cp\u003eGroup II: Vitamin C mesotherapy (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eChanges in pigmentation and repigmentation were assessed by graphical estimation.\u003c/p\u003e\n\u003cp\u003eVAS for pain\u003c/p\u003e\n\u003cp\u003eVerbal scale for itching\u003c/p\u003e\n\u003cp\u003e3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eDOPI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eThe non-significant difference in reduction of pigmentation area at 1 month (32.27 with the control group and 37.07 with the test group, p\u0026thinsp;=\u0026thinsp;0.932)\u003c/p\u003e\n\u003cp\u003eNon-significant influence on re-pigmentation (p\u0026thinsp;=\u0026thinsp;0.903)\u003c/p\u003e\n\u003cp\u003eSignificant reduction in VAS scores with the test group over the control group (0.73 and 3.33, respectively, p\u0026thinsp;=\u0026thinsp;0.001)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 297px;\" align=\"left\"\u003e\n\u003cp\u003eNon-quantitative classification of periodontal phenotypes\u003c/p\u003e\n\u003cp\u003eMaxillary sextants are compared with mandibular sextants, which may confound study results due to differences in area, phenotype, and intensity.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 439px;\"\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eDawar et al. (\u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003cp\u003eCase series\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;18 years\u003c/p\u003e\n\u003cp\u003e5 patients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eIntraepidermal injection (mesotherapy) using L-Ascorbic acid\u003c/p\u003e\n\u003cp\u003eNo control group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eChange in gingival luminescence (L*)\u003c/p\u003e\n\u003cp\u003ePigmented surface area (PSA)\u003c/p\u003e\n\u003cp\u003eMelanocyte count\u003c/p\u003e\n\u003cp\u003eVAS score for pain\u003c/p\u003e\n\u003cp\u003ePatient satisfaction survey\u003c/p\u003e\n\u003cp\u003e3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eDOPI\u003c/p\u003e\n\u003cp\u003eGPI 15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eSignificant reduction in the median GPI (p\u0026thinsp;=\u0026thinsp;0.05), DOPI (p\u0026thinsp;=\u0026thinsp;0.04), pigmented surface area (PSA) (p\u0026thinsp;=\u0026thinsp;0.04), and L* (p\u0026thinsp;=\u0026thinsp;0.04) at 1-month follow-up\u003c/p\u003e\n\u003cp\u003eBetween the 1st and 3rd months, a marked improvement in the only change in gingival luminescence was noted (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e\n\u003cp\u003eReduction in median melanocyte count from 102 to 52 at 3 months.\u003c/p\u003e\n\u003cp\u003eThree out of five patients gave a high satisfaction score of 4 (scale of 0\u0026ndash;4), and 2 gave a score of 3 at the 3-month follow-up.\u003c/p\u003e\n\u003cp\u003eMedian VAS pain score of 3 on the day of the procedure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 439px;\" align=\"left\"\u003e\n\u003cp\u003eNo consideration of gingival biotype.\u003c/p\u003e\n\u003cp\u003eShort-term follow-up.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 326px;\"\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eEsmat et al., (\u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eRandomized, parallel double-blinded clinical trial\u003c/p\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003e18 and 40\u0026thinsp;years\u003c/p\u003e\n\u003cp\u003e26 Patients\u003c/p\u003e\n\u003cp\u003e5.4% males and 84.6% females\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eIntra-mucosal injection of vitamin C (L-Ascorbic acid 1000\u0026thinsp;mg/5\u0026thinsp;ml)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eGroup 1: Intra-mucosal injection of vitamin C (L-Ascorbic acid 1000\u0026thinsp;mg/5\u0026thinsp;ml)\u003c/p\u003e\n\u003cp\u003eGroup 2:\u003c/p\u003e\n\u003cp\u003eDiode laser (980\u0026thinsp;nm, 1.5\u0026thinsp;W, continuous wave mode)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eClinical evaluation of pigmentation intensity and distribution was performed preoperatively and at 1, 2, and 3\u0026thinsp;months postoperatively. Dummett-Gupta Oral Pigmentation Index (DOPI), and Gingival Pigmentation Index (GPI). Pain intensity and patients\u0026rsquo; satisfaction were checked using VAS and questionnaires.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eDummett-Gupta Oral Pigmentation Index (DOPI), and Gingival Pigmentation Index (GPI).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003ePigmentation scores decreased significantly between pre-operative visits and different follow-up visits for both treatment modalities\u0026nbsp;\u003cem\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001*).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWhen compared to the vitamin C mesotherapy group, the laser group demonstrated significantly lower gingival pigmentation scores\u0026nbsp;\u003cem\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001*).\u003c/em\u003e\u0026nbsp;Both treatment modalities were equally satisfying for the patients.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 326px;\" align=\"left\"\u003e\n\u003cp\u003eLonger follow-up periods are required to assess the recurrence rate.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 128px;\"\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eSandhu et al., \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eCase series\u003c/p\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eTwo male patients aged 22 and 25 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eTopical application of Enshine Cream 15 g) along scalpel depigmentation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eCase 1: Vitamin C\u0026thinsp;+\u0026thinsp;scalpel depigmentation\u003c/p\u003e\n\u003cp\u003eCase 2: scalpel depigmentation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eDummett Oral Pigmentation Index (DOPI).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eDummett Oral Pigmentation Index (DOPI).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eImproved healing and positive effects of vitamin C in the healing phase of the gingival tissues following scalpel depigmentation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 128px;\" align=\"left\"\u003e\n\u003cp\u003eNo quantitative data were reported for the DOPI score for both cases, and no long-term follow-up was conducted.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 479px;\"\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eMostafa et al. (\u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eCase Series: prospective\u003c/p\u003e\n\u003cp\u003eRiyadh, KSA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003e16 patients\u003c/p\u003e\n\u003cp\u003e17\u0026ndash;35 years old; 8 women and 8 men\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eAscorbic acid powder (1000 mg) and a Dermapen (a pen-like instrument with a handle and 12\u0026ndash;24 needles arranged in rows moving at a speed of 700 cycles/min.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eMicroneedling technique using the Dermapen with needles of 1.5\u003c/p\u003e\n\u003cp\u003emm depth followed by topical Vitamin C powder\u003c/p\u003e\n\u003cp\u003e(1000 mg/ml) mixed with saline was applied for 10 minutes and repeated after two weeks.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eHedin melanin index and Dummett Oral Pigmentation Index (DOPI) at baseline and follow-up at one month\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eHedin melanin index and Dummett Oral Pigmentation Index (DOPI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eGenerally, healing was\u003c/p\u003e\n\u003cp\u003enormal and satisfactory, and all patients achieved excellent aesthetic results with a reduction in both\u003c/p\u003e\n\u003cp\u003eindices. Seven out of the 16 patients showed complete depigmentation of the gingiva, while nine patients\u003c/p\u003e\n\u003cp\u003edisplayed a reduction in their indices. The analysis using paired T-tests demonstrated a statistically significant reduction in the post-treatment DOPI score, with a mean difference of 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 (95% CI: 0.17\u0026ndash;1.49).\u003c/p\u003e\n\u003cp\u003eSimilarly, the HMI score was also lower post-treatment, with a mean difference of 3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 (95% CI: 2.74\u0026ndash;3.50).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 479px;\" align=\"left\"\u003e\n\u003cp\u003eThe discomfort was experienced in most cases.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 430px;\"\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eMeenakshi and Subasree, 2024\u003c/p\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003cp\u003eRandomized clinical trial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003e16 participants\u003c/p\u003e\n\u003cp\u003eMandible sites\u003c/p\u003e\n\u003cp\u003eMean age: 26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.67 years.\u003c/p\u003e\n\u003cp\u003e50% (n\u0026thinsp;=\u0026thinsp;8), and 50% women (n\u0026thinsp;=\u0026thinsp;8).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eNon-smokers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eDermapen (Dr. Pen, Las Vegas, NV) device and topical ascorbic acid powder (1,000 mg/mL) mixed with saline were applied over the gingiva for 10 minutes.\u003c/p\u003e\n\u003cp\u003ethree treatment sessions of microneedling, spaced out by 10 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eCase group: Microneedling with Vitamin C 1000 mg/ml) mixed with saline was applied for 10 minutes (three times)\u003c/p\u003e\n\u003cp\u003eControl group: surgical depigmentation with a scalpel\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eDummett-Gupta Oral Pigmentation Index (DOPI) and early wound healing index by Maria et al (2018)\u003c/p\u003e\n\u003cp\u003eAt baseline, one month, and three months follow-up.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eDummett-Gupta Oral Pigmentation Index (DOPI) and early wound healing index by Maria et al (2018)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003eDOPI scores at baseline: 2.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 and 2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17 in the scalpel and microneedling with Vitamin C.\u003c/p\u003e\n\u003cp\u003eThe mean DOPI score at the end of the third month was 1.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39 and 0.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17 in the surgical and MN with ascorbic acid groups, respectively.\u003c/p\u003e\n\u003cp\u003eThe healing index exhibited a statistically significant difference between the treated groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.04), both at baseline and after one week. The healing index scores did not show a statistically significant difference within the same group in the surgical technique group at baseline and on the seventh day.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 430px;\" align=\"left\"\u003e\n\u003cp\u003ePatients treated with conventional surgical techniques showed incomplete healing and ulceration on the first and seventh days after the procedure when compared to the microneedling technique with ascorbic acid.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eNature, type, mode, dosage, and frequency of application of Vitamin C\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eEfficacy of Vitamin C in reducing gingival melanin pigmentation compared to other depigmentation procedures\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eEffect of Vitamin C on the gingival tissues\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eRecurrence of pigmentation after Vitamin C depigmentation compared to other conventional treatments.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eVitamin-C Depigmentation and Patient-reported Outcomes\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient-reported outcomes and the presence of any side effects were noted.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe quantitative data in terms of mean and standard deviation, standard mean difference, gingival pigmentation score, pain score, and aesthetic score were noted. Qualitative data, if present, about the procedure and pain score, were noted. The critical appraisal of included studies was assessed for their risk of bias using the Joanna Briggs Institute (JBI) scale. The risk of bias analysis was scored according to JBI risk of bias analysis and scored as follows: Studies with scores 0\u0026ndash;4 were considered to have a high risk of bias; 5\u0026ndash;7 were considered to have a moderate risk of bias, and more than equal to 8 were considered to have a low risk of bias.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eCharacteristics of the individual studies\u003c/h2\u003e\u003cp\u003eA total of 119 articles were obtained from all databases (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After removing duplicates, 103 articles were eligible for titles and abstracts. Following title and abstract screening, 16 articles were included, out of which 4 articles were removed as they did not pertain to our particular focus question. Thus, a total of 12 studies were eligible for the review (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Meenakshi and Subasree, 2024). Out of the 12 research articles, five were case reports/ case series (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; ), one was an animal-model study (goat model) (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e); five were clinical trials (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Meenakshi and Subasree, 2024); one was a hybrid study with cell-culture assessment as well as clinical evaluations on human patients (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Six studies were conducted in Egypt (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), five in India (Sheel et al.,2015; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Meenakshi and Subasree, 2024), and one in Japan (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). The sample size ranged from 20\u0026ndash;73 subjects (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; El-Mofty et al, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). One study included both smokers and non-smokers, whereas four studies excluded smokers at the eligibility check (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al.,2019; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The subjects included in two case-report studies were self-reported non-smokers (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The mean age of the samples from all the studies ranged from 27.2 years to 37.2 years (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al.,2019) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The detailed characteristics of the demographic data from the included studies are also mentioned in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. One case report showed high risk of bias (Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); four studies depicted a moderate risk of bias (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); whereas seven studies had a low risk of bias (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Tricco et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e, Mostafa et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Meenakshi and Subasree, 2024) (Supplementary Table\u0026nbsp;1 to Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eType of gingival pigmentation and method used for analysis\u003c/h3\u003e\n\u003cp\u003eAll studies carried out depigmentation for the removal of physiologic melanin pigments. The depigmentation was done for maxillary and mandibular anterior regions only (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Meenakshi and Subasree, 2024). The classification and evaluation of changes in pigmentation were assessed using \u0026lsquo;Dummet-Gupta\u0026rsquo;s Oral Pigmentation Index (DOPI) (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Meenakshi and Subasree, 2024); Hanioka\u0026rsquo;s melanin index (Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e); Spectrophotometric analysis (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e); inhibition of tyrosinase activity and melanin composition (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e); Kumar\u0026rsquo;s gingival pigmentation index (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); early wound healing score by Marini et al. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) (Meenakshi and Subasree, 2024), and qualitative assessment of histological and immunohistochemical outcomes (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Five studies reported patient-reported outcomes in terms of pain, discomfort, or itching using the visual analog scale (VAS) (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); and the McGill pain and patient satisfaction questionnaire (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eResults of Individual Sources of Evidence and Synthesis of Results\u003c/h2\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003eMode, dosage, and frequency of application of Vitamin C\u003c/h2\u003e\u003cp\u003eStudies tested the efficacy of Vitamin C as an adjunct to scalpel depigmentation (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) and as a stand-alone therapy (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Two studies compared the efficacy of Vitamin C to Scalpel depigmentation (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), and one study compared two modes of application of Vitamin C (mesotherapy and topical) (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e); two case series compared the role of Vitamin C to Scalpel (Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); one RCT compared the role of Vitamin C to LASER (diode LASER) (Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). One animal study compared different concentrations of Vitamin C as mesotherapy (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). One clinical study compared the topical application of Vitamin C to a placebo gel (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). The mode of application of vitamin C included: topical application of ascorbic acid powder-saline slurry (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); cotton roll-assisted topical application of vitamin C capsule contents (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e); topical application of a vitamin-C derivative gel composed of 10% ascorbic acid 2-glucoside (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) and intraepidermal injections (oral mesotherapy) of L-ascorbic acid (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). L-ascorbic acid and ascorbic acid 2-glucosides were two derivatives of Vitamin C that were employed for depigmentation procedures (Boo \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Yokota and Yahagi, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDifferent doses of vitamin C (ascorbic acid) were used such as 1000mg/ml (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); 10% ascorbic acid (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e); 10% ascorbic acid-glucoside gel (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e) and 1-2ml of 1mg/5mL L-ascorbic acid (ampoules) equivalent to 200-300mg vitamin C concentration as 0.1 ml for each point with 2\u0026ndash;3 mm apart, once a week for four to five weeks (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). One study also compared the effect of 0.1ml and 0.3ml of vitamin C mesotherapy (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Another study applied Vitamin C using an alternate approach and carried out micro-needling for 30\u0026ndash;40 seconds per tooth, followed by a topical application for 10 minutes, twice at an interval of two weeks (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). When used as an adjunct to scalpel depigmentation, topical Vitamin C was applied to surgically treated sites at weekly intervals for a month, followed by monthly intervals for 9 months (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In two prospective clinical trials, topical gel application once daily after brushing at night, for 12 weeks, was also tested (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The intraepidermal injections of Vitamin C were done using different protocols. In three studies that carried out non-surgical Vitamin C mesotherapy, the agent was delivered using 30-gauge syringes/insulin syringes either once a week for a maximum duration of 4 weeks (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) or thrice at intervals of one week (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e describes the characteristics of the included studies.\u003c/p\u003e\u003cp\u003e\u003cem\u003eEfficacy of Vitamin C in reducing gingival melanin pigmentation compared to other depigmentation procedures.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eVitamin C was found to be effective in reducing gingival pigmentation in all of the included studies. Mesotherapy (intra-epithelial injection) was the most employed technique for Vitamin C depigmentation (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). A study by El-Mofty et al (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) compared the efficacy of mesotherapy versus topical depigmentation and found that intra-epidermal injection has better reduction at 6 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The DOPI value of two at baseline reduced to one at six months for epidermal injection; however, for topical application, the DOPI remained unchanged at six months (p\u0026thinsp;=\u0026thinsp;0.223). Both groups revealed a significant reduction in melanin area fraction at six months when compared to the baseline (p\u0026thinsp;=\u0026thinsp;0.005 and p\u0026thinsp;=\u0026thinsp;0.012, respectively), with an insignificant inter-group difference (p\u0026thinsp;=\u0026thinsp;0.082). At one week and six months, there was a significant improvement in patient-reported cosmetic changes for group I (p\u0026thinsp;=\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Shimada et al. evaluated the effect of the topical application of Vitamin C compared to the placebo gel and found a significant change in luminescence value, which changed from 54.47 at baseline to 57.04 at 12 weeks in the vitamin C group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). After nine months, the pigmentation has decreased subjectively, and there has been no recurrence. There was a decrease in VAS score from 1.8 intraoperatively to 1.5 at 10 days after surgery. In addition, a high patient satisfaction score of three was recorded (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAnother study by Yussif et al. compared Vitamin C mesotherapy with scalpel depigmentation and revealed a significantly improved reduction in Kumar\u0026rsquo;s Gingival pigmentation index for the scalpel group after one month (p\u0026thinsp;=\u0026thinsp;0.003). At the end of nine months, the results of the scalpel and vitamin C groups were comparable when measured using Hanioka's Melanin Index and Kumar's Gingival pigmentation. The itching sensation score (from 5 at baseline to 0 on the 7th day postoperatively) and pain score (on the 2nd, 3rd, and 7th day postoperatively) reduced significantly compared to scalpel depigmentation, which then became non-significant at the 9th month (p\u0026thinsp;=\u0026thinsp;0.46) (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Chaudhary et al. assessed the effect of Vitamin C mesotherapy compared to scalpel and found no difference in the reduction of pigmentation area at one month (32.27 for the control group and 37.07 for the Vitamin C group, p\u0026thinsp;=\u0026thinsp;0.932). No significant influence on repigmentation was noted (p\u0026thinsp;=\u0026thinsp;0.903). A significantly favorable reduction in VAS scores with the Vitamin C group over the control group was also observed (0.73 and 3.33, respectively, p\u0026thinsp;=\u0026thinsp;0.001) (Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). A case series using oral Vitamin C mesotherapy revealed a significant reduction in gingival pigmentation as evident by median gingival pigmentation index (p\u0026thinsp;=\u0026thinsp;0.05), DOPI (p\u0026thinsp;=\u0026thinsp;0.04), pigmented surface area (PSA) (p\u0026thinsp;=\u0026thinsp;0.04), and change in luminescence(p\u0026thinsp;=\u0026thinsp;0.04) at 1-month follow-up. When comparing one- and three-month follow-ups, only luminescence showed a marked improvement (p\u0026thinsp;=\u0026thinsp;0.04). Another study showed that micro-needling with adjunct topical administration of Vitamin C resulted in excellent aesthetic outcomes after two applications at the end of one month. They observed that DOPI and melanin index scores of 3 and 2, respectively, reduced to 0 after two applications (Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Topical application after scalpel depigmentation produced a significant improvement in DOPI (Sandhu et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). In 2023, Mostafa et al (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) also reported a significant reduction in melanin pigmentation upon the use of micro-needling with topical application of Vitamin C (twice application after two weeks). A statistically significant lower DOPI score posttreatment (mean difference 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7, 95% confidence interval (CI): 0.17\u0026ndash;1.49, p\u0026thinsp;\u0026le;\u0026thinsp;0.001) at the end of one month. Seven out of the 16 patients showed complete depigmentation of the gingiva, while nine patients displayed a reduction in their indices (Mostafa et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). A randomized clinical trial compared the efficacy of vitamin C mesotherapy to diode LASER and found that the pigmentation decreased significantly between pre-operative visits and at three-month follow-up visits for both the Vitamin C and LASER group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001*). However, the laser was found to have better results and lower gingival pigmentation scores compared to Vitamin C at the follow-up visits (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001*) (Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eEffect of Vitamin C on the gingival tissues\u003c/h3\u003e\n\u003cp\u003eAs evidenced by in-vitro and histopathological studies, Vitamin C was found to induce biochemical and histological changes in the gingiva (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). A Vitamin C derivative gel composed of 10% ascorbic acid 2-glucoside resulted in a proportional, marked inhibition in the tyrosinase activity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), along with a significant decrease of 48% in the melanin composition (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in mouse melanoma cells when compared to placebo (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Similarly, another study on goats revealed a definite qualitative histologic reduction in melanin, causing perinuclear vacuolating and disruption of the intercellular contact between melanocytes and keratinocytes (Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The study reported that the depigmenting effect was enhanced with a higher dose of Vitamin C. The test groups also revealed a strong HMB-45 antibody reaction with low levels of residual melanin granules concerning basal and suprabasal epithelial layers. Another study comparing Vitamin C as mesotherapy, and topical form reported a significant reduction in histologic melanin area fraction at six months when compared to the baseline for both modalities (p\u0026thinsp;=\u0026thinsp;0.005 and p\u0026thinsp;=\u0026thinsp;0.012 respectively) (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). However, the inter-group difference at six months was non-significant. (p\u0026thinsp;=\u0026thinsp;0.082). A case-series study assessing melanocyte-histopathologic count after Vitamin C mesotherapy showed a reduction in median values from 102 at baseline to 52 at three months (Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eRecurrence of pigmentation after Vitamin C depigmentation\u003c/h2\u003e\u003cp\u003eThe recurrence rate of pigmentation following Vitamin C application was measured both quantitatively and qualitatively. Based on the quantitative data it was found that a recurrence of 32.59% was observed after three months of Vitamin-C mesotherapy compared to 32.87% in the scalpel group (p\u0026thinsp;=\u0026thinsp;0.903) (Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Based on qualitative data, multiple studies reported the occurrence of re-pigmentation (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Light brown solitary pigmented areas were observed at six months follow-up with micro-needling-assisted Vitamin C depigmentation (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). However, when used as a topical adjunct to scalpel depigmentation, no recurrence was observed up to a follow-up of nine months (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). A prospective clinical trial using topical vitamin C gel revealed no recurrence at 12 weeks (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Intramucosal injections of Vitamin C revealed no recurrence at nine months which was comparable to scalpel depigmentation (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). There are no studies comparing recurrence rates between different modalities of Vitamin C or comparing Vitamin C and LASER/cryotherapy-assisted depigmentation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eVitamin-C depigmentation and patient-reported outcomes\u003c/h2\u003e\u003cp\u003eFive studies evaluated pain and satisfaction following Vitamin C depigmentation, out of which four utilized the visual analog score (VAS) (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Simultaneously, two studies quantitatively evaluated patient satisfaction (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The topical application of vitamin C on the scalpel depigmentation site exhibited a VAS score of 1.8 on the day of the procedure and 1.5 after 10 days (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Vitamin C mesotherapy revealed a significant reduction in VAS scores for itching and pain compared to scalpel depigmentation, thus rendering it comparatively atraumatic (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Similarly, scalpel depigmentation depicted a significantly higher mean VAS score when compared to Vitamin C mesotherapy after 24 hours of the procedure (p\u0026thinsp;=\u0026thinsp;0.001) (Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). A case series of five patients who received Vitamin C mesotherapy revealed a median pain score of three on the day of the procedure (Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The study comparing Vitamin C mesotherapy and topical application reported that 100% of the patients in both study groups experienced no pain on the day of the surgery, as well as one week after the procedure (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The study evaluating the micro-needling approach only mentioned a qualitative reduction in pain and discomfort after the third postoperative day (Mostafa and Alotaibi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). In terms of patient satisfaction, a comparison between mesotherapy and topical Vitamin C showed significant differences in favor of the former in terms of patient-reported cosmetic change at one week and 6 months (p\u0026thinsp;=\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively) (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). 100% of the patients in the topical application group were unsatisfied with the treatment outcome compared to 40% in the mesotherapy group (p\u0026thinsp;=\u0026thinsp;0.011) (El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In the case series using Vitamin C mesotherapy, three out of five patients gave a high satisfaction score of four, and two patients gave a score of three at the three-month follow-up (Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Multiple studies have corroborated that pain, itching, and discomfort are prominently reduced using Vitamin C, regardless of the mode of application (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Dawar et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Even intraepidermal injections of Vitamin C have shown excellent patient acceptance when contrasted with scalpel depigmentation (Yussif et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Chaudhary et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Esmat et al (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) compared the patient satisfaction score and pain score using a questionnaire and VAS between patients treated with LASER and Vitamin C mesotherapy for depigmentation. The authors found A statistically significant difference (P\u0026thinsp;=\u0026thinsp;0.005) in immediate postoperative pain scores between the two groups, favoring the LASER group. However, no significant differences in pain scores on the 1st and 7th postoperative days were detected between the two groups. No difference was seen in the patient's satisfaction and acceptance of the treatment method between the two groups as assessed by the questionnaire for assessing the aesthetic/cosmetic appearance after three months, fulfilment of expectation, and willingness to repeat the procedure (Esmat et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion and summary of evidence","content":"\u003cp\u003eThe aim of this review is to provide an evaluation of the effectiveness of vitamin C in the management of gingival pigmentation. Vitamin C is known for its anti-inflammatory, antioxidant, and wound-healing properties, which have led to its common use in dermatology and cosmetics for depigmentation and skin lightening. It is also being considered for use in the management of gingival hyperpigmentation. It is noted that studies have compared both topical and mesotherapy for vitamin C application to reduce the melanin pigments in the gingiva. It has been observed that microneedling with a dermapen can create pinpoint holes in the gingival epithelium, with a depth of up to 0.2 to 1 mm. Subsequently, vitamin C is applied to the affected area and left for approximately 10 to 20 minutes, during which the vitamin C is permitted to enter the epithelium. Vitamin C can be injected into the gingiva via microneedles or applied directly, with the latter being less effective. It can be used as an atraumatic method of reducing heavy physiologic melanin deposits in the gingiva. It would seem that the most effective results in reducing clinical pigmentation can be achieved by repeating the application of vitamin C, either via intradermal injection or micro-needling, with a gap of 10\u0026ndash;15 days between each application. Studies have indicated that vitamin C may be an effective approach to reducing gingival pigmentation, and it may offer a less invasive alternative to other methods such as scalpel, bur, and electrocautery (Hanioka et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Miot et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). It is thought that the use of vitamin C with microneedling may help to improve patient acceptance and ease of procedure compared to surgical de-epithelization. Additionally, the anti-inflammatory and antioxidant properties of vitamin C may help to accelerate wound healing and reduce post-operative inflammation and pain following de-epithelization of gingiva with a scalpel/bur.\u003c/p\u003e\u003cp\u003eVitamin C depigmentation is an effective treatment for young adults with special needs, including those with mental retardation and developmental anomalies. It is important to note, however, that a mesotherapy technique involving multiple injections may be unacceptable and uncomfortable for some patients, particularly those with a needle phobia. Furthermore, the necessity for multiple visits for vitamin C mesotherapy presents a significant challenge in terms of patient compliance.\u003c/p\u003e\u003cp\u003eHowever, we must highlight some of the limitations of the current evidence. There is insufficient evidence that quantitatively evaluates the recurrence rate and efficacy of vitamin C depigmentation in the long term. It is crucial to acknowledge that one study evaluated the impact of vitamin C on smokers, which could potentially bias the results due to the detrimental effects of smoking on gingival tissues. Future studies must therefore compare the effect of re-pigmentation following vitamin C application in smokers versus non-smokers. We could find no studies comparing the role of vitamin C with laser depigmentation. Furthermore, it is essential to determine whether vitamin C can be used as a monotherapy or if it should always be used in conjunction with scalpels or lasers, as no studies have done so. The limited number of studies that evaluated the effect of topical vitamin C preparations demonstrated unequivocally that a reduction in oral pigmentation indices was observed even after topical application for one week (Shimada et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; El-Mofty et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). One case report evaluated the effect of topical vitamin C as an adjunct to scalpel depigmentation and found a reduction in pigmentation that did not recur over a nine-month follow-up period (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). A clinical trial is required to validate the suggestion that its efficacy will extend over a longer period, given the absence of a control group and the fact that the results were observed only in one patient (Sheel et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Furthermore, no studies have considered the biotype/phenotype of the gingiva when assessing the role of vitamin C as an adjunct to gingival depigmentation. The maxillary gingiva is thicker than the mandibular region, so the depth of penetration of vitamin C will vary among patients. The gingiva ranges from 0.2 mm to 3 mm in thickness/phenotype. Furthermore, a quantitative assessment of wound healing following vitamin C depigmentation, along with a comparison with existing treatment modalities, must be conducted. Furthermore, the application of vitamin C to treat pathologic gingival pigmentation represents another potential research area. However, future studies should assess the long-term effect of using different modes of application of Vitamin C for gingival depigmentation and compare its effectiveness and recurrence rate compared to other depigmentation procedures.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eVitamin C application either topically or via microneedling is a good treatment option for managing gingival pigmentation, with mesotherapy (intra-epithelial injection) being the most effective outcome. Vitamin C application for gingival pigmentation is a less invasive alternative to other methods such as scalpel, bur, and electrocautery. Vitamin C with micro-needling has better patient acceptance and ease of procedure compared to scalpel de-epithelization. Vitamin C has shown good anti-inflammatory and antioxidant properties that help accelerate wound healing and reduce post-operative inflammation and pain.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompliance with Ethical Standards\u003c/h2\u003e\u003cp\u003eConflict of Interest: Author Shubhankar Mehrotra declares that she has no conflict of interest. Author Malvika Shyam Kumar R declares that she has no conflict of interest. Author Shravya M declares that she has no conflict of interest. Author Aditi Chopra declares that she has no conflict of interest. Author Marwa Madi declares that she has no potential conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNo funding for this review\u003c/p\u003e\u003cp\u003eEthical approval: not applicable.\u003c/p\u003e\u003cp\u003eInformed consent: not applicable.\u003c/p\u003e\u003cp\u003eNo AI or generative AI writing tools were used.\u003c/p\u003e\u003cp\u003eData will be available upon request via email to the corresponding author.\u003c/p\u003e\u003ch2\u003eAuthor contribution:\u003c/h2\u003e\u003cp\u003e\u003cb\u003eConceptualization\u003c/b\u003e: SM, MS, AC; \u003cb\u003eMethodology: SM\u003c/b\u003e, MS, SHM, AC; \u003cb\u003eDevelopment or design of methodology; creation of models: Software\u003c/b\u003e: MS, AC; \u003cb\u003eValidation\u003c/b\u003e: MS, SM, AC, MM; \u003cb\u003eFormal analysis\u003c/b\u003e: MS, SM, AC; \u003cb\u003eInvestigation\u003c/b\u003e: MS, AC, SM, SHM; \u003cb\u003eResources\u003c/b\u003e: MS, AC, SM; \u003cb\u003eData Curation\u003c/b\u003e: MS, AC, SM, SHM; \u003cb\u003eWriting: Original Draft\u003c/b\u003e: MS, AC, SM, SHM, MM, \u003cb\u003eWriting: Review \u0026amp; Editing\u003c/b\u003e: MS, AC, SM, SHM \u003cb\u003eVisualization\u003c/b\u003e: AC \u003cb\u003eSupervision\u003c/b\u003e: AC; \u003cb\u003eProject administration\u003c/b\u003e: AC; \u003cb\u003eFunding acquisition\u003c/b\u003e: AC; \" all authors approved the final version to be published-\"\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlasmari DS (2018) An insight into gingival depigmentation techniques: The pros and cons. 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Clin Nutr Exp 24:54\u0026ndash;65\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gingival depigmentation, Gingiva, Melanin, Vitamin C, Pigmentation, Aesthetics, Mucogingival surgery, periodontal plastic surgery","lastPublishedDoi":"10.21203/rs.3.rs-7803852/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7803852/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjectives: Excessive gingival pigmentation can be treated by surgically removing the pigmented gingival tissue with a scalpel, bur, LASER, electrocautery, cryotherapy, chemical peeling, and masking with free gingival grafts. Recently, Vitamin C in gel, powder, or liquid has been used alone or as an adjunct to micro-needling or a scalpel. This paper aims to critically appraise current evidence on the role of Vitamin C in gingival depigmentation.\u003c/p\u003e\n\u003cp\u003eMaterial and Method: The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis for Scoping Review (PRISMA-Scoping Review). Studies using ‘vitamin C’ in any form, via any application method, frequency, duration, and dosage for gingival depigmentation were compared to the scalpel, LASER, bur abrasion, or cryotherapy, including.\u003c/p\u003e\n\u003cp\u003eResults: Out of 119, 103 articles were excluded, and 16 articles were taken up for full-text screening. Of 16, 12 articles were included in the review. The results showed that vitamin C can be used along with scalpel depigmentation or as a stand-alone therapy (as mesotherapy or topical application). Vitamin C effectively reduced gingival pigmentation; however, with no statistical difference between the scalpel and Vitamin C application. No studies have compared the efficacy of Vitamin C to Cryotherapy. Microneedling of the gingiva followed by vitamin C application was also done. The recurrence rate of pigmentation following Vitamin C mesotherapy application was 32.59% after three months, compared to 32.87% with the scalpel. Vitamin C mesotherapy also revealed a significant reduction in VAS scores for itching and pain, and better patient acceptance than scalpel depigmentation.\u003c/p\u003e\n\u003cp\u003eConclusion: Vitamin C application with microneedle or mesotherapy is a promising atraumatic alternative to a scalpel for gingival depigmentation.\u003c/p\u003e","manuscriptTitle":"How effective is Vitamin C for gingival depigmentation? a scoping review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-12 14:38:04","doi":"10.21203/rs.3.rs-7803852/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f67a539a-a846-4909-8513-dea64a465ed3","owner":[],"postedDate":"October 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55934629,"name":"Clinical Pharmacology"},{"id":55934630,"name":"Dentistry"}],"tags":[],"updatedAt":"2025-10-12T14:38:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-12 14:38:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7803852","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7803852","identity":"rs-7803852","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}