An electronic search was conducted in databases including PubMed, Cochrane, Web of Science, ProQuest, and Scopus, limited to English articles published until March 2022. The search employed a model using Boolean operators: (Interdental papilla OR papilla*) AND (PRF OR L-PRF OR PRP) in TITLE/SUBJECT/ABSTRACT, tailored to each database’s specific search strategy [Supplementary Table 2]. In addition, the reference sections of included studies were scrutinized for further relevant studies.

The search aimed to identify randomized-controlled clinical trials, prospective or retrospective clinical studies, cohort studies, and case series. Excluded were animal studies, in vitro studies, case reports, finite element analysis studies, and reviews. Eligible studies provided data on PRF usage in baseline assessments and had a minimum follow-up period of 3 months.

Duplicate studies were removed both automatically and manually. Titles and abstracts were initially screened by two independent authors (Z.A. and M.A.). For papers with insufficient information on papilla fill, corresponding authors were contacted for clarification or additional data.

Quality assessment of the controlled clinical trials was performed by the Cochrane risk of bias tool. When the study met all criteria, the degree of bias was considered as low risk; if one or some components were unclear, the degree of bias was considered as moderate risk; and if at least one component was at high risk, the degree of bias was considered as high. Quality assessment of the observational studies was performed using the Joanna Briggs Institute (JBI) checklist which includes 9 items. For the answer “yes,” the item is scored 1 point and scored 0 point for a “no,” “not clear,” or “not applicable” answer. Studies scoring seven points or more were considered to be of high quality.

Meta-analysis of mean differences (MDs) was performed using R Statistical Software (Version 4.1.1, R Core Team, Vienna, Austria) according to the published procedures.^[11,12] The analyses were performed in the following categories: CPTP, CI, PI, CAL and PPD.

Data wrangling and manipulation were performed using the statistical packages “tidyverse,”^[13] “dplyr”^[14] and “ggplot2”^[15] in Rstudio (Rstudio Inc., Boston, MA, USA).^[16] Meta-analytic syntheses and further investigations were done by “meta” and “dmetar” in RStudio (Rstudio Inc., Boston, MA, USA).^[17,18] Raw effect size data in the form of means and standard deviations of two groups can be pooled using metacont function provided by “meta.” Heterogeneity was assessed using Cochran’s Q and I²-statistics. A random effects model was retained to pool effect sizes to better account for the differences in design among the included studies. The restricted maximum likelihood estimator was used to calculate the heterogeneity variance τ².^[19] Knapp-Hartung adjustments were used to calculate the confidence interval (CI) around the pooled effect.^[20] Funnel plots for investigating publication bias were made using the functionalities of the “meta” package. In addition, drapery plots were produced based on P value functions.

Altogether, the search strategy yielded 191 papers in the first selection step. One hundred and twenty-eight articles remained after the elimination of duplicate records. Of them, 121 were omitted on the assessment of titles and abstracts. Full text assessment was performed on 8 remaining articles. Finally, 7 publications were included in the systematic review and 5 of them were includable for the meta-analysis [Supplementary Figure 1].^[1,5,21-23] Detailed characteristics of the 8 included studies are described in Table 1.

A total of 84 sites were treated with PRF and 83 other sites were treated with CTGs, and 112 patients were enrolled in these studies.^[1,5,21-23] Moreover, two prospective studies^[6,24] evaluated 50 sites treated with PRF in 38 patients. All the sites were located in the maxillary esthetic area, and the papillary classification was class I and class II according to Nordland and Tarnow classification.^[25] Four studies^[1,6,21,23] used the surgical technique introduced by Han and Takei,^[26] while one study^[22] performed microsurgical Azzi technique^[27] and another one^[24] used pouch technique. Other study prepared a minimal labial and palatal tunneling across the interdental gingiva.^[5] The PRF was made in regard to the first Choukroun Protocol which centrifuged the blood sample at 3000 rpm for 10 min^[1,5,21] or 12 min.^[22] All studies used one PRF membrane for the test group. Original data from included studies for meta-analysis are provided in Table 2.

All four studies^[1,5,21,22] were deemed low risk due to clear randomization methods. Except one study, the other three did not describe the allocation concealment and thus were judged to be at unclear risk of bias in this regard.^[1,5,21] As the interventions were completely different by nature, double-blinding to include operators or patients was not possible. Nevertheless, three of the studies^[1,5,22] reported blinding of the assessors and were grouped as low risk of bias and one study had no information regarding blinding of participants. For attrition and reporting biases, all the studies were rated as low risk and two studies^[1,21] had unclear risk for “other bias” due to some issues with the reported mean and SD in their results [Supplementary Figure 2]. According to JBI checklist, both prospective studies and the retrospective study were scored high quality^[6,24] [Supplementary Table 3].

Four studies^[1,21-23] compared the changes in CPTP after 3 month of papilla augmentation with CTG or PRF with the baseline [Figure 1a] and three studies^[1,5,23] compared the parameter after 6 month with the baseline [Figure 1b]. They all reported significant differences in this regard (weighted MD [WMD]: −0.39; 95% CI: −0.57 to −0.21; P < 0.01) and (WMD: −0.74; 95% CI: −1.30 to −0.17; P = 0.03).

Four studies^[1,21-23] evaluated changes in GI after 3 month from the surgery [Figure 2a] and two studies compared the parameter after 6 months [Figure 2b], and the results showed no significant difference (P = 0.50) and (P = 0.59).

Plaque index was evaluated in three studies^[1,22,23] after 3 month of papilla augmentation [Figure 2c] and significant difference was identified (WMD: 0.10; 95% CI: 0.08–0.12; P < 0.01) and two studies compared the parameter after 6 months [Figure 2d]. Moreover, the results showed no significant difference (P = 0.28).

When comparing PPD between groups, four studies^[1,21-23] compared the parameter after 3 months [Figure 2e] and three other studies after 6 months with the baseline^[1,5,23] [Figure 2f]. The results showed no significant differences for both time periods (P = 0.38) and (P = 0.54).

In regard to CAL, two studies^[21,22] compared the parameter after 3 month and significant difference was reported (WMD: 0.05; 95% CI: 0.00–0.10; P = 0.05) [Figure 2g].

The results of Cochran’s Q and I²-statistics, and the corresponding P values indicated that between-study heterogeneity existed in GI and PPD categories and that the use of a random-effects model was appropriate. The heterogeneity among other categories was low; nevertheless, caution should be applied when interpreting these results, due to small sample sizes and statistical power [Supplementary Figure 3a-h].

The resulting drapery plots are documented in the supplemental content [Supplementary Figure 4a-i]. Each plot contains a P value curve, in the shape of an upside down V, for each effect size under the normality assumption. The peak of the P value functions represents the exact value of the effect size in our meta-analysis. Gray curves correspond to primary studies, while the thick red line represents the average effect according to the random-effects model (studies in dark gray shows higher precision and those in light gray shows low precision). Y-axis shows the P values and while it gets smaller, the CI gets bigger, until we reach conventional significance thresholds, indicated by the dashed horizontal lines.

Our meta-analysis delineates a clear advantage for CTG over PRF in papilla reconstruction, particularly evident in the dimensional changes of CPTP at 3 and 6 months postsurgery. This advantage extends to PI improvements favoring CTG after 3 months. However, for CAL, GI, and PPD, our findings reveal no significant disparities between the groups.

The survival rate and efficacy of CTG in papilla reconstruction were posited by earlier studies.^[1,21,22,28] Correlate with the graft’s vascular supply and its intrinsic biological properties. The composition of CTG, inclusive of nerve structures, adipose tissues, and glands, contrasts with the simpler structure of PRF membranes, potentially contributing to CTG’s resilience against postsurgical shrinkage.^[22] Beagle suggested the roll technique primarily, which is a combination of a pedicle flap with papilla preservation.^[29] Subsequently, Han and Takei introduced a technique with a semilunar incision and a subepithelial CTG beneath the papilla.^[26] Later, in a case report by Azzi et al., split-thickness buccal and palatal flaps were used in the company of CTG.^[27] In a case report in 2012, PRF was placed in a pouch in the interdental area, created with a semilunar incision.^[3]

Studies by Ahila et al.^[6] and Raval et al.^[24] highlight the efficacy of PRF in achieving substantial papillary fill, with noted rapid healing and significant reductions in black triangle dimensions. This rapid tissue regeneration is likely attributed to the unique properties of PRF, particularly its high affinity for growth factors such as fibroblast growth factor-b, vascular endothelial growth factor, angiopoietin, and PDGF, and their subsequent role in enhancing angiogenesis.^[8] The ability of PRF to promote fibroblast proliferation and migration, vital for wound healing, underscores its potential in periodontal regeneration.^[6,8]

Despite these advantages, PRF is not without limitations. Its rapid degradation and consequent diminished release of biomolecules may impede the initial stabilization of periodontal tissues.^[30] However, its ease of preparation, cost-effectiveness, and reduced morbidity make it an attractive option in specific clinical scenarios.^[31] Advancements in PRF technology, particularly the potential increase in its layers, could significantly enhance its efficacy, possibly even surpassing that of CTG. This prospect opens up new avenues for research and clinical application.

Esthetic outcomes, a critical aspect of periodontal treatments, have shown encouraging results with PRF, as indicated by improvements in Visual Analog Scale scores.^[5,6] However, studies have demonstrated marginally superior esthetic outcomes with CTG,^[22,23] highlighting the need for a balanced approach when considering patient-specific parameters and treatment objectives. Given that this is the first systematic review and meta-analysis evaluating PRF’s efficacy in papilla augmentation, and considering the limited number of randomized-controlled trials available, a definitive conclusion on its success remains elusive. Our findings suggest that exploring alternative surgical approaches or newer generations of PRF might be beneficial.

This meta-analysis faces limitations due to the heterogeneity of study designs, follow-up durations, and variability in PRF production methods. The influence of site-specific factors such as tissue phenotype and tooth shape, as well as the nuances of CTG harvesting methods, need clearer reporting in future studies. Furthermore, the short-term nature of follow-up in these studies limits the long-term applicability of our findings. Future research should focus on addressing these gaps, possibly exploring newer generations of PRF or alternative surgical approaches.

The study is funded by Isfahan University of Medical Sciences. (Grant number: IR.ARI.MUI.REC.1401.138).

The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article.