Abstract
Background
Gingival phenotype (GP), comprising gingival thickness (GT) and keratinized tissue width (KTW), plays a crucial role in preserving the integrity of gingival and periodontal tissues, thereby enhancing their resistance to trauma and mechanical irritation. This systematic review and meta-analysis aimed to evaluate the current evidence about the changes in GT and KTW following the injection of injectable platelet-rich fibrin (i-PRF) in patients with thin GP.
Methods
A thorough search was conducted up to April 2024 across the following nine databases: The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed®, Scopus®, Web of Science®, Google Scholar, Trip, CINAHL via EBSCO, EMBASE via OVID, and ProQuest. This review covered parallel-group and split-mouth randomized controlled trials (RCTs) which investigated the changes in GT and KTW following i-PRF injection on the buccal anterior region in both jaws for individuals with thin GP. The risk of bias in the included studies was evaluated using Cochrane’s tool (RoB 2), and the GRADE framework was utilized to assess the overall strength of evidence. Agreement between the authors was assessed using Cohen’s kappa statistic.
Results
Seven RCTs were included in this review, five of which were appropriate for the quantitative synthesis of data. The meta-analysis showed a statistically significant increase in the GT in the i-PRF group at all assessment times compared to baseline (MD ranged from 0.12 mm to 0.38 mm). Regarding KTW, 4-time injections led to a significant increase in KTW after 3-month and 6-month follow-ups compared to baseline (MD = 0.31 mm, and MD = 0.37 mm, respectively). In contrast, 3-time injections yielded a non-significant increase in KTW after 1 and 3 months of follow-up (MD = 0.14 mm at both assessment times). The strength of evidence supporting these findings ranged from low to moderate. However, when comparing the i-PRF group and the i-PRF + microneedling (MN) group, the pooled estimate exhibited significant differences in the GT at both assessment times, with superiority for the MN + i-PRF group (MD = 0.04 mm after 3 months, MD = 0.11 mm after 6 months). In contrast, there were no statistically significant differences in KTW between the two comparisons (MD = 0.03 mm at both assessment times). The strength of evidence supporting these findings was moderate.
Conclusions
For patients with a thin GP, i-PRF administration resulted in a significant increase in GT at all assessment times compared to baseline. Regarding the KTW, the results varied depending on the number of injection sessions. When the injections were carried out four times, there was an observed increase in KTW, while repeating the intervention three times revealed a non-significant increase in KTW.
Protocol registration
The protocol was registered in the PROSPERO database (CRD42024543374) on 16 May 2024.
Level of evidence
According to the GRADE recommendations, the strength of evidence regarding the effect of i-PRF injection on GT and KTW ranged from low to moderate. The evidence strength for differences between the i-PRF group and the i-PRF + MN group in both GT and KTW was moderate. The overall quality of evidence for these outcomes is presented in Table 4.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12903-024-05109-5.
Keywords: Injectable platelet-rich fibrin, Gingival thickness, Keratinized tissue width
Introduction
Gingival phenotype (GP) has a crucial effect on restorative and regenerative dentistry outcomes. The variance in treatment outcome is possibly due to differences in tissue response to inflammation and trauma. Therefore, identifying the GP is important in clinical practice for each patient before making treatment decisions [1]. The periodontal phenotype has been defined as the combination of GP and bone morphotype [2]. GP, in turn, refers to gingival thickness (GT) and keratinized tissue width (KTW) [3]. However, both these elements play an important role in maintaining periodontal health [4]. Recently, the GP was classified into three categories: thin-scalloped, thick-flat, or moderate [5]. The thin GP is usually associated with a narrow band of keratinized tissue and thin and translucent gingiva with a thickness of less than 1.5 mm. In return, the thick phenotype is characterized by a heavy gingival margin and wide zones of keratinized tissue with a thickness of ≥ 2 mm [6, 7].
Several factors may affect the GT and KTW either individually or in combination, mainly including genetics and race, which is the most important factor in determining the GP [8, 9]. Many other factors have a potential effect including low-level and long-lasting trauma especially due to inappropriate daily brushing, occlusal trauma, decreased alveolar bone crest thickness, dehiscence, and frenulum insertion [10]. These factors play a crucial role in reducing the KTW and affecting the GP. Unfortunately, the most limitation facing periodontitis in this topic is the incapacity for modulating the genetic factor [8].
Current evidence suggests that patients with thin tissue and limited gingival width are inclined to have more gingival recessions compared to those with thick and wide gingival tissue, who were more resistant to mechanical irritation and gingival regression [1, 11, 12]. Therefore, there is a necessity to modify the thin GP to a thick one to maintain healthy periodontal tissue.
It has become known that periodontal plastic procedures using autogenous grafts such as connective tissue grafts (CTGs) and free gingival grafts (FGG), or substitutes such as acellular dermal matrix (ADM) and collagen matrices (CM), can significantly enhance the amount of GT and keratinized tissue [13–17]. However, these methods are invasive and may lead to severe postoperative pain, discomfort, and donor-site morbidity. In addition, they have other disadvantages such as longer operating time and limited availability of donor tissue [18]. Hence, recent scientific advancements have favored minimally invasive treatment options over surgical procedures as they help to achieve satisfactory therapeutic results with minimum trauma to the affected tissues [19].
Platelet-rich concentrates have been utilized for the last three decades as a minimally invasive procedure, demonstrating their capacity to release high levels of growth factors, which are crucial in promoting tissue regeneration [20, 21]. Platelet-rich fibrin (PRF), considered the second generation of platelet-rich concentrates, has gained immense popularity in dentistry for treating various therapeutic cases including periodontal defects, gingival recessions, palatal wound closure, post-extraction alveolar ridge preservation [22, 23], osteonecrosis management [24], and inducing the recovery process of the mental nerve neurosensory disturbances [25]. and promoting extraction socket healing [22]. However, in 2014, injectable platelet-rich fibrin (I-PRF), having the same qualities as PRF, was introduced by utilizing non-glass tubes and modifying spin centrifugation forces [22]. Much like traditional PRF, i-PRF contains a high amount of growth factors, cytokines, leucocytes, and stem cells [26, 27].
PRF and its various forms offer numerous benefits, including ease of handling, cost-effectiveness, no side effects, minimal pain, and no need for anticoagulants [12, 18, 28]. Many studies have used i-PRF alone or in combination with other methods to investigate its effect on gingival tissue augmentation and modification of the thin GP. Concerning KTW, some studies reported that i-PRF injection was associated with a statistically significant increase in KTW [7, 18, 20, 29]. In contrast, other studies pinpointed no differences between baseline and follow-up sessions [12, 30–33]. Regarding GT, several studies have observed that i-PRF can enhance GT [7, 29–35]. However, when comparing the increase with other intervention methods, the reported findings varied among studies. In other words, there is no clear evidence regarding the definitive effect of i-PRF on GP modification. No previous systematic reviews have tried to address the available evidence regarding this point. Therefore, this systematic review (SR) is the first attempt to fill in the gap by comprehensively reviewing all the existing evidence in the literature and answering the question: Does i-PRF injection have the potential to increase tissue thickness and keratinized tissue width in patients with a thin gingival phenotype?
Methods
Reporting format
This SR adheres to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions [36] and was reported according to the PRISMA statement Guidelines [37]. Likewise, the protocol was registered on the PROSPERO database (CRD42024543374) on 16 May 2024.
Eligibility criteria
Inclusion Criteria
The PICOS approach (Population, Intervention, Comparison, Outcomes, and Study design) was utilized to define the eligibility criteria.
Population (P): Adult patients of any gender or ethnic group having a thin GP.
Intervention (I): Local injection of i-PRF, regardless of the injection numbers.
Comparison (C): No intervention, placebo intervention, local administration of other biological agents, application of any mechanical method alone or in combination with local injection of i-PRF.
Outcomes (O): Gingival thickness (GT) and keratinized tissue width (KTW).
Study design (S): Parallel-group and split-mouth randomized controlled trials (RCTs) were only included in this review.
Exclusion Criteria
Non-randomized studies, case reports, case series reports, reviews, cross-sectional studies, retrospective studies, personal opinions, non-sufficient abstracts, animal trials, and non‑English language studies were excluded.
Search strategy
A thorough search was carried out independently by two authors, without restriction on language. The electronic search was set from inception up to 9 April 2024 across the following nine databases: The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed®, Scopus®, Web of Science®, Google Scholar, Trip, CINAHL via EBSCO, EMBASE via OVID, and ProQuest. The ongoing and unpublished trials were electronically detected through the World Health Organization’s International Clinical Trials Registry Platform (ICTRP) and Clinical Trials databases. Further details about the search strategy are provided in Table 1.
Table 1.
The electronic search strategy
| Databases | Search strategy | n |
|---|---|---|
| Cochrane |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
56 |
| PubMed® |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
67 |
| Scopus® |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
42 |
| Web of Science™ |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
92 |
| Google Scholar |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
286 |
| Trip |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
91 |
| CINAHL |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
2 |
| EMBASE |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
12 |
| ProQuest |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
36 |
| WHO |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
44 |
| Clinical Trials |
#1 injectable platelet-rich fibrin OR i-PRF OR platelet-rich concentrates #2 gingival augmentation OR periodontal augmentation OR gingival thickness OR keratinized tissue width OR gingival phenotype #3 #1 AND #2 |
75 |
Study selection
Two team members (MII and ASB) independently extracted studies in accordance with the inclusion criteria, and the level of agreement between the two researchers was evaluated based on Cohen’s kappa statistic. In case of disagreement, the third researcher (MYH) was consulted to reach the final judgment. In the beginning, duplicate articles were removed utilizing Endnote software (version X9). Subsequently, the records were screened by evaluating titles and abstracts using the Rayyan® QCRI software [38]. Finally, the full text of the remaining articles was assessed by the same two authors to make the decision. Studies that did not meet the inclusion criteria were eliminated.
Data extraction
After filtration, the following items were extracted from all the included studies: author name, publication year, study design, sample size, participants (gender, age), intervention and comparison group, number of injection sessions, receiving region, site of injection, follow-up periods, and study outcomes.
Risk of bias in individual studies
The research authors (MII and ASB) separately evaluated the quality of the included trials depending on Cochrane guidelines. In case of a difference in their judgment, the author (MYH) was consulted to solve the matter. RoB-2 tool [39] was utilized for the risk of bias assessment of the included randomized studies. The tool assesses five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. Every single field can be evaluated as having a low risk of bias, some concerns, or a high risk of bias. The overall assessment of each article was concluded as follows: “low risk of bias” if all domains were assessed as a low risk of bias; “some concerns” if at least one field was evaluated as some concerns, but not to be at high risk for any domain, “high risk of bias” if at least one or more domains were assessed as a high risk of bias.
The Risk of Bias Visualization tool (ROBVIS) was utilized to visualize the risk of bias findings [40].
Statistical analysis
Meta-analysis was reported using Review Manager software (RevMan) Version 5.4. (Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration). Studies included in this review were assessed for heterogeneity both clinically and statically. Clinical heterogeneity was assessed by comparing the treatment protocols used, including the number of injection sessions, outcomes, and the intervention received in the comparison group. Statistical heterogeneity was determined using the chi-square test, where a P-value of less than 0.05 was considered significant. The I² index was also utilized to characterize the level of heterogeneity among the studies.
Quality of evidence
The strength of evidence concerning each outcome was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [41].
Results
Literature flow
The search strategy yielded 803 articles. After taking off the duplicates, 412 articles were reviewed. Both independent reviewers applied exclusion criteria, which led to the exclusion of 400 articles deemed irrelevant to this review, the inter-reviewer reliability based on the kappa statistic was (K = 0.92). Thus, twelve articles were potentially relevant for the review and were chosen for full-text assessment. Out of the twelve full-text articles assessed, five were excluded [12, 18, 20, 29, 42], the inter-reviewer reliability based on the kappa statistic was (K = 1). Supplementary Table 1 presents the excluded studies and the exclusion reason. Seven studies were appropriate for the final analysis, and five of these were included in the meta-analysis. The PRISMA flow chart is provided in Fig. 1.
Fig. 1.
PRISMA flow chart of the included studies
Characteristics of the included studies
Seven split-mouth RCTs including 178 patients were included in this review [7, 30–35], and five of them were included in the meta-analysis [7, 31–34]. All studies were published in English between 2020 and 2024, and were carried out in India [30, 31, 33, 35], Turkey [32], Syria [7], and Iraq [34]. Regarding gender distribution, the studies showed varied results in male-to-female ratio, being approximately 1:1 in one study [31], 1:2 in two studies [7, 35], almost all female patients in two studies [30, 32], and two studies did not mention the gender distribution [33, 34]. The patients’ ages ranged from 18 to 35 years.
In the intervention group, all studies locally applied the i-PRF to investigate its effect on GT and KTW. GT was measured using 15–20 endodontic spreader with a silicone disk as a stopper. The spreader was inserted perpendicularly at 1.5–2 mm apical to the gingival margin till felling the hard tissue. The penetration depth was measured between the spreader tip and the silicone disk using digital calipers. Measurement of KTW was done with the same technique. Regarding teeth that received the injection, five studies administered the i-PRF in the buccal region of the mandibular anterior teeth [7, 31–33, 35], while the other two studies injected the i-PRF in the buccal anterior region for both upper and lower arches [30, 34].
In the studies by Faour et al., Ozsagir et al., Adhikary et al., and Shaker et al., the i-PRF injection was administered in the apical region of the mucogingival margin [7, 32–34]. In the studies of Manasa et al. and Yadav et al., the i-PRF was injected in the attached gingiva at the mid-buccal aspect of the teeth [30, 31], whereas Soundarajan et al. injected the i-PRF in the gingival sulcus [35].
The amount of venous blood centrifuged to obtain the i-PRF sample ranged between 5 ml in the study of Faour et al. [7], 10 ml in the studies of Manasa et al., Yadav et al., and Shaker et al. [30, 31, 34], and 20 ml in the studies of Ozsagir et al., Adhikary et al., and Soundarajan et al. [32, 33, 35]. Concerning the gauge of the needle utilized in the i-PRF injection, four studies depended on a 27-gauge needle [30, 32, 33, 35], two studies utilized a 30-gauge needle [7, 31], and one study used a 31-gauge needle [34].
The comparison group varied among the studies. In the study by Manasa et al. [30], the comparison group was kept as a negative control without any intervention. In the study by Yadav et al. [31], micro-needling (MN) was applied to determine its effect on the gingival and periodontal outcomes. In Faour et al. and Shaker et al. studies [7, 34], hyaluronic acid (HA) and concentrated platelet-rich fibrin (c-PRF) were used, respectively for the same purpose. Meanwhile, Ozsagir et al., Adhikary et al., and Soundarajan et al. applied MN along with i-PRF in the comparison group [32, 33, 35].
As for the repetition of injections, three studies carried out the intervention in 4 sessions at 10-day intervals [31–33], one study repeated it in 3 sessions at 10-day intervals [35], two studies repeated it in 3 sessions at 7-day intervals [7, 34], and one study involved only a single injection [30].
Concerning the follow-up time, four of the seven included studies had follow-up sessions extending up to six months [30–33], whereas the other three studies extended the observation to three months [7, 34, 35]. When analyzing the comparability of baseline values among the various groups, balance was observed in all included studies. The characteristics of the seven included studies are listed in Table 2.
Table 2.
Characteristics of the included studies
| Study ID | No. of participants (female/ male) |
Age mean (range) | Intervention/Comparison | No. of repeat injections | Receiving region | Site of injection | Follow-up | Outcomes |
|---|---|---|---|---|---|---|---|---|
|
Yadav et al., 2024 [31] |
21(11/10) | 25.23 (18–35) |
Group 1: I-PRF Group 2: MN |
4 sessions at 10-day intervals | Mandibular anterior teeth | In the midpoint of the attached gingiva | 1st, 3rd, and 6th months. |
GT KTW, PI, GI, PPD, BOP |
|
Adhikary et al., 2023 [33] |
32 | (18–34) |
Group 1: I-PRF Group 2: I-PRF + MN |
4 sessions at 10-day intervals | Mandibular anterior teeth | The apical region of the MGM in AM | 3rd and 6th months. |
GT KTW |
|
Soundarajan et al., 2023 [35] |
36(23/13) | 32.4 |
Group 1: I-PRF Group 2: I-PRF + MN |
3 sessions at 10-day intervals | Mandibular anterior teeth | The gingival sulcus | 1st, 2nd and 3rd months. | GT |
|
Manasa et al., 2023 [30] |
30(24/6) | 28.53 (18–35) |
Group 1: I-PRF Group 2: Control |
One session | Maxillary and mandibular incisors | The attached gingiva at the mid-buccal aspect of the teeth | 3rd and 6th months. |
GT KTW |
|
Shakir et al., 2023 |
10 |
Group 1: I-PRF Group 2: C-PRF |
3 sessions at 7-day intervals | Maxillary and mandibular anterior teeth | The alveolar mucosa near the MGM | 1st and 3rd months. |
GT KTW |
|
|
Faour et al., 2022 [7] |
14(9/5) | 29.71 |
Group 1: I-PRF Group 2: HA |
3 sessions at 7-day intervals | Mandibular anterior teeth | The apical region of the MGM | 1st and 3rd months. |
GT KTW, GI, BOP, PPD |
|
Ozsagir et al., 2020 [32] |
33(28/5) | 22.2 (18–34) |
Group 1: I-PRF Group 2: I-PRF + MN |
4 sessions at 10-day intervals | Mandibular anterior teeth | The apical region of the MGM in AM | 1st, 2nd, 3rd, 4th, 5th, and 6th months. |
GT KTW |
I-PRF: Injectable Platelet-Rich Fibrin, MN: Micro-needling, c-PRF: Concentrated Platelet-Rich Fibrin, HA: Hyaluronic Acid, MGM: Mucogingival Margin, AM: Alveolar Mucosa, GT: Gingival Thickness, KTW: Keratinized tissue width, PI: Plaque Index, GI: Gingival Index, PPD: Pocket Probing Depth, BOP: Bleeding on Probing
Risk of bias in the included studies
The risk of bias in the included RCTs was evaluated according to the ROB-2 tool, and presented in Fig. 2, while the overall risk of bias across all domains was illustrated in Fig. 3. Three RCTs [30–32] were assessed as having a “low risk of bias”, three as having “some concerns” [7, 34, 35], and one RCT [33] was identified with a “high risk of bias”. Bias in the measurement of the outcome process was identified as the primary reason for the risk of bias in all four studies.
Fig. 2.
Risk of bias in the included RCTs
Fig. 3.
The overall risk of bias score for each field of RCTs
Further details about the risk of bias assessment are presented in the Supplementary Table 2.
Effect of intervention
Intra-group comparison
Gingival thickness (GT)
All seven included trials studied the changes in GT as a result of i-PRF injection.
Yadav et al., Ozsagir et al., and Adhikary et al. aimed to evaluate the effect of i-PRF injection administered in 4 sessions at 10-day intervals, with assessment performed after 3 and 6 months after the last injection [31–33]. The pooled estimate showed a statistically significant increase in GT at 3 months compared to the baseline, with high heterogeneity between these three studies (MD = 0.12; 95% CI: 0.08,0.16; p < 0.00001; χ² = 8.06; p = 0.02; I² = 75%; Fig. 4A). The strength of evidence concerning this finding was low. Additionally, at 6 months, the pooled estimate showed a statistically significant increase in GT compared to the baseline, with low heterogeneity between these three studies (MD = 0.17; 95% CI: 0.13,0.21; p < 0.00001; χ² = 1.52; p = 0.47; I² = 0%; Fig. 4B). The strength of evidence regarding this finding was moderate.
Fig. 4.
Forest plot of the comparison between baseline and 3-month follow-up, baseline and 6-month follow-up. The outcome measure: GT (mm) with 4 time injections
Faour et al. and Shaker et al. administered the i-PRF injection in 3 sessions at 7-day intervals, with outcome assessment done at 1 month and 3 months of follow-up [7, 34]. The pooled estimate showed a statistically significant increase in GT after 1 month compared to the baseline, with high heterogeneity between these two studies (MD = 0.38; 95% CI: 0.29,0.46; p < 0.00001; χ² = 4.53; p = 0.03; I² = 78%; Fig. 5A). The strength of evidence supporting this finding was low. After 3 months of follow-up, the pooled estimate showed a statistically significant increase in GT compared to the baseline, with low heterogeneity between these two studies (MD = 0.26; 95% CI: 0.16,0.37; p < 0.00001; χ² = 0.05; p = 0.82; I² = 0%; Fig. 5B). The strength of evidence for this finding was moderate.
Fig. 5.
Forest plot of the comparison between baseline and 1-month follow-up, baseline and 3-month follow-up. The outcome measure: GT (mm) with 3 time injections
Soundarajan et al. [35] also evaluated the effect of i-PRF injection on GT. The injection was repeated three times at 10-day intervals, with outcome measurements taken at baseline, and at the 1st, 2nd, and 3rd months after the last injection. The results showed a statistically significant increase in the GT at all assessment times compared to baseline (p < 0.01).
Manasa et al. [30] reported a statistically significant increase in GT in the i-PRF group at both 3-month and 6-month follow-ups compared to baseline (p < 0.05). The overall increase in GT was 26.56% after 3 months and 29% after 6 months.
Keratinized tissue width (KTW)
All the included trials, except one [35], studied the changes in KTW in the i-PRF group.
Yadav et al., Ozsagir et al., and Adhikary et al. aimed to evaluate the effect of i-PRF injection on KTW, with the injection repeated 4 times at 10-day intervals. Outcome measures were performed at 3 and 6 months after the last injection [31–33]. The pooled estimate showed a statistically significant increase in KTW after 3 months compared to the baseline, with high heterogeneity between these three studies (MD = 0.31; 95% CI: 0.07,0.56; p = 0.01; χ² = 6.32; p = 0.04; I² = 68%; Fig. 6A). The strength of evidence concerning this finding was low. Additionally, after 6 months, a statistically significant increase was observed in KTW compared to the baseline, with high heterogeneity between these three studies (MD = 0.37; 95% CI: 0.13,0.61; p = 0.002; χ² = 8.41; p = 0.01; I² = 76; Fig. 6B). The strength of evidence concerning this finding was low.
Fig. 6.
Forest plot of the comparison between baseline and 3-month follow-up, baseline and 6-month follow-up. The outcome measure: KTW (mm) with 4 time injections
Faour et al. and Shaker et al. administered the i-PRF injection in 3 sessions at 7-day intervals, with outcome assessment done at 1 month and 3 months of follow-up [7, 34]. The pooled estimate showed no statistically significant difference in KTW after 1 month compared to the baseline, with moderate heterogeneity between these two studies (MD = 0.14; 95% CI: -0.37,0.66; p = 0.59; χ² = 1.81; p = 0.18; I² = 45%; Fig. 7A). The strength of evidence for this finding was moderate. After 3 months of follow-up, the pooled estimate also showed no statistically significant increase in KTW compared to the baseline, with moderate heterogeneity between these two studies (MD = 0.14; 95% CI: -0.37,0.66; p = 0.58; χ² = 1.71; p = 0.19; I² = 41%; Fig. 7B). The strength of evidence supporting this finding was moderate. Manasa et al. [30] concluded that there were no statistically significant differences in KTW at both 3-month and 6-month follow-ups compared to baseline (p > 0.05).
Fig. 7.
Forest plot of the comparison between baseline and 1-month follow-up, baseline and 3-month follow-up. The outcome measure: KTW (mm) with 3 time injections
Inter-group comparison
Gingival thickness (GT)
All seven included trials studied the changes in GT between the i-PRF group and the comparison group.
Ozsagir et al. and Adhikary et al. found no statistically significant differences between the i-PRF group and the i-PRF + MN group at all assessment times compared to baseline (p < 0.05), except at the 6th month, which showed a statistically significant superiority in the MN + i-PRF group compared to the i-PRF group (p = 0.007), (p = 0.035), respectively [32, 33].
Soundarajan et al. [35] aimed to investigate the effect of combining MN with i-PRF compared to i-PRF alone on GT, using a different injection frequency (three times at 10-day intervals). Outcome measures were taken at baseline, and at the 1st, 2nd, and 3rd months after the last injection. The inter-group comparison showed different results across the evaluation times: there was no statistically significant difference in the 1st and 2nd months (p = 0.12, p = 0.08, respectively), while a statistically significant difference was observed between the two groups in the 3rd month, with the MN + i-PRF group showing superiority (p = 0.04).
Manasa et al. [30] compared the i-PRF group to a negative control group (no intervention) in their split-mouth study. they reported a statistically significant increase in GT in the test group compared to the control at both the 3-month and 6-month follow-ups (p < 0.05).
Faour et al. [7] aimed to evaluate the effectiveness of i-PRF in comparison with HA in increasing GT, measured at baseline, 1 month, and 3 months of follow-up. They found no statistically significant difference between the two groups at these assessment times (p > 0.05).
Shaker et al. [34] Studied the efficacy of c-PRF compared to i-PRF injection for increasing GT in their split-mouth RCT. The inter-group comparison showed no statistically significant difference after 1 month for both upper and lower arches (p = 0.16 and p = 0.57, respectively). Similarly, after 3 months, there was no statistically significant difference for both upper and lower arches (p = 0.81 and p = 0.29, respectively).
The split-mouth RCT conducted by Yadaf et al. aimed to evaluate the effect of i-PRF in comparison with MN on GT [31]. Assessment of the GT was done at baseline and at the 1st, 3rd, and 6th months. They concluded that the MN group showed a statistically significant superiority compared to the i-PRF group at all assessment times (p < 0.05).
Keratinized tissue width (KTW)
All the included trials studied the changes in KTW between the i-PRF group and the other comparison group except one [35].
Ozsagir et al. and Adhikary et al. aimed to evaluate the effect of i-PRF alone or in combination with MN on KTW after 3 and 6 months of the intervention [32, 33]. These two studies pinpointed no statistically significant difference between the two groups at all assessment times compared to baseline (P < 0.05).
Manasa et al. [30], when comparing the i-PRF and the negative control groups, found no statistically significant differences in KTW between the two groups at both 3-month and 6-month follow-ups (p > 0.05).
Faour et al. [7] also found no statistically significant difference in KTW between the i-PRF group and the HA group at all the assessment times (p > 0.05).
Shaker et al. [34] compared i-PRF and c-PRF in both arches. Inter-group comparison after 1 month showed no statistically significant difference (p > 0.05). However, after 3 months, the results showed a significant difference in favor of the c-PRF group (p = 0.048).
Yadaf et al. [31] aimed to evaluate the effect of i-PRF compared with MN on KTW. Inter-group comparison of the changes in KTW showed no statistically significant difference between the groups at the 1st and 3rd months compared to baseline (p = 0.19, p = 0.27, respectively). However, there was a significant difference between the groups at the 6th month compared to the baseline, with superiority for the MN group (p = 0.01). Table 3 presents the meta-analysis data summary.
Table 3.
Meta-analysis data summary
| Mean difference | 95% CL | Test for heterogeneity | Overall Effect | Conclusion | |||
|---|---|---|---|---|---|---|---|
| Outcome/ follow-up | Lower | Upper | χ² | P Value | P Value | ||
| Intra-group comparison (baseline vs. follow-up), 4 sessions at 10-day intervals | |||||||
| GT: 3-month follow-up. | 0.12 | 0.08 | 0.16 | 9.06 | 0.02 | p < 0.00001 | A statistically significant increase in GT. |
| GT: 6-month follow-up. | 0.17 | 0.13 | 0.21 | 1.52 | 0.47 | p < 0.00001 | A statistically significant increase in GT. |
| KTW: 3-month follow-up. | 0.38 | 0.29 | 0.46 | 4.53 | 0.03 | p < 0.00001 | A statistically significant increase in KTW. |
| KTW: 6-month follow-up. | 0.26 | 0.16 | 0.37 | 0.05 | 0.82 | p < 0.00001 | A statistically significant increase in KTW. |
| Intra-group comparison (baseline vs. follow-up), 3 sessions at 7-day intervals | |||||||
| GT: 1-month follow-up. | 0.31 | 0.07 | 0.56 | 6.32 | 0.04 | P = 0.01 | A statistically significant increase in GT. |
| GT: 3-month follow-up. | 0.37 | 0.13 | 0.61 | 8.41 | 0.01 | P = 0.002 | A statistically significant increase in GT. |
| KTW: 1-month follow-up. | 0.14 | -0.37 | 0.66 | 1.81 | 0.18 | P = 0.59 | No statistically significant increase in KTW. |
| KTW: 3-month follow-up. | 0.14 | -0.37 | 0.66 | 1.71 | 0.19 | P = 0.58 | No statistically significant increase in KTW. |
GT: Gingival Thickness, KTW: Keratinized tissue width, i-PRF: injectable Platelet-Rich Fibrin
Table 4.
Summary of the findings according to the GRADE guidelines for included studies
| Quality assessment criteria | Summary findings | Comments | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Outcome/ follow-up | Number of studies | Risk of bias | Inconsistency | Indirectness | Imprecision | Other Consideration | Effect | Relative (95% cl) | Certainty | ||
| Number of patients | Absolute (95% cl) | ||||||||||
| Intra-group comparison (baseline vs. follow-up), 4 sessions at 10-day intervals | |||||||||||
| GT: 3-month follow-up. |
3 RCTs (SP) |
Serious | Serious | Not serious | Not serious | None | 86 | - | Mean 0.12 mm, Cl 95%, 0.08,0.16 |
Low ⊕⊕⊖⊖a |
There was a statistically significant increase in GT compared to baseline. |
| GT: 6-month follow-up. |
3 RCTs (SP) |
Serious | Not serious | Not serious | Not serious | None | 86 | - | Mean 0.17 mm, Cl 95%, 0.31,0.21 |
Moderate ⊕⊕⊕⊖b |
There was a statistically significant increase in GT compared to baseline. |
| KTW: 3-month follow-up. |
3 RCTs (SP) |
Serious | Serious | Not serious | Not serious | None | 86 | - | Mean 0.31 mm, Cl 95%, 0.07,0.56 |
Low ⊕⊕⊖⊖a |
There was a statistically significant increase in KTW compared to baseline. |
| KTW: 6-month follow-up. |
3 RCTs (SP) |
Serious | Serious | Not serious | Not serious | None | 86 | - | Mean 0.37 mm, Cl 95%, 0.31,0.61 |
Low ⊕⊕⊖⊖a |
There was a statistically significant increase in KTW compared to baseline. |
| Intra-group comparison (baseline vs. follow-up), 3 sessions at 7-day intervals | |||||||||||
| GT: 1-month follow-up. |
2 RCTs (SP) |
Serious | Serious | Not serious | Not serious | None | 24 | - | Mean 0.38 mm, Cl 95%, 0.29,0.46 |
Low ⊕⊕⊖⊖a |
There was a statistically significant increase in GT compared to baseline. |
| GT: 3-month follow-up. |
2 RCTs (SP) |
Serious | Not serious | Not serious | Not serious | None | 24 | - | Mean 0.26 mm, Cl 95%, 0.16,0.37 |
Moderate ⊕⊕⊕⊖b |
There was a statistically significant increase in GT compared to baseline. |
| KTW: 1-month follow-up. |
2 RCTs (SP) |
Serious | Not serious | Not serious | Not serious | None | 24 | - | Mean 0.14 mm, Cl 95%, -0.37,0.66 |
Moderate ⊕⊕⊕⊖b |
There was no statistically significant increase in KTW compared to baseline. |
| KTW: 3-month follow-up. |
2 RCTs (SP) |
Serious | Not serious | Not serious | Not serious | None | 24 | - | Mean 0.14 mm, Cl 95%, -0.37,0.66 |
Moderate ⊕⊕⊕⊖b |
There was no statistically significant increase in KTW compared to baseline. |
RCTs: Randomized Controlled Trials, SP: Split-mouth, GT: Gingival Thickness, KTW: Keratinized tissue width, i-PRF: injectable Platelet-Rich Fibrin
a. Downgrade one level for risk of bias, and one level due to Inconsistency
b. Downgrade one level for risk of bias
Discussion
To our knowledge, this is the first systematic review that assessed the current evidence from RCTs concerning the changes in GT and KTW following i-PRF injection in patients with thin GP.
Regarding the risk of bias in the included studies, three RCTs were evaluated as having a “low risk of bias” [30–32], three as having “some concerns” [7, 34, 35], and one was assessed as having a “high risk of bias” [33]. Bias in measuring the outcome process was identified as the reason for the risk of bias in all four studies, since assessors were probably aware of the intervention received, which could have influenced the assessment.
Gingival thickness (GT)
All seven included studies reported a statistically significant increase in GT in the i-PRF group at all assessment times compared to baseline. The studies by Yadav et al., Ozsagir et al., and Adhikary et al. showed a significant increase in GT after 3 and 6 months, with MD = 0.12, and MD = 0.17, respectively [31–33]. The studies by Faour et al. and Shaker et al. also showed a significant increase in GT after 1 and 3 months, with MD = 0.38, and MD = 0.26, respectively [7, 34]. Manasa et al. and Soundarajan et al., in turn, pinpointed that a significant increase in GT was achieved in the i-PRF group at follow-up sessions compared to baseline, with a 29% increase after 6 months and MD = 0.16 mm after 3 months, respectively [30, 35].
These similar results can be attributed to several reasons. Firstly, the high concentrations of growth factors, platelets, leucocytes, and cytokines contained in i-PRF offer many advantages in the regeneration process and tissue repair. Moreover, i-PRF promotes higher fibroblast migration and increased expression of PDGF, type-1 collagen, and transforming growth factor [31]. Furthermore, the 3D fibrin matrix acts as a scaffolding biological material for the accumulation of adherent cells at the intervention sites [33]. All of these factors play a potential role in GT augmentation following i-PRF injection.
Keratinized tissue width (KTW)
Out of seven studies, six evaluated the changes in KTW following i-PRF injection [7, 30–34]. A meta-analysis assessing the changes in KTW following four session injections at 10-day intervals showed a significant increase in KTW after 3 and 6 months of follow-up compared to baseline, with MD = 0.31 mm, and MD = 0.37 mm, respectively [31–33]. This may be attributed to the unique properties of PRF, especially its ability to gradually release high concentrations of growth factors important for the periodontal regeneration process. These include vascular endothelial growth factor, fibroblast growth factor‑b, PDGF, and angiopoietin, and their potential role in enhancing angiogenesis and elastin fiber production, which in turns promote the regenerative process [43]. moreover, previous studies conducted by Afshari et al. and Ahila et al. concluded that PRF administration was accompanied with a statistically significant increase in KTW, and can yield better results in papilla reconstruction and satisfactory reductions in black triangle dimensions [43, 44].
On the other hand, a meta-analysis evaluating changes in KTW following three session injections at 7-day intervals demonstrated a non-significant increase in KTW after 1 and 3 months of follow-up compared to baseline, with MD = 0.14 mm at both assessment times [7, 34]. Furthermore, the study of Manasa et al. [30] found no statistically significant difference in KTW after 3 and 6 months of follow-up compared to baseline. However, these results can be attributed to the number of injections, short follow-up period, and limited number of participants included in these studies. Previous studies demonstrated that i-PRF gradually releases high doses of growth factors for 7 to 14 days post-injection [45, 46]. Therefore, to maintain a lasting release of these concentrations, it is essential to administer i-PRF injections multiple times. However, the studies included in this review differed in this aspect. All three studies included in the first meta-analysis, which found a significant increase in KTW after 3 and 6 months of follow-up, repeated the injection four times at 10-day intervals [31–33]. In contrast, the two studies included in the second meta-analysis, which showed no significant increase in KTW after 1 and 3 months of follow-up, repeated the injection three times at 7-day intervals [7, 34]. Moreover, the last study [30], which found no statistically significant difference between the follow-up sessions and baseline, administered the i-PRF injection once. Furthermore, with regard to the number of individuals included in this meta-analysis, there was a limited number of patients, as only 24 participants were involved.
Moving to the last point, combining MN and i-PRF together yields better results in the 6th month concerning GT compared to using i-PRF alone [32, 33]. This finding may be attributed to the positive effects of MN on neoangiogenesis, neocollogenesis, cytokines release, and elastin fiber production, which activate regenerative mechanisms [31, 33, 47, 48].
However, many confounding factors were observed across some individual studies concerning gender, age, and anatomical sites received the injection process. Regarding gender distribution within studies, the proportion of female patients was significantly higher in four out of the seven included studies. Whereas two studies did not mention the gender distribution at all. Looking at the ages of the patients, most studies accepted a wide range of patients age ranged between 18 and 35 years, and one study did not mention the patients’ ages at all. Concerning the particular sites that received the i-PRF injection; they were not similar, as the i-PRF was administered in the apical region of the mucogingival margin, in the attached gingiva at the mid-buccal aspect of the teeth, and in the gingival sulcus.
Many limitations were observed in the included studies and may affect the results obtained. Firstly, limited sample size across the studies by Faour et al. and Shaker et al., with less than 15 participants per individual study. Secondly, three out of the seven included studies were limited with 3 months follow-up after the last injection. Furthermore, Soundarajan et al. assessed the potential effect of the i-PRF on the gingival phenotype modification by evaluating the changes in GT only rather than investigating the KTW changes. Moreover, Manasa et al. administered the i-PRF once, which may affect the results obtained from their study compared with the rest included studies which repeated the injection 3–4 times. Finally, in the study by Shaker et al., the ages of the patients were not mentioned at all.
Limitations
The first limitation of this review was the lack of high-quality RCTs; only seven studies were included, with only three of them having a low risk of bias. Furthermore, a limited number of participants in some included studies was observed, with less than 15 individuals per study [7, 34]. Another limitation is the short follow-up periods after the last injection, as all studies were limited to 3–6 months of follow-up which limits the long‑term applicability of our findings. Moreover, in terms of comparison groups, only one study included a negative control group without any intervention [30], while the other studies depended in their assessment on the comparison between baseline and follow-up sessions, and compared the i-PRF group with either a biological material or a mechanical method in the intervention group. Future studies should focus on addressing these gaps, to ensure highly reliable and credible results.
Conclusions
According to the currently available data, it could be concluded:
1- A significant increase in GT was achieved following i-PRF injection in patients with a thin GP.
2- Regarding KTW, varied results were observed depending on the number of injection sessions:
A significant increase was reported following i-PRF injection over 4 sessions at 10-day intervals.
A non-significant increase was observed after 3 sessions at 7-day intervals.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Supplementary Material 1: Supplementary Table 1. Excluded studies and the reason for exclusion.
Supplementary Material 2: Supplementary Table 2. Risk of bias assessment for the included RCTs using ROB-2 tool.
Acknowledgements
Not applicable.
Author contributions
MII and ASB separately and independently searched the literature, examined full-text articles, determined which studies were appropriate for inclusion, extracted and processed data, assessed the risk of bias, analyzed and synthesized data both qualitatively and quantitatively, and wrote the initial drafts of this manuscript. ASB, in addition, helped in formulating the focused review question. MYH supervised the whole procedures, helped resolve disagreements that developed during the research selection and risk of bias assessment, and edited the final version of this manuscript. KS and FRN helped in data entry, data analysis, writing up the first drafts of this paper. All authors read and approved the final version of this paper.
Data availability
The datasets associated with this manuscript can be obtained from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Supplementary Table 1. Excluded studies and the reason for exclusion.
Supplementary Material 2: Supplementary Table 2. Risk of bias assessment for the included RCTs using ROB-2 tool.
Data Availability Statement
The datasets associated with this manuscript can be obtained from the corresponding author upon reasonable request.