The goals of periodontal therapies are twofold: arresting periodontal disease progression as well as regenerating the lost tooth structures. Periodontal regeneration is an intricate procedure that involves an orderly sequence of biological events such as cell adhesion, migration, proliferation, and differentiation. The regenerative process relies on interaction between osteoblasts, periodontal ligament cells, gingival fibroblasts, and epithelial cells. Periodontal regenerative procedures include guided tissue regeneration (GTR), root biomodifications, and bone grafts, alone or in combination. Untreated periodontal disease can destroy the attachment apparatus and supporting structure, ultimately resulting in tooth loss. Recent literature suggests that regenerative periodontal therapies can only partially restore the original tissue volume with a limited capacity to attain complete periodontal restoration. Conventional surgical approaches such as open flap debridement (OFD) have been commonly used to access root surfaces, decrease periodontal pockets, and achieve better periodontal architecture. These, however, have shown limited success in recovery of the tissue that was damaged during periodontitis. Other techniques, such as GTR and bone grafts, have also been employed for tissue regeneration, but these have yielded mixed and unpredictable results, thus limiting their use. Inflammation is the primary response of all living tissues upon injuries. The cellular reaction at the site of injury is a complex process involving several cytokines and growth factors. The process of wound healing involves the formation of fibrin as well as aggregation of platelets, along with the release of various growth factors via cytokine- and growth factor-mediated molecular signaling pathways. Various studies have explored the suitability of autologous platelet concentrates in regenerative medicine.
Platelet-rich plasma (PRP), the first generation of autologous platelet concentrates, is known to promote and modulate tissue healing, regeneration, as well as cell proliferation, making it an ideal growth factor delivery system. However, it is associated with drawbacks such as laborious preparation, using bovine thrombin which is linked with life-threatening coagulopathies, and short-term release of growth factors.
To mitigate these limitations, the second generation of platelet concentrates, termed platelet-rich fibrins (PRFs), has been developed, which replaces the need for two-step centrifugation, biochemical additives, and anticoagulants. The first delivered procedure for the preparation of PRF at 2700 rpm for 12-min centrifugation step is called leukocyte-rich–platelet-rich fibrin (L-PRF). The generated fibrin matrix had solid consistence and a dense structure with minimal space between the fibers. Recently, the protocols for the preparation of PRF have been modified. Advanced PRF (A-PRF) matrices have been developed using the low-speed centrifugation concept. This involves centrifugation in glass-based vacuum tubes at a slower speed of 1500 rpm for a greater time of 14 min. As a result, a more porous fibrin clot is prepared that contains a larger interfibrous space than PRF. The PRF so obtained was in gel form which was not conducive to be injected. To overcome this limitation, injectable PRF (I-PRF) was introduced, in which blood is drawn without anticoagulant in plastic tubes without any coatings and centrifuged at around 700 for 3 min. The time is considerably shorter than other two protocols (i.e., L-PRF and A-PRF), which is attributable to the fact that I-PRF requires only the separation of blood components that occurs in the initial 2–4 min. Titanium PRF (T-PRF) is a modified form of PRF that is prepared by blood centrifugation in titanium tubes at 2800 rpm for 12 min. As compared to L-PRF, T-PRF is more tightly woven and has thicker fibrin. Titanium also offers improved hemocompatibility than glass; therefore, the resulting fibrin is more polymerized.
Furthermore, plasma rich in growth factors (PRGFs) have been reported as improvised alternatives to platelet concentrate as these have added calcium chloride which improves natural thrombin formation for extended release of growth factors, as well as absence of bovine thrombin, thus eliminating the risk of disease transmission. These have an optimum platelet concentration, which improves their biological application.
Autologous platelet concentrates, alone or in combination with several regenerative strategies and biological agents, have shown positive effects in various randomized controlled trials (RCTs). These results suggest their role in improving bone fill and clinical attachment level (CAL). Despite abundant studies on the effectiveness of platelet concentrates, no confirmed conclusion has been established due to inconsistent results and diverse combinations. To the best of our knowledge, no systematic studies have compared and evaluated the differences in regenerative potential of different preparations of platelet concentrates in periodontal regenerative procedures. Therefore, this systematic review aims to compare the regenerative potential of different types of platelet concentrates as sole biomaterial or in combination with other bioactive materials in periodontal defect regeneration.
Search strategy and selection criteria
For the present systematic review, a comprehensive search was conducted on PubMed, Cochrane, and Medline electronic databases including articles published till April 2020. E-published ahead-of-print articles were also included. The last electronic search was carried out on May 2020. The following keywords were used for search: “chronic periodontitis,” “aggressive periodontitis,” “osseous defects,” “furcation defects,” “autologous platelet concentrate,” “platelet rich plasma,” “platelet rich fibrin,” “intrabony defects,” “ L-PRF,”“A-PRF,” “T-PRF,” “ I-PRF,” and “concentrated growth factor.” Language- or time-based stringencies were not applied. References in the relevant articles were manually searched for additional studies. The following journals were searched for relevant literature till April 2020: Journal of Periodontal Research, Journal of Clinical Periodontology, and Journal of Periodontology.
The inclusion criteria were (a) randomized controlled trial (RCT), either of a split-mouth or parallel-group design; (b) comparison of two groups where the presence of two different preparations of platelet concentrates as a sole biomaterial or in combination of platelet concentrates with other biomaterials used for the treatment of periodontal osseous defects; and (c) periodontal variables included were pocket depth (PD), CAL, periodontal intrabony defect (IBD) furcation defects, and radiographic evidence of bone fill as outcomes. The exclusion criteria were (a) follow-up period of <6 months; (c) periodontal IBDs that apically extend with endodontic involvements; and (d) individuals who smoke or those who have systemic diseases possibly affecting the outcomes of periodontal therapy.
Data comprising author information, publication year, study design, sample size, defect characteristics, patient age, follow-up, outcome parameters, and statistical test were evaluated.
The primary outcome was gain in CAL, whereas the secondary outcomes were PD reduction and radiological bone fill.
The qualities of all included RCTs were assessed following Cochrane Reviewer's Handbook. All the included studies were evaluated through sequence generation/randomization, allocation concealment, blinding, and data completeness. Other criteria evaluated were sample size, inclusion and exclusion criteria, baseline comparison, and presence or absence of errors in methodology. The studies were classified as low risk when all the criteria were met, and moderate-or high-risk if 1 or ≥2 criteria were missing, respectively. None of the studies were excluded based on the risk of bias [Table 1].
Overall, 224 studies were found using electronic databases, and an additional 13 studies were identified through other sources. After duplicate removal, forty studies were screened for eligibility, of which thirty studies were excluded after reviewing the title and abstract. Furthermore, three full-text studies were excluded based on the inclusion and exclusion criteria. Finally, seven studies were included in the systematic review. [Figure 1] demonstrates the search strategy for selecting eligible studies.
[Table 2] presents the main findings of the seven studies included in the present systematic review. Three studies compared PRP and PRF; of these, two studies compared combined platelet preparations (PRF + OFD and PRP + OFD), and one compared inter- and intra-group differences. Bone defect fill was evaluated as the primary outcome in two studies, whereas the secondary outcomes included probing depth (PD, n = 2), CAL (n = 3), modified sulcus bleeding index (n = 1), plaque index (PI, n = 3), gingival marginal index (n = 1), sulcus bleeding index (n = 1), probing pocket depth (PPD, n = 1), gingival recession (GR, n = 1), gingival index (GI, n = 1), and IBD depth (n = 1). Low risk of bias was found for two studies, whereas it was moderate for one study.
Two studies reported no significant differences in outcomes between PRF and PRP whereas one study reported a slightly superior effect of PRF over PRP. PRF and PRGF were compared in one study. The outcomes measured were IBD, PD, CAL, PI, and GI. The risk of bias was found low for this study. PRGF group showed higher baseline PD, IBD, and CAL values, though not statistically significant. PRF and T-PRF were compared in three studies. In one study, the outcomes measured were PPD, CAL, PI, and bone defect depth reduction. The risk of bias was found low for this study. No significant differences in the outcomes were observed between PRF and T-PRF. In the other study, the outcomes measured were GI, PI, PPD, relative attachment level, and defect depth reduction. However, efficacy of T-PRF was not significantly superior to that of PRF. The risk of bias was found moderate for this study. In the third study, L-PRF and T-PRF were compared. The primary outcome measured was percentage of defect fill and defect resolution, whereas the secondary outcomes were PI, CAL, PPD, and GI. The risk of bias was low for this study. T-PRF group displayed significantly greater defect fill compared with L-PRF, although other parameters were not significantly different.
The present systematic review aimed to compare the efficacy of different preparations of platelet concentrates in the surgical treatment of periodontal osseous defects based on randomized clinical trials (RCTs). In this systematic review, seven randomized controlled clinical trials met the inclusion criteria. Among the selected seven RCTs, Three studies compared the regenerative potential of PRP and PRF (OFD + PRF/PRP versus OFD). Two studies reported the comparison of PRF and T-PRF (OFD + PRF versus OFD + T-PRF) and only one study reported the comparison of PRF and L-PRF (OFD + PRF vs. OFD + L-PRF) and PRF and PRGF along with xenograft (OFD + xenograft + PRF/PRGF) with respect to periodontal osseous defect management. Overall analysis of the results of the included studies revealed that irrespective of the type of platelet concentrates used, there was a significant improvement in the outcome parameters as compared to baseline in all the studies. In most of the studies, there was a significant difference in outcome measures as compared to control group (i.e., OFD). While comparing different types of platelet concentrates, there was no significant difference in most of the parameters in majority of the studies except in two studies for a period of 9-month follow-up. To our knowledge, there are no systematic reviews comparing the differences in regenerative potential of different preparations of platelet concentrates as sole biomaterial or in combination with other bioactive materials in periodontal defect regeneration in periodontal regenerative procedures. Therefore, a direct comparison with other studies is not possible. Furthermore, it was not possible to perform a meta-analysis of the data because of the heterogeneity of the identified studies. Heterogeneity may also have partially originated from the types of IBDs. In this systematic review, one-, two-, and three-wall IBDs and furcation defects were indiscriminately considered together, whereas the number of intact osseous walls of defects may influence the prognosis of regenerative surgeries. CAL gains after periodontal regeneration seems to be related to native gingival regenerative capacity. Some other heterogeneity from sample size, methods of preparation, adjunct biomaterial used, surgical techniques, and durations of the RCTS also have effects on the results. Herein, three studies compared the differences in regenerative potential of PRP and PRF in periodontal intraosseous defects, of which two studies focused on IBDs and one on Grade II furcation defects. Evidence-based studies on the efficacy of platelet concentrates on furcation defect regeneration are relatively scarce as compared to IBDs. There was a statistically significant improvement in periodontal regenerative effects in both groups, with PRF showing a slightly superior effect in one study with respect to GR parameter in 9-month follow-up. Several randomized controlled trials have reported a positive impact of PRF on bone healing owing to its unique properties as compared to PRP clots. Moreover, synergistic effect for bone regeneration was reported when PRF combined with decalcified freeze-dried bone allograft in IBDs in chronic periodontitis.
The strong fibrin-rich membrane matrix of PRF is more suitable for manipulation and space maintenance. In addition to being placed into the defect, compressed PRF can be used to cover the defect similar to a GTR membrane, serving as a degradable scaffold that facilitates the development of vascularization and guides epithelial cell migration to its surface. A slight superior result was observed in PRF versus PRP in GR parameter owing to its partial fulfillment of GTR membrane characteristics and biological properties. In addition, the presence of anticoagulants in PRP may inhibit wound healing, and its more liquid nature may not support the sustained release of growth factors required for regeneration. Despite the fact that a favorable effect of PRF over PRP was observed in one study, a definite conclusive evidence is lacking due to small sample size and shorter follow in the study analyzed.
Comparison investigating L-PRF and T-PRF revealed a significant advantage of T-PRF over L-PRF as observed through significantly higher defect fills in the latter. These improvements could be explained by thicker fibrin meshwork with higher cellular entrapment, resulted in adequate growth factor release. In addition, longer T-PRF resorption time led to higher cell stimulation, ultimately increasing the osteoprotegerin levels, thus promoting the formation of new bone. However, no significant differences were observed between L-PRF and T-PRF for other outcomes such PD and CAL from baselines to 9 months postoperatively. This could be attributed to small sample size and shorter follow-up as observed in one randomized trial from the studies selected. Additional studies are required to establish the clinical efficacy of T-PRF over PRF.
Comparison between PRGF and PRF in combination with xenografts reported no significant differences, in parameters such as PD, CAL, and IBD depth in 6 months or 9 months. The use of PRGF was claimed to avoid many of the shortcomings of other platelet concentrate preparations. Addition of calcium chloride enhances the formation of natural thrombin, providing a more prolonged growth factor local delivery, which might be essential for proper periodontal wound healing. Many bone grafting materials, such as xenografts and the majority of synthetic materials, have no incorporation of extracellular matrix components or growth factors. Therefore, one hypothesized reason for the additional benefit of including PRF/PRGF to a bone graft could be its new incorporation of regenerative cells and growth factors that contribute to the regenerative process. As only one study reported related results with short follow-up periods, no conclusion about the clinical efficacy of PRF over PRGF could be drawn from this analysis.
Two studies included in this review compared PRF and T-PRF. The clinical parameters and radiographic outcomes showed marked improvement at 9 months with both PRF and T-PRF in the treatment of periodontal osseous defects from baseline values in intragroup comparison. PRF faces the drawback of using glass tubes, which has been modified in T-PRF by using titanium slides, which offers the advantage of increased biocompatibility, as it did not contain silica particles. Furthermore, histologically T-PRF had denser fibrin meshwork as compared to PRF which is giving it an added advantage over PRF. However, in these two studies, no statistical differences were observed between T-PRF and PRF in their clinical and radiological parameters in 9-month follow-up. Hence, the available clinical evidence is scarce to make a decisive statement with respect to periodontal osseous defect regeneration due to the small sample size and relatively shorter follow-ups from these studies analyzed.
There are some limitations for this systematic review. The search process led to the inclusion of only seven articles, the number of which was very small. All of the seven included studies excluded patients who smoked, and therefore, careful patient selection limits the applicability of results in real-world situation. Inconsistent characteristics of platelet concentrates from different studies may have limited the data interpretation as well as to compare the potential effects of different types of platelet concentrates. Various surgical differences such as flap design and surgical techniques should be further evaluated in future studies to better determine optimal surgical approaches when using platelet concentrates in regenerative therapy of IBDs. In order to make a precise assessment on bone regeneration, follow-up of RCTs should have extended more than a year to assess the significant bone fill and linear bone growth. None of the studies have evaluated true bone regeneration via surgical re-entry or histological methods. Unpublished data and language restrictions might have resulted in exclusion of some relevant studies. Henceforth, more large multicenter RCTs with higher sample size, longer follow-up duration, and standardized protocols to eliminate heterogeneities are required to identify the optimal regenerative potential of different types of platelet concentrates.
From this systematic review, we did not find any significant outcome between different platelet concentrates in the management of periodontal osseous defects. Most of the studies show similar effects. Limited evidences favor PRF over PRP and T-PRF over PRF. Hence, more large multicenter RCTs in future with higher sample size with standardized protocols to eliminate heterogeneities would help to make a definitive decision on the regenerative potential of different preparations of platelet concentrates in periodontal regenerative procedures.
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Conflicts of interest
There are no conflicts of interest.
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