Effectiveness of autologous platelet-rich fibrin in the treatment of intra-bony defects: A systematic review and meta-analysis.

The aim of the present meta-analysis is to determine the clinical and radiographic outcomes of using platelet-rich fibrin (PRF) for the treatment of periodontal intra-bony defect (IBD) compared with open flap debridement (OFD). MEDLINE/PubMed, EBSCO and Cochrane database were used to identify studies in English language published from January 1, 2005 to January 31, 2013. An additional hand search of the relevant journals and of the bibliographies of the paper identified was also performed. Articles retrieved were screened using specific inclusion criteria by five independent reviewers: Studies investigating the effect of platelet concentrate in surgical procedure for the treatment of periodontal intra osseous defects compared with the control group in which platelet concentrate was not used were included. Five relevant articles were selected for the meta-analysis of which 3 articles were retrieved after electronic search and two articles were included after hand search. The number of patients in studies ranged from 15 to 62 (32-90 sites) with mean age ranging from 29.47 to 39.7. A total of 298 sites were treated using PRF either in combination with graft or as a monotherapy in comparison to traditional OFD procedure. The meta-analysis showed a standard mean difference of 0.95 mm; 95% confidence interval (CI): 0.20-1.71 in clinical attachment level (CAL) and 2.33 mm; 95% CI: 1.43-3.23 in IBD after treatment of IBD with PRF compared with OFD. The meta-analysis showed clinically significant improvements in periodontal parameters such as CAL, IBD, and reduction in probing depth when IBDs were treated with PRF alone when compared to OFD.

INTRODUCTION

The primary goal of periodontal treatment is the maintenance of the natural dentition in optimum health and function. Reproduction or reconstitution of a lost or injured part to restore the architecture and function of the periodontium becomes the integral part of comprehensive periodontal therapy. Conventional open flap debridement (OFD) falls short of regenerating tissues destroyed by the disease, and current regenerative procedures offer a limited potential towards attaining complete periodontal restoration. Various biomaterials, based on endogenous regenerative technology,[1] have been used for periodontal tissue regeneration in addition to autogenous and allogenic bone grafts, but not a single graft material is considered as a gold standard in the treatment of intra-bony defects (IBD).

Of late, there is substantial increase in the evidence demonstrating the effectiveness of growth and differentiation factors in periodontal regeneration. The growth factors present in the alpha granules of platelets such as platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), endothelial growth factor, vascular endothelial growth factor (VEGF), and insulin growth factor-1 have shown to possess potential for enhanced and accelerated hard and soft tissue regeneration.[2345]

Platelet-derived growth factor along with bone morphogenetic proteins are among the most researched growth factors in periodontal regeneration. Various clinical and experimental studies have demonstrated the effectiveness of different PDGF.[67]

Clinical data reveal that this biomaterial may be a favorable matrix for the development of a coherent healing without inflammatory excess. Platelet-rich fibrin (PRF) affects biologic activities at cellular levels. The main angiogenesis soluble factors such as fibroblast growth factor-basic, VEGF, angiopoietin and PDGF are included in fibrin gel.[8] Fibrin and fibrinogen degradation products stimulate the migration of neutrophils, thus adding to the immune node property of PRF. Fibrin, fibronectin, PDGF, and TGF-β, present in PRF, are essential to modulate integrin expression, fibroblast proliferation and migration, thus aiding in healing. Hence, the clinician can expect less postsurgical discomfort, more rapid soft tissue healing with less edema compared with other techniques, and a relatively unlimited source of graft material.[910111213]

Platelet-rich fibrin has shown predictable outcomes when compared to different types of platelet concentrates.[14] Taken together, the available clinical evidence can be confounding for the clinicians. Therefore, the aim of the present evidence based systematic review and meta-analysis is to determine the clinical and radiographic outcomes of using PRF for the treatment of periodontal IBDs compared to OFD.

MATERIALS AND METHODS

Search strategy

A search was performed in the electronic databases of MEDLINE/PubMed, EBSCO and Cochrane databases using the following keywords – (PRF OR platelet derivatives OR autologous platelet concentrate OR platelet growth factor OR autologous growth factor) AND (periodont * OR periodontal regeneration OR IBDs) NOT Implant from January 1, 2005 to January 31, 2013. Filters used were human studies, English language and randomized control trial (RCT), clinical trials, and controlled clinical trials. The reference lists of identified relevant articles were hand searched for possible additional studies.

Inclusion/exclusion criteria

Studies investigating the effect of PRF in the treatment of periodontal intraosseous defects were included. The studies having a test group using PRF alone and a control group with OFD alone were included. No limitations were placed regarding the number of patients treated but follow-up of minimum 6 months was required. Study designs such as case series, case reports, retrospective studies, technical studies, animal studies and reviews were excluded.

Data extraction

The titles and the abstracts of all articles were screened independently by five reviewers for potential selection of articles based on the predefined inclusion/exclusion criteria. When title and abstract of an article did not provide sufficient information to make a decision, the full text was obtained and examined. The studies that did not meet the inclusion criteria were excluded. In case of disagreement a joint decision was achieved after discussion. The full text of all the included studies was obtained. Parameters of included studies were examined and relevant data was extracted.

Primary outcome variable

The primary outcome variables to determine periodontal regeneration considered for this meta-analysis were the changes in clinical attachment level (CAL) and changes in the depth of IBD measured at baseline and final follow-up.

Secondary outcome variable

Other clinical variable considered were changes in probing depth (PD) and changes in gingival margin position (GMP) at the baseline and the final follow-up.

Quality assessment of included studies

The internal quality of trials was assessed based on the Cochrane collaborations’ tool for assessment of bias, but no study was excluded for its risk of bias. The assessment criteria were randomization, concealment, blinding of the examiner, completeness of follow-up and explanations of drop-outs, similarity of groups at baseline. All criteria were judged as adequate, unclear, or not adequate. When all criteria except concealment (as it is not possible to conceal the treatment from the surgeon) were met, the risk of bias was estimated as low. Other than concealment, if more than one criterion was partially fulfilled, moderate risk of bias was assigned and when two or more criteria were not met, a high risk was assigned.

Data synthesis and statistical methods

A summary table was constructed using information collected on data-extraction forms. Pooled data was analyzed in a descriptive format. Studies were analyzed for similarities and their suitability for meta-analysis. A meta-analysis was performed using software “Open Meta Analyst”. A test for heterogeneity of included studies was performed and I2 was obtained. The test showed evidence of a statistically non-significant heterogeneity. A fixed-effects model was used to cope-up with differences in variance among studies. Similarly, differences among studies led to the use of a standardized mean difference as an alternative to the weighted mean difference as an estimate of differences among groups.

RESULTS

The five relevant studies were retrieved after the systematic search of the literature.[1516171819] Three relevant articles were retrieved after electronic search[151819] and two relevant articles were included after hand search,[1617] which were added in final list [Figure 1].

Figure 1

Results of the search

Characteristics of the participants

There was not much variation in the size of included studies. The number of patients in studies ranged from 15 to 62 patients (32-90 sites). The mean age of the subjects included ranged from 29.47 to 39.7. Most of the studies reported the subjects had already completed an initial course of periodontal therapy, including oral hygiene instructions and full-mouth scaling. Most of the studies reported that the participants were non-smokers, whereas one of the studies did not clearly mention about the smoking status of the participants. Subjects were generally categorized into chronic and aggressive periodontitis patients and only chronic periodontitis patients were included in the studies.

Characteristics of the defects

A total of 298 sites were treated. The inclusion criteria for a defect was radiographic evidence of an IBD >3 mm and interproximal PD ≥ 5 mm in four of the studies.[15161718] One study[19] was a split-mouth study where presence of paired, interproximal IBDs with PD ≥ 6 mm and CAL loss >5 mm and osseous depth >4 mm were considered.

Four of the selected studies[15161718] excluded furcation defects and considered vital and asymptomatic teeth whereas one of the study[19] did not mention anything regarding the same. The studies included all teeth except for one study[15] that included only first and second mandibular molars. Teeth with mobility ≥ Grade 2 were excluded in some of the studies.[161718]

Characteristics of the interventions

All the studies used PRF as a monotherapy in comparison to the traditional OFD procedure. One study used hydroxyapatite[18] as the graft material while another study compared efficacy of PRF to PRP.[17]

Platelet-rich fibrin was prepared following the protocol developed by Choukroun et al.,[10] with no variations in the centrifugation method (3,000 revolutions [equivalent 400 × g] per minute for 10 min) whereas PRP was prepared following the protocol developed by Lekovic et al.[20] One part of the PRF of the required size was filled into the defect, while the other part was used as a membrane to cover the defect. Autologous PRP in the form of gel was packed into the defect.

In all of the included studies, after the surgery the mucoperiosteal flaps were repositioned and secured in place using a 3-0 or 4-0 non-absorbable silk surgical suture. Interrupted or sling sutures were placed after the surgery followed by using a periodontal dressing. Suitable antibiotics (amoxicillin 500 mg) and analgesics (ibuprofen 400 mg/800 mg, paracetamol 500 mg) along with chlorhexidine rinses were prescribed in most of the studies.

In addition to the above mentioned procedures, one[19] of five selected studies used visual analog score to compare the patient's response to PRF and OFD treatment and the results showed that PRF resulted in slightly better results in experimental group for pain and healing.

Design and quality of included trials

All included trials reported adequate randomization while allocation concealment was ensured only in one trial.[16] Proper blinding was done in all studies and two trials[1519] had not reported any loss to follow-up. Baseline characteristics for periodontal parameters were similar in both the groups for all the included trials [Table 1]. Using Cochrane tool for assessing risk of bias, only one study[16] had low risk of bias whereas others had moderate risk of bias [Table 2].

Table 1

Details of design of included studies

Table 2

Quality analyses of included studies

Outcomes

Gain in clinical attachment level

Gain in CAL was reported in all studies. Gain in attachment observed in PRF group ranged from 3.03 ± 1.16 mm[18] to 4.73 ± 0.88 mm[19] and in OFD group it was 1.40 ± 1.06 mm[19]-2.83 ± 0.91 mm[17] [Table 3]. Gain in CAL was significant in intervention group treated with PRF compared with the control group in continuous fixed-effect model (standard mean difference [SMD]: 0.95; 95% confidence interval [CI]: 0.20-1.71) in all five included studies with nonsignificant heterogeneity (I2 = 86%, Q = 29.11, P < 0.001) [Figure 2].

Table 3

Changes in primary and secondary outcomes in the included studies

Figure 2

Results of meta-analysis for gain in clinical attachment level

Radiographic parameters

All five studies reported reduction in IBD and four[15161718] have also reported bone fill. PRF demonstrated significant difference when compared with OFD. Reduction in IBD when treated with PRF was reported between 1.93 ± 1.07 mm[19] and 3.20 ± 0.89 mm[18] where bonefill (%) was obtained after treatment with PRF ranged between 46.9%[15] and 56.46 ± 9.26%.[19] Range of IBD reduction and bone fill percentage in OFD group were 0.09 ± 0.11 mm[16]-1.24 ± 0.69 mm[15] and 1.56% ±15.12%[18]-28.66%[15] respectively [Table 2]. Significant reduction in IBD was found in intervention group treated with PRF compared to control group in continuous fixed-effect model (SMD: 2.33; 95% CI: 1.43-3.23) in all five included studies with significant heterogeneity (I2 = 86%, Q = 28.50, P < 0.001) [Figure 3].

Figure 3

Results of meta-analysis for reduction in depth of intra-bony defect

Reduction in probing depth

All five included studies had reported reduction in PD as clinical parameter to check efficacy of PRF. All results showed statistically significant improvement (P < 0.05). Reduction in PD reported in PRF group ranged from 3.77 ± 1.19 mm[18] to 4.69 ± 1.45 mm[15] and the same in OFD group was 2.40 ± 0.63 mm[19]-3.56 ± 1.09 mm[15] [Table 2]. Reduction in PD was significant in intervention group treated with PRF compared to control group in continuous fixed-effect model (SMD: 1.10; 95% CI: 0.56-1.64) in all five included studies with nonsignificant heterogeneity (I2 = 73%, Q = 14.59, P = 0.006) [Figure 4].

Figure 4

Results of meta-analysis for reduction in probing depth

Recession (gingival marginal position)

Difference in gingival marginal position were reported in all included studies and four out of them had compared the change in PRF group with OFD and found statistically significant results. Only one study15 had not statistically analyzed the difference. Difference observed in PRF group ranges from − 0.07 ± 0.26 mm[19] to 0.47 ± 0.73 mm,[18] while the same OFD group ranged from − 0.17 ± 0.53 mm[18] to 1.13 ± 0.74 mm[19] [Table 2]. Change in gingival marginal position was not significant in intervention group treated with PRF compared to control group in continuous fixed-effect model (SMD: −0.71; 95% CI: −2.08-0.65) in all five included studies with significant heterogeneity (I2 = 96%, Q = 56.95, P < 0.001) [Figure 5].

Figure 5

Results of meta-analysis for changes in gingival margin position

DISCUSSION

The regeneration of the lost periodontal structures is the ultimate aim of the periodontal therapy in order to restore the health, function and esthetics of periodontium.

The present systematic review and meta-analysis aimed to evaluate the clinical and radiological effectiveness of autologous PRF in the management of IBDs in chronic periodontitis patients. The scientific literature in the English language up to and including January 2013 was searched for RCT. To best of our knowledge, till date there is no published meta-analysis comparing PRF with OFD in chronic periodontitis patients.

The assessment of the quality of the study revealed moderate risk of bias. The results of the systematic analysis did not demonstrate any significant heterogeneity among different studies in relation to study design, surgical techniques, outcome variables, patient follow-up durations and method of preparation of PRF.

The CAL and IBD were used as primary variables for evaluation and the PD and GMP were used as secondary outcome variables. All the variables showed overall positive effects.

Summary of main results

Reduction in IBD and gain in CAL are the major clinical outcomes to determine success of regenerative periodontal therapy. All the included RCTs except one[15] performed the statistical analysis to compare the IBD and CAL and they observed statistically significant difference for IBD but not for CAL. The meta-analysis showed SMD for reduction in IBD as 2.33 (1.43, 3.23). The meta-analysis result for gain in CAL was found to be 0.95 mm (0.20, 1.71). Pradeep et al.[17] had also compared PRF with PRP and the difference was non-significant for CAL as well as IBD.

Probing depth reduction is the most desirable outcome variable of periodontal therapy. It is also the most important parameter in patient care for the treatment and maintenance thereof. A statistically significant difference was seen in four RCT[16171819] for reduction in probing depth. The comparison was nonsignificant in a study, which compared PRP with PRF.[17] The meta-analysis demonstrated SMD for reduction in PD as 1.10 mm (0.56, 1.64).

Gingival marginal position is one of the significant clinical parameter as it has direct impact on esthetics and long-term stability of the periodontal therapy. The results of included RCTs showed statistically significant difference when change in GMP in both the groups were evaluated except for one RCT,[15] which had not analyzed the difference statistically. Two RCTs favored OFD group[1619] where other two are in favor of PRF group.[1718] The difference was non-significant in a study comparing PRP with PRF.[17] The meta-analysis also showed the SMD for difference in GMP was − 0.71 (−2.08, 0.65).

Analysis of study design and quality assessment

All included trials reported adequate randomization while allocation concealment was ensured only in one trial.[16] Proper blinding was done in all studies and two trials[1519] had not reported any loss to follow-up. Baseline characteristics for periodontal parameters were similar in both the groups for all the included trials. Using Cochrane tool for assessing risk of bias, all have moderate risk of bias.

Limitations of the present systematic review and meta-analysis

One of the primary limitations of this analysis is the inclusion of only English language RCTs. The reviewers were not able to procure any unpublished data or data from any ongoing trials.

CONCLUSION

The systematic appraisal of current evidence of PRF in IBDs has confirmed the benefits and advantages of using PRF alone compared to OFD. This meta-analysis showed a standardized mean difference of 0.95 mm in CAL (0.20-1.71) and 2.33 mm for IBD (1.43, 3.23) after treatment of IBDs with PRF when compared to OFD.

Clinical implications

This meta-analysis showed clinically significant improvements in the periodontal parameters like CAL, IBD and reduction in PD when IBDs were treated with PRF alone compared to OFD. As PRF is easy to obtain autologous material, effective and user friendly, can be more widely used in periodontal regeneration.

Implications for future research

Efficacy of PRF can be studied and compared with other bone graft materials alone or as combination. The effectiveness of PRF can also be researched for other indications like furcation involvement, gingival recession, socket preservation, etc., Patients’ preference can also be analyzed as well as economic analysis can be performed in future. Evidence based systematic review and meta-analysis can be performed to include all published/unpublished data in all languages.