Effect of platelet rich fibrin on stability of dental implants: A systematic review and meta-analysis

Introduction

The conventional replacement for lost teeth has been removable and fixed partial or full dentures. The need for a fixed, esthetic, and functional restoration makes dental implants a reliable alternative. Today, dental implants are used to support fixed prosthesis or removable partial-dentures.

Implant stability is essential for the long-term success of implant treatment. It can be divided into primary and secondary types. Primary stability is achieved at implant surgery and is determined by the implant design, the surgical technique, and the density of the bone. Secondary stability is dependent on the tissue response to the implant surgery and an ultimate bone healing.[1] A wide range of articular events and various signaling proteins mediate and regulate the healing process of both hard and soft tissues, respectively. It is known that platelets play a crucial role not only in hemostasis, but also in the wound healing process.[2] Choukroun et al. 2000, developed the production protocol of Platelet rich fibrin (PRF), attempted to accumulate platelets and released cytokines in a fibrin clot.[3]

There are various protocols used to produce platelet concentrates which lead to different products with different characteristics. There are four principal classes of platelet derivatives based on the content of leukocytes and the architecture of fibrin. These are pure platelet-rich plasma, leukocyte and platelet-rich plasma (L-PRP), pure PRF (P-PRF), and leukocyte and PRF (L-PRF). PRF is a second-generation platelet concentrate developed by Choukroun and defined as an autologous L-PRP material.[4]

PRF is inexpensive and quick to prepare and does not require any anticoagulant for preparation.[5] This material provides and stimulates neo angiogenesis.[6] Strong fibrin mesh of PRF prevents it from dissolving fast after application and permits gradual release of growth factors such as platelet-derived growth factor, insulin like growth factor, vascular endothelial growth factor, and transforming growth factor that enhances both angiogenesis and osteoblastic proliferation and differentiation.[7,8]

PRF is considered as a healing biomaterial and it has a robust stimulating effect on various aspects of healing of soft and osseous tissue including angiogenesis, immune control, and harnessing the circulating stem cells.[9-11] PRF efficacy in optimizing and preserving the existing osseous structure and gingival architecture across peri-implant tissue needs to be corroborated. Oncu and Alaaddinoglu in 2015 observed that PRF application appeared to increase implant stability during the early healing period, as evidenced by higher implant stability quotient (ISQ) values and they stated that simple application of this material seems to provide faster osseointegration.[6]

The purpose of this systematic review is to assess the stability of dental implant with and without the use of PRF using Osstell device by radiofrequency analysis.

Methods

According to the preferred reporting items for systematic review and meta-analysis (PRISMA) statement, the study protocol was designed before the start of review. Based on PRISMA guidelines, the population, intervention, comparison, outcome, and study design (PICOS) structure was used to develop the search strategy.

Results

Search and publication characteristics

The searches resulted in 630 publications in total. After screening the titles and abstract according to the inclusion criteria for this review, independently and in duplicate, discarding publications in the process, the literature search identified 265 potential publications in PubMed/Medline, 202 in Cochrane, four in Embase, 89 in Scopus, and 22 in Web of Science. Another 48 records were identified through hand searching and Google Scholar. Following removal of duplicates, 612 publications remained. Following the title and abstract screening, 18 papers were identified as in need of full-text assessment. A total of 10 articles were excluded at this stage leaving a final selection of eight studies for qualitative data extraction and six studies for meta-analysis. The search flow and the article selection process are demonstrated in Figure 1 and the reasons of exclusion of the full text articles are shown in Table 1.

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Figure 1

Flow chart depicting the search strategy and study selection process

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Table 1 Excluded studies and reason for exclusion

Quality assessment of included publications

Eight included studies were RCTs. All studies were of split mouth design which compared implant stability using platelet-rich fibrin versus implant stability without platelet-rich fibrin. Cochrane’s domain-based, two part tool was used to assess risk of bias of each included study. Six studies did not give information about performance bias while two studies assigned of low risk of bias as they have mentioned about the examiner collecting and analyzing the data were blinded to allocation. Four studies mentioned about randomization but no further details, so assigned unclear risk of bias. Three studies did not give any information regarding randomization, so high risk of bias. Only one study mentioned about randomization, so considered under low risk of bias. All included studies were deemed low risk of bias while considering attrition, reporting, and other bias category shown in Figures 2 and 3.

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Figure 2

Risk of bias graph: Judgement about each risk of bias item presented as percentage across all included studies

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Figure 3

Risk of bias summary: Judgement about each risk of bias item for each included studies

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Description of included publications

There were eight studies (Ragab et al. 2013,[15] Oncu et al. 2015,[6] Hussein et al. 2017,[16] Tabrizi et al. 2018,[17] Torkazaban et al. 2018,[18] Diana et al. 2018,[19] Birant et al. 2019,[20] and Oncu et al. 2019)[21] that analyzed total of 153 patients. Immediate implant placement was carried in three of the studies, Ragab et al. 2013, Diana et al. 2018, and Oncu et al. 2019. The implants were placed at least 6 months post-extraction in other five studies. Total of 367 implants were placed in 153 patients. One hundred and eighty-three implants were placed in study group where PRF was given and 184 implants were placed in non-PRF group which served as control. The participants were of age group ranging from 20 to 66 years. A detailed summary of the characteristics of studies is mentioned in Table 2.

Table 2 Study characteristics

Results of individual studies and synthesis of results

Implant stability was reported in all the included studies by means of ISQ values by measurements of RFA by Osstell.

Baseline

At the time of implant insertion, baseline ISQ values were reported by five studies, Oncu et al. 2015,[6] Hussein et al. 2017,[16] Diana et al. 2018,[19] Birant 2019,[20] and Oncu et al. 2019.[21] A forest plot was constructed using a fixed-effect model. Degree of freedom (df) was 4. Tau2 is 0.00 which describes the between study variance. The value of Chi-square is 1.53 which describes the statistical test for heterogeneity. The heterogeneity of the studies at baseline was deemed no heterogeneity as I² = 0%.The confidence interval (CI) estimated at 95% CI for baseline value was found to be −3.55,0.79. As the CI in baseline contained zero, there was no statistically significant difference between two groups at the time of insertion. The P-value is 0.82 which indicates that it is not statistically significant. Pooled results for each study are shown in Figure 4.

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Figure 4

Forest plot of mean difference in Implant stability at baseline immediately post-insertion

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1 week post-insertion

Data at 1-week post-implant insertion were provided by four studies (Oncu et al. 2015, Torkzaban et al. 2018, Birant 2019, and Oncu et al. 2019) and result showed a statistically significant difference in the ISQ values between the two groups in favor of intervention. A random effect model was used to construct a forest plot. I² was calculated to be 76 % (substantial heterogeneity) and df was 3. The p-value for heterogeneity was P = 0.006. Tau² is 7.44 which describes the between study variance. The CI estimated at 95% CI for 1-week post-insertion was found to be 1.22, 7.76. As the CI did not contain zero, there was strong evidence that the treatment was effective favoring the intervention (PRF). Pooled results for each study are shown in Figure 5.

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Figure 5

Forest plot of mean difference in implant stability at 1-week post-insertion

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4-week post-insertion

Five studies (Oncu et al. 2015, Hussein et al.2017, Torkzaban et al. 2018, Birant 2019, Oncu et al. 2019) reported ISQ at 4-week post-implant-insertion and again the difference was deemed statistically significant favoring the intervention group. A forest plot was constructed using a random-effect model. df=4 and P < 0.00001. The pooled MDs was 3.65 with 95% CI of 2.21, 5.09. The results were in favor of the intervention and pooled results for each study are found in Figure 6.

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Figure 6

Forest plot of mean difference in Implant stability at 4-week post-insertion

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8-week post-insertion

Two studies (Hussein et al. 2017, Birant 2019) reported ISQ at 2-month post-implant-insertion and the difference was deemed statistically insignificant (P = 0.05). A forest plot was constructed using a random-effect model. df=1 and P = 0.05. The I² was 0% and was interpreted as no heterogeneity. Tau² is 0.00 which describes the between study variance. The pooled MDs was 3.25 with 95% CI of 0.03, 6.47. The results were statistically insignificant (P = 0.05). The results were in favor of the intervention and pooled results for each study are found in Figure 7.

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Figure 7

Forest plot of mean difference in implant stability at 8-week post-insertion

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12-week post-insertion

Four studies (Hussein et al. 2017, Diana et al. 2018, Birant 2019, and Oncu et al. 2019,) reported ISQ at 3 months post-implant-insertion and the difference was deemed statistically significant favoring the intervention (P = 0.02).A forest plot was constructed using a random effect model with df=3 and P=0.02. The I² was 0% and was interpreted as no heterogeneity.Tau² is 0.00 which describes the between study variance. The pooled MDs was 2.79 with 95% CI of 0.48, 5.10. The results were statistically significant (P = 0.02) favoring the use of intervention (PRF) and pooled results for each study are found in Figure 8.

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Figure 8

Forest plot of mean difference in implant stability at 12-week post-insertion

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Discussion

Implant stability is essential for the long-term success of implant placement. It consists of two variants, mechanical (Primary) and biological (secondary) stability. Simunek et al. placed 90 alkali-treated surface implants interforaminally, whose stability was measured in different time intervals from 1 to 10 weeks, demonstrated that ISQ values were more prominently decreased in the 1^st week post-insertion.[22] Rodrigo et al. presented implant failures of 19% for ISQ <60 and 100% survival for ISQ >60 when measurements were taken before loading.[23] Baltayan et al. demonstrated a correlation between growing ISQ values and increased sensitivity in detection of implant failure. They suggested that the stability of implant with ISQ <60 should be considered questionable while an implant with ISQ >70 should be very stable.[24]

Studies in vitro and in vivo have demonstrated a beneficial effect of PRF on osteoblastic activity. He et al. in their in vitro study of rat osteoblasts concluded that PRF enhanced osteoblastic proliferation and differentiation in a clearer and longer lasting way than PRP.[7] Temmerman et al. described a better quality and quantity of newly formed bone in the PRF-induced growth in comparison to unassisted bone healing in their split mouth RCT micro CT/CBCT quantitative analysis.[25] The present systematic review findings suggest that PRF does not have effect on primary stability of implants, but has a beneficial effect on the secondary stability. The five studies that presented baseline values immediately post-insertion showed no statistical significance between ISQ values of the test and control group. On the other hand, there was a statistically significant increase in secondary stability as this has been demonstrated by four studies in 1^st week, five studies in 4 week, and four studies in 12-week post-implant insertion.

At the present time, numerous protocols have been suggested for production of PRF. There are also different centrifuge machines used with different properties and different results by means of the clot’s content of cells, fibrin, and growth factors release potential. Recent studies have shown that the differences in centrifuge produce different vibration level and lower the vibration level, better the PRF clot produced.[26] Furthermore, the speed of centrifugation is another parameter with an effect to the quality of the clot with a demonstrated superiority of a low speed centrifugation concept with reduction of RCF.[27] Likewise, there has been recent evidence in relation to the different qualities of PRF clots with different types of tubes and different types of centrifugation (horizontal vs. fixed angle).[28,29] As a result, it is yet to be established with combination of the above mentioned parameters. It would produce highest quality product with the highest beneficial potential which would then need to be measured through high quality studies.

The present systematic review suggests that PRF does not have an effect on primary stability of the implants, but has a beneficial effect on secondary stability. Implant stability at 1-week and 4-week post-insertion provided by four studies, (Oncu et al. 2015, Torkzaban et al. 2018, Birant 2019, and Oncu et al. 2019) showed a statistically significant difference in ISQ values favoring PRF group. Four studies (Hussein et al. 2017, Diana et al. 2018, Birant 2019, and Oncu et al. 2019) reported ISQ values at 3-month post-implant-insertion and the difference was statistically significant favoring the PRF group. Although all the seven studies were split mouth RCTs, they were assessed as at high risk of bias overall, as they had at least one domain rated at high risk of bias. The reason that all studies were assessed as at high risk of bias was due to the problems with randomization method, allocation concealment, blinding of participants, and personnel. Six studies had no information regarding blinding of participants and personnel and in one study, participants were not blinded. Despite most studies included in the meta-analysis being assessed as at high risk of bias, we did not downgrade the assessments for Radio frequency analysis (RFA). This is because we believe that further research is very unlikely to change our confidence in the estimate of effect for this outcome. Although there was high heterogeneity for most of the meta-analysis, we did not downgrade this due to consistency of the direction of effect.

To prevent judgments about the eligibility criteria for studies to be included in this review, only the split mouth RCTs were selected. Clarification regarding the types of participants and type of intervention was obtained for inclusion of studies. Amendment for the assessment of the blinding domains in the “Risk of bias” tool to allow studies to obtain a judgment of “low” or “unclear” risk of bias in certain circumstances compared to the blanket judgment of high risk of bias that was stated in the published protocol was done. A hierarchy to guide data extraction and analysis was developed to facilitate data extraction and analysis. Each decision was appropriately justified and was made to improve the scientific quality and clinical applicability of the review. Estimation of the standard deviation was done for two studies that measured radiofrequency analysis at 8 weeks and four studies that measured radiofrequency analysis for 12 weeks using data from the same outcomes measured at the same time point in other similar studies so that we could include it in meta-analysis.

There is variation of the quality of included studies and risk of bias was deemed unclear or high. The moderate number of patients and implants of the included studies could lead to an overestimation of the treatment effect. Another important limitation is the limited number of studies included in this systematic review and the evident heterogeneity among these studies. The different implant types, lengths, and diameters used in the included trials, the different qualities of bone and the resultant insertion torque, different centrifugation protocols, and varieties of centrifugation tubes used bear the risk of compromised results of the overall treatment effect.

There were hardly any reviews of the effect of PRF on implant stability but recently we could find a systematic review by Lyris et al. 2021 accepted for publication in British Journal of Oral and Maxillofacial surgery.[30] Although the results of our meta-analysis are similar to this review, there is broader electronic database with more number of included studies and intervention type. In spite of limitations of this study, the results demonstrate a potential of PRF in shifting the implant stability curve to the left and as a result of that displays a possible implication for clinical practice.

Conclusion

The present systematic review revealed that there is a clinically and statistically significant difference between the stability of implants with and without PRF. Implant stability was enhanced by covering the implant surface with PRF. Thereby displays a possible implication for clinical practice by means of decreasing the time interval needed between implant placement and leading to shorter treatment periods which may improve the implant treatment acceptance.

It would be reasonable to suggest that long follow-up time clinical trials and histologic studies with a greater number of patients and implants placed are needed to reach more definitive conclusions. Interventional designs should be in keeping with the consolidated standards of reporting trials (CONSORT) statement (www.consort-statement.org). Information on various confounding factors should be reported to facilitate multivariable analysis of risk factors. Studies should have proper documentation and follow-up of dropouts, as described by the CONSORT statement.

Finally, a desirable next step would be the conduction of more number of clinical trials on comparing the loading times between a control group and PRF group with loading being performed on a pre-set ISQ value for different populations with proper control selection and adequate sample size. Implant types, lengths, and diameters as well as centrifugation protocols and tubes used for centrifugation should be standardized in these trials and long-term follow-up is needed to reach more definitive conclusions.

Authors’ Declaration Statements