View of Evaluate the Clinical and Radiological Outcomes of Platelet-Rich Fibrin in of Periodontal Intrabony Defects: A Systematic Review and Meta‐Analysis

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Evaluate the Clinical and Radiological Outcomes of Platelet-Rich Fibrin in of Periodontal Intrabony Defects: A Systematic Review and Meta‐ Analysis

HormozDehghani Soltani¹, Farid Abbasi², Navid Ghazipour³, SeyedAmirhosseinMoussavi Jahanabadi⁴, SeyedMasoud Sajedi^5*

1Postgraduate Student, Department of Periodontics, Faculty of Dentistry, Shahed University, Tehran, Iran.

2Associate Professor, Oral Medicine Department, Faculty of Dentistry, Shahed University, Tehran, Iran.

3DDS, Tehran, Iran.

4Postgraduate Student, Department of Periodontics, Faculty of Dentistry, Shahed University, Tehran, Iran.

5Postgraduate Student, Department of Oral and Maxillofacial Medicine, Faculty of Dentistry, Shahed University,

Tehran, Iran.

*Corresponding Author: SeyedMasoudSajedi, Email: [email protected]

ABSTRACT

Background and aim: In the present study, tried to obtain strong evidence by comparing Platelet- rich fibrin in the treatment of both intrabony defects with other treatment methods used for periodontal reconstruction, so the aim of present systematic review and meta‐ analysis was evaluate the clinical and radiological outcomes of Platelet-rich fibrin in of periodontal intrabony defects.

Method: From the electronic databases, PubMed, Embase, Cochrane Library have been used to perform a systematic literature over the last five years between February 2015 and May 2021. For Data extraction, two reviewers blind and independently extracted data from abstract and full text of studies that included.Moreover mean difference with 95% confidence interval (CI), fixed effect model and invariance method were calculated. Random effects were used to deal with potential heterogeneity and I²showed heterogeneity. I² values above 50% signified moderate-to-high heterogeneity. The Meta analysis have been evaluated with the statistical software Stata/MP v.16 (The fastest version of Stata).

Result:A total of 314 potentially relevant titles and abstracts were found during the electronic search, Finally21 studies required for this systematic review. Overall Mean difference of PD and Clinical attachment level between platelet-rich fibrin and control group was 0.65mm (MD, 0.65 95% CI 0.59, 0.71. P= 0.0.00) and 0.23mm (MD, 0.23 95% CI 0.18, 0.28. P= 0.00), Respectively.

Conclusion: The present study shows that open flap debridement / platelet-rich plasma can reduce Probing depth, clinical attachment level and Radiographic bone fill, also lead to clinical improvements.

Keywords: Platelet-rich fibrin, periodontal intrabony defects, open flap debridement, Probing depth

1 INTRODUCTION

One of the most common chronic diseases for humans is periodontal disease, which begins with gingivitis and ends with periodontitis[1, 2]. Studies show that more than 47% of the adult population is affected by periodontal disease, of which 38.5% are in stage III or stage IV [3]. The

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treatment of this disease is of great importance, studies have shown that there is a direct link between periodontal disease and cardiovascular disease, Alzheimer's, diabetes, obesity and preterm labor[4], also this disease is much more difficult to diagnose and regenerate after advanced progression characterized[5]. It is important that periodontal disease is treated promptly to prevent the disease from progressing and to use strategies to repair it[6]. True and complete periodontal reconstruction is complex because it involves a complex interaction of the epithelium, gingival connective tissue, periodontal ligament, and alveolar bone[1, 7]. True periodontal regeneration should also include sharp fibers drawn from the cementum through the periodontal ligament (PROBING DEPTHL) to the closed alveolar bone[8, 9]. So far, studies have suggested the use of various methods such as bone grafting, barrier membranes and biological agents, however, complete periodontal reconstruction is still the most challenging treatment [10-13]. The use of platelet concentrates is one of the strategies reported for regeneration of intrabony defects[14].

Platelet-rich plasma (PRP) was reported as the first irst-generation platelet concentrate, the results of studies showing that the use of anticoagulants in angiogenic and regenerative reactions mediated by platelets[15, 16]. Subsequently, the second-generation platelet concentrate, which was platelet- rich fibrin (Platelet-rich fibrin), was introduced [17-19]. For about two decades, Platelet-rich fibrin has been used in regenerative medicine. Studies have shown that one of the benefits of Platelet-rich fibrin is that following centrifugation, it creates a dense fibrin clot that traps host platelets and leukocytes. And causes more growth factors to be secreted over time [20-22]. Previous systematic reviews of the use of Platelet-rich fibrin in regenerative dentistry have reported that particularly favor soft tissue healing over hard tissue healing[23, 24]. In the present study, tried to obtain strong evidence by comparing Platelet-rich fibrin in the treatment of both intrabony defects with other treatment methods used for periodontal reconstruction, so the aim of present systematic review and meta‐ analysis was evaluate the clinical and radiological outcomes of Platelet-rich fibrin in of periodontal intrabony defects.

2METHODS 2.1 Search strategy

From the electronic databases, PubMed, Embase, Cochrane Library have been used to perform a systematic literature over the last five years between February 2015 and May 2021. The reason for choosing studies in the last five years is to be able to provide sufficient evidence in this area and use newer studies. Therefore, a software program (Endnote X8) has been utilized for managing the electronic titles. Searches were performed with mesh terms:

("Periodontal Abscess"[Mesh]) AND "Surgical Procedures, Operative"[Mesh]) AND "Platelet-Rich Fibrin"[Mesh]) AND "enamel matrix proteins" [Supplementary Concept]) OR "Metformin"[Mesh]) OR "Periodontal Index"[Mesh]) OR "Bone Transplantation"[Mesh]) OR "Diphosphonates"[Mesh]

OR ―statins "[Mesh]) OR ―barrier membrane "[Mesh].

This systematic review has been conducted on the basis of the key consideration of the PRISMA Statement–Preferred Reporting Items for the Systematic Review and Meta-analysis[25], and PICO strategy (Table1).

2.2 Selection criteria Inclusion criteria

1. Randomized controlled trials studies 2. Surgical treatment of bone defects

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3. At least six months follow-up 4. English language

Exclusion criteria

1. In vitro studies, reviews, case-Control Studies, case report and animal studies 2. Incomplete or inconsistent data for the purpose of the present study.

Table1: PICO strategy PECO

strategy Description

P Population: adult patientswith periodontal intrabony defects I Intervention: Platelet-rich fibrin alone or in combination with other

biomaterials

C Comparison: Platelet-rich fibrin versus open flap debridement alone or in combination with other biomaterials.

O Outcome: pocket depth, clinical attachment level, and radiographic bone fill

2.3 Data Extraction and method of analysis

The data have been extracted from the research included with regard to the study, years, study design, Sample Size, intervention group, control group,bone defect type, and outcome. Cochrane Collaboration’s tool [26] used to assessed quality of the RCT studies that included in present meta- analysis. The scale scores for low risk was 1 and for High and unclear risk was 0, Scale scores range from 0 to 6 and higher score means higher quality.

For Data extraction, two reviewers blind and independently extracted data from abstract and full text of studies that included.Prior to the screening, kappa statistics was carried out in order to verify the agreement level between the reviewers. The kappa values were higher than 0.80.

Moreover mean difference with 95% confidence interval (CI), fixed effect model and invariance method were calculated. Random effects were used to deal with potential heterogeneity and I² showed heterogeneity. I² values above 50% signified moderate-to-high heterogeneity. The Meta analysis have been evaluated with the statistical software Stata/MP v.16 (The fastest version of Stata).

3 RESULTS

According to the purpose of the study, in the initial search with keywords, 314 articles were found.

In the first step of selecting studies 311 studies were selected to review the abstracts. Then, studies that did not meet the inclusion criteria were excluded from the study (277 article). In the second step, the full text of 34 studies was reviewed in this step, 13 studies that data extraction is not consistent with the present study were excluded, finally, 21 studies were selected (Figure1).

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3.1 Characteristics

21 studies (Randomized controlled trial) have been included in present article. The Number of male and female patients was 402 and 393, respectively. The Number of patients a total was 795 with mean age of 40.34 years (Table2).

In intervention group used Open flap debridement + Emdogain + Platelet-rich fibrin, Open flap debridement + 1% Metformin, 13, Open flap debridement + Platelet-rich fibrin, Open flap debridement + Platelet-rich fibrin, Open flap debridement + Platelet-rich fibrin + hydroxyapatite, Open flap debridement + bioactive glass + Platelet-rich fibrin, Open flap debridement + Anorganic bovine bone mineral membrane + Platelet-rich fibrin, Open flap debridement + Platelet-rich fibrin/1% Alendronate, Open flap debridement + Platelet-rich fibrin + 1.2% Rosuvastatin and Open flap debridement + Barrier membrane + Platelet-rich fibrin(Table2).

In control group used Open flap debridement + Emdogain, Open flap debridement, Open flap debridement + bioactive glass, Open flap debridement + Anorganic bovine bone mineral membrane, Open flap debridement + bioactive glass, Open flap debridement + demineralized freeze-dried bone allograft, Open flap debridement + hydroxyapatite, Open flap debridement + Autogenous bone graft and Open flap debridement + Barrier membrane(Table2).

Bone defect type in most studies was 2 and 3 walls, in two studies was 1, 2, and 3 walls and in five studies was 3 walls. The range of follow-up period 6-12month with 8.42 months (Table2).

Figure 1:Study Attrition

Table2:Studies selected for systematic review and meta-analysis.

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Study. Years

Stud y desi

gn

Number of patients Mea

n of age (year s)

Intervention group

Control group

Bon e defe

ct type

Follo w-up (mont h) ma

le

fema le Emdogaino

gain vs.

Emdogaino gain + platelet-rich

fibrin

AydemirTu rkal et al.,2016

[27]

RCT 14 14 38.5

25, Open flap debridement +

Emdogain + Platelet-rich

fibrin

24, Open flap debrideme

nt + Emdogain

1, 2, and

3 wall

s

6

platelet-rich fibrin vs.

platelet-rich fibrin + metformin

Pradeep et al.,2015

[28]

RCT 60 60 41

1%

Metformin

nt

3 wall

s 9

open flap debridement

vs. platelet- rich fibrin

Patel et al.,

2017 [29] RCT 4 9 44

Platelet-rich fibrin

nt

1, 2, and

3 wall

s

12

Bajaj et al.,

2017 [30] RCT 9 8 30

27 Open flap debrideme

nt

2 and

3 wall

s

9

Thorat et al., 2017

[31]

RCT 4 9 44

nt

2 and

3 wall

s

12

Pradeep et al., 2017

[32] RCT 34 28 40

Platelet-rich fibrin 20, Open flap debridement +

Platelet-rich fibrin + hydroxyapatit

e

nt

3 wall

s 9

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Ajwani et al., 2017

[33]

RCT 10 10 30.5 20, Open flap debridement +

nt

2 and

3 wall

s

9

bone graft vs. bone

graft + platelet-rich

fibrin

Bodhare et al., 2019

[34]

RCT 11 9 36

bioactive glass + Platelet-rich

fibrin

nt + bioactive

glass

2 and

3 wall

s

6

Sezgin et al., 2017

[35]

RCT 8 7 35

Anorganic bovine bone

mineral membrane +

nt + Anorganic

bovine bone mineral membrane

2 and

3 wall

s

6

Naqvi et al., 2017

[36] RCT 7 3 35

bioactive glass + Platelet-rich

fibrin

nt + bioactive

glass

2 and

3 wall

s

9

Agarwal et al.,2016

[37]

RCT 15 15 52

demineralized freeze-dried

bone allograft/Plate

let-rich fibrin

nt+

deminerali zed freeze- dried bone

allograft 2 and

3 wall

s

12

Elgendy et al., 2015[38]

RCT 10 10 44

hydroxyapatit e + Platelet-

rich fibrin

nt + hydroxyap

atite

2 and

3 wall

s

6

bone graft vs. platelet- rich fibrin

Yajamanya et al., 2017

[39]

RCT 16 16 45 28, Open flap debridement+

bioactive

2 and

3

9

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glass 28, Open flap debridement +

nt wall

s

Galav et al., 2016

[40] RCT 10 10 45

nt + Autogenou

s bone graft

2 and

3 wall

s

9

Chadwick et al., 2016

[41] RCT 20 16 55

nt + deminerali zed freeze- dried bone

allograft 2 and

3 wall

s

6

Mathur et al.,2015

[42] RCT 14 11 40

nt + Autogenou

s bone graft

2 and

3 wall

s

6

Shah et al.,

2015 [43] RCT 10 10 41

nt + deminerali zed freeze- dried bone

allograft 2 and

3 wall

s

6

platelet-rich fibrin + bisphospho

nates

Kanoriya et al., 2016

[44] RCT 43 47 40.3

Platelet-rich fibrin/1%

ALENDRON ATE

nt

3 wall

s 9

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platelet-rich fibrin +

statins

Martande et al., 2016

[45]

RCT 48 48 38

Platelet-rich fibrin + 1.2%

atorvastatin

nt

3 wall

s 9

Pradeep et al., 2016

[46]

RCT 45 45 35

Platelet-rich fibrin + 1.2%

ROSUVAST ATIN

nt

2 and

3 wall

s

9

barrier membrane vs. platelet- rich fibrin

Panda et al., 2016[47]

RCT 10 8 38

Barrier membrane +

nt + Barrier membrane

3 wall

s 9

3.2 Bias assessment

According to Cochrane Collaboration’s tool, four studies had a total score of 6/6, seventeen studies had a total score of 5/6. This result showed High Quality in all studies and judgment low risk of bias in all studies (Table3).

Table3: Risk of bias assessment (Low (+), unclear (?), high (-))

study

Random sequence generation allocation concealment blinding of participants and personnel blinding of outcome assessment incomplete outcome data selective reporting

Total score

AydemirTurkal et

al.,2016 [27] + ? + + + + 5

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Pradeep et al.,2015

[28] 5

Patel et al., 2017

[29] 5

Bajaj et al., 2017 [30]

5

Thorat et al., 2017 [31]

5

Pradeep et al.,

2017 [32] 6

Ajwani et al., 2017 [33]

5

Bodhare et al., 2019 [34]

6

Sezgin et al., 2017 [35]

5

Naqvi et al., 2017 [36]

5 Agarwal et

al.,2016 [37]

5

Elgendy et al., 2015[38]

5

Yajamanya et al.,

2017 [39] 5

Galav et al., 2016

[40] 5

Chadwick et al.,

2016 [41] 5

Mathur et al.,2015 [42]

5 +

+ +

+

+ +

+

+ +

+

+ +

? + +

+ -

+ ? +

+ +

+

+ +

+ + + +

+ +

+

+ +

+ + +

+ +

?

+

?

+

-

+

-

+

-⁺

+

+ ? +

+

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Shah et al., 2015

[43] 5

Kanoriya et al., 2016 [44]

5 Martande et al.,

2016 [45]

6

Pradeep et al., 2016 [46]

6

Panda et al., 2016

[47] 5

3.3 Probing depth (PD)

Overall Mean difference of PD between platelet-rich fibrin and control group was 0.65mm (MD, 0.65 95% CI 0.59, 0.71. P= 0.0.00), among 21 studies and heterogeneity found (I²=94.09%; P

=0.00). According to Figure2, subgroup meta-analysis showed no statistically significant difference between in favor of control group vs platelet-rich fibrin, none of the subgroups showed none of the subgroups showed significant results in favor of the control groups.

3.4Subgroup meta-analysis of event reduction Probing depth Emdogainogain vs. Emdogainogain + platelet-rich fibrin

Mean difference of PD between two groups was 0.20mm (MD, 0.20 95% CI -0.50, 0.90), among one study (Figure2).

Platelet-rich fibrin vs. platelet-rich fibrin + metformin

Mean difference of PD between two groups was 0.90mm (MD, 0.90 95% CI 0.79, 0.100), among one study (Figure2).

Open flap debridement vs. platelet-rich fibrin

Mean difference of PD between two groups was 1.55mm (MD, 1.55 95% CI 1.33, 1.78), among five studies and heterogeneity found (I²=93.71%; P =0.00) (Figure2).

Bone graft vs. bone graft + platelet-rich fibrin

Mean difference of PD between two groups was 0.06mm (MD, 0.06 95% CI -0.06, 0.19), among five studies and heterogeneity found (I²=61.24%; P =0.04) (Figure2).

Bone graft vs. platelet-rich fibrin

+

+ +

+

+ +

+

+ +

+

+ + +

+

+ +

?

+

?

+

+ -

+

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Mean difference of PD between two groups was -0.19mm (MD, -0.19 95% CI -0.40, 0.02), among six studies and heterogeneity found (I²=77.49%; P =0.00) (Figure2).

Platelet-rich fibrin vs. platelet-rich fibrin + bisphosphonates

Platelet-rich fibrin vs. platelet-rich fibrin + statins

Barrier membrane vs. platelet-rich fibrin

Mean difference of PD between two groups was 0.70mm (MD, 0.70 95% CI -0.10, 1.50), among one study (Figure2).

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Figure2:Forest plot showed mean difference of event reduction in PD

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3.5 Clinical attachment level

Overall Mean difference of Clinical attachment level between platelet-rich fibrin and control group was 0.23mm (MD, 0.23 95% CI 0.18, 0.28. P= 0.00), among all studies and heterogeneity found (I²=95.28%; P =0.00). According to Figure3, subgroup meta-analysis showed no statistically significant difference between in favor of control group vs platelet-rich fibrin, none of the subgroups showed significant results in favor of the control groups,except Bone graft vs. platelet- rich fibrin subgroup.

3.6 Subgroup meta-analysis of event reduction Probing depth Emdogainogain vs. Emdogainogain + platelet-rich fibrin

Mean difference of Clinical attachment level between two groups was 0.22mm (MD, 0.22 95% CI - 0.50, 0.94), among one study (Figure3).

Platelet-rich fibrin vs. platelet-rich fibrin + metformin

Mean difference of Clinical attachment level between two groups was 0.87mm (MD, 0.87 95% CI 0.74, 0.100), among one study (Figure3).

Open flap debridement vs. platelet-rich fibrin

Mean difference of Clinical attachment level between two groups was 1.19mm (MD, 1.19 95% CI - 0.04, 1.74), among five studies and heterogeneity found (I²=94.6%; P =0.00) (Figure3).

Bone graft vs. bone graft + platelet-rich fibrin

Mean difference of Clinical attachment level between two groups was 0.00mm (MD, 0.06 95% CI - 0.06, 0.06), among five studies and heterogeneity found (I²=92.87%; P =0.00) (Figure3).

Bone graft vs. platelet-rich fibrin

Mean difference of Clinical attachment level between two groups was -0.45mm (MD, -0.45 95% CI -0.68, -0.12), among six studies and heterogeneity found (I²=0.00%; P =0.45) (Figure3).

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Figure3:Forest plot showed mean difference of reduction in clinical attachment level Platelet-rich fibrin vs. platelet-rich fibrin + bisphosphonates

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Platelet-rich fibrin vs. platelet-rich fibrin + statins

Mean difference of Clinical attachment level between two groups was 0.54mm (MD, 0.54 95% CI 0.25, 0.83), among two studies (Figure3).

Barrier membrane vs. platelet-rich fibrin

3.7Bone graft

Overall Mean difference of Bone graft between platelet-rich fibrin and control group was 0.51 (MD, 0.51 95% CI 0.45, 0.57. P= 0.00), among all studies and heterogeneity found (I²=93.33%; P =0.00).

According to Figure4, subgroup meta-analysis showed no statistically significant difference between in favor of control group vs platelet-rich fibrin, none of the subgroups showed significant results in favor of the control groups.

4 DISCUSSION

The aim of present systematic review and meta‐ analysis was evaluate the clinical and radiological outcomes of Platelet-rich fibrin in of periodontal intrabony defects. All selected studies were RCT, which was high quality studies with low risk of bias. Attempts were made to carefully review the studies conducted in the last 5 years in order to provide sufficient evidence.In the present study, meta-analysis showed that the relative reduction of PD between the experimental and control groups was significant and PD reduction was 0.65 mm. The meta-analysis showed that the clinical attachment level decreased by about 0.23 mm. bone fill was about 0.51% in terms of radiographic examination. The results of subgroup meta-analysis are reported in the findings section. One study showed statistically significantly better results for platelet-rich fibrin(39) and one study showed statistically better results for bone graft(40). Following meta-analysis, it was found that additional use of platelet-rich fibrin to bone graft leads to a statistically significant increase of 0 mm in Clinical attachment level, which is comparable only to bone graft and also has a

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Figure4:Forest plot showed mean difference of event in Bone graft

-statistically significant improvement in radial basis function. Thus, when platelet-rich fibrin was combined with a bone graft substance, some clinical benefits were observed. The potential reasons

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for these findings are probably several factors. Many bone grafts, such as xenografts and most synthetic materials, lack extracellular matrix components or growth factors. Thus, a hypothetical reason for the added benefit of including platelet-rich fibrin to a bone graft could be its new combination with regenerative cells and growth factors that aid in the regeneration process(48).

Studies show that platelet-rich fibrin has the ability to support macrophage polarization M2 and also reduce tissue inflammation(49). Each of the parameters is thought to contribute at least partially to periodontal regeneration when platelet-rich fibrin is used in combination with bone graft(50).The results of the present study showed that statistically significant improvements were observed for Clinical attachment level and Radiographic bone fill in favor of the platelet-rich fibrin group.

Therefore, future research on specific populations of patients may potentially and more specifically target the local use of additional biomolecules (such as bisphosphonates) that support more specific biological activities (anti-degradation properties). And has a more personalized treatment protocol.

In addition, the use of antibiotic therapy in certain patients with invasive periodontitis may benefit from more "personal" antibiotic therapy.Because platelet-rich fibrin may be used as a three- dimensional matrix with long-term delivery of small biomolecules, platelet-rich fibrin may be used as a pharmacotherapy system as previously reported(51). However, how some strategies work, such as adding metformin to PRF, is somewhat unclear. Future research on platelet-rich fibrin as a potential drug system for various local therapeutic agents / biomolecules with a better understanding of them may have further clinical benefits. Currently, the above trends are simply reported in individual RCTs, which requires further research. Platelet-rich fibrin is only commonly used in conventional therapies for the treatment of interosseous defects. It is interesting to note that 27 RCTs have so far evaluated its potential for periodontal regeneration. Periodontal disease is caused by bacterial pathogens and increased growth factors and regenerating cells, and its combination of anti-defense leukocytes is definitely presumed to be beneficial in repairing the defect and potentially reducing tissue inflammation. . In addition, angiogenesis is an important factor in tissue regeneration, and PRF releases a number of anti-angiogenic and profibrotic agents that are able to rapidly increase the periodontal tissue population(52). Since periodontitis is characterized not only by PDL degradation but also by cementum and alveolar bone, ideally in human studies, the regenerative potential of each of these tissues should be further evaluated. In addition, it is surprising that very few experiments involving this research are valid on these instruments: membranes, etc. In addition, there are a number of different surgical procedures for treating infra-bony defects. Previously, it has been shown that a wide variety of surgical approaches have been discussed when using platelet-rich fibrin to treat gingival depression(53).Future research that examines in more detail the various surgical differences, such as flap design and surgical techniques, should be further evaluated in future studies to better determine the optimal surgical techniques when using platelet-rich fibrin in the treatment of infra-bony defects resuscitation.

5CONCLUSIONS

The present study shows that open flap debridement / platelet-rich plasma can reduce Probing depth, clinical attachment level and Radiographic bone fill, also lead to clinical improvements.

Comparable results are obtained. Future research may be needed to evaluate the use of platelet-rich plasma in combination with other additional small biomolecules such as metformin, bisphosphonates, statins, and / or antibiotics to improve clinical outcomes. In addition, histological evidence from animals and humans is needed to investigate whether platelet-rich plasma actually leads to periodontal regeneration.

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