HEALING POTENTIAL OF PLATELET-RICH FIBRIN IN THIRD MOLAR SOCKETS ON BOTH SIMPLE AND SURGICAL EXTRACTIONS WITH PRESERVATION OF SOFT TISSUE HEALING AND POSTOPERATIVE COMPLAINTS: A SYSTEMATIC LITERATURE REVIEW

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Sivan Najar

5th Course, Group 12

HEALING POTENTIAL OF PLATELET-RICH FIBRIN IN

THIRD MOLAR SOCKETS ON BOTH SIMPLE AND

SURGICAL EXTRACTIONS WITH PRESERVATION OF

SOFT TISSUE HEALING AND POSTOPERATIVE

COMPLAINTS:

A SYSTEMATIC LITERATURE REVIEW

Master’s Thesis

Supervisor: DDS, PhD Povilas Daugėla

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FINAL MASTER‘S THESIS IS CONDUCTED

AT THE DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY

STATEMENT OF THESIS ORIGINALITY

I confirm that the submitted Final Master‘s Thesis “Healing Potential of Platelet-Rich Fibrin in Third Molar Sockets on Both Simple and Surgical Extractions With Preservation of Soft Tissue

Healing and Postoperative Complaints: systemic review”

1. Is done by myself.

2. Has not been used at another university in Lithuania or abroad.

3. I did not used any additional sources that are not listed in the Thesis, and I provide a complete list of references.

I confirm by e-mail, and the work will be signed after the end of the quarantine and emergency situation due to the COVID-19 pandemic in the republic of Lithuania.

(2021/04/29) (Sivan Najar) ) (signature)

CONCLUSION OF FINAL MASTER‘S THESIS ACADEMIC SUPERVISOR

ON THE DEFENSE OF THE THESIS

(2021/04/29) (Povilas Daugėla) (signature)

FINAL MASTER‘S THESIS IS APPROVED AT THE DEPARTMENT

(date of approval) (name of the Department and full name of the Head of the Department) (signature)

Final Master‘s Thesis reviewer

(full name) (signature)

Evaluation of Final Master‘s Thesis Defense Board:

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

FACULTYOFODONTOLOGY

CLINIC OF ORAL AND MAXILLOFACIAL SURGERY

HEALING POTENTIAL OF PLATELET-RICH FIBRIN IN THIRD MOLAR SOCKETS ON BOTH SIMPLE AND SURGICAL EXTRACTIONS WITH PRESERVATION OF SOFT

TISSUE HEALING AND POSTOPERATIVE COMPLAINTS

Master’s Thesis

The thesis was done

by student Supervisor

Sivan Najar Povilas Daugėla

5th_{year DDS, PhD}

29th_{of April 2021 29}th_{of April 2021}

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EVALUATION TABLE OF THE MASTER’S THESIS

OF THE TYPE OF SYSTEMATIC REVIEW OF SCIENTIFIC LITERATURE

Evaluation: ... Reviewer: ...

(scientific degree. name and surname) Reviewing date: ...

No. MT parts MT evaluation aspects

Compliance with MT requirements and evaluation Yes Partially No 1 Summary (0.5 point)

Is summary informative and in compliance with the thesis

content and requirements? 0.3 0.1 0

2 Are keywords in compliance with the thesis essence? 0.2 0.1 0

3

Introduction, aim and tasks

(1 point)

Are the novelty, relevance and significance of the work

justified in the introduction of the thesis? 0.4 0.2 0

4 Are the problem, hypothesis, aim and tasks formed

clearly and properly? 0.4 0.2 0

5 Are the aim and tasks interrelated? 0.2 0.1 0

6 Selection criteria of the studies, search methods and strategy (3.4 points)

Is the protocol of systematic review present? 0.6 0.3 0

7

Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language, publication condition, etc.)

0.4 0.2 0

8

Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and is the last search day indicated?

0.2 0.1 0

9

Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and selected articles according to the combinations of keywords)?

0.4 0.1 0

10

Is the selection process of studies (screening, eligibility, included in systematic review or, if applicable, included in the meta-analysis) described?

0.4 0.2 0

11

Is the data extraction method from the articles (types of investigations, participants, interventions, analyzed factors, indexes) described?

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12

Are all the variables (for which data were sought and any assumptions and simplifications made) listed and defined?

0.4 0.2 0

13

Are the methods, which were used to evaluate the risk of bias of individual studies and how this information is to be used in data synthesis, described?

0.2 0.1 0

14 Were the principal summary measures (risk ratio,

difference in means) stated? 0.4 0.2 0

15

Systemization and analysis

of data (2.2 points)

Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented?

0.6 0.3 0

16

Are the characteristics of studies presented in the included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented?

0.6 0.3 0

17

Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect estimates and confidence intervals)

0.4 0.2 0

18 Are the extracted and systemized data from studies

presented in the tables according to individual tasks? 0.6 0.3 0

19

Discussion (1.4 points)

Are the main findings summarized and is their relevance

indicated? 0.4 0.2 0

20 Are the limitations of the performed systematic review

discussed? 0.4 0.2 0

21 Does author present the interpretation of the results? 0.4 0.2 0

22

Conclusions (0.5 points)

Do the conclusions reflect the topic, aim and tasks of the

Master’s thesis? 0.2 0.1 0

23 Are the conclusions based on the analyzed material? 0.2 0.1 0

24 Are the conclusions clear and laconic? 0.1 0.1 0

25

References (1 point)

Is the references list formed according to the

requirements? 0.4 0.2 0

26 Are the links of the references to the text correct? Are the

literature sources cited correctly and precisely? 0.2 0.1 0

27 Is the scientific level of references suitable for Master’s

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28

Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%?

0.2 0.1 0

Additional sections, which may increase the collected number of points

29 Annexes Do the presented annexes help to understand the analyzed

topic? +0.2 +0.1 0

30

Practical

recommen-dations

Are the practical recommendations suggested and are

they related to the received results? +0.4 +0.2 0

31

Were additional methods of data analysis and their results used and described (sensitivity analyses, meta-regression)?

+1 +0.5 0

32

Was meta-analysis applied? Are the selected statistical methods indicated? Are the results of each meta-analysis presented?

+2 +1 0

General requirements, non-compliance with which reduce the number of points

33

General requirements

Is the thesis volume sufficient (excluding annexes)?

15-20 pages (-2 points)

<15 pages (-5 points)

34 Is the thesis volume increased artificially? -2 points -1 point

35 Does the thesis structure satisfy the

requirements of Master’s thesis? -1 point -2 points

36 Is the thesis written in correct language,

scientifically, logically and laconically? -0.5 point -1 points

37 Are there any grammatical, style or computer

literacy-related mistakes? -2 points -1 points

38 Is text consistent, integral, and are the

volumes of its structural parts balanced? -0.2 point -0.5 points

39 Amount of plagiarism in the thesis. >20%

(not evaluated)

40

Is the content (names of sections and sub-sections and enumeration of pages) in compliance with the thesis structure and aims?

-0.2 point -0.5 points

41

Are the names of the thesis parts in compliance with the text? Are the titles of sections and sub-sections distinguished logically and correctly?

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42 Are there explanations of the key terms and

abbreviations (if needed)? -0.2 point -0.5 points

43 Is the quality of the thesis typography (quality

of printing, visual aids, binding) good? -0.2 point -0.5 points

*In total (maximum 10 points):

*Remark: the amount of collected points may exceed 10 points.

Reviewer’s comments: ___________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ _________________________________________ ___________________________

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SUMMARY

Introduction: The purpose of this study was to evaluate the impact of platelet-rich fibrin (PRF) on the healing potential in a third molar socket on both simple and surgical extractions with preservation of soft tissue healing and postoperative complaints.

Materials and methods: The search of all chosen publications for the performed review was done in databases including PubMed/Medline, Cochrane, Google Scholar and manual search in the electronic Journal of Oral & Maxillofacial Research. Data were extracted from the full articles after the screening of the abstracts and titles, according to PRISMA guidelines. Reports included studies on humans and published in the English language from January 2011 until February 2021.

Results: A total of 243 articles were screened from which two prospective clinical studies and five randomized controlled trials met the inclusion criteria and were included in the final data synthesis. A total of 360 extractions of mandibular third molar were placed in 232 patients that participated in the included studies. The follow-up period ranged from the 1st postoperative day to 6 months. In this literature review, the majority of articles reported improvement of soft tissue healing and decrease in patient sign and symptom of pain, swelling, trismus, oedema and neighbouring tooth sensitivity using the application of PRF.

Conclusion: Within limitations of this systematic review the application of PRF demonstrated benefits in promoting soft tissue healing and reduction of patient postoperative complaints after the third molar removal. Nevertheless, additional studies with a larger sample size and longer follow up duration are needed to facilitate more conclusive results and evidence of the efficacy of PRF in the promotion of soft tissue healing and reduction of postoperative complaints.

Keywords: platelet-rich fibrin, leukocyte- and platelet-rich fibrin, third molar, tooth extraction, postoperative complaints, soft tissue healing.

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10

INTRODUCTION

Nowadays, healing of both hard and soft tissues has become one of the great challenges faced in dental clinical research in developing bioactive surgical additives responsible for regulating inflammation and increasing healing [1]. Among this, removal of mandibular third molar is common and frequent surgery performed by dental surgeons in daily clinic [2]. Third molar extraction is

associated with clinically significant postoperative morbidity including swelling, pain, trismus, fever, and infection, which influence the patient quality of life in the immediate postoperative period [3]. The main goal in mandibular third molar extraction procedure is to remove the tooth with minor consequences and complication-free treatment, and by that to reduce the postoperative outcomes and the patient discomfort to the lowest grade level. Therefore, different strategies have been developed to reduce the risk of these complications and improve tissue healing, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), cryotherapy, compression, soft laser, piezo surgery and eventually, platelet concentrates [4].

In recent years, the use of platelet concentrates to promote wound healing and reduce postoperative complaints has aroused particular interest among scientists and include procedures as the implantation of platelet-rich fibrin/leukocyte- and platelet-rich fibrin (PRF/L–PRF) immediately after tooth extraction. Platelet-rich fibrin was first introduced in 2001 by Joseph Choukroun et al. in France [5].

Choukroun used autologous whole blood to establish a platelet-rich fibrin clot with a centrifuge. It does not require any addition and averts of any kind of material compared to platelet-rich plasma (PRP), which needs biochemical modification, and its cost and preparation method are considered limiting factors for its routine use [6]. The platelet-rich fibrin (PRF) is produced through immediate centrifugation, after blood collection, and without the addition of anticoagulant [7], which overcomes the legal issues of concern in handling blood or blood products outside the body and their re-implantation [8].

PRF, a second-generation platelet concentrate, has been widely used to accelerate soft- and hard-tissue healing [9,10]. PRF is a bioactive material that collecting platelet concentrate on a single fibrin membrane, containing all the constituents of blood favorable for healing and immunity [11].

This autologous blood-derived biomaterial creates a slow polymerization process during the PRF preparation, which is similar in the manner of natural healing, and generates a fibrin network that

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11 enhances cell migration and proliferation, as well as increased concentrations of essential growth factors and cytokines that will assist in tissue repair, especially concerning soft tissue healing [2,10]. Viable platelets in PRF have shown to release various growth factors [GFs]: transforming growth factor beta (TGF–阝1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), leukocytic cells and their cytokines (interleukin 1β, IL-6, IL-4) and tumor necrosis factor α (TNF α). PRF was also shown to stimulate proliferation and enhancement in osteoblasts, fibroblasts, and keratinocytes as well as release of these mediators by the PRF [2,12,13]. The effects of PRF have already been assessed in vitro, in vivo and clinical studies. PRF has multiple applications in implant and dentoalveolar surgery. The autologous fibrin-matrix conducted as a resorbable membrane and was primarily used in implantology, but at the present day, PRF is utilized in many disciplines of dentistry [14]. PRF may be used alone or combined with bone grafts as socket preservation after extraction of teeth and for treatment of periodontal bony defects, implant placement for adequate osseous regeneration and soft tissue healing [15]. PRF is used to enhance tissue healing and to minimize postoperative inflammatory complications after mandibular third molar extractions [10].

PRF have shown evaluations that indicated better postoperative and substantial improvements in soft tissue healing and pain reduction, employing tools such as the Landry index for soft tissue repair, and the Visual Analogue Scale (VAS) for pain. These analyses contribute to a qualitative assessment related to the patient recovery in the postoperative period. The beneficial effect of the subtract postoperative discomfort may be supposed to the continuous release of growth factors, previously described by different in vitro studies [2]. However, there is a lack of information on the release of growth factors and cytokines by the placement of PRF in the management of lower third molar extractions and their association with improving soft tissue healing and pain. The assessment of the local release of the growth factors and cytokines is challenging to invert from in vitro to clinical settings, and several methods using swab extraction method and tapes have been successfully used in clinical studies [13,14].

The purpose of the preceding systematic review was to evaluate the impact of platelet-rich fibrin on the healing potential in third molar socket on both simple and surgical extractions with preservation of soft tissue healing and reduction of postoperative complaints.

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12 Task: To compare soft tissue healing and postoperative complains (pain, swelling, trismus, oedema, and neighbouring tooth sensitivity) in third molar extraction procedure with application of PRF and regular third molar extractions (without application of PRF) by the means of systematic literature review.

Hypothesis: This systematic review hypothesizes that the administration of autologous platelet-rich fibrin may promote soft tissue healing and reduce postoperative complaints such as pain, swelling, trismus, oedema, and neighbouring tooth sensitivity.

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13

1. SEARCH METHODS AND STRATEGY

1.1 Protocol and registration

The protocol for this systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement [16]. Approval was acquired by the local bioethics committee (No. BEC-OF-77).

1.2 Focus Question:

The focus question was developed by using the population, intervention, comparison, and the outcome framework, which is presented in Table 1 (PICO):

Does the administration of autologous platelet-rich fibrin may promote soft tissue healing and reduce postoperative complaints such as pain, swelling, trismus, oedema, and neighbouring tooth sensitivity?

Table 1. PICO framework of the framed clinical question.

Component Description

Population (P) Patients ≥18 years of age requiring extraction of mandibular third molar.

Intervention (I) Simultaneous application of platelet-rich fibrin in patients that were subjected to extraction of mandibular third molar.

Comparison (C) Platelet-rich fibrin placement in the area of the mandibular third molar extraction versus control group – for natural clot healing process evaluation.

Outcome (O) Soft tissue healing process and postoperative complaints (pain, swelling, trismus, oedema, and neighbouring tooth sensitivity) after the third molar extractions.

Study Design Prospective clinical studies and randomized controlled clinical trials.

1.3 Types of Publications

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14 1.4 Types of Studies

The systematic review included all human randomized controlled clinical trials and prospective cohort studies published between 2011 and 2021, which reported on the healing potential of third molar sockets using platelet-rich fibrin on both simple and surgical extractions with preservation of soft tissue healing and postoperative complaints.

1.5 Information Sources

The information sources were published in English language and were searched on PubMed/Medline, Cochrane, Google Scholar, and manual search in the electronic Journal of Oral & Maxillofacial Research from January 2011 until February 2021. Furthermore, the bibliography of the selected articles was manually searched to identify additional relevant articles.

1.6 Type of population

Patients ≥18 years of age requiring extraction of mandibular third molar.

1.7 Literature Search and screening

The electronic databases that were used to literature search are PubMed/Medline, Cochrane, Google Scholar, and manual search in the electronic Journal of Oral & Maxillofacial Research. The articles were selected based on the inclusion and exclusion criteria. The process started with an analysis of titles and abstracts. In the second step, full-text papers were chosen for evaluation.

1.8 Selection criteria

Clinical studies assessing the effect of platelet-rich fibrin in treatment of third molar extraction sockets in simple and complex surgical procedures and preservation of postoperative complains and soft tissue healing were analyzed in this systematic review.

Articles were selected according to the following inclusion criteria: • Male and female patients ≥ 18 years old.

• Healthy patients absent of systemic diseases.

• At least one lower third molar (ILTM) requiring extraction. • English language articles.

• Studies published from January 2011 until February 2021. • Studies conducted on humans.

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15 • Clinical studies with the amount of more than 20 individuals.

• Comparative studies between PRF used alone and socket free of PRF used as control group. • Preoperative/postoperative measurements on soft tissue or bone healing, or patients

postoperative complains and follow-up.

• Follow-up measurements of pain using a visual analog scale (VAS) and swelling using vertical

and horizontal guides in 3rd molar extraction sockets.

Articles were selected according to the consequent exclusion criteria: • Age below 18 years.

• Patients with smoking, tobacco habits or poor oral hygiene.

• Medically compromised patients or patients on medications that may interfere with wound healing.

• Pregnant or breastfeeding women. • Absence of the adjacent second molar. • In vitro and laboratory studies.

• Animal studies.

• Abstracts, discussions, literature reviews, and case studies. • Unclear or incomplete data on PRF preparation protocol. 1.9 Data extraction

The data were independently extracted from studies in the form of variables, according to the aims and themes of the present review, as listed onwards.

1.10 Data items

Data were collected from the included articles and arranged in the following fields: • “Type of study” – describe the type of the study.

• “Author” – revealed the author of publication. • “Year” – revealed the year of publication.

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16 • “Test group” – patients received PRF into their extraction sockets immediately after tooth

extraction.

• “Control group” – patients did not receive PRF and blood clot was formed naturally. • “Sample size” – indicated the number of patients examined.

• “Mean age” – indicated the average age of the participants in each group in the study.

• “Female: male ratio” – described the number of males or females in the study or in each group. • “Number of extractions” – reported the number of extractions done.

• “Follow-up” – indicated the amount of time during which patients were followed up.

• “VAS” assessment – described the follow-up measurements of pain using a visual analog scale.

1.11 Statistical analysis

No meta-analysis was performed.

1.12 Search strategy Literature search strategy

To identify the appropriate studies, a detailed electronic search was carried out according to PRISMA guidelines [16] within PubMed/Medline, Cochrane, Google Scholar and additional records identified through manual search in the electronic Journal of Oral & Maxillofacial Research. The following keyword combinations were employed for the electronic search:

#1 ‘platelet-rich fibrin’ [All Fields] OR ‘leukocyte platelet-rich fibrin’ [All Fields]; #2 ‘third molar’ [All Fields] OR ‘wisdom tooth’ [All Fields] OR ‘impacted tooth’ [All Fields] OR ‘tooth extraction’ [All Fields]; #3 ‘postoperative complaints’ [All Fields] OR ‘pain’ [All Fields] OR ‘swelling’ [All Fields] OR ‘trismus’ [All Fields] OR ‘soft tissue healing’ [All Fields] OR ‘healing’ [All Fields]. Search combinations performed were #1 AND #2 AND #3.

The search was limited to English language. Articles published from January 2011 until February 2021 were searched.

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17 1.13 Selection of Studies

The resulting articles were independently subjected to clarify inclusion and exclusion criteria. Firstly, titles and abstracts were obtained in the first step of the process to identify full articles that were considered adequate for inclusion in this review.

1.14 Results

The database search showed 135 articles in PubMed, 108 articles in Cochrane and three articles in additional records identified through manual search in Google Scholar and the electronic Journal of Oral & Maxillofacial Research. A synopsis of the article's selection process is described in Figure 1 using the PRISMA flow chart. After the removal of 152 duplicate articles, 91 articles remained. During the screening process's preliminary step, 73 articles were excluded because they were irrelevant based on the exclusion criteria. During the next step of the screening process, 11 more articles were removed because they did not meet the inclusion criteria. As a result, seven studies were included in this systematic review (Figure 1).

A total of 232 patients, divided into test (placing of PRF in the extraction socket) and control group (without incorporation of PRF), were included in this study. All the patients underwent extraction of mandibular third molars in either simple or surgical extraction procedures. In total, 360 extraction sockets were examined and reviewed.

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18 Figure 1. PRISMA flow diagram.

•PubMed/Medline and Cochrane Library database advanced search.

•Search keywords: platelet-rich fibrin, leukocyte- and platelet-rich fibrin, third molar, tooth extraction, postoperative complaints, soft tissue healing •Language: English

(N = 243)

Identificati

o

n

Additional records identified through manual search in Google Scholar and the electronic Journal of Oral & Maxillofacial Research (N = 3)

Filtered

Remove of duplication (N = 152) Records after duplicates removed

(N=91) (n = 400 ) Screening Records screened (N = 91)

Filtered

Eligibility

Full-text articles assessed for eligibility (N = 18)

Exclusion criteria

-Not relevant title and abstract

records excluded (N = 69) -Review (N = 2)

-Case report (N = 2)

Full-text articles

reviewed and excluded: - not relevant results (N = 11)

Filtered

Included

Studies included in qualitative synthesis (N = 7)

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19 1.15 Risk of bias assessment

The seven studies that met the inclusion criteria were assessed for methodological quality by two researchers using the JBI Critical Appraisal Checklist for randomized controlled trials (Annex 1) [17] and JBI Critical Appraisal Checklist for cohort studies (Annex 2) [18].

The RCT checklist contains 13 assessment criteria, while the index for cohort studies contains 11 assessment criteria. Every criterion was given a rating of ‘yes’, ‘no’, ‘unclear’ or ‘not applicable. Both checklists do not have a specific way to summarize if the risk is high or low, so there was no appropriate way to classify them as having high or low risk of bias, but whether a study is of low, moderate, or high quality. In this systematic review, all the prospective studies have high quality and low probability of containing bias, with strategies that did not mention addressing incomplete follow-up [1,11]. In contrast, the randomized controlled clinical trials in this review followed some protocol to reduce the risk of bias: the study conducted by Da Silva et al., 2021 [2] and Sheetal et al., 2018 [8] revealed high quality with minimal/low risk of bias, while the other three studies [3,9,10] had a moderate risk of bias. The results on risk of bias assessment are summarized in Table 3A and Table 3B. Systematization of data of included studies is presented in Table 4.

Table 3A. JBI critical appraisal checklist for randomized controlled trials.

Table 3B. JBI critical appraisal checklist for cohort studies.

Study Year Study design Checklist Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q 10 Q 11 Q 12 Q 13 Da Silva et al. [2] 2021 RCT + + + + - + + + + + + + + Jeyaraj PE et al. [3] 2018 RCT + + + ? - ? + + + + + + + Sheetal et al. [8] 2018 RCT + + + + - + + + + + + + + Sybil et al. [9] 2020 RCT + + + + - + + + ? + ? + + Al-Hamed et al. [10] 2016 RCT + + + + - ? ? + ? + + + +

Study Year Study design Checklist Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q 10 Q 11 Dar et al. [1] 2018 Prospectiv e + + + + + + + + + - + Singh et al. [11] 2012 Prospectiv e + + + + + + + - + - +

? = unclear; + = yes; - = no.

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20

2. SYSTEMIZATION AND ANALYSIS OF DATA

PRF application in 3rd molar extraction sockets Table 4.Characteristics of included studies.

Auth or /Year Study Design Inclusion criteria Test (T) and Control (C) Groups, N: number of patients, Extr: no. of extractions Gender, sample age (SA), and mean age (MA) ± SE PRF preparation technique Surgical procedure Postoperativ e medicine prescribed Observation period (follow up) Investigation

method Results Conclusion

Dar et al., 2018 [1] Prospective study Patients requiring bilateral mesioangular ILTM planned for extraction. T: 30 PRF vs. C: 30 non-PRF. N: 30 Extr: 60 I: 17 (F) II:13 (M) SA: 18-50 years MA: 23.6 ± 4.385 years 10 ml of blood was drawn into the test tubes without anticoagulant and immediately centrifuge. Standard Ward’s incision was given with blade No. 15 and mucoperioste al flap was raised. - Amoxicillin tablet was prescribed with potassium clavulanate (625 mg BD for 5 days). - Acefenac tablet was prescribed (100 mg BD for 5 days). - Tablet pantoprazole was prescribed (40 mg OD for 5 days). T0: Pre-operative: (OPG) / (IOPAR). T1-immediately after treatment: 1.Periodontal health. 2.Radiograph ic assessment for bone healing evaluation. T1: Post-operative re-evaluation: 1. Pain – 1st_, 3rd_{, 7}th_{, and} 14th_day. Bone healing: OPG, IOPAR Lamina dura score Overall density score Trabecular pattern score Pain: VAS Swelling: measuring the distance from the tragus point of the external ear to the soft tissue pogonion. (Schultze et al., 1995). Bone density: SS difference between both groups (p < 0.001). Trabecular pattern: SS higher for the test group (p < 0.001). Pain: score was lower for the PRF group at all investigated time points when comparing with the control group with SS results of (p < 0.05). The present study shows better soft tissue healing in PRF group. The 3rd_month follow-up radiograph revealed a comparativel y higher bone density level in the PRF group. Reduction of postoperative pain and swelling after ILTM surgical extractions.

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21 2. Swelling – 1st_{, 3}rd_{, 7}th_, and 14th_day. 3. Periodontal health - on 4th week, and 12th_week. 4. Bone healing + IOPAR – on 4th_{and 12}th week. Soft tissue healing: Landry wound healing index (Landry et al., 1988). Soft tissue healing: NSS difference between the results of both groups. Swelling: higher score with SS different (p < 0.001) favor to control group. Lamina dura: SS (p < 0.001) increase in lamina dura score for test group. Da Silva et al., 2021 [2] RCT Patients requiring lower third molar planned for extractions. T: 20 PRF vs. C: 20 non-PRF. N: 20 Extr: 40 I:14 (F) II:6 (M) MA: 23 ± 3.28 years 10 ml of blood was drawn into the two sterile tubes without anticoagulant and immediately centrifuge. Local anaesthesia to block the inferior alveolar lingual and buccal nerves. Soft tissue release around the tooth was performed using a No.3. - Paracetamol was prescribed (500 mg every six hours for pain control). - In the case of severe pain, including an emergency Ibuprofen T0: Pre-operative: 1. Medical and dental history. 2. OPG. T1: Post-operative re-evaluation: 1. Pain -primary outcome Bone healing: OPG Pain: VAS Soft tissue healing: Landry index which used parameters as the color of tissues, epithelializati Pain: SS lower on the L–PRF sites (p < 0.05). pain using the time weighted NSS. (p < 0.05) Healing process: SS improvement The study observed better soft tissue healing in PRF group. Reduction of postoperative pain and improvement on bone healing after lower third molar

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22 scalpel handle and a No. 15 blade. was prescribed (400 mg every 8 hours for 3 days). measures included the pain experienced until the 7th day after surgery – (on days 1, 2, 3, and 7), and Pain intensity Differences (SPID) - 24 hours to 48 hours, 72 hours, or 196 hours after the procedure. 2. Soft tissue healing – 7th and 14th_day. 3.Inflamma-tory mediators - 24 hour and seven days after the surgery. on of wound margins, the presence of bleeding on palpation, granulation, and suppuration to assess the healing. (Landry et al., 1985). Quantificatio n of cytokines and growth factors: BioPlex MAGPIX system. in healing process for the L–PRF group (p = 0.0215). GFs and several cytokines: SS increased in the levels of L–PRF site at day 1. Growth factor: (VEGF), IL– 10, and IL1– RA remained higher for seven days. (p < 0.05). extractions. Correlation was found between the healing process and increase in local concentration of growth factors such as PDGF and FGFb. Jeyara j et al., 2018 [3] RCT Patients requiring clinically and radiologically (mesio-angular, distoangular, horizontally) ILTM planned for extractions. T: 30 PRF vs. C: 30 non-PRF. N: 60 Extr: 60 Not mentioned 20 ml of blood drawn into two 10 ml test tubes without anticoagulant and immediately centrifuge. Mucoperios-teal flap. - Ibuprofen was prescribed (400 mg). - Paracetamol was prescribed (325 mg). T0: Pre-operative: 1. Periodontal health – PD. 2. Extra + intraoral photographs including IOPAR and OPG. Bone healing: IOPAR Pain: VAS Periodontal health: PD Swelling: measuring the distance Bone density: SS improvement compared to control group. Pain, swelling, PP and The present study shows better soft tissue healing in PRF group. The 8th_week follow-up radiograph revealed a comparativel

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23 - Amoxicillin was prescribed (500 mg TID for 5 days). 3. Maximum mouth opening with Vernier’s Caliper (inter ‑ incisal distance). 4.Hematolo-gical investigation. T1-immediately after treatment: Radiographic assessment including IOPAR and OPG. T2: Post-operative re-evaluation: 1. Pain, swelling and trismus - 3rd day. 2. Periodontal health ‑ 8th week. 3. Bone healing ‑ 8th week. from the tragus point of the external ear to the soft tissue pogonion and from the tragus to the angle of the mouth. The measurement recorded as nil, mild, moderate, and severe. Trismus: SS improve in postoperative complications in the test group compared to control group. Soft tissue healing exhibited quick, and complication free outcomes as compared to the control group in which no PRF was used. Control group, who underwent surgical extraction without incorporation of PRF, exhibited increase complication such as pain, swelling, trismus and deeper PP in relation to the y higher bone density level in the PRF group. Reduction of postoperative pain, swelling, oedema and trismus after ILTM extractions with the incorporation of PRF.

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24 adjacent tooth. Sheet al et al., 2018 [8] RCT Patients requiring bilaterally symmetrical ILTM planned for extraction. T: 30 PRF vs. C: 30 non-PRF. N: 30 Extr: 60 I: 17 (F) II: 13 (M) SA: 18-40 years MA: 25.47 ± 0.90 years 10 ml of venous blood was drawn into the test tubes without anticoagulant and immediately centrifuge. Local anaesthesia. Mucoperios-teal flap was raised. Later bone removal, tooth sectioning (if required) and socket irrigation with normal saline were done. Not mentioned T0: Pre-operative: Swelling. T1-immediately after treatment: Radiographic assessment. T1: Post-operative re-evaluation: 1. Pain + swelling: on 1st_{, 3}rd_{, 7}th_, and 14th_day. 2. Bone healing - 8th and 16th weeks. Bone healing: lamina dura, bone density, and trabecular pattern: modified Ogundipe OK criteria. (Ogundipe OK et al., 2011). Pain: VAS Swelling: Three facial measurement s were taken respectively from the lateral canthus to the angle of mandible, tragus of the ear to the corner of mouth and the tragus of ear to the soft tissue pogonion. The sum of Bone healing (lamina dura, bone density, and trabecular pattern): early bone healing in test group (p < 0.001). Pain: lower score for test group compared to control group (p < 0.05). Swelling: SS lower for test group (p < 0.05). Age, gender, and type of impaction in both groups: NSS. The present study presents better soft tissue healing in PRF group. The 4th_month follow-up radiograph revealed a comparativel y higher bone density level in the PRF group. Reduction of postoperative pain and swelling after ILTM extractions.

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25 these evaluations worked as the data for calculation of swelling. (Schultze et al., 1995, modified by (Ogundipe OK et al, 2011). Sybil et al., 2020 [9] RCT Patients requiring bilateral mandibular third molar planned for extractions. T: 25 PRF vs. C: 25 non-PRF. N:25 Extr: 50 I: 11 (F) II:14 (M) SA: 18-55 years MA: 32.3 years 10 ml of blood was drawn into the test tubes without anticoagulant and immediately centrifuge. Local anaesthesia and single stage surgical disimpactions . In pericoronitis case - AB was prescribed 3 days prior to extraction to facilitate mouth opening. T0: Pre-operative: 1. Periodontal health - SBI, CAL, PD, PI. 2. IOPAR and DC technique for bone height evaluation. It was measured from the crest of the interdental bone between the second and third molars to the cementoenam el junction (CEJ) of the second molar. T1 immediately after treatment: Bone healing: IOPAR Pain and tenderness: VAS Periodontal health: PP, SBI score Sensitivity and oedema: score of 1, 2, 3 depending on patient reporting and finding. Bone height: NSS difference between the results of both groups. Pain: SS on day 1 (p < 0.001) with a mean value of (2.08 ± 1.352) on control side compared to (0.80 ± 0.764 on test side). Edema: SS less on the test side compared to the control side (p < 0.001). Tenderness: SS less This study showed significant improvement on soft tissue healing in PRF group. The 2nd month follow-up radiograph revealed a low bone density level in the PRF group with respect to cortical bone. Reduction of postoperative pain, edema, tenderness, and sensitivity after ILTM extractions.

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26 Radiographic assessment. T2: Post-operative re-evaluation: 1. Pain, tenderness, and edema- day 1,3rd_, after 1 week, and 1 month. 2. Sensitivity in response to cold, air spray and probing - 1 week, 1, 3, 6 months. 3. SBI + PI - 1 week, 1,3,6 months. 4. CAL, PD, bone height - after 3, 6 months.

values for test side.

Sensitivity: SS difference in values being always less for the test side (p < 0.001). SBI: NSS difference between the results of both groups. PI: SS difference (p < 0.001) with better results for test group. CAL: NSS difference between the results of both groups. All the extracted impacted third molars had either horizontal or mesioangular impaction.

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27 Al-Hame d et al., 2016 [10] RCT Patients requiring at least one ILTM planned for extraction. T: 25 PRF vs. C: 25 non-PRF. N: 47 Extr: 50 I: 34 (F) II:13 (M) SA: 18-55 years MA: 25.24 ± 7.04 years 5 ml of blood was drawn into a 10 ml test tube without anticoagulant and immediately centrifuge. Inferior alveolar nerve block with buccal infiltration. Mucoperios-teal flap was raised. - Amoxicillin tablet was prescribed (500 mg QID for 5 days). - Ibuprofen was prescribed (400 mg TID as an analgesic for the day of surgery). - Chlorhexidin e mouthwash (BD for 7 days). T0: Pre-operative: 1.OH evaluation 2. IOPAR 3. OPG T1: Post-operative re-evaluation: 1. Pain - from the 2nd_-7th day. 2. Soft tissue healing - 7th day. 3. Analgesics consumption - one week follow up. Pain: VAS Soft tissue: Landry wound healing index (Landry et al., 1988). Socket complication: Cheung criteria. (Cheung et al., 2001). Level of ILTM: Pederson classification (Pederson et al., 1988). Pain: SS difference for test group (p = 0.041, 0.031 and 0.005 respectively). Soft tissue Healing: NSS difference between the results of both groups. (p = 0.187). AO: PRF significantly reduce the incidence in AO for test group. (p = 1.00 and 0.312 respectively). Age, sex, tooth angulation, anesthetic used, and the difficulty level of mandibular third molar: NSS difference between the results of both groups. Analgesic consumption: Comparing to other studies, which revealed better soft tissue healing using platelet-rich fibrin, this present study observed an insignificant difference between the two groups regarding soft tissue healing. Reduction of postoperative AO, pain and analgesic consumption after ILTM extractions.

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28

AO = alveolar osteitis, BD = 2 times / day, BioPlex MAGPIX system = Biorad Inc., Hercules, CA, USA, C = control group, CAL = clinical attachment level, Extr = number of extractions, FGFB = Fibroblast growth factor, ILTM = impacted lower third molar, IOPAR = intraoral periapical radiographs, MA±SE = mean age with standard error, N = number of patients ,NSS = not statistically significant, OD = once / day, OPG = panoramic x-ray, PB = periodontal probe, PD = pocket depth, PDGF = platelet-derived growth factor, PI = plaque index, PP = periodontal pocket, PRF = platelet-rich fibrin, QID = 4 times / day, RCT = randomized controlled trial, SA =sample age, SBI = sulcus bleeding index, SS = statistically significant, T = test group, TID = 3 times/ day, VAS = visual analog scale.

SS less consumption for test group. (p = 0.019, 0.039, 0.045 and 0.020, respectively). Singh et al., 2012 [11] Prospective study Patients requiring bilateral mandibular third molar planned for extractions. T: 20 PRF vs. C: 20 non-PRF. N: 20 Extr: 40 I: 10 (F) II:10 (M) MA: 32 years 5-10 ml of blood was drawn into test tubes with a 5cc syringe to immediately centrifuge. Not mentioned Not mentioned T0: Pre-operative: 1. IOPAR radiograph. T1: Post-operative re-evaluation: 1. Pain, soft tissue healing - 1st_{, 3}rd_{, 7}th day. 2. IOPA radiograph - 4th_{, 8}th_{, 12}th week. Bone density assessment: IOPAR Pain: VAS Soft tissue healing: Landry wound healing index (Landry et al., 1988). Radiographic assessment of bone density: higher bone density for the test group compares to control group. Pain assessed by VAS: mean value post extraction pain: 1st _,3rd_day and 7th_day (p > 0.05) => NSS difference. Healing Index: on 3rd_{day (p =} 0.022) and on 7th_{day (P =} 0.015) => SS. Better soft tissue healing observed in PRF group. The 3rd month follow-up radiograph revealed a comparativel y higher bone density level in the PRF group. No significant difference on pain between control and test groups.

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3. RESULTS

The studies that have been included in this review were about the effect of platelet-rich fibrin on soft tissue healing and postoperative complaints in mandibular third molar extraction socket. Five randomized controlled trials [2,3,8,9,10] and two prospective studies [1,11] were included for the final review. A total of 232 patients were enlisted in this systematic review, with 360 extraction sockets in the third molar area. The observation period ranging up to 6 months. All studies are written in the English language and were performed on human and published during the last nine years. In the research operated by Dar et al., 2018 [1], a total of 30 patients and 60 extraction sockets were included in the research, with the mean age of 23.6 ± 4.385 years. The patients were measured at different intervals immediately after the procedure and for a maximum of 12 weeks. Estimating the effect of PRF over bone density showed a significant difference between the test and control group (p < 0.001) at all time points. The trabecular pattern shows a significant increase in the PRF group. Lamina dura evaluation score increased with time and was higher in the test group than the control group with (p < 0.001) at 4th and 12th weeks. The mean total bone density increased over time and was higher in the PRF group. The soft‑tissue healing distinction with time was statistically insignificant. The mean percentage for swelling was lower for the PRF group at all points and showed a significant (p < 0.001) decrease in swelling score over time.

A randomized controlled trial written by Da Silva et al., 2021 [2] included 20 patients with 40 extraction sockets, with an average age of 23 ± 3.28 years. The observation period was for a maximum of 2 weeks. Follow-up during the post-operative period indicated a good recovery in all cases without severe complications and intolerance to the medication used. Regarding pain assessment, the mean score for VAS was significantly lower at PRF sites for all days assessed (p < 0.05). When comparing the pain using time-weighted SIPD, there was no significant difference (p > 0.05) between the control and PRF groups 24 and 48 hours. Soft tissue healing showed statistically significant better healing to the PRF group, with (p = 0.0215). Growth factors and several cytokines showed an increase in the PRF site level at day one, with (VEGF), IL–10, and IL1–RA present with significantly increased levels at PRF sites (p < 0.05).

In a study by Jeyaraj et al., 2018 [3], a total of 60 extractions were done in 60 patients and were measured at different intervals immediately after the procedure at a maximum period of 8 weeks. The evaluation of bone density was statistically significantly improved and showed faster bone regeneration results within eight weeks. It was observed beneficial results in patients using PRF,

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30 resulting in quicker postoperative recovery and reduced morbidity, with fewer postoperative complications such as pain, swelling, trismus, and lower incidence of periodontal pocket formation [3]. The randomized controlled trial conducted by Sheetal et al., 2018 [8] included 30 patients with 60 extraction sockets, with an average of 25.47 ± 0.90 years. Regarding bone healing (including bone density, lamina dura and trabecular pattern), records were mainly higher for the test group on both the 8th and 16th week. Pain assessment showed a lower observation for the test group compared to the control group (p = 0.05). The swelling assessment was lower for the PRF group at all time point (p < 0.05). Other unfavorable outcomes like a dry socket, infection at the surgical site, and prolong trismus did not show up at all follow-up visits. The age, gender, and type of impaction in both groups were not statistically significant.

In the study conducted by Sybil et al. in 2020 [9], 50 transalveolar extractions of the mandibular third molars were done in 25 patients with an average age of 32.3 years. They were measured at different time intervals for a maximum period of 6 months. As opposed to the previous study, there was no statistically significant difference in bone height between the two sides. (p = 0.863). Following the procedure, there was a loss of bone height on the control and experimental sides; however, bone height was still more preserved on the control side than the test side and showed no difference between both sides after 3 and 6 months. Similarly, to the bone evaluation, CALs were not affected by PRF, while there was a statistically significant improvement in patients favors in the aspect of signs and symptoms like pain (p < 0.001), tenderness, oedema (p < 0.001), and sensitivity (p < 0.001), with the use of PRF with values always being fewer for the test side compared to the control side. Improvement was seen in SBI, plaque index, and probing depths, with values being lesser for the test side than that of the control side.

In a study by Al-Hamed et al., 2016 [10], A total of 47 patients and 50 extraction sockets were included in the research, with the mean age of 25.24 ± 7.04 years. The patients were measured at different intervals immediately after the procedure and for a maximum period of 7 days – the shortest follow up evaluation between all included studies. In the present study, the assessment of bone was not evaluated. The mean values of Landry and Turnbull index in study and control groups were 4.52 (0.71) and 4.20 (0.95), respectively. Soft tissue healing showed no statistically significant results following the removal of an impacted mandibular third molar (p = 0.187). Correspondingly to the other two clinical studies [3,9], less pain was observed for the fifth, sixth and seventh postoperative days (p = 0.041, p = 0.032 and p = 0.005, respectively). In contrast, no statistically significant differences were observed for the second, third, and fourth postoperative days (p = 0.152, 0.078 and

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31 0.057 respectively). Also, less analgesic consumption was recorded in the PRF group for the 2nd, 3rd, 6th, and 7th postoperative day (p= 0.019, 0.039, 0.045 and 0.020 respectively) with no statistically

difference for the fourth and fifth postoperative days (p = 0.054 and 0.070 respectively). Regarding the socket complications, the application of PRF resulted in a significantly lower incidence of AO compared with the control group (p = 0.037) [10].

Another prospective study designed by Singh et al., 2012 [11] included 20 patients with 40 extraction sockets, with a mean age of 32 years. Post-operative re-evaluation was for a maximum period of 12 weeks and showed improvement in the soft tissue healing in test which platelet-rich fibrin was placed in the extraction area. The trabecular bone formation was seen in 8 patients at the study site, but absent in all the 20 control sites. In the 8th_{week, the bone formation was seen in 18 patients in the} study site and only in 10 patients on the control side (p = 0.063). Only at the last week of evaluation (12th week), the bone formation was seen in all 20 patients, and the total score of bone density by radiological assessment showed the grey level value calculated and was higher in the PRF group compared to non-PRF group. Regarding pain evaluation, no statistically significant difference between the study and control groups on the 1st, 3rd and 7th day (p > 0.05). The Landry wound healing index (Landry et al., 1988) was better in the study site comparing to the control site in all 20 patients over time.

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4. DISCUSSION

This systematic review of the literature aimed to evaluate the use of PRF for the enhancement of soft and hard tissue healing and diminish postoperative complaints following impacted and non-impacted mandibular third molar extractions. The review compared the outcomes (such as pain, swelling, trismus, oedema, and neighbouring tooth sensitivity) after mandibular third molar extraction of filling the extraction sockets with platelet-rich fibrin versus a natural blood clot acting as the control. Majority of the included studies showed the efficiency of platelet-rich fibrin over the third molar extraction sockets by restoring the tissue integrity and functional capacity after the injury [3]. Since the 1990s and until today, the role of platelets and growth factors in the blood become more recognized in innovative medicine. Ross et al., 1974 [19] was one of the pioneers to introduce the platelets regenerative potential and was the first to describe the growth potential from platelets. In 2001, Choukroun J et al. [5] developed a new generation of platelets concentrate from the patient own blood and termed it PRF. The preparation of PRF is based on natural coagulation process and includes collection of whole venous blood ( ~5 ml) in sterile tube with the absence of anticoagulant. The tubes are placed in centrifuged machine that leads to activation of most platelet in the collected blood and the release of intrinsic coagulation cascade. When the centrifugation process ends, three layers are formed in which acellular plasma at the top, with lower fraction containing red blood cells (RBCs), the middle layer containing the fibrin clot, the upper straw-coloured layer is then removed and middle layer is collected, few mm below to the lower dividing line, which is the PRF. This process results in forming a fibrin network that is very similar to natural, enhancing cell migration and eventually proliferation. Being a reservoir of platelets, leukocytes, cytokines, and immune cells, PRF is reported to allow slow release of cytokines; TGF, PDGF, VEGF, and EGF, which play a critical role in angiogenesis, tissue healing and synthesis of a collagen matrix with the favour of tissue repair [10]. In contrast to PRP and plasma rich in growth factors (PRGF), the production technique of PRF is simple and less costly. It does not require multiple pipetting for separation, and biochemical modification of the blood by adding anticoagulants, bovine thrombin, or calcium chloride is also unnecessary [20].

A total of seven studies [1-3, 8-11] were included in the review. The study of Dar et al., 2018 [1] and Al-Hamed et al., 2016 [10] investigated the impact of PRF on post-extraction soft tissue healing in the third molar extraction sockets and revealed an insignificant difference between the control and test group. Landry wound healing index (Landry et al., 1988) was used in both studies to evaluate if

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33 the PRF influences soft tissue healing over the extraction sockets. The patients were followed up for more than one week, and they assessed on the 1st postoperative day. Dar et al., 2018 [1] revealed a statistically significant difference on the soft‑tissue healing in the first postoperative week for the test group (p < 0.001) and showed improvement in soft tissue healing, while insignificant results were found on test group on 14th day (p = 0.179). In contrast to the study of Dar et al., 2018 [1], Al-Hamed et al., 2016 [10] revealed statistically insignificant soft tissue healing in all-time points (p = 0.187) and was explained to be related to the smaller sample size, surgical extraction of teeth included in the present study, and the difficulty in distinguishing between good and very good categories of the healing index of Landry et al., 1988 [21].

Da Silva et al., 2021 [2] proved that the effect of PRF on soft tissue healing is due to its clinical potential to increase angiogenesis which helps in symptom relief and healing. This finding corresponds with the conclusion of Jain et al., 2012 [22], state that PRF supports three aspects of wound healing - angiogenesis, immunity, and epithelial proliferation, with relation to the mechanical function of cytokines (IL-1b, IL-6, and TNF-a) to promote ability and easier remodeling of fibrin in a more resistant connective tissue [22]. The study of Da silva et al., 2012 [2] found that PRF acting as a soft tissue healing accelerator in the 7th and 14th day (p < 0.05), a timeframe where several recent studies report good clinical results of PRF and which is in accordance with recent studies [3,8,9,11]. Additionally, authors provide direct evidence of the connection between released growth factors and clinical improvement by different outcome measures, represented mainly by the strong correlation of PDGF (platelet-derived growth factor) concentration at the L–PRF site with the reduction of pain on the third day after surgery, and the moderate correlation with the cicatrization index at the 7th and the 14th days after surgery. Recently, studies have evaluated the effect of PRF on 3rd molar extraction socket and noted better healing outcomes in bone density which includes the lamina dura and trabecular pattern [1,3,8,9,11]. The evaluation revealed an increase of bone fill on the PRF group after one month, which is explained by numerous studies and points to the growth factors as an essential factor for bone regeneration to occur. The study of Singh et al., 2012 [8] state that growth factors released from the PRF (PDGF, IGF, and TGF) can stimulate the osteoblast precursors and increase the collagen matrix's deposition of wound healing and bone formation. Concerning postoperative complaints, all the included studies [1-3,8-11] have measured the pain by VAS score, and they were recorded daily for the 1st postoperative day for a maximum of two weeks follow up. All the studies except Singh et al., 2012 [11] reported that the pain score was lower for the PRF group at all time points when compared with the control group, with statistically significant difference. The reduction

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34 in pain values on the test sites with PRF could be associated to the reduced inflammation and following lower oedema formation. Singh et al., 2018 [11] reported not statistically significant difference on pain between the study and control side on the 1st, 3rd day and 7th day. In the study of Al- Hamed et al., 2016 [10], the decrease in pain and analgesic consumption was statistically lower in the test group as well, however it should be taken into consideration because the measurements are based on personal VAS, response to analgesics and pain sensation that is chosen by the patients itself and can be different from one patient to another. Relief of postoperative swelling and oedema is critical for the reduction of patient discomfort and success of mandibular third molar extractions. Four studies [1,3,8,9] evaluated the swelling after removing the third molar and showed a significant reduction in postoperative swelling compared to the adjacent second molar with the use of PRF. Swelling measurements were taken on days 1, 3, and 7 after the surgery, respectively. In all the reported cases [2,3,9] there was no oedema observed after one month of evaluation. The reason for a low incident of oedema is the reduction in the inflammation surrounding the soft tissue. Concerning trismus, three articles [3,8,9] reported low occurrence of trismus in the test group in which PRF was used. A gradual decrease in neighboring teeth sensitivity was seen in both test and control groups one month after the surgery and was always less pronounced for the test side significantly [3,8,9]. There are several limitations of this systematic review that should be mentioned. Firstly, majority of the included studies have small sample size. A larger sample size of patients would be helpful to improve the significance of the study. Another important aspect is the differences in PRF preparation protocols and quantities within included studies. Differences management of the blood concentrate preparation may influence its biochemical composition and exhibit variations within clinical results of the presented studies.

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5. CONCLUSIONS

1. Most of the included studies revealed PRF as an effective method in promotion of soft tissue healing and reduction of postoperative pain, swelling, trismus, oedema, and neighbouring tooth sensitivity following mandibular third molar extraction procedure in the PRF groups over the non-PRF groups.

2. Further clinical trials and studies with larger sample size and longer duration of follow up are necessary to provide more solid evidence of the effect of PRF in the promotion of soft tissue healing and postoperative complaints.

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6. PRACTICAL RECOMMENDATIONS

According to this systematic review, platelet-rich fibrin is effective in the outcome results of accelerating soft tissue healing and reducing postoperative complaints. Using PRF is accessible both for treating doctors and low cost for the patient itself, with no additional risks on disease transmission. Clinicians may use PRF for accelerating soft tissue healing and reduction of patient’s postoperative discomfort. In the future studies researchers need to take care on the larger sample size and longer follow-up duration, which includes at least one month to assess the soft tissue healing, and a longer period to observe the postoperative complaints such as pain and swelling.

7. ACKNOWLEDGMENT

I would like to thank Doctor Povilas Daugėla for his expert advice, guidance and encouragement throughout this review.

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Sivan Najar