Efficacy of a New-generation Platelet-rich Fibrin in the Treatment of Periodontal Intrabony Defects: a Randomized Clinical Trial

Efficacy of a New-generation Platelet-rich Fibrin in the Treatment of Periodontal Intrabony Defects: a Randomized Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Efficacy of a New-generation Platelet-rich Fibrin in the Treatment of Periodontal Intrabony Defects: a Randomized Clinical Trial Boroka Klara Csifo-Nagy, Eleonora Solyom, Vera Lili Bognar, Annamaria Nevelits, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-525471/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Nov, 2021 Read the published version in BMC Oral Health → Version 1 posted 6 You are reading this latest preprint version Abstract Background: The aim of the study was to clinically evaluate the healing of intrabony defects after treatment with a new generation of platelet-rich fibrin (A-PRF+) respect to enamel matrix derivatives (EMD). Methods: Thirty (30) intrabony defects of 18 patients (9 males, 9 females) were randomly treated with A-PRF+ (test, n=15) or EMD (control, n=15). The following clinical parameters were recorded at baseline and 6 months after surgery: pocket depth (PD), gingival recession (GR) and clinical attachment level (CAL). After debridement the intrabony defects were filled with A-PRF+ in the test group, respectively with EMD in the control group, and fixed with sutures to ensure wound closure and stability. Results: Both treatment methods resulted in statistically significant PD reductions, respectively CAL gains six months post-operatively. No statistically significant differences were found between the two groups as the mean CAL gain was 2.33±1.58 mm in the A-PRF+ group, respectively 2.60±1.18 mm in the EMD group (p < 0.001). Conclusion: Within the limits of this study the new-generation platelet-rich fibrin seems to be as clinically effective as EMD in the surgical treatment of intrabony defects. Treatment with A-PRF+ or EMD resulted in reliable clinical outcomes. The use of A-PRF+ as a human autologous product can give a positive impact on periodontal healing. Clinical Relevance: A-PRF+ may be suitable for the treatment of intrabony periodontal defects. Trial registration number (TRN): NCT04404374 ( ClinicalTrials.gov ID) Date of registration: 19.05.2020., retrospectively registered Dentistry Head & Neck Surgery intrabony defects periodontal healing advanced platelet-rich fibrin enamel matrix derivatives Figures Figure 1 Figure 2 Figure 3 Background The main goal of the comprehensive periodontal treatment is to eliminate inflammation and to prevent further destruction of the periodontium, as well as to achieve long-term sustainable condition. Over the past decades, significant efforts have been made to develop materials and also surgical techniques that can predictably contribute to periodontal regeneration [1]. Nowadays, regenerative periodontal therapy can only restore a part of the original tissue to some extent, while the complete periodontal restoration remains idealistic [2]. More than 20 years have passed since enamel matrix derivatives (EMD) were introduced to enhance periodontal regeneration by mimicking the formation of periodontal attachment tissues. They play an important role as chemical barriers and biological mediators in periodontal regeneration and healing [3]. Advances in cell and molecular biology have contributed to an increased understanding of wound healing. There is evidence that polypeptide growth and differentiation factors (GDF’s) can support wound healing and regeneration by regulating chemotaxis, differentiation, proliferation of cells and matrix synthesis. However, only a few factors have reached clinical evaluation, earlier research has just targeted finding of the optimal dosage and the combination of growth and differentiation factors [4]. Data from long-term follow-up clinical studies demonstrated that treatment of deep periodontal intrabony defects with EMD resulted in a significant increase of clinical attachment gain and bone fill compared to the “open flap debridement” [5–8]. In periodontal application of chemical-biological factors, a new period followed by the introduction of autologous platelet concentrates (Platelet-Rich Plasma - PRP, Platelet-Rich Gel - PRG, Platelet-Rich Fibrin - PRF) [9–13]. A strategy to promote wound healing is to amplify and accelerate the effect of released growth factors (GF’s), which can accelerate the healing of bone defects and promote periodontal regeneration. The simplest way to achieve these goals is to activate the local release of platelet-derived growth factors, which are common triggers in almost all wound healing processes. A method for the intraoral application of concentrated autologous products (CAP) has been developed for more than two decades. The use of PRP is based on the effect of growth factors released from concentrated platelets on healing and tissue regeneration [14–15]. With the advancements made in platelet - rich concentrates formulations over the past decade, PRF has been introduced and utilized as a supra-physiological concentration of autologous growth factors without necessitating the use of anticoagulants [13,16]. The PRF is a product that enhances wound healing, unlike PRP. The beneficial effects of PDGF’s, TGF-beta (platelet-derived growth factor, transforming growth factor beta) and other GF’s released from platelets can be recorded not only in the early stages of wound healing, but also its effects last longer and appear at a slower rate [9, 17]. A new generation of platelet-rich fibrin formulation has been introduced in 2014 by Choukroun et al., the Advanced Platelet Rich Fibrin (A-PRF), which is obtained by a lower speed centrifugation [18]. Standard leukocyte-rich PRF (L-PRF) and A-PRF obtained through the experimental “low-force modified procedure” are ideal sources of leukocytes that act directly on the release of chemokines and growth factors. Although A-PRF “traps” the same number of leukocytes as L-PRF and releases the same amount of inflammatory cytokines, it contains higher amounts of PDGF and VEGF [19]. Another study found that A-PRF also contained significantly more TGF-β1, EGF, and IGF, and had shown significantly higher human fibroblast migration and proliferation than L-PRF. From this study, it appears that reducing the centrifugation rate favors the growth factors released from the PRF clot [20]. The new version of A-PRF (2017) is the A-PRF + product, in which case the centrifugation takes even less time (low-speed + time procedure). Described by Fujioka-Kobayashi et al., the newer formulation of A-PRF (A-PRF + means not only lower centrifugation speed, but also less time − 1300 rpm for 8 min) and demonstrated an increased growth factor release of TGF-beta1, PDGF-AA, PDGF-AB, PDGF-BB, VEGF, IGF, and also EGF. When compared to L-PRF and A-PRF, A-PRF + it has demonstrated a significant increase in growth factor release within either 1, 3, or 10 days [20]. In conclusion, results show that the total growth factor release could be enhanced by reducing both centrifugation speed and time in A-PRF+. The examination of the fibrin network in terms of structural integrity, A-PRF + showed similar porosity to A-PRF, furthermore over the entire clot the cellular distribution pattern showed evenly dispersed platelets. These observations emphasize the improved regenerative capacity of advanced PRF matrices. The research and application of EMD as practically non-human biological mediators (Emdogain®, Straumann®, Basel, Switzerland) in periodontal regenerative surgery, although dating back more than two decades still raises a number of unanswered or ambiguously answered questions. Research on the use of autologous growth and differentiation factors as well as recombinant growth factors (rhGF’s) as biological mediators in periodontal regenerative procedures has a relatively shorter history and offers many additional opportunities for researchers. Examining the new generation of PRF is an even more topical task. Methods Our aim was to investigate the further role of human autologous platelet concentrates in periodontal healing and regeneration. We tested the role and clinical applicability of a new generation of platelet-rich fibrin, “Advanced Platelet-Rich Fibrin (A-PRF+)”, in periodontal wound healing. The clinical data obtained during the study were compared with the results of a well-known and successfully applied regenerative method. The null hypothesis of the study was whether an autologous material (A-PRF+) can be a reliable alternative in surgery of intrabony defects. Study design This study was planned as a randomized, controlled, prospective clinical trial, performed in accordance with the Helsinki Declaration of 1975, as updated in 2013, and the protocol was approved by the ethics committee of the Semmelweis University Budapest (SE TUKEB: 254/2017). The study protocol was retrospectively registered at ClinicalTrials.gov with ID number NCT04404374. The study was conducted in the Department of Periodontology, Semmelweis University, Budapest, Hungary. It was initiated in June 2018 and completed in November 2019 by the same experienced periodontist (BCSN). Each participant has been explained the risks, benefits, and the procedure in his/her native language and written informed consent was obtained. Study population According to the new classification proposed by the World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions (2017), the patients were classified into stage III. periodontitis [21]. The patients initially received cause-related periodontal therapy, consisting of oral hygiene instruction, motivation and sub-gingival scaling/root planing under local anaesthesia. The patients were consecutively enrolled when the following inclusion criteria was met: 1) no systemic diseases that could influence the outcome of the therapy; 2) no smoking [22]; 3) good level of oral hygiene with Full-Mouth Bleeding Score < 20% [23] and Full- Mouth Plaque Index Score < 20% [24]; 4) presence of a minimum one or more 2-, 3-, or combined 2-3-wall intrabony defect with a defect angle of 20–40 (+/- 5) degrees, as the radiographic defect angle influences the outcome of regenerative surgical therapy in intrabony defects [25] and with a minimum probing depth (PD) of 6 mm and intrabony component of a minimum 4 mm. Clinical parameters The following clinical parameters were assessed at baseline (1 week before surgery) and at six months after the surgery, using the same type of periodontal probe (UNC-15, Hu-Friedy, Chicago, IL, USA): Full-Mouth Plaque Score (FMPS) [24] and Full-Mouth Bleeding Score (FMBS) [23], pocket depth (PD), gingival recession (GR), clinical attachment level (CAL) and transgingival bone sounding (BS). The primary outcome was CAL gain. Radiographs were performed with “long cone” technique before surgery, and 6 month post-surgically. The clinical measurements were made at six sites per tooth, mesio-buccal, mid-buccal, disto-buccal, mesio-lingual, mid-lingual, and disto-lingual, by the same experienced, calibrated investigator (ES), and the highest PD value was taken in consideration. Blinding and calibration The examiner was not aware of the type of treatment rendered in any of the cases. The measurements were rounded up to the nearest millimeter. To calibrate the examiner five patients were used, each showing 10 teeth (single and multi- rooted) with PDs > 6 mm on at least one aspect of each tooth. The examiner evaluated the patients on two separate occasions, 48 hours apart. Calibration was accepted if > 90% of the recordings could be reproduced within 1.0-mm difference. Randomization The defects were randomly allocated by computerised random number generator ( https://www.sealedenvelope.com ) and treated with either A-PRF+ (test group) and EMD (control group). Preparation of A-PRF+ Immediate before surgery A-PRF + was prepared for the test group using a commercially available PRF Kit [Process for PRF® (A-PRF), J. Choukroun, Nice, France] and "Process for PRF Duo” (Choukroun) centrifuge. Cubital venous blood was drawn from the patient without the addition of anticoagulant into two 10 ml vacuum tubes (A-PRF + tube, Choukroun 2017) and immediately centrifuged at 1300 rpm for 8 minutes, then allowed to rest for 5 minutes [20]. During centrifugation, 3 layers are formed in the tube at the start of the coagulation cascade. The top layer is the Platelet-Poor Plasma (PPP), the middle layer is the Platelet-Rich Fibrin “clot” (PRF) is to be used, and the bottom layer is the Red Blood Cells (RBC’s) layer. The PRF "clot" still in the gel condition is removed from the tube, cleaned of red blood cells and used as a gel. Surgical procedure Surgery was performed by a single experienced operator (BCSN). After administration of local anesthesia intracrevicular incisions were performed extending to the adjacent teeth, with the additional precaution to preserve the maximum of interdental gingival tissue. Full-thickness buccal and oral extended flaps were raised, and all granulation tissue was removed from the defect without bone recontouring. The roots were thoroughly scaled and planed by means of hand and ultrasonic instruments. After defect debridement, in the test group A-PRF + was applied. (Fig. 1 .) In the control group after debridement the root surface adjacent to the defect was conditioned for 2 minutes with 24% ETDA gel (pH 6.7) (PrefGel, Straumann®, Basel, Switzerland) [26]. The defect and the adjacent mucoperiosteal flap were then thoroughly rinsed with sterile saline to remove all EDTA residue, and then Straumann® Emdogain® was applied. (Fig. 2 .) Finally, the flap was repositioned coronally and closed thoroughly with 5.0. non-absorbable modified vertical or horizontal mattress sutures (Dafilon® 5.0. monofilament and uncoated polyamide, B. Braun Surgical S.A. Barcelona, Spain). Postoperative care All patients have received antibiotics for a week, two times daily (Augmentin Duo, 875mg amoxycillin/125mg clavulanic acid, GlaxoSmithKline, Brentford, United Kingdom). The postoperative care consisted of 0.2% chlorhexidine (Curasept ADS 220, Curaden AG, Kriens, Switzerland) rinses two times daily for 3 weeks. Patients were advised not to use mechanical means of plaque control in the surgical area for more weeks. Sutures were removed 14 days after surgery. Instructions for maintenance of proper oral hygiene were reinforced. Study participants were scheduled for a follow-up visit weekly for one-month post-surgery and subsequently at three and respectively six months interval. Statistical analyses For the clinical parameters, data was evaluated using descriptive analysis with results illustrated as mean ± SD, range at baseline and 6 months interval. The statistical package Stata (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) was used for data handling and analysis. Defects identified (rather than patients) were treated as the unit of observation. Generally, two samples of 15 observations each are adequately powered (80%) to detect a between-groups difference of 1.06 standard deviations (SD) in a continuous variable, assuming equal SDs across groups. Post-hoc power calculations were carried out for between-groups comparisons at 6 months and within-group comparisons (6 months vs baseline) for each outcome. Within-group changes were evaluated using paired t-tests (or Wilcoxon’s matched-pairs signed-ranks test if parametric assumptions were not satisfied), and between-groups comparisons were made using two-sample t-tests (or Wilcoxon’s rank-sum tests if parametric assumptions were not satisfied). P values < 0.05 were considered to indicate statistical significance. Regarding frequency distribution changes from baseline to 6 months were categorized in each outcome as decrease, no change, and increase. To compare the two groups in terms of these, Fisher’s exact test was used. (Table 4 .) Results Participants and Recruitment The study flowchart is illustrated on Fig. 3 . This study has enrolled thirty (30) intrabony defects of 18 non-smoking patients (nine males and nine females) age 55.5 +/- 14.5 years, suffering from chronic periodontitis. Among patients the defect distribution was proportional. Baseline and postoperative FMBS and FMPS values were comparable, FMBS values decreased after surgery. (Table 1 .) Post-hoc power calculations for between-groups comparison of PD and BS values were not estimable because the two group means at 6 months were identical. For GR and CAL values, there was an estimated 11% power. For within-group comparisons, power estimates of at least 99.8% were obtained for all outcomes. Table 1 Baseline and postoperative FMBS and FMPS values A-PRF+ EMD FMBS Baseline 23% 22% 6 months postop. 10% 12% FMPS Baseline 17% 18% 6 months postop. 16% 19% All patients have completed the respective study. The postoperative healing was uneventful in all cases. No complications such as allergic reactions, abscesses or infections were identified throughout the entire study period. The trial was terminated after the completion of the six-month follow-up and analysis of the data of 30 intrabony defects, which displayed a comparable distribution and configuration in the two groups. (Table 2 .) Table 2 Distribution and configuration of treated defects A-PRF+ EMD Tooth Location Maxilla 6 7 Mandible 9 8 Anterior teeth 4 3 Premolars 6 5 Molars 5 7 Defect Configuration 2-wall 4 3 3-wall 4 4 2-3-wall combined 7 8 No statistically significant differences were found between the two groups regarding the mean values of the baseline clinical parameters. After 6 months, the mean PD has decreased significantly in both groups compared to baseline data (p < 0.001). The mean PD reduction was 4.67 ± 0.62 mm in the A-PRF + group and identically 4.67 ± 0.62 mm in the EMD group. No statistically significant difference between the groups was found. (Table 3 .) Table 3 Within group comparisons / Intergroup changes (significance: p < 0.05) Baseline 6 months postop. p Diff. p PD A-PRF+ 8.27 ± 1.58 4.67 ± 0.62 p < 0.0001 -3.6 ± 1.68 p = 0.0000 EMD 8.13 ± 1.60 4.67 ± 0.62 p < 0.0001 -3.46 ± 1.30 p = 0.0000 p = 0,999 Cohen's d d = -0.092 GR A-PRF+ 2.67 ± 1.88 3.93 ± 2.73 p < 0.0025 1.26 ± 1.33 p = 0.0025 EMD 2.47 ± 1.46 3.33 ± 1.58 p < 0.0044 0.86 ± 0.99 p = 0.0044 p = 0,469 Cohen's d d = 0.352 CAL A-PRF+ 10.93 ± 2.79 8.6 ± 2.56 p < 0.0001 -2.33 ± 1.588 p = 0.0001 EMD 10.60 ± 1.76 8.00 ± 1.77 p < 0.0001 -2.6 ± 1.18 p = 0.0000 p = 0,461 Cohen's d d = 0.197 BS A-PRF+ 9.60 ± 1.68 5.67 ± 0.89 p < 0,0001 -3.93 ± 1.98 p = 0.0000 EMD 9.47 ± 1.68 5.67 ± 0.81 p 0.999) A-PRF+ EMD total PD decrease 15 15 30 total 15 15 30 GR decrease 0 1 1 no change 5 4 9 increase 10 10 20 total 15 15 30 Fisher's exact 1.000 CAL decrease 13 15 28 no change 2 0 2 15 15 30 Fisher's exact 0.483 BS decrease 14 14 28 no change 1 1 2 15 15 30 Fisher's exact 1.000 After 6 months, the mean GR increase was 3.93 ± 2.73 mm in the test group and 3.33 ± 1.58 mm in the control group. The increase in GR was statistically significant for both groups (p < 0.01), but no difference between the groups was observed. The mean CAL gain was 2.33 ± 1.58 mm in the A-PRF + group and 2.60 ± 1.18 mm in the EMD group (p < 0.001). In both groups, the CAL has improved significantly compared to baseline, but no statistically significant difference was found between the two groups. After 6 months, the mean BS has decreased to 5.67 ± 0.89 mm in the test group and to 5.67 ± 0.81 mm in the control group. Compared to baseline data 9.60 ± 1.68 mm in the test group, respectively 9.47 ± 1.68 mm in the control group, the mean BS reduction was significant (p < 0.001), but no difference between the groups was observed, the results obtained with both materials were similar. (Table 3 .) Discussion One of the main benefits of PRF is the fibrin network that promote not only blood clot formation but also tissue repair mechanisms [27]. Compared to PRP, the kinetics of growth factor release appear to be slower, thus affecting regeneration over a longer period of time [28]. More and more studies are drawing attention to the beneficial effect of leukocytes on healing as well as tissue regeneration, and not least the importance of the quality of the fibrin network. The leukocytes it contains have both anti-infective and immunoregulatory functions [29–32], but also produce significant amounts of VEGF [33]. These factors, in addition to platelet-derived angiogenesis-stimulating factors, may have a positive impact on proper blood supply of the healing wound. White blood cells are involved in the early stimulation of osteo-progenitor cells and promote the differentiation of monocytes into macrophages [16, 33–36]. Many controlled randomized clinical trials investigated the use of PRF for the repair/regeneration of periodontal intrabony defects [37–41]. All studies demonstrated that the additional application of PRF increased PD reductions and CAL gains compared to open flap debridement alone. In a recent publication the supplementation of PRF with EMD did not result in a difference between the study and control (EMD only) groups [42]. The efficacy of PRF and EMD in the treatment of intrabony defects was compared in a clinical and a cone beam computed tomography study. Based on the obtained results, both materials were effective in the treatment of intrabony defects, however EMD was significantly superior in terms of percentage defect resolution [43]. Although these clinical trials have all shown that the use of PRF results in statistically significant CAL gains and PD reduction, it is important to emphasize that histological examination would be necessary to confirm whether the obtained results correspond to a periodontal regeneration or a periodontal repair. It has been demonstrated that the biological benefits of PRF act locally by rapidly stimulating a large number of cell types by influencing their recruitment, proliferation and/or differentiation [15]. Based on the available literature, it seems that PRF favours the regeneration of soft tissues rather than hard tissues [44]. In the treatment of intrabony defects where space maintenance is not an issue, blood clot formation alone could be enough [45], the additional use of PRF acts primarily as a scaffold, inserted into the periodontal pocket may promote tissue regeneration [17]. More research is needed to determine which factors in the PRF clots (cells/leukocytes, growth factors, or fibrin matrix) are most required to accelerate the regeneration of periodontal tissues. Data from in vitro studies indicates that EMD may also influence periodontal wound healing by an indirect stimulatory effect on the release of growth factors during periodontal wound healing and by inhibiting or at least retarding epithelial down-growth [46]. The modification of the preparation protocol by reducing the applied centrifugation force (RCF), resulted in an improved preparation protocol for advanced PRF (A-PRF) using 208 g RCF. Compared to PRF the A-PRF clot showed a more porous structure with a larger interfibrous space, where cells (particularly platelets) were observed in even distributions throughout the entire clot, furthermore histological analysis of A-PRF has showed a significantly higher number of neutrophile granulocytes [44]. Described by Fujioka-Kobayashi et al., it has been found that the total growth factor release could be enhanced by reducing both centrifugation speed and time. A-PRF + showed similar porosity to A-PRF, furthermore over the entire clot the cellular distribution pattern it has showed evenly dispersed platelets. These observations emphasize the improved regenerative capacity of advanced PRF matrices [20]. The results of the present study obtained after six months post-surgically clearly indicate the significant improvement of the following parameters: PD, CAL, BS in both groups. No adverse reactions have been observed throughout the first six months, which clearly indicates that the use of autologus test material has been well tolerated. As a result of surgery and cessation of inflammation, the rate of gingival recession became significantly higher in both groups compared to the baseline. Upon intergroup comparison the GR increase was found to be non-significantly different. The cause of gingival recession observed after periodontal surgery does not necessarily depend on the methods. However, the gingival biotype can significantly affect the extent of the recession. At the same time, a significant improvement in clinical probing pocket depth resulted in a significant enhancement of the clinical attachment level. In addition to the significant improvement of bone sounding values, radiographs taken with the “long-cone” technique also suggest the presence of bone filling. (Fig. 1 .,2.) There was no significant difference between the test and control groups in the first 6 months after surgery and the results obtained with both materials were similar. The amount of gingival recession seems to be lower in the control group. Thus, it appears that the clinical benefit of both treatments is not only treats intrabony defects, but also improves PD values by facilitating plaque control and maintenance. However, when interpreting these findings, we must keep in mind that currently no other data evaluating the treatment of intrabony defects with A-PRF+ / EMD is available. Therefore, direct comparisons with other studies are not possible at this point in time. On the other hand, it also needs to be considered that the lack of a difference between the two groups can additionally be related to the rather limited number of treated defects (e.g. 15 defects in each group) and therefore, the study may not have the statistical power to rule out the possibility of a difference between the two groups. For superiority trials in the treatment of periodontal intrabony defects, a sample size of approximately 30 persons per group has been estimated to be required [47]. Finally, the present study using a new generation of PRF seems to open new horizons in the investigation of the effects of platelet-concentrates on periodontal healing. However, other randomized, clinical trials with a bigger population and with histological evaluation of periodontal regeneration will be necessary to confirm the results of this study. Conclusion In view of above findings and within the limitations of the current study, the results indicate that the new-generation platelet rich fibrin behaves just as effectively as enamel matrix derivatives in the surgical treatment of intrabony periodontal defects. Based on the 6-month results, both methods resulted in comparable outcomes and presented no significant differences between the test and control groups. A-PRF + seems to be suitable for the treatment of intrabony periodontal defects. List of abbreviations A-PRF : advanced platelet-rich fibrin EMD : enamel matrix derivative PRP : platelet-rich plasma PRG : platelet-rich gel PRF : platelet-rich fibrin GDF’s : growth and differentiation factors CAP : concentrated autologous products PDGF : platelet-derived growth factor TGF-β : transforming growth factor beta L-PRF : leukocyte- and platelet-rich fibrin EGF : epidermal growth factor IGF : insulin-like growth factor VEGF : vascular endothelial growth factor rhGF : recombinant human growth factors PD : probing depth GR : gingival recession CAL : clinical attachment level BS : bone sounding FMBS : full-mouth bleeding score FMPS : full-mouth plaque score EDTA : ethylenediamine tetraacetic acid Declarations Ethics approval and consent to participate This study was planned as a randomized, controlled, prospective clinical trial. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol was approved by the ethics committee of the Semmelweis University Budapest (approval number: SE TUKEB: 254/2017). The study protocol was registered at ClinicalTrials.gov with ID number NCT04404374. All the included patients signed an informed consent which was previously approved by an institutional ethic committee. Consent for publication Written informed consent for publication was obtained. Availability of data and materials Authors can confirm that all relevant data are included in the article and/or its supplementary information files. Competing interests The authors declare that they have no competing interests. Funding The study materials have been procured as a result of a tender organized by the Semmelweis University, School of Dental Medicine, Budapest, Hungary. Authors' contributions BCsN participated in the design of the study, carried out surgical procedures, analysis and interpretation of data and drafting the manuscript. ES contributed to acquisition of data. VLB contributed to patient administration. AN contributed to pre- and postsurgical periodontal management. FD had the main responsibility for conception and design of the study, involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final version of the manuscript. Acknowledgements The authors acknowledge to Laszlo Dr Kardos, who performed the statistical analysis and contributed to interpretation of data. 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Oral Implantol. 2014, 40:679–DOI: 10.1563/aaid-joi-D-14-00138 Cabaro S , D'Esposito V , Gasparro R , Borriello F , Granata F , Mosca G , Passaretti F , Sammartino JC , Riccitiello F , Beguinot F , Formisano P , Sammartino G : White cell and platelet content affects the release of bioactive factors in different blood-derived scaffolds. Platelets . 2017, 21:1-5. DOI: 1080/09537104.2017.1319046 Fujioka-Kobayashi M , Miron RJ , Hernandez M , Kandalam U , Zhang Y , Choukroun J : Optimized Platelet-Rich Fibrin With the Low-Speed Concept: Growth Factor Release, Biocompatibility, and Cellular Response. J Periodontol . 2017, 88:112-121. DOI: 1902/jop.2016.160443 Tonetti MS, Greenwell H, Kornman KS: Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Periodontol. 2018, 89:S159-72. DOI: 1002/JPER.18-0006 Tonetti MS, Pini-Prato GP, Cortellini P: Effect of cigarette smoking on periodontal healing following GTR in infrabony defects. A preliminary retrospective study. J Clin Periodontol. 1995, 22:229-234.DOI: 1111/j.1600-051x.1995.tb00139.x Cortellini P, Prato GP, Tonetti M: Periodontal regeneration of human infrabony defects. I. Clinical measures. J Periodontol. 1993, 64:254-260. DOI: 1902/jop.1993.64.4.254 O’Leary TJ, Drake RB, and Naylor JE : The Plaque Control Record. Journal of Periodontology. 1972, 43(1):38–38. DOI: 1902/jop.1972.43.1.38 Cortellini P, Tonetti M: Radiographic defect angel influences the outcome of GTR therapy in intrabony defects. J Dent Res. 1999, 78:381. Blomlöf JPS, Blomlöf LB, Lindskog SF: Smear removal and collagen exposure after non-surgical root planing followed by etching with an EDTA gel preparation. J Periodontol . 1996, 67:841-845.DOI: 1902/jop.1996.67.9.841 Toffler M, Toscano N, Holtzclaw D, Corso M, Dohan D: Introducing Choukroun’s platelet rich fibrin (PRF) to the reconstructive surgery milieu. J Implant Adv Clin Dent. 2009, 1:22–31. Kobayashi E, Fluckiger L, Fujioka-Kobayashi M, Sawada K, Sculean A, Schaller B, et al: Comparative release of growth factors from PRP, PRF, and advanced-PRF. Clinical Oral Investigations. 2016, 20(9):2353-2360.DOI: 1007/s00784-016-1719-1 Dohan DM et al: Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part III: leucocyte activation: a new feature for platelet concentrates? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006, 101(3):51-55.DOI: 1016/j.tripleo.2005.07.010 Everts PA et al: What do we use: platelet-rich plasma or platelet-leukocyte gel? J Biomed Mater Res A. 2008, 85:1135-1136. Cieslik-Bielecka A et al: Why the platelet-rich gel has antimicrobial activity? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007, 103:303-305.DOI: 1016/j.tripleo.2006.08.034 Moojen DJ et al: Antimicrobial activity of platelet-leukocyte gel against Staphylococcus aureus. J Orthop Res. 2008, 26:404-410.DOI: 1002/jor.20519 Werther K et al. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets. Scand J Clin Lab Invest . 2002, 62:343-350. DOI: 1080/00365510260296492 Ghanaati S, Booms P, Orlowska A, Kubesch A, Lorenz J, Rutkowski J, Landes, Sader R, Kirkpatrick C, Choukroun J: Advanced platelet-rich fibrin: a new concept for cell-based tissue engineering by means of inflammatory cells. J Oral Implantol. 2014, 40:679-89. DOI: 1563/aaid-joi-D-14-00138 Kawase T et al: Platelet-rich plasma-derived fibrin clot formation stimulates collagen synthesis in periodontal ligament and osteoblastic cells in vitro. J Periodontol. 2003, 74:858-864.DOI: 1902/jop.2003.74.6.858 Clark RA: Fibrin and wound healing. Ann of the New York Academy of Sciences. 2001, 936:355–67. DOI: 1111/j.1749-6632.2001.tb03522.x Sharma A and AR Pradeep: Treatment of 3-wall intrabony defects in patients with chronic periodontitis with autologous platelet-rich fibrin: a randomized controlled clinical trial. J Periodontol. 2011, 82(12):1705-12.DOI: 1902/jop.2011.110075 Thorat M, AR Pradeep, and B Pallavi: Clinical effect of autologous platelet-rich fibrin in the treatment of intrabony defects: a controlled clinical trial. J Clin Periodontol. 2011, 38(10):925-32.DOI: 1111/j.1600-051X.2011.01760.x Pradeep AR et al: Comparative evaluation of autologous platelet-rich fibrin and platelet-rich plasma in the treatment of 3-wall intrabony defects in chronic periodontitis: a randomized controlled clinical trial. J Periodontol. 2012, 83(12):1499-507.DOI: 1902/jop.2012.110705 Ajwani H, Shetty S, Gopalakrishnan D, Kathariya R, Kulloli A, Dolas RS, et al. Comparative evaluation of platelet-rich fibrin biomaterial and open flap debridement in the treatment of two and three wall intrabony defects. Journal of International Oral Health: JIOH. 2015, 7(4): 32–37. PMCID: PMC4409793 Patel GK, Gaekwad SS, Gujjari SK: Platelet-Rich Fibrin in Regeneration of Intrabony Defects: A Randomized Controlled Trial. J Periodontol. 2017, 88(11):1192-1199. DOI: 1902/jop.2017.130710 Aydemir Turkal H, Demirer S, Dolgun A, Keceli HG: Evaluation of the adjunctive effect of platelet-rich fibrin to enamel matrix derivative in the treatment of intrabony defects. Six-month results of a randomized, split-mouth, controlled clinical study. Journal of Clinical Periodontology. 2016, 43(11):955–64. DOI: 1111/jcpe.12598 Gupta SJ, Jhingran R, Gupta V, Bains VK, Madan R and Rizvi I: Efficacy of platelet-rich fibrin vs. enamel matrix derivative in the treatment of periodontal intrabony defects: a clinical and cone beam computed tomography study. J Int Acad Periodontol. 2014, 16:86-96. Miron RJ, Fujioka-Kobayashi M, Bishara M, Zhang Y, Hernandez M, Choukroun J: Platelet-Rich Fibrin and Soft Tissue Wound Healing: A Systematic Review. Tissue engineering Part B, Reviews. 2017 Feb;23(1):83-99. DOI: 1089/ten.TEB.2016.0233 Cortellini T, Tonetti M: Improved wound stability with a modified minimally invasive surgical technique in the regenerative treatment of isolated interdental intrabony defects. J Clin Periodontol. 2009, 36(2):157-63. DOI: 1111/j.1600-051X.2008.01352.x Van der Pauw MT, Van den Bos T, Everts V and Beertsen W: Enamel matrix- derived protein stimulates attachment of periodontal ligament fibroblast and enhances alkaline phosphatase activity and transforming growth factor b1 release of periodontal ligament and gingival fibroblasts. Journal of Periodontology. 2000, 71:31–43. Gunsolley JC, Elswick RK and Davenport JM: Equivalence and superiority trials in regeneration clinical trials. Journal of Periodontology. 1998, 69:521–527. DOI: 1902/jop.1998.69.5.521 Supplementary Files CONSORT2010Checklist.docx Cite Share Download PDF Status: Published Journal Publication published 15 Nov, 2021 Read the published version in BMC Oral Health → Version 1 posted Editor assigned by journal 13 May, 2021 Reviewers invited by journal 13 May, 2021 Reviewer # 1 agreed at journal 13 May, 2021 Submission checks completed at journal 13 May, 2021 Editor invited by journal 13 May, 2021 First submitted to journal 05 May, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-525471","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":27052058,"identity":"fed31afd-40de-4b52-8ef3-fc39c6ea3c49","order_by":0,"name":"Boroka Klara Csifo-Nagy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYDCCA0CcYMMgB2Y/IF5LGoMxmJ1AtBaGNIbEBhBNlBa+24cff3iQYJM+P+zwQ6AtdnK6DQS0SJ5LM5NISEjL3Xg7zQCoJdnY7AABLQZneNgYEn8czt04OwGk5UDiNiK0MH9ISDicbjg7/QPRWhiADjucIC+dQ6QtkmfYwH4x3CCdU3AgwYAIv/CdYX788UeCjbz87PTNHz5U2MkR1IJwIVilAbHKQUC+gRTVo2AUjIJRMKIAAC4/R6jU0djdAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9454-2916","institution":"Semmelweis Egyetem Fogorvostudomanyi Kar","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Boroka","middleName":"Klara","lastName":"Csifo-Nagy","suffix":""},{"id":27052059,"identity":"22b2a573-be22-4eec-b5bd-c6c4fdc106bc","order_by":1,"name":"Eleonora Solyom","email":"","orcid":"","institution":"Semmelweis Egyetem Fogorvostudomanyi Kar","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eleonora","middleName":"","lastName":"Solyom","suffix":""},{"id":27052060,"identity":"de97dccb-cde1-4c2f-a77e-002d75199d8a","order_by":2,"name":"Vera Lili Bognar","email":"","orcid":"","institution":"Semmelweis Egyetem Fogorvostudomanyi Kar","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vera","middleName":"Lili","lastName":"Bognar","suffix":""},{"id":27052061,"identity":"03833aa3-be7a-4efb-8448-7e13237ad4a1","order_by":3,"name":"Annamaria Nevelits","email":"","orcid":"","institution":"Semmelweis Egyetem Fogorvostudomanyi Kar","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Annamaria","middleName":"","lastName":"Nevelits","suffix":""},{"id":27052062,"identity":"fc57c4ae-7836-416c-bdd2-3138dd0f42f2","order_by":4,"name":"Ferenc Dori","email":"","orcid":"","institution":"Semmelweis Egyetem Fogorvostudomanyi Kar","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ferenc","middleName":"","lastName":"Dori","suffix":""}],"badges":[],"createdAt":"2021-05-14 13:57:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-525471/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-525471/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12903-021-01925-1","type":"published","date":"2021-11-15T11:49:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":9313221,"identity":"28b814d0-e77a-4912-925e-933aef75ae1b","added_by":"auto","created_at":"2021-05-18 20:33:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129283,"visible":true,"origin":"","legend":"Treatment of an intrabony defect at a lawer jaw premolar with A-PRF+ \na - Preoperative measurements\nb - Defect after debridement - intraoperative measurements\nc - Product after centrifugation in the PRF Box (Process for PRF®)\nd - Prepared product (RBC + A-PRF+)\ne - Intrabony defect filled with A-PRF+\nf - Wound closure\ng - 6 months after surgery\nh - i - Radiographic evaluation before and 6 months after surgery ","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-525471/v1/358572d87855aa4617715044.jpg"},{"id":9313442,"identity":"c310f01b-27be-4e3d-b80a-b7eae03b0c3a","added_by":"auto","created_at":"2021-05-18 20:36:35","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82646,"visible":true,"origin":"","legend":"Treatment of an intrabony defect at an upper jaw molar with EMD \na - Defect after debridement - intrabony defect filled with EMD\nb - Wound closure\nc - 6 months after surgery\nd - e - Radiographic evaluation before and 6 months after surgery","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-525471/v1/83a7c6ef6823543b3a9bdd80.jpg"},{"id":9313488,"identity":"711bb828-769c-43a4-81be-2f4dd3b80370","added_by":"auto","created_at":"2021-05-18 20:39:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":89322,"visible":true,"origin":"","legend":"Flow diagram of patient enrollment and study process","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-525471/v1/0d42b5dd8eac5c8cf331c05c.jpg"},{"id":15539660,"identity":"dfd7ccf1-795e-41dc-a1ad-a8a042083443","added_by":"auto","created_at":"2021-11-15 11:49:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":581483,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-525471/v1/3a026ceb-b528-4265-afc9-94e822b62e7f.pdf"},{"id":9313444,"identity":"7b07345f-0f49-4c2a-996c-5efa6f66a3d7","added_by":"auto","created_at":"2021-05-18 20:36:36","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":153795,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-525471/v1/aee1566162c80184c63e5cfe.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEfficacy of a New-generation Platelet-rich Fibrin in the Treatment of Periodontal Intrabony Defects: a Randomized Clinical Trial\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eThe main goal of the comprehensive periodontal treatment is to eliminate inflammation and to prevent further destruction of the periodontium, as well as to achieve long-term sustainable condition. Over the past decades, significant efforts have been made to develop materials and also surgical techniques that can predictably contribute to periodontal regeneration [1]. Nowadays, regenerative periodontal therapy can only restore a part of the original tissue to some extent, while the complete periodontal restoration remains idealistic [2]. More than 20 years have passed since enamel matrix derivatives (EMD) were introduced to enhance periodontal regeneration by mimicking the formation of periodontal attachment tissues. They play an important role as chemical barriers and biological mediators in periodontal regeneration and healing [3]. Advances in cell and molecular biology have contributed to an increased understanding of wound healing. There is evidence that polypeptide growth and differentiation factors (GDF\u0026rsquo;s) can support wound healing and regeneration by regulating chemotaxis, differentiation, proliferation of cells and matrix synthesis. However, only a few factors have reached clinical evaluation, earlier research has just targeted finding of the optimal dosage and the combination of growth and differentiation factors [4]. Data from long-term follow-up clinical studies demonstrated that treatment of deep periodontal intrabony defects with EMD resulted in a significant increase of clinical attachment gain and bone fill compared to the \u0026ldquo;open flap debridement\u0026rdquo; [5\u0026ndash;8]. In periodontal application of chemical-biological factors, a new period followed by the introduction of autologous platelet concentrates (Platelet-Rich Plasma - PRP, Platelet-Rich Gel - PRG, Platelet-Rich Fibrin - PRF) [9\u0026ndash;13]. A strategy to promote wound healing is to amplify and accelerate the effect of released growth factors (GF\u0026rsquo;s), which can accelerate the healing of bone defects and promote periodontal regeneration. The simplest way to achieve these goals is to activate the local release of platelet-derived growth factors, which are common triggers in almost all wound healing processes. A method for the intraoral application of concentrated autologous products (CAP) has been developed for more than two decades. The use of PRP is based on the effect of growth factors released from concentrated platelets on healing and tissue regeneration [14\u0026ndash;15].\u003c/p\u003e \u003cp\u003eWith the advancements made in platelet - rich concentrates formulations over the past decade, PRF has been introduced and utilized as a supra-physiological concentration of autologous growth factors without necessitating the use of anticoagulants [13,16]. The PRF is a product that enhances wound healing, unlike PRP. The beneficial effects of PDGF\u0026rsquo;s, TGF-beta (platelet-derived growth factor, transforming growth factor beta) and other GF\u0026rsquo;s released from platelets can be recorded not only in the early stages of wound healing, but also its effects last longer and appear at a slower rate [9, 17].\u003c/p\u003e \u003cp\u003eA new generation of platelet-rich fibrin formulation has been introduced in 2014 by Choukroun et al., the Advanced Platelet Rich Fibrin (A-PRF), which is obtained by a lower speed centrifugation [18]. Standard leukocyte-rich PRF (L-PRF) and A-PRF obtained through the experimental \u0026ldquo;low-force modified procedure\u0026rdquo; are ideal sources of leukocytes that act directly on the release of chemokines and growth factors. Although A-PRF \u0026ldquo;traps\u0026rdquo; the same number of leukocytes as L-PRF and releases the same amount of inflammatory cytokines, it contains higher amounts of PDGF and VEGF [19]. Another study found that A-PRF also contained significantly more TGF-β1, EGF, and IGF, and had shown significantly higher human fibroblast migration and proliferation than L-PRF. From this study, it appears that reducing the centrifugation rate favors the growth factors released from the PRF clot [20]. The new version of A-PRF (2017) is the A-PRF\u0026thinsp;+\u0026thinsp;product, in which case the centrifugation takes even less time (low-speed\u0026thinsp;+\u0026thinsp;time procedure). Described by Fujioka-Kobayashi et al., the newer formulation of A-PRF (A-PRF\u0026thinsp;+\u0026thinsp;means not only lower centrifugation speed, but also less time \u0026minus;\u0026thinsp;1300 rpm for 8 min) and demonstrated an increased growth factor release of TGF-beta1, PDGF-AA, PDGF-AB, PDGF-BB, VEGF, IGF, and also EGF. When compared to L-PRF and A-PRF, A-PRF\u0026thinsp;+\u0026thinsp;it has demonstrated a significant increase in growth factor release within either 1, 3, or 10 days [20]. In conclusion, results show that the total growth factor release could be enhanced by reducing both centrifugation speed and time in A-PRF+. The examination of the fibrin network in terms of structural integrity, A-PRF\u0026thinsp;+\u0026thinsp;showed similar porosity to A-PRF, furthermore over the entire clot the cellular distribution pattern showed evenly dispersed platelets. These observations emphasize the improved regenerative capacity of advanced PRF matrices.\u003c/p\u003e \u003cp\u003eThe research and application of EMD as practically non-human biological mediators (Emdogain\u0026reg;, Straumann\u0026reg;, Basel, Switzerland) in periodontal regenerative surgery, although dating back more than two decades still raises a number of unanswered or ambiguously answered questions. Research on the use of autologous growth and differentiation factors as well as recombinant growth factors (rhGF\u0026rsquo;s) as biological mediators in periodontal regenerative procedures has a relatively shorter history and offers many additional opportunities for researchers. Examining the new generation of PRF is an even more topical task.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eOur aim was to investigate the further role of human autologous platelet concentrates in periodontal healing and regeneration. We tested the role and clinical applicability of a new generation of platelet-rich fibrin, \u0026ldquo;Advanced Platelet-Rich Fibrin (A-PRF+)\u0026rdquo;, in periodontal wound healing. The clinical data obtained during the study were compared with the results of a well-known and successfully applied regenerative method. The null hypothesis of the study was whether an autologous material (A-PRF+) can be a reliable alternative in surgery of intrabony defects.\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design\u003c/h2\u003e\n\u003cp\u003eThis study was planned as a randomized, controlled, prospective clinical trial, performed in accordance with the Helsinki Declaration of 1975, as updated in 2013, and the protocol was approved by the ethics committee of the Semmelweis University Budapest (SE TUKEB: 254/2017). The study protocol was retrospectively registered at ClinicalTrials.gov with ID number NCT04404374.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in the Department of Periodontology, Semmelweis University, Budapest, Hungary. It was initiated in June 2018 and completed in November 2019 by the same experienced periodontist (BCSN). Each participant has been explained the risks, benefits, and the procedure in his/her native language and written informed consent was obtained.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy population\u003c/h2\u003e\n\u003cp\u003eAccording to the new classification proposed by the World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions (2017), the patients were classified into stage III. periodontitis [21]. The patients initially received cause-related periodontal therapy, consisting of oral hygiene instruction, motivation and sub-gingival scaling/root planing under local anaesthesia. The patients were consecutively enrolled when the following inclusion criteria was met: 1) no systemic diseases that could influence the outcome of the therapy; 2) no smoking [22]; 3) good level of oral hygiene with Full-Mouth Bleeding Score\u0026thinsp;\u0026lt;\u0026thinsp;20% [23] and Full- Mouth Plaque Index Score\u0026thinsp;\u0026lt;\u0026thinsp;20% [24]; 4) presence of a minimum one or more 2-, 3-, or combined 2-3-wall intrabony defect with a defect angle of 20\u0026ndash;40 (+/- 5) degrees, as the radiographic defect angle influences the outcome of regenerative surgical therapy in intrabony defects [25] and with a minimum probing depth (PD) of 6 mm and intrabony component of a minimum 4 mm.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eClinical parameters\u003c/h2\u003e\n\u003cp\u003eThe following clinical parameters were assessed at baseline (1 week before surgery) and at six months after the surgery, using the same type of periodontal probe (UNC-15, Hu-Friedy, Chicago, IL, USA): Full-Mouth Plaque Score (FMPS) [24] and Full-Mouth Bleeding Score (FMBS) [23], pocket depth (PD), gingival recession (GR), clinical attachment level (CAL) and transgingival bone sounding (BS). The primary outcome was CAL gain. Radiographs were performed with \u0026ldquo;long cone\u0026rdquo; technique before surgery, and 6 month post-surgically. The clinical measurements were made at six sites per tooth, mesio-buccal, mid-buccal, disto-buccal, mesio-lingual, mid-lingual, and disto-lingual, by the same experienced, calibrated investigator (ES), and the highest PD value was taken in consideration.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eBlinding and calibration\u003c/h2\u003e\n\u003cp\u003eThe examiner was not aware of the type of treatment rendered in any of the cases. The measurements were rounded up to the nearest millimeter.\u003c/p\u003e\n\u003cp\u003eTo calibrate the examiner five patients were used, each showing 10 teeth (single and multi- rooted) with PDs\u0026thinsp;\u0026gt;\u0026thinsp;6 mm on at least one aspect of each tooth. The examiner evaluated the patients on two separate occasions, 48 hours apart. Calibration was accepted if\u0026thinsp;\u0026gt;\u0026thinsp;90% of the recordings could be reproduced within 1.0-mm difference.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eRandomization\u003c/h2\u003e\n\u003cp\u003eThe defects were randomly allocated by computerised random number generator (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.sealedenvelope.com\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"Underline\"\u003e)\u003c/span\u003e and treated with either A-PRF+ (test group) and EMD (control group).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003ePreparation of A-PRF+\u003c/h2\u003e\n\u003cp\u003eImmediate before surgery A-PRF\u0026thinsp;+\u0026thinsp;was prepared for the test group using a commercially available PRF Kit [Process for PRF\u0026reg; (A-PRF), J. Choukroun, Nice, France] and \"Process for PRF Duo\u0026rdquo; (Choukroun) centrifuge. Cubital venous blood was drawn from the patient without the addition of anticoagulant into two 10 ml vacuum tubes (A-PRF\u0026thinsp;+\u0026thinsp;tube, Choukroun 2017) and immediately centrifuged at 1300 rpm for 8 minutes, then allowed to rest for 5 minutes [20]. During centrifugation, 3 layers are formed in the tube at the start of the coagulation cascade. The top layer is the Platelet-Poor Plasma (PPP), the middle layer is the Platelet-Rich Fibrin \u0026ldquo;clot\u0026rdquo; (PRF) is to be used, and the bottom layer is the Red Blood Cells (RBC\u0026rsquo;s) layer. The PRF \"clot\" still in the gel condition is removed from the tube, cleaned of red blood cells and used as a gel.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eSurgical procedure\u003c/h2\u003e\n\u003cp\u003eSurgery was performed by a single experienced operator (BCSN). After administration of local anesthesia intracrevicular incisions were performed extending to the adjacent teeth, with the additional precaution to preserve the maximum of interdental gingival tissue. Full-thickness buccal and oral extended flaps were raised, and all granulation tissue was removed from the defect without bone recontouring. The roots were thoroughly scaled and planed by means of hand and ultrasonic instruments. After defect debridement, in the test group A-PRF\u0026thinsp;+\u0026thinsp;was applied. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.) In the control group after debridement the root surface adjacent to the defect was conditioned for 2 minutes with 24% ETDA gel (pH 6.7) (PrefGel, Straumann\u0026reg;, Basel, Switzerland) [26]. The defect and the adjacent mucoperiosteal flap were then thoroughly rinsed with sterile saline to remove all EDTA residue, and then Straumann\u0026reg; Emdogain\u0026reg; was applied. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.) Finally, the flap was repositioned coronally and closed thoroughly with 5.0. non-absorbable modified vertical or horizontal mattress sutures (Dafilon\u0026reg; 5.0. monofilament and uncoated polyamide, B. Braun Surgical S.A. Barcelona, Spain).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003ePostoperative care\u003c/h2\u003e\n\u003cp\u003eAll patients have received antibiotics for a week, two times daily (Augmentin Duo, 875mg amoxycillin/125mg clavulanic acid, GlaxoSmithKline, Brentford, United Kingdom). The postoperative care consisted of 0.2% chlorhexidine (Curasept ADS 220, Curaden AG, Kriens, Switzerland) rinses two times daily for 3 weeks. Patients were advised not to use mechanical means of plaque control in the surgical area for more weeks. Sutures were removed 14 days after surgery. Instructions for maintenance of proper oral hygiene were reinforced. Study participants were scheduled for a follow-up visit weekly for one-month post-surgery and subsequently at three and respectively six months interval.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analyses\u003c/h2\u003e\n\u003cp\u003eFor the clinical parameters, data was evaluated using descriptive analysis with results illustrated as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, range at baseline and 6 months interval. The statistical package Stata (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) was used for data handling and analysis.\u003c/p\u003e\n\u003cp\u003eDefects identified (rather than patients) were treated as the unit of observation. Generally, two samples of 15 observations each are adequately powered (80%) to detect a between-groups difference of 1.06 standard deviations (SD) in a continuous variable, assuming equal SDs across groups. Post-hoc power calculations were carried out for between-groups comparisons at 6 months and within-group comparisons (6 months vs baseline) for each outcome. Within-group changes were evaluated using paired t-tests (or Wilcoxon\u0026rsquo;s matched-pairs signed-ranks test if parametric assumptions were not satisfied), and between-groups comparisons were made using two-sample t-tests (or Wilcoxon\u0026rsquo;s rank-sum tests if parametric assumptions were not satisfied). P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance. Regarding frequency distribution changes from baseline to 6 months were categorized in each outcome as decrease, no change, and increase. To compare the two groups in terms of these, Fisher\u0026rsquo;s exact test was used. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants and Recruitment\u003c/h2\u003e\n\u003cp\u003eThe study flowchart is illustrated on Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. This study has enrolled thirty (30) intrabony defects of 18 non-smoking patients (nine males and nine females) age 55.5 +/- 14.5 years, suffering from chronic periodontitis. Among patients the defect distribution was proportional. Baseline and postoperative FMBS and FMPS values were comparable, FMBS values decreased after surgery. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.) Post-hoc power calculations for between-groups comparison of PD and BS values were not estimable because the two group means at 6 months were identical. For GR and CAL values, there was an estimated 11% power. For within-group comparisons, power estimates of at least 99.8% were obtained for all outcomes.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline and postoperative FMBS and FMPS values\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFMBS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 months postop.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFMPS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 months postop.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients have completed the respective study. The postoperative healing was uneventful in all cases. No complications such as allergic reactions, abscesses or infections were identified throughout the entire study period. The trial was terminated after the completion of the six-month follow-up and analysis of the data of 30 intrabony defects, which displayed a comparable distribution and configuration in the two groups. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDistribution and configuration of treated defects\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTooth Location\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaxilla\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMandible\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnterior teeth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePremolars\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMolars\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDefect Configuration\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2-wall\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3-wall\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2-3-wall combined\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo statistically significant differences were found between the two groups regarding the mean values of the baseline clinical parameters. After 6 months, the mean PD has decreased significantly in both groups compared to baseline data (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The mean PD reduction was 4.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62 mm in the A-PRF\u0026thinsp;+\u0026thinsp;group and identically 4.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62 mm in the EMD group. No statistically significant difference between the groups was found. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" style=\"width: 470px;\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eWithin group comparisons / Intergroup changes (significance: p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth style=\"width: 55px;\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth style=\"width: 71px;\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e6 months postop.\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"width: 76px;\" align=\"left\"\u003e\n\u003cp\u003eDiff.\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e4.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-3.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e4.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-3.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ep =\u0026nbsp;0,999\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eCohen's d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ed = -0.092\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e3.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0025\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0025\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e2.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e3.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0044\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0044\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,469\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eCohen's d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ed\u0026thinsp;=\u0026thinsp;0.352\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCAL\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e10.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.588\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e10.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e8.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,461\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eCohen's d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ed\u0026thinsp;=\u0026thinsp;0.197\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eA-PRF+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e9.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e5.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0,0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-3.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eEMD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e9.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003e5.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0,0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e-3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\n\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ep =\u0026nbsp;0,999\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 55px;\" align=\"left\"\u003e\n\u003cp\u003eCohen's d\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 108px;\" align=\"left\"\u003e\n\u003cp\u003ed = -0.077\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 76px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"width: 60px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 4\u003c/p\u003e\n\u003cp\u003eFrequency distribution of the results (intergroup comparison, p \u0026gt; 0.999)\u003c/p\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eA-PRF+\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eEMD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003etotal\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003edecrease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003etotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eGR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003edecrease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eno change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eincrease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003etotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35.375px;\"\u003e\n\u003ctd style=\"height: 35.375px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;Fisher's exact\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.375px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.375px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.375px;\" width=\"158\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eCAL\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003edecrease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eno change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eFisher's exact\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e0.483\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u003cstrong\u003eBS\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003edecrease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eno change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003eFisher's exact\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"158\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter 6 months, the mean GR increase was 3.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73 mm in the test group and 3.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58 mm in the control group. The increase in GR was statistically significant for both groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), but no difference between the groups was observed.\u003c/p\u003e\n\u003cp\u003eThe mean CAL gain was 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58 mm in the A-PRF\u0026thinsp;+\u0026thinsp;group and 2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18 mm in the EMD group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In both groups, the CAL has improved significantly compared to baseline, but no statistically significant difference was found between the two groups.\u003c/p\u003e\n\u003cp\u003eAfter 6 months, the mean BS has decreased to 5.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89 mm in the test group and to 5.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81 mm in the control group. Compared to baseline data 9.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68 mm in the test group, respectively 9.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68 mm in the control group, the mean BS reduction was significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but no difference between the groups was observed, the results obtained with both materials were similar. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eOne of the main benefits of PRF is the fibrin network that promote not only blood clot formation but also tissue repair mechanisms [27]. Compared to PRP, the kinetics of growth factor release appear to be slower, thus affecting regeneration over a longer period of time [28]. More and more studies are drawing attention to the beneficial effect of leukocytes on healing as well as tissue regeneration, and not least the importance of the quality of the fibrin network. The leukocytes it contains have both anti-infective and immunoregulatory functions [29\u0026ndash;32], but also produce significant amounts of VEGF [33]. These factors, in addition to platelet-derived angiogenesis-stimulating factors, may have a positive impact on proper blood supply of the healing wound. White blood cells are involved in the early stimulation of osteo-progenitor cells and promote the differentiation of monocytes into macrophages [16, 33\u0026ndash;36].\u003c/p\u003e \u003cp\u003eMany controlled randomized clinical trials investigated the use of PRF for the repair/regeneration of periodontal intrabony defects [37\u0026ndash;41]. All studies demonstrated that the additional application of PRF increased PD reductions and CAL gains compared to open flap debridement alone. In a recent publication the supplementation of PRF with EMD did not result in a difference between the study and control (EMD only) groups [42]. The efficacy of PRF and EMD in the treatment of intrabony defects was compared in a clinical and a cone beam computed tomography study. Based on the obtained results, both materials were effective in the treatment of intrabony defects, however EMD was significantly superior in terms of percentage defect resolution [43]. Although these clinical trials have all shown that the use of PRF results in statistically significant CAL gains and PD reduction, it is important to emphasize that histological examination would be necessary to confirm whether the obtained results correspond to a periodontal regeneration or a periodontal repair.\u003c/p\u003e \u003cp\u003eIt has been demonstrated that the biological benefits of PRF act locally by rapidly stimulating a large number of cell types by influencing their recruitment, proliferation and/or differentiation [15]. Based on the available literature, it seems that PRF favours the regeneration of soft tissues rather than hard tissues [44]. In the treatment of intrabony defects where space maintenance is not an issue, blood clot formation alone could be enough [45], the additional use of PRF acts primarily as a scaffold, inserted into the periodontal pocket may promote tissue regeneration [17]. More research is needed to determine which factors in the PRF clots (cells/leukocytes, growth factors, or fibrin matrix) are most required to accelerate the regeneration of periodontal tissues.\u003c/p\u003e \u003cp\u003eData from in vitro studies indicates that EMD may also influence periodontal wound healing by an indirect stimulatory effect on the release of growth factors during periodontal wound healing and by inhibiting or at least retarding epithelial down-growth [46].\u003c/p\u003e \u003cp\u003eThe modification of the preparation protocol by reducing the applied centrifugation force (RCF), resulted in an improved preparation protocol for advanced PRF (A-PRF) using 208 g RCF. Compared to PRF the A-PRF clot showed a more porous structure with a larger interfibrous space, where cells (particularly platelets) were observed in even distributions throughout the entire clot, furthermore histological analysis of A-PRF has showed a significantly higher number of neutrophile granulocytes [44].\u003c/p\u003e \u003cp\u003eDescribed by Fujioka-Kobayashi et al., it has been found that the total growth factor release could be enhanced by reducing both centrifugation speed and time. A-PRF\u0026thinsp;+\u0026thinsp;showed similar porosity to A-PRF, furthermore over the entire clot the cellular distribution pattern it has showed evenly dispersed platelets. These observations emphasize the improved regenerative capacity of advanced PRF matrices [20].\u003c/p\u003e \u003cp\u003eThe results of the present study obtained after six months post-surgically clearly indicate the significant improvement of the following parameters: PD, CAL, BS in both groups. No adverse reactions have been observed throughout the first six months, which clearly indicates that the use of autologus test material has been well tolerated.\u003c/p\u003e \u003cp\u003eAs a result of surgery and cessation of inflammation, the rate of gingival recession became significantly higher in both groups compared to the baseline. Upon intergroup comparison the GR increase was found to be non-significantly different. The cause of gingival recession observed after periodontal surgery does not necessarily depend on the methods. However, the gingival biotype can significantly affect the extent of the recession. At the same time, a significant improvement in clinical probing pocket depth resulted in a significant enhancement of the clinical attachment level. In addition to the significant improvement of bone sounding values, radiographs taken with the \u0026ldquo;long-cone\u0026rdquo; technique also suggest the presence of bone filling. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e.,2.)\u003c/p\u003e \u003cp\u003eThere was no significant difference between the test and control groups in the first 6 months after surgery and the results obtained with both materials were similar. The amount of gingival recession seems to be lower in the control group. Thus, it appears that the clinical benefit of both treatments is not only treats intrabony defects, but also improves PD values by facilitating plaque control and maintenance. However, when interpreting these findings, we must keep in mind that currently no other data evaluating the treatment of intrabony defects with A-PRF+ / EMD is available. Therefore, direct comparisons with other studies are not possible at this point in time.\u003c/p\u003e \u003cp\u003eOn the other hand, it also needs to be considered that the lack of a difference between the two groups can additionally be related to the rather limited number of treated defects (e.g. 15 defects in each group) and therefore, the study may not have the statistical power to rule out the possibility of a difference between the two groups. For superiority trials in the treatment of periodontal intrabony defects, a sample size of approximately 30 persons per group has been estimated to be required [47].\u003c/p\u003e \u003cp\u003eFinally, the present study using a new generation of PRF seems to open new horizons in the investigation of the effects of platelet-concentrates on periodontal healing. However, other randomized, clinical trials with a bigger population and with histological evaluation of periodontal regeneration will be necessary to confirm the results of this study.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn view of above findings and within the limitations of the current study, the results indicate that the new-generation platelet rich fibrin behaves just as effectively as enamel matrix derivatives in the surgical treatment of intrabony periodontal defects. Based on the 6-month results, both methods resulted in comparable outcomes and presented no significant differences between the test and control groups. A-PRF\u0026thinsp;+\u0026thinsp;seems to be suitable for the treatment of intrabony periodontal defects.\u003c/p\u003e"},{"header":"List of abbreviations ","content":"\u003cp\u003e\u003cstrong\u003eA-PRF\u003c/strong\u003e: advanced platelet-rich fibrin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEMD\u003c/strong\u003e: enamel matrix derivative\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePRP\u003c/strong\u003e: platelet-rich plasma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePRG\u003c/strong\u003e: platelet-rich gel\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePRF\u003c/strong\u003e: platelet-rich fibrin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGDF\u0026rsquo;s\u003c/strong\u003e: growth and differentiation factors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCAP\u003c/strong\u003e: concentrated autologous products\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePDGF\u003c/strong\u003e: platelet-derived growth factor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTGF-\u0026beta;\u003c/strong\u003e: transforming growth factor beta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eL-PRF\u003c/strong\u003e: leukocyte- and platelet-rich fibrin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEGF\u003c/strong\u003e: epidermal growth factor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIGF\u003c/strong\u003e: insulin-like growth factor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e: vascular endothelial growth factor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003erhGF\u003c/strong\u003e: recombinant human growth factors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e: probing depth\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGR\u003c/strong\u003e: gingival recession\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCAL\u003c/strong\u003e: clinical attachment level\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBS\u003c/strong\u003e: bone sounding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFMBS\u003c/strong\u003e: full-mouth bleeding score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFMPS\u003c/strong\u003e: full-mouth plaque score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEDTA\u003c/strong\u003e: ethylenediamine tetraacetic acid\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was planned as a randomized, controlled, prospective clinical trial. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol was approved by the ethics committee of the Semmelweis University Budapest (approval number: SE TUKEB: 254/2017). The study protocol was registered at ClinicalTrials.gov with ID number NCT04404374.\u003c/p\u003e\n\u003cp\u003eAll the included patients signed an informed consent which was previously approved by an institutional ethic committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors can confirm that all relevant data are included in the article and/or its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study materials have been procured as a result of a tender organized by the Semmelweis University, School of Dental Medicine, Budapest, Hungary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCsN participated in the design of the study, carried out surgical procedures, analysis and interpretation of data and drafting the manuscript. ES contributed to acquisition of data. VLB contributed to patient administration. AN contributed to pre- and postsurgical periodontal management. FD had the main responsibility for conception and design of the study, involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge to Laszlo Dr Kardos, who performed the statistical analysis and contributed to interpretation of data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSculean A, Nikolidakis D, Nikou G, Ivanovic A, Chapple IL, Stavropoulos A: Biomaterials for promoting periodontal regeneration in human intrabony defects: a systematic review. Periodontol 2000. 2015, Jun;68(1):182-216. doi: 10.1111/prd.12086. 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Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006, 101(3):51-55.DOI: \u003ca href=\"https://doi.org/10.1016/j.tripleo.2005.07.010\"\u003e1016/j.tripleo.2005.07.010\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eEverts PA et al: What do we use: platelet-rich plasma or platelet-leukocyte gel? J Biomed Mater Res A. 2008, 85:1135-1136.\u003c/li\u003e\n\u003cli\u003eCieslik-Bielecka A et al: Why the platelet-rich gel has antimicrobial activity? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007, 103:303-305.DOI: \u003ca href=\"https://doi.org/10.1016/j.tripleo.2006.08.034\"\u003e1016/j.tripleo.2006.08.034\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eMoojen DJ et al: Antimicrobial activity of platelet-leukocyte gel against Staphylococcus aureus. J Orthop Res. 2008, 26:404-410.DOI: \u003ca href=\"https://doi.org/10.1002/jor.20519\"\u003e1002/jor.20519\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eWerther K et al. 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J Periodontol. 2003, 74:858-864.DOI: \u003ca href=\"https://doi.org/10.1902/jop.2003.74.6.858\"\u003e1902/jop.2003.74.6.858\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eClark RA: Fibrin and wound healing. Ann of the New York Academy of Sciences. 2001, 936:355\u0026ndash;67. DOI: \u003ca href=\"https://doi.org/10.1111/j.1749-6632.2001.tb03522.x\"\u003e1111/j.1749-6632.2001.tb03522.x\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eSharma A and AR Pradeep: Treatment of 3-wall intrabony defects in patients with chronic periodontitis with autologous platelet-rich fibrin: a randomized controlled clinical trial. J Periodontol. 2011, 82(12):1705-12.DOI: \u003ca href=\"https://doi.org/10.1902/jop.2011.110075\"\u003e1902/jop.2011.110075\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eThorat M, AR Pradeep, and B Pallavi: Clinical effect of autologous platelet-rich fibrin in the treatment of intrabony defects: a controlled clinical trial. J Clin Periodontol. 2011, 38(10):925-32.DOI: \u003ca href=\"https://doi.org/10.1111/j.1600-051x.2011.01760.x\"\u003e1111/j.1600-051X.2011.01760.x\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003ePradeep AR et al: Comparative evaluation of autologous platelet-rich fibrin and platelet-rich plasma in the treatment of 3-wall intrabony defects in chronic periodontitis: a randomized controlled clinical trial. J Periodontol. 2012, 83(12):1499-507.DOI: \u003ca href=\"https://doi.org/10.1902/jop.2012.110705\"\u003e1902/jop.2012.110705\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eAjwani H, Shetty S, Gopalakrishnan D, Kathariya R, Kulloli A, Dolas RS, et al. Comparative evaluation of platelet-rich fibrin biomaterial and open flap debridement in the treatment of two and three wall intrabony defects. Journal of International Oral Health: JIOH. 2015, 7(4): 32\u0026ndash;37. PMCID: \u003ca href=\"http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4409793/\"\u003ePMC4409793\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003ePatel GK, Gaekwad SS, Gujjari SK: Platelet-Rich Fibrin in Regeneration of Intrabony Defects: A Randomized Controlled Trial. J Periodontol. 2017, 88(11):1192-1199. DOI: \u003ca href=\"https://doi.org/10.1902/jop.2017.130710\"\u003e1902/jop.2017.130710\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eAydemir Turkal H, Demirer S, Dolgun A, Keceli HG: Evaluation of the adjunctive effect of platelet-rich fibrin to enamel matrix derivative in the treatment of intrabony defects. Six-month results of a randomized, split-mouth, controlled clinical study. Journal of Clinical Periodontology. 2016, 43(11):955\u0026ndash;64. DOI: \u003ca href=\"https://doi.org/10.1111/jcpe.12598\"\u003e1111/jcpe.12598\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eGupta SJ, Jhingran R, Gupta V, Bains VK, Madan R and Rizvi I: Efficacy of platelet-rich fibrin vs. enamel matrix derivative in the treatment of periodontal intrabony defects: a clinical and cone beam computed tomography study. J Int Acad Periodontol. 2014, 16:86-96.\u003c/li\u003e\n\u003cli\u003eMiron RJ, Fujioka-Kobayashi M, Bishara M, Zhang Y, Hernandez M, Choukroun J: Platelet-Rich Fibrin and Soft Tissue Wound Healing: A Systematic Review. Tissue engineering Part B, Reviews. 2017 Feb;23(1):83-99. DOI: \u003ca href=\"https://doi.org/10.1089/ten.teb.2016.0233\"\u003e1089/ten.TEB.2016.0233\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eCortellini T, Tonetti M: Improved wound stability with a modified minimally invasive surgical technique in the regenerative treatment of isolated interdental intrabony defects. J Clin Periodontol. 2009, 36(2):157-63. DOI: \u003ca href=\"https://doi.org/10.1111/j.1600-051x.2008.01352.x\"\u003e1111/j.1600-051X.2008.01352.x\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eVan der Pauw MT, Van den Bos T, Everts V and Beertsen W: Enamel matrix- derived protein stimulates attachment of periodontal ligament fibroblast and enhances alkaline phosphatase activity and transforming growth factor b1 release of periodontal ligament and gingival fibroblasts. Journal of Periodontology. 2000, 71:31\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003eGunsolley JC, Elswick RK and Davenport JM: Equivalence and superiority trials in regeneration clinical trials. Journal of Periodontology. 1998, 69:521\u0026ndash;527. DOI: \u003ca href=\"https://doi.org/10.1902/jop.1998.69.5.521\"\u003e1902/jop.1998.69.5.521\u003c/a\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"intrabony defects, periodontal healing, advanced platelet-rich fibrin, enamel matrix derivatives","lastPublishedDoi":"10.21203/rs.3.rs-525471/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-525471/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The aim\u003cstrong\u003e \u003c/strong\u003eof the study was to clinically evaluate the healing of intrabony defects after treatment with a new generation of platelet-rich fibrin (A-PRF+) respect to enamel matrix derivatives (EMD). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThirty (30) intrabony defects of 18 patients (9 males, 9 females) were randomly treated with A-PRF+ (test, n=15) or EMD (control, n=15). \u0026nbsp;The following clinical parameters were recorded at baseline and 6 months after surgery: pocket depth (PD), gingival recession (GR) and clinical attachment level (CAL). After debridement the intrabony defects were filled with A-PRF+ in the test group, respectively with EMD in the control group, and fixed with sutures to ensure wound closure and stability.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBoth treatment methods resulted in statistically significant PD reductions, respectively CAL gains six months post-operatively. No statistically significant differences were found between the two groups as the mean CAL gain was 2.33±1.58 mm in the A-PRF+ group, respectively 2.60±1.18 mm in the EMD group (p \u0026lt; 0.001).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWithin the limits of this study the new-generation platelet-rich fibrin seems to be as clinically effective as EMD in the surgical treatment of intrabony defects. Treatment with A-PRF+ or EMD resulted in reliable clinical outcomes. The use of A-PRF+ as a human autologous product can give a positive impact on periodontal healing.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eClinical Relevance: \u003c/strong\u003eA-PRF+ may be suitable for the treatment of intrabony periodontal defects. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration number (TRN):\u003c/strong\u003e NCT04404374 (\u003ca href=\"http://clinicaltrials.gov/\" rel=\"noopener noreferrer\" target=\"_blank\"\u003eClinicalTrials.gov\u003c/a\u003e ID)\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDate of registration: \u003c/strong\u003e19.05.2020., retrospectively registered\u003c/p\u003e","manuscriptTitle":"Efficacy of a New-generation Platelet-rich Fibrin in the Treatment of Periodontal Intrabony Defects: a Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-18 20:33:33","doi":"10.21203/rs.3.rs-525471/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2021-05-14T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-05-14T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-05-14T00:00:00+00:00","index":1,"fulltext":""},{"type":"checksComplete","content":"","date":"2021-05-13T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-05-13T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2021-05-06T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"64aa62c1-675e-4f6d-aa50-9bdd01c973c5","owner":[],"postedDate":"May 18th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":4387075,"name":"Dentistry"},{"id":4387076,"name":"Head \u0026 Neck Surgery"}],"tags":[],"updatedAt":"2021-11-15T11:49:06+00:00","versionOfRecord":{"articleIdentity":"rs-525471","link":"https://doi.org/10.1186/s12903-021-01925-1","journal":{"identity":"bmc-oral-health","isVorOnly":false,"title":"BMC Oral Health"},"publishedOn":"2021-11-15 11:49:06","publishedOnDateReadable":"November 15th, 2021"},"versionCreatedAt":"2021-05-18 20:33:33","video":"","vorDoi":"10.1186/s12903-021-01925-1","vorDoiUrl":"https://doi.org/10.1186/s12903-021-01925-1","workflowStages":[]},"version":"v1","identity":"rs-525471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-525471","identity":"rs-525471","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}