Fifteen Years of Platelet Rich Fibrin in Dentistry and Oromaxillofacial Surgery: How High is the Level of Scientific Evidence?

The development and application of biomaterials has increased over the past years. In dentistry and maxillofacial surgery, biomaterials of autologous, allogenic, and xenogeneic sources are widely used,^1–4  and there are advantages and disadvantages associated with each.⁵  Surgical techniques performed to obtained autografts can be difficult and are associated with higher morbidity. Despite the difficulties, they are considered the gold-standard method in bone and soft tissue regeneration, particularly because of their autologous regenerative capacity.⁶  However, alternative autologous techniques introduced platelet concentrates (PC), autologous blood derivatives that are characterized by the ease of the technique used to obtain them.⁷  The history of PC can be traced back to 1940, when Young and Medawar⁷  described that they successfully reunited peripheral nerves in animals, sealing them in blood plasma. Based on these findings, Helena Matras⁷  developed the fibrin sealant technique during experiments on rat skin and later through clinical applications in maxillofacial surgery in 1982. This fibrin sealant product consisted of a mixture of fibrinogen and thrombin, which formed a clot that was used for wound covering.⁸  The natural evolution turned fibrin sealants into PC when platelets were added to the formula.⁹  The first PC protocols were described by the so-called autologous platelet-derived wound healing factors (PDWHF) and were published in 1986 by Knighton et al and in 1998, by Marx, with the name “platelet-rich plasma” (PRP), emphasizing platelets and growth factor content.^10–12  This PC system requires the addition of anticoagulants during its processing procedure and concentrates platelets but eliminates blood-derived leukocytes. In 2001, as an alternative to PRP with numerous advantages, Choukroun developed platelet-rich fibrin (PRF), a second generation of PCs that does not require the addition of anticoagulants.¹³ 

PRF is a one-step standardized method of obtaining PCs. Through centrifugation of peripheral blood, physiologic clot formation and fractioning are induced without the requirement of additives such as anticoagulants; thus, PRF is the only PC system that is fully autologous.¹⁴  Using specific tubes with a glass surface initiates the coagulation cascade and activates platelets during centrifugation. The resulting PRF consists of a fibrin scaffold that contains platelets, leukocytes, and plasma proteins. After centrifugation, the resulted 3D matrix of the PRF clot serves as a reservoir of growth factors.¹⁵  Bioactive molecules—growth factor, cytokines, fibrinogen, fibronectin, thrombospondin, adhesive proteins, and coagulation factor—are primarily released from the alpha and dense platelet's granules.¹⁶  Additionally, cell interaction between activated platelets and the included leukocytes and their subfamilies, such as neutrophils, seems to substantially increase the degranulation of inflammatory cytokines (IL-1β, IL-8) and chemokine (MCP-1).¹⁷ 

The initial protocol to obtain PRF described the need of the application of high relative centrifugal forces (RCF).^18,19  As a first attempt to understand PRF, our group reduced RCF through a further histological analysis of the PRF clot and found that reducing the RCF increases the number of platelets and leukocytes, with a balanced distribution of cells within the matrix.²⁰  In that manner, a systematic analysis (gradual reduction approach) of the influence of RCF on the PRF-based matrices was conducted: By further reducing the RCF, an even higher increase of cell concentration was obtained, as well as the release of growth factors.²¹ 

Basic science and translational research investigated the influence of PRF in soft and bone regeneration in vitro. The behavior of osteoblasts treated with PRF in vitro found a significantly improved activity compared to the nontreated osteoblasts.²²  In addition, a significantly higher migration rate, collagen formation and growth factor release activity was observed in gingival fibroblasts treated with PRF compared to fibroblasts treated with PRP or without PRF treatment in vitro.²³ 

Based on the previous results, the low-speed centrifugation concept (LSCC) was introduced as a possible tool to create solid and liquid matrices of PRF, thereby generating more bioactive PRF matrices. These matrices contain high leukocyte and platelet concentrations, as well as advanced growth factor release, according to the clinical requirements.²¹ 

Since PRF was first introduced in 2001 as a second-generation PC, it has found its way into different fields of dentistry and oral maxillofacial surgery. In the last decade, there has been a constant increase in the number of published papers related to PRF's clinical applications with a great diversity of experimental methods and results. This diversity has caused uncertainty about the level of scientific evidence of published articles and whether the results are reproducible. This review is focused on individual evaluation of these published articles with a certain level of scientific evidence and reports their contributions to dentistry and maxillofacial surgery.

An electronic literature research was conducted using the biomedical search engine “National Library of Medicine” (PubMed-MEDLINE) in May 2017. To obtain results that involved the whole scope of dentistry and PRF, the keywords used for the search were “PRF,” “PRF and bone,” and “PRF and soft tissue.” The search resulted in a total of 392 articles. The articles were selected by reviewing the titles and abstracts of the articles; 72 were selected, according to the following inclusion criteria:

• •

  Articles with the word platelet rich fibrin (PRF) in the title

• •

  Articles related only to clinical applications in general dentistry and its different application fields

• •

  Human studies

• •

  Articles published in English

Systematic reviews obtained through the electronic literature research were not included in the study but were used to identify potentially relevant information. If needed, the references of the selected articles were examined to search for the description of the used methodology. The full texts of the selected articles were examined by three authors (S.G., C.H., and S.A.), and data was extracted using a standardized Excel data sheet as a collection tool. The following information was recorded: name of the first author, publication year, field of dentistry (endodontics, implantology, maxillofacial surgery, orthodontics, periodontology), follow-up, number of patients involved, use of biomaterials, country, and level of scientific evidence. All collected data was arranged in tables, bars, or maps using Microsoft Excel Power View 2013 (Redmond, Wash) and analyzed. The results were grouped and presented in each field (Figure 1, Table 1).

All articles were independently examined by three authors (S.G., C.H., and S.A.), and after a consensus, a level of scientific evidence was assigned to each article, according to the US Agency for Healthcare and Quality (Table 2). The result of the search was 21 randomized clinical trials (Ib), 21 nonrandomized controlled prospective studies (IIa), 13 quasi-experimental studies (IIb), and 17 case control studies (III). The method of assigning a level of scientific evidence was initiated in 1979 by the Canadian Task Force on the Periodic Health Examination, with the intention of supporting its literature recommendations on evidence-based medicine. Since the first description, randomized clinical trials have been placed at the highest level of the scientific hierarchy because they are designed to be unbiased and create less risk of systematic errors. Evaluation of the published clinical articles of PRF by their level of scientific evidence could help clinicians select the best treatment options for their patients.^24–28 

In the second step, the most used evaluation parameters in the field of periodontology (ie, pocket depth [PD] and clinical attachment level [CAL]) were selected, and the results between the control and test groups (level of scientific evidence Ib, IIa, and IIb) were extracted as the mean values of PD and CAL and calculated as the difference between the baseline and the reevaluation after 6, 9, or 12 months for each study separately. The data was presented graphically using Graph-Pad Prism version 6.0 (GraphPad Software, La Jolla, Calif). The results from each paper were reported individually without comparison or statistical analysis among the studies. Statistical differences were reported in this manuscript only when the article being examined demonstrated a significant difference in their results. The results from the studies with a level III of scientific evidence (case reports) were extracted and reported in the corresponding field. In addition, the biomaterials being evaluated in the studies and the ratio (when included) in which they were mixed with PRF were arranged and cross-referenced, as shown in Table 3.

The flowchart demonstrates the number of examined articles grouped by their level of scientific evidence and fields of dentistry (Figure 2). The rated 72 articles selected for the review showed that in the last decade, most papers were published in 2015 and 2016. By adding all patients found in the rated 72 articles, we obtained a result of 1822 patients involved in PRF studies; 708 (38.8%) participated in randomized level Ib studies, 566 (31.0%) participated in well-designed controlled prospect level IIa studies, 293 (22.1%) participated in quasi-experimental level IIb studies, and 144 (7.9%) participated in level III case control studies (Figure 1). The field of dentistry that showed a higher development in PRF was oral and maxillofacial surgery (40.2%), followed by periodontology (36.1%; Figure 1).^19,29–99  In recent years, the use of PRF in different fields has expanded, according to the selection of published papers in the last two years (Figure 3). There were no complications reported in 28 dental pathologies treated with PRF (Table 1). Furthermore, as seen in the extracted information, India is the country with the highest number of published PRF articles, particularly in the field of periodontology. The world map proportionally shows the number of papers published in each country, represented by different circle sizes (Figure 4).

Six studies were associated with the endodontic field. Five articles were case control studies (level III),^{29,31–33,93}  while one was a randomized study (level Ib).³⁰  In this field, a total of 55 patients were treated with PRF by placing it into the dental canals or in the periradicular lesions. One study reported 5 patients with incomplete healing. Two patients did not respond to treatment at all³⁰ ; in the remaining 48 patients, complete resolution and bone regeneration of the apical lesions were achieved. The treated pathologies were immature teeth with necrotic pulps, acute chronic apical abscess, and suppurative chronic apical periodontitis. Apical closure and root lengthening were observed in all cases diagnosed with immature necrotic pulps of the teeth.^{29,31–33,93} 

A total of 255 patients participated in 10 studies related to the use of PRF in implantology, with the level of scientific evidence Ib,^39–42  IIa,^{34–36,38,41}  IIb,³⁷  and III.^40,94  The treated pathologies were severe maxillary or mandibular resorption and peri-implant bone defects.^36.37.39 Several treatment options were also described, in which PRF was used as a sole biomaterial or in combination with other biomaterials.^34,40  Follow-up care ranged from 6 months to 6 years without implant loss.³⁶  The articles reported successful osseointegration,⁴²  enhancement of biomechanical quality,^41,94  safe and reliable sinus floor elevation,⁴⁰  significant crestal bone gain compared to a control group without the use of PRF,³⁹  and an increase of the secondary stability of implants.³⁷  An additional study reported dehiscence in 31 patients after performing implant placement and tissue augmentation with PRF using a double-layer technique. After 6 months, all implants were osseointegrated, without any signs of infections.⁴²  Furthermore, rinsing dental implants prior to treatment significantly increased secondary stability over time³⁷  and significantly reduced bone resorption when PRF was used to cover the implant site.³⁹  A total a total of 19 patients presenting with peri-implantitis defect classes Ib+II, Ic+II, Id+II (38 implants) were treated with PRF and demonstrated a survival rate of 100% after 6 months of follow-up.^36,100 

In the field of oral and maxillofacial surgery, 4 groups were identified: sinus lift, socket preservation, bone regeneration/augmentation, and medication related osteonecrosis of the jaw (MRONJ).

Eight articles and 198 patients were identified in this group, with IIa,^{19,34,35,38,50,62}  IIb,⁹⁵  and III levels of evidence.⁴⁰  Two studies evaluated PRF as a sole filling biomaterial using the lateral or crestal approach,^34,40  and the results demonstrated that the regenerated bone was sufficient for implant insertion and without bone resorption for up to 6 years; the final bone gain was significant, between 8.5 and 12 mm (10.4 ± 1.2).^34,40  After a 1-year prospective study, PRF as a sole graft material was also said to be reliable and stable.⁴⁰  In a case control study, PRF was mixed with deproteinized bovine bone, and the study reported a 31% increase in the peri-implant bone density.⁹⁵  Five studies evaluated PRF in combination with biomaterial versus biomaterial alone. In the PRF group, accelerated regeneration was observed; however, no statistically significant between-group differences was observed in new bone formation.^{19,35,38,50,62} 

A total of 14 articles investigated the effect of PRF in the treatment of socket preservation with the level of scientific evidence Ib,^51,66  IIa,^{43,44,46,48,54,65}  IIb,^45,55,58  and III.^47,53,56  The evaluation parameters focused on bone regeneration and pain assessment. Nine studies, with a total of 343 patients, evaluated the influence of PRF on bone regeneration (PRF vs blood clot).^{43–45,54–56,58,65,66}  Six studies showed significant improvement of socket bone fill,^56,65,66  vertical gain of oral cortical plate,⁵⁸  alveolar ridge contour,⁵³  and bone density⁵⁵  in the groups using PRF compared to the control group without PRF. Three studies showed improved bone regeneration in the PRF group but were not statistically significant.^43,45,56 

Pain was evaluated using the visual analog scale score (PRF vs natural healing); the group treated with PRF showed significantly reduced pain compared to natural alveolus healing.⁴⁵  However, Abhishek Singh et al⁴³  reported that although pain could be reduced in the study group, it was not statistically significant.

A further study with a IIa level of scientific evidence evaluated the use of PRF as a tool to manage hemorrhagic complications. Fifty patients with records of heart surgery and anticoagulant therapy were treated by placing PRF in 168 post-extraction sockets; only 2 complications were reported in patients, with an international normalized ratio (INR) of 3.7. The study showed that PRF could serve as a sealing material to avoid hemorrhagic complications.⁴⁸  Furthermore, a case study evaluated the stability of implants inserted in PRF-preserved sockets vs no socket preservation. Significantly higher implant stability and significantly lower bone resorption were achieved compared to implants inserted in nonpreserved sockets.⁴⁷ 

One study with a Ib level of scientific evidence involved 24 patients diagnosed with cleft alveolar ridge reported statistically significant new bone formation after the treatment with iliac crest graft combined with PRF (test group) compared to iliac crest grafts without PRF (control group).⁴⁹  In an additional study, 20 patients with cyst lesions were treated with PRF; the bone defects were filled with PRF after cyst enucleation (evidence level III, without controls). The bone defects partially regenerated after 3 months, with complete bone healing after 6 months.⁶⁸ 

In total, 5 articles investigated the effect of PRF in the treatment of MRONJ (level of scientific evidence IIa, IIb, III). Two studies with a IIa and IIb level of evidence reported statistically significant improvement of wound healing compared to the control group. Epithelization was observed in the PRF group within 2–4 weeks and in the control group within 2–8 weeks.^59,64  The remaining 3 case control studies with a level of evidence IIb and III reported positive clinical results.^52,53,61  A total of 101 patients with MRONJ were treated using PRF as a multilayer coverage of the bone; 3 studies reported a complete healing of all the cases^53,61,64 ; the remaining two articles reported no resolution in 1/15 cases⁵²  and 4/55 of the cases.⁵⁹  The studies showed a fast epithelialization within 4 weeks to 3 months and a total bone closure of the defect in 96 patients (during antiresorptive treatment or with an interrupted treatment prior to surgery). A group of 25 patients were treated with a mixture of PRF plus recombinant human bone morphogenetic proteins 2 (rhBMP2) and compared to a control group of 30 patients treated with PRF only; the results showed statistically significant improvements in healing in the PRF+BMP2 group.⁵⁹ 

Only 1 article was found in this field with a level III of scientific evidence. An orthodontic-surgical treatment using Wilcko's modified periodontally accelerated osteogenic orthodontics (PAOO) was performed in 11 patients; PRF was minced or applied as a membrane combined with mineralized human cancellous bone allograft + deproteinized bovine bone material (3:2) and metronidazole (500 mg). All patients healed without any problems; orthodontic treatment took, on average, 9.3 months, with stable treatment after 2 years.⁶⁹ 

A total of 26 articles were selected with different levels of scientific evidence Ib,^* IIa,^{76,82,84,86,98}  IIb,^70,77,87,88  and III.^78,99  More randomized studies with control and test groups were found in this field. The pathologies treated were chronic periodontitis with different levels of bone defects, gingival recession, and gingiva hyperpigmentation. A total of 13 of the 26 articles included a PRF study-group as a sole treatment compared to conventional treatments (eg, open flap debridement, connective tissue graft, and autogenous bone graft).^† Ten of these studies reported that the use of PRF improved equally (4 articles)^70,83,91,97  or significantly (6 articles)^{73,74,79,81,85,90}  for PD or CAL compared to the conventional surgical treatments. An additional study showed no significant differences in PD reduction and CAL gain⁸²  (Figures 5 and 6). As opposed to measuring PD and CAL, the previously mentioned articles and 2 others obtained improvements in pain reduction, healing index^83,87,92,97  and bone-defect fill.^79,70 

A total of 14 studies investigated the combination of PRF with different biomaterials (eg, hydroxyapatite bone graft,^71,99  freeze-dried bone allograft [DFDBA],^72,75,77,90  autogenous bone graft,⁷⁶  amnion allograft membrane,⁸⁴  bioactive glass calcium phosphosilicate,^86,88  anorganic bovine bone mineral,⁸⁹  enamel matrix derivative,⁹⁷  bovine porous bone mineral,⁹⁸  and bioactive Gengigel hyaluronic acid).⁷⁸  The most frequent combination used was PRF+DFDBA; the used ratio of the mixture was reported only in 6 articles (1:1 or 1:2); Table 3. Three studies reported statistically significant improvements in PD and CAL compared to the sole use of biomaterial or PRF.⁹⁰  Six studies that combined PRF with biomaterials of allogenic or xenogeneic source showed significantly improved CAL and PD in the PRF group compared to the control group (biomaterial without PRF). Two studies did not show significant results between the evaluated groups,⁹⁷  and 1 reported better root coverage in the control group.⁹⁶  Furthermore, the use of autogenous bone graft was compared to the use of PRF as a sole filling material for bone regeneration, and no statistical significant improvement was observed between the evaluated groups after the intervention.⁷⁶  Two studies observed that the use of bioactive Gengigel or hydroxyapatite graft combined with PRF seemed to have advantages in terms of the bone regeneration of furcation intrabony defects.^78,99 

In the present review, a level of scientific evidence was assigned to each article to establish a parameter of comparison and to give guidance to clinicians. To avoid bias in the selection of the articles, the initial inclusion criteria was based on the title of the articles and, second, on the content of the abstract to verify its relationship to dentistry and its different fields. The extracted data was reported based on the articles in Table 1.

As seen in the results of this review, over 70% of the patients were part of a randomized or controlled prospective study. The subsequent data can serve as a compendium for clinical practitioners combining dental pathologies and treatments where PRF is used (Table 1). Note that 1822 patients participated in 72 articles included in this review, resulting in 28 different diagnosis and pathologies. In recent years, the application of PRF in different fields has expanded, as the selection of published papers in the last 2 years indicates (Figure 3). This result may be primarily because of the absence of complications, positive results, autologous source, and the simplified and clinically applicable preparation method.

The PRF map illustrates the presence throughout the world of PRF to give an idea of how research in the clinical environment has developed (Figure 4). All fields of dentistry are involved; however, periodontology and oral-maxillofacial surgery remain the primary areas of application. The properties of PRF to accelerate the healing process of soft and hard tissue, while controlling pain and inflammation opens up a broad area of application to clinicians.

The essence of PRF may rely on the delivery of blood components at an early stage of healing, which diminishes the noxious phases of stress-induced hypermetabolism in response to injury.¹⁰¹  Additionally, PRF from humans can regulate inflammation, promote vascularization, provide a matrix for cells, and improve the healing of tissue and bone.²⁰ 

Continuous research in the field of PRF has shown that PRF, which is a bioactive autologous system, can be considered as a drug delivery system.²⁰  Current studies aim to optimize the regenerative capacity of PRF using the low-speed centrifugation concept (LSCC). In this context, PRF matrices that are centrifuged using a low relative centrifugation force (RCF) show higher leukocyte and platelet concentrations compared to PRF matrices that are centrifuged using a high RCF.²¹  Consequently, matrices generated in the low RCF range release a higher concentration of growth factors (VEGF, EGF, TGF ß-1) compared to those generated in a high RCF range.^21,102 

The results of the clinical application of PRF in different fields of dentistry and oral-maxillofacial surgery demonstrated that, presently, there is a considerable group of published articles with a high scientific evidence of the effectivity of PRF in bone and soft tissue regeneration.

In the field of periodontology, 23 studies with a scientific evidence of Ib, IIa, or IIb have shown that the application of PRF led to a significantly improved pocket depth (PD) and clinical attachment level (CAL) compared to the groups treated without PRF, and one study with a scientific evidence of Ib reported better root coverage in the control group. Additionally, the results in this review highlight the fact that in the field of periodontology, the use of biomaterials in combination with PRF seems to significantly improve the regeneration potential of the used biomaterials, which may be related to the “biologization” of the acellular biomaterial prior to their application and could facilitate cell-cell communication and biomaterial integration in the application region.¹⁰³ 

Most studies regarding the surgical-periodontal treatment have focused on periodontitis with different diagnoses. Only 1 study with a scientific evidence of IIa has evaluated the effect of PRF application in peri-implantitis (ie, 100% survival rate of the implants),³⁶  with significantly improved PD compared to treatment without PRF. A recent Cochrane review focused on the effectiveness of current treatments for peri-implantitis; it associated the use of bovine-derived xenograft with PD and CAL improvement.¹⁰⁴  Interestingly, 6 of the studies included in this review obtained statistically significant improvement of PD and CAL using PRF+biomaterial compared to the sole use of a biomaterial. Furthermore, the most frequent used biomaterial was found to be demineralized freeze-dried bone allograft (DFDBA), showing significant positive results. In particular, it has been described that biomaterials derived from natural bone sources, such as DFDBA, contain BMPs.⁷⁵  An additional study included in the review combined PRF+BMPs and obtained significant clinical improvement compared to sole PRF. The observed interaction between PRF and BMPs could help explain how PRF could enhance the regenerative potential in the case of biomaterials derived from natural bone sources. Some points still need to be clarified (eg, if the mixing ratio of PRF and the autologous grafts or biomaterials has any effect over the obtained clinical results). As observed in our review, only 6 of the included articles reported the mixing ratio (1:1 or 1:2; Table 3).^{38,70,71,75,91,98}  Today, due to the increased application of dental implants in the last decades, peri-implantitis has become a key area in periodontology, as the primary long-term complication after implant placement. The results of the present review could encourage clinicians to use PRF for peri-implantitis treatment, and this process requires further research in this area.

Interestingly, a further application field, such as bone regeneration within the sinus cavity (sinus-lift), showed no statistically significant difference between the new bone regeneration using biomaterials in combination with PRF compared to biomaterials alone in studies with a scientific evidence of Ib, IIa, or IIb. PRF as a sole material was shown to support bone regeneration in the sinus lift. However, the level of scientific evidence of these studies is low due to the lack of a control group. Moreover, there is a general lack of research investigating the bone regeneration in this field.

Bone regeneration after socket preservation with PRF was shown to accelerate/improve bone density and tissue healing compared to physiological defect healing. These results were underlined by 14 of the studies with a level of scientific evidence of Ib, IIa, or IIb. The contribution of PRF to bone healing should be further evaluated in critical bone defects and more complex augmentations, such as the challenge of vertical and horizontal bone augmentation. In this manner, higher evidence can be obtained regarding the benefits in bone and tissue regeneration. A comparison between the combination of PRF with biomaterials and biomaterials alone has not yet been investigated. Therefore, further studies are required to evaluate the role of PRF in combination with biomaterials and their bioactivity.

These studies all utilized clinical and radiological methods to investigate regeneration capacity and bone stability. However, only a few single studies used histological methods to analyze bone regeneration in humans.

In addition, the application of PRF in socket of extracted third molars led to significantly reduced pain compared to conventional socket healing.^45,47,51  These observations could be explained by the ability of PRF's release of different pro- and anti-inflammatory cytokines, such as IL-4, that modulate the inflammatory response and are involved in the cascade of pain.

In addition, the quality of new bone formation and stability seemed to be improved by the PRF treatment; thus, the mechanical stability and osseointegration of implants inserted in the bone regions treated with PRF or covered by PRF have been shown to exhibit significantly higher secondary stability and experienced significantly less bone resorption compared to implants inserted in non-treated bones.^37,60 

Additionally, five studies have shown that PRF is beneficial in the treatment of medication related to osteonecrosis of the jaw. Reepithelialization and bone regeneration was achieved in 96 of the 101 treated cases. In this context, PRF provided a less invasive treatment option for multimorbid patients. Among others, this disease pattern is related to impaired vascularization and wound healing.⁵⁹  Thereby, these results may be achieved due to the bioactivity of PRF and its capability of releasing VEGF and EGF, which primarily contribute to angiogenesis and epithelialization.¹⁰² 

In other fields of dentistry, such as endodontics and orthodontics, little research has been performed, with a low level of scientific evidence. There is a general lack of long-term or retrospective studies evaluating the long-term results of implants inserted in bones treated with PRF compared to non-treated bones.

Our results provide published evidence of high scientific level that PRF (38 articles) is a beneficial tool that significantly enhances bone and soft tissue regeneration. Furthermore, 17 articles have reported that with the use of PRF as a sole biomaterial, similar results were obtained compared to the conventional treatment. In contrast, only 1 study reported statistically significant root coverage in the control group (conventional treatment) compared to the test group (PRF). There may be other cases with similar results in this field that have remained unpublished thus far. The remaining 16 articles, with a scientific evidence level III, observed clinical resolution of the treated cases with PRF. In summary, this review serves as an overview of the level of scientific evidence of studies that analyzed the role of PRF in dentistry and oral and maxillofacial surgery. To promote studies with a higher scientific level of evidence, the clinical community requires a standardization of PRF protocols and more well-designed and conducted studies.

The present review provides an overview of the literature regarding the existing clinical research of PRF and its level of scientific evidence. Over 70% of patients participated in studies with a high level of scientific evidence (randomized and controlled prospect studies). In 9 of the studies, the application of PRF in periodontology showed significantly improved pocket depth and clinical attachment level compared to the conventional treatment. Significantly enhanced new bone formation was reported during socket preservation and ridge augmentation procedures (7 articles) comparing the used of PRF to the normal bone healing without PRF. No statistically significant differences were found in the addition of PRF to biomaterial in sinus lift compared to sole biomaterials. When patients were diagnosed with medication-related osteonecrosis of the jaw (MRONJ) treated with PRF, the results obtained are also relevant, resulting in 96 of 101 of the patients healing uneventfully. Thus, the present review highlights the existing studies with a high scientific level of evidence that equally show the contribution of PRF in bone and soft tissue regeneration. From the 72 articles involved in the review, only 1 reported statistically significant results favoring the control group against the PRF group. Although 16 articles with a level III of scientific evidence reported good outcomes, they have the lowest level of scientific evidence. To promote reproducible studies with a higher scientific level of evidence, the clinical community requires a standardization of PRF protocols to show the benefit of PRF in tissue regeneration.

The authors would like to thank Dr Booms for his support during preparing this review and Prof Henrik Dommisch for his support during preparing the periodontology part of this review.

The authors confirm that they have no conflicts of interest. This work was funded by the FORM-lab. J. Choukroun is the owner of PRF, Nice, France.