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AMSTAR: A Measurement Tool To Assess Systematic Reviews; APC: Autologous Platelet Concentrate; PCS: Platelet Concentrates; PRP: Platelet Rich Plasma; PRGF: Platelet Rich In Growth Factors; PRF: Platelet Rich Fibrin; TGF-Β1: Transforming Growth Factor Beta-1; PDGF-AB: Platelet Derived Growth Factor AB; VEGF: Vascular Endothelial Growth Factor; IL: Interleukin; OFD: Open Flap Debridement; PPD: Probing Pocket Depth; CAL: Clinical Attachment Level; CAF: Coronally Advanced Flap; CTG: Connective Tissue Graft; MRONJ: Medication-Related Osteonecrosis Of The Jaws; ISQ: Implant Stability Quotient

Healing of the intraoral soft tissues occurs with a cascade of events mediated by different signaling molecules and growth factors. Growth factors in autologous platelets play a vital role in the acceleration of wound healing. Autologous platelet concentrates (APCs) available for surgical procedures include the following: platelet rich plasma (PRP), platelet rich in growth factors (PRGF), and platelet rich fibrin (PRF). The common feature of these heme products is their increased baseline platelet concentrations that has been demonstrated to increase wound healing at the surgical site. The effectiveness in enhanced wound healing is due to their ability to continually release various growth factors throughout the course of wound healing at various times [1,2].

Growth factors are capable of binding to specific cellular substrates on the cell surface that can regulate cellular events such as cell differentiation, proliferation, migration and synthesis of the extracellular matrix [3]. Such growth factors include the following: transforming growth factor beta-1 (TGF-β1), platelet derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF), interleukin (IL)-1beta, IL-4 and IL-6 [4]. All the growth factors are involved in differentiation and proliferation of osteoblasts, chondrocytes, endothelial cells and fibroblasts [5,6].

The two APCs produced, PRP and PRGF, requires an anticoagulant and bovine thrombin that acts as an activator, while PRF can be produced without either additive [7]. All variations of APCs require a sample of venous blood that is collected in a tube and immediately centrifuged. In terms of biologic activity, thrombin induces a rapid release of growth factors from the platelet alpha granules during the first 24 hours that slowly decreases by day 14 [8]. PRP has been shown to release the largest amount of TGF-β1 and PDGF-AB on the first day of surgical activity that slowly decreases by day 14 [9]. The effects of cytokine activity are very brief on wound healing, but have been demonstrated to increase bone regeneration by facilitating neogenesis, cell chemotaxis, mitosis, stem cell proliferation and osteo conduction [3,10].

In contrast, as PRF requires no thrombin activator during the centrifugation process to obtain a fibrin matrix, cytokine activity is prolonged as it is incorporated within the matrix in addition to platelets, leukocytes and stem cells [5,9,11]. PRF has been shown to stimulate wound healing at the site of tissue injury by the recruitment of cells, such as osteoblasts, endothelial cells, chondrocytes and fibroblasts. These specialized cells are involved in wound healing and angiogenesis [12,13].

As the fibrin matrix is slow to dissolve, it has been demonstrated that by the seventh day of wound healing, PRF releases the largest amount of PDGF-AB. By day 14, enormous quantities of TGF-β1 are observed [5]. PRF has been demonstrated to also contain substantial amounts of VEGF [4]. Therefore, PRF enhances epithelial healing, tissue vascularization and soft tissue regeneration. Such wound healing capacity may be due to fibrin matrix that contains the many growth factors and cytokines.

The aim of this systematic review is to provide a comprehensive overview of systematic reviews and meta-analyses on the intra-oral applications of platelet concentrates.

Focused question

What are the intra-oral applications of platelet concentrates?

Study design

A systematic search was conducted using PUBMED, EMBASE, Web of Science, Cochrane library, and Google Scholar for systematic reviews and meta-analyses of intra-oral applications of platelet concentrates published from inception until Dec 2016. The keywords used for the search were described in Table 1 . Gray literature was searched on Google Scholar using the advance search option to find articles with the word “platelet” and at least one of the words “systematic review” or “meta-analysis”. Hand searching was also done on the reference list of the selected systematic review.

Table 1: Database and keywords.

Inclusion and exclusion criteria

• Study must identify itself as a systematic review or meta-analysis.

• Study must review intra-oral applications of platelet concentrates in humans.

• Studies which included animal and human studies, but reported the human data separately were included.

• Must review at least 5 studies on platelet concentrates.

• Due to language limitations, only studies in English or have English translation.

• When other interventions are reviewed together with the use of platelet concentrates, only the data relevant to the use of platelet concentrates will be included.

• Based on AMSTAR checklist [14], only reviews scoring > 3 points out of 11 were included.

• In vitro studies, case reports, review articles that are not systematic reviews were excluded.

• Studies which included the use of other non-platelet derived biologics or recombinant platelet derived biologics in addition to the platelet concentrates were excluded.

Screening and data extraction

The “Title and Abstract” was screened by 2 reviewers (NST and MT) independently, articles that clearly did not meet the inclusion criteria were excluded. The full-text was then analyzed independently by 2 reviewers (NST and RK). A previously pilot tested data extraction sheet was used independently by 2 reviewers (RK, MT) for data extraction data. All disagreements were resolved via discussion with another reviewer (SMB).

Assessment of quality of systematic reviews and metaanalyses

The methodologic quality of the selected reviews was rated independently by 2 reviewers (NST and RK) using the AMSTAR checklist [14]. Studies were rated to be of high quality if scoring 8-11 out of a total of 11 points, of moderate quality if scoring 4-7 out of 11 points, or of low quality if scoring 0-3 out of 11 [15]. The AMSTAR ratings were verified by a third reviewer (MT) and any discrepancy was resolved via discussion with another reviewer (JBS). Studies scoring less than 3 out of 11 were excluded. Table 2 showed the selected reviews and their AMSTAR ratings.

Table 2: Characteristics of selected reviews on intraoral uses of platelet concentrates.

The initial search yielded 325 reviews in PUBMED, 859 in Web of Science, 535 in Cochrane Library, and 353 in Google Scholar. After abstract and title screening, 26 reviews were selected from PUBMED, 27 from Web of Science, 12 from the Cochrane Library, 34 from Google Scholar, and 8 from hand searching the reference list of the selected reviews. After duplicate elimination, a total of 51 reviews remained for full-text analysis. After full-text analysis and the elimination of 28 reviews, 23 were selected for data extraction (Figure 1).

Figure 1: Search strategy for platelet concentrates.

Of the 23 articles selected (Table 2), some articles reported on the use of platelet concentrates in more than one area. A total of 9 articles reviewed platelet concentrates used in sinus augmentation [16-24], 4 articles in ridge preservation [22-26], 4 articles in implant therapy [17,20,28,35], 13 articles in periodontal treatment [17,21-23,27-35], 2 articles in endodontic treatment [23,36], and 3 articles in osteonecrosis treatment [23,37,38]. AMSTAR ratings of the selected reviews comprised of 20 high quality reviews and 3 moderate quality reviews.

Of the 9 reviews selected on the use of platelet concentrates in sinus augmentation (Table 3), 5 reported reduced healing time of soft and hard tissue [16,18,19,22,23], 1 reported improved handling of particulate graft [16], 3 reported no significant benefit [16,17,21], and 2 reported no significant difference in new bone formation between test and control groups [23,24].

Table 3: Platelet concentrates used in sinus augmentation.

Of the 4 reviews selected on the use of platelet concentrates in ridge preservation (Table 4), 2 reported less post-extraction pain [22,25], 2 reported improved alveolar ridge preservation [22,23], 1 reported better soft tissue healing and less buccal bone resorption [22], 2 reported insignificant acceleration of osseous healing [23,25], and 1 reported limited histological evidence of better bone quality [26].

Table 4: Platelet concentrates used in ridge preservation.

Of the 13 reviews selected on the use of platelet concentrates in periodontal treatment (Table 5), 2 reported more improved periodontal parameters at follow-up than at baseline with significantly greater probing depth reduction and clinical attachment gain [23,34], and 4 reported some beneficial effects on clinical and radiographic outcomes for regeneration of periodontal intrabony defects [17,29,31,33]. However, when platelet concentrates were combined with guided tissue regeneration (GTR) techniques the beneficial effects are negligible [29,31]. Thus, the specific selection of specific agents or procedures combined with platelet concentrates could influence outcome [32]. In the treatment of gingival recession, platelet concentrates produced no significant benefit [28]. However, in chronic periodontitis, platelet concentrates improved gingival recession but not the clinical attachment [30].

Table 5: Platelet concentrates used in periodontal treatment.

Of the 4 reviews selected on the use of platelet concentrates in implant therapy (Table 6), 1 reported significantly higher implant stability quotients (ISQ values) measured through resonance frequency analysis [22], 1 reported no significant effect on the bone-to-implant contact [18], and 3 reported no significant effect on implant survival [18,20,24].

Table 6: Platelet concentrates used in implant therapy.

Of the 2 reviews selected on the use of platelet concentrates in endodontic treatment (Table 7), both reported complete bone regeneration of periapical lesions [23,36], and 1 reported faster healing of peri-apical lesions [36].

Table 7: Platelet concentrates used in endodontic treatment.

Of the 3 reviews selected on the use of platelet concentrates in osteonecrosis treatment (Table 8), 2 reported complete bone closure and resolution of lesion [23,38], and 1 reported a beneficial effect for preventing the post-surgical occurrence or recurrence of bisphosphonate related osteonecrosis of the jaw [37].

Table 8: Platelet concentrates used in osteonecrosis treatment.

The selected systematic reviews for each application (Table 9) were further categorized into the type of platelet concentrates (PCs) evaluated. Commonly evaluated forms of PCs included PRP, L-PRF, and unspecified compositions of PCs. The specific significant benefits of each form of PCs, as well as nonsignificant applications were outlined in Table 9. In sinus augmentation, more benefits of PRP [16,18], L-PRF [22,23], and PCs [19] were reported in the early postoperative. But in the longer term follow-up, there were no significant clinical benefits [16,17,20,21,23,24]. In ridge preservation, the use of LPRF [22] and PCs [25,26] contributed to immediate post-operative benefits. The use of L-PRF [22,23] can contribute to significant increase in bone quality and bone level, but it was not significant with respect to bone volume [23].

Table 9: Intraoral applications of different forms of platelet concentrates derived from this overview of the selected systematic reviews.

In periodontal treatment, beneficial effects were reported for PRP [17,21,28,29,33], and L-PRF [22,23,27,34]. Conflicting effects were reported for gingival recession [17,27,28,35]. Interestingly, the beneficial effects of PRP and PCs were negated when used with guided tissue regeneration [27,31]. In implant therapy, the use of PRP did not have any significant effect on the implant survival nor the bone to implant contact [18,20,24]. Although the use of L-PRF reported significantly higher implant stability [22]. In endodontic treatment, there is sparse evidence on the use of PCs. In treatment of osteonecrosis, use of L-PRF and PCs can aid in total bone closure of osteonecrotic lesions [23,38].

The goal of this comprehensive overview was to evaluate the available systematic reviews regarding the benefits of using APCs in all specialties of dental medicine on surgical wound healing and tissue regeneration. In many of the systematic studies reviewed, the effectiveness of APCs was compared to conventional treatment. It is hypothesized that APCs with their growth factors modulate wound healing by signals directed to specific target cell that bind to receptors [3,4,6,41,42]. However, the results of this comprehensive overview illustrate the heterogeneity of the different studies using APCs with regards to the study design, sample size, data reporting, surgical technique, graft material, endpoint variables, healing time; and most importantly, the method of preparation of the autologous concentrate and the type of centrifuge used in the study.

The use of APCs in sinus elevation procedures with bone graft augmentation is well recognized, but there is a lack of consistent clinical evidence regarding its healing potential. In this overview, the use of PRP in sinus elevation accelerated the healing and significantly increased early bone formation in the short-term and early postoperative [16,18]. The meta-analysis by Bae et al. [18]. consisting of 8 controlled clinical studies concluded that there were significant positive effects on early bone formation with the use of PRP when used with bone graft materials. This is consistent with PRP studies that showed beneficial effects in the first 3 to 6 months of graft maturation [3,4,6]. In 2000, Rosenberg and Torosian [43] further reported the benefits of PRP on bone quality and bone maturation in sinus grafting. However, studies with longer follow-up reported no significant clinical benefits of PRP in the healed maxillary sinus [16,17,20,21,24]. The systematic study by Arora et al. [16]. Determined that the use of PRP with autogenous bone and other graft substitute materials had no significant or clinical benefit on bone regeneration despite the increase in vertical bone height.

In comparison to PRP, the use of PRF in sinus graft procedures is relatively new. In an animal study using dogs, Xuan et al. [44]. showed that using a L-PRF membrane had a significant positive effect on bone formation in the grafted maxillary sinus. In a systematic review by Bastami and Khojasteh [23], PRF was shown to accelerate and increase new bone formation in humans. Similarly, in several sinus graft studies [45-47] conducted without the use of a graft material, the authors concluded that PRF alone improved bone healing and increased vertical bone height (7.5 mm to 10.4 mm) in the posterior maxilla when dental implants were simultaneously placed. The authors concluded that the use of PRF without bone graft materials may prove to be an alternative procedure that can correct atrophy in the vertical dimension for dental implants in the posterior maxilla [45-47].

On the contrary, a study consisting of 60 patients reported use of PRF with natural bovine graft material resulting in less new bone formation when compared to bovine bone alone [48]. Furthermore, the systematic review by Bastami and Khojasteh [23] could not find convincing evidence for the use of L-PRF on new bone formation. Other studies [11,49,50] also revealed that there were no significant differences when PRF was used alone, or with a bone graft material, to increase the vertical bone height to support dental implants in the posterior maxilla.

The conflicting results of PCs could be due to the cumulation of both shorter term and longer term follow-up results. Therefore, the use of PRP, L-PRF, and PCs for bone regeneration in the sinus required more randomized clinical trials focusing on the early post-operative and shorter term clinical effectiveness of PRP. This overview suggested that the application of PCs in the maxillary sinus can accelerate bone formation and tissue healing; and once the healing is complete, the final bone formed was the same as the control. This may be of significance because faster bone formation and healing may equate to early implant placement and shorter rehabilitation time.

The use of implant supported restorations to replace missing teeth is now becoming the primary treatment modality after tooth extraction. To prevent alveolar dimensional changes in the extraction site that occurs within 8 weeks after tooth extraction, the use of PRP and PRF has been investigated. Hauser et al. [51]. reported that the use of PRF prior to implant surgery reduced alveolar dimensional changes compared to natural wound healing. The use of PRF in extraction sites can improve soft tissue healing [22], improve bone quality [23], and reduce post-operative pain [22]. And when used in conjunction with biomaterials can significantly improve the bone level [22,23], but not the bone volume [23].

Although a systematic review of 8 studies by Del Fabbro et al. [25]. concluded that the use of APCs had a minimal positive effect on postextraction ridge preservation; the authors together with another study [26] also reported decreased post-operative pain and inflammation with PCs. In addition, the other study [26] also reported some evidence of accelerated bone healing.

The use of autologous platelet concentrates for the regeneration of periodontal bony defects has been well documented [31,34,52-54]. Similarly, the systematic reviews in this overview also reported beneficial effects for PRP used in surgical periodontal therapy [17,21,28,29,33]. The primary objective in periodontal treatment is to restore the health and function of the periodontium. Conventional open flap debridement (OFD) is unable to completely regenerate lost hard tissue destroyed from disease. Plachokova et al. [21] demonstrated the beneficial effects of PRP on bone regeneration when used for intra-bony defects. However, these beneficial effects were not significant when guided tissue regeneration techniques were used with PRP [28,29] or PCs [31]. Another systematic review [17], comparing PRP to open flap debridement was shown to have a moderate to high degree of clinical significance in four clinical variables of measurement consisting of pocket depth reduction, clinical attachment level, linear bone fill and gingival margin level.

Other clinical studies confirmed the benefits of PRF when used to manage intra-bony defects compared to conventional OFD [54,55]. The benefits of PRF was especially observed when used with bone grafting [31]. A systematic review and meta-analysis of 24 articles by Castro et al. [27]. compared the use of PRF and open flap debridement (OFD) in the management of intra-bony defects, it reported successful regeneration of osseous tissue. Improvements in probing pocket depth (PPD) reduction and clinical attachment level (CAL) gains were observed post-periodontal therapy. The authors concluded that the addition of L-PRF enhances periodontal wound healing. Overall, the use of L-PRF, in the surgical management of periodontitis and teeth with furcation involvement, can produced a significant decrease in probing depth, a significant gain in clinical attachment, and a significant increase in bone fill [22,23,27].

An explanation for the benefits of all forms of PCs can be attributed to the stimulatory effects of fibroblasts on gain in clinical attachment levels [3]. These findings suggest that the use of PCs may be beneficial in the use of surgical regenerative therapy in the treatment of periodontal defects. But, when evaluating clinical attachment level, the amount of bone formation compared to connective tissue formation cannot be determined. This is because a biopsy specimen of human histology would be required, and this is not possible in human studies where the goal is periodontal regeneration.

Surgical procedures were used to treat gingival recession to create a stable zone of attached gingival tissue. There is increased interest in the use of APCs to cover the exposed root, as growth factors may upregulate cellular activity to facilitate regeneration of periodontal tissue. Root coverage for gingival recession using PRP and the polymerized fibrin matrix of PRF has been reported [35]. Luo et al. [35] conducted a systematic review and their results concluded that the use of APCs may have a positive effect on gingival tissue regeneration, especially with recession depth and clinical attachment level.

Six studies compared the use of coronally advanced flap (CAF) to CAF and PRF. Four studies reported an increase in root coverage [30,56-58], while two other studies found no significant differences. In their review, Del Fabbro et al. [28] and Schliephake [17] concluded that autogenous platelet concentrates do not exert a positive effect on root coverage.

Comparing the use of connective tissue grafts (CTGs), it was reported that the use of PRF had similar success rates in Miller class I and II defects [59]. However, increased keratinized tissue was observed with the use of CTGs compared to using PRF as a fibrin matrix. Therefore, there is no consensus on the use of PRP or PRF in root coverage procedures for gingival recession. The overview reported conflicting outcomes for PRP [17,28,30], no significant effect for LPRF [27], and positive adjunctive effect for unspecified PCs [31]. Due to the diverse outcomes, APCs have limited benefit to improve root coverage compared with other treatment options.

At present, there are no accepted standard treatment protocol for medication-related osteonecrosis of the jaws (MRONJ) that results in a predictable favorable result, including the use of APCs [60]. MRONJ is associated with antiresorptive medications used to treat various bone disorders, such as osteoporosis and metastatic bone disease [61,62]. The lesion is characterized by exposed bone in the maxillofacial region that has been present for 8 weeks or more and the patient has had no exposure to radiation in the maxillofacial region. The pathophysiology remains unclear and there are no accepted standard treatment protocols [60]. However, the use of APC has been reported to be an effective treatment for MRONJ [63-66]. APCs contain the various growth factors that enhance wound healing and stimulates collagen production and angiogenesis and was shown to be effective in the treatment of MRONJ, many subsequent reports soon followed [63,65] demonstrating the effectiveness of APCs as an adjunctive treatment in the management of MRONJ [41,67]. Most recently, L-PRF has been shown to be an effective adjunctive treatment in the treatment of MRONJ [68]. In their study, 26 out of 34 patients had complete resolution of MRONJ.

The management of MRONJ remains controversial. A systematic review by Lopez-Jornet and colleagues [40], which due to an absence of published randomized clinical trials, consisted of studies with small sample sizes. This systematic review concluded that although published scientific data do not sufficiently support the use of APCs in the treatment of MRONJ, it and another study [25] reported that the majority of their included studies reported total bone closure. Thus, the use of APCs may have potential in the treatment of MRONJ due to its reported benefits of modulating cellular events in both soft and hard tissues.

The clinical value and strengths of this overview are the APC applications for the periodontal therapies [19,23-25,29-37] and for the clinical management of MRONJ [25,39,40]. Beneficial clinical outcome for periodontal soft tissue procedures and regeneration using bone grafting procedures appear to be consistent. However, it is interesting to note that APC in combination with GTR provides negligible benefits. MRONJ is consistently one of the most challenging infections in dentistry impacting on implants, site preparation, extractions, periodontal and endodontic therapies for patients taking bisphosphonates. The 3 reviews [25,39,40] were uniform in demonstrating a benefit for resolution of MRONJ lesions.

The weaknesses of this overview are that it is limited by the selected systematic reviews and the heterogeneity of their included studies. There is a variation of the clinical outcomes for implant surgeries [20,22,24,26]. The use of implant stability quotient (ISQ) values for implant stability showed consistent positive results for APC but is a relatively crude assessment of clinical success [24]. Furthermore, the lack of evidence for APC for endodontic therapies [25,38] do not permit conclusive evidence for clinical direction for this field.

Within the limits of this comprehensive overview, platelet concentrates can have benefits in intraoral tissue healing. It can be used successfully in intra-oral procedures like sinus augmentation, ridge preservation, periodontal treatments, and treatment of osteoradionecrosis. This overview suggested that the application of PCs in the oral cavity can accelerate bone formation and tissue healing; and once the healing is complete, the final bone or tissue formed was the same as the control. This may be of clinical significance because faster bone formation and healing may equate to early treatment interventions and shorter rehabilitation time. Of significance are the beneficial clinical outcome for resolution of MRONJ lesions, and for the periodontal soft tissue procedures and regeneration using bone grafting procedures. However, it has been difficult to state with absolute certainty that the use of APCs can benefit hard or soft tissue healing. Perhaps, the existence of conflicting and non-significant results may be a misunderstanding of which time point in the healing process, PCs outcomes should be evaluated. Thus, with a paucity of consistent clinical evidence regarding the benefits on the use of APCs, each clinician must proceed with caution should they decide to implement regenerative medicine into their clinical practice. Further research studies using randomized clinical trials evaluating the early postoperative APCs outcomes are needed to fully evaluate the clinical benefits of APCs on wound healing in the oral and maxillofacial region.

MT, NST, RK, SMB, CYSL, and JBS declare no competing interests regarding the content of this manuscript.