Platelet-Rich Plasma in Maxillary Sinus Augmentation: Systematic Review

Background: Sinus augmentation can be performed with or without grafting biomaterials, and to date, there is no quality evidence regarding the augmentation of the sinus floor using only platelet concentrates, which can improve the healing period and enhance bone regeneration by stimulating angiogenesis and bone formation. The main objective of this paper was to assess the effect of the sole use of platelet concentrates in sinus augmentation in terms of newly formed bone, augmented bone height, and clinical outcomes and to assess the additional beneficial effects of platelet-rich fibrin (PRF) in combination with other grafting biomaterials. Methods: A systematic review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Pooled analyses were performed with the Review Manager software. Results: For sinus elevation only using platelet concentrates, 11 studies met the inclusion criteria and were included for qualitative synthesis. Only one study was a clinical trial, which reported improved outcomes for the allograft group compared to the titanium-PRF (T-PRF) group. A total of 12 studies where PRF was used in addition to grafting biomaterials met eligibility criteria and were included in the review. Results from meta-analyses provided no additional beneficial effects of PRF in sinus augmentation in terms of bone height and percentage of soft tissue area. There was a statistically significant lower percentage of residual bone substitute material in the PRF (+) group compared to the PRF (−) group. The percentage of newly formed bone was slightly higher in the PRF (+) group, but this was not statistically significant. Conclusion: There is no robust evidence to make firm conclusions regarding the beneficial effects of the sole use of platelet concentrates in sinus augmentation. However, studies have shown favorable outcomes regarding implant survival, bone gain, and bone height. The use of PRF with other grafting biomaterials appears to provide no additional beneficial effects in sinus lift procedures, but they may improve the healing period and bone formation. Well-conducted randomized clinical trials (RCTs) are necessary to confirm the available results to provide recommendations for the clinical practice.

To date, there is no high-quality evidence regarding the augmentation of the sinus floor using only PRP, PRGF, or PRF. The combination of PRP and autologous bone for sinus lift seems to provide no additional beneficial effects in terms of implant survival rate, implant stability, bone height, marginal bone level, bone density, laminar bone and tissue volume, bone graft resorption, angiogenesis, and soft tissue healing, compared to the use of only autologous bone, as reviewed by Strauss et al. in 167 patients [39]. Another review, which analysed 81 patients, reported a short-term improvement in densitometry values and new bone formation, but its clinical relevance is unclear [40]. The use of PRP in combination with Beta-Tricalcium Phosphate (β-TCP), which was studied in 35 patients [30], or xenografts, in 127 patients [41,42], appears to show no additional clinical benefits. The addition of PRF to deproteinized bovine bone mineral (DBBM) has also not shown further benefits [30,41,42]. However, in vivo animal studies have shown that the sole use of platelet concentrates in sinus augmentation achieves a mean height of newly formed bone of up to 3.6 mm [43,44], and recent clinical studies have reported that they could be a successful procedure in sinus augmentation on residual ridges <5 mm [45] and achieve a mean height of newly bone of up to 4 mm when implants are simultaneously placed [46,47].

Objectives
The main objective was to assess the effect of the sole use of platelet concentrates in maxillary sinus augmentation in terms of newly formed bone, augmented bone height, and clinical outcomes such as implant stability and implant survival. Furthermore, to evaluate the additional effects of PRF in combination with other graft materials in sinus lift relative to the outcomes mentioned above, we conducted a systematic review that answered the following structure question (PICO): P = Patients requiring unilateral or bilateral maxillary sinus augmentation I = Sole use of platelet concentrates / PRF + grafting materials C = Grafting materials or nothing O = Newly formed bone, augmented bone height, implant stability and implant survival

Eligibility Criteria
The review included articles that met the following inclusion criteria: a.
Patients in need of unilateral or bilateral sinus augmentation before implant dental placement. b.
Randomized Clinical Trials (RCT), Controlled Clinical Trials (CCT), and comparative studies assessing histological, histomorphometric, clinical, and radiographic outcomes on the additional effects of PRF in sinus augmentation versus the non-use of PRF. c.
Specified follow-up period.
As the available literature on the effects of the sole use of platelet concentrates in sinus augmentation is scarce in terms of evidence provided by RCT and CCT, we considered including retrospective studies, prospective studies, and case series. Case series including fewer than five patients were excluded. In vitro and in vivo (animal) studies were also excluded from this review.

Information Sources
The electronic search was conducted in MEDLINE (PuBMed) and the Cochrane Central Register for Controlled Trials. No restriction on date publication was applied and only articles published in English were considered. References of relevant studies selected for potential inclusion were also searched. The last search was performed on 9 December 2019.

Study Selection
Three authors independently reviewed the titles and abstracts of the references located in the databases. Articles were selected whenever they appeared to meet the inclusion criteria. The same two authors independently reviewed the studies selected in the initial screening for full-text revision and final selection. Disagreements were resolved by discussion. If no consensus between the two authors could be achieved, a third reviewer was consulted.

Data Collection Process and Items
Two reviewers extracted the following data from the selected studies: year of publication, country, design, study period, follow-up, number of patients, number of sinuses, sinus lift complications, implant surgery, number of implants, intervention, and comparison group, which were arranged in a table. Outcome measures were arranged in another table, which included: radiographic, histomorphometric, clinical and postoperative complications assessment. Two authors revised the data collection.

Outcomes and Summary Measures
Primary outcomes were the percentage of newly formed bone, percentage of residual-bone substitute material, and percentage of soft tissue area assessed by histomorphometric analyses. Furthermore, augmented bone height (mm) was assessed by radiographic evaluation and clinical outcomes in terms of implant stability (implant stability quotient), implant survival (%), and postoperative complications.

Risk of Bias in Individual Studies
For RCT, the authors critically appraised each study for potential risk of bias by the Cochrane Collaboration's tool for assessing risk of bias. Studies were classified as "low risk", "unclear risk", and "high risk" of bias.

Synthesis of Results
Pooled analyses were performed using a random-effects model. Heterogeneity between studies was assessed by the I 2 statistics. Heterogeneity was considered statistically significant for a p value <0.1. Heterogeneity was interpreted as recommended by the Cochrane Handbook: 0%-40% was considered unimportant, 30%-60% was considered as moderate heterogeneity, 50%-90% was considered as substantial heterogeneity, and 75%-100% was considered as considerable heterogeneity. Outcomes were combined using the Review Manager software, version 5.3 (Cochrane community, available in: https://community.cochrane.org/help/tools-and-software/revman-5/revman-5-download; accessed in 1 November 2019)

Study Selection
The search among the literature for the sole use of platelet concentrates on maxillary sinus augmentation yielded 132 studies, which were screened for eligibility. After title and abstract evaluation, 18 studies were selected for full-text review. Of these, seven studies failed to meet inclusion criteria and were excluded from the review. Reasons for exclusion were in vivo (animal studies) [43,44,48], case series with <5 patients [49][50][51], and the use of a platelet concentrate in combination with a graft material [52]. Finally, 11 studies were included for qualitative synthesis ( Figure 1A). For the use of PRF in combination with other grafting materials, the search yielded 74 articles. After duplicates were removed, 62 articles were screened for eligibility based on their title and abstract, from which 21 were selected for full-text review. Eleven studies were excluded, as they did not meet the inclusion criteria, nine studies were excluded because they lacked a comparison group [53][54][55][56][57][58][59][60][61], one was excluded because it was compared with patients treated for another reason [62], and another was excluded because the intervention was not of interest for this study [63]. Additionally, two articles were identified through other sources and were incorporated in the review. Finally, 12 studies were included for qualitative synthesis ( Figure 1B).

Sole use of platelet concentrates in sinus floor augmentation:
Among the 11 included studies, two were case series [58,60], three were retrospective studies [53,64,65], five were prospective studies [46,47,[66][67][68], and one was an RCT [45]. The minimum follow-up was six months with a maximum of six years. In total, studies involved 301 patients requiring maxillary sinus elevation and 223 requiring sinuses lift procedures. Five studies did not

Sole Use of Platelet Concentrates in Sinus Floor Augmentation:
Among the 11 included studies, two were case series [58,60], three were retrospective studies [53,64,65], five were prospective studies [46,47,[66][67][68], and one was an RCT [45]. The minimum follow-up was six months with a maximum of six years. In total, studies involved 301 patients requiring maxillary sinus elevation and 223 requiring sinuses lift procedures. Five studies did not report on the number of sinus elevations [46,53,[64][65][66]. A total of 481 implants were placed, all with an immediate protocol. The majority of the studies used PRF as the sole grafting material. The descriptive characteristics of the studies are shown in Table 1. The only RCT [45] had a follow-up of nine months, involving 18 patients, from whom 10 were allocated to the intervention group (titanium-PRF) and the others were allocated to the control group (Cells & Tissue Bank Austria, Cells & Tissue Bank Austria (CTBA) allograft). There were 18 maxillary sinus elevations, with no reported complications and 37 implant placements in a delayed protocol ( Table 2).

PRF + Grafting Biomaterials in Sinus Floor Augmentation:
Among the 12 studies, two were retrospective studies [69,70], one was a CCT [71], and nine were RCTs [41,42,45,[72][73][74][75][76][77], of which three had a split mouth design [41,42,74]. Follow-up ranged from one week to two years. Studies involved 246 patients in need of unilateral or bilateral sinus floor augmentation, and a total of 298 sinus lift procedures were performed, of which 149 were allocated to the intervention group (PRF + grafting biomaterial). A total of 498 implants were placed with a delayed protocol. Only one study allocated patients in an early, intermediate, or late protocol for implant placement [76]. The majority of the studies combined PRF with bovine bone mineral (Bio-Oss) [41,42,69,73,74,76,77], while two combined PRF with alloplastic grafts [71,72], two combined PRF with bone allograft [70,75], and one used titanium-PRF as the only grafting biomaterial [45]. Summary descriptive characteristics of included studies are shown in Table 2.

Risk of Bias within Studies
From the 12 studies assessing the effect of PRF on sinus floor augmentation, nine were RCT. The risk of bias for these trials is presented in Table 3. Seven studies were considered as having a high risk of bias, mainly because the lack of blinding of participants and personnel [41,45,72,73,[75][76][77]. These studies also did not specify their methods for allocation concealment, and some did not report the methods for random sequence generation, potentially introducing selection bias. One study was assessed as having an unclear risk of bias [74], and only one study was assessed as having a low risk of bias [42].

Results of Individual Studies
Summary data of the results of included studies for the sole use of platelet concentrates on sinus floor augmentation are presented in Table 1. Results of individual studies for the use of PRF in combination with other grafting materials on sinus lift are illustrated in Table 4. Histomorphometric assessment (%) (mean ± standard deviation) New bone formation:

Postoperative complications of direct sinus lifting
Gradual improvements in the L-PRF group regarding postoperative pain, swelling, sleeping, eating, phonetics, activities of daily living and missed work days, but not statistically significant (p > 0.05) Wound healing in both groups was uneventful Healing index scores of the L-PRF group were higher than the control group on the 7 th (4.

Sole Use of Platelet Concentrates in Sinus Floor Augmentation
i-Radiographic assessment: Data on bone gain and/or bone height was available for nine studies. Anitua et al. [53] reported a mean bone height of 8.8 ± 1.4 mm and a mean bone gain of 4.3 ± 2.0 mm using plasma-rich in growth factors (PRGF) as the only graft material after three years of follow-up in an immediate protocol for short implant placement. Mean bone gain in the other studies varied between a minimum of 3.2-3.4 mm [66][67][68] and a maximum of 10 mm [58,60]. Kanayama et al. [46] reported a statistically significant mean bone gain in sandblasted acid-etched implants compared to hydroxyapatite implants, and Molemans et al. [67] reported a higher mean bone gain (5.4 ± 1.5 mm) with the lateral sinus floor elevation approach versus the transalveolar technique (3.4 ± 1.2 mm). Two studies additionally reported similar mean bone height values of 11.5 mm after six months of follow-up [47,65] (Table 1).
ii-Histomorphometric assessment: Data on the percentage of newly formed bone was available for only one study [58], which reported a mean of 33 ± 5% after six months of follow-up (Table 1).
iii-Clinical assessment: Data on implant survival rate was available in eight studies. Six studies reported an implant survival rate >95% after different periods of follow-up. The study by Simonpieri et al. [60], with the longest follow-up, reported an implant survival rate of 100% after six years. Aoki et al. [64] reported an 85.5% chance of implant survival after a mean follow-up of 3.5 years (range: 1-7 years). In subgroup analyses, the cumulative survival rates were 100% for the residual bone height ≥4 mm group and 69.6% for the residual bone height <4 mm group (p = 0.004) ( Table 1).

PRF + Grafting Biomaterials in Sinus Floor Augmentation
i-Radiographic assessment: Data on radiographic outcomes was available for four studies. Results from Bolukbasi et al. [69] showed that during the study period (2 years), the PRF + Bio-Oss group had less change in the height of grafted sinus floor for implant compared to the Bio-Oss + Bio-Gide group (p = 0.02). Two years after the prosthetic loading, both groups had similar values for the mean change in the height of grafted sinus with a slightly higher value in the intervention group (4.49 ± 0.29 mm versus 4.14 ± 0.20 mm) ( Table 4). Pichotano et al. [42] did not find differences in graft volume dimensional changes between the leukocyte-platelet rich fibrin (L-PRF) + Bio-Oss group and the control group after healing periods of four and eight months, respectively (Table 4). Similarly, Nizam et al. [41] did not find statistically significant differences in the augmented bone height between the test and control group after six months of sinus lift procedure. However, the results from Olgun et al. [45] showed that there was a statistical significant difference in the augmented bone height between the titanium-PRF (T-PRF) group (used as only grafting material) and the Cells & Tissue Bank Austria (CTBA) allograft, favoring the latter (11.7 ± 2.4 mm versus 19.9 ± 7.4 mm, respectively). Authors reported that the CTBA allograft group had 53% better volume, 86% better density, and 69% better height compared to the T-PRF group (Table 4). Our pooled analyses yielded no statistically significant difference in the mean augmented bone height between the combination of PRF + grafting biomaterial versus use of a graft material (Figure 2A ii-Histomorphometric assessment: Ten studies provided data on histomorphometric assessment. Regarding the percentage of new bone formation, the majority of the studies reported a similar mean percentage of newly formed bone for both the test and control groups, without a statistically significant difference between them, showing no apparent additional effects of PRF when combined with other grafting biomaterial ( Table  4). The percentage of new bone formation varied across studies between 17% and 45% in the PRF + grafting biomaterial group and 13% and 33% in the grafting biomaterial group. Only Pichotano et al. [42] demonstrated an increased percentage of newly formed bone in the L-PRF + Bio-Oss group compared to the Bio-Oss group (44.6 ± 13.9% versus 30.0 ± 8.4%, respectively). Zhang et al. [77] reported that the percentage of new bone formation in the PRF group was 1.4 times higher compared to the control group (Bio-Oss) (p = 0.14). Results from meta-analyses showed that the percentage of new bone formation was 1.98% higher in the PRF (+) group compared to the PRF (−) group, although these findings were not statistically significant and had moderate heterogeneity ( Figure 2B). ii-Histomorphometric assessment: Ten studies provided data on histomorphometric assessment. Regarding the percentage of new bone formation, the majority of the studies reported a similar mean percentage of newly formed bone for both the test and control groups, without a statistically significant difference between them, showing no apparent additional effects of PRF when combined with other grafting biomaterial ( Table 4). The percentage of new bone formation varied across studies between 17% and 45% in the PRF + grafting biomaterial group and 13% and 33% in the grafting biomaterial group. Only Pichotano et al. [42] demonstrated an increased percentage of newly formed bone in the L-PRF + Bio-Oss group compared to the Bio-Oss group (44.6 ± 13.9% versus 30.0 ± 8.4%, respectively). Zhang et al. [77] reported that the percentage of new bone formation in the PRF group was 1.4 times higher compared to the control group (Bio-Oss) (p = 0.14). Results from meta-analyses showed that the percentage of new bone formation was 1.98% higher in the PRF (+) group compared to the PRF (−) group, although these findings were not statistically significant and had moderate heterogeneity ( Figure 2B).
Five studies reported outcomes regarding the soft tissue (fibrous) area in the maxillary sinus cavity. Three of them [42,69,72] showed a slightly higher increase in the amount of soft tissue component in the control group compared to the intervention group (PRF + grafting biomaterial), but differences were not statistically significant (Table 4). Meta-analyses results showed a higher percentage of soft tissue area in the control group than in the PRF (+) group (mean difference: −0.53, 95% CI −4.21, 3.16), but differences were not statistically significant ( Figure 2D).
iii-Clinical assessment: Data on implant survival and implant stability was available for three studies. Studies reported a 100% implant survival rate for both the intervention and control groups after one year of follow-up [41,42] and three years of follow-up [76]. Implant stability was assessed through the implant stability quotient (ISQ), and there were no significant differences between compared groups in terms of stability values [45,76]. Pichotano et al. [42] reported higher ISQ values in the control group (75.1 ± 5.7) compared to the L-PRF group (60.9 ± 9.3) immediately after implant placement but no statistically significant difference between groups at implant loading (p = 0.99) ( Table 4).
iv-Patient outcomes: Two studies provided data on patients' outcomes. Gurler et al. [75] described gradual improvement in the L-PRF group compared to the control group regarding postoperative pain, swelling, sleeping, eating, phonetics, activities of daily living, and missed work days, but the differences were not statistically significant (p > 0.05). Del Fabbro et al. [73] stated that the use of PRGF combined with Bio-Oss resulted in a significant reduction of the perceived pain during the second and third postoperative day as compared to the control group (Bio-Oss). Patients in the test group also reported consistently less swelling, less hematoma, and less discomfort regarding chewing and speaking throughout the evaluation period (one week) ( Table 4).

Summary of Evidence
The existing evidence proved to be scarce in terms of the use of only platelet concentrates in maxillary sinus augmentation, with a lack of available studies that compare the use of only platelet concentrates as the grafting material versus other commonly used biomaterials, indicating that the clinical application of PRF in sinus lift procedures is relatively new. The majority of the studies included small cohorts of patients needing sinus floor augmentation with short-term follow-up (6-12 months). Efficacy of the sole use of platelet concentrates could not be assessed given the nature of the study design and lack of a control group. However, results from the studies showed that the use of PRF as the sole filling material during sinus lift with immediate implant placement is a reliable method that could lead to new bone formation and bone gain. The study by Olgun et al. [45] was the only RCT that compared the use of T-PRF versus CTBA allograft. Their results showed no differences in terms of new bone formation and implant stability, but radiographic assessment demonstrated that the CTBA allograft group had a statistical significant better bone volume (53%), bone density (86%), and height (69%) compared to the T-PRF group.
The evidence regarding the use of PRF in combination with other grafting biomaterials in maxillary sinus floor augmentation seems to provide no additional beneficial effects in terms of augmented bone height, percentage of soft tissue area, implant survival rate, and implant stability. A statistically significant difference revealed a lower percentage of residual bone substitute material favoring the PRF (+) group when compared to the use of grafting biomaterials alone (mean difference: −4.60, 95% CI −8.41, −0.78) with no significant heterogeneity (I 2 = 38%). In addition, our pooled analyses showed a slightly higher percentage of new bone formation in the PRF group when compared to the use of grafting biomaterials alone. This advantage may be possible due to its osteoinductive properties and the enhanced revascularization process, which allows for improved healing periods of the bone tissue as well. In that context, Choukroun et al. [70] reported no differences in newly formed bone between the PRF + freeze-dried bone allograft (FDBA) protocol versus the FDBA alone protocol, after 4 and 8 months of healing period, respectively, concluding that the addition of PRF could reduce the healing time prior to implant placement [70].
Our results are consistent with other previous systematic reviews [40,[78][79][80] and, to our knowledge, this is the second systematic review to provide pooled analyses. The previous systematic review [40] included five RCTs, so we broadened the search and included 12 studies, from which nine were RCTs. Included studies varied in their methodological quality, the majority of the included studies being assessed as high risk of bias. Only one study [42] was assessed as low risk of bias and reported a statistical high percentage of new bone formation in the L-PRF group compared to the control group (44.6 ± 16.9% versus 30.0 ± 8.45, respectively) and no differences between groups regarding graft volume dimensional changes, implant stability, and implant survival rate.

Limitations
Due to the lack of high-quality evidence, results must be interpreted with caution. Most of the included studies failed to specify their methods for allocation concealment, and some did not report the methods for random sequence generation, potentially introducing selection bias. Due to the nature of the intervention of interest, the majority of the studies lack any blinding of participants and personnel introducing, theoretically, performing bias. The degree to which the lack of blinding can affect the outcome assessment depends somewhat on the type of outcome measure. However, most of the studies included in this review assessed objective outcomes. Controlled clinical trials, retrospective, and prospective cohort studies have an inherent higher risk of bias. Most of them failed to control other variables that could influence the results. The majority of the available studies are heterogeneous in terms of intervention, comparison, and outcome measures, hindering direct comparisons on a much larger scale and precluding assessing a precise estimate of the beneficial effects of PRF. Another limitation is the language restriction, as only studies published in English were included in this review.

Innovation and Challenges
Traditionally, autogenous bone has been used in sinus floor augmentation to increase the bone height needed for implant placement. Although it is a predictable and effective technique, it has a high morbidity rate and takes approximately six months to be integrated and substituted by osteoconduction [70], delaying the implant placement and, consequently, extending patient treatment. Autologous graft materials partially account for these inconveniences, avoiding the morbidity associated with the use of autogenous bone. The use of PRF clots is a simple, low-cost, and low-resource technique that could be used as a treatment option for sinus lift procedures, improving the healing period, regeneration, and maturation of bone tissue and thus shortening the implant placement stage. In addition to its osteoinductive property, PRF promotes angiogenesis reduces tissue inflammation and infectious reactions [75], and promotes an immune regulation through the gradual release of anti-inflammatory cytokines [81]. These properties and advantages made PRF a promising biomaterial for clinicians and maxillofacial surgeons in different fields of dentistry. Clinical applications of PRF in sinus lift augmentation have recently been investigated. Moreover, there is a lack of evidence provided by RCTs related to the effects of PRF as the sole grafting material in sinus lift procedures with atrophic maxillaries (<5 mm). Preliminary studies have described positive results in one-stage implant placement protocols regarding bone gain and implant survival, but it is necessary to compare the use of only PRF with the use of other biomaterials or the use of PRF in addition to other biomaterials to assess its effectiveness.

Conclusions
There is no sufficient robust evidence to make firm conclusions regarding the beneficial effects of the sole use of platelet concentrates in sinus augmentation procedures. Although case series and cohort studies have shown favorable outcomes regarding implant survival, bone gain, and bone height, RCTs are required to assess whether platelet concentrates used as the only grafting materials are at least not inferior to autologous bone or other biomaterials used in sinus floor augmentation. The addition of PRF to other biomaterials appears to provide no further beneficial effects or to improve the outcomes in sinus lift procedures. Due to their biological properties, it could be considered as a reliable treatment option with the advantages of an improved healing period with a consequent earlier implant placement stage, enhanced new bone formation, and improved postoperative complications. Nevertheless, well-designed and conducted RCTs with the same PRF protocol preparation, blinding of personnel in charge of outcome assessment, and long follow-up periods are necessary to confirm the available results, determining their clinical implications and recommendations for the clinical practice.

Conflicts of Interest:
The authors declare no potential conflict of interest.