Therapeutic outcomes of non-grafted and platelet concentrations-grafted transcrestal maxillary sinus elevation (TSFE): a systematic review and meta-analysis

To evaluate and compare the stability, quantity and quality of bone augmentation at maxillary sinus elevation sites by non-grafted transcrestal sinus floor elevation (TSFE) and platelet concentration grafted transcrestal sinus floor elevation (PC-TSFE). A complete literature search was performed up to April 2019. Clinical controlled trials, retrospective cohort studies, and prospective cohort studies were selected based on inclusion criteria. The clinical outcomes were implant survival rate (ISR), marginal/crestal bone loss (MBL/CBL) and endo-sinus bone gain (ESBG). Meta‐analysis was conducted on these 1-year based values. Furthermore, another meta-analysis on 1-year ISR value was conducted among studies with different residual bone heights (RBH) within the non-grafted TSFE group. A total of 18 studies were included: 13 in TSFE group and 5 in PC-TSFE group. No significant differences were displayed between the 1-year ISR of TSFE (97%, 95%CI = 0.96–0.99) and PC-TSFE group (99%, 95%CI = 0.97–1.00). Among the various studies with different RBH within TSFE group, no significant differences in 1-year ISR were displayed. The 1-year MBL/CBL value of PC-TSFE group (0.73 mm, 95%CI = 0.43–1.13 mm) did not show significant difference as compared to TSFE group (0.60 mm, 95%CI = 0.10–1.10 mm). Furthermore, no significant enhancement was observed on 1-year ESBG value on PC-TSFE group (3.51 mm, 95%CI = 2.31–4.71 mm) in comparison with the TSFE group (2.87 mm, 95%CI = 2.18m–3.55 mm). Grafting platelet concentrations around dental implants at TSFE sites did not significantly enhance the adjacent bone regeneration. Moreover, TSFE was shown to be a reliable therapeutic option for implant sites that need simultaneous maxillary sinus augmentation, even under limited RBH.

The maxillary sinus is a cavity of pyramid shape in the maxilla with a volume of 12-15 mL. Its anterior border extends into the premolar roots or distal surface of canine roots, and the posterior border reaches the maxillary tuberosity 1,2 . Due to its structure and location, the maxillary sinus sometimes challenges the proper placement of the implant and also compromises its long-term functioning 2 .
To address this challenge and establish an adequate bone site for implantation, direct (lateral approach) maxillary sinus lift has been suggested since its first introduction in the 1980s 3 . That lateral approach is reliable to augment large quantity of bone at surgical sites, however it has strict limitations including excessive surgical trauma and prolonged healing time, which must be addressed 3 . In that attempt, transcrestal maxillary sinus elevation (TSFE), which is proceeded via alveolar crest, has been suggested and well implemented in clinical dentistry 4 . It compresses and apically pushes the maxillary bone from alveolar crest, and thus elevates maxillary sinus

Results
Literature search and selection. The process for searching and selecting literature is shown in Fig. 1. A total of 1891 studies were searched and saved in Endnote X9 (n = 1891). After 978 duplications were removed, title of residual literatures (n = 913) were scanned and identified, which led to removal of 746, which did not fulfil the inclusion criteria. Then abstract assessments were performed on the remaining studies (n = 167), from which 136 studies were excluded. A final full-text reading was conducted on the remaining studies (n = 31). Furthermore, a total of 13 articles were excluded for the following reasons: 5 for repeat with subsequent studies [22][23][24][25][26] , 3 for inconsistent follow-up visit time [27][28][29] , 3 for the inaccurate and insufficient data [30][31][32] , 1 where grafted material did not fulfil the inclusion criteria 33 , and 1 was excluded for the inaccurate demographic data 34 . Finally, 18 studies were included in this systematic review and meta-analysis, among which were 13 non-grafted TSFE [35][36][37][38][39][40][41][42][43][44][45][46][47] , 5 TSFE grafted with various platelet concentrations (PRP, PRF, CGF or PRGF) 7,18-21 . Literature quality assessments. Tables 1 and 2 shows the literature quality assessments of the 3 controlled studies and 15 non-randomized studies. For the controlled studies, the literature reported by Si et al. in 2013 qualified as low risk of bias, while the studies by Lai H C (2010) and Nedir (2017) were regarded with moderate risk of bias. For the non-randomized studies (prospective and retrospective cohort studies), all the 15 studies scored 7 or more and were assessed as high quality with low risk of bias. Table 3, among the 13 studies on non-grafted TSFE, Straumann implants were applied in 6 studies; Astra-tech implants were applied in 3 studies; 2 used both Neoss and Nobel Biocare implant systems; and 1 study used both Osstem and Bego implant systems. Furthermore, 1 study by Lai et al. did not clearly describe the implants' brand name. There were 6 retrospective studies, 4 prospective studies, 2 randomized controlled tests and 1 clinical controlled test for the non-grafted TSFE group. All the 3 controlled tests compared the therapeutic outcomes of non-grafted TSFE with TSFE grafted with bone substitutions, and for these studies the data of the non-grafted group were extracted and analyzed in the meta-analysis. 5 studies had reported the platelet-grafted TSFE ( Table 3), among which were 2 retrospective studies, 2 prospective studies, while the other 1 was not clearly defined. Considering the various grafted platelet Implant survival rate. As presented in Table 3, for the non-grafted TSFE group, the cumulated implant survival rates ranged between 90.6% and 100%, within the varied follow-up visit time (6-120 months). For the studies with longest follow-up visit time (10 years), the 10-year cumulative implant survival rate was 100% in Nedir's study (25 implants), and 91.2% in Caban's study (31/34 implants, 3 failed implants occurred within the 1 st year) 35,36 . The lowest implant survival rate was 90.6% (87 out of 96 implants survived) over 108 months, as is reported by Si et al. 38 . For the platelet-grafted TSFE, 4 out of 5 studies reported their 1-year implant survival rates, which ranged between 97.1% and 100% 7,18-20 . The only failed implant occurred in the study by Diss A et al., which reported 1 out of 35 implants failed at 1 year after treatment with PRF-grafted TSFE 21 . The meta-analysis on the 1-year implant-based survival rate of non-grafted TSFE showed an average value of 97% (95%CI = 0.96-0.99), while the PC-TSFE was 99% (95%CI = 0.97-1.00) (Fig. 2). Although slightly higher average ISR was obtained in the PC-TSFE group, the non-grafted TSFE group still obtained a favorable 1-year ISR, which indicated that it is a reliable treatment modality for augmenting bone quantity in maxillary edentulous region. Furthermore, another meta-analysis on 1-year implant-based survival rate among different RBH within non-grafted TSFE studies indicated that the survival rate for studies with RBH < 4 mm was 97% (95%CI 0.92-1.00), for whose RBH = 4~6 mm was 98% (95%CI 0.94-1.00), and those with RBH > 6 mm was 97% (95%CI 0.95-0.99) (Fig. 3). Finally, all the subgroups obtained favorable 1-year ISR values, which indicated that insufficient RBH is not restriction for non-grafted TSFE on maxillary edentulous region.

Discussion
The chamber of augmented maxillary sinus created by the apical displacement of maxillary sinus membrane (Schneiderian membrane) has active osteogenic potential 48,49 . As previous study indicated, cells extracted from the Schneiderian membrane can express osteogenic differentiation cytokines including CD105, CD73 and CD166 48 . Moreover, there also are numerous ALP and STRO-I positive staining cells that can be separated from the Schneiderian membrane, which revealed the existence of osteoprogenitor cells and osteoblasts 49 . Based on these facts, it is indicated that bone grafts are not mandatory for a successful MSFA, as long as we could maintain the integrity of Schneiderian membrane and obtain a stabilized chamber for bone regeneration 50 . Studies focused on non-grafted TSFE have been performed and confirmed that such technique is reliable for MSFA sites, even in cases with limited residual bone height (RBH) 51 . Considering the longevity of non-grafted TSFE, some studies have even shown that there were no differences in implant survival rates between bone substitutions grafted and non-grafted TSFE sites 8,11 . However, for the lateral MSFA, bone grafts are still recommended as a beneficial strategy, for both improving the implant survival rates and maintaining the stability of ESBG 52 . Platelet concentrations (PCs) are extracted by centrifuging autologous blood and formed by the co-aggregate process of platelets, and they could be fabricated into the liquid form including PRP, PRGF or gel-like substrates such as PRF and CGF 9,53-55 . All these concentrations are rich in various cytokines that promote tissue regeneration, which include vascular endothelial growth factor (VEGF), insulin growth factor (IGF) and platelet-derived growth factor (PDGF) 12  www.nature.com/scientificreports www.nature.com/scientificreports/ upregulating osteoblast proliferation and regeneration of periodontal ligament cells 59 . Furthermore, the slow platelets aggregation allows for more cytokines to be embedded within such mesh-like structures, and their slow degradation rates allows for sustained release of growth factors into the surrounding tissue 12 .
Another distinguished feature of platelet concentrations is their softness and flexibility, which can act like a buffer material between protruded bone fragments/implant screws and Schneiderian membrane 9,53-55 . Compared with the traditional bone grafts that contain particles with sharp edges, the liquid/gel-like substrates of platelet concentrations are protective to the delicate Schneiderian membrane from being penetrated 9,53-55 .
In this study, initially we analyzed the implant survival rate (ISR) within non-grafted TSFE studies among different RBH, and no significant differences were observed on 1-year ISR among groups with different average RBH within non-grafted TSFE group, even cases with limited RBH (<4 mm) obtained favorable 1-year ISR 51,60,61 . This confirmed that limited RBH does not impact the implant survival for non-grafted TSFE surgeries, as long as secured primary stabilities are obtained on implants 51,60,61 . Furthermore, the increase in bone-implant contact area and the compression of bone during TSFE augments the bone density around implant sites. This in turn can enhance the primary stability of implant at TSFE sites, which effectively reduces the fretting of implants and promotes osseointegration at implant-bone interface 51 .
To investigate the enhancement of osseointegration and bone stability by adding PCs in TSFE sites, we performed meta-analysis on average 1-year ISR between non-grafted TSFE and PC-TSFE, which has not been reported before. Result showed no significant differences on 1-year ISR between the two groups, indicating that adding PCs in TSFE sites will not significantly enhance the strength and stability of osseointegration around implants. It is noteworthy that TSFE will press implant screws and adjacent bone into maxillary sinus, which are capable of supporting the apically displaced Schneiderian membrane, thus maintaining the stable osteogenic chamber 62 .
Furthermore, in the studies with MBL, there was no significant difference between the non-grafted TSFE and PC-TSFE groups. This can be attributed to the fact that PCs were lifted to the apical region of surgical sites, not the crestal region which could not directly influence the MBL during the constant masticatory cycles. It is noteworthy that MBL around implants is influenced by various factors including smoking, platform-switching technique at implant-abutment interfere, surface characteristics of implants/abutments, surgical trauma and functional loadings [63][64][65] . In the current study, the average 1-year MBL of non-grafted TSFE (0.73 mm, with 95%CI = 0.33-1.13 mm) was shown to be acceptable for the clinical application. Enhancement of peri-implant bone density alleviates the MBL, and the TSFE increases the density of peri-implant cancellous bone; hence the non-grafted TSFE can supports primary stability and peri-implant bone density (towards long term implant success) [66][67][68] .
For the ESBG data, although the PC-TSFE group showed a slightly higher 1-year average ESBG, there was no significant difference with non-grafted TSFE group. This is because PCs are flexible and gel-like substrates,   www.nature.com/scientificreports www.nature.com/scientificreports/ which are not mechanically rigid to maintain extra augmentations of Schnederian membrane in TSFE sites. Furthermore, although PCs are are known to stimulate proliferation, migration and differentiation of adjacent osteoblasts/fibroblasts, their biodegradation characteristics does not continuously support the elevated Schneiderian membrane [69][70][71] . It is noteworthy that the chamber for bone regeneration at TSFE sites is maintained by the pressed implants and the displaced maxillary bone, thus the non-grafted TSFE is sufficient towards maintaining the vertical bone gain. These results correlates with the study by Liu et al., which reported that applying PCs as adjunctive to bone substitutions into MSFA sites did not show significant enhancement of regeneration and formation of new bone around implants 72 . Moreover, PCs will resorb within a few days after being implanted in human body. Such rapid degradation prevents them from constantly releasing cytokines during the bone regeneration phase in surgical sites 72 .
In summary, PCs contain various cytokines to promote bone regeneration. However, they are unable to significantly enhance the stability and vertical quantity of newly regenerated bone around the implant surfaces in TSFE sites. This is attributed to the inappropriate mechanical (softness and flexibility) and biodegradation characteristics of platelet concentrations, which prevents them from maintaining an osteogenic chamber by continuously supporting the Schneiderian membrane. Moreover, non-grafted TSFE is a reliable treatment modality for sites needing MSFA, even with limited RBH (<4 mm). To optimize their osteogenic potential, combining PCs with mechanically rigid and slow degrading bone substitutions to continuously support osteogenic chamber, can promote bone quantity and quality in TSFE sites. However, this represents a research gap and hence needs further investigations. Additionally, for further enhancement of PC-induced bone regeneration, more histological studies on bone formation pattern and process (including vascularizationand mineralization) are needed. Finally, the clinical studies on PC-TSFE are limited and most of them are based on short-term post-surgical data (mainly 1 year), which is a shortcoming for the current systematic review and requires long-term investigations for further advancements.

conclusion
This systematic review and meta-analysis compared the therapeutic outcomes of non-grafted transcrestal sinus floor elevation (TSFE) with platelet concentrations grafted TSFE (PC-TSFE). The results indicated no significant enhancements on 1-year implant survival rates, marginal bone loss (MBL) and endosinus bone gain (ESBG) of PC-TSFE group as compared to non-grafted TSFE group. Moreover, among subgroups of different residual bone height (RBH) within the non-grafted TSFE group, no significant differences were shown on their implant survival rates. The results confirm that adding platelet concentrations into maxillary sinus could not provide significant enhancements to the therapeutic outcomes of TSFE. However, to provide strong evidence on the therapeutic outcomes non-grafted and platelet grafted TSFE long term clinical studies must be conducted. Finally, to utilize the osteogenic potential of platelet concentrations and obtain an optimized bone quality/quantity in TSFE sites, further clinical and histological studies are needed, specially with the combined graft of platelet concentrations with    www.nature.com/scientificreports www.nature.com/scientificreports/ other bone substitutes into TSFE sites. To date, the non-grafted TSFE remains a reliable therapeutic option for surgical sites that need maxillary sinus floor elevation (MSFA), even in cases with limited RBH.

Methods and materials
Search strategies. The PICO elements for this study are P (Problem): insufficient bone quantity at maxillary molar sites; I (intervention/indicator): grafting platelet concentrations in TSFE sites; C (comparison): non-grafted TSFE surgeries; O (outcome of interest): enhanced bone regeneration and osseointegration. The initial literature search was conducted in the Scopus, Pubmed and Cochrane library database. All relevant studies until April 2019 were included relating to indirect/transcrestal maxillary sinus elevation (TSFE). A search strategy of Mesh term or Keywords included a combination of ["maxillary sinus floor augmentation (MSFA)" OR "maxillary sinus lift" OR "maxillary sinus augmentation" OR "maxillary sinus elevation"] and ["transcrestal" OR "osteotomy" OR "transcrestal sinus floor elevation (TSFE)" OR "indirect sinus floor elevation" OR "osteotomy sinus floor elevation (OSFE)"] (processed by TG and ZF). After removing the duplications, a sequential selection of title, abstract and full text reading were performed on the residual literatures and finally selected. These articles included the studies relating to non-grafted TSFE and PC-grafted TSFE. Search and selection of literature was conducted by two reviewers (TG and ZF). If disagreements occurred between these two reviewers, a third reviewer (ZS) was recommended to judge the disagreement. All the literature were managed by Endnote X9.
Inclusion criteria. Randomized controlled trials (RCTs), controlled clinical trials and observational studies (prospective and retrospective cohort studies) on the studies related to non-grafted TSFE or PC-grafted TSFE were included in this study. Minimum implants enrolled in each study was 15, and the shortest post-surgical observation period was 6 months. Moreover, demographic data of implants and patients (brand of implants, surgical methods, implant and patient numbers) must be clearly described. For studies that compare the therapeutic outcomes between non-grafted TSFE and bone-substitutions grafted TSFE, the outcomes of the non-grafted groups were extracted and analyzed in this paper. For studies which compared PC-grafted TSFE with bone substitutions grafted TSFE, data of the PC-TSFE group were extracted and compared.
Exclusion criteria. Case reports, technical reports, conference articles, animal experiments, in vitro studies, finite element analysis, reviews and letters to the editors were all excluded. Clinical studies with insufficient post-surgical follow-up visiting periods, or inaccurately described therapeutic outcomes, and those unable to clearly define demographics were also excluded.
Study selection and data extraction. Study selections were conducted by two researchers (TG and ZF), and the detailed process is presented in Fig. 1. When disagreements occurred, a third person (ZS) was asked to review and decide. Data of each selected study was extracted by two reviewers (TG and ZF), including: (1) demographics: authors, year of publishing, implant systems, numbers of implants and patients; (2) individual information: surgical methods and residual bone height (RBH); and (3) therapeutic outcomes: implant survival rate (ISR), endo-sinus bone gain (ESBG) and crestal/marginal bone loss (CBL/MBL). For studies that reported the therapeutic outcomes in sequential follow-up visit time, the data at all follow-up visit time points were extracted into the systematic review.
Literature quality assessment. Quality assessment on the selected literature was performed by two researchers (TG and FZ). As showed in Table 1, these controlled studies were assessed by eight criteria under the Cochrane Collaboration guidelines 73 . An assessed study was confined as "low risk of bias" if all the criteria were answered "Yes". If 1-2 clauses were "No", the risk bias was defined as "moderate". If more than 2 clauses were "No", the risk of bias was outlined as "high". Newcastle-Ottawa Scale (NOS) was applied for assessing the quality of non-randomized studies (prospective and retrospective cohort studies), just as Table 2 describes, with the maximum possible score 9. Any study scored 7 or more was determined as high quality with low risk of bias 73 . Data synthesis and meta-analysis. Stata MP 14.1 software was applied to process the meta-analysis, randomized model was applied to process the meta-analysis, with heterogeneity indicated by I-square values. To include studies having a 100% implant survival rate, we modified the rates with the formula: [modified survival rate = (number of survived implants − 0.25)/(number of total implants) *100%] in Stata MP 14.1. Considering the data of ISR, MBL and ESBG were based on the 1-year follow-up in majority of the literature, the 1-year post-surgical data of these parameters were considered in the meta-analysis. Moreover, to investigate the clinical reliability of non-grafted TSFE in cases with limited RBH, study on 1-year ISR of non-grafted TSFE was performed among its subgroups with varied RBH values.
Variables processing and comparison. Since the 1-year ISR values pooled by Stata 14.0 were only accurate to their single digital units (eg. 0.99 = 99%), thus observation and descriptions were applied on these pooled values. For exploring the differences of 1-year MBL and ESBG between non-grafted and PC-grafted TSFE, these data were pooled and compared as described below: Stata 14.0 applies 95% confidence interval (CI) to display the distribution of continuous variables, as indicated by Cochrane Handbook for Systematic Reviews (Version 5.0.2 Chapter 7.7.3.2.), to calculate the standard deviation (SD) of each group from the 95%CI, the equation below was applied 74 : = × − . SD n upper limit lower limit ( ) /3 92 (2020) 10:5935 | https://doi.org/10.1038/s41598-020-62407-y www.nature.com/scientificreports www.nature.com/scientificreports/ As grafting PC is the intervention (I) in this study, thus the changes of average value, SD and standard error (SE) of each variable after intervention were calculated as the equations below, indicated by Cochrane Handbook for Systematic Reviews (Version 5.0. In the equations above, Non represents non-grafted TSFE group and PC represents PC-grafted TSFE group, and Corr value was determined as 0.40, if the 95% CI (Mean (E, change) ± 1.96×SE (E, change) ) of changes in any variables contain 0, it is indicated that such variable had no significant enhancements/differences after grafted by PC, which is the intervention (I).