Effectiveness of Autologous Platelet Concentrates in the Sinus Lift Surgery: Findings from Systematic Reviews and Meta-Analyses

Maxillary sinus augmentation is one of the most predictable procedures for the rehabilitation of the posterior maxilla. The current overview aimed to summarize the findings provided by systematic reviews (SRs) and meta-analyses on the effectiveness of autologous platelet concentrates (APCs) in sinus lift and to assess the methodological quality of the included SRs. Three electronic databases have been explored. SRs and meta-analyses addressing the effectiveness of APCs in sinus lift technique were included. Clinical, radiographic and histomorphometric findings were considered for APCs as solely grafting materials and APCs in combination with biomaterials. Outcomes were implant survival rate (ISR), implant stability (IS), implant failure (IF), postoperative complications, histomorphometric findings, radiographic bone gain, bone volume and bone density. The methodological quality of the included SRs was assessed using the updated version of “A Measurement Tool to Assess Systematic Review” (AMSTAR-2). Thirty SRs were included. The methodological quality of the included reviews ranged from critically low (3 studies) to high (9 studies). The included SRs showed favorable clinical outcomes, short-term new bone formation and no biological complications when APCs were used both as solely graft material or in combination with other biomaterials. However, no significant additional effects in the long-term period were observed. APCs did not add any further positive effects compared to the physiological healing derived by the natural blood clot. The current overview of SRs highlighted the need for high-quality SRs evaluating the role of APCs in sinus lift though network meta-analyses, in order to identify the most powerful material for sinus lift augmentation. The use of APCs improves the healing of soft tissues and the postoperative quality of life in the short-term period. Thus, its application can be recommended.


Introduction
Implantology has become a well-established treatment option to rehabilitate totally or partially edentulous jaws.An imperative necessity for an implant placement ensuring long-term stability is a proper osseointegration based on a minimum amount of bone width and height of the recipient site.In this regard, one of the challenges for clinicians is represented by the rehabilitation of the atrophic posterior upper jaw, where the progressive expansion of maxillary sinus over the years and the loss of posterior teeth reduces the available bone for a standard implant-prosthetic rehabilitation [1][2][3].Lateral and transcrestal sinus floor elevation represent the most widely techniques to increase alveolar bone height by the formation of new bone in the maxillary posterior region.A controversial still open issue concerns the material used to fill the newly formed cavity following sinus lift.
Numerous biomaterials and bone substitutes have been proposed for application in the maxillary sinus floor lift procedures, mainly to sustain the lifted space.Those include (yet not limited to) autogenous/autograft, freeze-dried bone allograft, xenograft, and alloplastic bone with different successful results [4][5][6][7].Other authors, instead, have highlighted the considerable regenerative potential deriving from the blood clot alone, not recommending the addition of other grafting material; in these cases, Schneiderian membrane is supported only by the implant apex [8].To stabilize the blood clot and enhance the healing, biological active molecules, such as bone morphogenic proteins (rhBMPs) [9][10][11], autologous platelet concentrates (APCs) [11,12] and mesenchymal stem cells (MSCs) [13], have been recently introduced as additional or replacement materials in bone augmentation procedures.APCs are biological products derived from the patient's centrifuged venous blood [14][15][16][17].Through different methods of centrifugation, it is possible to obtain white blood cells and especially platelets, in a higher quantity than the basal level in peripheral blood.They represent important sources of growth factors and cytokines able to accelerate healing and regeneration of tissues through modulating tissue inflammation, promoting local hemostasis, vascularization of tissues, accelerating new bone formation and improving scaffold mechanics [18].These biological properties have allowed its use in oral and maxillofacial surgery [19][20][21], dermatology [22], ear-nose-throat surgery [23], plastic surgery [24][25][26], orthopedics [27], sports medicine [28], gynecology [29], cardiovascular surgery [30] and ophthalmology [31].Systematic reviews (SRs) are considered the best type of publication for gathering existing evidence and providing clinicians with a summary of the latest findings on a clinical question.However, several SRs have been conducted to evaluate the impact of APC in the sinus lift surgery with or without other grafting materials leading to conflicting results due to varying inclusion/exclusion criteria and the quality of primary studies [32][33][34].To address these difficulties in evaluating evidence and making decisions, the next step is to conduct overviews of SRs.These overviews provide a comprehensive summary of the results from multiple SRs and meta-analyses in an easily understandable format, and they assess the quality of existing SRs on a topic.They are also valuable tools for clinicians to make treatment plans based on the highest level of evidence and for researchers to identify priorities for future research.To the best of our knowledge, this is the first overview conducted on this topic.Therefore, the aim of this overview was to summarize the results from systematic reviews and meta-analyzes regarding the efficacy of the different autologous platelet concentrates, as solely filling material or in association with other biomaterials in the sinus lift surgery and to assess the methodological quality of the included systematic reviews.

Materials and Methods
This review was compiled following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for improving the reporting of systematic reviews and meta-analyses.According to the PICO (P: population, I: intervention, C: comparison, O: outcome) protocol, this overview aimed to answer the following question: "Does the use of autologous platelet concentrates (APCs) as solely grafting material or in association with other biomaterials (Intervention) improve clinical, radiographic and hystomorphometric outcomes (Outcome), in patients undergoing sinus lift surgery, with both crestal and lateral access (Population)?"All APCs described in the current scientific literature were considered "Interventions", while spontaneous healing of the intervention site associated with the only regenerative power of the blood clot or addition of other different biomaterials were considered as "Comparisons".Postoperative discomfort and patient-centered outcomes, such as quality of life problems (functional limitations in chewing, speaking, sleeping and inability to perform daily routines and work activities correctly), were considered as secondary outcomes.The protocol was registered on the PROSPERO National Institute of Health Research Database (CRD42023391448).

Literature Search and Review Selection
Initially, a pilot search was conducted on PubMed to check for the presence of existing overviews and collate enough systematic reviews (SRs) that could serve as a solid foundation for the creation of the above-mentioned overview.Literature research was conducted for reviews and meta-analysis published up to 31 March 2023, using three electronic databases (PubMed, Scopus, The Cochrane Library).Different combinations of keywords and MeSH terms, according to the database's rules, were developed to identify suitable studies.The search strategy is reported in Table 1.A manual search was performed in oral surgery journals (Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, Journal of Prosthodontic Research Journal of Cranio-Maxillo-Facial Surgery, International Journal of Oral and Maxillofacial Surgery, International Journal of Oral and Maxillofacial Implants, International Journal of Oral Implantology, Journal of Osseointegration) and a further search was performed among the references of the included articles.The grey literature was explored by searching among the conference abstracts published on Web of Science and Scopus and on the databases of scientific dental congresses (International Congress of Oral Implantologists (ICOI), International Association for Dental Research (IADR), European Federation of Periodontology (EFP)).Review selection was performed by two independent reviewers (MDC, RG).Eligibility criteria were SRs and meta-analyses addressing the effectiveness of APCs, as solely grafting materials or in association with other biomaterials, in crestal and lateral sinus lift surgery, in the English language, published up to 31 March 2023.Exclusion criteria were the following: clinical controlled trials (CCTs) and randomized controlled trials (RCTs), dual publications, narrative reviews, case series, questionnaires, radiographic studies, studies with histological data only, animal studies, case reports, letters to the editor, and in vitro studies.Also, abstract and articles written in any language other than English were excluded.After title and abstract screening, the articles were selected for full-text eligibility.Whenever differences in the judgement of the eligibility of title and abstract occurred, full texts were included for final assessment.Disagreements between the two authors were solved by the intervention of a third reviewer (GS).

Data Extraction
Data were independently extracted by two authors (MDC, RG) using a predetermined extraction form.Whenever the information provided in the SRs was not clear, the individual studies were consulted.The authors were not contacted for further details.The following characteristics of each study were extracted: author, publication year, search period, databases, study design (SR with or without meta-analysis), total number of subjects included, intervention and control groups, outcome measures, methods of measurement, quality tool and quality of the individual studies, and the author's conclusion.

Methodological Quality of Included Reviews
The methodological quality of the included SRs was independently assessed by two reviewers [MDC, NR] using the revised and updated version of A Measurement Tool to Assess Systematic Review (AMSTAR-2).AMSTAR-2 is a valid and reliable instrument made of 16 items, which correspond to three possible responses: "yes", "partial yes" or "no."After interpreting the weaknesses detected in critical and non-critical items, the overall quality rating of a SR was reported as "high", "moderate", "low" or "critically low".

Search Results
Figure 1 shows the flow diagram of study selection.A total of 92 records were identified through electronic and manual search.After duplicates removal, the title and abstracts of 71 records were screened.Of these, 42 manuscripts were included for full-text reading, while 29 were excluded according to the application of the exclusion criteria.For the references of the excluded full-text and reasons, consult the Supplementary Table S1.
predetermined extraction form.Whenever the information provided in the SRs w clear, the individual studies were consulted.The authors were not contacted for f details.The following characteristics of each study were extracted: author, publi year, search period, databases, study design (SR with or without meta-analysis) number of subjects included, intervention and control groups, outcome mea methods of measurement, quality tool and quality of the individual studies, an author's conclusion.

Methodological Quality of Included Reviews
The methodological quality of the included SRs was independently assessed b reviewers [MDC, NR] using the revised and updated version of A Measurement T Assess Systematic Review (AMSTAR-2).AMSTAR-2 is a valid and reliable instru made of 16 items, which correspond to three possible responses: "yes", "partial y "no."After interpreting the weaknesses detected in critical and non-critical item overall quality rating of a SR was reported as "high", "moderate", "low" or "cri low".

Search Results
Figure 1 shows the flow diagram of study selection.A total of 92 records identified through electronic and manual search.After duplicates removal, the tit abstracts of 71 records were screened.Of these, 42 manuscripts were included for fu reading, while 29 were excluded according to the application of the exclusion criter the references of the excluded full-text and reasons, consult the Supplementary Tab   Finally, 30 SRs were included for the qualitative analysis [7,.

Characteristics of Included Reviews
Data extracted from the thirty (30) SRs are summarized in Table 2.The number of primary studies included in each SR ranged between two (2) and forty-two (42).Fourteen ( 14) SRs were integrated with a meta-analysis [34][35][36]39,40,46,47,50,51,[54][55][56]60].Most of the SRs included as primary study clinical controlled studies (CCTs) and randomized clinical trials (RCTs), but eight (8) SRs also included non-controlled studies, case series and case reports [32,34,38,49,52,53,56,59]. None of the included reviews were based on non-controlled studies only; but, in two articles [33,42], the type of included clinical studies is not specified.The number of total subjects included in each review was not always clarified.The initial diagnosis was not clearly reported in some of the included reviews.The surgical procedures studied were lateral and crestal sinus augmentation.APCs were compared to other biomaterials or to the healing provided by blood clot alone or there was no control group.The primary outcomes in most of the studies were clinical (implant success and implant survival), radiographical (bone volume, bone height, bone density) and histomorphometric (percentage of new bone formation).Other reported outcomes were soft-tissue healing, postoperative complications and patient-centered outcomes.

Methodological Quality of Included Reviews
The methodological quality of the included reviews as measured with the AMSTAR-2 ranged from critically low (3 studies) to high (9 studies).The most common critical weakness in the included reviews was the absence of clearly a prior established review methods and any significant deviations from the protocol (Table 3).

Clinical, Radiographical and Histomorphometric Results
To make the reading of the results simpler, we divided them into two specific categories: APCs as solely grafting material and APCs in combination with other biomaterials.

APCs as Solely Grafting Material
There is only one SR [34] that discusses the effects of APCs alone vs. blood clot.Eight SRs include studies that examined APCs alone and APCs in association with other biomaterials as control [33,38,42,49,52,53,56,60].
Guo T. et al. [34] reported no significant differences between the 1-year implant survival rate of the non-grafted group (97%) and the APCs group (99%).Moreover, Ali and coworkers [33] reported high implant survival rates although only one primary study [61,62] provided a long-term follow-up (2-6 years).No postoperative complications were observed during the healing period.In the few cases in which a sinus membrane's perforation occurred, it was solved by PRF membrane thanks to its good intrinsic adherence to the Schneiderian membrane [33,53].
In relation to radiographic bone height, volume and density and marginal bone loss (MBL), most of the included SRs agreed that APCs were a reliable method that could lead to short-term new bone formation but without long-term significant differences [38,42,53,55].
According to Guo T. [34], there was postsurgical endo-sinus bone gain with the highest value of 8.23 + 2.88 mm at 14 months postsurgery.Similarly, other SRs [38,42,49,52] reported the highest level of vertical bone gain between 8.5 and 12 mm, using L-PRF as sole filling material.
Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?
Did the review authors report on the sources of funding for the studies included in the review?
Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?
If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?
Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?
Did the research questions and inclusion criteria for the review include the components of PICO?Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
Did the review authors explain their selection of the study designs for inclusion in the review?
Did the review authors use a comprehensive literature search strategy?
Regarding soft-tissue healing, the studies in which APCs were also used as a membrane [44] reported superior outcomes in terms of tissue color, response to palpation, presence/absence of granulation tissue, and incision margin opening but the differences were not statistically significant versus the control group.
About bone gain, Otero et al. [53] reported that the application of PRF either alone or in conjunction with another biomaterial is an effective biomaterial, reducing the time for new bone formation and, consequently, the time necessary for implant rehabilitation.Two SRs [37,39] showed a statistically higher bone volume and bone density in the short-term period (6 months/1-year) between the test and control groups but, in the long term, no statistically significant differences were found.Also, when PRF was mixed with deproteinized bovine bone, the authors reported a 31% increase in the perimplant bone density [49].Nevertheless, Fujioka-Kobayashi M. et al. did not report any significant improvement in bone gain when PRF was added to biomaterials [48].
Regarding histological and histomorphometric evaluation, in lateral sinus lift, NBF in the L-PRF group was 1.4-fold higher than that in the control group (deproteinized bovine bone alone) but without statistical significance [41,42].Therefore, no differences were found in the bone grafts remnants, fibrous tissue within the sinus and percentage of the bone graft in contact with the newly formed bone.
With similar results, pooled analysis of Ortega-Meja [52] showed a slightly higher percentage of NBF in the PRF group when compared to graft materials alone.Anitua et al. [36] discussed that most of the included studies indicated a higher new bone formation in the P-PRP group while only one study showed no differences [64].
Although L-PRF and PRGF did not show a greater proportion of vital bone formation and residual grafting material [33,44,45], they seemed to accelerate bone maturation, reduce the amount of biomaterial needed and reduce the healing time.
Moreover, several SRs [37,39,43,55] demonstrated a significant increase in vital bone regeneration (over 22 + 9% of bone formation) and a decrease in residual graft particles in test sites with a slow resorption of biomaterials and with the capacity of APCs to enhance the osteoconductive nature of freeze-dried bone allograft.Meanwhile, Otero et al. [53] mentioned that the histomorphometric examination of FDBA/PRF revealed 65% of vital new bone and 35% of inert bone within the trabecular areas after 4 months versus, respectively, 69% and 31% in the control group after eight months.
In addition, Stahli et al. [58] reported that PRP can improve the regenerative potential of anorganic bovine bone by increasing the newly formed bone volume (31%) thanks to the stimulation of the vascularization process through the release of growth factors.Finally, the percentage of soft-tissue area was higher in the PRF group (3.73%, 95% CI. 10.11 to 2.66; p = 0.25) but no significant difference was detected [32,51].

Discussion
Rehabilitation of the atrophic posterior maxilla is a challenge for clinicians.Maxillary sinus floor elevation is considered a reliable standardized procedure to achieve a more suitable condition for implant placement in terms of bone height and volume.Many bone substitutes have been proposed to fill the subsinusal neocavity.In this overview, emphasis was focused on the use of growth factors directly derived from centrifugation of patients' blood samples.Due to wide and conflicting conclusions in the scientific literature discussing the use of APCs in sinus lift surgery, the rationale of this article based on the assessment of systematic reviews dealing with this topic.So, an overview of thirty (30) SRs and metaanalyses regarding the effectiveness of APCs in maxillary sinus augmentation surgery was created.Hence, the purpose was to provide surgeons with some clinical indications about the use of platelet concentrates, both as sole grafting material or in combination with other different bone substitutes in lateral and transalveolar sinus lift surgery.Most SRs provided positive results in terms of clinical, radiographic and histomophometric findings when APCs were used as solely grafting material or in combination with biomaterials.Specifically, better results in implant stability and implant survival rate were found in test groups rather than control groups [37].APCs also seemed to induce an increased radiographic density and accelerate bone formation and maturation of biomaterial used in combination with [33,37,38,41,42,53,58], although in a short period of follow-up.In fact, a follow-up higher than 6 months/1 year showed a no statistically difference between the APCs group and the non-APCs group in terms of implant stability and implant survival rate [32,39,43,44,47,[49][50][51][52][53][54][55][56], radiographic bone gain and bone density and percentage of NBF [32,34,41,42,[44][45][46][49][50][51][52][54][55][56]60].The idea to use APCs in that case derived from the potential role of these concentrates to accelerate and promote soft and hard-tissue healing.Indeed, platelets and leucocytes contain high levels of bioactive mediators such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-β1 (TGF-b1), β2 (TGF-b2) and insulin-like growth factor (IGF), which stimulate angiogenesis, cell proliferation and matrix remodeling [65].Different types of APCs have been introduced and different methods of preparations have been proposed, producing different percentages of platelets, leukocytes, growth factors and fibrin matrix.For example, tetramolecular fibrin network of PRP release more FGF and PRGF than PRF, so it can improve tissue repair stimulating fibroblast cells.Instead, tridimensional fibrin complex of PRF allow a slow release of a greater amount of VEGF and TGF-β up to seven days later.For this reason, its main role is to improve angiogenesis and tissue regeneration.Similarly to PRF, an even greater amount of growth factors, such as VEGF and FGF, are isolated in CGF so it would seem to show superior regenerative capacity, as reported for sinus and alveolar ridge augmentation [66].In the current overview, there were no restrictions regarding the inclusion of all types of APCs, so the abovementioned variability can influence the macroscopic characteristics of the APCs and biological properties and, consequently, have an impact on the final outcomes.
Another limit can be represented by the fact that, when APCs are used with other biomaterials, the role of APCs may be hidden by the bone graft material.So, the contribution of each of them was not clearly specified.The use of APCs as a membrane also had to be taken into account.In fact, in this form, they represent an easy and successful method to cover the Schneiderian membrane or osteotomy window.So, they might repair an eventual sinus membrane perforation and improve soft-tissue healing beyond bone/hard-tissue healing when using as a filling material [33,41,44].We also must consider that in some studies [33,35,39,41,42], the type of surgical approach (lateral or crestal) and the time of implant insertion were not always specified.However, we can suppose that, by using APCs alone with a lateral approach, the time of implant placement is contemporary to surgery.In fact, APCs alone could not have supported the raised sinus floor as implants can.Similarly, when authors report histomorphometric analysis, the type of surgery could be clarified because bone biopsies have been obtained during second stage of implant surgery.Furthermore, most of the studies cited in this review do not account for a multitude of data, beyond type of surgical approach and implant placement protocols: patients' number, specific diagnosis of the sample selected, especially in terms of residual bone height, absence of a control group that made not possible the evaluation of the effectiveness of APCs in sinus elevation [33,49,56,60].Beyond these considerations, the majority of the clinical trials did not also account for the maxillary sinus width which represents a significant value, with the residual bone height, in the choice between lateral or crestal surgical approach [67].This parameter can influence the percentage of new bone formation after sinus lift surgery.Indeed, the wider is the sinus, the longer is the path that osteoprogenitor cells derived from sinus walls have to go through.On the contrary, the narrower the sinus, the more bone formation [68,69].Another limitation is that most of the included studies reported a high or unclear risk of bias, while it was not even explained in other ones.Therefore, the quality of primary studies is highly variable, and the risk of bias is judged as low only in a few cases.Thus, it is critical for clinicians and researchers to assess the reliability of the results derived from these studies.Qualitative analysis of the included SRs was made using the AMSTAR scale, which is a validated tool for the methodological quality assessment of SRs [70].The current overview showed a range from critically low (3 studies) to high (9 studies) methodologically quality, indicating a moderate overall quality.The main critical weakness was the absence of an explicit statement that the review methods were established prior to the conduct of the review, such as the presence of a registered protocol on PROSPERO (International Prospective Register of Ongoing Systematic Reviews), an online database which informs the whole scientific community about topics covered providing a pre-established review's method [71].Justification of any significant deviations from the protocol were also absent.The results of the current overview should be interpreted with caution due to certain limitations.Despite the thorough search process, it is possible that some relevant literature may have been overlooked.Furthermore, most of the existing literature has only reported short-term results with an average follow-up time of 3-6 months.

Conclusions
The current overview of SRs highlighted that the quality level of the published SRs focusing on the topic of APCs in sinus lift was extremely variable, thus ranging from low to high.According to clinical and histological results, it has demonstrated that the use of APCs seems to be a reliable surgical option promoting natural bone regeneration, providing a superior support for the elevated sinus membrane, and working as a shield against soft-tissue invagination and ingrowth.However, there is limited evidence on the potential benefits of APCs in long-term bone regeneration and soft-tissue healing.In fact, there still appears to be a lack of sufficient scientific support to justify their convenience.Thus, the search for components not only able to maintain the space necessary for bone regeneration but also to stimulate new bone formation continues.Therefore, this overview emphasizes the need to further investigate the role of APCs in the future through studies characterized by a higher sample size, standardization of the preparation protocol of the concentrates, and a longer follow-up.

Figure 1 .
Figure 1.PRISMA flow diagram of the included and excluded records.

Finally, 30
SRs were included for the qualitative analysis[7,.

Figure 1 .
Figure 1.PRISMA flow diagram of the included and excluded records.

Table 1 .
The search strategy for each database and relative results.

Table 3 .
Quality assessment of the included systematic reviews, according to the AMSTAR-2.