## 4 Discussion  
Several techniques and materials have been suggested for the alveolar ridge preservation after dental extraction and before implant placement. A recent review has investigated oral-derived mesenchymal stem cells (ODSC) and their value in bone regeneration for dental and maxillofacial surgeries [6]. However, mesenchymal stem cells (MSC) in regenerative medicine are still not applicable in the daily reconstructive surgery, even knowing that all mesenchymal stem cells from oral tissues are highly committed to differentiate towards osteoblasts and precursors of bone tissue, but may be a promising treatment in the future [5]. The controlled delivery of therapeutic substances by nanostructured biomaterials has been proposed as a viable approach to enhance the bone healing capacity, which ultimately results in the significant improvement of bone regeneration. This overview aimed to evaluate the methods, quality, and outcomes of previous systematic reviews conducted to investigate the effects of platelet-rich fibrin (PRF) in dental sockets of third molars. This overview searched the systematic evidence for the effect of human alveolar socket preservation with PRF compared to spontaneous healing on dimensional alveolar changes, pain, bleeding, swelling, osteitis, and trismus. Only studies that evaluated PRF were evaluated and selected. By aggregating only SR data, the present study was able to analyze the most conclusive scientific evidence. Among the SRs included, the selection of primary studies was very distinct. A complete search strategy is decisive in increasing the trustworthiness of results and decreasing the risk of bias. As PRF is a reservoir of cytokines, platelets, immune cells, and leukocytes, this characteristic led to the hypothesis that PRF could allow for a slow release of cytokines (transforming growth factor, platelet-derived growth factor, vascular endothelial growth factor, and epidermal growth factor), which play a critical role in angiogenesis and tissue healing [24]. From the 13 SRs evaluated, only four evaluated alveolar bone regeneration through meta-analysis. The results of two SRs concluded that PRF use did not significantly affect bone regeneration [20] (335 analyzed sockets). For osteoblastic activity [17] (935 analyzed sockets), however, two SRs [1; 9] (756 analyzed sockets) observed positive results between the use of PRF and alveolar bone regeneration. Another five SRs [15; 16; 24; 25; 26] (1374 analyzed sockets) conducted qualitative analyzes (without meta-analysis) and also observed positive results of PRF concerning alveolar bone regeneration. The data shown by the SRs and analyzed by the present overview present a divergence of results, and do not allow for a definitive conclusion regarding the use of the isolated PRF for alveolar bone regeneration. Factors such as the type of treated socket (number of wall defects), surgical technique, and methodology for making the PRF directly influence the results and add possible bias to the conclusions. Most SRs observed a significant reduction in pain in the sockets preserved with PRF. The simple fact of closing the entering of the socket with a membrane avoids food and debris entry, which can certainly decrease painful stimuli compared with an open socket [27]. Other hypotheses are the expression of immunological factors by supra-physiological living leukocytes release [16; 28]. Blocking the entrance of the alveolus through the PRF membrane also helps stabilize the clot formed immediately after extraction. The fibrin mesh present in the PRF helps in the adherence and stability of the clot cells, which reduces bleeding as observed by the analyzed SRs [14; 17; 20]. In addition, the stabilization of the clot inside the alveolus is essential to prevent the occurrence of osteitis. The maintenance of clot biology associated with increased expression of immunological cells and cytokines may explain a lower number of osteitis when PRF was used [29].