## 4 Discussion  
In this study, a meta-analysis was conducted to analyze the effect of platelet-rich fibrin in mixture form with bone substitute, as a membrane, or in combination. The study  
Figure 5: Forest plot illustrating the comparison between platelet-rich fibrin and control for obtaining bone fill [19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36]. (**A**) Subgroup analysis categorized by application method. (**B**) Subgroup analysis categorized by types of graft material. demonstrated the effectiveness of platelet-rich fibrin as a valuable addition to periodontal regeneration procedures. In general, this meta-analysis demonstrated that platelet-rich fibrin offered substantial advantages in periodontal regeneration, as evidenced by a reduction in probing depth, an improvement in clinical attachment level, and an enhancement of bone fill. The application of a mixture, membrane, or a combination of both produced varying outcomes, which need to be considered clinically. The importance of customizing platelet-rich fibrin applications for particular clinical situations becomes evident due to the variability observed and the need to achieve optimal healing and regeneration. The utilization of platelet-rich fibrin in a mixture could potentially provide significant advantages due to its increased adaptability and interaction with the treatment site. This allows for a more direct and concentrated release of growth factors and cytokines, which are crucial for tissue regeneration. The use of platelet-rich fibrin as a membrane may be limited by its physical form, which could impede its ability to integrate and interact with the host tissue, potentially reducing its effectiveness. The application of the combined approach did not produce enhanced effects. Similarly, previous research indicated that the pairing of bone grafting material and enamel matrix derivative did not offer any additional advantages compared to using enamel matrix derivative alone [37; 38]. Different outcomes emerged from using various bone graft materials, such as synthetic materials, allografts, and xenografts. The employment of synthetic materials as the graft choice yielded the most favorable outcomes when applied with platelet-rich fibrin. A previous report demonstrated the significance of choosing appropriate graft materials for successful treatment [39]. Synthetic materials are inorganic, biocompatible substitutes designed to mimic the properties of natural bone, effectively filling and repairing bone defects [40]. Indeed, beyond biocompatibility, the versatility of synthetic materials lies in their ability to be tailored in terms of pore diameter, porosity, and interconnectivity [41]. These modifications can significantly influence the material's integration with surrounding tissues, promoting better bone ingrowth and vascularization, which are essential for effective bone regeneration and healing. Through this study, we propose that the type of bone graft should also be considered when applying platelet-rich fibrin. A biological substance called platelet-rich fibrin, which is created from a patient's own blood, has been employed in a number of surgical and dental procedures, including the repair of periodontal defects [42]. In an earlier study, platelet-rich fibrin was utilized to address endo-perio lesions, and the findings demonstrated an improvement in periodontal attachment along with a reduction in the depth of periodontal pockets [43]. A systematic review and meta-analysis assessing the impact of platelet-rich fibrin on periodical healing and the alleviation of clinical symptoms in patients undergoing periapical surgery revealed significant advantages, suggesting it could be regarded as a valuable complement to periapical surgical procedures [44]. Platelet-rich fibrin finds application in regenerative endodontic therapy due to its capacity to stimulate cellular proliferation and differentiation [45; 46].