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Purpose: The aim of the present systematic review with meta-analysis was to investigate the clinical effectiveness of EMD (enamel matrix derivative) using a minimally invasive surgical technique (MIST) or flapless approach for the treatment of severe periodontal probing depths. Materials and Methods: A systematic review of the literature including searches in PubMed/Medline, Cochrane Library, Google Scholar, and Grey Literature databases as well as manual searches was performed on September 1st, 2021. Studies utilising EMD in a non-surgical or minimally invasive approach were included. The eligibility criteria comprised randomised controlled trials (RCTs) comparing minimally-invasive/flapless approaches with/without EMD for the treatment of probing depths >5 mm. Results: From 1525 initial articles, 7 RCTs were included and 12 case series discussed. Three studies investigated a MIST approach, whereas 3 studies utilised a flapless approach. One study compared EMD with either a MIST or a flapless approach. The RCTs included ranged from 19–49 patients with at least 6 months of follow-up. While 5 of the studies included smokers, patients smoking >20 cigarettes/day were excluded from the study. The meta-analysis revealed that EMD with MIST improved recession coverage (REC) and bone fill (BF) when compared to MIST without EMD. However, no difference in CAL or PD was observed between MIST + EMD vs MIST without EMD. No statistically significant advantage was found for employing the EMD via the flapless approach. Conclusions: Implementing EMD in MIST procedures displayed statistically significant improvement in REC and BF when compared to MIST alone. These findings suggest that MIST in combination with EMD led to improved clinical outcomes while EMD employed in nonsurgical flapless therapy yielded no clinical benefits when compared to nonsurgical therapy alone without EMD. More research is needed to substantiate these findings. Keywords: EMD, enamel matrix derivative, enamel matrix proteins, intrabony defect, minimally invasive surgery

Purpose: To investigate the effect of platelet-rich fibrin on bone formation by investigating its use in guided bone regeneration, sinus elevation and implant therapy. Materials and methods: This systematic review and meta-analysis were conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The eligibility criteria comprised human controlled clinical trials comparing the clinical outcomes of platelet-rich fibrin with those of other treatment modalities. The outcomes measured included percentage of new bone formation, percentage of residual bone graft, implant survival rate, change in bone dimension (horizontal and vertical), and implant stability quotient values. Results: From 320 articles identified, 18 studies were included. Owing to the heterogeneity of the investigated parameters, a meta-analysis was only possible for sinus elevation. There is a general lack of data from comparative randomised clinical trials evaluating platelet-rich fibrin for guided bone regeneration procedures (only two studies), with no quantifiable advantages in terms of new bone formation or dimensional bone gain found in the platelet-rich fibrin group. For sinus elevation, the meta-analysis demonstrated no advantage in terms of histological new bone formation in the control group (bone graft alone) compared with the test group (bone graft and platelet-rich fibrin). Two studies demonstrated that platelet-rich fibrin may shorten healing periods prior to implant placement. Platelet-rich fibrin was also shown to slightly enhance primary implant stability (implant stability quotient value < 5) as assessed using implant stability quotients and resonance frequency analysis parameters, with no histological data evaluating bone–implant contact yet available on this topic. In one study, platelet-rich fibrin was shown to improve the clinical parameters when utilised as an adjunct for the treatment of peri-implantitis. Conclusions: In the majority of studies, platelet-rich fibrin offered little or no clear advantage in terms of new bone formation as evaluated in various studies on guided bone regeneration and sinus elevation, nor in implant stability and treatment of peri-implantitis. Various authors and systematic reviews on the topic have now expressed criticism of the various study designs and protocols, and the lack of appropriate controls and available information regarding patient selection. Well-controlled human studies on these specific topics are required. Conflict-of-interest statement: Richard J Miron holds intellectual property on platelet-rich fibrin. All other authors declare no conflicts of interest. Keywords: biomaterials, bone graft, growth factors, platelet-rich fibrin, platelet concentrates

Purpose: To investigate the use of platelet-rich fibrin for alveolar ridge preservation compared to natural healing, bone graft material and platelet-rich fibrin in combination with bone graft material. Materials and methods: The present systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The review examined randomised controlled trials comparing the clinical outcomes of platelet-rich fibrin with those of other modalities for alveolar ridge preservation. Studies of third molar extraction site healing were excluded. The studies were classified into three categories: natural wound healing vs platelet-rich fibrin; bone graft material vs platelet-rich fibrin; and bone graft material vs bone graft material and platelet-rich fibrin. Results: From 179 articles identified, 16 randomised controlled trials were included. Owing to the heterogeneity of the investigated parameters, it was not possible to perform a meta-analysis. In total, 10 randomised controlled trials compared platelet-rich fibrin to natural wound healing, with seven of these demonstrating favourable outcomes to either limit postextraction dimensional changes or improve new bone formation in the platelet-rich fibrin group. Three of four studies comparing healing with bone graft material to platelet-rich fibrin found that the latter led to significantly greater horizontal or vertical bone resorption, and the bone graft material was more able to maintain the ridge dimensions. Two out of three randomised controlled trials investigating healing with both bone graft material and platelet-rich fibrin reported better outcomes using this combined approach than with bone graft material alone. All studies investigating soft tissue healing with platelet-rich fibrin demonstrated better outcomes in the platelet-rich fibrin group. Conclusions: The majority of studies comparing healing with platelet-rich fibrin to natural healing concluded that the former more successfully limits postextraction dimensional changes than the latter. However, 75% of studies investigating platelet-rich fibrin vs bone graft material reported better results in the bone graft group with respect to its ability to maintain postextraction dimensional changes. The addition of platelet-rich fibrin to bone graft material may improve clinical outcomes, although data are limited. Keywords: advanced platelet-rich fibrin, alveolar ridge preservation, biomaterials, extraction site management, growth factors, leucocyte- and platelet-rich fibrin, platelet concentrates, platelet-rich fibrin, systematic review Conflict-of-interest statement: Richard J Miron holds intellectual property on platelet-rich fibrin. All other authors declare no conflicts of interest related to this study.

Purpose: Bone grafting materials are frequently utilized in oral surgery and periodontology to fill bone defects and augment lost or missing bone. The purpose of this study was to compare new bone formation in bone defects created in both normal and osteoporotic animals loaded with three types of bone grafts from different origins. Materials and Methods: Forty-eight female Wistar rats were equally divided into control normal and ovariectomized animals. Bilateral 2.5-mm femur defects were created and filled with an equal weight of (1) natural bone mineral (NBM, BioOss) of bovine origin, (2) demineralized freeze-dried bone allograft (DFDBA, LifeNet), or (3) biphasic calcium phosphate (BCP, Vivoss). Following 3 and 6 weeks of healing, hematoxylin and eosin and TRAP staining was performed to determine new bone formation, material degradation, and osteoclast activity. Results: All bone substitutes demonstrated osteoconductive potential at 3 and 6 weeks with higher osteoclast numbers observed in all ovariectomized animals. NBM displayed continual new bone formation with little to no sign of particle degradation, even in osteoporotic animals. DFDBA particles showed similar levels of new bone formation but rapid particle degradation rates with lower levels of mineralized tissue. BCP bone grafts demonstrated significantly higher new bone formation when compared with both NBM and DFDBA particles; however, the material was associated with higher osteoclast activity and particle degradation. Interestingly, in osteoporotic animals, BCP displayed synergistically and markedly more rapid rates of particle degradation. Conclusion: Recent modifications to synthetically fabricated materials were shown to be equally or more osteopromotive than NBM and DFDBA. However, the current BCP utilized demonstrated much faster resorption properties in osteoporotic animals associated with a decrease in total bone volume when compared with the slowly/nonresorbing NBM. The results from this study point to the clinical relevance of minimizing fastresorbing bone grafting materials in osteoporotic phenotypes due to the higher osteoclastic activity and greater material resorption. Keywords: Bio-Oss, bone formation, DFDBA, graft consolidation, guided bone regeneration, osteoporosis

Purpose: To investigate the bone-inducing properties of two types of collagen membranes in combination with recombinant human bone morphogenetic protein (rhBMP)-2 and rhBMP-9 on osteoblast behavior. Materials and Methods: Porcine pericardium collagen membranes (PPCM) and porcine dermis-derived collagen membranes (PDCM) were coated with either rhBMP-2 or rhBMP-9. The adsorption and release abilities were first investigated via enzyme-linked immunosorbent assay up to 10 days. Moreover, murine bone stromal ST2 cell adhesion, proliferation, and osteoblast differentiation were assessed by MTS assay; real-time polymerase chain reaction for genes encoding runt-related transcription factor 2 (Runx2); alkaline phosphatase (ALP); and osteocalcin, ALP assay, and alizarin red staining. Results: Both rhBMP-2 and rhBMP-9 adsorbed to collagen membranes and were gradually released over time up to 10 days. PPCM showed significantly less cell attachment, whereas PDCM demonstrated comparable cell attachment with the control tissue culture plastic at 8 hours. While both rhBMPs were shown not to affect cell proliferation, collagen membranes combined with rhBMP-9 significantly increased ALP activity at 7 days and ALP mRNA levels at either 3 or 14 days compared with the control tissue culture plastic. Furthermore, rhBMP-9 increased osteocalcin mRNA levels and alizarin red staining at 14 days compared with the control tissue culture plastic. Conclusion: The results from this study suggest that both porcine-derived collagen membranes combined with rhBMP-9 accelerated the osteopromotive potential of ST2 cells. Interestingly, rhBMP-9 demonstrated additional osteogenic differentiation compared with rhBMP-2 and may serve as a suitable growth factor for future clinical use. Keywords: bone regeneration, BMP-2, BMP-9, collagen membrane, guided bone regeneration, porcine collagen membrane

Purpose: Collagen barrier membranes were first introduced to regenerative periodontal and oral surgery to prevent fast ingrowing soft tissues (ie, epithelium and connective tissue) into the defect space. More recent attempts have aimed at combining collagen membranes with various biologics/growth factors to speed up the healing process and improve the quality of regenerated tissues. Recently, a new formulation of enamel matrix derivative in a liquid carrier system (Osteogain) has demonstrated improved physico-chemical properties for the adsorption of enamel matrix derivative to facilitate protein adsorption to biomaterials. The aim of this pioneering study was to investigate the use of enamel matrix derivative in a liquid carrier system in combination with collagen barrier membranes for its ability to promote osteoblast cell behavior in vitro. Materials and Methods: Undifferentiated mouse ST2 stromal bone marrow cells were seeded onto porcine-derived collagen membranes alone (control) or porcine membranes + enamel matrix derivative in a liquid carrier system. Control and enamel matrix derivative- coated membranes were compared for cell recruitment and cell adhesion at 8 hours; cell proliferation at 1, 3, and 5 days; and real-time polymerase chain reaction (PCR) at 3 and 14 days for genes encoding Runx2, collagen1alpha2, alkaline phosphatase, and bone sialoprotein. Furthermore, alizarin red staining was used to investigate mineralization. Results: A significant increase in cell adhesion was observed at 8 hours for barrier membranes coated with enamel matrix derivative in a liquid carrier system, whereas no significant difference could be observed for cell proliferation or cell recruitment. Enamel matrix derivative in a liquid carrier system significantly increased alkaline phosphatase mRNA levels 2.5-fold and collagen1alpha2 levels 1.7-fold at 3 days, as well as bone sialoprotein levels twofold at 14 days postseeding. Furthermore, collagen membranes coated with enamel matrix derivative in a liquid carrier system demonstrated a sixfold increase in alizarin red staining at 14 days when compared with collagen membrane alone. Conclusion: The combination of enamel matrix derivative in a liquid carrier system with a barrier membrane significantly increased cell attachment, differentiation, and mineralization of osteoblasts in vitro. Future animal testing is required to fully characterize the additional benefits of combining enamel matrix derivative in a liquid carrier system with a barrier membrane for guided bone or tissue regeneration. Keywords: bone graft, emdogain, enamel matrix derivative, enamel matrix proteins, periodontal regeneration

Objective: Over 15 years have passed since an enamel matrix derivative (EMD) was introduced as a biologic agent capable of periodontal regeneration. Histologic and controlled clinical studies have provided evidence for periodontal regeneration and substantial clinical improvements following its use. The purpose of this review article was to perform a systematic review comparing the eff ect of EMD when used alone or in combination with various types of bone grafting material. Data Sources: A literature search was conducted on several medical databases including Medline, EMBASE, LILACS, and CENTRAL. For study inclusion, all studies that used EMD in combination with a bone graft were included. In the initial search, a total of 820 articles were found, 71 of which were selected for this review article. Studies were divided into in vitro, in vivo, and clinical studies. The clinical studies were subdivided into four subgroups to determine the eff ect of EMD in combination with autogenous bone, allografts, xenografts, and alloplasts. Results: The analysis from the present study demonstrates that while EMD in combination with certain bone grafts is able to improve the regeneration of periodontal intrabony and furcation defects, direct evidence supporting the combination approach is still missing. Conclusion: Further controlled clinical trials are required to explain the large variability that exists amongst the conducted studies. Keywords: animals, bone grafts, Emdogain, enamel matrix derivative, intrabony periodontal defects, osteoinduction, preclinical studies, systematic review

Purpose: To systematically evaluate implant success rates with different loading protocols. Materials and Methods: A search was conducted of electronic databases, including The Cochrane Oral Health Group's Trials Register, PubMed, SciSearch, Medline, and EMBASE, for all randomized controlled trials published between 1997 and 2011 to compare implant success rates among different loading methods. The quality of randomized controlled trials was critically appraised, and the data were extracted by two independent reviewers. Meta-analyses were conducted of the eligible randomized controlled trials. Results: A total of 26 randomized controlled trials met the criteria for meta-analysis. The quality of these articles was moderate. Eight trials compared immediate and early loading (relative risk [RR] = 0.90, 95% confidence interval [CI] 0.42-1.93, P = .79), 7 compared early with delayed loading (RR = 1.19, 95% CI 0.52-2.72, P = .69), and 11 compared immediate and delayed loading (RR = 1.19, 95% CI 0.52-2.72, P = .69). Conclusions: The limited evidence shows that there is no significant difference in implant success rates with different loading protocols. Keywords: delayed loading, dental implants, early loading, immediate loading, meta-analysis