The mode and mechanism of diabetic periodontitis-induced alveolar-osteocyte death are still unclear. This study aimed to investigate the occurrence of ferroptosis in alveolar osteocytes during diabetic periodontitis and the therapeutic potential of resveratrol to alleviate osteocyte ferroptosis. Diabetic periodontitis was induced in C57/BL6-male mice and treated with or without resveratrol. Periodontitis pathogenicity was analyzed by micro-CT and histology, and alveolar-osteocyte ferroptosis was analyzed by immunohistochemistry. MLOY4 osteocytes were treated with P. gingivalis-derived lipopolysaccharide (LPS)+advanced glycosylated end products (AGEs) mimicking diabetic periodontitis condition in vitro, with or without resveratrol or ferrostatin-1 (ferroptosis inhibitor). Osteocyte ferroptosis and expression of inflammatory mediators were analyzed. Diabetic periodontitis aggravated periodontitis pathogenicity and inhibited the expression of GPX4 and SLC7A11 in alveolar osteocytes and resveratrol alleviated these effects. LPS+AGEs triggered osteocyte ferroptosis in vitro as indicated by the downregulated GPX4 and SLC7A11, upregulated malondialdehyde, disrupted mitochondrial morphology, and overexpressed pro-inflammatory mediators IL-1β, TNF-α, SOST, RANKL, and IL-6, and ferrostatin-1 or resveratrol treatment reversed these effects. LPS+AGEs upregulated pIKBα and pNF-κB p65 expression in osteocytes, and resveratrol or ferrostatin-1 reversed this effect. In conclusion, diabetic periodontitis triggers alveolar osteocyte ferroptosis possibly via disruption of the SLC7A11/GPX4 axis, and resveratrol has therapeutic potential to correct this biological event.

Bone grafts or prosthetic implant designing for clinical application is challenging due to the complexity of integrated physiological processes. The revolutionary advances of nanotechnology in the biomaterial field expedite and endorse the current unresolved complexity in functional bone graft and implant design. Rare earth (RE) materials are emerging biomaterials in tissue engineering due to their unique biocompatibility, fluorescence upconversion, antimicrobial, antioxidants, and anti‐inflammatory properties. Researchers have developed various RE smart nano‐biomaterials for bone tissue engineering and implantology applications in the past two decades. Furthermore, researchers have explored the molecular mechanisms of RE material‐mediated tissue regeneration. Recent advances in biomedical applications of micro or nano‐scale RE materials have provided a foundation for developing novel, cost‐effective bone tissue engineering strategies. This review attempted to provide an overview of RE nanomaterials' technological innovations in bone tissue engineering and implantology and summarized the osteogenic, angiogenic, immunomodulatory, antioxidant, in vivo bone tissue imaging, and antimicrobial properties of various RE nanomaterials, as well as the molecular mechanisms involved in these biological events. Further, we extend to discuss the challenges and prospects of RE smart nano‐biomaterials in the field of bone tissue engineering and implantology.

Periodontitis is a chronic inflammatory oral disease that affects almost half of the adult population. NF-κB activator 1 (Act1) is mainly expressed in immune cells, including macrophages, and modulates immune cells’ function to regulate inflammation in inflammatory diseases. Macrophages play a vital role in the pathophysiology of periodontitis. However, the effect of macrophage-specific Act1 on periodontitis has not been investigated yet. This study aims to unravel the role of macrophage-specific Act1 on the pathophysiology of periodontitis. The expression of Act1 in healthy and periodontitis periodontal tissue was confirmed by immunohistochemistry. Macrophage-specific Act1 expression downregulated (anti-Act1) mice were developed by inserting anti-Act1 antisense oligonucleotides after the CD68 promoter of C57BL/6 mice. Ligature-induced periodontitis (LIP) was induced in anti-Act1 mice and wildtype mice. Micro-CT, histology, and TRAP staining analyzed the periodontal tissue status, alveolar bone loss, and osteoclast numbers. Immunohistochemistry, RT-qPCR, and ELISA analyzed the inflammatory cells infiltration, expression of inflammatory cytokines, and M1/M2 macrophage polarization. mRNA sequencing of in vitro bacterial lipopolysaccharide (LPS)-treated peritoneal macrophages analyzed the differentially expressed genes in anti-Act1 mice during inflammation. Anti-Act1 mice showed aggravated periodontitis and alveolar bone loss compared to wildtype. Periodontitis-affected periodontal tissue (PAPT) of anti-Act1 mice showed a higher degree of macrophage infiltration, and M1 macrophage polarization compared to wildtype. Levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and macrophage activity-related factors (CCL2, CCL3, and CCL4) were robustly high in PAPT of anti-Act1 mice compared to wildtype. mRNA sequencing and KEGG analysis showed activated TNF/NF-κB signaling in LPS-treated macrophages from anti-Act1 mice. In vitro studies on LPS-treated peritoneal macrophages from anti-act1 mice showed a higher degree of cell migration and expression of inflammatory cytokines, macrophage activity-related factors, M1 macrophage-related factors, and TNF/NF-κB signaling related P-p65 protein. In conclusion, downregulation of macrophage-specific Act1 aggravated periodontitis, alveolar bone loss, macrophage infiltration, inflammation, and M1 macrophage polarization. Furthermore, LPS-treated macrophages from anti-Act1 mice activated TNF/NF-κB signaling. These results indicate the distinct role of macrophage-specific Act1 on the pathophysiology of periodontitis possibly via TNF/NF-κB signaling.

Objective: An evidence regarding which bony flap for reconstruction of mandibular defects following tumour resection is associated with the highest survival rate is still lacking. This network meta-analysis (NMA) aimed to guide surgeons selecting which vascularized osseous flap is associated with the highest survival rate for mandibular reconstruction. Methods: From inception to March 2021, PubMed, Embase, Scopus, and Cochrane library were searched to identify the eligible studies. The outcome variable was the flap survival rate. The Bayesian NMA accompanied by a random effect model and 95% credible intervals (CrI) was calculated. Results: Twenty-two studies with a total of 1513 patients, comparing four osseous flaps namely fibula free flap (FFF), deep circumferential iliac artery flap (DCIA), scapula flap, and osteocutaneous radial forearm flap (ORFF) were included. The respective survival rates of FFF, DCIA, Scapula, and ORFF were 94.50%, 93.12%, 97%, and 95.95%. The NMA failed to show a statistically significant difference between all comparators (FFF versus DCIA (Odd ratio, 1.8; CrI, 0.58,5.0); FFF versus ORFF (Odd ratio, 0.57; CrI, 0.077; 2.9); FFF versus scapula flap (Odd ratio, 0.25; CrI, 0.026; 1.5); DCIA versus ORFF (Odd ratio, 0.32; CrI, 0.037; 2.1); DCIA versus scapula flap (Odd ratio, 0.14; CrI, 0.015; 1.1) and ORFF versus scapula flap (Odd ratio, 2.3; CrI, 0.16; 34)). Conclusion: Within the limitations of the current NMA, FFF, DCIA, Scapula, and ORFF showed a comparable survival rate for mandibular reconstruction. Although the scapula flap reported the highest survival rate compared to other osseous flaps for mandibular reconstruction; however, the decision making when choosing an osseous flap should be based on many factors rather than simply flap survival rate.

Objective: The clinical benefits of simultaneous implant placement and soft tissue augmentation using different treatment modalities are unclear. The current meta-analysis aimed to compare the effect of simultaneous soft tissue augmentation using subepithelial connective tissue graft (SCTG) around immediate or delayed dental implant placement with other treatment modalities on the peri-implant tissue health and esthetic. Methods: Up to May 2021, four databases (PubMed, EMBASE, Cochrane Central, and Google Scholar) were searched. Randomized control trials with follow-up >3 months, evaluating simultaneous implant placement (immediate or delayed) and soft tissue augmentation using SCTG compared with other treatment modalities were included. The predictor variables were SCTG versus no augmentation with/without guided bone regeneration (GBR) or other augmentation techniques (Acellular dermal matrix (ADM), Xenogeneic collagen matrix (XCM). The outcome variables were buccal tissue thickness (BTT), mid-buccal gingival level (MGL), marginal bone loss (MBL), and pink esthetic scores (PES). Cumulative mean differences (MD) and 95% confidence interval (CI) were estimated. Results: Twelve studies were included. SCTG along with immediate implant placement (IIP) or delayed implant placement (DIP) showed a statistically significant improvement in BTT (Fixed; MD, 0.74; 95% CI, 0.51; 0.97), MGL (Fixed; MD, 0.5; 95% CI, 0.21; 0.80), PES (Fixed; MD, 0.79; 95% CI, 0.29; 1.29), and less MBL (Fixed; MD, -0.11; 95% CI, -0.14; -0.08) compared to no graft (P<0.05). A statistically insignificant differences in BTT (Random; MD, 0.62; 95% CI, -0.41; 1.65), MGL (Fixed; MD, -0.06; 95% CI, -0.23; 0.11), MBL (Fixed; MD, 0.36; 95% CI, -0.05; 0.77) and PES (Fixed; MD, 0.28; 95% CI, -0.10; 0.67) was observed when SCTG along with DIP was compared with no augmentation plus GBR. Similarly, no statistically significant difference was observed when comparing SCTG along with DIP with acellular dermal matrix (ADM) concerning BTT (MD:0.71, P = 0.18) and KMW (MD: 0.6, P = 0.19). Conclusion: There is a very low quality of evidence to provide recommendations on whether simultaneous dental implant placement (IIP or DIP) and soft tissue augmentation using SCTG is superior to no augmentation or is comparable to the other tissue augmentation materials in improving the quality and quantity of peri-implant tissues. Therefore, further, well-designed RCTs with larger sample sizes and long follow-up times are still needed.