Alveolar Bone Regeneration Research Articles

Combination of Moringa oleifera leaf extract and demineralized freeze-dried bovine bone xenograft (DFDBBX) on woven bone area post tooth extraction

Background: Tooth extraction is one of the most frequently performed procedures in dental practice. Resorption without bone regeneration can change the maxillary and mandibular bone structure, resulting lack of retention, stability, and comfort of the denture. Hence, adequate regeneration of alveolar bone is considered an important factor for successful dentures. Moringa oleifera is a plant rich in flavonoids, saponins, alkaloids and tannins. Purpose: This study aims to find out the effect of induction from combination of Moringa oleifera extract and demineralized freeze-dried bovine bone xenograft (DFDBBX) on woven bone area post tooth extraction procedure. Methods: Cavia cobaya was divided into eight groups, each group consists of seven. The lower incisors of Fifty-six Cavia cobaya were extracted. The first group (control group) was given polyethylene glycol, the second group with DFDBBX, the third group with Moringa leaf extract, and the fourth group with a combination of DFDBBX and Moringa leaf extract. Cavia cobaya were sacrificed on day 7 and 14. Histopathological examinations of woven bone area was observed under a 400x magnification light microscope. Kruskal-Wallis and Mann-Whitney tests were performed to analyze the data. Results: There was a significant difference in woven bone area between the groups (P<0.05). The highest mean of woven bone area was found in the combination group on both day 7 and 14. Conclusion: The combination of Moringa leaf extract and DFDBBX could effectively formed new woven bone during the alveolar bone regeneration.

TERIPARATIDE - THE FUTURE OFHOST MODULATION ANDPERIODONTAL REGENERATION? A SHORT REVIEW

Periodontal disease is multifactorial and infectious, and can lead to loss of the dentition. Multiple treatment modalities have been used and experimented upon over several years. The main objective of periodontal therapy is to arrest the bone loss and help in its regeneration. Teriparatide is a type of recombinant human parathyroid hormone, which can aid in alveolar bone regeneration in treating periodontal conditions. This review discusses the mechanism and applications of teriparatide in periodontics and its potential use in host modulation and periodontal regeneration.

Resolvin D1 improves allograft osteointegration and directly enhances osteoblasts differentiation.

Allografts are the most common bone grafts for repairing osseous defects. However, their use is associated with an increased risk for infections, donor disease transmission and osteointegration deficiency. Resolvin D1 (RvD1) is an endogenous lipid with a scientifically proven pivotal role in inflammation resolution and osteoclastogenesis inhibition. Yet, its biological relevance as a potential bone regenerative drug has been scarcely studied. Here, we aim to investigate the RvD1 effect on allograft osteointegration in the alveolar bone regeneration (ABR) murine model. ABR model consisted of osseous defects that were generated by the extraction of the maxillary first molar in C57BL/6 mice. The sockets were filled with allograft and analyzed via RNA sequencing. Then they were locally injected with either RvD1 or saline via single or repeated administrations. The mice were sacrificed 2W after the procedure, and regenerated sites were analyzed using µCT and histology. First, MC3T3-E1 preosteoblasts were plated with IL-17 pro-inflammatory medium, and RANKL/OPG ratio was measured. Secondly, the MC3T3-E1 were cultured w/o RvD1, for 3W. Osteoblasts' markers were evaluated in different days, using qRT-PCR and Alizarin Red staining for calcified matrix. In vivo, neither allograft alone nor single RvD1 administration promote bone regeneration in comparison to the control of spontaneous healing and even triggered an elevation in NR1D1 and IL1RL1 expression, markers associated with inflammation and inhibition of bone cell differentiation. However, repeated RvD1 treatment increased bone content by 135.92% ± 45.98% compared to its specific control, repeated sham, and by 39.12% ± 26.3% when compared to the spontaneous healing control group (n=7/group). Histologically, repeated RvD1 reduced the number of TRAP-positive cells, and enhanced allograft osteointegration with new bone formation. In vitro, RvD1 rescued OPG expression and decreased RANKL/OPG ratio in IL-17 pro-inflammatory conditions. Furthermore, RvD1 increased the expression of RUNX2, OSX, BSP and OC/BGLAP2 and the mineralized extracellular matrix during MC3T3-E1 osteoblasts differentiation. Repeated administrations of RvD1 promote bone regeneration via a dual mechanism: directly, via enhancement of osteoblasts' differentiation and indirectly, through reduction of osteoclastogenesis and RANKL/OPG ratio. This suggests that RvD1 may be a potential therapeutic bioagent for osseous regeneration following allograft implantation.

Role of periosteum in alveolar bone regeneration comparing with collagen membrane in a buccal dehiscence model of dogs

To investigate the role of periosteum on the treatment of buccal dehiscence defects comparing with collagen membrane in canine model. Bilateral dehiscence-type defects at the buccal side on the distal root of the lower 3rd/4th premolars were created in six beagle dogs with a total of 24 defects and assigned into three groups: Group A: blood clot in an untreated defect; Group B: deproteinized bovine bone material (DBBM) covered with an absorbable membrane; Group C: DBBM covered with the periosteum. The structural parameters for trabecular architecture and vertical bone regeneration were evaluated. Histological and histomorphometric evaluation were carried out to observe new bone formation and mineralization in the graft site. Immunohistochemical analysis was performed to identify the expression of osteopontin (OPN) and osteocalcin (OCN) at postoperative 3 months. Group C achieved greater vertical alveolar bone gain than that of group A and group B. The periosteum-covered group showed significantly greater new bone formation and accelerated mineralization. The greater immunolabeling for OPN and OCN was observed in group C than in group A. Periosteal coverage has explicit advantages over collagen membranes for the quality and quantity of new bone regeneration in dehiscence defects repairing.

Inhibition of Sphingosine-1-Phosphate Receptor 2 by JTE013 Enhanced Alveolar Bone Regeneration by Promoting Angiogenesis.

Sphingosine-1-phosphate receptor 2 (S1PR2) is a G protein-coupled receptor that regulates various immune responses. Herein, we report the effects of a S1PR2 antagonist (JTE013) on bone regeneration. Murine bone marrow stromal cells (BMSCs) were treated with dimethylsulfoxide (DMSO) or JTE013 with or without infection by an oral bacterial pathogen Aggregatibacter actinomycetemcomitans. Treatment with JTE013 enhanced vascular endothelial growth factor A (VEGFA), platelet derived growth factor subunit A (PDGFA), and growth differentiation factor 15 (GDF15) gene expression and increased transforming growth factor beta (TGFβ)/Smad and Akt signaling. Eight-week-old male C57BL/6J mice were challenged with ligatures around the left maxillary 2nd molar for 15 days to induce inflammatory bone loss. After ligature removal, mice were treated with diluted DMSO or JTE013 in the periodontal tissues 3 times per week for 3 weeks. Calcein was also injected twice to measure bone regeneration. Micro-CT scanning of maxillary bone tissues and calcein imaging revealed that treatment with JTE013 enhanced alveolar bone regeneration. JTE013 also increased VEGFA, PDGFA, osteocalcin, and osterix gene expressions in the periodontal tissues compared to control. Histological examination of periodontal tissues revealed that JTE013 promoted angiogenesis in the periodontal tissues compared to control. Our findings support that inhibition of S1PR2 by JTE013 increased TGFβ/Smad and Akt signaling; enhanced VEGFA, PDGFA, and GDF15 gene expression; and subsequently promoted angiogenesis and alveolar bone regeneration.

Antibacterial polyurethane composite scaffolds for minimally invasive alveolar bone repair

Traditional stimuli responsible scaffolds could avoid large volume trauma during implantation, however, for alveolar bone repair, the complexity and diversity of oral environment requested antibacterial and biocompatible materials. In this study, 3D porous scaffold was prepared by in-situ polymerization and gas foaming method for minimally invasive alveolar bone repair. Citrate functionalized amorphous calcium phosphate (CACP) was incorporated into the polytetrahydrofuran (PTHF) based polyurethane (PU) scaffolds, functioning as antibacterial factor and simultaneously enhancing the osteogenesis expression. The obtained scaffolds presented high porosity and proper pore size as extracellular matrix as well as adequate mechanical strength for cell adhesion and structural support. The bending experiments suggested the PU scaffolds achieved good shape memory effect at temperature of 37 °C In addition, excellent antibacterial rate was observed with increasing content of citrate, and in vitro experiments confirmed the excellent biocompatibility and cell osteoconductive capacity. The developed 3D programmable antibacterial scaffold could be a potential candidate for the minimally invasive alveolar bone regeneration.

PSAT1 positively regulates the osteogenic lineage differentiation of periodontal ligament stem cells through the ATF4/PSAT1/Akt/GSK3β/β-catenin axis

BackgroundPeriodontal ligament stem cells (PDLSCs) are important seed cells for tissue engineering to realize the regeneration of alveolar bone. Understanding the gene regulatory mechanisms of osteogenic lineage differentiation in PDLSCs will facilitate PDLSC-based bone regeneration. However, these regulatory molecular signals have not been clarified.MethodsTo screen potential regulators of osteogenic differentiation, the gene expression profiles of undifferentiated and osteodifferentiated PDLSCs were compared by microarray and bioinformatics methods, and PSAT1 was speculated to be involved in the gene regulation network of osteogenesis in PDLSCs. Lentiviral vectors were used to overexpress or knock down PSAT1 in PDLSCs, and then the proliferation activity, migration ability, and osteogenic differentiation ability of PDLSCs in vitro were analysed. A rat mandibular defect model was built to analyse the regulatory effects of PSAT1 on PDLSC-mediated bone regeneration in vivo. The regulation of PSAT1 on the Akt/GSK3β/β-catenin signalling axis was analysed using the Akt phosphorylation inhibitor Ly294002 or agonist SC79. The potential sites on the promoter of PSAT1 that could bind to the transcription factor ATF4 were predicted and verified.ResultsThe microarray assay showed that the expression levels of 499 genes in PDLSCs were altered significantly after osteogenic induction. Among these genes, the transcription level of PSAT1 in osteodifferentiated PDLSCs was much lower than that in undifferentiated PDLSCs. Overexpressing PSAT1 not only enhanced the proliferation and osteogenic differentiation abilities of PDLSCs in vitro, but also promoted PDLSC-based alveolar bone regeneration in vivo, while knocking down PSAT1 had the opposite effects in PDLSCs. Mechanistic experiments suggested that PSAT1 regulated the osteogenic lineage fate of PDLSCs through the Akt/GSK3β/β-catenin signalling axis. PSAT1 expression in PDLSCs during osteogenic differentiation was controlled by transcription factor ATF4, which is realized by the combination of ATF4 and the PSAT1 promoter.ConclusionPSAT1 is a potential important regulator of the osteogenic lineage differentiation of PDLSCs through the ATF4/PSAT1/Akt/GSK3β/β-catenin signalling pathway. PSAT1 could be a candidate gene modification target for enhancing PDLSCs-based bone regeneration.

Epigenetic regulation of osteogenic differentiation of periodontal ligament stem cells in periodontitis.

Periodontitis is an inflammatory disease characterized by alveolar bone loss. Periodontal ligament stem cells (PDLSCs) have osteogenic differentiation potential, which can be influenced by epigenetics regulation in periodontitis. Therefore, this review aimed to shed light on the role of different epigenetic mechanisms in the osteogenic differentiation of PDLSCs and to consider the prospects of their possible therapeutic applications in periodontitis. Databases MEDLINE (through PubMed) and Web of Science were searched for the current knowledge of epigenetics in osteogenic differentiation of PDLSCs using the keywords "periodontal ligament stem cells", "epigenetic regulation", "epigenetics", "osteogenic differentiation", and "osteogenesis". All studies introducing epigenetic regulation and PDLSCs were retrieved. This review shows that epigenetic factors like DNMT, KDM6A, HDACi, some miRNAs, and lncRNAs can induce the osteogenic differentiation of PDLSCs in the noninflammatory microenvironment. However, the osteogenic differentiation of PDLSCs is inhibited in the inflammatory microenvironment through the upregulated DNA methylation of osteogenesis-related genes and specific changes in histone modification and noncoding RNA. Epigenetics of osteogenic differentiation of PDLSCs in inflammation exhibits the contrary effect compared with a noninflammatory environment. The application of epigenetic drugs to regulate the abnormal epigenetic status in periodontitis and focus on alveolar bone regeneration is promising.

The Establishment of a Murine Mandibular Molar Extraction Socket Healing Model.

This study introduces the development of a molar extraction model in the murine mandible to provide a practicable model for studying alveolar bone regeneration and intramembranous ossification. C57/J6 mice were used to extract the mandibular first molar to establish this model. They were executed, and the bilateral mandibles harvested, at 1 week and 4 weeks post-surgery, respectively. Subsequent serial stereoscopic harvest, histological assessment, and immunofluorescence staining were performed to demonstrate successful surgery. Immediately after surgery, the stereoscopic images displayed an empty extraction socket. The hematoxylin and eosin (H&E) at 1 week and Masson staining at 4 weeks post-surgery showed that the area of the original root was partially and fully filled with bone trabeculae, respectively. The immunofluorescence staining showed that, compared with the homeostasis side, the Sp7 expression increased at 1 week post-surgery, suggesting vigorous osteogenesis in the alveolar fossa. All these results demonstrated a practicable murine tooth extraction socket healing model. Upcoming studies revealing the mechanisms of jawbone defect healing or socket healing could adopt this method.

Role of various pharmacologic agents in alveolar bone regeneration: A review.

Alveolar bone and gingiva are components of the periodontium that house the tooth. It constantly adapts itself to the masticatory forces and position of the tooth. However, localized diseases like chronic periodontitis and certain systemic diseases destroy periodontal tissues, which include the alveolar bone. Various pharmacological agents are being explored for their pleiotropic properties to combat the destruction of alveolar bone. This review focuses on the role of pharmacological agents in alveolar bone regeneration.

Polycaprolactone-based scaffolds for guided tissue regeneration in periodontal therapy: A systematic review.

Polycaprolactone (PCL) is a highly recognized synthetic polymer for its biocompatibility, ease of fabrication and mechanical strength in bone tissue engineering. Its applications have extended broadly, including regeneration of oral and maxillofacial lost tissues. Its usefulness has brought attention of researchers to regenerate periodontal lost tissues, including alveolar bone, periodontal ligament and cementum. The aim of this systematic review was to obtain an updated analysis of the contribution of PCL-based scaffolds in the alveolar bone regeneration process. This review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews. A computerized search of the PubMed, EBSCO, Scielo and Web of Science databases was performed, restricting literature search to published studies in English or Spanish between January 2002 and March 2023. Database search returned 248 studies which were screened based on title, author names and publication dates. Data from 17 studies were reviewed and tabulated. All studies combined PCL with other biomaterials (such as Alginate, hydroxyapatite, bioactive glass, poly (lactic-co-glycolic acid)), growth factors (BMP-2, rhCEMP1), and/or mesenchymal stromal cells (adipose-derived, bone marrow, periodontal ligament or gingiva mesenchymal stromal cells). PCL scaffolds showed higher cell viability and osteoinductive potential when combined with bioactive agents. Complementary, its degradation rates were affected by the addition or exposure to specific substances, such as: Dopamine, Cerium Oxide, PLGA and hydrogen peroxide. PCL is an effective biomaterial for alveolar bone regeneration in periodontally affected teeth. It could be part of a new generation of biomaterials with improved regenerative potential.

Platinum nanoparticles enhance osteogenic differentiation of human dental follicle stem cells via scavenging ROS

The over-accumulation of ROS during prolonged in vitro expansion could negatively affect the properties of stem cells. This leads to a reduced capacity for self-renewal and a lower potential for multiple differentiation, ultimately hindering their applicability in regenerative medicine. Herein, we fabricated platinum nanoparticles (PtNPs) as a potential biocompatible antioxidant to efficiently eliminate the ROS accumulation in human dental follicle stem cells (hDFSCs) during in vitro expansion, thereby enhancing hDFSCs proliferation and osteogenic differentiation. Transcriptome analysis revealed that PI3K/AKT signaling pathway was activated in PtNPs-treated hDFSCs. Transplantation of PtNPs-treated rDFSCs could facilitate new bone formation compared to transplantation of PBS or un-treated rDFSCs, leading to efficient regeneration of bone tissue in rat mandibular bone defect models. In conclusion, PtNPs offered a novel antioxidative strategy to improve stem cell properties and stem-cells-based alveolar bone regeneration.

Regenerative Therapies in the Treatment of Periodontal Defects

Regenerative therapies in periodontics have shown great potential in restoring damaged periodontal tissues. Techniques such as guided tissue regeneration (GTR) and guided bone regeneration (GBR) have been effective in promoting the regeneration of periodontal ligament, cementum, and alveolar bone. These approaches create a conducive environment for cell repopulation and exclusion of non-osteogenic cells, leading to successful periodontal tissue regeneration. Tissue engineering approaches, utilizing stem cells, growth factors, and biomaterial scaffolds, have also shown promise in regenerating multiple periodontal tissues simultaneously. However, challenges such as membrane exposure and infection need to be addressed. Emerging regenerative techniques, including enamel matrix derivatives (EMDs), stem cell-based therapies, growth factor delivery systems, and gene therapies, offer innovative strategies for periodontal defect treatment. Optimization of delivery systems, refinement of biomaterials, and advancements in gene therapy and tissue-specific biomaterials may further enhance the regenerative capacity of periodontal tissues. Despite challenges, regenerative therapies have the potential to revolutionize periodontics and improve clinical outcomes by addressing the root cause of periodontal diseases and promoting long-lasting tissue regeneration.

Эндогенная регенерация альвеолярной кости децеллюляризированным матриксом зуба

Эндогенная регенерация альвеолярной кости децеллюляризированным матриксом зуба

M5 - Osteogenic effect of hydroxyapatite scaffold covered with 45S5BG/PLGA composite microfiber for alveolar bone regeneration

M5 - Osteogenic effect of hydroxyapatite scaffold covered with 45S5BG/PLGA composite microfiber for alveolar bone regeneration

Pro-angiogenic photo-crosslinked silk fibroin hydrogel: a potential candidate for repairing alveolar bone defects.

This study aimed to develop a pro-angiogenic hydrogel with in situ gelation ability for alveolar bone defects repair. Silk fibroin was chemically modified by Glycidyl Methacrylate (GMA), which was evaluated by proton nuclear magnetic resonance (1H-NMR). Then, the photo-crosslinking ability of the modified silk fibroin was assessed. Scratch and transwell-based migration assays were conducted to investigate the effect of the photo-crosslinked silk fibroin hydrogel on the migration of human umbilical vein endothelial cells (HUVECs). In vitro angiogenesis was conducted to examine whether the photo-crosslinked silk fibroin hydrogel would affect the tube formation ability of HUVECs. Finally, subcutaneous implantation experiments were conducted to further examine the pro-angiogenic ability of the photo-crosslinked silk fibroin hydrogel, in which the CD31 and α-smooth muscle actin (α-SMA) were stained to assess neovascularization. The tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were also stained to evaluate inflammatory responses after implantation. GMA successfully modified the silk fibroin, which we verified by our 1H-NMR and in vitro photo-crosslinking experiment. Scratch and transwell-based migration assays proved that the photo-crosslinked silk fibroin hydrogel promoted HUVEC migration. The hydrogel also enhanced the tube formation of HUVECs in similar rates to Matrigel®. After subcutaneous implantation in rats for one week, the hydrogel enhanced neovascularization without triggering inflammatory responses. This study found that photo-crosslinked silk fibroin hydrogel showed pro-angiogenic and inflammation inhibitory abilities. Its photo-crosslinking ability makes it suitable for matching irregular alveolar bone defects. Thus, the photo-crosslinkable silk fibroin-derived hydrogel is a potential candidate for constructing scaffolds for alveolar bone regeneration.

Is sclerostin antibody an effective agent for alveolar bone regeneration in animal models? A scoping review

Objectives
 The use of Sclerostin Antibody(Scl-Ab) as a bone anabolic agent has shown significant benefit in bone disorders in preclinical animal models and human clinical trials. Currently available evidence on the use of Scl-Ab in alveolar bone regeneration is limited to animal studies and hence this scoping review encompasses the animal studies conducted to ascertain the effectiveness of Scl-Ab on alveolar bone regeneration. 
 Materials and methods
 The search strategy was aimed to locate published animal studies in which the treatment arm includes Sclerostin antibody administration for alveolar bone preservation or regeneration. The search terms used were (((Animal model) OR Rodent) AND Alveolar bone defect) AND Anti sclerostin antibody) OR Sclerostin antibody) AND Alveolar bone regeneration) OR Bone regeneration) AND Bone fill. 
 Results
 Of the 559 results from Medline/PubMed, Scopus, Web of Science, Google scholar and additional articles from the references, six were included in the review. Scl-Ab was found to be effective in improving the bone quality and quantity. It was also observed that Scl-Ab was useful in reduced bone density associated with diseases and conditiona affecting osteoblast activity. 
 Conclusion
 The review concluded that Scl-Ab promotes alveolar bone augmentation and improves bone quality without surgical interventions.

Microemulsion-thermosensitive gel composites as in situ-forming drug reservoir for periodontitis tissue repair through alveolar bone and collagen regeneration strategy

A satisfactory clinical effect in treating periodontitis is often difficult to achieve by conventional non-surgical systemic drug delivery due to the narrow anatomical structure of the periodontal pocket and insufficient drug concentration at lesion sites. In addition, the feasibility of combating periodontal tissue lesions by restoring the alveolar bone and allowing collagen regeneration has not been fully explored. The objective of this study was to prepare a microemulsion integrating the anti-inflammatory and osteogenic active ingredients of baicalin and clove oil (BC-MEs). Then, the composite hydrogel obtained by mixing poloxamer 407 and 188 was used as the thermosensitive gel matrix to load BC-MEs and form a drug reservoir (Gel-BC-MEs) injectable in situ. Gel-BC-MEs exhibited a significant, sustained release of baicalin for 12 h, gelation temperature was 33.4 ± 0.36 °C, and pH was 5.45 ± 0.12. The experiment on a rat periodontitis model demonstrated that Gel-BC-MEs significantly improved periodontal tissue repair by collagen regeneration and osteogenesis by inhibiting osteoclast infiltration. This study proposes a novel strategy for periodontal tissue repair by enhancing the therapeutic potential of a microemulsion using an in situ nano-gel delivery system.

Autogenous dentin combined with mesenchymal stromal cells as an alternative alveolar bone graft: an in vivo study.

Considering the chemical and structural properties of dentin, this study was aimed at evaluating the effect of dentin matrix alone or combined with mesenchymal stromal cells (MSC) on postextraction alveolar bone regeneration. Wistar rats were subjected to tooth extraction with osteotomy and allocated into groups according to the graft inserted: (1) Gelita-Spon®, (2) Bio-Oss®, (3) Dentin, (4) MSC, (5) Dentin/MSC, and (6) Control. Maxillae were analyzed by means of hematoxylin and eosin (H&E) staining, immunohistochemical (IHC) analysis, microcomputed tomography (micro-CT), and scanning electron microscopy (SEM). Serum levels of calcium and phosphorus were quantified. The Bio-Oss group showed less bone than Gelita-Spon and Dentin/MSC; no other significant differences were seen in H&E analysis. The Bio-Oss group showed higher expression of collagen type I compared to the Dentin and Dentin/MSC groups and also higher osteocalcin expression than the Dentin/MSC group. There was a tendency of higher expression of osteopontin in the MSC, Dentin, and Dentin/MSC groups and higher VEGF in the MSC group. On micro-CT analysis, the Bio-Oss and the Dentin/MSC groups exhibited greater bone volume than the Control. Serum calcium and phosphorus levels did not significantly differ between the groups. SEM analysis depicted particles of Bio-Oss and dentin in the respective groups, as well as significant cellularity in the MSC group. Autogenous nondemineralized dentin is an alternative for alveolar bone grafting, which can be improved by combination with MSC. This work provides support for the clinical applicability of dentin graft alone or combined with MSC.

Accelerating periodontal regeneration through injectable hydrogel-enabled sequential delivery of nanoceria and erythropoietin

Periodontitis is a chronic inflammatory disease characterized by persistent host immune overreaction, resulting in irregular alveolar shape after absorption, making local drug delivery a huge challenge. Herein, an injectable Fmoc-Phe3 hydrogel (FPH) with ceria nanoparticle (CNP) and erythropoietin (EPO) was prepared (EPO/CNP@FPH) for local drug delivery into the irregular periodontal pocket. The release of EPO and CNP was 61.33 % and 69.67 % respectively within the first 3 days and the release of CNP was faster than that of EPO during the process, which is the prerequisite for regeneration. The composite hydrogel enabled the switch in macrophage phenotype from M1 to M2 polarization by scavenging redundant ROS. It further increased the ability of angiogenesis and osteogensis. The EPO/CNP@FPH composite hydrogel exerted a remarkable therapeutic effects enabling irregular alveolar bone regeneration in rat model of periodontitis. Taken together, the hydrogel loaded with EPO and CNP showed a great potential for reducing inflammation and promoting periodontal regeneration in irregular regions, which may be a promising candidate for periodontitis treatment.