Unraveling the influence of channel size and shape in 3D printed ceramic scaffolds on osteogenesis.

Bone has the capacity to regenerate itself for relatively small defects; however, this regenerative capacity is diminished in critical-size bone defects. The development of synthetic materials has risen as a distinct strategy to address this challenge. Effective synthetic materials to have emerged in recent years are bioceramic implants, which are biocompatible and highly bioactive. Yet nothing suitable for the repair of large bone defects has made the transition from laboratory to clinic. The clinical success of bioceramics has been shown to depend not only on the scaffold's intrinsic material properties but also on its internal porous geometry. This study aimed to systematically explore the implications of varying channel size, shape, and curvature in tissue scaffolds on in vivo bone regeneration outcomes. 3D printed bioceramic scaffolds with varying channel sizes (0.3 mm to 1.5 mm), shapes (circular vs rectangular), and curvatures (concave vs convex) were implanted in rabbit femoral defects for 8 weeks, followed by histological evaluation. We demonstrated that circular channel sizes of around 0.9 mm diameter significantly enhanced bone formation, compared to channel with diameters of 0.3 mm and 1.5 mm. Interestingly, varying channel shapes (rectangular vs circular) had no significant effect on the volume of newly formed bone. Furthermore, the present study systematically demonstrated the beneficial effect of concave surfaces on bone tissue growth in vivo, reinforcing previous in silico and in vitro findings. This study demonstrates that optimizing architectural configurations within ceramic scaffolds is crucial in enhancing bone regeneration outcomes. STATEMENT OF SIGNIFICANCE: Despite the explosion of work on developing synthetic scaffolds to repair bone defects, the amount of new bone formed by scaffolds in vivo remains suboptimal. Recent studies have illuminated the pivotal role of scaffolds' internal architecture in osteogenesis. However, these investigations have mostly remained confined to in silico and in vitro experiments. Among the in vivo studies conducted, there has been a lack of systematic analysis of individual architectural features. Herein, we utilized bioceramic 3D printing to conduct a systematic exploration of the effects of channel size, shape, and curvature on bone formation in vivo. Our results demonstrate the significant influence of channel size and curvature on in vivo outcomes. These findings provide invaluable insights into the design of more effective bone scaffolds.

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice.

Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.

Association between healthy lifestyle combinations and periodontitis in NHANES.

BACKGROUND: Periodontitis is closely associated with chronic systemic diseases. Healthy lifestyle interventions have health-enhancing effects on chronic systemic disorders and periodontitis, but the extent to which healthy lifestyle combinations are associated with periodontitis is unclear. Therefore, this study aimed to investigate the association between periodontitis and different healthy lifestyle combinations. METHODS: 5611 participants were included from the National Health and Nutrition Examination Survey (NHANES, 2009-2014). Six healthy lifestyles factors were defined as fulfilling either: non-smoking, moderate drinking, moderate body mass index (BMI), physical activity, healthy sleep and appropriate total energy intake. Then, the adjusted logistic regression models were performed to identify the association between the periodontitis and the scoring system composed of six lifestyles (0-6 scale). Finally, different scenarios were dynamically and randomly combined to identify the optimal and personalized combination mode. RESULTS: Higher healthy lifestyle scores were significantly associated with lower periodontitis prevalence (p < 0.05). Four lifestyle factors (smoking, drinking, BMI, and sleep) significantly varied between the periodontitis and healthy groups (p < 0.05). Smoking was considered as a strong independent risk factor for periodontitis in both former and current smokers. Results further indicated that the combination of these four lifestyles played the most essential role in determining the magnitude of periodontitis occurrence (odds ratio [OR]: 0.33; 95% confidence interval [CI]: 0.21 to 0.50). In the total population, the majority of three lifestyle combinations outperformed the two combination models, whereas the two-combination of nonsmoking-drinking (OR: 0.39; 95% CI: 0.27 to 0.58) had relatively lower periodontitis prevalence than the three-combination of healthy drinking-BMI-sleep (OR: 0.42; 95% CI: 0.26 to 0.66). CONCLUSION: This cross-sectional study suggests that smoking, drinking, BMI, and sleep are significantly related with periodontitis and smoking is the principal risk factor related among them. This study provides various customized lifestyle combinations for periodontitis prevention.

Flexocatalytic Reduction of Tumor Interstitial Fluid/Solid Pressure for Efficient Nanodrug Penetration.

The practical efficacy of nanomedicines for treating solid tumors is frequently low, predominantly due to the elevated interstitial pressure within such tumors that obstructs the penetration of nanomedicines. This increased interstitial pressure originates from both liquid and solid stresses related to an undeveloped vascular network and excessive fibroblast proliferation. To specifically resolve the penetration issues of nanomedicines for tumor treatment, this study introduces a holistic "dual-faceted" approach. A treatment platform predicated on the WS2/Pt Schottky heterojunction was adopted, and flexocatalysis technology was used to disintegrate tumor interstitial fluids, thus producing oxygen and reactive oxygen species and effectively mitigating the interstitial fluid pressure. The chemotherapeutic agent curcumin was incorporated to further suppress the activity of cancer-associated fibroblasts, minimize collagen deposition in the extracellular matrix, and alleviate solid stress. Nanomedicines achieve homologous targeting by enveloping the tumor cell membrane. It was found that this multidimensional strategy not only alleviated the high-pressure milieu of the tumor interstitium─which enhanced the efficiency of nanomedicine delivery─but also triggered tumor cell apoptosis via the generated reactive oxygen species and modulated the tumor microenvironment. This, in turn, amplified immune responses, substantially optimizing the therapeutic impacts of nanomedicines.

Strontium-Containing Piezoelectric Biofilm Promotes Dentin Tissue Regeneration.

It remains an obstacle to induce the regeneration of hard dentin tissue in clinical settings. To overcome this, a P(VDF-TrFE) piezoelectric film with 2 wt% SrCl2 addition is designed. The biofilm shows a high flexibility, a harmonious biocompatibility, and a large piezoelectric d33 coefficient of 14 pC N-1, all contributing to building an electric microenvironment that favor the recruitment of dental pulp stem cells (DPSCs) and their differentiation into odontoblasts during normal chewing, speaking, etc. On the other hand, the strontium ions can be gradually released from the film, thus promoting DPSC odonto-differentiation. In vivo experiments also demonstrate that the film induces the release of dentin minerals and regeneration of dentin tissue. In the large animal dentin defect models, this piezoelectric film induces in situ dentin tissue formation effectively over a period of three months. This study illustrates a therapeutic potential of the piezoelectric film to improve dentin tissue repair in clinical settings.

Urchin-like multiscale structured fluorinated hydroxyapatite as versatile filler for caries restoration dental resin composites.

Caries is one of the most prevalent human diseases, resulting from demineralization of tooth hard tissue caused by acids produced from bacteria, and can progress to pulpal inflammation. Filling restoration with dental resin composites (DRCs) is currently the most common treatment for caries. However, existing DRCs suffer from low fracture strength and lack comprehensive anti-caries bioactivity including remineralization, pulp protection, and anti-cariogenic bacteria effects. In this study, inspired by plant roots' ability to stabilize and improve soil, fluorinated urchin-like hydroxyapatite (FUHA) with a three-dimensional whisker structure and bioactive components of calcium, phosphorus, and fluorine was designed and synthesized by a dynamic self-assembly method. Furthermore, versatile FUHA particles with different loading fractions were used as functional fillers to fabricate methacrylate-based DRCs, where the urchin-like hydroxyapatite (UHA) filled DRCs and commercial DRCs (Z350XT and BEAUTIFIL II) served as the control groups. The results demonstrated that FUHA with 50 wt% loading in resin matrix endowed DRC (F5) with excellent physicochemical properties, dentin remineralization property, cell viability, promotion of dental pulp stem cells mineralization, and antibacterial properties. Meanwhile, F5 also presented good clinical handling and aesthetic characteristics. Therefore, structure/functional-integrated FUHA filled DRCs have potential as a promising strategy for tooth restoration and anti-caries bioactivity.

An Injectable silk-based hydrogel as a novel biomineralization seedbed for critical-sized bone defect regeneration.

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.

High-Performance Hydrogel-Encapsulated Engineered Exosomes for Supporting Endoplasmic Reticulum Homeostasis and Boosting Diabetic Bone Regeneration.

The regeneration of bone defects in diabetic patients still faces challenges, as the intrinsic healing process is impaired by hyperglycemia. Inspired by the discovery that the endoplasmic reticulum (ER) is in a state of excessive stress and dysfunction under hyperglycemia, leading to osteogenic disorder, a novel engineered exosome is proposed to modulate ER homeostasis for restoring the function of mesenchymal stem cells (MSCs). The results indicate that the constructed engineered exosomes efficiently regulate ER homeostasis and dramatically facilitate the function of MSCs in the hyperglycemic niche. Additionally, the underlying therapeutic mechanism of exosomes is elucidated. The results reveal that exosomes can directly provide recipient cells with SHP2 for the activation of mitophagy and elimination of mtROS, which is the immediate cause of ER dysfunction. To maximize the therapeutic effect of engineered exosomes, a high-performance hydrogel with self-healing, bioadhesive, and exosome-conjugating properties is applied to encapsulate the engineered exosomes for in vivo application. In vivo, evaluation in diabetic bone defect repair models demonstrates that the engineered exosomes delivering hydrogel system intensively enhance osteogenesis. These findings provide crucial insight into the design and biological mechanism of ER homeostasis-based tissue-engineering strategies for diabetic bone regeneration.

Advancing piezoelectric 2D nanomaterials for applications in drug delivery systems and therapeutic approaches.

Precision drug delivery and multimodal synergistic therapy are crucial in treating diverse ailments, such as cancer, tissue damage, and degenerative diseases. Electrodes that emit electric pulses have proven effective in enhancing molecule release and permeability in drug delivery systems. Moreover, the physiological electrical microenvironment plays a vital role in regulating biological functions and triggering action potentials in neural and muscular tissues. Due to their unique noncentrosymmetric structures, many 2D materials exhibit outstanding piezoelectric performance, generating positive and negative charges under mechanical forces. This ability facilitates precise drug targeting and ensures high stimulus responsiveness, thereby controlling cellular destinies. Additionally, the abundant active sites within piezoelectric 2D materials facilitate efficient catalysis through piezochemical coupling, offering multimodal synergistic therapeutic strategies. However, the full potential of piezoelectric 2D nanomaterials in drug delivery system design remains underexplored due to research gaps. In this context, the current applications of piezoelectric 2D materials in disease management are summarized in this review, and the development of drug delivery systems influenced by these materials is forecast.

Highly Active Frozen Nanovesicles Microneedles for Senile Wound Healing via Antibacteria, Immunotherapy, and Skin Regeneration.

Senile wound healing risks a variety of health complications and makes both economic and psychological burdens on patients greatly. Poor activity of aged dermal fibroblasts (A-FBs) and local disordered immunoreaction in the deep dermis contribute to delayed wound healing. Therefore, the locally complex microenvironment in deep requires additional processing. Herein, a novel double-layer hyaluronic acid methacrylate (HAMA)/polyvinyl alcohol (PVA) microneedle patch (MNP) coated by young fibroblast-derived exosomes (Y-EXOs) (Y-EXOs@HAMA/PVA MNP) is presented for deep drug delivery, aged wound healing and immunoregulation. A spraying and freeze-drying method is applied for keeping the bioactivity of the nanovesicles. An ideal loading of Y-EXOs and enhanced strength for penetration have realized after circulation for times. The Y-EXOs@HAMA/PVA MNP shows an excellent influence on delayed wound healing of aged skin with active A-FBs, more deposition of collagen and less production of IL-17A compared with application of aged fibroblast-derived exosomes (A-EXOs). Moreover, the content microRNAs in Y-EXOs and A-EXOs are sequenced for further study. This study initiatively demonstrates that Y-EXOs have effective function on both anti-aging and anti-inflammation and Y-EXOs@HAMA/PVA MNP is expected as a novel strategy for deep drug delivery for promoting hard wound healing in aged skin in future clinical application.

Fusion machine learning model predicts CAD-CAM ceramic colors and the corresponding minimal thicknesses over various clinical backgrounds.

OBJECTIVES: This study has developed and optimized a machine learning model to accurately predict the final colors of CAD-CAM ceramics and determine their required minimum thicknesses to cover different clinical backgrounds. METHODS: A total of 120 ceramic specimens (2 mm, 1 mm and 0.5 mm thickness; n = 10) of four CAD-CAM ceramics - IPS e.max, IPS ZirCAD, Upcera Li CAD and Upcera TT CAD - were studied. The CIELab coordinates (L*, a* and b*) of each specimen were obtained over seven different clinical backgrounds (A1, A2, A3.5, ND2, ND7, cobalt-chromium alloy (CC) and medium precious alloy (MPA)) using a digital spectrophotometer. The color difference (ΔE) and lightness difference (ΔL) results were submitted to 39 different models. The prediction results from the top-performing models were used to develop a fusion model via the Stacking integrated learning method for best-fitting prediction. The SHapley Additive exPlanation (SHAP) was performed to interpret the feature importance. RESULTS: The fusion model, which combined the ExtraTreesRegressor (ET) and XGBRegressor (XGB) models, demonstrated minimal prediction errors (R2 = 0.9) in the external testing sets. Among the investigated variables, thickness and background colors (CC and MPA) majorly influenced the final color of restoration. To achieve perfect aesthetic restoration (ΔE<2.6), at least 1.9 mm IPS ZirCAD or 1.6 mm Upcera TT CAD were required to cover the CC background, while two tested glass-ceramics did not meet the requirements even with thicknesses over 2 mm. SIGNIFICANCE: The fusion model provided a promising tool for automate decision-making in material selection with minimal thickness over various clinical background.

Salivary signatures of oral-brain communication in sleep bruxers.

Introduction: Microbiota and their interaction with hosts have been of great interest in brain research in recent years. However, the role of oral microbiota in mental illness and the underlying mechanism of oral-brain communication remains elusive. Sleep bruxism (SB) is an oral parafunctional activity related to the nervous system and is considered a risk factor for harmful clinical consequences and severe systemic conditions. Exploring the connection between oral microbiota and sleep bruxism may deepen our understanding of the complex relationship between oral-brain axis and provide insights for treatment. Methods: In this study, salivary samples were collected from 22 individuals with SB and 21 healthy controls, and metagenomics with metabolomics was performed. Nonparametric Wilcoxon test were applied for the statistical analysis between the two groups. Microbial dysbiosis and altered oral metabolites were found in the SB individuals. Results: The characteristic metabolite N-acetylglucosamine (GlcNAc) (VIP=8.4823, P<0.05) was correlated to a statistically lower Streptococcus mitis level in SB individuals. Salivary IFN-g level and IFN-g/IL-4 ratio were detected with significant changes in a chip assay. Amino acid metabolism pathways were upregulated, and the pathway with the largest number of differentially expressed genes is related to amino-tRNA charging pathway, while the most significantly enriched pathway is related to arginine biosynthesis. Neurotransmitter-associated pathways with glutamatergic and GABAergic synapses and cardiovascular system-related pathways were enriched in the SB group. Discussion: These results indicate a possible neuroimmune regulatory network of oral-brain communication in SB, which helps explain the mechanism of the oral microbiome with the host in sleep bruxers and provides a reference for early clinical and therapeutic intervention to improve the diagnosis and treatment of SB and similar diseases.

Dominoes with interlocking consequences triggered by zinc: involvement of microelement-stimulated MSC-derived exosomes in senile osteogenesis and osteoclast dialogue.

As societal aging intensifies, senile osteoporosis has become a global public health concern. Bone microdamage is mainly caused by processes such as enhancing osteoclast activity or reducing bone formation by osteoblast-lineage cells. Compared with young individuals, extracellular vesicles derived from senescent bone marrow mesenchymal stem cells(BMSCs) increase the transient differentiation of bone marrow monocytes (BMMs) to osteoclasts, ultimately leading to osteoporosis and metal implant failure. To address this daunting problem, an exosome-targeted orthopedic implant composed of a nutrient coating was developed. A high-zinc atmosphere used as a local microenvironmental cue not only could inhibit the bone resorption by inhibiting osteoclasts but also could induce the reprogramming of senile osteogenesis and osteoclast dialogue by exosome modification. Bidirectional regulation of intercellular communication via cargoes, including microRNAs carried by exosomes, was detected. Loss- and gain-of-function experiments demonstrated that the key regulator miR-146b-5p regulates the protein kinase B/mammalian target of rapamycin pathway by targeting the catalytic subunit gene of PI3K-PIK3CB. In vivo evaluation using a naturally-aged osteoporotic rat femoral defect model further confirmed that a nutrient coating substantially augments cancellous bone remodeling and osseointegration by regulating local BMMs differentiation. Altogether, this study not only reveals the close link between senescent stem cell communication and age-related osteoporosis but also provides a novel orthopedic implant for elderly patients with exosome modulation capability.

Synthesis of Pore-Size-Tunable Porous Silica Particles and Their Effects on Dental Resin Composites.

The filler/resin matrix interface interaction plays a vital role in the properties of dental resin composites (DRCs). Porous particles are promising fillers due to their potential in constructing micromechanical interlocking at filler/resin matrix interfaces, therefore improving the properties of the resulting DRCs, where the pore size is significantly important. However, how to control the pore size of porous particles via a simple synthesis method is still a challenge, and how their pore sizes affect the properties of resulting DRCs has not been studied. In this study, porous silica (DPS) with a dendritic structure and an adjustable pore size was synthesized by changing the amounts of catalyst in the initial microemulsion. These synthesized DPS particles were directly used as unimodal fillers and mixed with a resin matrix to formulate DRCs. The results showed that the DPS pore size affects the properties of DRCs, especially the mechanical property. Among various DPS particles with different pore sizes, DPS6 resulted in 19.5% and 31.4% improvement in flexural strength, and 24.4% and 30.7% enhancement in compression strength, respectively, compared to DPS1 and DPS9. These DPS particles could help to design novel dental restorative materials and have promising applications in biomedicine, catalysis, and adsorption.

Digitally printed custom trays assembled with occlusion rims and gothic arch tracing devices attached with tenon-and-mortise joints for biofunctional complete dentures: A dental technique.

A novel technique of digitally printed custom trays assembled with occlusion rims and gothic arch tracing devices attached with tenon-and-mortise joints for biofunctional complete dentures that could be delivered in 2 visits is presented. This technique takes advantage of closed-mouth impressions and objective jaw relation records by following the biofunctional prosthetic system concept with high efficiency and reduced labor.

CGRP-Loaded Porous Microspheres Protect BMSCs for Alveolar Bone Regeneration in the Periodontitis Microenvironment.

Periodontitis is a prevalent dental disease marked by progressive destruction of tooth-supporting tissues, and the recovery of bone defects after periodontitis remains challenging. Although stem cell-based therapy is a promising treatment for periodontal tissue regeneration, the function of mesenchymal stem cells is constantly impaired by the inflammatory microenvironment, leading to compromised treatment outcomes. Herein, calcitonin gene-related peptide (CGRP)-loaded porous microspheres (PMs) are prepared to protect bone marrow mesenchymal stem cells (BMSCs) against inflammatory mediators in periodontitis. The released CGRP can effectively ameliorate the inflammation-induced dysfunction of BMSCs, which may involve suppressing the ROS (reactive oxygen species)/NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3)/Caspase-1 (CASP1) pathway. Moreover, the porous architecture of PMs provides effective cell-carrying capacity and physical protection for BMSCs during transplantation. In vivo experiments demonstrate that CGRP/BMSC-loaded PMs can effectively inhibit inflammation and improve osteogenic activity, resulting in better periodontal bone regeneration. This study focuses on the protection of stem cell function in the inflammatory microenvironment, which is important for stem cell-mediated tissue regeneration and repair under inflammatory conditions.

Liver-Inspired Polyetherketoneketone Scaffolds Simulate Regenerative Signals and Mobilize Anti-Inflammatory Reserves to Reprogram Macrophage Metabolism for Boosted Osteoporotic Osseointegration.

Tissue regeneration is regulated by morphological clues of implants in bone defect repair. Engineered morphology can boost regenerative biocascades that conquer challenges such as material bioinertness and pathological microenvironments. Herein, a correlation between the liver extracellular skeleton morphology and the regenerative signaling, namely hepatocyte growth factor receptor (MET), is found to explain the mystery of rapid liver regeneration. Inspired by this unique structure, a biomimetic morphology is prepared on polyetherketoneketone (PEKK) via femtosecond laser etching and sulfonation. The morphology reproduces MET signaling in macrophages, causing positive immunoregulation and optimized osteogenesis. Moreover, the morphological clue activates an anti-inflammatory reserve (arginase-2) to translocate retrogradely from mitochondria to the cytoplasm due to the difference in spatial binding of heat shock protein 70. This translocation enhances oxidative respiration and complex II activity, reprogramming the metabolism of energy and arginine. The importance of MET signaling and arginase-2 in the anti-inflammatory repair of biomimetic scaffolds is also verified via chemical inhibition and gene knockout. Altogether, this study not only provides a novel biomimetic scaffold for osteoporotic bone defect repair that can simulate regenerative signals, but also reveals the significance and feasibility of strategies to mobilize anti-inflammatory reserves in bone regeneration.

Micromechanical interlocking structure at the filler/resin interface for dental composites: a review.

Dental resin composites (DRCs) are popular materials for repairing caries or dental defect, requiring excellent properties to cope with the complex oral environment. Filler/resin interface interaction has a significant impact on the physicochemical/biological properties and service life of DRCs. Various chemical and physical modification methods on filler/resin interface have been introduced and studied, and the physical micromechanical interlocking caused by the modification of fillers morphology and structure is a promising method. This paper firstly introduces the composition and development of DRCs, then reviews the chemical and physical modification methods of the filler/resin interface, mainly discusses the interface micromechanical interlocking structures and their enhancement mechanism for DRCs, finally give a summary on the existing problems and development potential.

Transcriptome landscape comparison of periodontium in developmental and renewal stages.

Objectives: Periodontium regeneration remains a significant challenge in clinics and research, and it is essential to understand the stage-specific biological process in situ. However, differing findings have been reported, and the mechanism has yet to be elucidated. The periodontium of adult mice molars is considered to be stable remodeling tissue. At the same time, the continuously growing incisors and the developing dental follicle (DF) of postnatal mice highly represent fast remodeling tissue. In this study, we attempted to explore different clues of temporal and spatial comparisons to provide improved references for periodontal regeneration. Methods: Periodontal tissues from the developing periodontium (DeP) of postnatal mice, and continuously growing periodontium (CgP) and stable remodeling periodontium (ReP) of adult mice were isolated and compared using RNA sequencing. Based on the Dep and CgP separately compared with the ReP, differentially expressed genes and signaling pathways were analyzed using GO, KEGG databases, and Ingenuity Pathway Analysis (IPA). The results and validation were obtained by immunofluorescence staining and RT-PCR assays. Data were expressed as means ± standard deviation (SD) and analyzed by GraphPad Prism 8 software package, and one-way ANOVA was used to test multiple groups. Results: Principal component analysis showed that the three groups of periodontal tissue were successfully isolated and had distinct expression profiles. A total of 792 and 612 DEGs were identified in the DeP and CgP groups compared with the ReP. Upregulated DEGs in the DeP were closely related to developmental processes, while the CgP showed significantly enhanced cellular energy metabolism. The DeP and CgP showed a common downregulation of the immune response, with activation, migration, and recruitment of immune cells. IPA and further validation jointly suggested that the MyD88/p38 MAPK pathway played an essential regulatory role in periodontium remodeling. Conclusion: Tissue development, energy metabolism, and immune response were critical regulatory processes during periodontal remodeling. Developmental and adult stages of periodontal remodeling showed different expression patterns. These results contribute to a deeper understanding of periodontal development and remodeling and may provide references for periodontal regeneration.

BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism.

Bromodomain-containing protein 9 (BRD9), a component of non-canonical BAF chromatin remodeling complex, has been identified as a critical therapeutic target in hematological diseases. Despite the hematopoietic origin of osteoclasts, the role of BRD9 in osteoclastogenesis and bone diseases remains unresolved. Here, we show Brd9 deficiency in myeloid lineage enhances osteoclast lineage commitment and bone resorption through downregulating interferon-beta (IFN-ß) signaling with released constraint on osteoclastogenesis. Notably, we show that BRD9 interacts with transcription factor FOXP1 activating Stat1 transcription and IFN-ß signaling thereafter. Besides, function specificity of BRD9 distinguished from BRD4 during osteoclastogenesis has been evaluated. Leveraging advantages of pharmacological modulation of BRD9 and flexible injectable silk fibroin hydrogel, we design a local deliver system for effectively mitigating zoledronate related osteonecrosis of the jaw and alleviating acute bone loss in lipopolysaccharide-induced localized aggressive periodontitis. Overall, these results demonstrate the function of BRD9 in osteoclastogenesis and its therapeutic potential for bone diseases.