Next-generation craniomaxillofacial implants (CMFIs) are redefining personalized bone reconstruction by balancing and optimizing biomechanics, biocompatibility, and bioactivity—the “3Bs”. This review highlights recent progress in implant design, material development, additive manufacturing, and preclinical evaluation. Emerging biomaterials, including bioresorbable polymers, magnesium alloys, and composites with bioactive ceramics, enable patient-specific solutions with improved safety and functionality. Triply periodic minimal surface (TPMS) architectures exemplify how structural design can enhance both mechanical performance and biological integration. Additive manufacturing technologies further allow the fabrication of geometrically complex, customized implants that meet individual anatomical and pathological needs. In parallel, multiscale evaluation techniques—from mechanical testing to in vitro and in vivo models—provide comprehensive insights into implant performance and safety. Looking ahead, the field is poised to benefit from several transformative trends: the development of smart and multifunctional biomaterials; AI-driven design frameworks that leverage patient-specific data and computational modeling; predictive additive manufacturing with real-time quality control; and advanced biological testing platforms for preclinical evaluation. Together, these advances form the foundation of a data-informed, translational pipeline from bench to bedside. Realizing the full potential of next-generation CMFIs will require close interdisciplinary collaboration across materials science, computational engineering, and clinical medicine.

Tooth morphogenesis is orchestrated by a complex interplay of signaling pathways and transcription factors that control cell proliferation, apoptosis, and differentiation, with the Wnt/β-catenin signaling pathway playing a pivotal role. However, the comprehensive regulatory mechanisms of Wnt/β-catenin signaling remain largely unclear. Smad7, a key antagonist of the TGF-β superfamily, is essential for maintaining tissue homeostasis and ensuring proper cellular function. Our previous study has demonstrated that Smad7 knockout in mice leads to impaired proliferative property of tooth germ cells, resulting in small molars. Here, we identified SMAD7 expression in human dental papilla and dental pulp, colocalized with β-CATENIN and cell proliferation-related proteins. RNA sequencing analysis revealed a significant reduction in Wnt signaling activity in Smad7-deficient mouse tooth germs. Using lentivirus transfection, we established SMAD7-knockdown human dental papilla stem cells, which manifested remarkably blunt proliferation rate, along with diminished Wnt signaling activity. In vivo transplantation investigations further revealed the indispensable role of SMAD7 in dentin formation. Mechanistically, we revealed that β-CATENIN interacts with P-SMAD2/3 and SMAD7 through co-immunoprecipitation and yeast two-hybrid assays. Inhibition of TGF-β pathway or disruption of SMAD7/β-CATENIN transcription factor complex formation potently impacted Wnt/β-catenin activities, indicating both direct and indirect regulatory mechanisms. These findings highlight the critical role of SMAD7 in the proliferation and differentiation of human dental stem cells, which could contribute to dental tissue regeneration and engineering.

Understanding the acid resistance mechanism of S. mutans is crucial for preventing dental caries. FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis. Our previous study revealed that the FtsZ in S. mutans (SmFtsZ) has higher self-assembly and GTPase activity under acidic stress, which may be responsible for acid resistance and cariogenesis of S. mutans. However, the functional structure mechanism of SmFtsZ under low pH conditions is still unclear. Here, we further reported the crystal structure of S. mutans FtsZ, revealing a unique lateral interface. Through protein polymerization and GTPase activity assay, we experimentally demonstrated that the mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment. The phenotype assay and rat caries model further showed that the mutation of Arg68 effectively inhibited the acid resistance of S. mutans and the occurrence and progress of dental caries in vivo. By employing a molecular dynamics simulation analysis, we conclude that the mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions. Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S. mutans in acidic environments.

Chronic obstructive pulmonary disease (COPD), a disease responsible for early mortality worldwide, is well accepted to be associated with periodontitis epidemiologically. Although both of the diseases are the multi-microbial inflammatory disease, the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown. Here, we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology, characterized by poorer respiratory function, thickened bronchial walls, and increased neutrophils infiltration in lung tissue. Mechanistically, periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) relocated in the lung through the respiratory tract and LPS from P. gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils. Furthermore, exposure to P. gingivalis of infiltrated neutrophils released matrix metallopeptidase-8 (MMP-8) and neutrophil elastase (NE), which aggravated airway inflammation and tissue damage. These findings indicated that periodontitis could exacerbate COPD via its pathogen P. gingivalis, which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.

Dentin, the main component of dental hard tissues, is produced by differentiated odontoblasts. How odontoblast differentiation is regulated remains understudied. Here, we screen that the expression of membrane-associated RING finger protein 2 (March2) is the highest among all March family members, with an increasing trend during odontoblast differentiation. In mouse incisors and molars, MARCH2 is moderately expressed in the undifferentiated dental papilla cells and strongly expressed in the odontoblasts. Knockdown and overexpression experiments demonstrate that MARCH2 inhibits odontoblastic differentiation of mouse dental papilla cells (mDPCs). Additionally, both March2 deficient mice and mice with odontoblast specific knockdown of March2 exhibit the phenotype of increased dentin thickness, accelerated dentin deposition as well as elevated expression levels of odontoblast markers compared with control littermates. Therefore, MARCH2 plays an inhibitory role in odontoblast differentiation. Mechanistically, MARCH2 interacts with protein tyrosine phosphatase receptor delta (PTPRD) and facilitates its K27-linked polyubiquitination and subsequent degradation, which is dependent on the ligase activity of MARCH2. The presence of MARCH2 promotes the translocation of PTPRD from the cell membrane to the lysosome, thereby enhancing its degradation via the lysosomal pathway. Further experiments show that knockdown of endogenous Ptprd impairs odontoblastic differentiation of mDPCs. Ptprd and March2 double knockdown in mDPCs apparently reversed the enhanced odontoblastic differentiation by knockdown of March2 alone, indicating that MARCH2 inhibits odontoblastic differentiation by promoting PTPRD degradation. This study unveils a novel mechanism where an E3 ubiquitin ligase regulates odontoblast differentiation through post-translational modification of a membrane protein, highlighting a promising direction for future exploration.

Rheumatoid arthritis (RA) is an autoimmune disorder that triggers progressive joint destruction by inducing excessive osteoclastogenesis. Porphyromonas gingivalis (Pg), the main pathogenic bacterium involved in periodontitis (PD), is closely related to RA. Pg can secrete extracellular vesicles (EVs), which carry numerous virulence factors. The aim of this study was to investigate whether Pg-derived EVs can be transported and exacerbate bone destruction in RA by promoting osteoclastogenesis and to elucidate the underlying mechanisms involved. EVs derived from Porphyromonas endodontalis (Pe), which is weakly associated with PD or RA, were used as controls. Pg and Pe EVs interact with osteoclasts after translocating into the marrow and metacarpal joints of mice. In vitro, Pg EVs induce osteoclastogenesis via various components, such as lipopolysaccharide, proteins, lipoproteins, and proteases. TNF-α, IL-1β, and IL-6 promote but cannot independently control Pg EV-induced osteoclastogenesis. RNA sequencing and verification experiments further demonstrated that Pg EVs induced osteoclastogenesis by promoting the phosphorylation of spleen tyrosine kinase (Syk). In vivo, Pg EVs exacerbated RA-induced bone destruction by activating Syk-dependent osteoclastogenesis. R406, a Syk inhibitor, significantly attenuated Pg EV-induced RA osteoclastogenesis and bone destruction. However, Pe-derived EVs presented an extremely weak ability to promote osteoclastogenesis and RA. Our findings reveal a new mechanism by which Pg EVs can exacerbate RA via transport through the circulation and the promote Syk-dependent osteoclastogenesis. This study deepens our understanding of the significant pathogenic role of EVs derived from oral bacterial in RA and explores targeted therapeutic strategies by inhibiting the activation of Syk.

Enamel, the inorganic tissue covering the crowns of teeth, is known for its remarkable resilience and hardness. These properties originate from its high proportion of mineralized matrix and complex internal microarchitecture. On an ultrastructural level, it consists of directionally arranged enamel prisms. Continuously growing rodent incisors are an exemplary case of this phenomenon. Their enamel has a consistent decussation pattern, providing teeth with extremely high resistance and ensuring they remain constantly sharp. While the decussation pattern has been described in detail, mechanisms behind its formation have not been experimentally proven. Here, we show that the highly organized enamel micropattern is generated by directional epithelial sliding of enamel-forming ameloblasts in vivo. Our results detail how enamel micropatterning stems from individual cell cluster segregation and subsequent reciprocal interweaving. Based on this determination, we introduce and experimentally demonstrate a new model of enamel decussation pattern formation.

Temporomandibular joint osteoarthritis (TMJ-OA) affects a significant proportion of the population worldwide. However, there has been no substantial progress in the development of FDA-approved drugs for treatment due to a lack of understanding of the specific factors regulating key TMJ-OA molecular mechanisms. Lysyl Oxidase-Like-2 (LOXL2) promotes knee joint cartilage protection and is downregulated in a TMJ-OA animal model. We evaluated the role of LOXL2 in TMJ cartilage, its molecular mechanism, and gene networks using in vivo Loxl2 knockout mice (Acan-Cre; Loxl2^flox/flox) and ex vivo goat TMJ cartilage. Our results show that Loxl2 knockout in mouse cartilage upregulates Il1b, Mmp9, Mmp13, Adamts4, and Adamts5, but reduces the levels of aggrecan and proteoglycan. Loxl2 deleted TMJ cartilage show a higher enrichment of inflammatory response, TNFA signaling via NF-κB, extracellular matrix (ECM), and collagen degradation pathway network. Conversely, LOXL2 treatment reduces interleukin-1 beta (IL-1β)-induced expression of Mmp13, protects mitochondrial function, and ECM from degeneration. Importantly, LOXL2 attenuates IL-1β-induced chondrocyte apoptosis via the phosphorylation of NF-κB and expression of the pain-related gene PTGS2 (encodes COX2). Taken together, Loxl2 knockout mice exacerbate TMJ-OA through cartilage/ECM degradation, mitochondrial dysfunction, chondrocyte apoptosis, and inflammatory gene expression, whereas LOXL2 treatment mitigate these effects.

The functional regeneration of the dentin-pulp complex is pivotal for tooth preservation, yet the molecular mechanisms governing odontoblast differentiation remain poorly understood. In the current study, we revealed a distinct NKD1⁺ subpopulation exhibiting secretory odontoblast characteristics, which was specifically induced in dental pulp stem cells (DPSCs) by Wnt3a, but not by Wnt5a or Wnt10a through single-cell transcriptomic profiling. We then found that the NKD1⁺ subpopulation was functional conservation, which were consistently identified in the odontoblast layers of developing tooth germs in both murine and miniature pig models, as well as within the apical open area in human molars. This conserved spatial distribution and co-localization with DSPP strongly indicates that NKD1⁺ cells were active dentin-secreting odontoblasts. Analysis of gene regulatory networks using SCENIC identified MSX1 as a key transcription factor regulating the specification of NKD1⁺ lineage. Mechanistically, Wnt3a orchestrates a tripartite cascade: upregulating NKD1/MSX1 expression, triggering NKD1 membrane detachment, and facilitating direct NKD1-MSX1 interaction to promote MSX1 nuclear translocation. CUT&Tag analysis demonstrated MSX1 occupancy at promoters of odontogenic regulators, establishing its necessity for odontogenic gene activation. Murine pulp exposure models validated that Wnt3a-activated NKD1-MSX1 signaling significantly enhances reparative dentin formation. This study delineates an evolutionarily conserved Wnt3a-NKD1-MSX1 axis that resolves stem cell heterogeneity into functional odontoblast commitment, providing both mechanistic insights into dentin-pulp regeneration and a foundation for targeted regenerative therapies.

Splice quantitative trait loci (sQTL) serve as another critical link between genetic variations and human diseases, besides expression quantitative trait loci (eQTL). Their role in oral squamous cell carcinoma (OSCC) development remains unexplored. We collected surgically resected cancer and adjacent normal epithelial tissue samples from 67 OSCC cases, and extracted RNA for sequencing after quality control. A genome-wide sQTL analysis was performed using the RNA sequencing data from 67 normal oral epithelial tissue samples. We included peripheral blood DNA samples from 1044 patients with OSCC and 3199 healthy controls to conduct a genome-wide association study. Systematic screening of sQTLs associated with OSCC risk identified a sQTL variant—the rs737540-T allele—independent of eQTLs, significantly associated with an increased risk of OSCC (OR = 1.2, P = 6.84 × 10⁻⁴). The rs737540-T allele reduced skipping of EGFR alternative exon 4 by enhancing TAR DNA binding protein (TARDBP) binding to the RNA sequence, leading to increased expression of the longer isoform (EGFR-001) and reduced expression of the truncated isoform (EGFR-004). Compared with EGFR-004, EGFR-001 promoted OSCC cell proliferation by reducing ATP-binding cassette subfamily A member 1 (ABCA1) ubiquitination through lower EGFR phosphorylation. ABCA1 was demonstrated to increase the cholesterol content of the plasma membrane via cholesterol efflux, thus affecting membrane fluidity and vimentin-mediated epithelial–mesenchymal transition. An antisense oligonucleotide targeting rs737540 significantly inhibited OSCC proliferation and reversed membrane cholesterol-induced resistance. This study provides novel insights into how genetic variants regulating alternative splicing contribute to OSCC risk and identifies potential therapeutic targets.

Excessive lighting is integral to dentists’ daily routines but can impair their vision, affecting personal and professional performance. Most studies focus on acute photodamage, neglecting chronic photo-injury from dental lighting and its impact on the blood-retinal barrier homeostasis. An epidemiological survey involving 14,523 individuals showed dentists had 3.6 times higher odds of vision-related issues compared to other occupations (OR=3.639, 95% CI: 3.064–4.323). Subsequently, chronic photodamage models in rats were created to accurately simulate dental working conditions. Using systematic imaging and gene analysis, including OCT, tissue clearing technology and RNA-sequencing, dental lighting was found to disrupted both inner and outer blood-retinal barriers, reduced retinal blood vessels, and promoted perivascular macrophage recruitment. Among them, the number of capillary branches decreased sharply. Moreover, the activation of inflammatory-related pathways such as NF-κB signaling resulted in the damage of vision-related functional structures in the retina. Notably, among three dental light sources, low-intensity halogen caused minimal retinal damage, whereas blue and white LEDs significantly disrupted blood-retinal barrier homeostasis. This study explored the potential mechanism of dental lighting environment inducing the disruption of blood-retinal barrier homeostasis, and provided essential guidance for dental professionals in selecting light sources, which is conducive to reducing the risk of occupational ocular diseases among dentists.

Tooth developmental anomalies are a group of disorders caused by unfavorable factors affecting the tooth development process, resulting in abnormalities in tooth number, structure, and morphology. These anomalies typically manifest during childhood, impairing dental function, maxillofacial development, and facial aesthetics, while also potentially impacting overall physical and mental health. The complex etiology and diverse clinical phenotypes of these anomalies pose significant challenges for prevention, early diagnosis, and treatment. As they usually emerge early in life, long-term management and multidisciplinary collaboration in dental care are essential. However, there is currently a lack of systematic clinical guidelines for the diagnosis and treatment of these conditions, adding to the difficulties in clinical practice. In response to this need, this expert consensus summarizes the classifications, etiology, typical clinical manifestations, and diagnostic criteria of tooth developmental anomalies based on current clinical evidence. It also provides prevention strategies and stage-specific clinical management recommendations to guide clinicians in diagnosis and treatment, promoting early intervention and standardized care for these anomalies.

Copper, predominantly present in bones, plays a crucial role in bone formation. However, when copper homeostasis is disrupted, excessive copper can trigger harmful inflammation and a novel form of cell death known as cuproptosis. The impact of cuproptosis on bone metabolism remains unclear. In this study, we demonstrated that excessive copper acts as an aggravator in osteoclastogenesis and bone resorption. We observed that the expression levels of the copper importer SLC31A1 and dihydrolipoamide S-acetyltransferase (DLAT) were positively correlated with bone loss in both human chronic apical periodontitis (CAP) tissues and mouse CAP models. Untargeted metabolomics analysis and screening of glucose metabolism enzymes revealed that glycogen synthesis was inhibited during cuproptosis. Mechanistically, excessive copper hindered glycogen synthesis via glycogen synthase 1 (GYS1), which limited the availability of glycogenolysis-derived glucose-6-phosphate (G6P) flux into pentose phosphate pathway (PPP), and was unable to yield abundant NADPH to ensure high demand of glutathione (GSH) for macrophage survival. The inhibition of glycogen synthesis intensified cuproptosis and bone-resorption activity. Moreover, excessive copper bound to H3K27me3, which further epigenetically inhibited the gene transcription of GYS1, thereby affecting glycogen synthesis and exacerbating cuproptosis and bone resorption. Furthermore, the disruption of glycogen metabolism intensified cuproptosis and promoted inflammatory bone loss in vivo. Our finding highlighted the complex interplay among copper homeostasis, glycogen metabolism, and the osteo-immune system, suggesting new therapeutic strategies for managing inflammatory bone diseases and other copper accumulation-related conditions through the metabolic reprogramming of cells.

Epidemiological studies have highlighted an association between periodontitis and osteoporosis. However, the mechanism underlining this association remains unclear. Here, we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients, with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria. Using an ovariectomized (OVX) mouse model, we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota. Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism. The tryptophan metabolite indole-3-lactic acid (ILA) directly inhibited osteoclast formation and differentiation. In OVX mice treated with periodontitis salivary microbiota, supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones. In summary, our data demonstrate that periodontitis can affect systemic bone metabolism via the oral–gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with high morbidity and mortality. Globally, about 400 000 people are affected, often with a poor quality of life. Its high mortality is mainly due to its aggressive growth and tendency to spread. Epithelial-mesenchymal transition (EMT) is a central regulatory hub driving tumor cell migration and invasion by enabling changes in cell characteristics. During EMT, epithelial cells gradually take on mesenchymal traits, gaining mobility and spreading more easily. Recent multi-omics studies show that many cancer cells exist in a hybrid or partial-EMT state, which lies between the full epithelial and mesenchymal forms. Cells in this state are especially invasive and metastatic, with high plasticity that promotes tumor progression. This review summarizes the role of partial-EMT in OSCC, with a focus on how it alters the tumor microenvironment (TME), promotes invasion and metastasis, and influences cancer stem cells (CSCs). We also highlight the link between partial-EMT and treatment resistance in OSCC. Based on these insights, we discuss therapeutic strategies targeting partial-EMT to improve outcomes. Targeting partial-EMT may offer promising strategies to enhance treatment effectiveness and improve patient survival and quality of life.

The onset and progression of periodontitis are closely associated with subgingival dysbiosis and excessive localized oxidative stress. While some oral probiotics exhibit certain inhibitory effects on periodontitis-related pathogens, they often struggle to effectively colonize and antagonize these pathogens due to the complex oxidative stress at the site of periodontitis. In this study, we engineer Lactobacillus reuteri with a reactive oxygen species (ROS)-responsive adhesive polymer (phenylboric acid-dopamine-hyaluronic acid) (LR@PDH). In the periodontitis microenvironment, this polymer can consume ROS and then expose the phenolic hydroxyl group of dopamine, promoting the selective adhesion and colonization of Lactobacillus reuteri at the site of inflammation to antagonize pathogens. The results show that, compared to conventional probiotic therapy, inflammation-responsive adhesive Lactobacillus reuteri effectively alleviates local oxidative stress, reduces the abundance of pathogenic bacteria in the subgingival microbiome, and inhibits the progression of periodontitis. Additionally, its good biocompatibility and safety highlight its potential as a therapeutic approach for clinical treatment of periodontitis.

Nanotechnology has provided thousands of novel nano-antimicrobials possessing features uncommon in clinically available antimicrobials. Here, nanocarriers loaded with conventional antimicrobials and responding to environmental changes upon entry into oral biofilms are reviewed. Supra-gingival biofilms are characterized by acidic pH, the presence of bacterial enzymes, and the development of hypoxia in deeper layers. Sub-gingival biofilms are slightly alkaline, with hypoxia occurring over their entire depth. Upon entering biofilms, negatively charged, pH- and/or hypoxia-responsive nanocarriers become positively charged. This charge reversal leads to electrostatic double-layer attraction between positively charged nanocarriers towards negatively charged, water-filled channel walls in biofilms, enhancing their accumulation in a biofilm. Degradation of bacterial enzyme-responsive nanocarriers causes in-biofilm release of antimicrobial cargo, yielding higher local antimicrobial concentrations than can be achieved through their direct, oral administration without harming soft tissues. Enhanced antibiofilm activity after in-biofilm antimicrobial release from biofilm-responsive micelles and liposomes has been demonstrated in vitro towards single-species Streptococcus mutans and Staphylococcus aureus biofilms or in vivo using specific-pathogen-free rodents inoculated with selected pathogens. This preferential antibacterial activity regulated the microbial composition of ex vivo human oral biofilm towards a more healthy microbiome composition. Although clinical confirmation is limited, the potential benefits of stimuli-responsive, antimicrobial-loaded nanocarriers for oral biofilm control and microbiome restoration are worth further investigation towards clinical translation.

Alveolar bone resorption during the socket healing process compromises subsequent restoration outcomes. Recent clinical evidence suggests that dental implant placement can effectively prevent such bone loss, yet the mechanisms remain elusive. In this study, combined multi-dataset screening pinpointed sorting nexin 5 (Snx5) as a potential regulator of mechanotransduction, whose expression was downregulated in early peri-implant bone remodeling zones following implant placement. Functional studies showed that loss of Snx5 abolished the additional osteogenic enhancement normally induced by mechanical stimulation. In vivo, Snx5 deficiency disrupted the mechanosensitive activation of LepR⁺ MSCs and compromised implant-induced osteogenesis. Mechanistically, Snx5 facilitates the recycling of phosphorylated EGFR (p-EGFR) back to the plasma membrane to sustain EGFR signaling. Loss of Snx5 redirects EGFR trafficking toward late endosomes and lysosomal degradation, thereby weakening its signaling. These findings uncover a previously unrecognized role for Snx5 in mediating the osteogenic fate of peri-implant BMSCs in response to mechanical cues, expanding the functional repertoire of the Snx family. Collectively, these findings highlight Snx5 as a novel regulator of mechanosensitive bone remodeling and suggest that its downregulation may contribute to peri-implant bone adaptation. This study provides new insights into how the mechanical microenvironment regulates bone repair and highlights Snx5 as a promising molecular target for modulating skeletal mechano-responsiveness in clinical bone regeneration.