OBJECTIVE:To enhance the stability of resin-dentin bonding interface, this study aimed to develop a multifunctional SACP-PEP/TMC film made up of silanized amorphous calcium phosphate (SACP), amelogenin-derived peptide PEP-QP5, and trimethyl chitosan (TMC) integrating biomimetic remineralization, collagenase suppression, and bacterial inhibition effect, and explore the film-based application under both etch-and-rinse and self-etch strategies. METHODS:The SACP-PEP/TMC film was fabricated by solution casting for the evaluation of its morphology, swelling, release behavior, and cytotoxicity. Recombinant collagen and demineralized dentin models were constructed to evaluate its biomimetic remineralization capacity. Live/dead staining, scanning electron microscopy were used to assess the bacterial inhibition effect against Streptococcus mutans. Micro-shear bond strength (μSBS), microleakage, and in-situ zymography were used to evaluate the resin-dentin bonding performance and durability, which were further evaluated in vivo using a rat model combined with Micro-CT and histological analyses. RESULTS:A homogeneous SACP-PEP/TMC film with a thickness of approximately 4-5 μm was successfully fabricated. The film rapidly swelled and dispersed within the adhesive and enabled sustained release of Ca2 +, PO₄3- and PEP-QP5 for up to 3 months after light curing. It effectively induced biomimetic mineralization while significantly inhibiting Streptococcus mutans. Improved μSBS, reduced interfacial microleakage, and suppressed endogenous matrix metalloproteinase activity were observed, accompanied by significantly increased immediate and long-term resin-dentin bond strength in vitro and in vivo. SIGNIFICANCE:The multifunctional SACP-PEP/TMC film improved resin-dentin bonding durability significantly by integrating biomimetic remineralization, collagenase suppression, and bacterial inhibition effect, suggesting the film-based application form a promising strategy for developing durable dentin bonding materials.

The acidic tumor microenvironment (TME) plays a critical role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC), which induces immunosuppression and allows tumor cells to evade immune surveillance. Peptide-based therapy can stimulate immune cells to elicit immune responses and gains increasing attention in the research field of tumor immunotherapy. In this study, we used a cationic amphiphilic peptide, LF-2, derived from the innate defense protein lactoferrin. This peptide with an alpha-helix structure could induce apoptosis, autophagy, and immunogenic cell death (ICD) in OSCC cell lines, demonstrating potent antitumor effects. Inspired by the feedback regulation mechanisms of biological systems, we applied CaCO3 nanoparticles (CCN) encapsulating LF-2 to construct self-adaptive LF-2@CCN nanoparticles. Acting as a pHresponsive switch, CCN could "sense" the acidic TME and exhibit efficient proton scavenging capacity, thereby alleviating immune suppression and enabling the rapid release of LF-2 to inhibit OSCC progression. Furthermore, LF-2@CCN nanoparticles could dynamically adapt to fluctuations in the acidity of the TME and significantly reduce the release of LF-2 at pH 7.4, thereby minimizing potential toxicity to normal tissues. In the mouse allograft tumor model, reversal of the acidic TME was observed, accompanied by ICD in tumor cells, maturation of dendritic cells, and the infiltration of cytotoxic T cells, demonstrating that this therapeutic strategy effectively enhanced systemic anti-tumor adaptive immune responses. Therefore, as a novel self-adaptive nanoagent with minimal compositional complexity, LF-2@CCN seems promising for OSCC immunotherapy.

Dental pulp stem cells (DPSCs) have garnered significant attention in regenerative dental medicine due to their robust self-renewal capacity and multi-lineage differentiation potential. Their ability to undergo odontogenic differentiation and facilitate dentin matrix formation is fundamental to the regeneration of a structural and functional dental pulp-dentin complex. Recent advances in understanding the cellular mechanical microenvironment have revealed that DPSCs can precisely perceive mechanical cues—such as matrix stiffness, elastic modulus, and fluid shear stress—within both native odontogenic niches and engineered biomimetic microenvironments. These mechanical signals are transduced into intracellular biochemical responses through mechanotransduction pathways, thereby directing lineage commitment toward odontogenic, angiogenic, and other fates, and ultimately influencing tissue regeneration outcomes. Consequently, by modulating static mechanical properties and dynamic mechanical loading within the DPSC microenvironment, specific mechanical signals can be precisely delivered to guide directed differentiation and promote organized regeneration of the pulp-dentin complex. This review summarizes the mechanisms of mechanotransduction and their roles in promoting DPSC differentiation, highlights recent progress in the design of biomaterials for pulp-dentin complex regeneration based on mechanical signaling, offers new perspectives for the development of bioactive materials, and discusses current challenges and future directions in the field.

Dentin hypersensitivity (DH) originates from collagen exposure and dentinal tubules (DTs) patency caused by mechanical abrasion or demineralization. For an effective long-term therapeutic desensitizing agent, the ability to achieve deep tubular occlusion, stable remineralization, and satisfactory biocompatibility simultaneously is essential. In this study, we designed a novel α-hairpin peptide, TKH, engineered by incorporating a flexible GKG linker into an α-helical template, and provide an analysis of its liquid-liquid phase separation (LLPS) and self-assembly properties. TKH effectively stabilized amorphous calcium phosphate and facilitated intrafibrillar mineralization within collagen fibrils. In vitro and in vivo remineralization studies combined with molecular dynamics (MD) simulations demonstrated that TKH promoted the peptide self-assembly through LLPS, hydroxyapatite (HA) adsorption, and amorphous calcium phosphate (ACP) stabilization, ultimately achieving intrafibrillar and extrafibrillar mineralization to seal DTs, alongside excellent biosafety. These findings highlight the potential of TKH as a promising peptide-based biomaterial for dentin remineralization and the treatment of dentin hypersensitivity.

Oral squamous cell carcinoma (OSCC) is a biologically heterogeneous malignancy with poor clinical outcomes. Hypoxia and lipid metabolic reprogramming are important drivers of OSCC progression and treatment adaptation, and these processes are biologically interconnected. However, prognostic studies integrating hypoxia- and lipid metabolism-related features in OSCC remain limited. Here, transcriptomic data from TCGA-HNSC-OSCC were integrated with curated hypoxia- and lipid metabolism-related genes to identify candidate genes, construct a prognostic signature, and characterize its biological relevance through enrichment analysis, immune profiling, single-cell RNA-sequencing analysis, and RT-qPCR validation. A four-gene signature consisting of STC2, CAV1, ACADL, and PLA2G2D showed stable prognostic performance in the TCGA-HNSC-OSCC cohort and the external validation cohort GSE41613. The risk signature remained significantly associated with overall survival after adjustment for clinicopathological factors and retained prognostic discrimination across stage- and nodal status-defined subgroups. The high- and low-risk groups displayed distinct pathway, immune, mutational, and predicted drug sensitivity features. Notably, PLA2G2D showed the strongest association with differential immune infiltration, whereas single-cell analysis identified endothelial cells as a major CAV1-enriched population with active intercellular communication and dynamic state transitions. These findings define a hypoxia- and lipid metabolism-related prognostic signature and support its relevance to immune remodeling and endothelial cell context in OSCC.

The chronic and refractory infected wounds of diabetes are primarily attributed to the persistent bacterial infection and the inhibition of wound healing caused by hypoxia. Hydrogel with intelligent drug delivery systems hold significant potential in the treatment of diabetic wounds. Herein, we have developed an glucose-responsive intelligent hydrogel named as CF-CPGaMPN, which incorporates polyvinylpyrrolidone-coated calcium peroxide (PVP@CaO2) nanoparticles, catalase, and gallium-polyphenol (GaMPN) nanoparticles. The borate ester bonds in the CF-CPGaMPN hydrogel break under high glucose conditions, releasing GaMPN nanoparticles, thereby achieving glucose-triggered on-demand drug release. The CF-CPGaMPN hydrogel not only inhibits various microorganisms but also continuously releases oxygen, thereby promoting the healing of diabetic infection wounds. Furthermore, the multicellular ecosystem surrounding the CF-CPGaMPN hydrogel is also explored, and the diverse cellular heterogeneity is analyzed by single-cell RNA sequencing, highlighting the critical roles of Neutrophils, Fibroblasts, and Epidermal cells in diabetic infected wound. In addition, CF-CPGaMPN hydrogel inhibits the Neutrophil extracellular trap (NET) formation and alleviates the cellular hypoxic environment to improve diabetic wound healing. In conclusion, the CF-CPGaMPN hydrogel not only provides a promising drug release strategy for the healing of diabetic infected wounds, but also contributes to the rational design of customized hydrogels for biomedical use targeting different cellular functions.

Dental caries has been one of the most prevalent diseases globally over the last few decades, threatening human oral and general health. The most critical aspect in caries control is to inhibit the dominant cariogenic bacteria Streptococcus mutans (S. mutans). Sulforaphane (SFN), a compound found in a wide range of cruciferous plants, has demonstrated bacteriostatic activities against various pathogenic bacteria. The objective of the present study was to investigate the effects of SFN on S. mutans though both in vitro and in vivo experiment. The minimum inhibitory concentration (MIC) against S. mutans was determined at 256 μg/mL. The growth of S. mutans and the biofilm formation were inhibited by SFN in a dose-dependent manner through suppressing the synthesis of extracellular polysaccharide (EPS) and acid production, as well as decreasing the acid tolerance. Meanwhile, SFN significantly weakened the cariogenic properties of S. mutans at sub-inhibitory concentrations, which were further illustrated by quantitative real-time PCR (qRT-PCR). Moreover, SFN were found to inhibit quorum sensing (QS) by downregulate comCDE system in S. mutans. Further investigation using a rat caries model displayed a prominent caries control in the SFN-treated group with no observed toxicity. The notable results demonstrated in this study highlight the potential of SFN as a natural substitute for current anti-caries agents, while also providing valuable insights into the potential applications of SFN in caries control.

Human dental pulp stem cells (hDPSCs) exhibit amazing therapeutic abilities in a variety of diseases due to their remarkable self-renewal capacity and multi-differentiation potential. However, their therapeutic potential could be weakened by various factors such as oxidative stress in cell survival microenvironment In Vivo. Here, we explored the protective effect and mechanism of melatonin (Mel) on hDPSCs transplanted in a type 1 diabetes mellitus (T1DM) rat model. Nicotinamide adenine dinucleotide (NAD+) metabolism and mitochondrial function were remarkably impaired in T1DM rats caused by oxidative stress, while the combination of Mel and post-hDPSCs transplantation could rebalance NAD+ homeostasis through regulating NAMPT-NAD+-SIRT1 axis. Furthermore, Mel significantly reduced intracellular and mitochondrial reactive oxygen species, and alleviated cell senescence and apoptosis of hDPSCs exposed to hydrogen peroxide through ameliorating NAD+ depletion and mitochondrial dysfunction. The protective role of Mel could be extremely essential to stem cells in tissue engineering and regenerative medicine.

Intrafibrillar mineralization, essential for dentin restoration, necessitates precise coordination of microenvironmental factors. Current research on peptide-mediated collagen mineralization often lacks a comprehensive exploration of multifunctionality, focusing instead on isolated aspects such as self-assembly, nucleation ability, or collagen binding. Bacterial S-layer proteins, with their intrinsic self-assembly, collagen-binding features, and ion-capturing functions, offer a blueprint for integrating multifunctionality. Building on these features, we engineer a multifunctional self-assembly peptide (SlpB-21) that integrates essential capabilities to promote collagen mineralization. This innovative peptide synergistically enhances interactions with Ca2+ and type I collagen, driving the biomimetic process of intrafibrillar mineralization, which is critical for dentin restoration. Functioning as an "intermediate gripper", SlpB-21 efficiently assembles onto demineralized dentin collagen fibrils and directs ordered mineral deposition. Utilizing molecular dynamics simulations and stochastic optical reconstruction microscopy, the research systematically investigates the peptide's self-assembly, its mechanisms of interaction with collagen fibrils and Ca2+, and its role in mediating intrafibrillar mineralization. In vitro and in vivo experiments demonstrate the potential of SlpB-21 for biomimetic dentin repair. This study highlights SlpB-21 as a pioneering material for dentin restoration, introducing a novel strategy for biomimetic repair and offering promising avenues for treating early dentin caries.

Extensive research has demonstrated that enamel matrix derivative (EMD) facilitates periodontal tissue regeneration, enabling the genuine regeneration of cementum, periodontal ligament, and alveolar bone. Its clinical formulation, Emdogain, is currently employed in the treatment of alveolar bone defects resulting from periodontitis, as well as in dental implantation and tooth replantation procedures. This review aims to synthesize recent findings on the application of EMD in periodontology, with a particular emphasis on its efficacy in addressing alveolar bone defects, peri-implantitis, and related conditions. Furthermore, this review examines the influence of EMD on the proliferation and differentiation of periodontal ligament stem cells, bone marrow stem cells, osteoblasts, and fibroblasts. It also assesses the secretion of various growth factors, including transforming growth factor-β1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), collagen type 1 (COL-1), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN). Additionally, the review seeks to identify the optimal concentration for EMD application. Collectively, the studies reviewed herein suggest that EMD significantly enhances the proliferation and differentiation of relevant cellular components. The optimal concentration of EMD varies by environment and cell type. In minimally invasive periodontal surgery for intrabony defects, EMD enhances periodontal health, gingival recession coverage, and bone filling. It also benefits open-flap debridement and non-surgical treatments. However, EMD offers no extra benefits for Class II furcation defects. In treating gingival recession with coronally advanced flap (CAF) and subepithelial connective tissue graft (SCTG), EMD significantly boosts root coverage, but not with the modified coronally advanced tunnel (MCAT) technique or the semilunar coronally advanced flap. EMD's anti-inflammatory and immunomodulatory properties reduce inflammation around implants. This review indicates that EMD shows potential for periodontal regeneration, but more randomized clinical trials are necessary to assess its effectiveness.

Dental caries at varying stages exhibits diverse microstructural damage in dental hard tissues and complex restorative needs. A key challenge lies in developing therapeutic materials capable of reversing multitype damage, including inorganic mineral loss, organic collagen demineralization, and pulpal irritation, while anchoring to differentiated enamel-dentin-pulp interfaces for multitissue repair. Herein, a simplified "all-in-one" biomimetic strategy inspired by the biomineralization microenvironment during tooth development is proposed, constructing QP5/ACP@MSN (MQA) nanounit for caries repair. This nanounit incorporates two pivotal modulators in biomineralization: the amelogenin-derived peptide QP5 as a thread-like regulator and amorphous calcium phosphate (ACP) as a mineral source. Through the orchestrated coordination of QP5 and ACP, MQA achieves efficient anchoring to residual hydroxyapatite in carious tissues. In vitro, it promotes biomineralization of enamel and dentin and odontogenic differentiation of pulp cells. In vivo, it demonstrates prevention-restoration-regeneration effects under highly cariogenic environment in a rat caries model. As a functional unit, MQA provides mineralization guidance, mineral supply, and pulp cell activation. As a structural unit, MQA self-assembles onto substrates to provide versatile applications for various intraoral tissue interfaces. This study introduces a unified solution for multitype and multitissue caries repair, while offering strategic inspiration for repairing lesions with complex tissue damage.

Dental caries is the most prevalent infectious disease affecting oral health, leading to the destruction of tooth hard tissues and dental pulp inflammation. The dentin-pulp complex, as the biological core of the tooth, can generate reparative dentin to protect the dental pulp from infection progression. However, untreated carious lesions chronically disrupt the structural integrity and reparative capacity of the dentin-pulp complex, thereby significantly compromising pulp vitality as deep caries progresses. In this study, a two-stepped pH-responsive peptide microsphere/carboxymethyl chitosan complex (PM/CS) was designed to offer comprehensive protection for the inflamed dentin-pulp complex. PM/CS has a three-dimensional network structure, and it constructs an intelligent drug delivery system by integrating TVH-19 self-assembled peptide microspheres that we developed earlier into carboxymethyl chitosan. This complex not only exhibited pH-controlled release characteristics, but also showed antibacterial properties against Streptococcus mutans and a mineralization-promoting effect on human dental pulp cells (hDPCs). PM/CS exerted acute anti-inflammatory effects on early pulpal lesions in rats, while longitudinal studies revealed its remarkable capacity to induce tertiary dentinogenesis, indicating therapeutic efficacy through biological modulation. This study provides a potential pulp capping complex material for the restoration treatment of the dentin-pulp complex under the influence of deep caries.

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The escalating growth and global dissemination of antimicrobial resistance underscore the urgency for the discovery of innovative antimicrobial agents. Antibacterial Peptides (AMPs) have emerged as promising candidates, distinctly outperforming conventional antibiotics due to their mitigated propensity for resistance development, expansive antibiofilm activity, and capacity to favorably modulate host immune responses. Consequently, AMPs have garnered significant attention in medical research circles and are anticipated to serve as novel therapeutic alternatives in combating microbial infections, particularly those involving drug-resistant bacteria, thereby inaugurating a novel paradigm in treatment strategies. This comprehensive review delves into the intricate structural and physicochemical attributes of AMPs, providing a concise overview. It further examines the advancements and anticipated clinical trajectories of AMP research, with a pivotal focus on elucidating their antimicrobial mechanisms and the intricate interplay between structure and activity. The aim of this review is twofold: firstly, to enhance the scientific community's comprehension of the antimicrobial mechanisms and Structure-Activity Relationships (SAR) across all classes of AMPs; secondly, to address existing research gaps in the SAR of AMPs, thereby laying a solid foundation for future research endeavors and facilitating the development of these promising therapeutic agents.

Dental caries is a multifactorial disease primarily mediated by biofilm formation, resulting in a net loss of mineral content and degradation of organic matrix in dental hard tissues. Caries lesions of varying depths can result in demineralization of the superficial enamel, the formation of deep cavities extending into the dentin, and even pulp infection. Electrospun nanofibers (ESNs) exhibit an expansive specific surface area and a porous structure, closely mimicking the unique architecture of the natural extracellular matrix (ECM). This unique topography caters to the transport of small molecules and facilitates localized therapeutic drug delivery, offering great potential in regulating cell behavior, and thereby attracting interest in ESNs' applications in the treatment of caries lesions and the reconditioning of the affected dental tissues. Thus, this review aims to consolidate the recent developments in ESNs' applications for caries lesions. This review begins with an introduction to the electrospinning technique and provides a comprehensive overview of the biological properties and modification methods of ESNs, followed by an introduction outlining the basic pathological processes, classification and treatment requirements of caries lesions. Finally, the review offers a detailed examination of the research progress on the ESNs' application in caries lesions and concludes by addressing the limitations.

Dental caries, one of the most prevalent infectious diseases, is the primary contributor to the early loss of natural teeth and is a significant public health issue. Known as the tooth's bioactive core, the dentin-pulp complex (DPCX) comprises tightly connected hard and soft tissues that not only serve as a biological barrier for the inner tooth tissue but also produce reparative dentin following mild disruptions. While efforts to preserve DPCX are numerous, most strategies focus on temporary antibacterial measures, inflammation reduction, or tissue regeneration, lacking a comprehensive, long-lasting solution. In this study, TVH-19, an autoadaptive peptide mimicking the pH- and ion-responsive capacity of amelogenin, was designed to exert multifaceted preservation of DPCX, providing a comprehensive strategy for preserving vital pulp. Leveraging its unique amphiphilicity-related cell penetration and ion/pH-responsive self-assembly properties, TVH-19 outperforms conventional pulp preservation materials by being capable of rapid cell penetration, minimizing diffused side effects, providing environment-responsive self-assembly/disassembly for balanced long-term antibacterial and cell protection, and facilitating the formation of lysosomal-escaping intracellular aggregates for the continuous activation of PDGFRα+ dental pulp stem cells.

Bioactive ceramics, primarily consisting of bioactive glasses, glass-ceramics, calcium orthophosphate ceramics, calcium silicate ceramics and calcium carbonate ceramics, have received great attention in the past decades given their biocompatible nature and excellent bioactivity in stimulating cell proliferation, differentiation and tissue regeneration. Recent studies have tried to combine bioactive ceramics with bioactive ions, polymers, bioactive proteins and other chemicals to improve their mechanical and biological properties, thus rendering them more valid in tissue engineering scaffolds. This review presents the beneficial properties and potential applications of bioactive ceramic-based materials in dentistry, particularly in the repair and regeneration of dental hard tissue, pulp-dentin complex, periodontal tissue and bone tissue. Moreover, greater insights into the mechanisms of bioactive ceramics and the development of ceramic-based materials are provided.

Dental caries, a chronic disease characterized by tooth decay, occupies the second position in terms of disease burden and is primarily caused by cariogenic bacteria, especially Streptococcus mutans, because of its acidogenic, aciduric, and biofilm-forming capabilities. Developing novel targeted anti-virulence agents is always a focal point in caries control to overcome the limitations of conventional anti-virulence agents. The current study represents an up-to-date review of in silico approaches of drug design against dental caries, which have emerged more and more powerful complementary to biochemical attempts. Firstly, we categorize the in silico approaches into computer-aided drug design (CADD) and AI-assisted drug design (AIDD) and highlight the specific methods and models they contain respectively. Subsequently, we detail the design of anti-virulence drugs targeting single or multiple cariogenic virulence targets of S. mutans, such as glucosyltransferases (Gtfs), antigen I/II (AgI/II), sortase A (SrtA), the VicRK signal transduction system and superoxide dismutases (SODs). Finally, we outline the current opportunities and challenges encountered in this field to aid future endeavors and applications of CADD and AIDD in anti-virulence drug design.

Severe burn injuries are among the most traumatic and physically debilitating conditions, impacting nearly every organ system and resulting in considerable morbidity and mortality. Given their complexity and the involvement of multiple organs, various animal models have been created to replicate different facets of burn injury. Methods used to produce burned surfaces vary among experimental animal models. This study describes a simple, cost-effective, and user-friendly mouse burn model for creating consistent full-thickness burns using a digital heating device. The tip of this device was applied to the dorsum of mice for 10 s at 97 °C to establish a chessboard-like burn and examine wound healing under the treatment of an experimental dressing. Skin samples were collected for histological analysis, including Hematoxylin and Eosin (H&E) staining and Masson's staining. Wound healing was assessed through analysis of the wound area and microscopic examination of inflammatory infiltration, re-epithelialization, and granulation tissue formation. The mouse burn injury model can serve as a fundamental tool in studying the pathophysiology of thermal injuries and evaluating therapeutic interventions.

Objective: This study aims to synthesize novel chitosan nanoparticles loaded with an amelogenin-derived peptide QP5 (TMC-QP5/NPs), investigate their remineralization capability and inhibitory effects on endogenous matrix metalloproteinases (MMPs), and evaluate the dentin bonding properties of remineralized dentin regulated by TMC-QP5/NPs. Methods: TMC-QP5/NPs were prepared by ionic crosslinking method and characterized by dynamic light scattering method, scanning electron microscopy, transmission electron microscope, atomic force microscope, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The encapsulation and loading efficiency of TMC-QP5/NPs and the release of QP5 were examined. To evaluate the remineralization capability of TMC-QP5/NPs, the mechanical properties, and the changes in structure and composition of differently conditioned dentin were characterized. The MMPs inhibitory effects of TMC-QP5/NPs were explored by MMP Activity Assay and in-situ zymography. The dentin bonding performance was detected by interfacial microleakage and microshear bond strength (mu SBS). Results: TMC-QP5/NPs were successfully synthesized, with uniform size, good stability and biosafety. The encapsulation and loading efficiency of TMC-QP5/NPs was respectively 69.63 +/- 2.22% and 13.21 +/- 0.73%, with a sustained release of QP5. TMC-QP5/NPs could induce mineral deposits on demineralized collagen fibers and partial occlusion of dentin tubules, and recover the surface microhardness of dentin, showing better remineralization effects than QP5. Besides, TMC-QP5/NPs significantly inhibited the endogenous MMPs activity. The remineralized dentin induced by TMC-QP5/NPs exhibited less interfacial microleakage and higher mu SBS, greatly improved dentin bonding. Significance: This novel peptide-loaded chitosan nanoparticles improved resin-dentin bonding by promoting dentin remineralization and inactivating MMPs, suggesting a promising strategy for optimizing dentin adhesive restorations.