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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational biology.Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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A simplified noncryogenic strategy to transport mesenchymal stem cells: Potential applications in cell therapy and regenerative medicine

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Genes & Diseases 2024年第3期11卷 26-29页

作者： Xiangyu Dong Yannian Gou Meichun Guo Jiamin Zhong Aohua Li Ailing Hao Wei Zeng Rex C.Haydon Hue H.Luu Russell R.Reid Tongchuan He Yan Xu Jiaming Fan Ministry of Education Key Laboratory of Diagnostic Medicine And Department of Clinical BiochemistryCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Laboratory of craniofacial Suture biology.and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Institute of Sports Medicine Beijing Key Laboratory of Sports InjuriesPeking University Third HospitalBejing 100191China

With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport *** for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.

关键词： transport methods simplified

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Prospective cohort study on facial profile changes in infants with Robin sequence and healthy controls

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World Journal of Pediatrics 2024年第6期20卷 581-589页

作者： Cornelia Wiechers Julian Sowula Karen Kreutzer Christoph E.Schwarz Christina Weismann Michael Krimmel Christian F.Poets Bernd Koos Department of Neonatology Tuebingen University HospitalCalwerstrasse 772076 TuebingenGermany center for Cleft Lip Palate and Craniofacial MalformationsTuebingen University HospitalTuebingenGermany Department of Orthodontics Tuebingen University HospitalTuebingenGermany Department of Oral and Maxillofacial Surgery Tuebingen University HospitalTuebingenGermany

Background Various conservative and surgical approaches exist to treat Robin sequence(RS),but their effects on facial profile and mandibular catch-up growth are unclear.A functional treatment concept,used in our centre for 25 years,includes an individualized palatal plate with a velo-pharyngeal extension and intensive feeding *** We performed a prospective study to objectively describe facial profiles in infants with RS treated with the above *** with isolated RS were admitted to our tertiary perinatal and national referral centre for craniofacial malformations between May 2018 and Nov *** with RS received 3D-photographs during clinically indicated *** controls were recruited from Dec 2018 to Sep 2019 and received 3D-photographs every 3 *** digitally measured jaw index(JI),defined as alveolar overjet(O)x maxillary arch(U)/mandibular arch(L),and the soft tissue reference points A’-point,Nasion’,B’-point angle(ANB’),describing the relative position of maxilla to mandible,were *** mixed models were used to examine time trajectories in JI and ANB’.Results A total of 2073D images,obtained in 19 infants with RS and 32 controls,were *** and ANB’decreased over time in both groups[for JI−0.18(95%CI−0.25 to−0.10);for ANB’:−0.40°per month[(95%CI−0.48 to−0.32)]]but remained lower in controls[for JI−2.5(95%CI−3.2 to−1.8);for ANB’-1.7°(95%CI−2.4 to−1.0)].Also,the ANB’model showed a significant effect of the interaction term diagnosis x *** Based on longitudinal 3D images,we describe changes in objective parameters of facial profile in infants with and without RS during the first year of *** findings indicate catch-up growth in infants treated for RS.

关键词： Infant Mandibular catch-up growth Pre-epiglottic Baton Plate Robin sequence Three-dimensional photography

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Unveiling the oral-gut connection:chronic apical periodontitis accelerates atherosclerosis via gut microbiota dysbiosis and altered metabolites in apoE^(−/−)Mice on a high-fat diet

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International Journal of Oral Science 2024年第3期16卷 515-527页

作者： Guowu Gan Shihan Lin Yufang Luo Yu Zeng Beibei Lu Ren Zhang Shuai Chen Huaxiang Lei Zhiyu Cai Xiaojing Huang Fujian Key Laboratory of Oral Diseases&Fujian Provincial Engineering Research center of Oral Biomaterial&Stomatology Key Laboratory of Fujian College and University School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Institute of Stomatology&Research center of Dental and craniofacial Implants School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Stomatology Fujian Medical University Union HospitalFuzhouChina

The aim of this study was to explore the impact of chronic apical periodontitis(CAP)on atherosclerosis in apoE^(−/−)mice fed high-fat diet(HFD).This investigation focused on the gut microbiota,metabolites,and intestinal barrier function to uncover potential links between oral health and cardiovascular disease(CVD).In this study,CAP was shown to exacerbate atherosclerosis in HFD-fed apoE^(−/−)mice,as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining.16S rRNA sequencing revealed significant alterations in the gut microbiota,with harmful bacterial species thriving while beneficial species *** profiling indicated disruptions in lipid metabolism and primary bile acid synthesis,leading to elevated levels of taurochenodeoxycholic acid(TCDCA),taurocholic acid(TCA),and tauroursodeoxycholic acid(TDCA).These metabolic shifts may contribute to atherosclerosis ***,impaired intestinal barrier function,characterized by reduced mucin expression and disrupted tight junction proteins,was *** increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions,highlighting the importance of the intestinal barrier in cardiovascular *** conclusion,this research underscores the intricate interplay among oral health,gut microbiota composition,metabolite profiles,and CVD *** findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues,as well as the need for further investigations into the intricate mechanisms linking oral health,gut microbiota,and metabolic pathways in CVD development.

关键词： atherosclerosis metabolism impaired

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz Jeffrey Hong Lily Song William Wagstaff Rex C.Haydon Hue H.Luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He Lewis L.Shi Chicago Medical School Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA Laboratory of craniofacial biology.and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and *** Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical *** of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling *** crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ ***-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic *** complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic ***,both stimulatory and inhibitory treatments come with potential risks that need to be *** review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt *** thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+*** description involved each of its components and their involvement in other cellular ***,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

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The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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Genes & Diseases 2024年第3期11卷 155-187页

作者： Michael Yu Kevin Qin Jiaming Fan Guozhi Zhao Piao Zhao Wei Zeng Connie Chen Annie Wang Yonghui Wang jiamin Zhong Yi Zhu William Wagstaff Rex C.Haydon Hue H.Luu Sherwin Ho Michael J.Lee Jason Strelzow Russell R.Reid Tong-Chuan He School of Medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopedic Surgery The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China Department of Orthopaedic Surgery Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of craniofacial Suture biology.and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China

The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across *** proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling *** behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling *** signaling has emerged as an important factor in stem cell biology.and is known to affect the self-renewal of stem cells in various *** includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem *** signaling has also been implicated in tumor cells that exhibit stem cell-like *** signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone *** surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including *** of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and ***,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt *** with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

关键词： β-Catenin Cancer Canonical Wnt Disease Non-canonical Wnt Stem cells Targeted therapy Wnt signaling

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ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds

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Regenerative Biomaterials 2024年第1期3卷 119-131页

作者： Bowen Qiao Jiaxin Wang Lipeng Qiao Aziz Maleki Yongping Liang Baolin Guo Key Laboratory of Shaanxi Province for craniofacial Precision Medicine Research College of StomatologyXi’an Jiaotong UniversityXi’an 710049China State Key Laboratory for Mechanical Behavior of Materials Frontier Institute of Science and TechnologyXi’an Jiaotong UniversityXi’an 710049China Zanjan Pharmaceutical Nanotechnology Research center(ZPNRC) Zanjan 45139-56184Iran Department of Orthopaedics The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061People’s Republic of China

For the treatment of MRSA-infected wounds,the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs is a promising *** this study,ROS-responsive HA-PBA/PVA(HPA)hydrogel was prepared by phenylborate ester bond cross-linking between hyaluronic acid-grafted 3-amino phenylboronic acid(HA-PBA)and polyvinyl alcohol(PVA)to achieve spatiotemporally controlled release of two kinds of drug to treat MRSA-infected *** hydrophilic antibiotic moxifloxacin(M)was directly loaded in the *** hydrophobic curcumin(Cur)with anti-inflammatory function was first mixed with Pluronic F127(PF)to form Cur-encapsulated PF micelles(Cur-PF),and then loaded into the HPA *** to the different hydrophilic and hydrophobic nature of moxifloxacin and Cur and their different existing forms in the HPA hydrogel,the final HPA/M&Cur-PF hydrogel can achieve different spatiotemporally sequential delivery of the two *** addition,the swelling,degradation,self-healing,antibacterial,anti-inflammatory,antioxidant property,and biocompatibility of hydrogels were ***,in the MRSA-infected mouse skin wound,the hydrogel-treated group showed faster wound closure,less inflammation and more collagen *** experiments further confirmed that the hydrogel promoted better repair by reducing inflammation(TNF-a)and promoting vascular(VEGF)*** conclusion,this HPA/M&CurPF hydrogel that can spatiotemporally sequential deliver antibacterial and anti-inflammatory drugs showed great potential for the repair of MRSA-infected skin wounds.

关键词： MRSA-infected wounds spatiotemporally sequential delivery antibacterial anti-inflammatory

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Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

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Journal of Genetics and Genomics 2024年第2期51卷 222-229页

作者： Wenbin Huang Shiying Zhang Jiuxiang Lin Yi Ding Nan Jiang Jieni Zhang Huaxiang Zhao Feng Chen Department of Orthodontics Peking University School and Hospital of StomatologyBeijing100081China Key Laboratory of Shaanxi Province for craniofacial Precision Medicine Research College of StomatologyXi’an Jiaotong UniversityXi’anShaanxi710004China Guangdong Provincial High-level Clinical Key Specialty Guangdong Province Engineering Research Center of Oral Disease Diagnosis and TreatmentDepartment of OrthodonticsStomatological CenterPeking University Shenzhen HospitalShenzhen Peking University-The Hong Kong University of Science and Technology Medical CenterShenzhenGuangdong 518036China Department of Physiology and Pathophysiology School of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710049China National center for Stomatology National Clinical Research Center for Oral DiseasesNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory for Digital StomatologyResearch Center of Engineering and Technology for Computerized Dentistry Ministry of HealthNMPA Key Laboratory for Dental MaterialsBeijing100101China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081China

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

关键词： Or ofacial clefts FLNB Loss-of-function mutati on Cleft palate Filamin B Actin flannent Knockout mouse

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Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects

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International Journal of Oral Science 2024年第3期16卷 539-552页

作者： Fen Liu Bofeng Zhu Ying An Zhifei Zhou Peiying Xiong Xuan Li Yang Mi Tongqiang He Faming Chen Buling Wu Shenzhen Stomatology Hospital(Pingshan) Southern Medical UniversityShenzhenChina Key Laboratory of Shaanxi Province for craniofacial Precision Medicine Research Laboratory Center of StomatologyDepartment of Paediatric DentistryCollege of StomatologyXi’an Jiaotong UniversityXi’anChina State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi International Joint Research Center for Oral DiseasesDepartment of PeriodontologySchool of StomatologyThe Fourth Military Medical UniversityXi’anChina Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification School of Forensic MedicineSouthern Medical UniversityGuangzhouChina Microbiome Medicine center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina Department of Stomatology General Hospital of Tibetan Military CommandLhasaChina Department of Stomatology center Shenzhen HospitalSouthern Medical UniversityShenzhenChina Department of Obstetrics Northwest Women’s and Children’s HospitalXi’anChina

Periodontitis is a critical risk factor for the occurrence and development of *** gingivalis may participate in insulin resistance(IR)caused by periodontal inflammation,but the functional role and specific mechanisms of *** in IR remain *** the present study,clinical samples were analysed to determine the statistical correlation between *** and IR *** culturing of hepatocytes,myocytes,and adipocytes,and feeding mice *** orally,the functional correlation between *** and IR occurrence was further studied both in vitro and in *** data suggested that the amount of *** isolated was correlated with the Homeostatic Model Assessment for IR *** vitro studies suggested that coculture with *** decreased glucose uptake and insulin receptor(INSR)protein expression in hepatocytes,myocytes,and *** fed *** tended to undergo *** was detectable in the liver,skeletal muscle,and adipose tissue of experimental *** distribution sites of gingipain coincided with the downregulation of *** proteolysed the functional insulin-binding region of *** with *** significantly decreased the INSR–insulin binding *** out gingipain from *** alleviated the negative effects of *** on IR in *** together,these findings indicate that distantly migrated *** may directly proteolytically degrade INSR through gingipain,thereby leading to *** results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

关键词： gingivalis inflammation resistance

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Bioinspired mineral-in-shell nanoarchitectonics:Functional empowerment of mineral precursors for guiding intradentinal mineralization

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Nano Research 2024年第5期17卷 4338-4349页

作者： Xiaoran Zheng Yang Liu Mingjing Li Yuyan Li Wanshan Gao Rongmin Qiu Jiaqi Xing Jiaojiao Yang Yantao Chen Xinyuan Xu Mingming Ding Jun Luo Jianshu Li College of Polymer Science and Engineering State Key Laboratory of Polymer Materials EngineeringSichuan UniversityChengdu 610065China College of Stomatology Hospital of Stomatology Guangxi Medical UniversityGuangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and ReconstructionGuangxi Clinical Research Center for Craniofacial DeformityGuangxi Key Laboratory of Oral and Maxillofacial Surgery Disease TreatmentGuangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious DiseasesNanning 530021China State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041China Shenzhen Key Laboratory of Environmental Chemistry and Ecological Remediation College of Chemistry and Environmental EngineeringShenzhen UniversityShenzhen 518060China Med-X center for Material Sichuan UniversityChengdu 610041China

Effective mineralization of biological structures poses a significant challenge in hard tissue engineering as it necessitates overcoming geometric complexities and multistep biomineralization *** this regard,we propose“mineral-in-shell nanoarchitectonics”,inspired by the nanostructure of matrix vesicles,which can influence multiple mineralization *** nanostructural design empowers mineral precursors with tailorable properties through encapsulating amorphous calcium phosphate within a multifunctional tannic acid(TA)and silk fibroin(SF)*** bioinspired nanosystem facilitates efficient recruitment of mineral precursors throughout the dentin structures,followed by large-scale intradentinal mineralization both in vitro and in vivo,which provides persistent protection against external *** simulations combined with experimental studies attribute the success of intradentinal mineralization to the TA-SF nanoshell,which exhibits a strong affinity for the dentin structure,stabilizing amorphous precursors and thereby facilitating concomitant mineral ***,this bioinspired mineral-in-shell nanoarchitectonics shows a promising prospect for hard tissue repair and serves as a blueprint for next-generation biomineralization-associated materials.

关键词： mineral-in-shell nanohybrids self-assembly biomineralization dentinal tubule occlusion dental hypersensitivity

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