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Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp

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International Journal of oral Science 2019年第2期11卷 119-130页

作者： Jianfei Zhang Wenbin Zhang Jiewen Dai Xudong Wang Steve Guofang Shen department of oral & cranio-maxillofacial surgery Shanghai Ninth People’s Hospital Shanghai Jiao Tong University School of Medicine Shanghai Key Laboratory of Stomatology

Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues.The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells.Initially,we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells.Moreover,Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line.In addition,micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo.Unexpectedly,Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2,Dlx5,Msx2,and Osterix,but led to upregulation of Alp and Osteocalcin (OCN),both of which play critical roles in promoting osteoblast maturation.Importantly,luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity.Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis,we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes.Based on these findings,we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene,suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.

关键词： BMSCs MC3T3-E1 Osteocalcin

Decellularized extracellular matrix:A promising strategy for skin repair and regeneration

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Engineered Regeneration

Engineered Regeneration 2023年第4期4卷 357-374页

作者： Shengjie Jiang Yu Zhuang Ming Cai Xudong Wang Kaili Lin Department of Oral and Cranio-maxillofacial Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of Medicine/College of StomatologyShanghai Jiao Tong University/National Center for Stomatology/National Clinical Research Center for Oral Diseases/Shanghai Key Laboratory of Stomatology/Shanghai Research Institute of StomatologyShanghai 200011China

The skin is an important organ of the human body that resists external threats but lacks sufficient self-regeneration ability when severe damage occurs.However,most of the available skin substitutes cannot achieve ideal restoration of complex structures and multiple functions of native skin tissues.Fortunately,the advent of decellularized extracellular matrix(dECM)offers a promising approach to overcome these obstacles.The dECM,derived from the natural extracellular matrix(ECM),possesses a similar structure and composition,which constructs an environment favorable for cell performance in regeneration.Moreover,dECM retains good bioactivity,low immunogenicity,and high availability,making it a suitable biomaterial for skin repair and regeneration.In this review,various decellularization methods and subsequent evaluations of dECM are introduced first,and the main sources of dECM are then presented.Furthermore,the recent progress of dECM-based biomaterials applied in skin regeneration and future perspectives are summarized.

关键词： Decellularization Extracellular matrix Skin regeneration Biomaterial Bioink

Effect of quercetin on chondrocyte phenotype and extracellular matrix expression

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Chinese Journal of Natural Medicines 2020年第12期18卷 922-933页

作者： GUI Zhi-Peng HU Yue ZHOU Yu-Ning LIN Kai-Li XU Yuan-Jin department of oral&cranio-maxillofacial surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200000China National Clinical Research Center for oral Diseases Shanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyShanghai 200000China department of oral surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200000China

Due to the poor repair ability of cartilage tissue,regenerative medicine still faces great challenges in the repair of large articular cartilage defects.Quercetin is widely applied as a traditional Chinese medicine in tissue regeneration including liver,bone and skin tissues.However,the evidence for its effects and internal mechanisms for cartilage regeneration are limited.In the present study,the effects of quercetin on chondrocyte function were systematically evaluated by CCK8 assay,PCR assay,cartilaginous matrix staining assays,immunofluorescence assay,and western blotting.The results showed that quercetin significantly up-regulated the expression of chondrogenesis genes and stimulated the secretion of GAG(glycosaminoglycan)through activating the ERK,P38 and AKT signalling pathways in a dose-dependent manner.Furthermore,in vivo experiments revealed that quercetin-loaded silk protein scaffolds dramatically stimulated the formation of new cartilage-like tissue with higher histological scores in rat femoral cartilage defects.These data suggest that quercetin can effectively stimulate chondrogenesis in vitro and in vivo,demonstrating the potential application of quercetin in the regeneration of cartilage defects.

关键词： Chondrocyte Phenotype Quercetin Silk protein Cartilage Regeneration

Nanoparticles modified by polydopamine: Working as “drug” carriers

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Bioactive Materials 2020年第3期5卷 522-541页

作者： Anting Jin Yitong Wang Kaili Lin Lingyong Jiang department of oral&cranio-maxillofacial surgery Shanghai Ninth People's HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyShanghai200011PR China

Inspired by the mechanism of mussel adhesion,polydopamine(PDA),a versatile polymer for surface modification has been discovered.Owing to its unique properties like extraordinary adhesiveness,excellent biocompatibility,mild synthesis requirements,as well as distinctive drug loading approach,strong photothermal conversion capacity and reactive oxygen species(ROS)scavenging facility,various PDA-modified nanoparticles have been desired as drug carriers.These nanoparticles with diverse nanostructures are exploited in multifunctions,consisting of targeting,imaging,chemical treatment(CT),photodynamic therapy(PDT),photothermal therapy(PTT),tissue regeneration ability,therefore have attracted great attentions in plenty biomedical applications.Herein,recent progress of PDA-modified nanoparticle drug carriers in cancer therapy,antibiosis,prevention of inflammation,theranostics,vaccine delivery and adjuvant,tissue repair and implant materials are reviewed,including preparation of PDA-modified nanoparticle drug carriers with various nanostructures and their drug loading strategies,basic roles of PDA surface modification,etc.The advantages of PDA modification in overcoming the existing limitations of cancer therapy,antibiosis,tissue repair and the developing trends in the future of PDA-modified nanoparticle drug carriers are also discussed.

关键词： Surface modification Polydopamine Nanoparticles Drug carriers

Application and prospects of computer-assisted surgery in oral and maxillofacial oncology

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Science Bulletin 2023年第3期68卷 236-239页

作者： Xin Peng Julio Acero Guang-Yan Yu department of oral and maxillofacial surgery Peking University School and Hospital of StomatologyNational Clinical Research Center for Oral DiseasesNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory of Digital StomatologyBeijing 100081China department of oral and maxillofacial surgery Ramón y Cajal and Puerta de Hierro University HospitalsUniversity of AlcalaRamón y Cajal Research Institute(IRYCIS)Madrid 28034Spain

The primary treatment modality for tumors affecting the oral and maxillofacial region is surgery.Surgical treatment of tumors affecting this region is a challenge and poses relatively high surgical risk,especially in lesions affecting the deep regions of the head and the neck due to the complex anatomy of this region including structures of great importance such as the internal carotid artery,the internal jugular vein,and the cavernous sinus at the skull base,the cranial nerves and the orbital contents with the eye globes,extraocular muscles,and the lacrimal gland.Oncologic resection often results in devastating defects in the oral and maxillofacial region,which adversely affect patients’facial appearance and important functions such as speech,chewing,deglutition,or vision and significantly impact patients’quality of life.In order to obtain a good result concerning tumor excision in the oral and cranio-maxillofacial region as well as a correct aesthetic and functional reconstruction,an adequate presurgical evaluation of the patient and accurate planning of the surgical resection and the reconstructive approach must be carefully designed.

关键词： surgery anatomy computer

Reducing relapse and accelerating osteogenesis in rapid maxillary expansion using an injectable mesoporous bioactive glass/fibrin glue composite hydrogel

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Bioactive Materials 2022年第12期7卷 507-525页

作者： Hanjiang Zhao Xiangyu Wang Anting Jin Minjiao Wang Zeying Wang Xingtai Huang Jiewen Dai Xudong Wang Dan Lin Steve GF.Shen department of oral&cranio-maxillofacial surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyShanghai200011PR China Shanghai University of Medicine and Health Sciences Shanghai201318China

Rapid maxillary expansion(RME),as a common treatment for craniomaxillofacial deformity,faces the challenge of high relapse rates and unsatisfactory therapeutic effects.In this study,a standardized Sprague-Dawley(SD)rat RME model was first established with a modified expander as well as retainer design and optimized anterior maxillary expanding force of 100 g which exerted the most synchronized mobility of mid-palatal suture and incisors.Via the standardized model,the high relapse rate was proven to be attributed to insufficient osteogenesis in expanded suture,requiring long-term retainer wearing in clinical situations.To reduce the relapse rate,mesoporous bioactive glass/fibrin glue(MBG/FG)composite hydrogels were developed for an in situ minimal invasive injection that enhance osteogenesis in the expanded palate.The component of 1 wt%MBG was adopted for enhanced mechanical strength,matched degradation rate and ion dissolution,excellent in vitro biocompatibility and osteoinductivity.Effects of 1%MBG/FG composite hydrogel on osteogenesis in expanded mid-palatal sutures with/without retention were evaluated in the standardized model.The results demonstrated that injection of 1%MBG/FG composite hydrogel significantly promoted bone formation within the expanded mid-palatal suture,inhibited osteoclastogenesis and benefited the balance of bone remodeling towards osteogenesis.Combination of retainer and injectable biomaterial was demonstrated as a promising treatment to reduce relapse rate and enhance osteogenesis after RME.The model establishment and the composite hydrogel development in this article might provide new insight to other craniomaxillofacial deformity treatment and design of bone-repairing biomaterials with higher regenerative efficiency.

关键词： Rapid maxillary expansion Sutural distraction osteogenesis Injectable hydrogel Mesoporous bioactive glass Bone regeneration

Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery

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Bioactive Materials 2023年第10期28卷 402-419页

作者： Richard Frank Richter Corina Vater Margarete Korn Tilman Ahlfeld Martina Rauner Winnie Pradel Bernd Stadlinger Michael Gelinsky Anja Lode Paula Korn Centre for Translational Bone Joint and Soft Tissue ResearchUniversity Hospital Carl Gustav Carus and Faculty of MedicineTechnische Universitat DresdenDresdenGermany department of oral and maxillofacial surgery University Hospital Carl Gustav CarusTechnische Universitat DresdenGermany department of Medicine III and Center for Healthy Aging University Hospital Carl Gustav CarusTechnische Universitat DresdenGermany Clinic of cranio-maxillofacial and oral surgery Center of Dental MedicineUniversity of ZurichSwitzerland

Calcium phosphate cements (CPC) are currently widely used bone replacement materials with excellent bioactivity, but have considerable disadvantages like slow degradation. For critical-sized defects, however, an improved degradation is essential to match the tissue regeneration, especially in younger patients who are still growing. We demonstrate that a combination of CPC with mesoporous bioactive glass (MBG) particles led to an enhanced degradation in vitro and in a critical alveolar cleft defect in rats. Additionally, to support new bone formation the MBG was functionalized with hypoxia conditioned medium (HCM) derived from rat bone marrow stromal cells. HCM-functionalized scaffolds showed an improved cell proliferation and the highest formation of new bone volume. This highly flexible material system together with the drug delivery capacity is adaptable to patient specific needs and has great potential for clinical translation.

关键词： Drug delivery 3D plotting Alveolar cleft defect Calcium phosphate cement Mesoporous bioactive glass

3D-printed surface promoting osteogenic differentiation and angiogenetic factor expression of BMSCs on Ti6Al4V implants and early osseointegration in vivo

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Journal of Materials Science & Technology 2019年第2期35卷 336-343页

作者： Jinkai Zhang Wenhui Zhou Hui Wang Kaili Lin Fengshan Chen department of Orthodontics School & Hospital of Stomatology Tongji University Shanghai Engineering Research Center of Tooth Restoration and Regeneration department of oral & cranio-maxillofacial surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai Key Laboratory of Stomatology Shanghai Research Institute of Stomatology

Three-dimensional-printed(3 D-P) titanium implants display many advantages, such as design flexibility,higher efficiency, the capability to easily construct complex or customized structures, etc., and is believed to potentially replace traditional implants. However, the biological performance of the 3 D-P titanium surface has not been investigated systematically. Herein, we analyzed the surface characteristics of 3 D-P Ti6 Al4 V implants and evaluated the biological responses of bone marrow derived mesenchymal stromal cells(BMSCs) to the 3 D-P surface in vitro. Moreover, after implantation into the rat femoral condyle for3 and 6 weeks, the osseointegration performance was evaluated. The results showed the 3 D-P Ti6 Al4 V implant presented distinct fluctuant macroscale rough surface and relatively better hydrophilicity which enhanced the adhesion, proliferation, osteogenic differentiation and angiogenetic factor expression of BMSCs. Moreover, the in vivo osseointegration performance was also better than that of the control group at the early stage. The present study suggested the 3 D-P titanium alloy is a promising candidate to be used as implant material.

关键词： Three-dimensional printing Titanium alloy BMSCs Osteogenesis Osseointegration

Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration

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Bone Research 2022年第1期10卷 46-64页

作者： Hongpu Wei Jinjie Cui Kaili Lin Jing Xie Xudong Wang department of oral&cranio-maxillofacial surgery Shanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyShanghai 200011China State Key Laboratory of oral Diseases West China Hospital of StomatologySichuan UniversityChengdu 610041China

Bone defects combined with tumors, infections, or other bone diseases are challenging in clinical practice. Autologous and allogeneic grafts are two main traditional remedies, but they can cause a series of complications. To address this problem,researchers have constructed various implantable biomaterials. However, the original pathological microenvironment of bone defects, such as residual tumors, severe infection, or other bone diseases, could further affect bone regeneration. Thus, the rational design of versatile biomaterials with integrated bone therapy and regeneration functions is in great demand. Many strategies have been applied to fabricate smart stimuli-responsive materials for bone therapy and regeneration, with stimuli related to external physical triggers or endogenous disease microenvironments or involving multiple integrated strategies. Typical external physical triggers include light irradiation, electric and magnetic fields, ultrasound, and mechanical stimuli. These stimuli can transform the internal atomic packing arrangements of materials and affect cell fate, thus enhancing bone tissue therapy and regeneration. In addition to the external stimuli-responsive strategy, some specific pathological microenvironments, such as excess reactive oxygen species and mild acidity in tumors, specific p H reduction and enzymes secreted by bacteria in severe infection, and electronegative potential in bone defect sites, could be used as biochemical triggers to activate bone disease therapy and bone regeneration.Herein, we summarize and discuss the rational construction of versatile biomaterials with bone therapeutic and regenerative functions. The specific mechanisms, clinical applications, and existing limitations of the newly designed biomaterials are also clarified.

关键词： biomaterials smart rational