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Fabrication and evaluation of a BMP-2/dexamethasone co-loaded gelatin sponge scaffold for rapid bone regeneration

Regenerative Biomaterials 2022年第1期9卷 303-313页

作者： Qi Gan Hao Pan Wenjing Zhang Yuan Yuan Jiangchao Qian Changsheng Liu Key Laboratory for Ultrafine Materials of Ministry of Education East China University of Science and TechnologyShanghai 200237PR China The State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai 200237PR China Engineering Research Center for Biomedical Materials of the Ministry of Education East China University of Science and TechnologyShanghai 200237PR China Frontiers Science Center for Materiobiology and Dynamic Chemistry East China University of Science and TechnologyShanghai 200237PR China

Improving the osteogenic activity of BMP-2 in vivo has significant clinical application value.In this research,we use a clinical gelatin sponge scaffold loaded with BMP-2 and dexamethasone(Dex)to evaluate the osteogenic activity of dual drugs via ectopic osteogenesis in vivo.We also investigate the mechanism of osteogenesis induced by BMP-2 and Dex with C2C12,a multipotent muscle-derived progenitor cell.The results show that the gelatin scaffold with Dex and BMP-2 can significantly accelerate osteogenesis in vivo.It is indicated that compared with the BMP-2 or Dex alone,100nM of Dex can dramatically enhance the BMP-2-induced alkaline phosphatase activity(ALP),ALP mRNA expression and mineralization.Further studies show that 100nM of Dex can maintain the secondary structure of BMP-2 and facilitate recognition of BMP-2 with its receptors on the surface of C2C12 cells.We also find that in C2C12,Dex has no obvious effect on the BMP-2-induced Smad1/5/8 protein expression and the STAT3-dependent pathway,but Runx2-dependent pathway is involved in the Dex-stimulated osteoblast differentiation of BMP-2 both in vitro and in vivo.Based on these results,a potential mechanism model about the synergistic osteoinductive effect of Dex and BMP-2 in C2C12 cells via Runx2 activation is proposed.This may provide a theoretical basis for the pre-clinical application of Dex and BMP-2 for bone regeneration.

关键词： BMP-2 dexamethasone Runx2 pre-clinical bone regeneration

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Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration

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Bioactive Materials 2023年第8期26卷 1-13页

作者： Shi Liu Zhengzhe Han Ji-Na Hao Dapeng Zhang Xianglong Li Yuanyuan Cao Jinghuan Huang Yongsheng Li Lab of Low-Dimensional Materials Chemistry Key Laboratory for Ultrafine Materials of Ministry of EducationFrontier Science Center of the Materials Biology and Dynamic ChemistryShanghai Engineering Research Center of Hierarchical NanomaterialsSchool of Materials Science and EngineeringEast China University of Science and TechnologyShanghai200237China Department of Orthopedic Surgery and Shanghai Institute of Microsurgery on Extremities Shanghai Jiao Tong University Affiliated Sixth People’s Hospital600 Yishan RoadShanghai200233PR China Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan School of Chemistry and Chemical EngineeringShihezi UniversityShihezi832003China

Osteogenesis,osteoclastogenesis,and angiogenesis play crucial roles in bone regeneration.Parathyroid hormone(PTH),an FDA-approved drug with pro-osteogenic,pro-osteoclastogenic and proangiogenic capabilities,has been employed for clinical osteoporosis treatment through systemic intermittent administration.However,the successful application of PTH for local bone defect repair generally requires the incorporation and delivery by appropriate carriers.Though several scaffolds have been developed to deliver PTH,they suffer from the weaknesses such as uncontrollable PTH release,insufficient porous structure and low mechanical strength.Herein,a novel kind of NIR-activable scaffold(CBP/MBGS/PTHrP-2)with dual-mode PTHrP-2(a PTH derivative)release capability is developed to synergistically promote osteogenesis and angiogenesis for high-efficacy bone regeneration,which is fabricated by integrating the PTHrP-2-loaded hierarchically mesoporous bioactive glass(MBG)into the N-hydroxymethylacrylamide-modified,photothermal agent-doped,poly(N-isopropylacrylamide)-based thermosensitive hydrogels through assembly process.Upon on/off NIR irradiation,the thermoresponsive hydrogel gating undergoes a reversible phase transition to allow the precise control of on-demand pulsatile and long-term slow release of PTHrP-2 from MBG mesopores.Such NIR-activated dual-mode delivery of PTHrP-2 by this scaffold enables a well-maintained PTHrP-2 concentration at the bone defect sites to continually stimulate vascularization and promote osteoblasts to facilitate and accelerate bone remodeling.In vivo experiments confirm the significant improvement of bone reparative effect on critical-size femoral defects of rats.This work paves an avenue for the development of novel dual-mode delivery systems for effective bone regeneration.

关键词： Parathyroid hormone Dual-mode release Thermosensitive hydrogel Angiogenesis bone regeneration

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Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment

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Bioactive Materials 2023年第3期21卷 403-421页

作者： Ao Zheng Xiao Wang Xianzhen Xin Lingjie Peng Tingshu Su Lingyan Cao Xinquan Jiang Department of Prosthodontics Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai Engineering Research Center of Advanced Dental Technology and Materials639 Zhizaoju RoadShanghai200011China

Injectable hydrogel is suitable for the repair of lacunar bone deficiency.This study fabricated an injectable,self-adaptive silk fibroin/mesoporous bioglass/sodium alginate(SMS)composite hydrogel system.With controllable and adjustable physical and chemical properties,the SMS hydrogel could be easily optimized adaptively to different clinical applications.The SMS hydrogel effectively showed great injectability and shapeability,allowing defect filling with no gap.Moreover,the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation,responsive to the concentration of Ca2+and inflammatory-like pH value in the microenvi-ronment of bone deficiency,respectively.In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway.The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells.Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2,which could create a specific favorable environment to induce new bone formation and angiogenesis.Meanwhile,SMS hydrogel was proved to be antibacterial,especially for gram-negative bacteria.Furthermore,in vivo study indicated that SMS could be easily applied for maxillary sinus elevation,inducing sufficient new bone formation.Thus,it is convincing that SMS hydrogel could be potent in a simple,minimally invasive and efficient treatment for the repair of lacunar bone deficiency.

关键词： Injectable hydrogel Oral and maxillofacial Silk fibroin Lacunar bone deficiency bone regeneration

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Enhancement of critical-sized bone defect regeneration by magnesium oxide-reinforced 3D scaffold with improved osteogenic and angiogenic properties

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Journal of Materials Science & Technology 2023年第4期135卷 186-198页

作者： Bo Chen Zhengjie Lin Qimanguli Saiding Yongcan Huang Yi Sun Xinyun Zhai Ziyu Ning Hai Liang Wei Qiao Binsheng Yu Kelvin W.K.Yeung Jie Shen Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China D Printing Clinical Translational and Regenerative Medicine Center Shenzhen Qianhai Shekou Free Trade Zone HospitalShenzhen 518067China Shenzhen Key Laboratory of Spine Surgery Department of Spine SurgeryPeking University Shenzhen HospitalShenzhen 518036China Department of Orthopaedics and Traumatology the University of Hong KongChina Hong Kong Special Administrative RegionChina Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma the University of Hong Kong Shenzhen HospitalShenzhen 518053China School of Materials Science and Engineering Nankai UniversityTianjin 300071China Department of Pathology Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China Department of Stomatology Shenzhen Qianhai Shekou Free Trade Zone HospitalShenzhen 518067China Applied Oral Sciences and Community Dental Care Faculty of Dentistrythe University of Hong KongChina Hong Kong Special Administrative RegionChina China Orthopaedic Regenerative Medicine Group(CORMed) Hangzhou 310000China

The healing of critical-sized bone defects(CSD)remains a challenge in orthopedic medicine.In recent years,scaffolds with sophisticated microstructures fabricated by the emerging three-dimensional(3D)printing technology have lighted up the treatment of the CSD due to the elaborate microenvironments and support they may build.Here,we established a magnesium oxide-reinforced 3D-printed biocompos-ite scaffold to investigate the effect of magnesium-enriched 3D microenvironment on CSD repairing.The composite was prepared using a biodegradable polymer matrix,polycaprolactone(PCL),and the disper-sion phase,magnesium oxide(MgO).With the appropriate surface treatment by saline coupling agent,the MgO dispersed homogeneously in the polymer matrix,leading to enhanced mechanical performance and steady release of magnesium ion(Mg^(2+))for superior cytocompatibility,higher cell viability,advanced osteogenic differentiation,and cell mineralization capabilities in comparison with the pure PCL.The in-vivo femoral implantation and critical-sized cranial bone defect studies demonstrated the importance of the 3D magnesium microenvironment,as a scaffold that released appropriate Mg^(2+) exhibited remarkably increased bone volume,enhanced angiogenesis,and almost recovered CSD after 8-week implantation.Overall,this study suggests that the magnesium-enriched 3D scaffold is a potential candidate for the treatment of CSD in a cell-free therapeutic approach.

关键词： 3D printing Magnesium Critical-sized defect bone regeneration Angiogenesis Scaffold

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Injectable composite hydrogel based on carbon particles for photothermal therapy of bone tumor and bone regeneration

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Journal of Materials Science & Technology 2022年第23期118卷 64-72页

作者： Chengxiong Wei Xin Jin Chengwei Wu Wei Zhang State Key Laboratory of Structure Analysis for Industrial Equipment Department of Engineering MechanicsDalian University of TechnologyDalian 116024China

Surgical resection,as the most efficient treatment for bone tumor,still faces a dilemma between the complete removal of tumor tissue and the maximum reservation of healthy bone tissue.In response to this,an injectable composite hydrogel with chitosan/hyaluronic acid/β-sodium glycerophosphate as the matrix and carbon particles as the photothermal agent is developed.Owing to the temperature sensitivity,the composite hydrogel can be injected into the irregular bone defect and exhibit the sol-gel phase transition upon body temperature,facilitating the conformal therapy.The composite hydrogel can ablate the human osteosarcoma on Balb/c nude mice model with the tumor inhibition rate of 98.4%after near-infrared laser irradiation(808 nm).The assessment of bone regeneration on calvarial-defect model of Sprague-Dawley rats reveals that the composite hydrogel can promote new bone formation with the bone volume/total volume ratio of 76.2%after 8 weeks,in sharp contrast to the control group of 23.9%.)

关键词： Hydrogel Carbon particle Photothermal therapy bone regeneration

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Functionalize d 3D-printe d porous titanium scaffold induces in situ vascularized bone regeneration by orchestrating bone microenvironment

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Journal of Materials Science & Technology 2023年第22期153卷 92-105页

作者： Bo Yuan Pin Liu Rui Zhao Xiao Yang Zhanwen Xiao Kai Zhang Xiangdong Zhu Xingdong Zhang National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610064China College of Biomedical Engineering Sichuan UniversityChengdu 610064China

Titanium(Ti)and its alloys have been extensively explored for treating load-bearing bone defects.How-ever,high-stress shielding,weak osteogenic activity,and insufficient vascularization remain key chal-lenges for the long-term clinical outcomes of Ti-based implants.Herein,inspired by structural and func-tional cues of bone regeneration,a silicon-doped nano-hydroxyapatite(nSiHA)/titanium dioxide(TiO_(2))composite coating with a hierarchical micro/nano-network structure is constructed on the surface of a 3D-printed porous Ti scaffold via a combined strategy of acid-alkali(AA)treatment and electrochemi-cal deposition technique,which not only endows the scaffold with excellent osteoinduction ability but can also effectively immobilize and release vascular endothelial growth factor(VEGF).The results of the in vitro cell experiments show that the functionalized Ti scaffold significantly promotes osteogenesis in bone marrow mesenchymal stem cells(BMSCs)and angiogenesis in human umbilical vein endothelial cells(HUVECs)by activating the extracellular signal-regulated protein kinase(ERK)and HIF-1αsignaling pathways.After being implanted into a rat femoral condyle defect model,the functionalized Ti scaffold can induce in situ vascularized bone regeneration by orchestrating the two coupled processes of angio-genesis and osteogenesis.These findings indicate that the functionalized Ti scaffold has great potential in bone tissue regeneration and is a promising candidate for load-bearing bone defect repair.

关键词： Porous titanium 3D-printing Hierarchical micro/nano-structure bone microenvironment Vascularization bone regeneration

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Exosome-functionalized magnesium-organic framework-based scaffoldswith osteogenic, angiogenic and anti-inflammatory properties foraccelerated bone regeneration

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Bioactive Materials 2022年第12期7卷 26-41页

作者： Yue Kang Chang Xu Ling’ao Meng Xufeng Dong Min Qi Daqing Jiang Department of Breast Surgery Cancer Hospital of China Medical University44 Xiaoheyan RoadDadong DistrictShenyang110042PR China School of Materials Science and Engineering Dalian University of Technology2 Linggong RoadGanjingzi DistrictDalian116024China

Exosomes derived from human adipose-derived stem cells (hADSCs-Exos) have shown potential as an effectivetherapeutic tool for repairing bone defects. Although metal-organic framework (MOF) scaffolds are promisingstrategies for bone tissue regeneration, their potential use for exosome loading remains unexplored. In this study,motivated by the potential advantages of hADSCs-Exos and Mg-GA MOF, we designed and synthesized anexosome-functionalized cell-free PLGA/Mg-GA MOF (PLGA/Exo-Mg-GA MOF) scaffold, taking using of thebenefits of hADSCs-Exos, Mg2+, and gallic acid (GA) to construct unique nanostructural interfaces to enhanceosteogenic, angiogenic and anti-inflammatory capabilities simultaneously. Our in vitro work demonstrated thebeneficial effects of PLGA/Exo-Mg-GA MOF composite scaffolds on the osteogenic effects in human bonemarrow-derived mesenchymal stem cells (hBMSCs) and angiogenic effects in human umbilical endothelial cells(HUVECs). Slowly released hADSCs-Exos from composite scaffolds were phagocytosed by co-cultured cells,stabilized the bone graft environment, ensured blood supply, promoted osteogenic differentiation, and acceleratedbone reconstruction. Furthermore, our in vivo experiments with rat calvarial defect model showed thatPLGA/Exo-Mg-GA MOF scaffolds promoted new bone formation and satisfactory osseointegration. Overall, weprovide valuable new insights for designing exosome-coated nanocomposite scaffolds with enhanced osteogenesisproperty.

关键词： Metal-organic framework Exosomes Magnesium ions Gallic acid Osteogenesis Angiogenesis Anti-inflammation Rat calvarial defect model bone regeneration

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Black Mn-containing layered double hydroxide coated magnesium alloy for osteosarcoma therapy, bacteria killing, and bone regeneration

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Bioactive Materials 2022年第11期7卷 394-405页

作者： Dongdong Zhang Shi Cheng Ji Tan Juning Xie Yu Zhang Shuhan Chen Huihui Du Shi Qian Yuqing Qiao Feng Peng Xuanyong Liu State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai200050China Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of SciencesBeijing100049China Medical Research Center Department of OrthopedicsGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdong510080China School of Chemistry and Materials Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of Sciences1 Sub-lane XiangshanHangzhou310024China Cixi Center of Biomaterials Surface Engineering Ningbo315300China

Osteosarcoma (OS) tissue resection with distinctive bactericidal activity, followed by regeneration of bone de-fects, is a highly demanded clinical treatment. Biodegradable Mg-based implants with desirable osteopromotive and superior mechanical properties to polymers and ceramics are promising new platforms for treating bone-related diseases. Integration of biodegradation control, osteosarcoma destruction, anti-bacteria, and bone defect regeneration abilities on Mg-based implants by applying biosafe and facile strategy is a promising and challenging topic. Here, a black Mn-containing layered double hydroxide (LDH) nanosheet-modified Mg-based implants was developed. Benefiting from the distinctive capabilities of the constructed black LDH film, including near-infrared optical absorption and reactive oxygen species (ROS) generation in a tumor-specific microenvi-ronment, the tumor cells and tissue could be effectively eliminated. Concomitant bacteria could be killed by localized hyperthermia. Furthermore, the enhanced corrosion resistance and synergistic biofunctions of Mn and Mg ions of the constructed black LDH-modified Mg implants significantly facilitated cell adhesion, spreading and proliferation and osteogenic differentiation in vitro, and accelerated bone regeneration in vivo. This work offers a new platform and feasible strategy for OS therapeutics and bone defect regeneration, which broadens the biomedical application of Mg-based alloys.

关键词： Biodegradable magnesium Layered double hydroxides Anti-tumor Anti-bacterial bone regeneration

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Bio-inspired dual-adhesive particles from microfluidic electrospray for bone regeneration

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Nano Research 2023年第4期16卷 5292-5299页

作者： Lei Yang Xiaocheng Wang Yunru Yu Luoran Shang Wei Xu Yuanjin Zhao Department of Rheumatology and Immunology Nanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhou 325001China Shanghai Xuhui Central Hospital Zhongshan-Xuhui Hospitaland the Shanghai Key Laboratory of Medical Epigeneticsthe International Colaboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai 200032China Department of Orthopedics Tongren HospitalShanghai Jiao Tong University School of MedicineShanghai 200336China

Bioadhesive hydrogels have demonstrated great potential in bone regeneration.However,the relatively simple adhesion mechanism and lack of intricate structural design restrict their further applications.Herein,inspired by multiple adhesion mechanisms of pollen particles and marine mussels,we present a novel type of dual-adhesive hydrogel particles fabricated from microfluidic electrospray for bone regeneration.As the particles are rapidly solidified via liquid nitrogen-assisted cryogelation,they exhibit pollen-mimicking hierarchical porous morphology and gain structure-related adhesion.Besides,the particles are further coated by polydopamine(PDA)to achieve molecular-level adhesion especially to physiological wet surfaces of bone issues.Benefiting from such dual-adhesion mechanisms,the particles can strongly adhere to bone tissue defects,and function as porous scaffolds.Moreover,the dual-adhesive particles can serve as effective vehicles to release key growth factors more than two weeks.In vitro experiments showed that the growth factors-loaden particles have excellent biocompatibility and more significantly promote angiogenesis(~2-fold)and osteogenic differentiation(~3-fold)than control.In vivo experiments indicated that the dual-adhesive particles could significantly enhance bone regeneration(~4-fold)than control by coupling osteogenesis and angiogenesis effects.Based on these features,the bio-inspired dual-adhesive particles have great potentials for bone repair and wound healing applications.

关键词： microfluidics particles growth factors adhesion bone regeneration

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Cerium oxide nanoparticles loaded nanofibrous membranes promote bone regeneration for periodontal tissue engineering

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Bioactive Materials 2022年第1期7卷 242-253页

作者： Shuangshuang Ren Yi Zhou Kai Zheng Xuanwen Xu Jie Yang Xiaoyu Wang Leiying Miao Hui Wei Yan Xu Jiangsu Province Key Laboratory of Oral Diseases Nanjing Medical UniversityNanjing210029China Department of Periodontology The Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjing210029China Jiangsu Province Engineering Research Center of Stomatological Translational Medicine Nanjing 210029China Nanjing Stomatological Hospital Medical School of Nanjing UniversityNanjing210093China Department of Biomedical Engineering College of Engineering and Applied SciencesNanjing National Laboratory of MicrostructuresJiangsu Key Laboratory of Artificial Functional MaterialsNanjing UniversityNanjingJiangsu210023China State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjingJiangsu 210023China Institute of Biomaterials University of Erlangen-NurembergErlangen91058Germany

bone regeneration is a crucial part in the treatment of periodontal tissue regeneration,in which new attempts come out along with the development of nanomaterials.Herein,the effect of cerium oxide nanoparticles(CeO_(2)NPs)on the cell behavior and function of human periodontal ligament stem cells(hPDLSCs)was investigated.Results of CCK-8 and cell cycle tests demonstrated that CeO_(2)NPs not only had good biocompatibility,but also promoted cell proliferation.Furthermore,the levels of alkaline phosphatase activity,mineralized nodule formation and expressions of osteogenic genes and proteins demonstrated CeO_(2)NPs could promote osteogenesis differentiation of hPDLSCs.Then we chose electrospinning to fabricate fibrous membranes containing CeO_(2)NPs.We showed that the composite membranes improved mechanical properties as well as realized release of CeO_(2)NPs.We then applied the composite membranes to in vivo study in rat cranial defect models.Micro-CT and histopathological evaluations revealed that nanofibrous membranes with CeO_(2)NPs further accelerated new bone formation.Those exciting results demonstrated that CeO_(2)NPs and porous membrane contributed to osteogenic ability,and CeO_(2)NPs contained electrospun membrane may be a promising candidate material for periodontal bone regeneration.

关键词： CeO_(2)nanoparticles Periodontal ligament stem cells bone regeneration Electrospinning Fibrous membrane

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