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Bioceramic scaffolds with two-step internal/external modification of copper-containing polydopamine enhance antibacterial and alveolar bone regeneration capability

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 65-82页

作者： Xiaojian JIANG Lihong LEI Weilian SUN Yingming WEI Jiayin HAN Shuaiqi ZHONG Xianyan YANG Zhongru GOU Lili CHEN Department of Oral Medicine the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China Bio-nanomaterials and Regenerative Medicine Research Division Zhejiang–California International Nanosystem InstituteZhejiang UniversityHangzhou310058China

Magnesium-doped calcium silicate(CS)bioceramic scaffolds have unique advantages in mandibular defect repair;however,they lack antibacterial properties to cope with the complex oral microbiome.Herein,for the first time,the CS scaffold was functionally modified with a novel copper-containing polydopamine(PDA(Cu^(2+)))rapid deposition method,to construct internally modified(*P),externally modified(@PDA),and dually modified(*P@PDA)scaffolds.The morphology,degradation behavior,and mechanical properties of the obtained scaffolds were evaluated in vitro.The results showed that the CS*P@PDA had a unique micro-/nano-structural surface and appreciable mechanical resistance.During the prolonged immersion stage,the release of copper ions from the CS*P@PDA scaffolds was rapid in the early stage and exhibited long-term sustained release.The in vitro evaluation revealed that the release behavior of copper ions ascribed an excellent antibacterial effect to the CS*P@PDA,while the scaffolds retained good cytocompatibility with improved osteogenesis and angiogenesis effects.Finally,the PDA(Cu^(2+))-modified scaffolds showed effective early bone regeneration in a critical-size rabbit mandibular defect model.Overall,it was indicated that considerable antibacterial property along with the enhancement of alveolar bone regeneration can be imparted to the scaffold by the two-step PDA(Cu^(2+))modification,and the convenience and wide applicability of this technique make it a promising strategy to avoid bacterial infections on implants.

关键词： Copper-containing polydopamine Modification Antibacterial property bone regeneration Angiogenesis Bioceramic scaffold

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Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis

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World Journal of Stem Cells 2024年第5期16卷 499-511页

作者： Shuai Zhang Chuan Lu Sheng Zheng Guang Hong Division for International Collaborative and Innovative Dentistry Tohoku University Graduate School of DentistrySendai 980-8575MiyagiJapan School of Stomatology Zhejiang Chinese Medical UniversityHangzhou 310053Zhejiang ProvinceChina

BACKGROUND bone healing is a complex process involving early inflammatory immune regu-lation,angiogenesis,osteogenic differentiation,and biomineralization.Fracture repair poses challenges for orthopedic surgeons,necessitating the search for efficient healing methods.AIM To investigate the underlying mechanism by which hydrogel-loaded exosomes derived from bone marrow mesenchymal stem cells(BMSCs)facilitate the process of fracture healing.METHODS Hydrogels and loaded BMSC-derived exosome(BMSC-exo)gels were charac-terized to validate their properties.In vitro evaluations were conducted to assess the impact of hydrogels on various stages of the healing process.Hydrogels could recruit macrophages and inhibit inflammatory responses,enhance of human umbilical vein endothelial cell angiogenesis,and promote the osteogenic differen-tiation of primary cranial osteoblasts.Furthermore,the effect of hydrogel on fracture healing was confirmed using a mouse fracture model.RESULTS The hydrogel effectively attenuated the inflammatory response during the initial repair stage and subsequently facilitated vascular migration,promoted the formation of large vessels,and enabled functional vascularization during bone repair.These effects were further validated in fracture models.CONCLUSION We successfully fabricated a hydrogel loaded with BMSC-exo that modulates macrophage polarization and angiogenesis to influence bone regeneration.

关键词： Hydrogel bone marrow mesenchymal stem cells Macrophage polarization Angiogenesis bone regeneration

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Icariin accelerates bone regeneration by inducing osteogenesisangiogenesis coupling in rats with type 1 diabetes mellitus

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World Journal of Diabetes 2024年第4期15卷 769-782页

作者： Sheng Zheng Guan-Yu Hu Jun-Hua Li Jia Zheng Yi-Kai Li Department of Traditional Chinese Orthopedics and Traumatology Center for Orthopedic SurgeryThe Third Affiliated Hospital of Southern Medical UniversityGuangzhou 510630Guangdong ProvinceChina School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Endocrinology Peking University First HospitalBeijing 100034China

BACKGROUND Icariin(ICA),a natural flavonoid compound monomer,has multiple pharmacological activities.However,its effect on bone defect in the context of type 1 diabetes mellitus(T1DM)has not yet been examined.AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM.METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining,alizarin red S staining,quantitative real-time polymerase chain reaction,Western blot,and immunofluorescence.Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis.A bone defect model was established in T1DM rats.The model rats were then treated with ICA or placebo and micron-scale computed tomography,histomorphometry,histology,and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area.RESULTS ICA promoted bone marrow mesenchymal stem cell(BMSC)proliferation and osteogenic differentiation.The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers(alkaline phosphatase and osteocalcin)and angiogenesis-related markers(vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1)compared to the untreated group.ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs.In the bone defect model T1DM rats,ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation.Lastly,ICA effectively accelerated the rate of bone formation in the defect area.CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

关键词： Icariin Osteogenesis-angiogenesis coupling Type 1 diabetes mellitus bone defect bone regeneration

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Drug-loading ZIF-8 for modification of microporous bone scaffold to promote vascularized bone regeneration

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Chinese Chemical Letters 2024年第6期35卷 358-364页

作者： Xin Zhang Junyu Chen Xiang Pei Linxin Yang Liang Wang Luona Chen Guangmei Yang Xibo Pei Qianbing Wan Jian Wang State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesChengdu 610041China Department of Prosthodontics West China Hospital of StomatologySichuan UniversityChengdu 610041China

Surface modification of microporous bone scaffolds using nanoparticles has been broadly studied in bone tissue engineering.Aiming at improving vascularized bone regeneration(VBR),zeolitic imidazolate framework-8(ZIF-8)was encapsulated with dimethyloxallyl glycine(DMOG)and the drug-carrying nanoparticles(D@Z)could be uniformly coated onto the surface of the bone scaffold.The osteogenic and angiogenic actions of D@Z are closely correlated with the amount of slowly released DMOG,and in general,exhibited a favorable association.Then,the D7.5@Z group,which showed the greatest capacity to induce in vitro osteogenesis-angiogenesis coupling,was utilized for surface modification of the bone scaffold.Biological processes including phosphate-containing compound metabolic process,cell differentiation,cell proliferation and cell motility might contribute to enhanced ability to induce VBR by the coated scaffold and signaling pathways such as Rap1,Ras,phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT)and vascular endothelial growth factor(VEGF)signaling pathways participated in these processes.Finally,as depicted by in vitro real time-polymerase chain reaction(RT-PCR),Western blot(WB)and in vivo cranial bone defect model,the microporous scaffold coated with nano-D7.5@Z greatly promoted VBR.To conclude,nano-D@Z has significant promise for practical application in modification of microporous bone scaffolds to enhance VBR,and DMOG loading quantity has a beneficial influence on D@Z to improve osteogenesis-angiogenesis coupling.

关键词： Drug-loading nanoparticles Surface coating Microporous bone scaffold Vascularization bone regeneration

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Influence of Statins and Fibrates Drugs on bone Health and regeneration

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Journal of Biomaterials and Nanobiotechnology 2024年第1期15卷 1-24页

作者： Octavio Santiago Ivan Nadir Camal Ruggieri Marina Ribeiro Paulini Valéria Paula Sassoli Fazan João Paulo Mardegan Issa Sara Feldman LABOATEM Laboratory of Bone Biology and Tissue Engineering School of Medicine Rosario National University Ros&#225rio Argentina School of Dentistry of Ribeirã o Preto University of S&#227o Paulo (FORP/USP) Ribeir&#227o Preto S&#227o Paulo Brazil School of Medicine of Ribeirã o Preto University of S&#227o Paulo (FMRP/USP) Ribeir&#227o Preto S&#227o Paulo Brazil

In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause extensive loss of bone tissue is observed. bone is a specialized, vascularized and dynamic connective tissue that changes throughout the life of the organism. When injured, it has a unique ability to regenerate and repair without the presence of scars, but in some situations, due to the size of the defect, the bone tissue does not regenerate completely. Thus, due to its importance, there is a great development in therapeutic approaches for the treatment of bone defects through studies that include autografts, allografts and artificial materials used alone or in association with bone grafts. Pharmaceuticals composed of biomaterials and osteogenic active substances have been extensively studied because they provide potential for tissue regeneration and new strategies for the treatment of bone defects. Statins work as specific inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAreductase). They represent efficient drugs in lowering cholesterol, as they reduce platelet aggregation and thrombus deposition;in addition, they promote angiogenesis, reduce the β-amyloid peptide related to Alzheimer’s disease and suppress the activation of T lymphocytes. Furthermore, these substances have been used in the treatment of hypercholesterolemia and coronary artery disease. By inhibiting HMG-CoAreductase, statins not only inhibit cholesterol synthesis, but also exhibit several other beneficial pleiotropic effects. Therefore, there has been increasing interest in researching the effects of statins, including Simvastatin, on bone and osteometabolic diseases. However, statins in high doses cause inflammation in bone defects and inhibit osteoblastic differentiation, negatively contributing to bone repair. Thus, different types of studies with different concentrations of statins have been studied to posit

关键词： bone Statins Rosuvastatin Sinvastatin Fibrates Fenofibrate bone regeneration

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Repurpose dasatinib and quercetin:Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration

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Bioactive Materials 2023年第7期25卷 13-28页

作者： Ying Wang Lingbin Che Xi Chen Zirui He Dianwen Song Yuan Yuan Changsheng Liu Key Laboratory for Ultrafine Materials of Ministry of Education Frontiers Science Center for Materiobiology and Dynamic ChemistryEngineering Research Center for Biomaterials of Ministry of EducationSchool of Materials Science and EngineeringEast China University of Science and TechnologyShanghai200237PR China Department of Orthopedics Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai200080China

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

关键词： Postmenopausal osteoporosis Dasatinib and quercetin Senescent cells Mesenchymal stem cell bone regeneration

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Piezoresistive MXene/Silk fibroin nanocomposite hydrogel for accelerating bone regeneration by Re-establishing electrical microenvironment

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Bioactive Materials 2023年第4期22卷 1-17页

作者： Zhi-Chao Hu Jia-Qi Lu Tai-Wei Zhang Hai-Feng Liang Hao Yuan Di-Han Su Wang Ding Rui-Xian Lian Yu-Xiang Ge Bing Liang Jian Dong Xiao-Gang Zhou Li-Bo Jiang Department of Orthopaedic Surgery Zhongshan HospitalFudan UniversityShanghai200032China Key Laboratory of Advanced Display and System Applications of Ministry of Education Shanghai UniversityShanghai200072China Department of Orthopedics Surgery Minhang HospitalFudan UniversityShanghai201100China Key Laboratory for Ultrafine Materials of Ministry of Education Frontiers Science Center for Materiobiology and Dynamic ChemistryResearch Center for Biomedical Materials of Ministry of EducationSchool of Materials Science and EngineeringEast China University of Science and TechnologyShanghai200237China Department of Orthopedic Surgery Zhongshan Hospital(Xiamen)Fudan UniversityXiamen361015China

The electrical microenvironment plays an important role in bone repair.However,the underlying mechanism by which electrical stimulation(ES)promotes bone regeneration remains unclear,limiting the design of bone microenvironment-specific electroactive materials.Herein,by simple co-incubation in aqueous suspensions at physiological temperatures,biocompatible regenerated silk fibroin(RSF)is found to assemble into nanofibrils with aβ-sheet structure on MXene nanosheets,which has been reported to inhibit the restacking and oxidation of MXene.An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration.This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer,which can potentially be utilized to monitor the electrophysiological microenvironment.RNA sequencing is performed to explore the underlying mechanisms,which can activate Ca^(2+)/CALM signaling in favor of the direct osteogenesis process.ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages,as well as stimulating the neogenesis and migration of endotheliocytes.Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo.Collectively,the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis,regulating immune microenvironment and neovascularization under ES,leading to re-establish electrical microenvironment for bone regeneration.

关键词： bone regeneration Electrical microenvironment Regenerated silk fibroin MXene Electrical stimulation

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Multiscale design of stiffening and ROS scavenging hydrogels for the augmentation of mandibular bone regeneration

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Bioactive Materials 2023年第2期20卷 111-125页

作者： Yanlin Wu Xuan Li Yimin Sun Xiujun Tan Chenglin Wang Zhenming Wang Ling Ye State Key Laboratory of Oral Diseases West China Hospital of StomatologySichuan UniversityChengdu610041China

Although biomimetic hydrogels play an essential role in guiding bone remodeling,reconstructing large bone defects is still a significant challenge since bioinspired gels often lack osteoconductive capacity,robust mechanical properties and suitable antioxidant ability for bone regeneration.To address these challenges,we first engineered molecular design of hydrogels(gelatin/polyethylene glycol diacrylate/2-(dimethylamino)ethyl methacrylate,GPEGD),where their mechanical properties were significantly enhanced via introducing trace amounts of additives(0.5 wt%).The novel hybrid hydrogels show high compressive strength(>700 kPa),stiff modulus(>170 kPa)and strong ROS-scavenging ability.Furthermore,to endow the GPEGD hydrogels excellent osteoinductions,novel biocompatible,antioxidant and BMP-2 loaded polydopamine/heparin nanoparticles(BPDAH)were developed for functionalization of the GPEGD gels(BPDAH-GPEGD).In vitro results indicate that the antioxidant BPDAH-GPEGD is able to deplete elevated ROS levels to protect cells viability against ROS damage.More importantly,the BPDAH-GPEGD hydrogels have good biocompatibility and promote the osteo differentiation of preosteoblasts and bone regenerations.At 4 and 8 weeks after implantation of the hydrogels in a mandibular bone defect,Micro-computed tomography and histology results show greater bone volume and enhancements in the quality and rate of bone regeneration in the BPDAH-GPEGD hydrogels.Thus,the multiscale design of stiffening and ROS scavenging hydrogels could serve as a promising material for bone regeneration applications.

关键词： Biomimetic hydrogels Multiscale design ROS scavenging Stiffness bone regeneration

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Effects of pore interconnectivity on bone regeneration in carbonate apatite blocks

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Regenerative Biomaterials 2022年第1期9卷 30-40页

作者： Maab Elsheikh Ryo Kishida Koichiro Hayashi Akira Tsuchiya Masaya Shimabukuro and Kunio Ishikawa Department of Biomaterials Faculty of Dental ScienceKyushu University3-1-1 Maidashi Higashi-kuFukuoka 812-8582Japan

Porous architecture in bone substitutes,notably the interconnectivity of pores,is a critical factor for bone ingrowth.However,controlling the pore interconnectivity while maintaining the microarchitecture has not yet been achieved using conventional methods,such as sintering.Herein,we fabricated a porous block using the crystal growth of calcium sulfate dihydrate,and controlled the pore interconnectivity by limiting the region of crystal growth.The calcium sulfate dihydrate blocks were transformed to bone apatite,carbonate apatite(CO_(3)Ap)through dissolution–precipitation reactions.Thus,CO_(3)Ap blocks with 15%and 30%interconnected pore volumes were obtained while maintaining the microarchitecture:they were designated as CO_(3)Ap-15 and CO_(3)Ap-30,respectively.At 4 weeks after implantation in a rabbit femur defect,new bone formed throughout CO_(3)Ap-30,whereas little bone was formed in the center region of CO_(3)Ap-15.At 12 weeks after implantation,a large portion of CO_(3)Ap-30 was replaced with new bone and the boundary with the host bone became blurred.In contrast,CO_(3)Ap-15 remained in the defect and the boundary with the host bone was still clear.Thus,the interconnected pores promote bone ingrowth,followed by replacement of the material with new bone.These findings provide a useful guide for designing bone substitutes for rapid bone regeneration.

关键词： bone substitutes carbonate apatite pore interconnectivity bone regeneration

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3D printed pore morphology mediates bone marrow stem cell behaviors via RhoA/ROCK2 signaling pathway for accelerating bone regeneration

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Bioactive Materials 2023年第8期26卷 413-424页

作者： Qiji Lu Jingjing Diao Yingqu Wang Jianlang Feng Fansen Zeng Yan Yang Yudi Kuang Naru Zhao Yingjun Wang School of Materials Science and Engineering South China University of TechnologyGuangzhou510641PR China National Engineering Research Center for Tissue Restoration and Reconstruction South China University of TechnologyGuangzhou510006PR China NMPA Key Laboratory for Research and Evaluation of Innovative Biomaterials for Medical Devices.Guangzhou 510006PR China Medical Devices Research&Testing Center of SCUT Guangzhou510006PR China School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International CampusGuangzhou511442PR China Guangdong Institute of Advanced Biomaterials and Medical Devices Guangzhou510535PR China

bone bionics and structural engineering have sparked a broad interest in optimizing artificial scaffolds for better bone regeneration.However,the mechanism behind scaffold pore morphology-regulated bone regeneration remains unclear,making the structure design of scaffolds for bone repair challenging.To address this issue,we have carefully assessed diverse cell behaviors of bone mesenchymal stem cells(BMSCs)on theβ-tricalcium phosphate(β-TCP)scaffolds with three representative pore morphologies(i.e.,cross column,diamond,and gyroid pore unit,respectively).Among the scaffolds,BMSCs on theβ-TCP scaffold with diamond pore unit(designated as D-scaffold)demonstrated enhanced cytoskeletal forces,elongated nucleus,faster cell mobility,and better osteogenic differentiation potential(for example,the alkaline phosphatase expression level in D-scaffold were 1.5-2 times higher than other groups).RNA-sequencing analysis and signaling pathway intervention revealed that Ras homolog gene family A(RhoA)/Rho-associated kinase-2(ROCK2)has in-depth participated in the pore morphology-mediated BMSCs behaviors,indicating an important role of mechanical signaling transduction in scaffold-cell interactions.Finally,femoral condyle defect repair results showed that D-scaffold could effectively promote endogenous bone regeneration,of which the osteogenesis rate was 1.2-1.8 times higher than the other groups.Overall,this work provides insights into pore morphology-mediated bone regeneration mechanisms for developing novel bioadaptive scaffold designs.

关键词： bone mesenchymal stem cells 3D-printed scaffold Pore morphology bone regeneration Structure-osteogenesis relationship

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