Journal of Orthopaedic Translation
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2025
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IF 7.8
Jiaxin Zhang,Haotian Bai,He Liu,Xiaonan Wang,Mingwei Xu,Guokun Zhang,Zexin Di,Xin Zhao,Jincheng Wang,Luquan Ren
Rationale Imbalances in the osteogenic–osteoclastic microenvironment hinder effective osseointegration between the prosthesis and host bone, which is a key factor contributing to the high incidence of prosthesis loosening and periprosthetic fractures in osteoporosis patients. Developing an implant interface that can reverse the dysregulated osteogenic microenvironment is an effective strategy to address this challenge. Methods A novel bioinspired interface with a spatial gradient structure was engineered by 3D-printed porous titanium alloy implants and hollow mesoporous silica nanoparticles coating. Apart from the bioinspired bone microstructure, the amine-functionalized nanocoating of the bioactive interface could also load and temporally sustain the zoledronic acid (ZOL) release. A series of in vitro experiments were carried out to characterize the bioactive interface and to clarify the regulation of osteogenic–osteoclastic balance by ZOL temporal release from the nanocoatings. Afterward, an osteoporotic model was utilized to validate the in vivo bioactive interface osseointegration effect. Results Based on the structural features and chemical properties of the bioactive interface, efficient ZOL loading was achieved. Additionally, the temporal release mechanism of ZOL through free diffusion and ionic bond ionization enabled long-term sustained release. Meanwhile, the early high-concentration local release of ZOL effectively inhibited osteoclast formation and activation in the microenvironment. As the ZOL release decreased over time, the focus shifted to promoting the process of bone formation, thereby reversing the dysregulated osteogenic microenvironment. According to this, we identified the optimal gradient concentration (10 -5 M) of the ZOL temporal release system that efficiently exerts bidirectional regulatory effects. Most notably, the spatial gradient structured interface loaded with this optimal concentration of ZOL (10 -5 M) significantly augmented osseointegration under in vivo osteoporotic conditions. Conclusion Overall, our study provides a novel nanocoating capable of temporally releasing ZOL to reverse the dysregulated osteogenic microenvironment, aiming to maintain the long-term stability of artificial prostheses for osteoporosis patients. The translational potential of this article This study validates the structure–performance-effect relationship of ZOL-releasing nanocoatings with a temporal release mechanism, providing a novel approach to addressing the high incidence of postoperative complications in osteoporotic patients undergoing prosthetic replacement.
研究领域:
生物医学工程
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骨科
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材料科学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2023
·Vol. 14
·期 2
·1-14
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IF 9
Zhang Shouyi,Lv Chengcheng,Niu Yichen,Li Changqi,Li Xiuming,Shang Yu,Zhang Yunchao,Zhang Yue,Zhang Yong,Zeng Yu
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m 6 A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
Bioactive Materials
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2023
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IF 18.9
Han Sun,Juan Xu,Yangyufan Wang,Siyu Shen,Xingquan Xu,Lei Zhang,Qing Jiang
Large bone defects resulting from fractures and disease are a major clinical challenge, being often unable to heal spontaneously by the body's repair mechanisms. Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration. However, replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells. Therefore, reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair. Herein, we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels (CPP-L/GelMA) as a “bone microenvironment regulative hydrogel” to reverse the hypoxic microenvironment in bone defects region. CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase (CAT) and ROS-responsive oxygen-releasing nanoparticles ( [email protected] /PPS) co-loaded liposome (CCP-L) and GelMA hydrogels. Under hypoxic condition, CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks. The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis. Finally, CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway. Hence, CPP-L/GelMA, as a bone microenvironment regulative hydrogel for bone tissue respiration, can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region, possessing of great clinical therapeutic potential.
研究领域:
组织工程
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生物材料
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再生医学
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骨科
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
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2023
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IF 14.3
Yutong Wu,Hongbo Ai,Yuhang Xi,Jiulin Tan,Ying Qu,Jianzhong Xu,Fei Luo,Ce Dou
Summary The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8 + T cell infiltrations and a higher survival rate. We uncover that the membranous Siglec15 on osteoclast-derived ABs binds with sialylated Toll-like receptor 2 (TLR2) and blocks downstream co-stimulatory signaling, leading to the inhibition of naive CD8 + T cell activation. In addition, our study shows that treatment with Siglec15 neutralizing antibodies significantly reduces the incidence of secondary metastases and improves the survival rate of mice with advanced breast cancer bone metastasis. Our findings reveal the immunosuppressive function of osteoclast-derived ABs in the bone-tumor niche and demonstrate the potential of Siglec15 as a common target for anti-resorption and immunotherapy.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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癌症转移
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DOI
PubMed
高影响因子
Biomaterials Science
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2025
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IF 5.7
Hang Yao,Chirun Wang,Qi Tao,Jian Yang,Dianwei Liu,Xianfeng Shang,Zhonglian Wu,Xu Hu,Zehao Gu,Zhilin Cheng,Jihang Dai,Dong-an Wang
Osteoarthritis (OA) is an irreversible disease of continuous degradation of cartilage, and natural joint super-lubrication is thought to provide hydrated lubrication to articular cartilage. Synovial joint fluid consists of hyaluronic acid (HA) and numerous brush-like macromolecules, exhibits a high affinity for cartilage proteins, and forms a hydrated layer on the cartilage surface. When cartilage friction increases, the surface layer of the cartilage becomes ruptured or damaged, and the cartilage hydration layer is destroyed, subsequently evolving into early OA. In this study, dopamine (DOPA) was coupled with HA to modify it by utilizing the hydrophilicity of HA and the adhesive properties of DOPA. On the one hand, it enhances cartilage lubrication by prolonging the retention time of HA in cartilage and restoring the hydrated layer on the cartilage surface by adhering to the type II collagen network. The successful synthesis of hyaluronic acid−DOPA (HAD) was confirmed by nuclear magnetic resonance (NMR) hydrogen spectroscopy, infrared spectroscopy, and ultraviolet (UV) absorption spectroscopy. The morphology and hydrophilicity of HAD were demonstrated using atomic force microscopy (AFM) and contact angle measurements. Additionally, the interaction of HAD with cartilage matrix proteins was verified through confocal microscopy imaging, while the biocompatibility and feasibility of injection of HAD were confirmed by cellular and animal experiments. On the other hand, the effect of protecting and even regenerating cartilage was achieved by remodeling the cartilage microenvironment. The cartilage protection and even regeneration ability of HAD was confirmed by injecting HAD at different times after OA modeling and characterizing the joints in sections.
研究领域:
生物医学工程
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材料科学
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骨科学
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生物化学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Nano Today
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2021
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IF 20.722
Na Yan,Bin Hu,Junchao Xu,Rong Cai,Zhenhai Liu,Dapeng Fu,Beibei Huo,Zhenhua Liu,Yuliang Zhao,Chunying Chen,Weihua Xu
Periodontitis places a substantial burden on healthcare worldwide. Due to the complexity of the periodontium, regenerative periodontal therapy in healing periodontal tissue damage caused by periodontitis has long been difficult using traditional tissue engineering techniques. The current clinical treatment, guided tissue regeneration (GTR), has shown limitations in reconstructing an osteogenic microenvironment . Here, we designed a stem cell-containing patch (stem cell “Janus” patch; SCJP) to acclimatize stem cells in the osteogenic and odontogenic microenvironment for periodontal regeneration. The SCJP promoted periodontal regeneration within its functional layer, while its barrier layer blocked gingival epithelial cells (GECs) invasion. Specifically, embedded dental pulp stem cells (DPSCs) in the functional layer facilitated the regeneration of dentin, cementum and alveolar bone, all of which orchestrated complete periodontal structure regeneration. We characterized the biophysical properties of the SCJP barrier layer, which has a compact structure and appreciable resistance to mechanical stress, suggesting the patch may be effective in preventing epithelium invasion. Successful ectopic mineralization and further osteogenic and odontogenic differentiation in mouse, rat and swine periodontal defect models further validated the patch’s potential in accelerating periodontal tissue regeneration. Our study describes a safe and effective stem cell-base strategy for a therapeutic that not only realizes periodontal repair but also protects the restoring periodontium from epithelial cell invasion.
研究领域:
牙科
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组织工程
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再生医学
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生物材料
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产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2023
·Vol. 12
·期 12
·2201548
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IF 10
Yanyan Zhou,Zihe Hu,Wenjing Jin,Haiyan Wu,Minghao Zuo,Changyu Shao,Yanhua Lan,Yang Shi,Ruikang Tang,Zhuo Chen,Zhijian Xie,Jue Shi
Inspired by the bionic mineralization theory, organic–inorganic composites with hydroxyapatite nanorods orderly arranged along collagen fibrils have attracted extensive attention. Planted with an ideal bone scaffold will contribute greatly to the osteogenic microenvironment; however, it remains challenging to develop a biomimetic scaffold with the ability to promote intrafibrillar mineralization and simultaneous regulation of immune microenvironment in situ. To overcome these challenges, a scaffold containing ultra-small particle size calcium phosphate nanocluster (UsCCP) is prepared, which can enhance bone regeneration through the synergetic effect of intrafibrillar mineralization and immunomodulatory. By efficient infiltration into collagen fibrils, the UsCCP released from the scaffold achieves intrafibrillar mineralization. It also promotes the M2-type polarization of macrophages, leading to an immune microenvironment with both osteogenic and angiogenic potential. The results confirm that the UsCCP scaffold has both intrafibrillar mineralization and immunomodulatory effects, making it a promising candidate for bone regeneration.
研究领域:
生物材料
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组织工程
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生物医学工程
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材料科学
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免疫学
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再生医学
✓ 已验证
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2019
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IF 4.959
Yimin Sun,Cheng Hu,Yuanyi Yang,Bin Dong,Yi Deng
The surface-inspirable biomaterials have captured extensive attention in simulating microenvironments by mimicking nanoscale architectures and signal molecules in the extracellular matrix (ECM). To activate osteogenic differentiation through biomimetic nanostructures, osteoid-like calcium titanate nanorods (CT) were fabricated via anodization and hydrothermal treatment. SEM, EDS, and XPS were employed to confirm the morphology and chemical composition. The functional fibroin and peptide layers on CT (PFCT) were subsequently applied to provide binding sites and bioactive molecules for osteoblast growth and differentiation. The hydrophilicity obviously increased with the protein layers. PFCT presented enhanced cell viability with pronounced pseudopod extension and continuous proliferation. The osteogenic differentiation analysis revealed that the alkaline phosphatase expression improved in the early stage. The calcium nodes and the collagen secretion were also enhanced. Quantitative polymerase chain reaction assessment indicated that osteogenesis-related markers including ALP , Col1 , and Runx2 , were up-regulated. The in vitro results demonstrated that fibroin/peptide co-functionalized calcium titanate nanorods were efficient to stimulate osteoblasts and improve cell adhesion, proliferation, and differentiation. Therefore, the nanorods can create an osteogenic niche on titanium implants, which can be a promising modification strategy in bone tissue engineering application.
研究领域:
材料科学
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生物医学工程
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组织工程
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纳米技术
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生物材料
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产品关联
DOI
PubMed
高影响因子
Theranostics
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2024
·Vol. 14
·期 18
·7140
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IF 12.4
Yufan Zhu,Huifan Liu,Ping Wu,Yun Chen,Zhouming Deng,Lin Cai,Minhao Wu
Background: Factor-free biomaterial scaffolds play an increasingly important role in promoting in situ bone reconstruction and regeneration. However, the complicated and variable pathophysiological microenvironments of the injury sites under diabetic conditions, including the vicious cycle of oxidative stress and inflammatory response, impaired osteo/angiogenesis function and hyperactive osteoclastogenesis, as well as increased susceptibility to bacterial infection, may largely weaken the therapeutic potential of implanted scaffolds, leading to uncontrolled and poor outcomes of bone defect healing. Methods and Results: To tackle the aforementioned challenges, a mild photothermal-assisted multifunctional therapeutic platform (denoted as GAD/MC) that integrates copper-containing two-dimensional Ti 3 C 2 T x MXene nanosheets, gelatin methacrylate, and alginate-graft-dopamine was proposed to achieve efficient and synergistic therapy for diabetic bone defects. Thereinto, copper-decorated MXene (MC) nanosheets were employed as both functional crosslinkers and nanofillers to participate in the construction of an interpenetrating polymer network structure through multiple covalent and noncovalent bonds, which conferred the hydrogel with advantageous traits like enhanced mechanical properties, injectability and moldability, strong bone tissue adhesion and self-healing ability, as well as excellent anti-swelling and near-infrared (NIR) photothermal conversion capabilities. On account of the NIR/pH dual-responsive properties, the resulting hydrogel system was capable of achieving the controlled and stimuli-responsive release of bioactive Cu 2+ , allowing on-demand delivery at the site of injury. Moreover, with the assistance of mild photothermal effects, this integrated hydrogel system demonstrated remarkable antibacterial and antioxidant properties. It effectively scavenged excessive reactive oxygen species (ROS), inhibited inflammatory responses, and promoted macrophage polarization towards the pro-healing M2 phenotype. Such characteristics were beneficial for recreating an optimized microenvironment that supported the adhesion, proliferation, migration, and differentiation of osteoblasts and endothelial cells, while concurrently inhibiting osteoclast function. In a critical-sized cranial defect model using diabetic rats, the injectable GAD/MC hydrogel system combined with on-demand mild hyperthermia further synergistically accelerated new bone formation and bone healing processes by eliminating intracellular ROS, ameliorating inflammation, orchestrating M2 macrophage polarization, promoting osteo/angiogenesis, and suppressing osteoclastogenesis. Conclusions: Overall, the constructed multifunctional injectable hydrogel system has emerged as a promising therapeutic candidate for addressing complex bone-related challenges by remodeling the disordered immune microenvironment and expediting the bone healing process.
研究领域:
生物材料
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组织工程
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再生医学
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糖尿病研究
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骨愈合
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光热疗法
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炎症生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
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2023
·Vol. 15
·期 20
·9148-9161
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IF 6.7
Zheng Liu,Hong Ding,Miaomiao He,Yulin Jiang,Lin Qi,Meixuan Du,Jing Wang,Yubao Li,Limin Liu,Ganjun Feng,Li Zhang
Desirable antibacterial and osseointegration abilities are essentially important for long-term survival of a Ti-orthopedic implant. Herein, a near-infrared light (NIR) excited antibacterial platform with excellent osseointegration composed of perovskite calcium titanate/nickel hydroxide on a Ti implant (Ni(OH)2@CaTiO3/Ti) was designed and successfully fabricated. The construction of the heterostructure efficiently separated the photogenerated electron–hole pairs to produce sufficient reactive oxygen species (ROS), which enabled the photoactivated bacterial inactivation (PBI) of Ti implants. The results showed that the surface-modified Ti implant displayed remarkable antibacterial ability with bacterial inhibition rates of 95.5% for E. coli and 93.8% for S. aureus under NIR excitation. Also, the intervention of Ni(OH)2 could create a slightly alkaline surface on the Ti implant, which synchronized with Ca-rich CaTiO3 to regulate the osteogenic microenvironment in favor of the adhesion, proliferation and differentiation of MC3T3-E1 cells as well as the up-regulation of osteogenesis-related gene expressions. The in vivo implantation experiments further confirmed that the heterostructured coating prominently accelerated the formation of new bone and promoted the osseointegration of Ti implants. Our work may provide a novel concept for improving the antibacterial and osseointegration abilities of Ti implants in orthopedic and dental applications.
研究领域:
材料科学
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生物材料
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骨科
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牙科科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 30
·6056-6067
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IF 6.331
Qian Li,He Zhang,Jijia Pan,Binhong Teng,Ziqian Zeng,Yang Chen,Yu Hei,Siqi Zhang,Shicheng Wei,Yuhua Sun
Due to the ability to combine multiple osteogenic induction “cues” at the same time, hydrogels are widely used in the three-dimensional (3D) culture of human mesenchymal stem cells (hMSCs) and osteoinduction. However, the survival and proliferation of stem cells in a 3D culture system are limited, which reduces their osteogenic differentiation efficiency. In addition, the cells inside the hydrogel are prone to apoptosis due to hypoxia, which is a serious challenge for tissue engineering based on stem cells. In this study, a tripeptide-based macroporous alginate hydrogel was prepared to improve the osteogenic microenvironment of stem cells. The arginine–glycine–aspartate (RGD) peptide promoted the adhesion and proliferation of stem cells, and the degradation of gelatin microspheres (GMs) produced a macroporous structure to enhance further the migration and aggregation of stem cells. Mesoporous silica nanoparticles (MSNs) sustained-release bone-forming peptide-1 (BFP-1) induced osteogenic differentiation, and the sustained release of the QK peptide from the GMs promoted angiogenesis. In vitro experiments have shown that this functionalized hydrogel stimulates the proliferation of hMSCs, encourages larger cell cluster formation, and enhances the osteogenic differentiation efficiency. The released QK facilitates the proliferation and migration of endothelial cells. In vivo experiments have also verified that this system has a better osteogenic effect, and more blood vessels were observed inside the hydrogel, than in other systems. In general, this research has led to the development of a tripeptide macroporous hydrogel that can simultaneously promote osteogenesis and angiogenesis, showing great promise for applications of 3D cultures and stem cell-based tissue engineering.
研究领域:
生物材料
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组织工程
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干细胞生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Wenxiao Shi,Yu Feng,Jincheng Tang,Yichang Xu,Wang Wei,Lichen Zhang,Xinzhao Jiang,Zhouye Ding,Kun Xi,Liang Chen,Yong Gu
The innate immune response is crucial to the inflammation, but how neutrophils and macrophages act in bone repair and tissue engineering treatment strategies await clarification. In this study, we found N2 neutrophils release stronger “eat me” signals to induce macrophage phagocytosis which then polarize into the M2c anti-inflammatory phenotype. This is beneficial for bone repair. Guided by this biological mechanism, we filled a mesoporous bioactive glass scaffold (MBG) with HAMA hydrogel loaded with TGFβ1 adenovirus (Ad@H), constructing a genetically engineered composite scaffold (Ad@H/M). The scaffold not only has good hydrophilicity and biocompatibility, but also provides mechanical stress support for bone repair. Adenovirus infection quickly induces N2 neutrophils, upregulating NF-κB and MAPK signaling pathways through Toll-like receptor 4 (TLR4) to promote the inflammatory response and macrophage phagocytosis. Macrophages perform phagocytosis and polarize towards the M2 phenotype, mediating the inflammatory response by inhibiting the PI3K-AKT-NF-κB pathway, maintaining homeostasis of the osteogenic microenvironment. The role of Ad@H/M scaffold in regulating early inflammation and promoting long-term bone regeneration was further validated in vivo. In brief, this study focuses on the cascade of reactions between neutrophils and macrophage subtypes, and reports a composite scaffold that coordinates the innate immune response to promote bone repair. This article is protected by copyright. All rights reserved
研究领域:
生物医学工程
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免疫学
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组织工程
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骨再生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）