Journal of Orthopaedic Surgery and Research
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2023
·Vol. 18
·期 1
·1-12
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IF 2.6
Huang Jun,Zhou Hongxiang,He Liang,Zhong Lin,Zhou Ding,Yin Zongsheng
Background Nonunion is a failure of fracture healing and a major complication after fractures. Ubiquitin-specific protease 1 (USP1) is a deubiquitinase that involved in cell differentiation and cell response to DNA damage. Herein we investigated the expression, function and mechanism of USP1 in nonunion. Methods and results Clinical samples were used to detect the USP1 expression in nonunion. ML323 was selected to inhibit USP1 expression throughout the study. Rat models and mouse embryonic osteoblasts cells (MC3T3-E1) were used to investigate the effects of USP1 inhibition on fracture healing and osteogenesis in vivo and in vitro, respectively. Histological changes were examined by micro-computerized tomography (Micro-CT), hematoxylin & eosin (H&E) staining and Masson staining. Alkaline phosphatase (ALP) activity detection and alizarin red staining were used for osteogenic differentiation observation. The expression of related factors was detected by quantitative real-time PCR, western blot or immunohistochemistry (IHC). It was shown that USP1 was highly expressed in nonunion patients and nonunion rats. USP1 inhibition by ML323 promoted fracture healing in nonunion rats and facilitated the expression of osteogenesis-related factors and the signaling of PI3K/Akt pathway. In addition, USP1 inhibition accelerated osteogenic differentiation and promoting PI3K/Akt signaling in MC3T3-E1 cells. Conclusions USP1 inhibition plays a promotive role in coordinating osteogenic differentiation and fracture healing during nonunion. PI3K/Akt may be the downstream pathway of USP1.
研究领域:
骨科
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Bioactive Materials
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2025
·
IF 20.3
Shengming Zhang,Weixian Hu,Yanzhi Zhao,Yuheng Liao,Kangkang Zha,Wenqian Zhang,Chenyan Yu,Jiewen Liao,Hui Li,Wu Zhou,Faqi Cao,Bobin Mi,Guohui Liu
Fracture healing in patients with type 2 diabetes mellitus (T2D) is markedly impaired, characterized by a prolonged inflammation phase and defective osteoblast differentiation at the fracture site. In this study, we identified aberrant cellular glycolysis at T2D fracture sites, with bone marrow mesenchymal stem cells (BMSCs) exhibiting suppressed glycolysis and macrophages displaying enhanced glycolysis, mediated by the dysregulation of hypoxia-inducible factor-1α (HIF-1α). To rectify these metabolic imbalances, we developed a multifunctional nanocomposite PN@MHV hydrogel. Myricitrin, a flavonoid glycoside, forms the MHV hydrogel by cross-linking with HA-PBA and PVA via hydrogen bonds, and upregulates glycolysis through HIF-1α, thus promoting osteoblast differentiation under high glucose environment. To further regulate the inflammatory microenvironment, we incorporated nanoparticles loaded with PX-478, a HIF-1α specific inhibitor, into the hydrogel, with folic acid covalently modified to target proinflammatory M1 macrophages. This PN@MHV hydrogel bidirectionally regulated glycolysis via HIF-1α, enhancing osteoblast differentiation while attenuating macrophage-mediated inflammation. Comprehensive in vitro and in vivo experiments in a T2D fracture mouse model confirmed the hydrogel's ability to improve the inflammatory microenvironment and accelerate bone healing. Our findings underscore the therapeutic potential of targeting cellular glycolysis as a promising approach for enhancing fracture healing in diabetic patients.
研究领域:
医学
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生物材料学
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代谢生物学
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DOI
PubMed
高影响因子
Bioactive Materials
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2020
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IF 8.724
Mingxue Chen,YangYang Li,Shuyun Liu,Zhaoxuan Feng,Hao Wang,Dejin Yang,Weimin Guo,Zhiguo Yuan,Shuang Gao,Yu Zhang,Kangkang Zha,Bo Huang,Fu Wei,Xinyu Sang,Qinyu Tian,Xuan Yang,Xiang sui,Yixin Zhou,Yufeng Zheng,Quanyi Guo
Tissue engineering provides a promising avenue for treating cartilage defects. However, great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration. In this study, decellularized cartilage extracellular matrix (ECM) and waterborne polyurethane (WPU) were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing (LDM) system, which combines rapid deposition manufacturing with phase separation techniques. The scaffolds successfully achieved hierarchical macro‐microporous structures. After adding ECM, WPU scaffolds were markedly optimized in terms of porosity, hydrophilia and bioactive components. Moreover, the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution, adhesion, and proliferation than the WPU scaffolds. Most importantly, the WPU-ECM scaffold could facilitate the production of glycosaminoglycan (GAG) and collagen and the upregulation of cartilage-specific genes. These results indicated that the WPU-ECM scaffold with hierarchical macro‐microporous structures could recreate a favorable microenvironment for cell adhesion, proliferation, differentiation, and ECM production. In vivo studies further revealed that the hierarchical macro‐microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model. Six months after implantation, the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage. In conclusion, the hierarchical macro‐microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.
研究领域:
组织工程学
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再生医学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
·
IF 13.2
Dongming Duan,Song Liu,Tianhua Xiao,Aiju Lou,Haiyan Huang,Yu Cai,Zunlei Gong,Lei Zhou,Le Wang
The increased risk of diabetic fractures, driven by high oxidative stress and a proinflammatory response at the site of bone injury, remains a treatment challenge. Traditional internal fixation materials pose numerous limitations, prompting the emergence of new biomaterials as superior alternatives due to advancements in bone tissue engineering research. This study develops an injectable magnesium-gallate (MgGA) bioenzyme-reinforced hydrogel bone adhesive to remodel the local inflammatory microenvironment and enhance diabetic fracture healing. The MgGA bioenzyme significantly improves toughness and bone adhesive strength owing to its interaction with polymer chains. The MgGA-containing, catalyst-like injectable bone adhesive facilitates the scavenging of overexpressed reactive oxygen species, promotes macrophage polarization to the M2 phenotype, and attenuates early-stage inflammation. The pathological tissue microenvironment-responsive MgGA enables the self-sacrificial and sustained release of Mg 2+ and gallic acid, regulating redox balance and promoting angiogenesis and osteogenesis. The developed MgGA hydrogel serves as a promising multifunctional bone adhesive, offering fracture fixation and accelerating diabetic bone regeneration in vivo, thereby representing a novel strategy for treating diabetic fractures.
研究领域:
生物材料学
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骨组织工程
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再生医学
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产品关联
DOI
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Xudan Xing,Zunlei Gong,Chuke Chen,Yeyin Lin,Peiyi Liu,Tianhua Xiao,Hui Yu,Yuanxin Li,Yucong Lin,Guoxin Tan,Chengyun Ning,Zenghui Wu,Le Wang,Lei Zhou
Diabetes is associated with excessive inflammation, which negatively impacts the fracture healing process and delays bone repair. Previously, growing evidence indicated that activation of the nod-like receptor (NLR) family, such as nod-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome induces a vicious cycle of chronic low-grade inflammatory responses in diabetic fracture. Here, we describe the synthesis of a bone adhesive hydrogel that can be locally injected into the fracture site and releases a natural inhibitor of NLRP3 (rutin) in response to pathological cue reactive oxygen species activity (ROS). The hydrogel (denoted as RPO) was facilely formed by the cross-linking of rutin-functionalized gelatin, poly(vinyl alcohol), and oxidized starch based on the dynamic schiff base and boronate ester bond. Specifically, rutin is conjugated in the RPO hydrogel via a ROS linker and is released as the linker is cleaved by active ROS. In vitro studies demonstrate that RPO hydrogel effectively mitigates oxidative stress, alleviates mitochondrial dysfunction, and limits the overactivation of NLRP3 inflammasome in bone marrow derived macrophages, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In a diabetic rat fracture model, RPO hydrogel significantly accelerates bone repair by modulating the inflammatory microenvironment. Our results demonstrate that local, on-demand NLRP3 inhibition for the treatment of diabetic fracture is achievable by using an injectable bioresponsive adhesive RPO hydrogel.
研究领域:
生物材料学
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炎症生物学
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骨科医学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Jiaqi Zhong,Xiaodong Hu,Jieyang Dong,Yujiong Chen,Botao Liu,Mingming Hao,Haijiao Xie,Chunhai Ke,Zhaoxiang Peng
Bone fractures pose significant clinical challenges and require innovative solutions for effective treatment and rapid recovery. Nanoscale protein-based materials are prominent in biotechnology and biomedicine, demonstrating versatility in biological processes and drug delivery. Herein, we designed and fabricated self-assembled keratin nanoparticles via a bisphosphonate (BP)-activated conformation-conservative assembly process. We determined the structural properties of the nanoparticles and explored the immunomodulatory and osteoinductivity functions retained from keratin. In addition, the keratin-BP nanoparticles could repair bone fractures. This study on multifunctional self-assembled protein-drug nanoparticles provides useful baseline data for exploring novel therapeutic options for acute bone fracture and other diseases.
研究领域:
生物技术
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生物医学
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纳米技术
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骨科
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DOI
高影响因子
Heliyon
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2024
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IF 3.4
Yingjie Wu,Mingxiang Fan,Shixiang Tan,Qiucheng Guo,Hegui Xu
Objective To examine and talk about the mechanism of the Huoxue Jiegu compound capsule's effects on osteoblasts and the PI3K/Akt/mTOR signal pathway in rabbits suffering from tibial fractures. Method In vitro, CCK8 was used to assess the survival rates. Alizarinred staining was used to evaluate mineralized nodules. ALP staining was used to observe the osteoblasts. qRT-PCR was used to determine the mRNA expression of the bone formation-related factors BMP-2, bFGF, and TGF-β. In vivo, three groups of nine male rabbits each were randomly assigned to three groups: the Model group, the Huoxue Jiegu compound capsule group (HXJGC group), and the inhibitor group (HXJGC+3-MA), four weeks following the intervention. HE staining was employed to examine the rabbits' bone histology. immunohistochemistry was employed to examine the relative expression of the proteins VEGF and LC3-II. Western Blot was utilized to examine the relative expression of the proteins Beclin-1, LC3-II/Ⅰ, p62, p-PI3K, p-AKT, and p-mTOR. Results Compared to the control group, the medium- and high-dose groups exhibited considerably higher survival rates ( P < 0.05), as well as enhanced cell proliferation and differentiation ( P < 0.05) and more pronounced mineralized nodules. ( P < 0.05), but the low-dose groups showed no appreciable variation. In the low, medium, and high-dose groups, there was a substantial reduction in the expression of bFGF mRNA, whereas the levels of BMP-2 and TGF-β mRNA were considerably higher than in the control group ( P < 0.05). In vivo, after four weeks of treatment, the model control group and inhibito group had a large amount of fibrous hyperplasia accompanied by bleeding and a small amount of inflammatory cell infiltration. But in the HXJGC group, new cartilage appeared, and the surface of the cartilage was smooth and flat. Beclin-1 and LC3-II/I expression in the HXJGC+3 MA group was significantly lower than in the HXJGC and Model groups ( P < 0.05). The HXJGC group showed lower p62 expression than the HXJGC+3 MA and model groups ( P < 0.05). The HXJGC group exhibited significantly reduced levels of p-PI3K, p-AKT, and p-mTOR expression in comparison to HXJGC+3 MA groups ( P < 0.05). Conclusion Rabbits with tibial fractures can be treated with HXJGC, which can control the expression of the PI3K/Akt/mTOR signal pathway. It can promote the differentiation and maturation of osteoblasts at the fracture end of rabbits, accelerate the recovery of fractures, and achieve the purpose of treating the disease.
研究领域:
医学
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生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-22
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IF 15.7
Xiao Tianhua,Gong Zunlei,Duan Dongming,Yu Hui,Liu Song,Jiang Yuhe,Xing Xudan,Wu Zenghui,Wang Le,Yang Xuebin B.,Tronci Giuseppe,Ning Chengyun,Tan Guoxin,Zhou Lei
Current treatments for osteoporotic fractures primarily target bone-resorbing osteoclasts, but they often fail to address fibrosis—a buildup of fibrous tissue that disrupts bone healing. This fibrosis is frequently triggered by bisphosphonates, which, while effective in reducing bone loss, also activate fibroblasts and impair callus formation. Here we show that an injectable hydrogel bone adhesive composed of magnesium-alendronate metal-organic frameworks (Mg-ALN MOF) embedded in a gelatin/dialdehyde starch network can simultaneously suppress bone resorption and reduce fibrosis. The Mg-ALN MOF adhesive binds firmly to irregular bone surfaces and degrades under acidic osteoporotic conditions, gradually releasing Mg 2+ ions. These ions competitively bind to sclerostin (SOST), thereby interrupting the SOST/TGF-β signaling pathway that promotes fibroblast activation and abnormal collagen deposition. This dual-action mechanism significantly enhances fracture healing, resulting in a 27.8% improvement in flexural strength. Our findings suggest a promising therapeutic strategy that combines mechanical support with targeted regulation of both bone resorption and pathological fibrosis.
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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产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOTECHNOLOGY
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2023
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IF 2.6
Liu Hu,Li Tao,Ma Ben,Wang Yue,Sun Jun
Osteoblast regeneration, characterized by osteoblast differentiation, is the basis of fracture healing and accelerates fracture repair. It has been reported that hyaluronan and proteoglycan link protein 1 (HAPLN1) is overexpressed during osteoblast differentiation and regulates cartilage regeneration, but its function in fracture healing remains unclear. To elucidate this issue, we collected clinical blood samples of fracture healing, established a femoral fracture rat model, and induced an osteoblast differentiation cell model. We found that HAPLN1 was overexpressed in the serum of patients with fracture healing and the bone tissues of rats with fracture healing. Furthermore, the expression of HAPLN1 was increased time dependently during the osteogenic differentiation of MC3T3-E1 cells. HAPLN1 silencing prevented osteoblast differentiation and mineralization in MC3T3-E1 cells as evidenced by decreased osteoblast differentiation-related factors, suppressed alkaline phosphatase activities, and reduced alizarin red positive staining. Mechanically, the bone morphogenic protein 4 (BMP4)/Smad1/5/8 pathway, a facilitator of osteoblastic differentiation, was found to be inhibited by HAPLN1 knockdown, and inhibition of BMP4/Smad1/5/8 signaling enhanced the effects caused by HAPLN1 silencing. These findings demonstrated that HAPLN1 might promote fracture healing by facilitating osteogenic differentiation through the BMP4/Smad1/5/8 pathway, indicating that targeting HAPLN1 may be a feasible therapeutic candidate for fracture repair. Graphical Abstract
研究领域:
骨科
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 38
·2102465
·
IF 18.808
Jincheng Tang,Kun Xi,Hao Chen,Lingjun Wang,Dongya Li,Yun Xu,Tianwen Xin,Liang Wu,Yidi Zhou,Jiang Bian,Zhengwei Cai,Huilin Yang,Lianfu Deng,Yong Gu,Wenguo Cui,Liang Chen
Osteogenic glue that reproduces the natural bone composition represents the final frontier of orthopedic adhesives with the potential to revolutionize surgical strategies against comminuted fractures. However, it is difficult to achieve an all-in-one formula, which could provide flexible and reliable adhesiveness while avoiding interfering with or even promoting the healing of glued fractures. Herein, an osteogenic glue characterized by inorganic-in-organic integration between amine-modified mesoporous bioactive glass nanoparticles (AMBGN) and bioadhesive gelatin-dextran network (GelDex) is introduced as an all-in-one tool to flexibly adhere and splice bone fragments and subsequently guide fracture healing during degradation. Relying on such integration, a 4-fold improvement in cohesiveness is presented, followed by a nearly 5-fold enhancement in adhesive strength in ex vivo porcine bone samples. The reversible and re-adjustable adhesiveness also enables glue to effectively splice intricate fragments from highly comminuted fractures in the rabbit radius in an in vivo environment. Moreover, well-preserved organic–inorganic integrity during degradation of the glue guides sustained interfacial osteogenesis and achieve satisfying healing outcomes in glued fractures, as observed by the 2-fold improvement in biomechanical and radiological performance compared with commercially available cyanoacrylate adhesives. The current findings propose an all-in-one solution for the fixation of bone fragments during surgery.
研究领域:
骨科
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材料科学
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生物医学工程
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DOI
高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Haonan Xiu,Kaili Yang,Li Dong,Haohua Lai,Zhangyu Zhu,Dongdong Jiang,Junwei Yan,Chen Shi,Shaowei Pan,Zhaowei Yin,Lihui Yuwen,Bin Liang
Managing fracture infections is a significant challenge in trauma orthopedics, given the limited self-healing capacity of fractures and the difficulty in eradicating infections. In this study, Cu 2 MoS 4 nanoparticles (CMSs) with are prepared enzyme-like activity and both pH and near-infrared (NIR) light responsiveness. These CMSs are combined with methacrylated gelatin (GelMA) to synthesize CMSs hydrogels (CMSs@Gel) with antimicrobial and bone tissue repair-promoting capabilities. In vitro and in vivo experiments, the CMSs@Gel demonstrated good biocompatibility; peroxidase-like (POD), oxidase-like (OXD), and catalase-like (CAT) activities; excellent photothermal conversion efficiency; and immunomodulatory capacity. Furthermore, the CMSs@Gel exhibited slow degradation, enabling it to exert different pH-responsive enzyme activities and modulate the production of reactive oxygen species (ROS) and the polarization of macrophages throughout the treatment process. Notably, these effects are significantly enhanced under near-infrared (NIR) light. Additionally, under NIR irradiation, the CMSs@Gel maintained the fracture environment at a mild temperature (40–42 °C), promoting osteogenesis and angiogenesis. In summary, the CMSs@Gel enhances bactericidal activity during fracture infection and effectively promotes fracture healing after infection control, providing long-term therapeutic effects. This study offers a robust theoretical basis for the staged and long-term treatment of fracture infections in the future.
研究领域:
生物医学工程
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材料科学
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骨科
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组织工程
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光热治疗
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抗菌技术
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骨再生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Yuan Wang,Zhen Pan,Qianliang Wang,Yuexia Shu,Zhenyu Tan,Yujie Chen,Jieming He,Jia Wang,Jielin Wang,Jun Yan
Osteoporotic fractures typically exhibit delayed healing due to impaired cell recruitment, chronic inflammation, and disrupted neurovascular signaling. Sensory nerve signaling plays a crucial role in fracture repair, and its deficiency is a significant factor leading to delayed healing. Addressing these deficiencies is crucial to overcoming the challenges associated with delayed bone repair in osteoporosis. In this study, a smart composite hydrogel (denoted as OCS-MPC) was synthesized by embedding CGRP-functionalized polydopamine-coated MXene nanosheets (MXene/PDA/CGRP) into boronic acid-modified oxidized hyaluronic acid-crosslinked carboxymethyl chitosan (OHA-PBA/CMCS) hydrogel loaded with SDF-1. OCS-MPC hydrogel enables the controlled release of SDF-1 and CGRP, aiming to promote early callus formation and late-stage callus remodeling in osteoporotic fractures. Due to dynamic crosslinking via imine and borate ester bonds, OCS-MPC exhibits rapid gelation, injectability, and self-healing properties. In vitro experiments demonstrated excellent osteogenic, angiogenic, and neurogenic properties of OCS-MPC hydrogel. In vivo studies using an osteoporotic femoral fracture model showed that OCS-MPC hydrogel enhanced MSCs recruitment via the SDF-1/CXCR4 signaling axis, significantly improving callus formation in the early stages of fracture repair. Additionally, OCS-MPC hydrogel significantly promoted callus mineralization and remodeling in the later stages of osteoporotic fracture healing through enhancing CGRP signaling. Immunofluorescence analysis further confirmed increased expression of TUBB3, CGRP, and CD31, indicating successful regeneration of the neurovascular network. These findings highlight the potential of OCS-MPC hydrogel in addressing both early and late-stage challenges of osteoporotic fracture healing, providing a promising therapeutic strategy for enhancing bone regeneration in osteoporotic patients.
研究领域:
生物医学工程
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骨科
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再生医学
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产品关联
DOI
PubMed
高影响因子
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