|
1
|
Chen CK, Chiu HW, Nguyen HT, Lu HT, Chuang AEY. Transdermally administered nanozymes-infused F127/methylcellulose hydrogel for osteoarthritis relief via immunomodulatory pathways. Int J Biol Macromol 2025:144114. [PMID: 40354857 DOI: 10.1016/j.ijbiomac.2025.144114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/22/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
Osteoarthritis (OA) is a debilitating condition characterized by chronic inflammation, oxidative stress, hypoxia, angiogenesis-driven pain, and cartilage degradation, thus presenting significant therapeutic challenges. Herein, we introduce a wearable percutaneous hydrogel (Pluronic F127/methylcellulose) encapsulation platform, designed to address the multifaceted pathology of OA through a synergistic integration of multifunctional components. This nanomedicine-hydrogel system incorporates platelet-derived extracellular vesicles (pEVs) for inflammation delivery, phototherapeutic molybdenum disulfide (MoS2), capsaicin (CAP) and diferuloylmethane (DIF) for potent anti-inflammatory and antioxidative effects and hydrogen-bonded organic frameworks (HOFs) to enhance drug encapsulation and conductivity. Experimental findings demonstrated the pEV/MoS2/DIF/CAP NZHOF@F127/MC's ability to mitigate inflammation by promoting macrophage polarization from the M1 to the M2 phenotype, alleviate oxidative stress, inhibit angiogenesis, and modulate hypoxic microenvironments through the percutaneous phototherapeutic pEV/MoS2/DIF/CAP NZ-HOF@F127/MC. In vivo studies in a rat model of OA revealed substantial reductions in joint inflammation, enhanced cartilage regeneration, and improved mobility following near-infrared (NIR)-triggered phototherapy. The pEV/MoS2/DIF/CAP NZ-HOF@F127/MC's multifaceted mechanisms, including precise drug delivery, controlled release, and on-demand photo-responsiveness, underscore its transformative potential for OA management. These findings present a promising therapeutic strategy for OA, addressing inflammation, oxidative stress, and joint lesion mitigation, with strong potential for clinical translation.
Collapse
Affiliation(s)
- Chih-Kuang Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hui-Wen Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Hieu Trung Nguyen
- Department of Orthopedics and Trauma, Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Viet Nam
| | - Hsien-Tsung Lu
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Orthopedic, Taipei Medical University Hospital, Taipei City 11031, Taiwan.
| | - Andrew E-Y Chuang
- Cell Physiology and Molecular Image Research Center, Taipei Medical University-Wan Fang Hospital, Taipei 11696, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City 235603, Taiwan.
| |
Collapse
|
|
2
|
Xue P, Wang J, Fu Y, He H, Gan Q, Liu C. Material-Mediated Immunotherapy to Regulate Bone Aging and Promote Bone Repair. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2409886. [PMID: 39981851 DOI: 10.1002/smll.202409886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/19/2025] [Indexed: 02/22/2025]
Abstract
As the global population ages, an increasing number of elderly people are experiencing weakened bone regenerative capabilities, resulting in slower bone repair processes and associated risks of various complications. This review outlines the research progress on biomaterials that promote bone repair through immunotherapy. This review examines how manufacturing technologies such as 3D printing, electrospinning, and microfluidic technology contribute to enhancing the therapeutic effects of these biomaterials. Following this, it provides detailed introductions to various anti-osteoporosis drug delivery systems, such as injectable hydrogels, nanoparticles, and engineered exosomes, as well as bone tissue engineering materials and coatings used in immunomodulation. Moreover, it critically analyzes the current limitations of biomaterial-mediated bone immunotherapy and explores future research directions for material-mediated bone immunotherapy. This review aims to inspire new approaches and broaden perspectives in addressing the challenges of bone repair and aging by exploring innovative biomaterial-mediated immunotherapy strategies.
Collapse
Affiliation(s)
- Pengfei Xue
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Jiayi Wang
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Yu Fu
- School of Aerospace Engineering and Applied Mechanics, Tongji University, Zhangwu Road 100, Shanghai, 200092, China
| | - Hongyan He
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Qi Gan
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, P. R. China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, P. R. China
| |
Collapse
|
|
3
|
Ni F, Li J, Yin Q, Chen Y, Shao Z, Wang H. Novel lncRNA LncMSTRG.11341.25 Promotes Osteogenic Differentiation of Human Bone Marrow Stem Cells via the miR-939-5p/PAX8 Axis. RESEARCH (WASHINGTON, D.C.) 2025; 8:0601. [PMID: 39916798 PMCID: PMC11798881 DOI: 10.34133/research.0601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/09/2025] [Accepted: 01/11/2025] [Indexed: 02/09/2025]
Abstract
Human bone marrow stem cells (hBMSCs) play an important role during the fracture healing phase. Previous clinical studies by our research group found that fracture healing time was obviously delayed in patients who underwent splenectomy, for combined traumatic fractures and splenic rupture, which is most likely related to the dysregulation of immune inflammatory function of the body after splenectomy. A large number of studies have reported that the inflammatory factor interleukin-1β plays an important role in the multi-directional differentiation ability and immune regulation of BMSC, but its specific regulatory mechanism needs to be further studied. Recently, long noncoding RNAs (lncRNAs) have attracted remarkable attention owing to their close relationship with stem cell osteogenesis and potential role in various bone diseases. In this study, we explored the molecular mechanism of a novel lncRNA, LncMSTRG.11341.25 (LncMSTRG25), in terms of its effects on osteogenic differentiation of hBMSCs. Our results reveal significant up-regulation of LncMSTRG25, osteogenic differentiation markers during the osteogenic differentiation of hBMSCs, and decreased expression of miR-939-5p with an increase in differentiation time. LncMSTRG25 knockdown significantly inhibited the osteogenic ability of hBMSCs. When we knocked down PAX8 alone, we found that the osteogenic ability of hBMSCs was also significantly reduced. The interaction between LncMSTRG25 and PAX8 was verified using the RNA immunoprecipitation assay, RNA pull-down assays, silver staining, and the dual-luciferase reporter. The results show that LncMSTRG25 can function as a sponge to adsorb miR-939-5p, inducing the osteogenic differentiation of hBMSCs by activating PAX8. These findings deepen our understanding of the regulatory role of lncRNA-miRNA-mRNA networks in the immune microenvironment of bone marrow, and highlight the important role played by the spleen as an immune organ in fracture healing.
Collapse
Affiliation(s)
- Feifei Ni
- Department of Orthopedics, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianjun Li
- Department of Orthopaedics,
Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Qin Yin
- Department of Orthopedics, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi 214000, Jiangsu, China
| | - Yangyang Chen
- Department of Orthopedic,
The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hong Wang
- Department of Orthopedics, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
|
4
|
Liu L, Yang Y, Sun P. LINC00941 affects the proliferation, apoptosis and differentiation of osteoblasts by regulating the miR-335-5p/KAT7 axis. J Orthop Surg Res 2025; 20:75. [PMID: 39838460 PMCID: PMC11749574 DOI: 10.1186/s13018-025-05469-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/07/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Fractures are the prevalent traumatic conditions encountered in orthopedic practices. The rising incidence of fractures has emerged as a pressing global health concern. Although the majority of individuals with fractures experience complete recovery of bone structure and function, approximately 10% of those with fractures exhibit delayed fracture healing (DFH). The objective of this investigation was to explore the function and underlying mechanisms of LINC00941 in the advancement of DFH, as well as its involvement in the regulation of osteoblastic differentiation by regulating the miR-335-5p/KAT7 axis. METHODS The expression levels of LINC00941, miR-335-5p, KAT7 and osteoblast differentiation-related markers were assessed using RT-qPCR. The proliferation of MC3T3-E1 cells was evaluated through the CCK-8 assay, and cell apoptosis was analyzed via flow cytometry. The targeted regulatory relationships between LINC00941 and miR-335-5p, as well as between miR-335-5p and KAT7 were verified by a dual-luciferase reporter gene assay. RESULT The expression of LINC00941 was significantly up regulated, while miR-335-5p exhibited a notable downregulation in DFH patients, both of LINC00941 and miR-335-5p have been identified as potential predicted markers for DFH. Furthermore, LINC00941 has been demonstrated to inhibit osteoblast proliferation, promote apoptosis, and suppress osteoblast differentiation through the regulation of the miR-335-5p/KAT7 axis. CONCLUSION LINC00941/ miR-335-5p/KAT7 axis may be a therapeutic target for DFH.
Collapse
Affiliation(s)
- Longjin Liu
- Department of Orthopedic 2, Zhongxian People's Hospital of Chongqing, Chongqing, 404300, China
| | - Ye Yang
- Orthopedic Joint Trauma Ward, General Hospital of Southern Theater Command of PLA, Guangzhou, 510030, China
| | - Pengxiao Sun
- Department of Joint 1, Xi'An International Medical Center Hospital, No.777, Xitai Road, Gaoxin District, Xi'An, 710000, China.
| |
Collapse
|
|
5
|
Yang S, Zhu Y, Ji C, Zhu H, Lao A, Zhao R, Hu Y, Zhou Y, Zhou J, Lin K, Xu Y. A five-in-one novel MOF-modified injectable hydrogel with thermo-sensitive and adhesive properties for promoting alveolar bone repair in periodontitis: Antibacterial, hemostasis, immune reprogramming, pro-osteo-/angiogenesis and recruitment. Bioact Mater 2024; 41:239-256. [PMID: 39149594 PMCID: PMC11324614 DOI: 10.1016/j.bioactmat.2024.07.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 07/07/2024] [Accepted: 07/13/2024] [Indexed: 08/17/2024] Open
Abstract
Periodontitis is a chronic inflammatory disease caused by plaque that destroys the alveolar bone tissues, resulting in tooth loss. Poor eradication of pathogenic microorganisms, persistent malignant inflammation and impaired osteo-/angiogenesis are currently the primary challenges to control disease progression and rebuild damaged alveolar bone. However, existing treatments for periodontitis fail to comprehensively address these issues. Herein, an injectable composite hydrogel (SFD/CS/ZIF-8@QCT) encapsulating quercetin-modified zeolitic imidazolate framework-8 (ZIF-8@QCT) is developed. This hydrogel possesses thermo-sensitive and adhesive properties, which can provide excellent flowability and post-injection stability, resist oral fluid washout as well as achieve effective tissue adhesion. Inspirationally, it is observed that SFD/CS/ZIF-8@QCT exhibits a rapid localized hemostatic effect following implantation, and then by virtue of the sustained release of zinc ions and quercetin exerts excellent collective functions including antibacterial, immunomodulation, pro-osteo-/angiogenesis and pro-recruitment, ultimately facilitating excellent alveolar bone regeneration. Notably, our study also demonstrates that the inhibition of osteo-/angiogenesis of PDLSCs under the periodontitis is due to the strong inhibition of energy metabolism as well as the powerful activation of oxidative stress and autophagy, whereas the synergistic effects of quercetin and zinc ions released by SFD/CS/ZIF-8@QCT are effective in reversing these biological processes. Overall, our study presents innovative insights into the advancement of biomaterials to regenerate alveolar bone in periodontitis.
Collapse
Affiliation(s)
- Shiyuan Yang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yan Zhu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Chunxiao Ji
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huimin Zhu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - An Lao
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Zhao
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Hu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yuning Zhou
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Jia Zhou
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Kaili Lin
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanjin Xu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| |
Collapse
|
|
6
|
Ma Y, Wang Y, Tong S, Wang Y, Wang Z, Sui R, Yang K, Witte F, Yang S. Porous metal materials for applications in orthopedic field: A review on mechanisms in bone healing. J Orthop Translat 2024; 49:135-155. [PMID: 40226784 PMCID: PMC11993841 DOI: 10.1016/j.jot.2024.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/16/2024] [Accepted: 08/01/2024] [Indexed: 04/15/2025] Open
Abstract
Background Porous metal materials have been widely studied for applications in orthopedic field, owing to their excellent features and properties in bone healing. Porous metal materials with different compositions, manufacturing methods, and porosities have been developed. Whereas, the systematic mechanisms on how porous metal materials promote bone healing still remain unclear. Methods This review is concerned on the porous metal materials from three aspects with accounts of specific mechanisms, inflammatory regulation, angiogenesis and osteogenesis. We place great emphasis on different cells regulated by porous metal materials, including mesenchymal stem cells (MSCs), macrophages, endothelial cells (ECs), etc. Result The design of porous metal materials is diversified, with its varying pore sizes, porosity material types, modification methods and coatings help researchers create the most experimentally suitable and clinically effective scaffolds. Related signal pathways presented from different functions showed that porous metal materials could change the behavior of cells and the amount of cytokines, achieving good influence on osteogenesis. Conclusion This article summarizes the current progress achieved in the mechanism of porous metal materials promoting bone healing. By modulating the cellular behavior and physiological status of a spectrum of cellular constituents, such as macrophages, osteoblasts, and osteoclasts, porous metal materials are capable of activating different pathways and releasing regulatory factors, thus exerting pivotal influence on improving the bone healing effect. The translational potential of this article Porous metal materials play a vital role in the treatment of bone defects. Unfortunately, although an increasing number of studies have been concentrated on the effect of porous metal materials on osteogenesis-related cells, the comprehensive regulation of porous metal materials on the host cell functions during bone regeneration and the related intrinsic mechanisms remain unclear. This review summarizes different design methods for porous metal materials to fabricate the most suitable scaffolds for bone remodeling, and systematically reviews the corresponding mechanisms on inflammation, angiogenesis and osteogenesis of porous metal materials. This review can provide more theoretical framework and innovative optimization for the application of porous metal materials in orthopedics, dentistry, and other areas, thereby advancing their clinical utility and efficacy.
Collapse
Affiliation(s)
- Yutong Ma
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Yi Wang
- The First Clinical College of China Medical University, Shenyang, 110001, China
| | - Shuang Tong
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Yuehan Wang
- The First Clinical College of China Medical University, Shenyang, 110001, China
| | - Zhuoya Wang
- The First Clinical College of China Medical University, Shenyang, 110001, China
| | - Rongze Sui
- The First Clinical College of China Medical University, Shenyang, 110001, China
| | - Ke Yang
- Institute of Metal Research, Chinese Academy of Sciences, Shenyang, 110016, China
| | - Frank Witte
- Department of Prosthodontics, Geriatric Dentistry and Craniomandibular Disorders, Charité Medical University, Assmannshauser Strasse 4–6, 14197, Berlin, Germany
| | - Shude Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
| |
Collapse
|
|
7
|
Kang R, Huang L, Zeng T, Ma J, Jin D. Long non-coding TRPM2-AS regulates fracture healing by targeting miR-545-3p/Bmp2. J Orthop Surg Res 2024; 19:466. [PMID: 39118176 PMCID: PMC11308420 DOI: 10.1186/s13018-024-04969-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVE Delayed fracture healing increases the suffering of patients. An in-depth investigation of the pathogenesis of delayed fracture healing may offer new direction for the prevention and treatment. METHODS The study included 63 normal healing tibial fractures and 58 delayed healing tibial fractures patients. Long non-coding RNA (lncRNA)TRPM2-AS, microRNA-545-3p (miR-545-3p), bone morphogenetic protein 2 (Bmp2) mRNA and osteogenic differentiation markers, including runt-related transcription factor 2 (Runx2), osteocalcin (Ocn), and alkaline phosphatase (Alp) mRNA expression were determined by Real-time quantitative reverse transcription-polymerase chain reaction in serum and MC3T3-E1 cells. The prediction potential of TRPM2-AS in delayed healing fracture patients was verified by receiver operating characteristic curves. The binding relationship of TRPM2-AS/miR-545-3p/Bmp2 was evaluated by dual luciferase reporter gene assay. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry. RESULTS TRPM2-AS was remarkably down-regulated in patients with delayed fracture healing and could better predict the fracture healing status. TRPM2-AS downregulation inhibited osteogenic markers mRNA expression, restrained proliferation, and promoted apoptosis of MC3T3-E1 cells (p < 0.05). In delayed fracture healing, miR-545-3p was dramatically up-regulated and was negatively regulated by TRPM2-AS. Reducing miR-545-3p eliminate the negative effect of TRPM2-AS down-regulation on osteoblast proliferation and differentiation (p < 0.05). miR-545-3p targets Bmp2, which plays a positive role in osteoblast differentiation (p < 0.05). CONCLUSION This study found that TRPM2-AS has the potential to be a diagnostic marker for delayed fracture healing and revealed that the TRPM2-AS/miR-545-3p/Bmp2 axis affects fracture healing by regulating osteoblast.
Collapse
Affiliation(s)
- Renjie Kang
- Department of Orthopedics, Peking University First Hospital Taiyuan Hospital, Taiyuan, 030000, China
| | - Lina Huang
- Department of Rehabilitation Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Teng Zeng
- Department of Orthopedics, The First People's Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, No. 8, Hangkong Road, Shashi District, Jingzhou, 434000, China
| | - Jinliang Ma
- Department of Orthopedics, The First People's Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, No. 8, Hangkong Road, Shashi District, Jingzhou, 434000, China.
| | - Danjie Jin
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, No. 68, Gehu Middle Road, Wujin District, Changzhou, 213000, China.
| |
Collapse
|
|
8
|
Nair A, Chandrashekhar H R, Day CM, Garg S, Nayak Y, Shenoy PA, Nayak UY. Polymeric functionalization of mesoporous silica nanoparticles: Biomedical insights. Int J Pharm 2024; 660:124314. [PMID: 38862066 DOI: 10.1016/j.ijpharm.2024.124314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/25/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
Mesoporous silica nanoparticles (MSNs) endowed with polymer coatings present a versatile platform, offering notable advantages such as targeted, pH-controlled, and stimuli-responsive drug delivery. Surface functionalization, particularly through amine and carboxyl modification, enhances their suitability for polymerization, thereby augmenting their versatility and applicability. This review delves into the diverse therapeutic realms benefiting from polymer-coated MSNs, including photodynamic therapy (PDT), photothermal therapy (PTT), chemotherapy, RNA delivery, wound healing, tissue engineering, food packaging, and neurodegenerative disorder treatment. The multifaceted potential of polymer-coated MSNs underscores their significance as a focal point for future research endeavors and clinical applications. A comprehensive analysis of various polymers and biopolymers, such as polydopamine, chitosan, polyethylene glycol, polycaprolactone, alginate, gelatin, albumin, and others, is conducted to elucidate their advantages, benefits, and utilization across biomedical disciplines. Furthermore, this review extends its scope beyond polymerization and biomedical applications to encompass topics such as surface functionalization, chemical modification of MSNs, recent patents in the MSN domain, and the toxicity associated with MSN polymerization. Additionally, a brief discourse on green polymers is also included in review, highlighting their potential for fostering a sustainable future.
Collapse
Affiliation(s)
- Akhil Nair
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Raghu Chandrashekhar H
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Candace M Day
- UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Sanjay Garg
- UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Yogendra Nayak
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Padmaja A Shenoy
- Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Usha Y Nayak
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| |
Collapse
|
|
9
|
Liao J, Lu L, Chu X, Xiong Y, Zhou W, Cao F, Cheng P, Shahbazi MA, Liu G, Mi B. Cell membrane coated nanoparticles: cutting-edge drug delivery systems for osteoporosis therapy. NANOSCALE 2024; 16:8236-8255. [PMID: 38584466 DOI: 10.1039/d3nr06264c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Osteoporosis, characterized by a reduction in bone mineral density, represents a prevalent skeletal disorder with substantial global health implications. Conventional therapeutic strategies, exemplified by bisphosphonates and hormone replacement regimens, though effective, encounter inherent limitations and challenges. Recent years have witnessed the surge of cell-membrane-coated nanoparticles (CMNPs) as a promising intervention for osteoporosis, leveraging their distinct attributes including refined biocompatibility, heightened pharmaceutical payload capacity, as well as targeted drug release kinetics. However, a comprehensive review consolidating the application of CMNPs-based therapy for osteoporosis remains absent within the existing literature. In this review, we provide a concise overview of the distinctive pathogenesis associated with osteoporosis, alongside an in-depth exploration of the physicochemical attributes intrinsic to CMNPs derived from varied cellular sources. Subsequently, we explore the potential utility of CMNPs, elucidating emerging trends in their deployment for osteoporosis treatment through multifaceted therapeutic approaches. By linking the notable attributes of CMNPs with their roles in mitigating osteoporosis, this review serves as a catalyst for further advances in the design of advanced CMNPs tailored for osteoporosis management. Ultimately, such progress is promising for enhancing outcomes in anti-bone loss interventions, paving the way for clinical translation in the near future.
Collapse
Affiliation(s)
- Jiewen Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Li Lu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Xiangyu Chu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| | - Wu Zhou
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Faqi Cao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Peng Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Mohammad-Ali Shahbazi
- Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
| |
Collapse
|
|
10
|
Zhan M, Sun H, Wang Z, Li G, Yang R, Mignani S, Majoral JP, Shen M, Shi X. Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis. ACS NANO 2024; 18:10625-10641. [PMID: 38563322 DOI: 10.1021/acsnano.4c00909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.
Collapse
Affiliation(s)
- Mengsi Zhan
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Huxiao Sun
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Zhiqiang Wang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Gaoming Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Rui Yang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Serge Mignani
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal
| | - Jean-Pierre Majoral
- Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, CEDEX 4, 31077 Toulouse, France
- Université Toulouse, 118 Route de Narbonne, CEDEX 4, 31077 Toulouse, France
| | - Mingwu Shen
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal
| |
Collapse
|
|
11
|
Wang B, Huang Y, Cai Q, Du Z, Li X. Biomaterials for diabetic bone repair: Influencing mechanisms, multi-aspect progress and future prospects. COMPOSITES PART B: ENGINEERING 2024; 274:111282. [DOI: 10.1016/j.compositesb.2024.111282] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2025]
|
|
12
|
Xiao B, Liu Y, Chandrasiri I, Adjei-Sowah E, Mereness J, Yan M, Benoit DSW. Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2305336. [PMID: 37797180 PMCID: PMC10922143 DOI: 10.1002/smll.202305336] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/03/2023] [Indexed: 10/07/2023]
Abstract
Despite decades of progress, developing minimally invasive bone-specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) functionalized with a peptide that targets tartrate-resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase-3 beta (GSK3β) inhibitor, via the TRAP binding peptide-NP (TBP-NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture-associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP-NP is comprehensively investigated herein. TBP-NPAR28 promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast-macrophage co-cultures in vitro. Longitudinal analysis of TBP-NPAR28 -mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti-inflammatory and downregulated pro-inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone-targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone-associated diseases.
Collapse
Affiliation(s)
- Baixue Xiao
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Yuxuan Liu
- Materials Science Program, University of Rochester, Rochester, NY, 14623, USA
| | - Indika Chandrasiri
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Emmanuela Adjei-Sowah
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Jared Mereness
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Ming Yan
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
| | - Danielle S W Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14623, USA
- Materials Science Program, University of Rochester, Rochester, NY, 14623, USA
- Department of Chemical Engineering, University of Rochester, Rochester, NY, 14623, USA
- Department of Bioengineering, Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR, 97403, USA
| |
Collapse
|
|
13
|
Xiao B, Adjei-Sowah E, Benoit DSW. Integrating osteoimmunology and nanoparticle-based drug delivery systems for enhanced fracture healing. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 56:102727. [PMID: 38056586 PMCID: PMC10872334 DOI: 10.1016/j.nano.2023.102727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/23/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023]
Abstract
Fracture healing is a complex interplay of molecular and cellular mechanisms lasting from days to weeks. The inflammatory phase is the first stage of fracture healing and is critical in setting the stage for successful healing. There has been growing interest in exploring the role of the immune system and novel therapeutic strategies, such as nanoparticle drug delivery systems in enhancing fracture healing. Advancements in nanotechnology have revolutionized drug delivery systems to the extent that they can modulate immune response during fracture healing by leveraging unique physiochemical properties. Therefore, understanding the intricate interactions between nanoparticle-based drug delivery systems and the immune response, specifically macrophages, is essential for therapeutic efficacy. This review provides a comprehensive overview of the relationship between the immune system and nanoparticles during fracture healing. Specifically, we highlight the influence of nanoparticle characteristics, such as size, surface properties, and composition, on macrophage activation, polarization, and subsequent immune responses. IMPACT STATEMENT: This review provides valuable insights into the interplay between fracture healing, the immune system, and nanoparticle-based drug delivery systems. Understanding nanoparticle-macrophage interactions can advance the development of innovative therapeutic approaches to enhance fracture healing, improve patient outcomes, and pave the way for advancements in regenerative medicine.
Collapse
Affiliation(s)
- Baixue Xiao
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14623, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14623, USA
| | - Emmanuela Adjei-Sowah
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14623, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14623, USA
| | - Danielle S W Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, NY 14623, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14623, USA; Department of Chemical Engineering, University of Rochester, Rochester, NY 14623, USA; Materials Science Program, University of Rochester, Rochester, NY 14623, USA; Department of Bioengineering, Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR 97403, USA.
| |
Collapse
|
|
14
|
Zhong L, Chang W, Luo B, Gao W, He H, Fang M, Li H, Wen Z, Chen Y. Development and validation of a disulfidptosis and disulfide metabolism-related risk index for predicting prognosis in lung adenocarcinoma. Cancer Cell Int 2024; 24:2. [PMID: 38167017 PMCID: PMC10763446 DOI: 10.1186/s12935-023-03204-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Disulfidptosis is a recently proposed novel cell death mode in which cells with high SLC7A11 expression induce disulfide stress and cell death in response to glucose deficiency. The purpose of the research was to explore the function of disufidptosis and disulfide metabolism in the progression of lung adenocarcinoma (LUAD). METHODS The RNA-seq data from TCGA were divided into high/low expression group on the base of the median expression of SLC7A11, and the characteristic of differentially expressed disulfide metabolism-related genes. Least absolute shrinkage and selection operator (LASSO) algorithm was conducted the disulfidptosis and disulfide metabolism risk index. The tumor mutation burden (TMB), mechanism, pathways, tumor microenvironment (TME), and immunotherapy response were assessed between different risk groups. The role of TXNRD1 in LUAD was investigated by cytological experiments. RESULTS We established the risk index containing 5 genes. There are significant differences between different risk groups in terms of prognosis, TMB and tumor microenvironment. Additionally, the low-risk group demonstrated a higher rate of response immunotherapy in the prediction of immunotherapy response. Experimental validation suggested that the knockdown of TXNRD1 suppressed cell proliferation, migration, and invasion of LUAD. CONCLUSION Our research highlights the enormous potential of disulfidptosis and disulfide metabolism risk index in predicting the prognosis of LUAD. And TXNRD1 has great clinical translational ability.
Collapse
Affiliation(s)
- Leqi Zhong
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Wuguang Chang
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China
| | - Bin Luo
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Wuyou Gao
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Huanhuan He
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat sen University Cancer Center, Guangzhou, 510060, China
| | - Mouxiang Fang
- Institute of Biophotonics, South China Normal University, Guangzhou, China
| | - Hongmu Li
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Zhesheng Wen
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Youfang Chen
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| |
Collapse
|
|
15
|
Wang X, Li Y, Pu X, Liu G, Qin H, Wan W, Wang Y, Zhu Y, Yang J. Macrophage-related therapeutic strategies: Regulation of phenotypic switching and construction of drug delivery systems. Pharmacol Res 2024; 199:107022. [PMID: 38043691 DOI: 10.1016/j.phrs.2023.107022] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/05/2023]
Abstract
Macrophages, as highly phenotypic plastic immune cells, play diverse roles in different pathological conditions. Changing and controlling the phenotypes of macrophages is considered a novel potential therapeutic intervention. Meanwhile, specific transmembrane proteins anchoring on the surface of the macrophage membrane are relatively conserved, supporting its functional properties, such as inflammatory chemotaxis and tumor targeting. Thus, a series of drug delivery systems related to specific macrophage membrane proteins are commonly used to treat chronic inflammatory diseases. This review summarizes macrophages-based strategies for chronic diseases, discusses the regulation of macrophage phenotypes and their polarization processes, and presents how to design and apply the site-specific targeted drug delivery systems in vivo based on the macrophages and their derived membrane receptors. It aims to provide a better understanding of macrophages in immunoregulation and proposes macrophages-based targeted therapeutic approaches for chronic diseases.
Collapse
Affiliation(s)
- Xi Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Yixuan Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Xueyu Pu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Guiquan Liu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Honglin Qin
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Weimin Wan
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Yuying Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Yan Zhu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Jian Yang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China.
| |
Collapse
|
|
16
|
Xia B, Gao X, Qian J, Li S, Yu B, Hao Y, Wei B, Ma T, Wu H, Yang S, Zheng Y, Gao X, Guo L, Gao J, Yang Y, Zhang Y, Wei Y, Xue B, Jin Y, Luo Z, Zhang J, Huang J. A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2305374. [PMID: 37652460 DOI: 10.1002/adma.202305374] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/03/2023] [Indexed: 09/02/2023]
Abstract
Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves.
Collapse
Affiliation(s)
- Bing Xia
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xue Gao
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Jiaqi Qian
- College of Chemical Engineering, Fuzhou University, Xueyuan Road, Fuzhou, 350108, P. R. China
| | - Shengyou Li
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Beibei Yu
- Department of Neurosurgery, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710032, P. R. China
| | - Yiming Hao
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Bin Wei
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Teng Ma
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Haining Wu
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Shijie Yang
- Department of Neurosurgery, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710032, P. R. China
| | - Yi Zheng
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xueli Gao
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, 710072, P. R. China
| | - Lingli Guo
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Jianbo Gao
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Yujie Yang
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Yongfeng Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710032, P. R. China
| | - Yitao Wei
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Borui Xue
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Yan Jin
- Research and Development Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Zhuojing Luo
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Jin Zhang
- College of Chemical Engineering, Fuzhou University, Xueyuan Road, Fuzhou, 350108, P. R. China
| | - Jinghui Huang
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, P. R. China
| |
Collapse
|
|
17
|
Guan H, Wang W, Jiang Z, Zhang B, Ye Z, Zheng J, Chen W, Liao Y, Zhang Y. Magnetic Aggregation-Induced Bone-Targeting Nanocarrier with Effects of Piezo1 Activation and Osteogenic-Angiogenic Coupling for Osteoporotic Bone Repair. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023:e2312081. [PMID: 38102981 DOI: 10.1002/adma.202312081] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/07/2023] [Indexed: 12/17/2023]
Abstract
Osteoporosis, characterized by an imbalance in bone homeostasis, is a global health concern. Bone defects are difficult to heal in patients with osteoporosis. Classical drug treatments for osteoporotic bone defects have unsatisfactory efficacy owing to side effects and imprecise delivery problems. In this study, a magnetic aggregation-induced bone-targeting poly(lactic-co-glycolic acid, PLGA)-based nanocarrier (ZOL-PLGA@Yoda1/SPIO) is synthesized to realize dual-targeted delivery and precise Piezo1-activated therapy for osteoporotic bone defects. Piezo1 is an important mechanotransducer that plays a key role in regulating bone homeostasis. To achieve dual-targeting properties, ZOL-PLGA@Yoda1/SPIO is fabricated using zoledronate (ZOL)-decorated PLGA, superparamagnetic iron oxide (SPIO), and Piezo1-activated molecule Yoda1 via the emulsion solvent diffusion method. Bone-targeting molecular mediation and magnetic aggregation-induced properties can jointly and effectively achieve precise delivery to localized bone defects. Moreover, Yoda1 loading enables targeted and efficient mimicking of mechanical signals and activation of Piezo1. Experiments in vivo and in vitro demonstrate that ZOL-PLGA@Yoda1/SPIO can activate Piezo1 in bone defect areas of osteoporotic mice, improve osteogenesis through YAP/β-catenin signaling axis, promote a well-coordinated osteogenesis-angiogenesis coupling, and significantly accelerate bone reconstruction within the defects without noticeable side effects. Overall, this novel dual-targeting nanocarrier provides a potentially effective strategy for the clinical treatment of osteoporotic bone defects.
Collapse
Affiliation(s)
- Haitao Guan
- The School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Wei Wang
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China
| | - Zichao Jiang
- Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China
| | - Boyu Zhang
- The School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Zhipeng Ye
- The School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Judun Zheng
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China
| | - Wei Chen
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
- Orthopaedic Research Institute of Hebei Province, Shijiazhuang, 050051, China
| | - Yuhui Liao
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China
| | - Yingze Zhang
- The School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
- Orthopaedic Research Institute of Hebei Province, Shijiazhuang, 050051, China
| |
Collapse
|
|
18
|
Gong JS, Zhu GQ, Zhang Y, Chen B, Liu YW, Li HM, He ZH, Zou JT, Qian YX, Zhu S, Hu XY, Rao SS, Cao J, Xie H, Wang ZX, Du W. Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells. Mater Today Bio 2023; 23:100854. [PMID: 38024846 PMCID: PMC10665677 DOI: 10.1016/j.mtbio.2023.100854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/22/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023] Open
Abstract
Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.
Collapse
Affiliation(s)
- Jiang-Shan Gong
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Guo-Qiang Zhu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Yu Zhang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Bei Chen
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yi-Wei Liu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Hong-Ming Li
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Ze-Hui He
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Jing-Tao Zou
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Yu-Xuan Qian
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Sheng Zhu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Xin-Yue Hu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
| | - Shan-Shan Rao
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
| | - Jia Cao
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
| | - Hui Xie
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
| | - Zhen-Xing Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
| | - Wei Du
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China
- Department of Rehabilitation Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| |
Collapse
|
|
19
|
Majrashi M, Kotowska A, Scurr D, Hicks JM, Ghaemmaghami A, Yang J. Sustained Release of Dexamethasone from 3D-Printed Scaffolds Modulates Macrophage Activation and Enhances Osteogenic Differentiation. ACS APPLIED MATERIALS & INTERFACES 2023; 15. [PMID: 38016086 PMCID: PMC10726309 DOI: 10.1021/acsami.3c09774] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/08/2023] [Accepted: 11/14/2023] [Indexed: 11/30/2023]
Abstract
Enhancing osteogenesis via modulating immune cells is emerging as a new approach to address the current challenges in repairing bone defects and fractures. However, much remains unknown about the crosstalk between immune cells and osteolineage cells during bone formation. Moreover, biomaterial scaffold-based approaches to effectively modulate this crosstalk to favor bone healing are also lacking. This study is the first to investigate the interactions between macrophages and mesenchymal stem cells (MSCs) in co-cultures with the sustained release of an anti-inflammatory and pro-osteogenesis drug (dexamethasone) from three-dimensional (3D)-printed scaffolds. We successfully achieved the sustained release of dexamethasone from polycaprolactone (PCL) by adding the excipient-sucrose acetate isobutyrate (SAIB). Dexamethasone was released over 35 days in the 17-163 nM range. The osteogenic differentiation of MSCs was enhanced by M1 macrophages at early time points. The late-stage mineralization was dominated by dexamethasone, with little contribution from the macrophages. Besides confirming BMP-2 whose secretion was promoted by both dexamethasone and M1 macrophages as a soluble mediator for enhanced osteogenesis, IL-6 was found to be a possible new soluble factor that mediated osteogenesis in macrophage-MSC co-cultures. The phenotype switching from M1 to M2 was drastically enhanced by the scaffold-released dexamethasone but only marginally by the co-cultured MSCs. Our results offer new insight into macrophage-MSC crosstalk and demonstrate the potential of using drug-release scaffolds to both modulate inflammation and enhance bone regeneration.
Collapse
Affiliation(s)
- Majed Majrashi
- School
of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
- Biodiscovery
Institute, University of Nottingham, Nottingham NG7 2RD, U.K.
| | - Anna Kotowska
- School
of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
| | - David Scurr
- School
of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
| | - Jacqueline M. Hicks
- Nanoscale
and Microscale Research Centre, University
of Nottingham, Nottingham NG7 2RD, U.K.
| | - Amir Ghaemmaghami
- School
of Life Sciences, University of Nottingham, Nottingham NG7 2RD, U.K.
| | - Jing Yang
- School
of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
- Biodiscovery
Institute, University of Nottingham, Nottingham NG7 2RD, U.K.
| |
Collapse
|
|
20
|
Ren Y, Zhang S, Weeks J, Rangel-Moreno J, He B, Xue T, Rainbolt J, Morita Y, Shu Y, Liu Y, Kates SL, Schwarz EM, Xie C. Reduced angiogenesis and delayed endochondral ossification in CD163 -/- mice highlights a role of M2 macrophages during bone fracture repair. J Orthop Res 2023; 41:2384-2393. [PMID: 36970754 PMCID: PMC10522791 DOI: 10.1002/jor.25564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 02/24/2023] [Accepted: 03/24/2023] [Indexed: 04/10/2023]
Abstract
While recent studies showed that macrophages are critical for bone fracture healing, and lack of M2 macrophages have been implicated in models of delayed union, functional roles for specific M2 receptors have yet to be defined. Moreover, the M2 scavenger receptor CD163 has been identified as a target to inhibit sepsis following implant-associated osteomyelitis, but potential adverse effects on bone healing during blockage therapy have yet to be explored. Thus, we investigated fracture healing in C57BL/6 versus CD163-/- mice using a well-established closed, stabilized, mid-diaphyseal femur fracture model. While gross fracture healing in CD163-/- mice was similar to that of C57BL/6, plain radiographs revealed persistent fracture gaps in the mutant mice on Day 14, which resolved by Day 21. Consistently, 3D vascular micro-CT demonstrated delayed union on Day 21, with reduced bone volume (74%, 61%, and 49%) and vasculature (40%, 40%, and 18%) compared to C57BL/6 on Days 10, 14, and 21 postfracture, respectively (p < 0.01). Histology confirmed large amounts of persistent cartilage in CD163-/- versus C57BL/6 fracture callus on Days 7 and 10 that resolves over time, and immunohistochemistry demonstrated deficiencies in CD206+ M2 macrophages. Torsion testing of the fractures confirmed the delayed early union in CD163-/- femurs, which display decreased yield torque on Day 21, and a decreased rigidity with a commensurate increase in rotation at yield on Day 28 (p < 0.01). Collectively, these results demonstrate that CD163 is required for normal angiogenesis, callus formation, and bone remodeling during fracture healing, and raise potential concerns about CD163 blockade therapy.
Collapse
Affiliation(s)
- Youliang Ren
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Shiyang Zhang
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Jason Weeks
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Javier Rangel-Moreno
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Bin He
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Thomas Xue
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Joshua Rainbolt
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Yugo Morita
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Ye Shu
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Yuting Liu
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Stephen L. Kates
- Department of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Edward M. Schwarz
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| | - Chao Xie
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
| |
Collapse
|
|
21
|
Weng J, Fan H, Liu H, Tang S, Zheng Y. Abnormal Decrease of Macrophage ALKBH5 Expression Causes Abnormal Polarization and Inhibits Osteoblast Differentiation. Stem Cells Int 2023; 2023:9974098. [PMID: 37519314 PMCID: PMC10372297 DOI: 10.1155/2023/9974098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 06/18/2023] [Accepted: 07/05/2023] [Indexed: 08/01/2023] Open
Abstract
Peri-implant tissue inflammation is an inflammatory injury that occurs in the soft and hard tissues surrounding the implant and is the main cause of short- or long-term failure of implant prosthetic restorations, which is compounded by bone loss and bone destruction in the alveolar bone of diabetes patients with peri-implantitis. However, the mechanisms underlying the persistence of diabetic peri-implantitis, as well as the essential connections and key molecules that regulate its start and progression, remain unknown. In this study, we discovered that M1 macrophage polarization was abnormally enhanced in diabetic peri-implantitis and influenced the osteogenic differentiation of mesenchymal stem cells. RNA sequencing revealed that ALKBH5 expression was abnormally reduced in diabetic peri-implantitis. Further mechanism study showed that ALKBH5 and its mediated m6A can influence osteogenic differentiation, which in turn influences the persistence of diabetic peri-implantitis. Our findings present a new mechanism for the suppression of osteoblast development in diabetic peri-implantitis and a new treatment strategy to promote anabolism by inhibiting ALKBH5.
Collapse
Affiliation(s)
- Junquan Weng
- Department of Stomatology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Haidong Fan
- Department of Stomatology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Huijuan Liu
- Department of Stomatology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Su Tang
- Department of Stomatology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yuyan Zheng
- Department of Stomatology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| |
Collapse
|
|
22
|
Chu X, Xiong Y, Knoedler S, Lu L, Panayi AC, Alfertshofer M, Jiang D, Rinkevich Y, Lin Z, Zhao Z, Dai G, Mi B, Liu G. Immunomodulatory Nanosystems: Advanced Delivery Tools for Treating Chronic Wounds. RESEARCH (WASHINGTON, D.C.) 2023; 6:0198. [PMID: 37456931 PMCID: PMC10348408 DOI: 10.34133/research.0198] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/02/2023] [Indexed: 07/18/2023]
Abstract
The increasingly aging society led to a rise in the prevalence of chronic wounds (CWs), posing a significant burden to public health on a global scale. One of the key features of CWs is the presence of a maladjusted immune microenvironment characterized by persistent and excessive (hyper)inflammation. A variety of immunomodulatory therapies have been proposed to address this condition. Yet, to date, current delivery systems for immunomodulatory therapy remain inadequate and lack efficiency. This highlights the need for new therapeutic delivery systems, such as nanosystems, to manage the pathological inflammatory imbalance and, ultimately, improve the treatment outcomes of CWs. While a plethora of immunomodulatory nanosystems modifying the immune microenvironment of CWs have shown promising therapeutic effects, the literature on the intersection of immunomodulatory nanosystems and CWs remains relatively scarce. Therefore, this review aims to provide a comprehensive overview of the pathogenesis and characteristics of the immune microenvironment in CWs, discuss important advancements in our understanding of CW healing, and delineate the versatility and applicability of immunomodulatory nanosystems-based therapies in the therapeutic management of CWs. In addition, we herein also shed light on the main challenges and future perspectives in this rapidly evolving research field.
Collapse
Affiliation(s)
- Xiangyu Chu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Samuel Knoedler
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02152, USA
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377 Munich, Germany
| | - Li Lu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Adriana C Panayi
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02152, USA
- Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Ludwigshafen/Rhine, Germany
| | - Michael Alfertshofer
- Division of Hand, Plastic and Aesthetic Surgery, Ludwig - Maximilian University Munich, Munich, Germany
| | - Dongsheng Jiang
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377 Munich, Germany
| | - Yuval Rinkevich
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377 Munich, Germany
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Zhiming Zhao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Suizhou Hospital, Hubei University of Medicine, Suizhou 441300, China
| | - Guandong Dai
- Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, Guangdong 518118, China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| |
Collapse
|
|
23
|
Zhang D, Dang Y, Deng R, Ma Y, Wang J, Ao J, Wang X. Research Progress of Macrophages in Bone Regeneration. J Tissue Eng Regen Med 2023; 2023:1512966. [PMID: 40226416 PMCID: PMC11919137 DOI: 10.1155/2023/1512966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/07/2022] [Accepted: 12/17/2022] [Indexed: 04/15/2025]
Abstract
Bone tissue regeneration plays an increasingly important role in contemporary clinical treatment. The reconstruction of bone defects remains a huge challenge for clinicians. Bone regeneration is regulated by the immune system, in which inflammation is an important regulating factor in bone formation and remodeling. As the main cells involved in inflammation, macrophages play a key role in osteogenesis by polarizing into different phenotypes during different stages of bone regeneration. Considering this, this review mainly summarizes the function of macrophage in bone regeneration based on mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, and vascular cells. In conclusion, anti-inflammatory macrophages (M2) have a greater potentiality to promote bone regeneration than M0 and classically activated proinflammatory macrophages (M1). In the fracture and bone defect models, tissue engineering materials can induce the transition from M1 to M2, alter the bone microenvironment, and promote bone regeneration through interactions with bone-related cells and blood vessels. The review provides a further understanding of macrophage polarization behavior in the evolving field of bone immunology.
Collapse
Affiliation(s)
- Dingmei Zhang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yi Dang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Renli Deng
- Nurse Department, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jing Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jun Ao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| |
Collapse
|
|
24
|
Ma Y, Yang J, Hu Y, Xia Z, Cai K. Osteogenic differentiation of the MSCs on silk fibroin hydrogel loaded Fe3O4@PAA NPs in static magnetic field environment. Colloids Surf B Biointerfaces 2022; 220:112947. [DOI: 10.1016/j.colsurfb.2022.112947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/30/2022] [Accepted: 10/15/2022] [Indexed: 11/05/2022]
|
|
25
|
Xiong Y, Mi BB, Lin Z, Hu YQ, Yu L, Zha KK, Panayi AC, Yu T, Chen L, Liu ZP, Patel A, Feng Q, Zhou SH, Liu GH. The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity. Mil Med Res 2022; 9:65. [PMID: 36401295 PMCID: PMC9675067 DOI: 10.1186/s40779-022-00426-8] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 10/30/2022] [Indexed: 11/21/2022] Open
Abstract
Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.
Collapse
Affiliation(s)
- Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Bo-Bin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yi-Qiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Le Yu
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | - Kang-Kang Zha
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.,Key Laboratory of Biorheological Science and Technology,Ministry of Education College of Bioengineering, Chongqing University, Shapingba, Chongqing, 400044, China
| | - Adriana C Panayi
- Department of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02152, USA
| | - Tao Yu
- Department of Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.,Department of Physics, Center for Hybrid Nanostructure (CHyN), University of Hamburg, Hamburg, 22761, Germany
| | - Zhen-Ping Liu
- Department of Physics, Center for Hybrid Nanostructure (CHyN), University of Hamburg, Hamburg, 22761, Germany.,Joint Laboratory of Optofluidic Technology and System,National Center for International Research on Green Optoelectronics, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou, 510006, China
| | - Anish Patel
- Skeletal Biology Laboratory, Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02120, USA
| | - Qian Feng
- Key Laboratory of Biorheological Science and Technology,Ministry of Education College of Bioengineering, Chongqing University, Shapingba, Chongqing, 400044, China.
| | - Shuan-Hu Zhou
- Skeletal Biology Laboratory, Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02120, USA. .,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA.
| | - Guo-Hui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
| |
Collapse
|
|
26
|
Song W, Yang F, Yang H, Xu Y, Song SJ, Meng Y, Wei ST, Wan T, Zhou Y, Zhou B, Kuang J, Yu T, Qiu WX. Enhanced Immunotherapy Based on Combining the Pro-phagocytosis and Anti-phagocytosis Checkpoint Blockade for Tumor Eradication. J Med Chem 2022; 65:14832-14842. [PMID: 36260348 DOI: 10.1021/acs.jmedchem.2c01351] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Compared to the activation of acquired immunity by the immune checkpoint blockade, the activation of innate immunity via anti-phagocytosis checkpoint blockade could significantly increase the beneficiary population of immunotherapy. However, the activation of innate immunity and the occurrence of phagocytosis are only accomplished when the interaction between pro-phagocytosis signals and anti-phagocytosis signals is realized. Herein, a versatile nanoplatform (DHMR) based on mesoporous silicon nanoparticles (MSNPs) has been constructed. Two drugs, doxorubicin, a chemotherapeutic drug which could initiate tumor cells to release pro-phagocytosis signals, and RRx-001, an immunoadjuvant that could effectively implement the anti-phagocytosis checkpoint blockade, were loaded in MSNPs. Further decoration of hyaluronic acid encapsulation endows DHMR with the function of tumor targeting and long circulation. Ultimately, the DHMR system could efficiently and accurately target tumor tissue, release the drugs in the tumor microenvironment, achieve the activation of innate immunity, and finally dramatically inhibit the growth and metastasis of tumor cells.
Collapse
Affiliation(s)
- Wen Song
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Fan Yang
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Hang Yang
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Yi Xu
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Shu-Jun Song
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Yan Meng
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P. R. China
| | - Si-Tian Wei
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Tao Wan
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Ying Zhou
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Bin Zhou
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| | - Jing Kuang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P. R. China
| | - Tao Yu
- Department of Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China
| | - Wen-Xiu Qiu
- Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P. R. China
| |
Collapse
|
|
27
|
IL-6 and Leptin Are Potential Biomarkers for Osteoporotic Fracture Risk Assessment and Prediction of Postmenopausal Women with Low Bone Mass: A Follow-Up Study Using a Regional Sample Cohort. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8691830. [PMID: 35993023 PMCID: PMC9385352 DOI: 10.1155/2022/8691830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022]
Abstract
Osteoporotic fracture, a major complication which is known as the outcome postmenopausal osteoporosis, seriously threatens the health of postmenopausal women. At present, the traditional osteoporotic fracture prediction methods are characterized by inconvenient application and time-consuming statistical results, while predictive serum biomarkers can make up for this shortcoming. Accurate and advanced risk prediction of osteoporotic fracture is meaningful to early prevention and intervention, effectively avoiding the risk of this disease and the secondary fracture in the surgical treatment. In this study, based on the BEYOND cohort, a 2-year follow-up study was conducted after subjects participated to survey if OF occurred. Independent sample t-test and Mann–Whitney U-test were used to analyze the differences of bone metabolism biomarkers between the OF and non-OF group. Cox proportional hazard model was used to screen the potential biomarkers might be used to predict OF risk. ROC curves and AUCs were used to analyze the predictive accuracy, and the Delong's test was used to compare the differences between the AUCs. 15 postmenopausal women with low bone mass and OF were found, and other 60 subjects without OF were matched with 1 : 4, age, and BMI classification as control group. The serum IL-6 (OR = 1.139, 95%CI = 1.058 − 1.226) and leptin (OR = 0.921, 95%CI = 0.848 − 1.000) were found as OF risk predictive biomarkers for postmenopausal women with low bone mass with high accuracy (IL − 6 = 0.871) (leptin = 0.813) and accuracy enhanced when they were combined (AUC = 0.898). The results of Delong's test showed that the difference of AUC between leptin and IL-6&Leptin was meaningful (P = 0.024) but meaningless between IL-6 and leptin (P = 0.436), IL-6 and IL-6&Leptin (P = 0.606). To sum up, IL-6 and leptin are the predictive biomarkers of OF for postmenopausal women with low bone mass. The IL-6 can improve the prediction accuracy of leptin (P = 0.024), but not vice versa (P = 0.606). Trial Information. Registered on the Chinese Clinical Trial Registry already. (Registration Number: ChiCTR-SOC-17013090).
Collapse
|
|
28
|
Metformin Facilitates Osteoblastic Differentiation and M2 Macrophage Polarization by PI3K/AKT/mTOR Pathway in Human Umbilical Cord Mesenchymal Stem Cells. Stem Cells Int 2022; 2022:9498876. [PMID: 35761829 PMCID: PMC9233575 DOI: 10.1155/2022/9498876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are the most promising multipotent stem cells that can differentiate into osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair and regeneration. The immune system is a key player in regulating bone remodeling. In recent years, the association between the immune system and bone metabolism has become an increasing focus of interest. Metformin, a glucose-lowering drug, exerts powerful impact on metabolic signaling. However, whether metformin can modulate bone metabolism or whether metformin can influence immune milieu by regulation of macrophages has not been thoroughly elucidated. Herein, we specifically explored the complex interactions between macrophages and human umbilical cord mesenchymal stem cells (UC-MSCs) in the context of metformin. Our research demonstrated that metformin not only stimulated osteogenesis of UC-MSCs but also influenced the immune system via promoting M2 but reducing M1 macrophages. Mechanically, we found that metformin-treated M2 macrophages possessed more potent osteoinductive capacity in our coculture system. Molecularly, these metformin-stimulated M2 macrophages facilitated osteogenesis via activating the PI3K/AKT/mTOR pathway. As demonstrated by using PI3K-specific inhibitor LY294002, we found that the pathway inhibitor partly reversed osteoinductive activity which was activated by coculture of metformin-treated M2 macrophages. Overall, our novel research illuminated the cooperative and synergistic effects of metformin and M2 macrophages on the dynamic balance of bone metabolism.
Collapse
|
|
29
|
Mi B, Chen L, Xiong Y, Yang Y, Panayi AC, Xue H, Hu Y, Yan C, Hu L, Xie X, Lin Z, Zhou W, Cao F, Xiao X, Feng Q, Liu G. Osteoblast/Osteoclast and Immune Cocktail Therapy of an Exosome/Drug Delivery Multifunctional Hydrogel Accelerates Fracture Repair. ACS NANO 2022; 16:771-782. [PMID: 34979087 DOI: 10.1021/acsnano.1c08284] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The osteoblast/osteoclast and M1/M2 macrophage ratios play critical roles in delayed fracture healing. Robust osteoblast differentiation and M2 macrophage polarization can substantiality promote fracture repair; however, the combined effect of these strategies has not been previously studied. In this study, we constructed a cocktail therapy to simultaneously regulate the osteoblast/osteoclast and M1/M2 macrophage balance. The cocktail therapy composed of a natural polymer hyaluronic-acid-based hydrogel (HA hydrogel, which has a tissue-adhesive, injectable, self-healing, anti-inflammation profile), engineered endothelial cell-derived exosomes (EC-ExosmiR-26a-5p), and APY29, an IRE-1α inhibitor. This allowed for specific delivery of EC-ExosmiR-26a-5p and APY29 for osteoblast/osteoclast and macrophage regulation, respectively. The results suggested that the cocktail therapy exerted pro-fracture repair effects with each of its components established as indispensable. The assessed cocktail therapy provides insight into synergistic strategies and is useful for developing more suitable pro-fracture repair therapy.
Collapse
Affiliation(s)
- Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yayan Yang
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
| | - Adriana C Panayi
- Department of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts 02152, United States
| | - Hang Xue
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yiqiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Chenchen Yan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Liangcong Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Xudong Xie
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Wu Zhou
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Faqi Cao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Xiufeng Xiao
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
| | - Qian Feng
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| |
Collapse
|