In Situ Regulation of Macrophage Polarization to Enhance Osseointegration Under Diabetic Conditions Using Injectable Silk/Sitagliptin Gel Scaffolds

Geng, Xianguo; Liu, Keyin; Wang, Tianji; Hu, Xiaofan; Wang, Jing; Gao, Zhiheng; Lei, Wei; Yan, Feng; Tao, Tiger H.

doi:10.1002/advs.202002328

Cited by 39 publications

(28 citation statements)

References 45 publications

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“…Mechanistically, M2 macrophages secrete osteogenic factors that stimulate the differentiation and activation of MSCs and subsequently increase bone mineralization. Recent data have demonstrated that the polarization of M2 macrophages is capable of stimulating MSCs into mature osteoblasts and increasing bone mineralization in vitro . , Consistently, our study indicated that interventions that favor M2 macrophage polarization might be a novel approach for bone fracture treatment.…”

Section: Resultssupporting

confidence: 86%

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Zhou

Lin

Xiong

et al. 2021

ACS Appl. Mater. Interfaces

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The immune system and skeletal system are closely linked. Macrophages are one of the most important immune cells for bone remodeling, playing a prohealing role mainly through M2 phenotype polarization. Baicalein (5,6,7-trihydroxyflavone, BCL) has been well documented to have a noticeable promotion effect on M2 macrophage polarization. However, due to the limitations in targeted delivery to macrophages and the toxic effect on other organs, BCL has rarely been used in the treatment of bone fractures. In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), which could be magnetically delivered to the fracture site. This induced macrophage recruitment in a targeted manner, polarizing them toward the M2 phenotype, which was demonstrated to induce mesenchymal stem cells (MSCs) toward osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with β-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW-targeting peptide to obtain the targeted nanosystem. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH), resulting in the removal of cyclodextrin (CD) gatekeeper, which is a key element in the pro-bone-remodeling functions such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation. This nanosystem passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

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Section: Resultssupporting

confidence: 86%

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Zhou

Lin

Xiong

et al. 2021

ACS Appl. Mater. Interfaces

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“…Mechanistically, M2 macrophages secrete osteogenic factors that stimulate the differentiation and activation of MSCs, and subsequently increase bone mineralization. Recent data have demonstrated that M2 macrophages polarization are capable to stimulate MSCs into mature osteoblasts and increase bone mineralization in vitro [34,35]. Consistently, our study indicated that interventions that favor M2 macrophage polarization may be a novel approach for bone fracture treatment.…”

Section: M2 Macrophage Polarization Induces Mscs Towards Osteoblasitc Differentiation In Vitrosupporting

confidence: 86%

Magnetically-Targeted Nanoparticle-Guided M2 Macrophage Polarization For Fracture Healing Promotion

Zhou

Lin

Xiong

et al. 2021

Preprint

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Background: Macrophages are essential for fracture healing, acting mainly through remodeling of the extracellular matrix and promotion of angiogenesis. The role of macrophages in regulating osteogenic differentiation, particularly that of the M2 phenotype, is increasingly researched. Baicalein (BCL) had also been shown to have pro-fracture-healing effects.Results: In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), that could be magnetically delivered to the fracture site. These induced macrophage recruitment in a targeted manner, polarizing them towards the M2 phenotype, and thereby inducing MSCs towards osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with β-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW targeting peptide to obtain the targeted nano-system. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH) resulting in the removing of CD gatekeeper, which is a key element in the pro-bone-remodeling functions, such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation.Conclusions: This nano-system passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

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“…The typical immunomodulatory mechanism of biomaterials for tissue repair is to switch the macrophage phenotypes from pro-inflammatory M1 to anti-inflammatory M2 21 , 54 , 55 . For bone implants, studies have showed that excessive M1 macrophages can cause bones absorption, which is an important factor leading to implant loosening or implantation failure 56 , 57 .…”

Section: Resultsmentioning

confidence: 99%

Engineering immunomodulatory and osteoinductive implant surfaces via mussel adhesion-mediated ion coordination and molecular clicking

et al. 2022

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Immune response and new tissue formation are important aspects of tissue repair. However, only a single aspect is generally considered in previous biomedical interventions, and the synergistic effect is unclear. Here, a dual-effect coating with immobilized immunomodulatory metal ions (e.g., Zn2+) and osteoinductive growth factors (e.g., BMP-2 peptide) is designed via mussel adhesion-mediated ion coordination and molecular clicking strategy. Compared to the bare TiO2 group, Zn2+ can increase M2 macrophage recruitment by up to 92.5% in vivo and upregulate the expression of M2 cytokine IL-10 by 84.5%; while the dual-effect of Zn2+ and BMP-2 peptide can increase M2 macrophages recruitment by up to 124.7% in vivo and upregulate the expression of M2 cytokine IL-10 by 171%. These benefits eventually significantly enhance bone-implant mechanical fixation (203.3 N) and new bone ingrowth (82.1%) compared to the bare TiO2 (98.6 N and 45.1%, respectively). Taken together, the dual-effect coating can be utilized to synergistically modulate the osteoimmune microenvironment at the bone-implant interface, enhancing bone regeneration for successful implantation.

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In Situ Regulation of Macrophage Polarization to Enhance Osseointegration Under Diabetic Conditions Using Injectable Silk/Sitagliptin Gel Scaffolds

Cited by 39 publications

References 45 publications

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Magnetically-Targeted Nanoparticle-Guided M2 Macrophage Polarization For Fracture Healing Promotion

Engineering immunomodulatory and osteoinductive implant surfaces via mussel adhesion-mediated ion coordination and molecular clicking

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