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      Injectable bone cement with magnesium-containing microspheres enhances osteogenesis via anti-inflammatory immunoregulation

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          Abstract

          Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects. Amongst different kinds of injectable bone cements, bioactive calcium phosphate bone cement (CPC) has been widely studied due to its biological activity. However, its dense structure and poor biodegradability prevent the ingrowth of living tissue, which leads to undesirable bone regeneration and clinical translation. To address this issue, we prepared bone cement based on Magnesium-containing microspheres (MMSs) that can not only be cured into a 3D porous scaffold but also have controllable biodegradability that continuously provides space for desired tissue ingrowth. Interestingly, magnesium ions released from MMSs cement (MMSC) trigger positive immunomodulation via upregulation of the anti-inflammatory genes IL-10 and M2 macrophage polarization with increased expression of CD206, which is beneficial to osteogenesis. Moreover, the physicochemical properties of MMSC, including heat release, rheology and setting time, can be tuned to meet the requirements of injectable bone cement for clinical application. Using a rat model, we have demonstrated that MMSC promoted osteogenesis via mediation of tissue ingrowth and anti-inflammatory immunomodulation. The study provides a paradigm for the design and preparation of injectable bone cements with 3D porous structures, biodegradability and anti-inflammatory immunoregulation to efficiently promote osteogenesis.

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          Highlights

          • Magnesium containing microspheres (MMSs) were prepared successfully by a modified liquid drop condensation method.

          • MMSs cement had 3D porous structure with biodegradability and anti-inflammatory osteoimmunomodulation mediated by the Mg 2+.

          • A new strategy was provided for the design and preparation of novel injectable bone cements with desired osteogenesis.

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          Most cited references38

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          Foreign body reaction to biomaterials.

          The foreign body reaction composed of macrophages and foreign body giant cells is the end-stage response of the inflammatory and wound healing responses following implantation of a medical device, prosthesis, or biomaterial. A brief, focused overview of events leading to the foreign body reaction is presented. The major focus of this review is on factors that modulate the interaction of macrophages and foreign body giant cells on synthetic surfaces where the chemical, physical, and morphological characteristics of the synthetic surface are considered to play a role in modulating cellular events. These events in the foreign body reaction include protein adsorption, monocyte/macrophage adhesion, macrophage fusion to form foreign body giant cells, consequences of the foreign body response on biomaterials, and cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells. Biomaterial surface properties play an important role in modulating the foreign body reaction in the first two to four weeks following implantation of a medical device, even though the foreign body reaction at the tissue/material interface is present for the in vivo lifetime of the medical device. An understanding of the foreign body reaction is important as the foreign body reaction may impact the biocompatibility (safety) of the medical device, prosthesis, or implanted biomaterial and may significantly impact short- and long-term tissue responses with tissue-engineered constructs containing proteins, cells, and other biological components for use in tissue engineering and regenerative medicine. Our perspective has been on the inflammatory and wound healing response to implanted materials, devices, and tissue-engineered constructs. The incorporation of biological components of allogeneic or xenogeneic origin as well as stem cells into tissue-engineered or regenerative approaches opens up a myriad of other challenges. An in depth understanding of how the immune system interacts with these cells and how biomaterials or tissue-engineered constructs influence these interactions may prove pivotal to the safety, biocompatibility, and function of the device or system under consideration.
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            Inflammation, fracture and bone repair.

            The reconstitution of lost bone is a subject that is germane to many orthopedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk among inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte-macrophage-osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair.
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              Osteoimmunomodulation for the development of advanced bone biomaterials

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                Author and article information

                Contributors
                Journal
                Bioact Mater
                Bioact Mater
                Bioactive Materials
                KeAi Publishing
                2452-199X
                19 March 2021
                October 2021
                19 March 2021
                : 6
                : 10
                : 3411-3423
                Affiliations
                [a ]Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China
                [b ]Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China
                [c ]Institute of Regulatory Science for Medical Devices, Huazhong University of Science and Technology, Wuhan, 430074, China
                [d ]Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland, 4059, Australia
                [e ]Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland, 4059, Australia
                Author notes
                []Corresponding author. Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China yingyingdu@ 123456hust.edu.cn
                [∗∗ ]Corresponding author. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland, 4059, Australia yin.xiao@ 123456qut.edu.au
                [∗∗∗ ]Corresponding author. Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China smzhang@ 123456hust.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2452-199X(21)00107-9
                10.1016/j.bioactmat.2021.03.006
                8010581
                33842737
                a63d9ae8-6804-491a-8cc4-c926303a3147
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 6 January 2021
                : 23 February 2021
                : 2 March 2021
                Categories
                Article

                injectable bone cement microsphere,mg,immunomodulation,anti-inflammation,osteogenesis

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