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      Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation.

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          Abstract

          The immediate tissue microenvironment of implanted biomedical devices and engineered tissues is highly influential on their long term fate and efficacy. The creation of a long-term anti-inflammatory microenvironment around implants and artificial tissues can facilitate their integration. Macrophages are highly plastic cells that define the tissue reactions on the implanted material. Local control of macrophage phenotype by long-term fixation of their healing activities and suppression of inflammatory reactions are required to improve implant acceptance. Herein, we describe the development of a cytokine cocktail (M2Ct) that induces stable M2-like macrophage phenotype with significantly decreased pro-inflammatory cytokine and increased anti-inflammatory cytokine secretion profile. The positive effect of the M2Ct was shown in an in vitro wound healing model; where M2Ct facilitated wound closure by human fibroblasts in co-culture conditions. Using a model for induction of inflammation by LPS we have shown that the M2Ct phenotype is stable for 12days. However, in the absence of M2Ct in the medium macrophages underwent rapid pro-inflammatory re-programming upon IFNg stimulation. Therefore, loading and release of the cytokine cocktail from a self-standing, transferable gelatin/tyraminated hyaluronic acid based release system was developed to stabilize macrophage phenotype for in vivo applications in implantation and tissue engineering. The M2Ct cytokine cocktail retained its anti-inflammatory activity in controlled release conditions. Our data indicate that the direct application of a potent M2 inducing cytokine cocktail in a transferable release system can significantly improve the long term functionality of biomedical devices by decreasing pro-inflammatory cytokine secretion and increasing the rate of wound healing.

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          Author and article information

          Journal
          Acta Biomater
          Acta biomaterialia
          Elsevier BV
          1878-7568
          1742-7061
          April 15 2017
          : 53
          Affiliations
          [1 ] Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany; Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, 36 Lenin Prospekt, Tomsk 634050, Russia.
          [2 ] Division of Immunology, Queen's Medical Centre, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
          [3 ] Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany.
          [4 ] Protip Medical, 8 Place de l'Hopital, 67000 Strasbourg, France.
          [5 ] INSERM UMR 1121, Biomaterials and Bioengineering, 11 rue Humann, 67000 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 3 rue Sainte Elisabeth, 67000 Strasbourg, France.
          [6 ] Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany; Red Cross Blood Service Baden-Württemberg-Hessen, Friedrich-Ebert Str. 107, D-68167 Mannheim, Germany.
          [7 ] Protip Medical, 8 Place de l'Hopital, 67000 Strasbourg, France; INSERM UMR 1121, Biomaterials and Bioengineering, 11 rue Humann, 67000 Strasbourg, France.
          [8 ] Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany; Red Cross Blood Service Baden-Württemberg-Hessen, Friedrich-Ebert Str. 107, D-68167 Mannheim, Germany; Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, 36 Lenin Prospekt, Tomsk 634050, Russia. Electronic address: julia.kzhyshkowska@medma.uni-heidelberg.de.
          Article
          S1742-7061(17)30080-6
          10.1016/j.actbio.2017.01.071
          28159717

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