Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds |
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| Institution: | 1. Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA;2. School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut St., Philadelphia 19104, PA, USA;1. McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA 15219, United States;2. Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 302 Benedum Hall, 3700 O''Hara Street, Pittsburgh, PA 15260, United States;3. Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, 440 Victoria Building, 3500 Victoria Street, Pittsburgh, PA 15213, United States;4. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 300 Halket Street, Pittsburgh, PA 15213, United States;1. Department of Biomedical Engineering, Tufts University, Medford, MA, USA;2. School of Biomedical Engineering, Drexel University, Philadelphia, PA, USA;3. New York Stem Cell Foundation Research Institute, New York, NY, USA;4. Department of Biomedical Engineering, Columbia University, New York, NY, USA;1. School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA, 19104, USA;2. Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N Broad St. Philadelphia, PA, 19107, USA;3. Deparment of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA;4. Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;5. Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA;1. Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, Dublin 2, Ireland;2. Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;3. Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland;4. Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland;1. Drexel University, School of Biomedical Engineering, Science, and Health Systems, Philadelphia, PA, United States;2. The New York Stem Cell Foundation Research Institute, New York, NY, United States;3. Bio-Hyperplane LLC, Berkeley Heights, NJ, United States;4. University of Maryland School of Medicine, Department of Microbiology and Immunology, Baltimore, MD, United States;5. Columbia University, Departments of Biomedical Engineering and Medicine, New York, NY, United States;6. Albert Einstein College of Medicine, Department of Pathology, Microbiology, and Immunology, Bronx, NY, United States |
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| Abstract: | In normal tissue repair, macrophages exhibit a pro-inflammatory phenotype (M1) at early stages and a pro-healing phenotype (M2) at later stages. We have previously shown that M1 macrophages initiate angiogenesis while M2 macrophages promote vessel maturation. Therefore, we reasoned that scaffolds that promote sequential M1 and M2 polarization of infiltrating macrophages should result in enhanced angiogenesis and healing. To this end, we first analyzed the in vitro kinetics of macrophage phenotype switch using flow cytometry, gene expression, and cytokine secretion analysis. Then, we designed scaffolds for bone regeneration based on modifications of decellularized bone for a short release of interferon-gamma (IFNg) to promote the M1 phenotype, followed by a more sustained release of interleukin-4 (IL4) to promote the M2 phenotype. To achieve this sequential release profile, IFNg was physically adsorbed onto the scaffolds, while IL4 was attached via biotin-streptavidin binding. Interestingly, despite the strong interactions between biotin and streptavidin, release studies showed that biotinylated IL4 was released over 6 days. These scaffolds promoted sequential M1 and M2 polarization of primary human macrophages as measured by gene expression of ten M1 and M2 markers and secretion of four cytokines, although the overlapping phases of IFNg and IL4 release tempered polarization to some extent. Murine subcutaneous implantation model showed increased vascularization in scaffolds releasing IFNg compared to controls. This study demonstrates that scaffolds for tissue engineering can be designed to harness the angiogenic behavior of host macrophages towards scaffold vascularization. |
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| Keywords: | Vascularization Macrophages Immunomodulation Cytokines Bone Regenerative medicine |
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