title: Controlled release of cytokines using silk-biomaterials for macrophage polarization.
abstract: Polarization of macrophages into an inflammatory (M1) or anti-inflammatory (M2) phenotype is important for clearing pathogens and wound repair, however chronic activation of either type of macrophage has been implicated in several diseases. Methods to locally control the polarization of macrophages is of great interest for biomedical implants and tissue engineering. To that end, silk protein was used to form biopolymer films that release either IFN-γ or IL-4 to control the polarization of macrophages. Modulation of the solubility of the silk films through regulation of β-sheet (crystalline) content enabled a short-term release (4-8 h) of either cytokine, with smaller amounts released out to 24 h. Altering the solubility of the films was accomplished by varying the time that the films were exposed to water vapor. The released IFN-γ or IL-4 induced polarization of THP-1 derived macrophages into the M1 or M2 phenotypes, respectively. The silk biomaterials were able to release enough IFN-γ or IL-4 to repolarize the macrophage from M1 to M2 and vice versa, demonstrating the well-established plasticity of macrophages. High β-sheet content films that are not soluble and do not release the trapped cytokines were also able to polarize macrophages that adhered to the surface through degradation of the silk protein. Chemically conjugating IFN-γ to silk films through disulfide bonds allowed for longer-term release to 10 days. The release of covalently attached IFN-γ from the films was also able to polarize M1 macrophages in vitro. Thus, the strategy described here offers new approaches to utilizing biomaterials for directing the polarization of macrophages.
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, MA, USA. Electronic address: andrew.reeves@tufts.edu.
authors.forename: Andrew R D
authors.initials: AR
authors.lastname: Reeves
authors.affiliation: School of Biomedical Engineering, Drexel University, Philadelphia, PA, USA. Electronic address: kls35@drexel.edu.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Spiller
authors.affiliation: New York Stem Cell Foundation Research Institute, New York, NY, USA. Electronic address: dfreytes@nyscf.org.
authors.forename: Donald O
authors.initials: DO
authors.lastname: Freytes
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY, USA. Electronic address: gv2131@columbia.edu.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vunjak-Novakovic
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, MA, USA. Electronic address: david.kaplan@tufts.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D015847:Interleukin-4 / Q000008:administration & dosage*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008855:Microscopy, Electron, Scanning; D010641:Phenotype; D017433:Protein Structure, Secondary; D060888:Real-Time Polymerase Chain Reaction; D047011:Silk / Q000737:chemistry*; D012995:Solubility; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D000814:Aniline Compounds; D001672:Biocompatible Materials; D016207:Cytokines; D003692:Delayed-Action Preparations; D047011:Silk; D014867:Water; D015847:Interleukin-4; D007371:Interferon-gamma; C023650:aniline
keywords: Cytokine; Macrophage; Polarization; Silk