Sequential release of immunomodulatory cytokines binding on nano-hydroxyapatite coated titanium surface for regulating macrophage polarization and bone regeneration

Abstract

Inflammation occurs when the material is implanted into the body. As one of the important immune cells in the regulation of inflammation, macrophages are able to remove pathogens and necrotic cells, and polarize to different phenotypes to regulate inflammatory response for tissue regeneration. Therefore, it is known that the sequential release of immunomodulatory cytokines from the surface of titanium (Ti) implants can regulate the polarization of macrophages and promote osseointegration of implants. In order to control the switch of macrophage phenotypes at desired time, we fabricated hydroxyapatite (HAp) nanotube arrays coating on Ti surface, by acid-etching, alkali-heating and HAp coating sequentially. Then we loaded the interleukin-4 (IL-4) encapsulated by poly (lactic-co-glycolic acid) (PLGA) on the bottom of the nanotube and the interferon-γ (IFN-γ) encapsulated by sodium hyaluronate (SH) on the top of the nanotube. Based on the physical and chemical properties of PLGA and SH and the spatial distribution of loaded cytokines, we hypothesized that the programmed release of IFN-γ and IL-4, which made the phenotypic transition of macrophages at a specific time, so as to regulate inflammation and promote osteogenic repair. Our hypothesis created a new type of drug sustained release system, which has high research value for improving the osseointegration of implants.