Alginate/chitosan multilayer films coated on IL-4-loaded TiO₂ nanotubes for modulation of macrophage phenotype

Macrophage phenotype conversion is crucial for improving post-traumatic angiogenesis and tissue repair. Biomaterials with the ability of skewing macrophage phenotype have attracted widespread attention in the field of tissue engineering. The aim of this study was to transform macrophage phenotype by a three-step process; anodizing, drug loading and coating with polyelectrolyte multilayer (PEM) films. Interleukin (IL)-4, an anti-inflammatory cytokine, was loaded into titania nanotubes (TNTs) on the titanium surface. Subsequently, sodium alginate (ALG) and chitosan (CS) were alternately assembled onto IL-4-loaded TNTs and cross-linked with genipin/calcium chloride, finally forming cross-linked PEM films. The IL-4 release profile and cellular immune response of the modified surface was investigated. In the simulated biological solution, only 20% of IL-4 were detected in the first 3 days, with a sustained release of approximately 5 ng over 10 days. The results of gene expression and protein secretion in macrophages indicated that IL-4-loaded PEM films significantly attenuated the inflammatory activity of macrophages at the later stage through down-regulating the mRNA and protein levels of inflammatory markers. In summary, IL-4 was controlled released from the cross-linked PEM films deposited on the nanotubes, leading to the temporal conversion of macrophage phenotype.