Immunomodulation and cellular response to biomaterials: the overriding role of neutrophils in healing

Neutrophils, the first immune cells infiltrating an implantation site, play a central role in the immune response to biomaterial-based implants. They initiate inflammation by secreting pro-inflammatory cytokines that signal the recruitment of other immune cells, mainly M1 macrophages. During this stage, neutrophils and macrophages are responsible for implantation site cleaning. Since they have a short lifespan, neutrophils ideally die by apoptosis ensued by efferocytosis that prompts a phenotypic transition of macrophages M1 to M2, resolving inflammation. Conversely, prolonged neutrophil recruitment and/or lifespan leads to the anarchic infiltration of M1 macrophages that fuse around the material, depositing fibrous collagen encapsulating the biomaterials and preventing their integration. The detailed role of neutrophils in the immune response to biomaterial-based implants, along with the different mechanisms involved, are summarized herein with an overview of recent advances in therapeutic strategies to control neutrophil behaviour, so as to modulate the immune response to implants. Neutrophils at the center of biomaterial design for optimal tissue regeneration.