FIGURE 1.

Onset, progression and resolution of the Foreign Body Reaction. Sequence of cellular events of the non-specific immune response elicited by the biomaterial surrounding the invasive electrode implanted into the nervous tissue, which is perceived as a nerve injury: (a) onset, similarly to the wound healing, the adsorption of blood and plasma proteins [in particular, fibrinogen and antibodies (IgG), which will be recognized by the white blood cells of the immune system, and the complement system providing specific binding sites and chemoattractants for circulating leukocytes and monocytes] to the surface of the implant leads to the second step of the process, (b) the progression of the FBR, during which leukocyte and monocyte extravasation that is due to the influence of various chemokines, such as TGF-β, promotes their attraction and adhesion to the electrode surface. Recruited monocytes differentiate into activated M1 macrophages that fuse together into multinucleated FBGCs, which carry out multiple functions including: the increase of the inflammatory response both through a positive feedback mechanism (mainly via additional TGF-β production) and through the recruitment of further monocytes and macrophages, the digestion of the electrode surface while promoting the recruitment of the fibroblasts and their activation to myofibroblasts in the last step of the process, (c) the resolution of the FBR, during which the myofibroblasts secrete the different ECM components around the implant that are responsible for the formation of the fibrotic capsule, which ultimately isolates the electrode from the surrounding tissue. IgG, immunoglobulin G; CCLs, CC chemokines; TGF-β, transforming growth factor β; FBGCs, foreign body giant cells. Created with BioRender.com.