Molecular Mechanisms of Foreign Body Responses to Neural Electrodes and Surface Biofunctionalization Strategies for Interface Modulation

Long-term implantable neural electrodes underpin brain–machine interfaces, deep brain stimulation, epilepsy monitoring, and closed-loop neuromodulation. Following chronic implantation, however, the foreign body response (FBR) at the electrode–tissue interface remains a major constraint on long-term performance, as reflected by increased interfacial impedance, lower signal-to-noise ratios, fewer resolvable units, and higher stimulation thresholds. This deterioration arises from interrelated events that include implantation injury, protein adsorption, blood–brain barrier disruption, complement activation, glial reactivity, oxidative stress, glial scar formation, and neuronal loss. It cannot be attributed solely to material ageing or encapsulation failure. This review examines the molecular mechanisms of neural-electrode FBR and relates them to surface-biofunctionalization strategies, including antifouling coatings, bioactive ligands, immobilized neurotrophic factors, drug-eluting electrodes, and emerging immunomodulatory interfaces. Establishing mechanistic links among molecular events, material interfaces, and functionalization strategies may guide the rational design of durable neural electrodes.