AbstractThe development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain–machine interfaces and electronic medicine. However, neuroelectrode‐based therapies require invasive neurosurgery and can subject neural tissues to micromotion‐induced mechanical shear, leading to chronic inflammation, the formation of a peri‐electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion‐induced peri‐electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis‐associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo‐type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri‐electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial‐dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri‐electrode void and micromotion‐induced glial scarring at the peri‐electrode region.