Micromotion derived fluid shear stress mediates peri-electrode gliosis through mechanosensitive ion channels

Clinical applications for neural implant technologies are steadily advancing. Yet, despite clinical successes, neuroelectrode-based therapies require invasive neurosurgery and can subject local soft-tissues to micro-motion induced mechanical shear, leading to the development of peri-implant scaring. This reactive glial tissue creates a physical barrier to electrical signal propagation, leading to loss of device function. Although peri-electrode gliosis is a well described contributor to neuroelectrode failure, the mechanistic basis behind the initiation and progression of glial scarring remains poorly understood. Here, we develop an in silico model of electrode-induced shear stress to evaluate the evolution of the peri-electrode fluid-filled void, encompassing a solid and viscoelastic liquid/solid interface. This model was subsequently used to inform an in vitro parallel-plate flow model of micromotion mediated peri-electrode fluid shear stress. Ventral mesencephalic E14 rat embryonic in vitro cultures exposed to physiologically relevant fluid shear exhibited upregulation of gliosis-associated proteins and the overexpression of two mechanosensitive ion channel receptors, PIEZO1 and TRPA1, confirmed in vivo in a neural probe induced rat glial scar model. Finally, it was shown in vitro that chemical inhibition/activation of PIEZO1 could exacerbate or attenuate astrocyte reactivity as induced by fluid shear stress and that this was mitochondrial dependant. Together, our results suggests that mechanosensitive ion channels play a major role in the development of the neuroelectrode micromotion induced glial scar and that the modulation of PIEZO1 and TRPA1 through chemical agonist/antagonist may promote chronic electrode stability in vivo. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/523766v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@962f03org.highwire.dtl.DTLVardef@1e8a6adorg.highwire.dtl.DTLVardef@116cbb6org.highwire.dtl.DTLVardef@19830da_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPeri-electrode void progression is mediated by fluid flow shear stress C_LIO_LIOscillatory fluid flow shear stress replicates neuroelectrode glial scarring in vitro C_LIO_LIAstrocyte PIEZO1 and TRPA1 are upregulated at the peri-electrode region in response to electrode micromotion C_LIO_LIPIEZO1 pharmaceutical activation diminishes shear stress-induced gliosis C_LIO_LIPIEZO1 chemical inhibition exacerbates gliosis and reduces mitochondrial functions C_LI