Micromotion derived fluid shear stress mediates perielectrode gliosis through mechanosensitive ion channels

Trotier, Alexandre
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 micromotion induced mechanical shear, leading to the development of peri-implant scarring. This reactive glial tissue creates a physical barrier to electrical signal propagation, which can lead 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. In this thesis, it was first demonstrated that the in vitro reproduction of shear stress deriving from both electrode insertion and in situ micromotion at the device/brain tissue interface through the use of a parallel plate flow chamber setup could trigger established markers of astrogliosis in immortalised and primary glial cell cultures. Next, an in silico model of electrode-induced shear stress was developed 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, this work findings suggest 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.
NUI Galway
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland