Genetic Modulation at the Neural Microelectrode Interface: Methods and Applications

Abstract

The use of implanted microelectrode arrays (MEAs), in the brain, has enabled a greater understanding of neural function, and new treatments for neurodegenerative diseases and psychiatric disorders. Glial encapsulation of the device and the loss of neurons at the device-tissue interface are widely believed to reduce recording quality and limit the functional device-lifetime. The integration of microfluidic channels within MEAs enables the perturbation of the cellular pathways, through defined vector delivery. This provides new approaches to shed light on the underlying mechanisms of the reactive response and its contribution to device performance. In chronic settings, however, tissue ingrowth and biofouling can obstruct or damage the channel, preventing vector delivery. In this study, we describe methods of delivering vectors through chronically implanted, single-shank, “Michigan”-style microfluidic devices, 1–3 weeks, post-implantation. We explored and validated three different approaches for modifying gene expression at the device-tissue interface: viral-mediated overexpression, siRNA-enabled knockdown, and cre-dependent conditional expression. We observed a successful delivery of the vectors along the length of the MEA, where the observed expression varied, depending on the depth of the injury. The methods described are intended to enable vector delivery through microfluidic devices for a variety of potential applications; likewise, future design considerations are suggested for further improvements on the approach.

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

“…This technique can be implemented to not only guide next-generation device designs (e.g., architecture, size, flexibility, surface chemistry/topography 9,44-47 ), but also intervention strategies (e.g., coatings, microfluidic delivery, etc. [82][83][84][85] ) aimed at improving long-term recording quality.…”

Gene Expression Changes in Cultured Reactive Rat Astrocyte Models and Comparison to Device-Associated Effects in the Brain

“…Armed with an increasing knowledge base of the relationship between devices and gene expression [15][16][17] , it may be possible to further refine culture models to more faithfully recreate these responses in future work. It may also be possible to directly test the impact of identified biomarkers on electrode function by implementing strategies to manipulate gene expression at the device interface 67 .…”

Spatially Precise Genetic Engineering at the Electrode‐Tissue Interface

“…[19][20][21][22][23][24][25][26][27] The latter can leverage the knowledge acquired through the study of neural tissues to engineer the biological components at the electrode-tissue interface. [28][29][30][31] Biotic engineering at the electrode-tissue interface has remained largely unexplored to date even though it holds significant potential to reshape our understanding of neural interfaces and their transformative applications. Notably, recent advancements in genetic engineering have unlocked exciting opportunities for introducing exogenous genes or manipulating the expression of endogenous genes in a cell-type-specific manner in vivo.…”