Figure 1.

Advantages of Axon-Based “Living Electrodes” for Neuromodulation: Mechanisms and specificity of neuronal stimulation for “living electrodes” (left) versus conventional electrodes (center) and optrodes (right). Living electrodes provide engineered axonal tracts, fully differentiated neurons, and a controlled 3D cytoarchitecture, potentially improving survival versus delivery of cell suspensions. Construct neurons may be transfected to express opsins in vitro (days prior to implant), thereby avoiding the injection of virus directly into the host while constraining the spatial extent of transfected cells. Living electrodes could offer high specificity, as the constructs can be designed to synapse with specific neuronal subtypes in a given anatomical region (as shown by living electrode axons synapsing with only blue neurons, not black) as opposed to conventional electrodes that inherently stimulate or record from a relatively large 3D volume around the electrode (as shown by large red area of stimulation affecting many layers and neurons). While optrodes can achieve a high level of specificity, the in vivo delivery of opsins generally relies on injection of virus that may diffuse and affect non-target regions (spread of optogenetic transduction is illustrated by yellow neurons in multiple layers). Also, optical methods may have a limited extent due to tissue absorption of light. Finally, living electrodes provide a soft pathway to route signals to/from deep brain structures compared to rigid materials used in electrodes/optrodes, thus potentially minimizing signal loss due to mechanical mismatch/micromotion and glial scarring.