Biological 'Living Electrodes' Using Tissue Engineered Axonal Tracts to Probe and Modulate the Nervous System

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DESCRIPTION (provided by applicant): Brain Machine Interfaces (BMIs) allow the nervous system to directly communicate with external devices in order to mitigate deficits associated with neurodegeneration or to drive peripheral prosthetics. There has been substantial progress using penetrating microelectrode arrays and optogenetics strategies; however, these approaches are limited in that they generally rely on placing non-organic electrodes/optrodes into the brain, inevitably leading to an inflammatory foreign body response that ultimately diminishes the quality of the recording and stimulation. In an alternative strategy, we are utilizig advanced micro-tissue engineering techniques to create the first biological "living electrodes" for chronic BMI. Novel micro-Tissue Engineered Neural Networks (micro-TENNs) serve as the living electrodes, which are composed of discrete population(s) of neurons connected by long axonal tracts within miniature tubular hydrogels. These living micron-scale constructs are able to penetrate the brain to a prescribed depth for integration with local neurons/axons, with the latter portion remaining externalized on the brain surface where functional information is gathered using a next-generation optical and electrical interface. Following transplant into rats, we have previously shown that micro-TENN neurons survive, integrate with local host neurons, and maintain their axonal architecture. These features are exploited in the current proposal to advance living electrodes as a functional relay to and from deep cortical layers. In this radical paradigm, only the biological component of these constructs penetrates the brain, thus attenuating a chronic foreign body response. Moreover, through custom cell and tissue engineering techniques, we may influence the specific host neuronal subtypes with which the micro-TENN neurons form synapses, thereby adding a level of specificity in local stimulation and recoding not currently attainable with conventional microelectrodes. In this proposal, we will utilize electrophysiological, optogenetic, and advanced microscopy techniques to reveal evidence of micro-TENN synaptic integration with brain neural networks and cross-communication with micro-TENN neurons on the cortical surface in rats. These studies will demonstrate the ability of this versatile platform technology to read out local sensorimotor activity and provide input to affect neural activity and function. This will be the first demonstration of tissue engineered "living electrodes" to functionally integrate into native neural networks and to serve as a conduit for bi-directional stimulation and recording. This potentially transformative technology at the interface of neuroscience and engineering lays the foundation for preformed implantable neural networks as a viable alternative to conventional electrodes.