Development of optically controlled “living electrodes” with long-projecting axon tracts for a synaptic brain-machine interface
For implantable neural interfaces, functional/clinical outcomes are challenged by limitations in specificity and stability of inorganic microelectrodes. A biological intermediary between microelectrical devices and the brain may improve specificity and longevity through (i) natural synaptic integration with deep neural circuitry, (ii) accessibility on the brain surface, and (iii) optogenetic manipulation for targeted, light-based readout/control. Accordingly, we have developed implantable “living electrodes,” living cortical neurons, and axonal tracts protected within soft hydrogel cylinders, for optobiological monitoring/modulation of brain activity. Here, we demonstrate fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and simultaneous optical stimulation and recording of these tissue engineered constructs in vitro. We also present their transplantation, survival, integration, and optical recording in rat cortex as an in vivo proof of concept for this neural interface paradigm. The creation and characterization of these functional, optically controllable living electrodes are critical steps in developing a new class of optobiological tools for neural interfacing.
Most devices for neuromodulation (e.g., deep brain stimulation electrodes for Parkinson’s disease) and neural recording [commonly called brain-computer interfaces (BCIs)] work by electrically stimulating or capturing neuronal activity within the brain (1). These neural interfaces have been developed across a range of medical applications; two notable milestones include cochlear prostheses for people with hearing loss and thought-driven computer control for people with neuromuscular disorders (1). Despite these achievements, the clinical impact of more advanced neural interfaces is beset by several underlying functional challenges. Implantable BCIs primarily use inorganic microelectrodes, which often exhibit diminished recording quality over time due to a host of biological factors (e.g., inflammation, neuronal loss, and glial scarring) and abiotic biostability issues (including decreasing impedance due to loss of insulation and mechanical failure) (1–5). In parallel, the effectiveness of electrical neuromodulation is limited by an inability to target specific neurons or neuronal subtypes (e.g., excitatory versus inhibitory neurons) within the volume of charge injection, as well as the thresholds for both safe and functional therapeutic stimulation (6). Specificity in neuromodulation may be improved with optogenetics, where inducing the expression of light-sensitive proteins in specific neuronal populations allows these subgroups to be controlled on a wavelength-specific basis through photostimulation. However, the longevity and immune response to viral optogenetic transduction in humans is currently unknown, with nonhuman primate studies suggesting an elevated immunogenic response (7). Further, light scattering properties of tissue block precise photostimulation of neurons more than a few hundred microns deep (8). Deeper tissue is accessible with implantable optical fibers, lenses, or micro–LEDs (light-emitting diodes), yet chronic performance must also address complications from the foreign body response to these materials and overheating of surrounding tissue (9, 10). Across electric and/or optical input-output paradigms, the information transfer bandwidth limits the quality of the neural interface. The ability to address these design challenges—compatibility with the brain, target specificity, and long-term stability—will direct the utility and clinical translation of future neuromodulation and neural recording technologies.
