Prominent neuropathology following trauma, stroke, and various neurodegenerative diseases includes neuronal degeneration as well as loss of long-distance axonal connections. While cell replacement and axonal pathfinding strategies are often explored independently, there is no strategy capable of simultaneously replacing lost neurons and re-establishing long-distance axonal connections in the central nervous system. Accordingly, we have created micro-tissue engineered neural networks (micro-TENNs), which are preformed constructs consisting of long integrated axonal tracts spanning discrete neuronal populations. These living micro-TENNs reconstitute the architecture of long-distance axonal tracts, and thus may serve as an effective substrate for targeted neurosurgical reconstruction of damaged pathways in the brain. Cerebral cortical neurons or dorsal root ganglia neurons were precisely delivered into the tubular constructs, and properties of the hydrogel exterior and extracellular matrix internal column (180-500 μm diameter) were optimized for robust neuronal survival and to promote axonal extensions across the 2.0 cm tube length. The very small diameter permits minimally invasive delivery into the brain. In this study, preformed micro-TENNs were stereotaxically injected into naive rats to bridge deep thalamic structures with the cerebral cortex to assess construct survival and integration. We found that micro-TENN neurons survived at least 1 month and maintained their long axonal architecture along the cortical-thalamic axis. Notably, we also found neurite penetration from micro-TENN neurons into the host cortex, with evidence of synapse formation. These micro-TENNs represent a new strategy to facilitate nervous system repair by recapitulating features of neural pathways to restore or modulate damaged brain circuitry.

Soft bioelectronic interfaces for mapping and modulating excitable networks at high resolution and at large scale can enable paradigm-shifting diagnostics, monitoring, and treatment strategies. Yet, current technologies largely rely on materials and fabrication schemes that are expensive, do not scale, and critically limit the maximum attainable resolution and coverage. Solution processing is a cost-effective manufacturing alternative, but biocompatible conductive inks matching the performance of conventional metals are lacking. Here, we introduce MXtrodes, a class of soft, high-resolution, large-scale bioelectronic interfaces enabled by Ti 3 C 2 MXene (a twodimensional transition metal carbide nanomaterial) and scalable solution processing. We show that the electrochemical properties of MXtrodes exceed those of conventional materials and do not require conductive gels when used in epidermal electronics. Furthermore, we validate MXtrodes in applications ranging from mapping largescale neuromuscular networks in humans to cortical neural recording and microstimulation in swine and rodent models. Last, we demonstrate that MXtrodes are compatible with standard clinical neuroimaging modalities.

Brain organoids are an exciting new technology with the potential to significantly change how diseases of the brain are understood and treated. These three-dimensional neural tissues are derived from the self-organization of pluripotent stem cells, and they recapitulate the developmental process of the human brain, including progenitor zones and rudimentary cortical layers. Brain organoids have been valuable in investigating different aspects of developmental neurobiology and comparative biology. Several characteristics of organoids also make them attractive as models of brain disorders. Data generated from human organoids are more generalizable to patients because of the match in species background. Personalized organoids also can be generated from patient-derived induced pluripotent stem cells. Furthermore, the three-dimensionality of brain organoids supports cellular, mechanical, and topographical cues that are lacking in planar systems. In this review, we discuss the translational potential of brain organoids, using the examples of Zika virus, autism-spectrum disorder, and glioblastoma multiforme to consider how they could contribute to disease modeling, personalized medicine, and testing of therapeutics. We then discuss areas of improvement in organoid technology that will enhance the translational potential of brain organoids, as well as the possibility of their use as substrates for repairing cerebral circuitry after injury.