Damage to the peripheral nervous system is surprisingly common and occurs primarily from trauma or a complication of surgery. Although recovery of nerve function occurs in many mild injuries, outcomes are often unsatisfactory following severe trauma. Nerve repair and regeneration presents unique clinical challenges and opportunities, and substantial contributions can be made through the informed application of biomedical engineering strategies. This article reviews the clinical presentations and classification of nerve injuries, in addition to the state of the art for surgical decision-making and repair strategies. This discussion presents specific challenges that must be addressed to realistically improve the treatment of nerve injuries and promote widespread recovery. In particular, nerve defects a few centimeters in length use a sensory nerve autograft as the standard technique; however, this approach is limited by the availability of donor nerve and comorbidity associated with additional surgery. Moreover, we currently have an inadequate ability to noninvasively assess the degree of nerve injury and to track axonal regeneration. As a result, wait-and-see surgical decisions can lead to undesirable and less successful "delayed" repair procedures. In this fight for time, degeneration of the distal nerve support structure and target progresses, ultimately blunting complete functional recovery. Thus, the most pressing challenges in peripheral nerve repair include the development of tissue-engineered nerve grafts that match or exceed the performance of autografts, the ability to noninvasively assess nerve damage and track axonal regeneration, and approaches to maintain the efficacy of the distal pathway and targets during the regenerative process. Biomedical engineering strategies can address these issues to substantially contribute at both the basic and applied levels, improving surgical management and functional recovery following severe peripheral nerve injury.

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High-resolution neural interfaces are essential tools for studying and modulating neural circuits underlying brain function and disease. Because electrodes are miniaturized to achieve higher spatial resolution and channel count, maintaining low impedance and high signal quality becomes a significant challenge. Nanostructured materials can address this challenge because they combine high electrical conductivity with mechanical flexibility and can interact with biological systems on a molecular scale. Unfortunately, fabricating high-resolution neural interfaces from nanostructured materials is typically expensive and time-consuming and does not scale, which precludes translation beyond the benchtop. Two-dimensional (2D) TiC MXene possesses a combination of remarkably high volumetric capacitance, electrical conductivity, surface functionality, and processability in aqueous dispersions distinct among carbon-based nanomaterials. Here, we present a high-throughput microfabrication process for constructing TiC neuroelectronic devices and demonstrate their superior impedance and in vivo neural recording performance in comparison with standard metal microelectrodes. Specifically, when compared to gold microelectrodes of the same size, TiC electrodes exhibit a 4-fold reduction in interface impedance. Furthermore, intraoperative in vivo recordings from the brains of anesthetized rats at multiple spatial and temporal scales demonstrate that TiC electrodes exhibit lower baseline noise, higher signal-to-noise ratio, and reduced susceptibility to 60 Hz interference than gold electrodes. Finally, in neuronal biocompatibility studies, neurons cultured on TiC are as viable as those in control cultures, and they can adhere, grow axonal processes, and form functional networks. Overall, our results indicate that TiC MXene microelectrodes have the potential to become a powerful platform technology for high-resolution biological interfaces.

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Conductive hydrogels are attractive to mimic electrophysiological environments of biological tissues and toward therapeutic applications. Injectable and conductive hydrogels are of particular interest for applications in 3D printing or for direct injection into tissues; however, current approaches to add conductivity to hydrogels are insufficient, leading to poor gelation, brittle properties, or insufficient conductivity. Here, an approach is developed using the jamming of microgels to form injectable granular hydrogels, where i) hydrogel microparticles (i.e., microgels) are formed with water‐in‐oil emulsions on microfluidics, ii) microgels are modified via an in situ metal reduction process, and iii) the microgels are jammed into a solid, permitting easy extrusion from a syringe. Due to the presence of metal nanoparticles at the jammed interface with high surface area in this unique design, the granular hydrogels have greater conductivity than non‐particle (i.e., bulk) hydrogels treated similarly or granular hydrogels either without metal nanoparticles or containing encapsulated nanoparticles. The conductivity of the granular hydrogels is easily modified through mixing conductive and non‐conductive microgels during fabrication and they can be applied to the 3D printing of lattices and to bridge muscle defects. The versatility of this conductive granular hydrogel will permit numerous applications where conductive materials are needed.

A mechanical insult to the brain drastically alters the microenvironment as specific cell types become reactive in an effort to sequester severely damaged tissue. Although injury-induced astrogliosis has been investigated, the relationship between well-defined biomechanical inputs and acute astrogliotic alterations are not well understood. We evaluated the effects of strain rate on cell death and astrogliosis using a three-dimensional (3-D) in vitro model of neurons and astrocytes within a bioactive matrix. At 21 days post-plating, co-cultures were deformed to 0.50 shear strain at strain rates of 1, 10, or 30 s −1 . We found that cell death and astrogliotic profiles varied differentially based on strain rate at two days post-insult. Significant cell death was observed after moderate (10 s −1 ) and high (30 s −1 ) rate deformation, but not after quasi-static (1 s −1 ) loading. The vast majority of cell death occurred in neurons, suggesting these cells are more susceptible to high rate shear strains than astrocytes for the insult parameters used here. Injury-induced astrogliosis was compared to co-cultures treated with transforming growth factor β, which induced robust astrocyte hypertrophy and increased glial fibrillary acidic protein (GFAP) and chondroitinsulfate proteoglycans (CSPGs). Quasi-static loading resulted in increased cell density and CSPG secretion. Moderate rate deformation increased cell density, GFAP reactivity, and hypertrophic process density. High rate deformation resulted in increased GFAP reactivity; however, other astrogliotic alterations were not observed at this time-point. These results demonstrate that the mode and degree of astrogliosis depend on rate of deformation, demonstrating astrogliotic augmentation at sub-lethal injury levels as well as levels inducing cell death.

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.

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or “concussion”. The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, “SNTF”, was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n=18) were compared to age-matched controls (n=16) from the Glasgow TBI archive. We also we examined brains from an established model of mild TBI at 6h, 48h and 72h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labelling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time-points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI.