Nerve and spinal injuries affect 10s of 1000s of people each year and accounts for over $150 billion in healthcare costs annually (Fadia et al., 2020). These injuries can result in life changing impairments to movement. Generally, nerve damage greater than 2-3cm usually requires the grafting of another nerve to facilitate recovery. This process, called autografting, proves problematic because there are often complications arising from the excision of the peripheral nerve used in the graph (Fadia et al., 2020). These complications include surgical risks as well as problems at the donor site such as neuroma formation (Fadia et al., 2020). In addition, the excised nerve may prove to be too small depending on the size of the injury. Nerve grafting is not an option for mixed nerves or in the spinal cord due to a morphology mismatch (Fadia et al., 2020). This is especially problematic for the spinal cord because any nervous tissue loss often becomes long lasting due to a failure of nervous tissue repair and the formation of a glial scar (Li et al., 2020). The development of more efficacious treatments for nerve damage in both peripheral nerves and the spinal cord is of great interest as current methodologies do not always produce great patient outcomes.
In a recent article published by Fadia et al., 2020 titled “Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates” the researchers examined the effect of using a synthetic conduit that continually releases glial cell line–derived neurotrophic factor (GDNF) in long-gap peripheral nerve repair in rhesus macaque monkeys. From previous experiments the researchers had designed an optimized polymeric nerve conduit combined with a microsphere delivery system. This conduit was surgically placed into a critical-sized 5 cm nerve defect in the monkeys. For controls, the researchers also used the more normal autografting technique. They also implanted some monkeys with a synthetic conduit that did not contain any GDNF. In order to test the functional recovery of the monkeys, the researchers trained the monkeys in a pinching task. In order to successfully complete the test, the primates had to use only their thumb and index finger to pick up sugar pellets from a board which has four wells of varying different diameters. The researchers found that pre surgery, the monkeys sat at about 90% correct pinches. After surgery and one year of healing, monkeys with the active conduit pinched correctly, on average, 75.49% of the time, those with a non-active conduit 49.95% of the time, and those with the traditional autograph, 77.49% of the time. Histological analysis was also performed. The researchers found that the axonal areas of distal nerves were greater in the autograft condition than the active conduit condition. This indicates that the axons and nerve fibers were more mature in the autograft condition. This is expected; however, the active conduit group was able to regenerate a significant amount of nerve fibers, significantly more than the non-active conduit condition. In addition, the active conduit appeared to generate more myelination in the regenerated nerve fibers than either of the other conditions. These results taken together suggest that a synthetic conduit that continually releases GDNF is efficacious in bridging large peripheral nerve gaps (Fadia et al., 2020).
As for spinal injuries, the researchers involved in the article by Li et al., 2020 titled “The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord” examined the effect of a nanofiber-hydrogel composite (NHC) on an induced spinal cord contusion in rats. The NHC is unique in that it relies on interfacial bonding between the fibers and the hydrogel network. This allows the composite to retain the rigidity needed to keep spinal contusions from collapsing while also retaining enough porosity to allow cellular migration within the gel matrix. This unique combination closely resembles the extracellular matrix (ECM) natively seen in the spinal cord. The researchers set up the experiment to compare the effects of NHC against three other conditions. Those conditions were a hydrogel with a G1 of 80 (H-80), a hydrogel with a G1 of 210 (H-210) (the same as the NHC), and a phosphate-buffered saline solution (PBS). The rats were precisely contused in the same spot and then given a subacute injection, at the site of injury, of either NHC, H-80, H-210, or PBS. After a determined amount of time (3 Days Post-Injury (dpi), 7 dpi or 28 dpi) the rats were anesthetized, and the spinal cords were dissected. Spinal cords were analyzed for their width, volume, extent of inflammation, vascularization, number of axons, and number of neuron-like cells. The researchers found that rats injected with NHC (as well as H-210) presented with reduced spinal cord thinning as well as a gradual increase in axon density at 28 dpi. In addition, NHC (as well as H-80 and H-210) seemed to facilitate vascularization measured through blood vessel density in the injury. Effects that were exclusive to NHC include a greater ratio of M2 to M1 macrophages in the injury as well as a greater number of neuron-like cells found in the injury. These data present the case that NHC is able to provide adequate mechanical strength to prevent spinal cord collapse while also being porous enough to allow cell infiltration and tissue formation. These unique characteristics encourage vascularization, neurogenesis, and an increased number of M2 macrophages in the injury compared to other hydrogels and substances. These properties make NHC a promising substance to be used to facilitate healing, potentially in human patients.
Taken together these articles demonstrate recent advancements in the development of efficacious treatments of nerve and spinal cord damage. It is possible that combining the knowledge gained from these studies could help further this area even more. For example, Li et al., 2020 mentions that NHC may prove to be more effective when used in combination with specific cells and growth factors. Based on the results of Fadia et al., 2020, GDNF could be a promising candidate for inclusion in NHC to facilitate myelination and axon maturation. Potentially, a combination of NHC and synthetic conduit could be used to treat nerve damage in mixed nerves. The conduit could help bridge the gap while NHC could provide growth factors and a strong porous surface for axons and nerve fibers to develop on. More research is needed into these possibilities as well as the efficacy of these treatments on their own. In particular, neither of these treatments have moved past the animal model testing phase. This means that their results could potentially not translate to success in human trials. Despite this, they are both promising techniques for the treatment of nerve and spinal cord damage.
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Fadia, N. B., Bliley, J. M., DiBernardo, G. A., Crammond, D. J., Schilling, B. K., Sivak, W. N., Spiess, A. M., Washington, K. M., Waldner, M., Liao, H.-T., James, I. B., Minteer, D. M., Tompkins-Rhoades, C., Cottrill, A. R., Kim, D.-Y., Schweizer, R., Bourne, D. A., Panagis, G. E., Asher Schusterman, M., … Marra, K. G. (2020). Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates. Science Translational Medicine, 12(527). https://doi.org/10.1126/scitranslmed.aav7753
Li, X., Zhang, C., Haggerty, A. E., Yan, J., Lan, M., Seu, M., Yang, M., Marlow, M. M., Maldonado-Lasunción, I., Cho, B., Zhou, Z., Chen, L., Martin, R., Nitobe, Y., Yamane, K., You, H., Reddy, S., Quan, D.-P., Oudega, M., & Mao, H.-Q. (2020). The effect of a nanofiber-hydrogel composite on Neural Tissue Repair and regeneration in the contused spinal cord. Biomaterials, 245, 119978. https://doi.org/10.1016/j.biomaterials.2020.119978
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