Peripheral nerve injury (PNI) is a common ailment that occurs after trauma such as lacerations of nerve tissue, crush injuries, gunshot wounds, drug injection injury, electrical injury and more. It can also occur due to autoimmune diseases, diabetes which is the leading cause of polyneuropathy, and vascular problems. PNI has more than 100 types of neuropathy and affects more than 20 million people in the United States. This condition currently has scare options for treatment. [iii] It can range from afflicted individuals experiencing a severe consistent burning sensation to total loss of sensation in the affected body part. The extent of the nerve injury is classified according to the Sunderland scale.[iv]  First degree, being the least extensive, consists of a focal segmental demyelination[ii] or reversible local conduction block.[iv] Patients with first degree peripheral nerve injury can recover within hours or weeks without the need of surgical intervention.  Second degree PNI is when there is no continuity of the axons, which means there is a loss of conduction. The axons in second degree are damaged however they have an intact endoneurium.[ii] To determine if there is a loss doctors can use electromyography and nerve conduction velocity. These tests measure the electrical currents through the nerves. [iv]

Third degree to fifth degree PNI require surgery as these involve physical damage to the axons themselves. The surgical interventions can range from a simple neurolysis to surgically putting a nerve back together due to a complete nerve transection. If a patient suffered from a ballistic injury, a gunshot wound for example, it is likely they would have a Grade five injury.[iv] When the end organ becomes denervated, the human body can regain innervation by using either the branching of intact axons or regenerating the injured axon itself. The method the human body uses to repair depends on the extent of the damage. If the injury affected about 30% of the axons, the branching of the other axons will be used to recover that area. The muscle fibers that still have innervation will hypertrophy to compensate for the muscle fibers who have lost sensation. However, the muscle will start to atrophy due to denervated muscle fibers shrinking.[ii]

Let’s consider a gunshot wound in which 90% of the axons within the localized nerve are damaged. The body will try to regenerate the axons themselves by using Wallerian degeneration, axonal regeneration, and end-organ re-innervation. These three processes must all work fluidly otherwise any disruption in one of them can lead to chronic pain and poor functionality for the patient. First, during the Wallerian degeneration, the damaged area is essentially cleaned out and induces axonal regrowth. The distal stump of the nerve will swell and lead to eventual breakdown in order to make place for the new axon. An overflow of Ca+ and Na+ will cause apoptosis and macrophages will come to the scene to clean up. [ii]

Wallerian degeneration is the most crucial part of the recovery process. The Schwann cells are one of the main cell types that run this process and therefore must be functioning properly. If axonal contact is nonexistent, which is the case for this injury, the Schwann cells “switch off” and become non-myelinating. To make them do their job again, downregulating the expression of proteins for this non-myelinating behavior, for example PMP22, Krox-20, P0, and connexin-32 is necessary. When the expression of these factors are lowered, making them not as effective, new Schwann cells will form and mature into the myelinating phenotype.[ii] Recent research has shown that Gpr126/Adgrg6 contributes to the Schwann cell response during this stage as well. [i]

Unfortunately, even if the affected area is able to be innervated again, it does not necessarily mean a full functional recovery. As stated in the beginning, patients with a higher degree of PNI can experience a constant burning sensation in the area after recovery due to possible disorganized outgrowth.[ii] There are not many treatments for such an ailment as of yet. The current gold standard of treatment for nerve lesions has been nerve autografting. This is the process that neurosurgeons use to reconstruct gaps in the nerve. Unfortunately, this process requires harvesting nerve grafts from donors which is in short supply, dangerous and could result in morbidity and sensory loss. A new treatment method involves using nerve guide conduits for PNI repair. These conduits can be engineered within a lab and “have the mechanical and biochemical cues for neural regeneration” They are artificial, biodegradable, nerve bridges for the axons to grow along, helping them form correctly.  There are currently several designs being tested with each having their own advantages and disadvantages. [v] If this procedure starts to replace nerve autografting and becomes more efficient, the large number of people suffering from Peripheral Nerve Injury can hopefully have a full recovery of their functionality and won’t experience constant pain in the area anymore. Their life would improve significantly and a previous injury or illness would no longer hold them back. Scientists are constantly improving upon past methods to improve the quality of life for patients, it is exciting to think about what new methods of treatment will arise within the next few decades.

[i]  Jablonka‐Shariff, A., Lu, C., Campbell, K., Monk, K. and Snyder‐Warwick, A., 2020. Gpr126/Adgrg6 contributes to the terminal Schwann cell response at the neuromuscular junction following peripheral nerve injury. Glia, 68(6), pp.1182-1200.

[ii] Menorca RM, Fussell TS, Elfar JC. Nerve physiology: mechanisms of injury and recovery. Hand Clin. 2013;29(3):317-330. doi:10.1016/j.hcl.2013.04.002

[iii] Ninds.nih.gov. 2021. Peripheral Neuropathy Fact Sheet | National Institute of Neurological Disorders and Stroke. [online] Available at: <https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet&gt; [Accessed 20 October 2021].

[iv] Peripheral Nerve Injury. [online] Available at: <https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-nerve-injury&gt; [Accessed 20 October 2021].

[v] Vijayavenkataraman, S., 2021. Nerve guide conduits for peripheral nerve injury repair: A review on design, materials and fabrication methods. Acta Biomaterialia, [online] 106, pp.54-69. Available at: <https://doi.org/10.1016/j.actbio.2020.02.003&gt; [Accessed 20 October 2021].