General Medical Information

Nerve Regeneration

David J. Terris

The healing of nerves comprises a particular area of interest to head and neck surgeons, because much of head and neck surgery, including oncologic head and neck surgery, neurotologic surgery, and skull base surgery, places cranial nerves at risk for injury and the healing of nerves has functional and cosmetic implications. As with other areas of wound healing, neural regeneration has seen an explosion in the understanding of mechanisms of repair and the birth of potential for manipulation of this repair process.

Nerve healing occurs as a dynamic complex interplay of several processes and is modulated by a number of factors. Much of the current appreciation for the complexities of nerve injuries and healing are a product of the work of Sir Sydney Sunderland, after whom the classification of nerve injuries is named. His classic volume paved the way for two decades of intense investigation into the microenvironment of the regenerating nerve.

Sunderland described three fundamental types of nerve injury: a transient interruption of nerve conduction without loss of axonal continuity (also called neuropraxia or conduction block); transection of axons (or conditions leading to loss of axonal integrity) but with preservation of the endoneurium during Wallerian degeneration (known also as axonotmesis); and complete disruption of the nerve fiber, with loss of the normal architecture (neurotmesis). The third level of injury can be further subdivided to include perineurial disruption (class IV injury) or epineurial transection (class V injury); all injuries that include neurotmesis may result in aberrant regrowth of axons into the “wrong” endoneurial tubes.

The response of the injured nerve in the first 12 to 48 hours includes Wallerian degeneration (degeneration of the distal axon to the motor endplate and of the proximal axon to the first node of Ranvier), axonal edema, and retraction of myelin. From 48 to 72 hours, the axons break into twisted fragments, and by the second week after injury, all traces of the axon are usually lost. The distal nerve fibers can be stimulated for approximately 72 hours after injury, an essential time frame to consider when contemplating exploration of traumatic nerve injuries. Macrophages are mobilized to phagocytize debris along the nerve, and Schwann cells contribute to this activity. The main role of Schwann cells, however, is to guide regeneration by forming dense cellular cords (called Bungner’s bands) along the site of the degenerating axon. These bands provide conduits for axons once regeneration ensues.
The duration of the regenerative process varies and may require 6 to 18 months, depending on the length of the nerve and the site of the lesion. Despite the commonly quoted regeneration rate of 1 mm/day, this figure varies considerably and can be used only as a rough estimate. On occasion, there may be very early signs of recovery, thought to be due to so-called pioneer axons, which very quickly navigate the pathway to the target tissue, ahead of most nerve fibers.

A review of relevant issues in nerve repair arrived at several generalizations in the approach to nerve repair. Despite prior evidence to the contrary, injured nerves should be repaired as early as possible. There is no advantage to waiting until the metabolic environment has been maximized. The current gold standard technique of repair remains epineurial suture approximation of transected nerves with fine (9-0 or 10-0) monofilament suture, with interposition grafting using an autologous nerve if a tensionless repair cannot be achieved. What comprises “tensionless” continues to be debated; however, if the resected nerve segment is greater than 2 cm, most investigators would advocate grafting.

The most immediate promising innovations in neural regeneration include the use of tubulization techniques combined with trophic substances such as neurocytokines, including nerve growth factor, BDNF, ciliary neurotrophic factor, and neurotrophins-3, -4/5, and -6. The complex interactions between these proteins and their target cells are still being elucidated. Although the enhancement in recovery using neurotrophic substances has only been achieved in animal models, in some instances the differences are impressive. In a rodent sciatic nerve model, Utley  reported statistically significant improvements in functional nerve recovery with the use of collagen tubulization or the delivery of BDNF to the nerve bed. The best recovery was achieved in those animals that received the BDNF by cross-linking it to the tubule itself. This enhancement has been confirmed in subsequent studies, and its effect is apparent even when nerve repair is delayed. There is great expectation that the future will bring even more precise pharmacologic options for the enhancement of nerve regeneration. For the present, careful microsurgical suture reapproximation remains the best way to facilitate the normal nerve healing process.