Page 62 - Read Online

Tanner et al. Plast Aesthet Res 2023;10:11 https://dx.doi.org/10.20517/2347-9264.2022.95 Page 3 of 12

Figure 1. Schematic presentation of a peripheral nerve. Source: Nicholls et al. [14] .

[16]
repair based on the degree of connective tissue disruption [Figure 2].

Since mature neurons are terminally differentiated cells that are incapable of mitosis, a nerve injury to the
[13]
cell body cannot be repaired and results in apoptosis . However, there are two main mechanisms for
axonal regeneration: terminal sprouting from injured axons and collateral axonal branching from intact
axons [13,18,19] . This is largely because Schwann cells, unlike neurons, can undergo mitosis if injured .
[13]
Understanding the fundamentals of peripheral nerve degeneration and regeneration after injury will help
inform targeted muscle reinnervation for the treatment of postamputation pain.

In limb amputation, peripheral nerve injury is unavoidable [8,20] . Amputation requires nerve transection and
can be considered a Sunderland grade 5 nerve injury, in which all connective tissue layers are disrupted and
[16]
the distal target for nerve regeneration is removed [Figure 2]. Injury begins the peripheral nerve
degeneration cascade. Within hours, degeneration of the axon and myelin begins in both directions from
[13]
the site of injury in a complex process known as Wallerian degeneration . Wallerian degeneration is the
rapid, vigorous process of degeneration of distal and some proximal segments of axon after nerve injury [13,17]
[Figure 3]. The disruption of the axon plasma membrane causes the influx of extracellular calcium ions,
which triggers proteolysis, fragmentation, and degradation of the myelin and axons . Schwann cells
[21]
dissociate from the axon and transition into repair cells to help digest myelin . Schwann cells initially
[21]
phagocytose debris before the macrophages are recruited and enter through the leaky blood-nerve
barrier . Macrophages are critical to Wallerian degeneration as they rapidly engulf and digest debris,
[21]
clearing the path for nerve regeneration to occur [17,21] . Wallerian degeneration begins within 24 h of injury
and completes after 3 weeks .
[22]
Wallerian degeneration traditionally refers to the degeneration of distal detached axon segments after nerve
injury but has also been found to extend proximally from the site of injury . Wallerian degeneration
[13]
proceeds proximally for about two internodes before the axon is sealed within hours of injury . This is
[13]
thought to protect the intact axon and cell body from the extracellular environment and apoptosis while