[2][3][4] The processes that occur in peripheral regeneration can be divided into the following major events: Wallerian degeneration, axon regeneration/growth, and reinnervation of nervous tissue.

The study of nerve injury began during the American Civil War and greatly expanded during modern medicine with such advances as use of growth-promoting molecules.

In this case, the axon remains intact, but there is myelin damage causing an interruption in conduction of the impulse down the nerve fiber.

In electrodiagnostic testing with nerve conduction studies, there is a normal compound motor action potential amplitude distal to the lesion at day 10, and this indicates a diagnosis of mild neurapraxia instead of axonotmesis or neurotmesis.

This type of nerve damage may cause paralysis of the motor, sensory, and autonomic functions, and is mainly seen in crush injury.

Electromyography (EMG) performed 2 to 4 weeks later shows fibrillations and denervation potentials in musculature distal to the injury site.

Loss in both motor and sensory spines is more complete with axonotmesis than with neurapraxia, and recovery occurs only through regenerations of the axons, a process requiring time.

Axonotmesis is usually the result of a more severe crush or contusion than neurapraxia, but can also occur when the nerve is stretched (without damage to the epineurium).

During Wallerian degeneration Schwann cells and macrophages interact to remove debris, specifically myelin and the damaged axon, from the distal injury site.

A number of signaling pathways have been shown to be turned on by axon injury and help to enable long distance regeneration including BMP, TGFβ, and MAPKs.

Similarly, a growing number of transcription factors also boost the regenerative capacity of peripheral neurons including ASCL1, ATF3, CREB1, HIF1α, JUN, KLF6, KLF7, MYC, SMAD1, SMAD2, SMAD3, SOX11, SRF, STAT3, TP53, and XBP1.

Several of these can also boost the regenerative capacity of CNS neurons, making them potential therapeutic targets for treating spinal cord injury and stroke.

Electron microscopy and immunohistochemical staining analysis of teased nerve fibers shows that before macrophages arrive at the injury site, myelin is fragmented and myelin debris and lipid droplets are found in the cytoplasm of Schwann cells, indicating phagocytic activity before macrophages arrive.

Northern blotting showed that peak lysozyme mRNA expression occurred at an appropriate time with respect to temporal models of myelin phagocytosis.

Macrophages secrete not only interleukin-1, a cytokine that induces expression of nerve growth factor (NGF) in Schwann cells but also an interleukin-1 receptor antagonist (IL-1ra).

Expression of IL-1ra in mice with transected sciatic nerves via implantation of a tube releasing IL-1ra showed the regrowth of fewer myelinated and unmyelinated axons.

[8][15] These neurotrophic factors have both autocrine and paracrine effects, as they promote growth of the damaged neurons as well as the adjacent Schwann cells.

This is a mechanism to increase growth and proliferation of Schwann cells at the distal stump in order to prepare for reception of the regenerating axon.

The Schwann cells that form the bands of Bungner at the distal injury site express NGF receptors as a guiding factor for the regenerating axon of the injured neuron.

NGF bound to the receptors on Schwann cells provides the growing neurons that are contacted with a trophic factor to promote further growth and regeneration[5][8][15] Ciliary neurotrophic factor (CNTF) typically has a high level of expression in Schwann cells associated with nerves that are healthy, but in response to nerve injury CNTF expression decreases in Schwann cells distal to the injury site and remains relatively low unless the injured axon begins to regrow.

[16] Insulin-like growth factors (IGFs) have been shown to increase the rate of peripheral nervous system axon regeneration.

IGF-I and IGF-II mRNA levels are significantly increased distal to the site of crush injury in rat sciatic nerves.

[24] The positive effect of electrical stimulation on nerve regeneration is due to its molecular influence on the damaged neuron and Schwann cells.

Electrical stimulation can directly accelerate the expression of cyclic adenosine monophosphate (cAMP) both in neurons and Schwann cells.

[25] cAMP is a molecule that stimulates multiple signaling pathways that aid nerve regeneration by enhancing the expression of several neurotrophic factors.

Localized delivery of soluble neurotrophic factors may help promote the rate of axon regeneration observed within these graft conduits.

Scaffolding developed from bio-compatible material would be useful in nerve regeneration if they successfully exhibit essentially the same role as the endoneurial tubes and Schwann cells do in guiding regrowing axons.