Page 61 - Read Online

Page 2 of 12 Tanner et al. Plast Aesthet Res 2023;10:11 https://dx.doi.org/10.20517/2347-9264.2022.95

[3]
residual limb pain (RLP), phantom limb sensations (PLS), and phantom limb pain (PLP) . RLP is pain at
[3]
the site where amputation occurred, often due to nerve injury and neuroma formation . PLS are non-
[3]
painful sensations in the amputated limb, which may lead to PLP . Meanwhile, PLP represents neuropathic
pain localized to the lost limb . Postamputation pain contains significant overlap, and patients with
[3]
neuromas are significantly more likely to suffer from PLS and PLP . Postamputation pain has a significant
[4,5]
[6]
impact on patient outcomes, including prosthetic use, return to work, and overall quality of life .
Unfortunately, postamputation pain is complex and poorly understood, and treatment of postamputation
pain remains difficult . Targeted muscle reinnervation (TMR) is an emerging surgical procedure to
[4,7]
manage nerves and treat pain in amputees. TMR involves transferring the proximal stump of transected
major peripheral nerves to nearby motor nerves of muscles that lack function after amputation . In surgery,
[8]
the major peripheral nerve being managed with TMR is identified, dissected, and cut distally to healthy
fascicles. The recipient motor nerve is identified using a nerve stimulator and cut just proximally to any
areas of branching into muscle. The small recipient motor nerve is sutured to the center of the large donor
nerve in an end-to-end fashion. Fibrin glue is used to reinforce the coaptation and prevent collateral axonal
sprouting and neuroma formation. TMR was originally performed by Kuiken et al. in 2004 to improve
myoelectric prosthetic control . Incidentally, TMR was found to successfully treat and prevent neuroma
[9]
pain in amputees, sparking an explosion of new research into TMR . Recent literature shows the clinical
[4,7]
success of TMR, the expansion of its use, and improvements in surgical technique [4,5,8] . However, there is a
paucity of literature exploring the basic science of nerve regeneration pertaining to TMR and how the
procedure actually prevents neuroma formation. Surprisingly, the procedure can be successful in preventing
neuromata despite a large size discrepancy between donor and recipient nerves [4,10] . No known studies have
explained a possible mechanism for axon behavior when there is a large size mismatch between transferred
nerves. The purpose of this review is to attempt to explain the process of nerve regeneration in TMR for
postamputation pain and to propose axonal pruning as a potential mechanism for axon behavior in the
setting of a large size mismatch between coapted nerves.

PERIPHERAL NERVE ANATOMY
The main functions of the PNS are to send sensory information to the CNS, transmit motor commands to
[11]
voluntary striated muscles in the body, and regulate autonomic functions such as blood pressure .
Therefore, the PNS contains motor, sensory, and autonomic nerve fibers that combine to form motor,
sensory, or mixed nerves [11,12] .

The PNS is myelinated by Schwann cells that increase the speed of action potential propagation . Schwann
[11]
cells are the supporting cells of the PNS that surround and protect axons . In addition to myelin,
[13]
peripheral nerves are surrounded by three well-organized connective tissue layers: endoneurium,
perineurium, and epineurium [Figure 1]. The endoneurium is the innermost compartment surrounding
[11]
individual nerve fibers, and it forms the blood-nerve barrier . The nerve fibers are grouped into fascicles,
[13]
which are enveloped by concentrically arranged perineurium . The epineurium is the outermost layer of
[13]
[13]
peripheral nerves, containing several nerve fascicles and the nerve’s blood supply . The well-organized
peripheral nerves and their tissue are essential for proper neurotransmission, as well as normal nerve
regeneration following peripheral nerve injury.

PERIPHERAL NERVE INJURY
Peripheral nerve injury (PNI) can have a significant impact on a patient’s quality of life . PNI frequently
[15]
develops into neuropathic pain, which is a complex form of pain that is modulated by both the PNS and
CNS [15,16] . Sunderland et al. were the first to classify peripheral nerve injuries and offer a prognosis for nerve