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Page 2 of 13 Eftekari et al. Plast Aesthet Res 2022;9:43 https://dx.doi.org/10.20517/2347-9264.2022.33

Keywords: Neuromas, regenerative peripheral nerve interface, targeted muscle reinnervation, osseointegrated
neural interface, amputation

INTRODUCTION
There are over 2 million Americans living with major limb loss in the United States alone, with this number
[1,2]
expected to double by 2050 . Limb amputations are the leading cause of major limb loss and are often a
devastating and debilitating life event that may lead to permanent effects on a patient’s career, personal
[3-5]
relations, and self-identity . Amputations are more common in the lower extremity and are often
indicated due to underlying vascular disease (54%), trauma (45%), or cancer (< 2%) . Although
[6]
amputations may provide life-saving and curative medical management for an underlying condition, these
[7]
major operations are not without complications . Peripheral nerve injury due to nerve transection at the
time of surgery creates a proximal nerve with interrupted continuity that is no longer able to communicate
[8]
with its distal innervating targets . This can contribute to postamputation pain, which is perhaps one of the
most prominent side effects following limb amputation and affects up to 95% of patients undergoing this
procedure . Postamputation pain can be categorized as phantom sensations, phantom limb pain, or
[9]
residual limb pain, all of which arise due to complex signaling between the healing nerves in the residual
[9]
limb and central nervous system . In many cases, regeneration of the nerves that were transected during
the amputation develops into a symptomatic neuroma, which has been shown to be the leading cause of
residual limb pain [10,11] . This generation of symptomatic neuromas and their underlying pathophysiology has
been well-described in the literature [10,11] . Moreover, a recent prospective cohort study demonstrated
significant improvement in residual limb pain and phantom limb pain of amputation patients following
[12]
surgical resection of their symptomatic neuroma . The goal of this narrative review is to (1) summarize the
underlying pathophysiology of neuroma formation and centralization of pain signaling; (2) discuss the
traditional methods of surgical neuroma treatment and prevention; and (3) describe three novel surgical
strategies that harness the pathophysiology of neuroma formation to their advantage.

PATHOPHYSIOLOGY OF NEUROMA GENERATION
Unlike neurons of the central nervous system, nerves of the peripheral nervous system have the capacity to
regenerate and create new synapses even after the most severe injury . This regeneration can provide
[8]
physiologic healing but, unfortunately, often occurs in a disorganized manner that leads to pathologic
[8]
dysfunction of the nerve instead . Central to this process are Schwann cells that are responsible for
[8]
initiating and sustaining nerve regeneration . In the setting of trauma, these cells dedifferentiate,
proliferate, and elongate within the endoneurial tubes to help guide the reconnection of a transected nerve
[8]
back into its distal nerve sheath . Schwann cells release hundreds of growth-associated genes that trigger a
nerve fiber to switch from a transmitting mode into a growth mode. This signaling cascade begins the
process of axonal growth, which is marked by the production of a growth cone at a fiber’s last healthy node
of Ranvier . Unfortunately, in amputation patients, the transected nerve will never reconnect with its distal
[8]
sheath and will continue its search for the sheath as long as it remains in the regenerative state. Proximal
axons randomly sprout from the proximal nerve with hopes of establishing a connection with the lost distal
nerve. To facilitate and sustain this growth, new connective tissue and blood vessels within the epineurium,
[13]
perineurium, and endoneurium are produced surrounding these growing axons . Over time, the
disorganized growth of axons, connective tissue, and blood vessels form a neurovascular sphere at the
[13]
proximal nerve ending, which is collectively termed a neuroma [Figure 1] .

Neuromas are fundamentally different than healthy peripheral nerve tissue in both structure and
composition. As axons continue to grow without an intact endoneurial tube or distal target to guide them,