Background: Management of painful neuromas continues to challenge clinicians. Controlling axon growth to prevent neuroma has gained considerable traction. A logical extension of this idea is to therefore develop an approach to control and arrest axon growth. Given the limits in axonal regeneration across acellular nerve allografts (ANAs), these constructs could provide a means to reliably terminate axon regeneration from an injured nerve. The purpose of this study was to determine if attaching an ANA to an injured nerve could provide a means to control and limit axon regeneration in a predictable manner. Methods: Twenty (20) adult rats received a sciatic nerve transection, where only the proximal nerve was repaired using an ANA of variable length (0.5, 2.5, and 5.0 cm) or left unrepaired (control). The nerves were harvested 5 weeks post-operatively for gross and histomorphometric analysis. The extent of myelinated axons in regenerated tissue was quantified. Results: At 5 weeks, limited axon regeneration within the ANAs was observed. All lengths of ANAs lead to reduced myelinated axon numbers in the most terminal tissue region compared to untreated injured nerve (P = .002). Additionally, ANA length 2.5 cm or greater did not contain any axons at the most terminal tissue region. Conclusions: This study demonstrates a proof of concept that ANAs attached to the proximal end of an injured nerve can limit axon growth in a controlled manner. Furthermore, the extent of axon growth from the injured nerve into the ANA is dependent on the ANA length.
MackinnonSE.Nerve Surgery. New York: Thieme; 2015.
4.
RussellWR.Painful amputation stumps and phantom limbs; treatment by repeated percussion to the stump neuromata. Br Med J. 1949;1(4614):1024-1026.
5.
RussellWRSpaldingJM.Treatment of painful amputation stumps. Br Med J. 1950;2(4670):68-73.
6.
WojtkiewiczDMSaundersJDomeshekL, et al. Social impact of peripheral nerve injuries. Hand. 2015;10(2):161-167.
7.
DomeshekLFKraussEMSnyder-WarwickAK, et al. Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life. Plast Reconstr Surg. 2017;139(2):407-418.
8.
NovakCBMackinnonSE.Evaluation of cold sensitivity, pain, and quality of life after upper extremity nerve injury. Hand. 2016;11(2):173-176.
9.
VernadakisAJKochHMackinnonSE.Management of neuromas. Clin Plast Surg. 2003;30(2):247-268, vii.
10.
PopplerLHParikhRPBichanichMJ, et al. Surgical interventions for the treatment of painful neuroma: a comparative meta-analysis. Pain. 2018;159(2):214-223.
11.
PopplerLHMackinnonSE.The role of the peripheral nerve surgeon in the treatment of pain. Neurotherapeutics. 2019;16:9-25.
12.
WallPDWaxmanSBasbaumAI.Ongoing activity in peripheral nerve: injury discharge. Exp Neurol. 1974;45(3):576-589.
13.
WallPDGutnickM.Ongoing activity in peripheral nerves: the physiology and pharmacology of impulses originating from a neuroma. Exp Neurol. 1974;43(3):580-593.
14.
CraviotoHBattistaA.Clinical and ultrastructural study of painful neuroma. Neurosurgery. 1981;8(2):181-190.
15.
PerkinsJRAntunes-MartinsACalvoM, et al. A comparison of RNA-seq and exon arrays for whole genome transcription profiling of the L5 spinal nerve transection model of neuropathic pain in the rat. Mol Pain. 2014;10:7.
16.
PerlER.Causalgia, pathological pain, and adrenergic receptors. Proc Natl Acad Sci USA. 1999;96(14):7664-7667.
17.
JensenTSKrebsBNielsenJRasmussenP.Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain. 1983;17(3):243-256.
18.
DellonALMackinnonSE.Treatment of the painful neuroma by neuroma resection and muscle implantation. Plast Reconstr Surg. 1986;77(3):427-438.
19.
MassDPCianoMCTortosaR, et al. Treatment of painful hand neuromas by their transfer into bone. Plast Reconstr Surg. 1984;74(2):182-185.
20.
GorkischKBoese-LandgrafJVaubelE.Treatment and prevention of amputation neuromas in hand surgery. Plast Reconstr Surg. 1984;73(2):293-299.
21.
YukselFKislaogluEDurakN, et al. Prevention of painful neuromas by epineural ligatures, flaps and grafts. Br J Plast Surg. 1997;50(3):182-185.
22.
TupperJWBoothDM.Treatment of painful neuromas of sensory nerves in the hand: a comparison of traditional and newer methods. J Hand Surg Am. 1976;1(2):144-151.
23.
NelsonAW.The painful neuroma: the regenerating axon versus the epineural sheath. J Surg Res. 1977;23(3):215-221.
24.
Saheb-Al-ZamaniMYanYFarberSJ, et al. Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp Neurol. 2013;247:165-177.
25.
PopplerLHEeXSchellhardtL, et al. Axonal growth arrests after an increased accumulation of Schwann cells expressing senescence markers and stromal cells in acellular nerve allografts. Tissue Eng Part A. 2016;22(13-14):949-961.
26.
MackinnonSEHudsonARHunterDA.Histologic assessment of nerve regeneration in the rat. Plast Reconstr Surg. 1985;75(3):384-388.
27.
PopplerLHEeXSchellhardtL, et al. Axonal Growth Arrests After an Increased Accumulation of Schwann Cells Expressing Senescence Markers and Stromal Cells in Acellular Nerve Allografts. Tissue Eng Part A. 2016; Jul;22(13-14):949-961.
28.
HunterDAMoradzadehAWhitlockEL, et al. Binary imaging analysis for comprehensive quantitative histomorphometry of peripheral nerve. J Neurosci Methods. 2007;166(1):116-124.
29.
Goheen-RobillardBMyckatynTMMackinnonSEHunterDA.End-to-side neurorrhaphy and lateral axonal sprouting in a long graft rat model. Laryngoscope. 2002;112(5):899-905.
