Biology and pathophysiology of symptomatic neuromas.


Journal

Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686

Informations de publication

Date de publication:
17 Oct 2023
Historique:
received: 28 11 2022
accepted: 07 06 2023
medline: 18 10 2023
pubmed: 18 10 2023
entrez: 18 10 2023
Statut: aheadofprint

Résumé

Neuromas are a substantial cause of morbidity and reduction in quality of life. This is not only caused by a disruption in motor and sensory function from the underlying nerve injury but also by the debilitating effects of neuropathic pain resulting from symptomatic neuromas. A wide range of surgical and therapeutic modalities have been introduced to mitigate this pain. Nevertheless, no single treatment option has been successful in completely resolving the associated constellation of symptoms. While certain novel surgical techniques have shown promising results in reducing neuroma-derived and phantom limb pain, their effectiveness and the exact mechanism behind their pain-relieving capacities have not yet been defined. Furthermore, surgery has inherent risks, may not be suitable for many patients, and may yet still fail to relieve pain. Therefore, there remains a great clinical need for additional therapeutic modalities to further improve treatment for patients with devastating injuries that lead to symptomatic neuromas. However, the molecular mechanisms and genetic contributions behind the regulatory programs that drive neuroma formation-as well as the resulting neuropathic pain-remain incompletely understood. Here, we review the histopathological features of symptomatic neuromas, our current understanding of the mechanisms that favor neuroma formation, and the putative contributory signals and regulatory programs that facilitate somatic pain, including neurotrophic factors, neuroinflammatory peptides, cytokines, along with transient receptor potential, and ionotropic channels that suggest possible approaches and innovations to identify novel clinical therapeutics.

Identifiants

pubmed: 37851396
doi: 10.1097/j.pain.0000000000003055
pii: 00006396-990000000-00421
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NINDS NIH HHS
ID : U19NS130617
Pays : United States

Informations de copyright

Copyright © 2023 International Association for the Study of Pain.

Références

Alant JDDV, Kemp SWP, Khu KJOL, Kumar R, Webb AA, Midha R. Traumatic neuroma in continuity injury model in rodents. J Neurotrauma 2012;29:1691–703.
Alves CJ, Alencastre IS, Neto E, Ribas J, Ferreira S, Vasconcelos DM, Sousa DM, Summavielle T, Lamghari M. Bone injury and repair trigger central and peripheral NPY neuronal pathways. PLoS One 2016;11:e0165465.
Anand P. Nerve growth factor regulates nociception in human health and disease. Br J Anaesth 1995;75:201–8.
Anand P, Terenghi G, Birch R, Wellmer A, Cedarbaum JM, Lindsay RM, Williams-Chestnut RE, Sinicropi DV. Endogenous NGF and CNTF levels in human peripheral nerve injury. Neuroreport 1997;8:1935–8.
Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessell IP, Anand P. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. PAIN 2008;138:667–80.
Atherton DD, Taherzadeh O, Facer P, Elliot D, Anand P. The potential role of nerve growth factor (NGF) in painful neuromas and the mechanism of pain relief by their relocation to muscle. J Hand Surg 2006;31:652–6.
Badalamente MA, Hurst LC, Ellstein J, McDevitt CA. The pathobiology of human neuromas: an electron microscopic and biochemical study. J Hand Surg 1985;10:49–53.
Bagnasco D, Ferrando M, Varricchi G, Passalacqua G, Canonica GW. A critical evaluation of Anti-IL-13 and Anti-IL-4 strategies in severe asthma. Int Arch Allerg Immunol 2016;170:122–31.
Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 2004;41:849–57.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009;139:267–84.
Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 2007;448:204–8.
Bernd P. The role of neurotrophins during early development. Gene Expr 2008;14:241–50.
Biggs JE, Yates JM, Loescher AR, Clayton NM, Boissonade FM, Robinson PP. Vanilloid receptor 1 (TRPV1) expression in lingual nerve neuromas from patients with or without symptoms of burning pain. Brain Res 2007;1127:59–65.
Bowen JB, Ruter D, Wee C, West J, Valerio IL. Targeted muscle reinnervation technique in below-knee amputation. Plast Reconstr Surg 2019;143:309–12.
Bowen JB, Wee CE, Kalik J, Valerio IL. Targeted muscle reinnervation to improve pain, prosthetic tolerance, and bioprosthetic outcomes in the amputee. Adv Wound Care 2017;6:261–7.
Bráz JM, Basbaum AI. Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli. PAIN 2010;150:290–301.
Brohawn SG, Campbell EB, MacKinnon R. Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature 2014;516:126–30.
Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 2004;16:1–7.
Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 2011;7:94.
Campos RMP, Barbosa-Silva MC, Ribeiro-Resende VT. Comparison of effect of crush or transection peripheral nerve lesion on lumbar spinal cord synaptic plasticity and microglial dynamics. IBRO Neurosci Rep 2021;10:225–35.
Caterina MJ. TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci 2014;5:1107–16.
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 1999;398:436–41.
Cattin AL, Burden JJ, Van Emmenis L, MacKenzie FE, Hoving J, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd AC. Macrophage-induced blood vessels guide schwann cell-mediated regeneration of peripheral nerves. Cell 2015;162:1127–39.
CDC. Hospital ambulatory medical care survey: 2017 emergency department summary tables, 2017. Available at: https://www.cdc.gov/nchs/data/nhamcs/web_tables/2017_ed_web_tables-508.pdf. Accessed April 22, 2022.
Chang BL, Mondshine J, Attinger CE, Kleiber GM. Targeted muscle reinnervation improves pain and ambulation outcomes in highly comorbid amputees. Plast Reconstr Surg 2021;148:376–86.
Chen H, Jiang L, Zhang D, Chen J, Luo X, Xie Y, Han T, Wang L, Zhang Z, Zhou X, Yan H. Exploring the correlation between the regulation of macrophages by regulatory T cells and peripheral neuropathic pain. Front Neurosci 2022;16:813751.
Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res 2008;33:1970–8.
Chiodo CP, Miller SD. Surgical treatment of superficial peroneal neuroma. Foot Ankle Int 2004;25:689–94.
Chung MK, Ro JY. Peripheral glutamate receptor and transient receptor potential channel mechanisms of craniofacial muscle pain. Mol Pain 2020;16:174480692091420.
Ciobanu C, Reid G, Babes A. Acute and chronic effects of neurotrophic factors BDNF and GDNF on responses mediated by thermo-sensitive TRP channels in cultured rat dorsal root ganglion neurons. Brain Res 2009;1284:54–67.
Coleman MP, Höke A. Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neurosci 2020;21:183–96.
Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW. Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 1997;387:505–8.
Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 2010;330:55–60.
Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, Patapoutian A. Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 2012;483:176–81.
Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894–8.
Cravioto H, Battista A. Clinical and ultrastructural study of painful neuroma. Neurosurgery 1981;8:181–90.
Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci 2004;24:8232–6.
Datta D, Selvarajah K, Davey N. Functional outcome of patients with proximal upper limb deficiency—acquired and congenital. Clin Rehabil 2004;18:172–7.
Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56–66.
Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 1993;13:1976–92.
Dib-Hajj SD, Black JA, Cummins TR, Kenney AM, Kocsis JD, Waxman SG. Rescue of α-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo. J Neurophysiol 1998;79:2668–76.
Dib-Hajj SD, Waxman SG. Sodium channels in human pain disorders: genetics and pharmacogenomics. Annu Rev Neurosci 2019;42:87–106.
Dilwali S, Roberts D, Stankovic KM. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. Cancer Biol Ther 2015;16:170–5.
Dubin AE, Schmidt M, Mathur J, Petrus MJ, Xiao B, Coste B, Patapoutian A. Inflammatory signals enhance piezo2-mediated mechanosensitive currents. Cell Rep 2012;2:511–7.
Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, Ertl WJ, Tintle SM, Nanos GP, Valerio IL, Kuiken TA, Apkarian AV, Porter K, Jordan SW. Targeted muscle reinnervation treats neuroma and phantom pain in major limb amputees: a randomized clinical trial. Ann Surg 2019;270:238–46.
Dun XP, Parkinson DB. Transection and crush models of nerve injury to measure repair and remyelination in peripheral nerve. Methods Mol Biol 2018;1791:251–62.
Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH, Gringhuis M, Minett MS, Hong GS, Lee E, Oh U, Ishikawa Y, Zwartkuis FJ, Cox JJ, Wood JN. A role for Piezo2 in EPAC1-dependent mechanical allodynia. Nat Commun 2013;4:1682.
Elmes SJR, Jhaveri MD, Smart D, Kendall DA, Chapman V. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci 2004;20:2311–20.
Ephraim PL, Wegener ST, MacKenzie EJ, Dillingham TR, Pezzin LE. Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Arch Phys Med Rehabil 2005;86:1910–9.
Fariñas I, Wilkinson GA, Backus C, Reichardt LF, Patapoutian A. Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo. Neuron 1998;21:325–34.
Frantz TL, Everhart JS, West JM, Ly TV, Phieffer LS, Valerio IL. Targeted muscle reinnervation at the time of major limb amputation in traumatic amputees. JBJS Open Access 2020;5:e0067.
Freeman MR. Signaling mechanisms regulating Wallerian degeneration. Curr Opin Neurobiol 2014;27:224–31.
Fried K, Brodin E, Theodorsson E. Substance P-CGRP- and NPY-immunoreactive nerve fibers in rat sciatic nerve-end neuromas. Regul Peptides 1989;25:11–24.
Fried K, Frisén J. End structure and neuropeptide immunoreactivity of axons in sciatic neuromas following nerve section in neonatal rats. Exp Neurol 1990;109:286–93.
Frise´n J, Risling M, Theodorsson E, Fried K. NPY-like immunoreactivity in sensory nerve fibers in rat sciatic neuroma. Brain Res 1992;577:142–6.
Fu W, Wessel CR, Taylor BK. Neuropeptide Y tonically inhibits an NMDAR➔AC1➔TRPA1/TRPV1 mechanism of the affective dimension of chronic neuropathic pain. Neuropeptides 2020;80:102024.
Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020;86:102017.
Geraghty TJ, Jones LE. Painful neuromata following upper limb amputation. Prosthetics Orthotics Int 1996;20:176–81.
Geremia NM, Pettersson LME, Hasmatali JC, Hryciw T, Danielsen N, Schreyer DJ, Verge VMK. Endogenous BDNF regulates induction of intrinsic neuronal growth programs in injured sensory neurons. Exp Neurol 2010;223:128–42.
Ghilardi JR, Freeman KT, Jimenez-Andrade JM, Mantyh WG, Bloom AP, Kuskowski MA, Mantyh PW. Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain. Mol Pain 2010;6:87.
Gibson SJ, Polak JM, Bloom SR, Sabate IM, Mulderry PM, Ghatei MA, Mcgregor GP, Morrison JFB, Kelly JS, Evans RM, Rosenfeldl MG. Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci 1984;4:3101–11.
Gouin O, L'Herondelle K, Lebonvallet N, Le Gall-Ianotto C, Sakka M, Buhé V, Plée-Gautier E, Carré JL, Lefeuvre L, Misery L, Le Garrec R. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 2017;8:644–61.
Griffin JW, Hogan MV, Chhabra AB, Deal DN. Peripheral nerve repair and reconstruction. J Bone Joint Surg 2013;95:2144–51.
Grinsell D, Keating CP. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. Biomed Res Int 2014;2014:1–13.
Guevara YMV, Yoshikawa H, Saito I, Maeda T, Seo K. Effect of local application of an antibody against brain-derived neurotrophic factor on neuroma formation after transection of the inferior alveolar nerve in the rat. Neuroreport 2014;25:1069–74.
Hartupee J, Mann DL. Role of inflammatory cells in fibroblast activation. J Mol Cell Cardiol 2016;93:143–8.
He FL, Qiu S, Zou JL, Gu FB, Yao Z, Tu ZH, Wang YY, Liu XL, Zhou LH, Zhu QT. Covering the proximal nerve stump with chondroitin sulfate proteoglycans prevents traumatic painful neuroma formation by blocking axon regeneration after neurotomy in Sprague Dawley rats. J Neurosurg 2021;134:1599–609.
Hochberg MC, Tive LA, Abramson SB, Vignon E, Verburg KM, West CR, Smith MD, Hungerford DS. When is osteonecrosis not osteonecrosis?: adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheumatol 2016;68:382–91.
Hsu E, Cohen SP. Postamputation pain: epidemiology, mechanisms, and treatment. J Pain Res 2013;6:121–36.
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. PAIN 2017;158:543–59.
Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science 2016;354:572–7.
Jiang L, Ma D, Grubb BD, Wang M. ROS/TRPA1/CGRP signaling mediates cortical spreading depression. J Headache Pain 2019;20:25.
Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 2004;427:260–5.
Julius D. TRP channels and pain. Annu Rev Cell Dev Biol 2013;29:355–84.
Jurecka W, Ammerer HP, Lassmann H. Regeneration of a transected peripheral nerve—an autoradiographic and electron microscopic study. Acta Neuropathol 1975;32:299–312.
Kang S, Tanaka T, Kishimoto T. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol 2015;27:21–9.
Karchewski LA, Gratto KA, Wetmore C, Verge VMK. Dynamic patterns of BDNF expression in injured sensory neurons: differential modulation by NGF and NT-3. Eur J Neurosci 2002;16:1449–62.
Karsy M, Palmer CA, Mahan MA. Pathologic remodeling of endoneurial tubules in human neuromas. Cureus 2018;10:e2087.
Karsy M, Watkins R, Jensen MR, Guan J, Brock AA, Mahan MA. Trends and cost analysis of upper extremity nerve injury using the national (nationwide) inpatient sample. World Neurosurg 2019;123:e488–500.
Khan J, Noboru N, Young A, Thomas D. Pro and anti-inflammatory cytokine levels (TNF-α, IL-1β, IL-6 and IL-10) in rat model of neuroma. Pathophysiology 2017;24:155–9.
Kiguchi N, Kobayashi Y, Kadowaki Y, Fukazawa Y, Saika F, Kishioka S. Vascular endothelial growth factor signaling in injured nerves underlies peripheral sensitization in neuropathic pain. J Neurochem 2014;129:169–78.
Ko JH, Kim PS, O'Shaughnessy KD, Ding X, Kuiken TA, Dumanian GA. A quantitative evaluation of gross versus histologic neuroma formation in a rabbit forelimb amputation model: potential implications for the operative treatment and study of neuromas. J Brachial Plex Peripher Nerve Inj 2014;06:e23–32.
Koch H, Haas F, Hubmer M, Rappl T, Scharnagl E. Treatment of painful neuroma by resection and nerve stump transplantation into a vein. Ann Plast Surg 2003;51:45–50.
Kopp DM, Trachtenberg JT, Thompson WJ. Glial growth factor rescues Schwann cells of mechanoreceptors from denervation-induced apoptosis. J Neurosci 1997;17:6697–706.
Kouyoumdjian JA, Graç C, Ferreira VM. Peripheral nerve injuries: a retrospective survey of 1124 cases. Neurol India 2017;65:551–5.
Kovalchuk O, Kovalchuk I. Cannabinoids as anticancer therapeutic agents. Cell Cycle 2020;19:961–89.
Kryger GS, Kryger Z, Zhang F, Shelton DL, Lineaweaver WC, Buncke HJ. Nerve growth factor inhibition prevents traumatic neuroma formation in the rat. J Hand Surg 2001;26:635–44.
Kubiak CA, Adidharma W, Kung TA, Kemp SWP, Cederna PS, Vemuri C. Decreasing postamputation pain with the regenerative peripheral nerve interface (RPNI). Ann Vasc Surg 2022;79:421–6.
Kubiak CA, Kemp SWP, Cederna PS. Regenerative peripheral nerve interface for management of postamputation neuroma. JAMA Surg 2018;153:681–2.
Kubiak CA, Kemp SWP, Cederna PS, Kung TA. Prophylactic regenerative peripheral nerve interfaces to prevent postamputation pain. Plast Reconstr Surg 2019;144:421e–30e.
Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2008;123:398–410.
Kung TA, Langhals NB, Martin DC, Johnson PJ, Cederna PS, Urbanchek MG. Regenerative peripheral nerve interface viability and signal transduction with an implanted electrode. Plast Reconstr Surg 2014;133:1380–94.
Lans J, Groot OQ, Hazewinkel MHJ, Kaiser PB, Lozano-Calderón SA, Heng M, Valerio IL, Eberlin KR. Factors related to neuropathic pain following lower extremity amputation. Plast Reconstr Surg 2022;150:446–55.
Lans J, Hoftiezer Y, Lozano-Calderón SA, Heng M, Valerio IL, Eberlin KR. Risk factors for neuropathic pain following major upper extremity amputation. J Reconstr Microsurg 2021;37:413–20.
Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, Pagani CA, Sun Y, Stepien DM, Sorkin M, Kubiak CA, Visser ND, Meyers CA, Wang Y, Rasheed HA, Xu J, Miller S, Huber AK, Minichiello L, Cederna PS, Kemp SWP, Clemens TL, James AW, Levi B. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun 2021;12:4939.
Leffler A, Cummins TR, Dib-Hajj SD, Hormuzdiar WN, Black JA, Waxman SG. GDNF and NGF reverse changes in repriming of TTX-sensitive Na+ currents following axotomy of dorsal root ganglion neurons. J Neurophysiol 2002;88:650–8.
List EB, Krijgh DD, Martin E, Coert JH. Prevalence of residual limb pain and symptomatic neuromas after lower extremity amputation: a systematic review and meta-analysis. PAIN 2021;162:1906–13.
Loescher AR, Boissonade FM, Robinson PP. Calcitonin gene-related peptide modifies the ectopic discharge from damaged nerve fibres in the ferret. Neurosci Lett 2001;300:71–4.
Logu Fd, Nassini R, Hegron A, Landini L, Jensen DD, Latorre R, Ding J, Marini M, Souza Monteiro de Araujo D, Ramírez-Garcia P, Whittaker M, Retamal J, Titiz M, Innocenti A, Davis TP, Veldhuis N, Schmidt BL, Bunnett NW, Geppetti P. Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice. Nat Commun 2022;13:1–19.
Long H, Ahmed M, Ackermann P, Stark A, Li J. Neuropeptide y innervation during fracture healing and remodeling: a study of angulated tibial fractures in the rat. Acta Orthop 2010;81:639–46.
Lu C, Sun X, Wang C, Wang Y, Peng J. Mechanisms and treatment of painful neuromas. Rev Neurosci 2018;29:557–66.
Lu G, Beuerman RW, Zhao S, Sun G, Nguyen DH, Ma S, Kline DG. Tumor necrosis factor-alpha and interleukin-1 induce activation of MAP kinase and SAP kinase in human neuroma fibroblasts. Neurochem Int 1997;30:401–10.
Ma W, Quirion R. Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy. J Neurochem 2006;98:180–92.
Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 1990;247:1446–51.
Maleci A, Moretto G, Fenzi F, Poppi M, Govoni E, Bragaglia MM, Rizzuto N. Studio istopatologico ed ultrastrutturale in alcuni neuromi da amputazione. Riv Patol Nerv Ment 1982;103:67–80.
Malykhina AP, Lei Q, Erickson CS, Epstein ML, Saban MR, Davis CA, Saban R. VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity. BMC Physiol 2012;12:15.
Marcol W, Kotulska K, Larysz-Brysz M, Kowalik JL. BDNF contributes to animal model neuropathic pain after peripheral nerve transection. Neurosurg Rev 2007;30:235–43.
McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–8.
Méndez-Maldonado K, Vega-López GA, Aybar MJ, Velasco I. Neurogenesis from neural crest cells: molecular mechanisms in the formation of cranial nerves and ganglia. Front Cell Dev Biol 2020;8:635.
Meng J, Wang J, Steinhoff M, Dolly JO. TNFα induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18–1/syntaxin1/SNAP-25 mediated fusion. Sci Rep 2016;6:21226.
Menorca RMG, Fussell TS, Elfar JC. Nerve physiology. Hand Clin 2013;29:317–30.
Meyer RA, Raja SN, Campbell JN, Mackinnon SE, Dellon AL. Neural activity originating from a neuroma in the baboon. Brain Res 1985;325:255–60.
Michael S, Achilleos C, Panayiotou T, Strati K. Inflammation shapes stem cells and stemness during infection and beyond. Front Cell Dev Biol 2016;4:118.
Miclescu A, Straatmann A, Gkatziani P, Butler S, Karlsten R, Gordh T. Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication. Scand J Pain 2019;20:95–108.
Miki K, Ohta M, Abe M, Yoshimatsu H, Fujii K, Ebata N, West CR, Brown MT, Pixton G, Isogawa N. Efficacy, general safety, and joint safety of tanezumab in Japanese patients with osteoarthritis: subgroup analyses from two randomized, phase 3 studies. Pain Ther 2022;11:827–44.
Minarelli J, Davis EL, Dickerson A, Moore WC, Mejia JA, Gugala Z, Olmsted-Davis EA, Davis AR. Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation. Mol Pain 2019;15:174480691983819.
Mokarram N, Merchant A, Mukhatyar V, Patel G, Bellamkonda RV. Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 2012;33:8793–801.
Moore AM, Ray WZ, Chenard KE, Tung T, Mackinnon SE. Nerve allotransplantation as it pertains to composite tissue transplantation. Hand 2009;4:239–44.
Moore DC, Elmes JB, Shibu PA, Larck C, Park SI. Mogamulizumab: an anti-CC chemokine receptor 4 antibody for T-cell lymphomas. Ann Pharmacother 2020;54:371–9.
Morgan CR, Bird EV, Robinson PP, Boissonade FM. TRPA1 expression in human lingual nerve neuromas in patients with and without symptoms of dysaesthesia. Neurosci Lett 2009;465:189–93.
Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci 2018;11:487.
Naono-Nakayama R, Sunakawa N, Ikeda T, Nishimori T. Differential effects of substance P or hemokinin-1 on transient receptor potential channels, TRPV1, TRPA1 and TRPM8, in the rat. Neuropeptides 2010;44:57–61.
Nassini R, Materazzi S, Benemei S, Geppetti P. The TRPA1 channel in inflammatory and neuropathic pain and migraine. Rev Physiol Biochem Pharmacol 2014;167:1–43.
Negri S, Faris P, Berra-Romani R, Guerra G, Moccia F. Endothelial transient receptor potential channels and vascular remodeling: extracellular Ca2 + entry for angiogenesis, arteriogenesis and vasculogenesis. Front Physiol 2019;10:1618.
Nigam M, Webb A, Harbour P, Devulapalli C, Kleiber G. Symptomatic neuromas in lower extremity amputees: implications for pre-emptive–targeted muscle reinnervation. Plast Reconstr Surg Glob Open 2019;7:80–1.
Noble J, Munro CA, Prasad VSSV, Midha R. Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma Inj Infect Crit Care 1998;45:116–22.
Novak CB, Anastakis DJ, Beaton DE, Katz J. Patient-reported outcome after peripheral nerve injury. J Hand Surg 2009;34:281–7.
Novak CB, Anastakis DJ, Beaton DE, Mackinnon SE, Katz J. Biomedical and psychosocial factors associated with disability after peripheral nerve injury. J Bone Joint Surg Am Vol 2011;93:929–36.
Oliveira KMC, Pindur L, Han Z, Bhavsar MB, Barker JH, Leppik L. Time course of traumatic neuroma development. PLoS One 2018;13:e0200548.
Onode E, Uemura T, Takamatsu K, Shintani K, Yokoi T, Okada M, Nakamura H. Nerve capping with a nerve conduit for the treatment of painful neuroma in the rat sciatic nerve. J Neurosurg 2020;132:856–64.
van Opijnen MP, Hazelbag HM, de Ruiter GCW. Targeted muscle reinnervation for a recurrent traumatic neuroma of the sural nerve: illustrative case. J Neurosurg Case Lessons 2022;3:CASE2264.
Ostrow KL, Donaldson KJ, Caterina MJ, Belzberg A, Hoke A. The secretomes of painful versus nonpainful human schwannomatosis tumor cells differentially influence sensory neuron gene expression and sensitivity. Sci Rep 2019;9:13098.
Pan D, Acevedo-Cintrón JA, Sayanagi J, Snyder-Warwick AK, Mackinnon SE, Wood MD. The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration. Exp Neurol 2020;331:113363.
Pan D, Bichanich M, Wood IS, Hunter DA, Tintle SM, Davis TA, Wood MD, Moore AM. Long acellular nerve allografts cap transected nerve to arrest axon regeneration and alter upstream gene expression in a rat neuroma model. Plast Reconstr Surg 2021;148:32E–41E.
Paricio-Montesinos R, Schwaller F, Udhayachandran A, Rau F, Walcher J, Evangelista R, Vriens J, Voets T, Poulet JFA, Lewin GR. The sensory coding of warm perception. Neuron 2020;106:830–41.e3.
Parrinello S, Napoli I, Ribeiro S, Digby PW, Fedorova M, Parkinson DB, Doddrell RDS, Nakayama M, Adams RH, Lloyd AC. EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell Sorting. Cell 2010;143:145–55.
Patel MK, Kaye AD, Urman RD. Tanezumab: therapy targeting nerve growth factor in pain pathogenesis. J Anaesthesiol Clin Pharmacol 2018;34:111–6.
Penna A, Konstantatos AH, Cranwell W, Paul E, Bruscino-Raiola FR. Incidence and associations of painful neuroma in a contemporary cohort of lower-limb amputees. ANZ J Surg 2018;88:491–6.
Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 2006;29:507–38.
Pfister BJ, Gordon T, Loverde JR, Kochar AS, Mackinnon SE, Cullen DK. Biomedical engineering strategies for peripheral nerve repair: surgical applications, state of the art, and future challenges. Crit Rev Biomed Eng 2011;39:81–124.
Pi W, Li C, Zhang M, Zhang W, Zhang PX. Myelin-associated glycoprotein combined with chitin conduit inhibits painful neuroma formation after sciatic nerve transection. Neural Regen Res 2022;17:1343–7.
Poppler LH, Parikh RP, Bichanich MJ, Rebehn K, Bettlach CR, Mackinnon SE, Moore AM. Surgical interventions for the treatment of painful neuroma: a comparative meta-analysis. PAIN 2018;159:214–23.
Pradhan L, Cai X, Wu S, Andersen ND, Martin M, Malek J, Guthrie P, Veves A, Logerfo FW. Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J Surg Res 2011;167:336–42.
Prasetyono TOH, Permatasari E, Soetrisno E. Implantation of nerve stump inside a vein and a muscle: comparing neuroma formation in rat. Int Surg 2014;99:807–11.
Prato V, Taberner FJ, Hockley JRF, Callejo G, Arcourt A, Tazir B, Hammer L, Schad P, Heppenstall PA, Smith ES, Lechner SG. Functional and molecular characterization of mechanoinsensitive “silent” nociceptors. Cell Rep 2017;21:3102–15.
Qin Q, Gomez-Salazar M, Cherief M, Pagani CA, Lee S, Hwang C, Tower RJ, Onggo S, Sun Y, Piplani A, Li Z, Ramesh S, Clemens TL, Levi B, James AW. Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma. Bone Res 2022;10:43.
Qiu S, Deng PJ, He FL, Yan LW, Tu ZH, Liu XL, Quan DP, Bai Y, Zheng CB, Zhu QT. A decellularized nerve matrix scaffold inhibits neuroma formation in the stumps of transected peripheral nerve after peripheral nerve injury. Neural Regen Res 2023;18:664.
Reichert F, Levitzky R, Rotshenker S. Interleukin 6 in intact and injured mouse peripheral nerves. Eur J Neurosci 1996;8:530–5.
Renthal W, Chamessian A, Curatolo M, Davidson S, Burton M, Dib-Hajj S, Dougherty PM, Ebert AD, Gereau RW, Ghetti A, Gold MS, Hoben G, Menichella DM, Mercier P, Ray WZ, Salvemini D, Seal RP, Waxman S, Woolf CJ, Stucky CL, Price TJ. Human cells and networks of pain: transforming pain target identification and therapeutic development. Neuron 2021;109:1426–9.
Renthal W, Tochitsky I, Yang L, Cheng YC, Li E, Kawaguchi R, Geschwind DH, Woolf CJ. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuron 2020;108:128–44.e9.
Rivera L, Gallar J, Pozo MA, Belmonte C. Responses of nerve fibres of the rat saphenous nerve neuroma to mechanical and chemical stimulation: an in vitro study. J Physiol 2000;527:305–13.
Rodriguez FJ, Giannini C, Spinner RJ, Perry A. 15—tumors of peripheral nerve. Practical surgical neuropathology: a diagnostic approach: a volume in the pattern recognition series. San Francisco/Chicago: Elsevier, 2018. p. 323–373.
Ruijs ACJ, Jaquet JB, Kalmijn S, Giele H, Hovius SER. Median and ulnar nerve injuries: a meta-analysis of predictors of motor and sensory recovery after modern microsurgical nerve repair. Plast Reconstr Surg 2005;116:484–94.
Ruohonen S, Khademi M, Jagodić M, Taskinen HS, Olsson T, Röyttä M. Cytokine responses during chronic denervation. J Neuroinflammation 2005;2:26.
Shin A, Saffari T, Bedar M, Hundepool C, Bishop A. The role of vascularization in nerve regeneration of nerve graft. Neural Regen Res 2020;15:1573–9.
Sakai Y, Ochi M, Uchio Y, Ryoke K, Yamamoto S. Prevention and treatment of amputation neuroma by an atelocollagen tube in rat sciatic nerves. J Biomed Mater Res B Appl Biomater 2005;73B:355–60.
Santosa KB, Oliver JD, Cederna PS, Kung TA. Regenerative peripheral nerve interfaces for prevention and management of neuromas. Clin Plast Surg 2020;47:311–21.
Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain 2017;18:34.
Schröder JM, May R, Weis J. Perineurial cells are the first to traverse gaps of peripheral nerves in silicone tubes. Clin Neurol Neurosurg 1993;95:78–83.
Scott BB, Winograd JM, Redmond RW. Surgical approaches for prevention of neuroma at time of peripheral nerve injury. Front Surg 2022;9:819608.
Scott BB, Wu RC, Nietlispach V, Randolph MA, Redmond RW. A photosealed cap prevents disorganized axonal regeneration and neuroma following nerve transection in rats. Plast Reconstr Surg Glob Open 2022;10:4168.
Selecki BR, Ring IT, Simpson DA, Vanderfield GK, Sewell MF. Trauma to the central and peripheral nervous systems part II: a statistical profile of surgical treatment new south wales 1977. ANZ J Surg 1982;52:111–6.
Seltzer Z, Paran Y, Eisen A, Ginzburg R. Neuropathic pain behavior in rats depends on the afferent input from nerve-end neuroma including histamine-sensitive C-fibers. Neurosci Lett 1991;128:203–6.
Shamoun F, Shamoun V, Akhavan A, Tuffaha SH. Target receptors of regenerating nerves: neuroma Formation and current treatment options. Front Mol Neurosci 2022;15:859221.
Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, Lee CH, Kim M, Oh U. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007;27:2331–7.
Shvartsman D, Storrie-White H, Lee K, Kearney C, Brudno Y, Ho N, Cezar C, Mccann C, Anderson E, Koullias J, Tapia JC, Vandenburgh H, Lichtman JW, Mooney DJ. Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling. Mol Ther 2014;22:1243–53.
Soroush M, Modirian E, Soroush MR, Masoumi M. Neuroma in bilateral upper limb amputation. Orthopedics 2008;31:1193.
Souza JM, Cheesborough JE, Ko JH, Cho MS, Kuiken TA, Dumanian GA. Targeted muscle reinnervation: a novel approach to postamputation neuroma pain. Clin Orthop Relat Res 2014;472:2984–990.
Stepien DM, Hwang C, Marini S, Pagani CA, Sorkin M, Visser ND, Huber AK, Edwards NJ, Loder SJ, Vasquez K, Aguilar CA, Kumar R, Mascharak S, Longaker MT, Li J, Levi B. Tuning macrophage phenotype to mitigate skeletal muscle fibrosis. J Immunol 2020;204:2203–15.
Stokvis A, Henk Coert J, Van Neck JW. Insufficient pain relief after surgical neuroma treatment: prognostic factors and central sensitisation. J Plast Reconstr Aesthet Surg 2010;63:1538–43.
Sunderland S. Nerve injuries and their repair: a critical appraisal. New York, NY: Churchill Livingstone, 1991.
Szczot M, Liljencrantz J, Ghitani N, Barik A, Lam R, Thompson JH, Bharucha-Goebel D, Saade D, Necaise A, Donkervoort S, Foley AR, Gordon T, Case L, Bushnell MC, Bönnemann CG, Chesler AT. PIEZO2 mediates injury-induced tactile pain in mice and humans. Sci Transl Med 2018;10:eaat9892.
Takeda M, Takahashi M, Matsumoto S. Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neurosci Biobehav Rev 2009;33:784–92.
Taylor CA, Braza D, Rice JB, Dillingham T. The incidence of peripheral nerve injury in extremity trauma. Am J Phys Med Rehabil 2008;87:381–5.
Tofaris GK, Patterson PH, Jessen KR, Mirsky R. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 2002;22:6696–703.
Toledo-Aral JJ, Moss BL, He ZJ, Koszowski AG, Whisenand T, Levinson SR, Wolf JJ, Silos-Santiago I, Halegoua S, Mandel G. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci U S A 1997;94:1527–32.
Valerio IL, Dumanian GA, Jordan SW, Mioton LM, Bowen BJ, West JM, Porter K, Ko JH, Souza JM, Potter BK. Preemptive treatment of phantom and residual limb pain with targeted muscle reinnervation at the time of major limb amputation. J Am Coll Surg 2019;228:217–26.
Vargas ME, Barres BA. Why is Wallerian degeneration in the CNS so slow? Annu Rev Neurosci 2007;30:153–79.
Vernadakis AJ, Koch H, Mackinnon SE. Management of neuromas. Clin Plast Surg 2003;30:247–68.
Vora AR, Bodell SM, Loescher AR, Smith KG, Robinson PP, Boissonade FM. Inflammatory cell accumulation in traumatic neuromas of the human lingual nerve. Arch Oral Biol 2007;52:74–82.
Vu PP, Vaskov AK, Irwin ZT, Henning PT, Lueders DR, Laidlaw AT, Davis AJ, Nu CS, Gates DH, Gillespie RB, Kemp SWP, Kung TA, Chestek CA, Cederna PS. A regenerative peripheral nerve interface allows real-time control of an artificial hand in upper limb amputees. Sci Transl Med 2020;12:eaay2857.
Wall PD, Devor M, Inbal R, Scadding JW, Schonfeld D, Seltzer Z, Tomkiewicz MM. Autotomy following peripheral nerve lesions: experimental anesthesia dolorosa. PAIN 1979;7:103–13.
Wall PD, Gutnick M. Ongoing activity in peripheral nerves: the physiology and pharmacology of impulses originating from a neuroma. Exp Neurol 1974;43:580–93.
Wall PD, Gutnick M. Properties of afferent nerve impulses originating from a neuroma. Nature 1974;248:740–3.
Wang XL, Cui LW, Liu Z, Gao YM, Wang S, Li H, Liu HX, Yu LJ. Effects of TRPA1 activation and inhibition on TRPA1 and CGRP expression in dorsal root ganglion neurons. Neural Regen Res 2019;14:140–8.
Wang Z, Yi XZ, Yu AX. Regenerative peripheral nerve interface prevents neuroma formation after peripheral nerve transection. Neural Regen Res 2023;18:814–8.
Wei Z, Fei Y, Su W, Chen G. Emerging role of schwann cells in neuropathic pain: receptors, glial mediators and myelination. Front Cell Neurosci 2019;13:116.
Weidner C, Klede M, Rukwied R, Lischetzki G, Neisius U, Schmelz M, Skov PS, Petersen LJ. Acute effects of substance P and calcitonin gene-related peptide in human skin—a microdialysis study. J Invest Dermatol 2000;115:1015–20.
Weis J, May R, Schröder JM. Fine structural and immunohistochemical identification of perineurial cells connecting proximal and distal stumps of transected peripheral nerves at early stages of regeneration in silicone tubes. Acta Neuropathol 1994;88:159–65.
Weng W, Zhao B, Lin D, Gao W, Li Z, Yan H. Significance of alpha smooth muscle actin expression in traumatic painful neuromas: a pilot study in rats. Sci Rep 2016;6:23828.
White DM, Leah JD, Zimmermann M. The localization and release of substance P and calcitonin gene-related peptide at nerve fibre endings in rat cutaneous nerve neuroma. Brain Res 1989;503:198–204.
White DM, Zimmermann M. The bradykinin-induced release of substance P from nerve fibre endings in the rat saphenous nerve neuroma is not related to electrophysiological excitation. Neurosci Lett 1988;92:108–13.
Woo SL, Kung TA, Brown DL, Leonard JA, Kelly BM, Cederna PS. Regenerative peripheral nerve interfaces for the treatment of postamputation neuroma pain: a pilot study. Plast Reconstr Surg Glob Open 2016;4:e1038.
Xu QG, Zochodne DW. Ischemia and failed regeneration in chronic experimental neuromas. Brain Res 2002;946:24–30.
Yan H, Gao W, Pan Z, Zhang F, Fan C. The expression of α-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. J Neurotrauma 2012;29:2791–7.
Yang DP, Zhang DP, Mak KS, Bonder DE, Pomeroy SL, Kim HA. Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: axon-dependent removal of newly generated Schwann cells by apoptosis. Mol Cell Neurosci 2008;38:80–8.
Yang XR, Lin MJ, McIntosh LS, Sham JSK. Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle. Am J Physiol Lung Cell Mol Physiol 2006;290:L1267–76.
Yang Y, Wang Z, Yang H, Wang L, Gillespie SR, Wolosin JM, Bernstein AM, Reinach PS. TRPV1 potentiates TGFβ-induction of corneal myofibroblast development through an oxidative stress-mediated p38-SMAD2 signaling loop. PLoS One 2013;8:e77300.
Yao C, Zhou X, Weng W, Poonit K, Sun C, Yan H. Aligned nanofiber nerve conduits inhibit alpha smooth muscle actin expression and collagen proliferation by suppressing TGF-β1/SMAD signaling in traumatic neuromas. Exp Ther Med 2021;22:1414.
Yi J, Jiang N, Li B, Yan Q, Qiu T, Swaminatha Iyer K, Yin Y, Dai H, Yetisen AK, Li S. Painful terminal neuroma prevention by capping PRGD/PDLLA conduit in rat sciatic nerves. Adv Sci 2018;5:1700876.
Yu J, Lou GD, Yue JX, Tang YY, Hou WW, Shou WT, Ohtsu H, Zhang SH, Chen Z. Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy. Neurosci Bull 2013;29:261–9.
Yue JX, Wang RR, Yu J, Tang YY, Hou WW, Lou GD, Zhang SH, Chen Z. Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain. CNS Neurosci Ther 2014;20:883–92.
Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;429:23–37.
Zochodne DW, Allison JA, Ho W, Ho LT, Hargreaves K, Sharkey KA. Evidence for CGRP accumulation and activity in experimental neuromas. Am J Physiol Heart Circulatory Physiol 1995;268:H584–90.
Zochodne DW, Theriault M, Sharkey KA, Cheng C, Sutherland G. Peptides and neuromas: calcitonin gene-related peptide, substance P, and mast cells in a mechanosensitive human sural neuroma. Muscle Nerve 1997;20:875–80.

Auteurs

Charles D Hwang (CD)

Division of Plastic and Reconstructive Surgery, Department of General Surgery, Massachusetts General Hospital, Harvard University, Boston, MA, United States.

Yannick Albert J Hoftiezer (YAJ)

Hand and Arm Center, Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, United States.
Department of Plastic, Reconstructive and Hand Surgery, Radboudumc, Nijmegen, the Netherlands.

Floris V Raasveld (FV)

Hand and Arm Center, Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, United States.
Department of Plastic, Reconstructive and Hand Surgery, Erasmus Medical Center, Rotterdam, the Netherlands.

Barbara Gomez-Eslava (B)

Hand and Arm Center, Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, United States.
F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, United States.

E P A van der Heijden (EPA)

Department of Plastic, Reconstructive and Hand Surgery, Radboudumc, Nijmegen, the Netherlands.
Department of Plastic, Reconstructive and Hand Surgery, Jeroen Bosch Ziekenhuis, Den Bosch, the Netherlands.

Selwyn Jayakar (S)

F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, United States.

Bryan James Black (BJ)

Department of Biomedical Engineering, UMass Lowell, Lowell, MA, United States.

Benjamin R Johnston (BR)

Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, United States.

Brian J Wainger (BJ)

Departments of Anesthesia, Critical Care & Pain Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

William Renthal (W)

Harvard Medical School, Boston, MA, United States.

Clifford J Woolf (CJ)

F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, United States.

Kyle R Eberlin (KR)

Division of Plastic and Reconstructive Surgery, Department of General Surgery, Massachusetts General Hospital, Harvard University, Boston, MA, United States.

Classifications MeSH