Covering the proximal nerve stump with chondroitin sulfate proteoglycans prevents traumatic painful neuroma formation by blocking axon regeneration after neurotomy in Sprague Dawley rats

View More View Less
  • 1 Department of Microsurgery and Orthopedic Trauma, First Affiliated Hospital of Sun Yat-sen University, Guangzhou;
  • 2 Center for Peripheral Nerve Tissue Engineering and Technology Research;
  • 3 School of Basic Medical Sciences, Guangzhou Medical University;
  • 4 Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication; and
  • 5 Department of Anatomy, School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

OBJECTIVE

Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs’ spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation.

METHODS

Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30).

RESULTS

Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p < 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p < 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α–smooth muscle actin were significantly lower in the CSPG group than in the positive group (p < 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)–17, and IL-1β levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p < 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p < 0.05).

CONCLUSIONS

The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.

ABBREVIATIONS CSPG = chondroitin sulfate proteoglycan; DRG = dorsal root ganglia; IL = interleukin; PNS = proximal nerve stump; RT-PCR = real-time polymerase chain reaction; SD = Sprague Dawley; TBST = Tris-buffered saline Tween; TEM = transmission electron microscopy; α-SMA = α–smooth muscle actin.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Qing-Tang Zhu: The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China. zhuqingt@mail.sysu.edu.cn.

INCLUDE WHEN CITING Published online May 29, 2020; DOI: 10.3171/2020.3.JNS193202.

F.L.H. and S.Q. contributed equally to this study.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Cahn LR. Traumatic (amputation) neuroma. Am J Orthod Oral Surg. 1939;25:190193.

  • 2

    Finnerup NB, Haroutounian S, Kamerman P, Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157(8):15991606.

    • Search Google Scholar
    • Export Citation
  • 3

    Foltán R, Klíma K, Spacková J, Sedý J. Mechanism of traumatic neuroma development. Med Hypotheses. 2008;71(4):572576.

  • 4

    Domeshek LF, Krauss EM, Snyder-Warwick AK, Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life. Plast Reconstr Surg. 2017;139(2):407418.

    • Search Google Scholar
    • Export Citation
  • 5

    Fayad JN, Linthicum FH Jr. Symptomatic postsurgical traumatic neuromas. Otol Neurotol. 2009;30(7):981984.

  • 6

    van der Avoort DJ, Hovius SE, Selles RW, The incidence of symptomatic neuroma in amputation and neurorrhaphy patients. J Plast Reconstr Aesthet Surg. 2013;66(10):13301334.

    • Search Google Scholar
    • Export Citation
  • 7

    Khan N, Smith MT. Neurotrophins and neuropathic pain: role in pathobiology. Molecules. 2015;20(6):1065710688.

  • 8

    Mackinnon SE, Dellon AL, Hudson AR, Hunter DA. Alteration of neuroma formation by manipulation of its microenvironment. Plast Reconstr Surg. 1985;76(3):345353.

    • Search Google Scholar
    • Export Citation
  • 9

    Marcol W, Kotulska K, Larysz-Brysz M, Kowalik JL. BDNF contributes to animal model neuropathic pain after peripheral nerve transection. Neurosurg Rev. 2007;30(3):235243.

    • Search Google Scholar
    • Export Citation
  • 10

    Yan H, Gao W, Pan Z, The expression of α-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. J Neurotrauma. 2012;29(18):27912797.

    • Search Google Scholar
    • Export Citation
  • 11

    Zhou X, Zhao B, Poonit K, An aligned nanofiber nerve conduit that inhibits painful traumatic neuroma formation through regulation of the RhoA/ROCK signaling pathway. J Neurosurg. 2019;132(3):837846.

    • Search Google Scholar
    • Export Citation
  • 12

    Poppler LH, Parikh RP, Bichanich MJ, Surgical interventions for the treatment of painful neuroma: a comparative meta-analysis. Pain. 2018;159(2):214223.

    • Search Google Scholar
    • Export Citation
  • 13

    Yao C, Zhou X, Zhao B, Treatments of traumatic neuropathic pain: a systematic review. Oncotarget. 2017;8(34):5767057679.

  • 14

    Erskine L, Herrera E. The retinal ganglion cell axon’s journey: insights into molecular mechanisms of axon guidance. Dev Biol. 2007;308(1):114.

    • Search Google Scholar
    • Export Citation
  • 15

    Treloar HB, Nurcombe V, Key B. Expression of extracellular matrix molecules in the embryonic rat olfactory pathway. J Neurobiol. 1996;31(1):4155.

    • Search Google Scholar
    • Export Citation
  • 16

    Dickendesher TL, Baldwin KT, Mironova YA, NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat Neurosci. 2012;15(5):703712.

    • Search Google Scholar
    • Export Citation
  • 17

    Walker BA, Ji SJ, Jaffrey SR. Intra-axonal translation of RhoA promotes axon growth inhibition by CSPG. J Neurosci. 2012;32(41):1444214447.

    • Search Google Scholar
    • Export Citation
  • 18

    Wall PD, Scadding JW, Tomkiewicz MM. The production and prevention of experimental anesthesia dolorosa. Pain. 1979;6(2):175182.

  • 19

    Zeltser R, Beilin B, Zaslansky R, Seltzer Z. Comparison of autotomy behavior induced in rats by various clinically-used neurectomy methods. Pain. 2000;89(1):1924.

    • Search Google Scholar
    • Export Citation
  • 20

    Buch NS, Qerama E, Finnerup NB, Nikolajsen L. Neuromas and postamputation pain. Pain. 2020;161(1):147155.

  • 21

    Barberá J, Albert-Pampló R. Centrocentral anastomosis of the proximal nerve stump in the treatment of painful amputation neuromas of major nerves. J Neurosurg. 1993;79(3):331334.

    • Search Google Scholar
    • Export Citation
  • 22

    Economides JM, DeFazio MV, Attinger CE, Barbour JR. Prevention of painful neuroma and phantom limb pain after transfemoral amputations through concomitant nerve coaptation and collagen nerve wrapping. Neurosurgery. 2016;79(3):508513.

    • Search Google Scholar
    • Export Citation
  • 23

    Onode E, Uemura T, Takamatsu K, Nerve capping with a nerve conduit for the treatment of painful neuroma in the rat sciatic nerve. J Neurosurg. 2019;8:19.

    • Search Google Scholar
    • Export Citation
  • 24

    Fathi HR, Fathi M, Ghannadan A, The healing effect of silicone gel on sciatic nerve injuries in experimental rat. World J Plast Surg. 2014;3(2):9398.

    • Search Google Scholar
    • Export Citation
  • 25

    Yi J, Jiang N, Li B, Painful terminal neuroma prevention by capping PRGD/PDLLA conduit in rat sciatic nerves. Adv Sci (Weinh). 2018;5(6):1700876.

    • Search Google Scholar
    • Export Citation
  • 26

    Kim PD, Hayes A, Amin F, Collagen nerve protector in rat sciatic nerve repair: a morphometric and histological analysis. Microsurgery. 2010;30(5):392396.

    • Search Google Scholar
    • Export Citation
  • 27

    Marcol W, Larysz-Brysz M, Kucharska M, Reduction of post-traumatic neuroma and epineural scar formation in rat sciatic nerve by application of microcrystallic chitosan. Microsurgery. 2011;31(8):642649.

    • Search Google Scholar
    • Export Citation
  • 28

    Sakai Y, Ochi M, Uchio Y, Prevention and treatment of amputation neuroma by an atelocollagen tube in rat sciatic nerves. J Biomed Mater Res B Appl Biomater. 2005;73(2):355360.

    • Search Google Scholar
    • Export Citation
  • 29

    Hong T, Wood I, Hunter DA, Neuroma management: capping nerve injuries with an acellular nerve allograft can limit axon regeneration. Hand (N Y). Published online May 29, 2019. doi:10.1177/1558944719849115

    • Search Google Scholar
    • Export Citation
  • 30

    Zou JL, Sun JH, Qiu S, Spatial distribution affects the role of CSPGs in nerve regeneration via the actin filament-mediated pathway. Exp Neurol. 2018;307:3744.

    • Search Google Scholar
    • Export Citation
  • 31

    Ughrin YM, Chen ZJ, Levine JM. Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. J Neurosci. 2003;23(1):175186.

    • Search Google Scholar
    • Export Citation
  • 32

    Ueda H. Peripheral mechanisms of neuropathic pain—involvement of lysophosphatidic acid receptor-mediated demyelination. Mol Pain. 2008;4:11.

    • Search Google Scholar
    • Export Citation
  • 33

    Gnavi S, di Blasio L, Tonda-Turo C, Gelatin-based hydrogel for vascular endothelial growth factor release in peripheral nerve tissue engineering. J Tissue Eng Regen Med. 2017;11(2):459470.

    • Search Google Scholar
    • Export Citation
  • 34

    Tao J, Hu Y, Wang S, A 3D-engineered porous conduit for peripheral nerve repair. Sci Rep. 2017;7:46038.

  • 35

    Ahmad AH, Ismail Z. c-fos and its consequences in pain. Malays J Med Sci. 2002;9(1):38.

  • 36

    Zieglgänsberger W. Substance P and pain chronicity. Cell Tissue Res. 2019;375(1):227241.

  • 37

    Gui WS, Wei X, Mai CL, Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain. Published online May 12, 2016. doi:10.1177/1744806916646784

    • Search Google Scholar
    • Export Citation
  • 38

    Sun C, Zhang J, Chen L, IL-17 contributed to the neuropathic pain following peripheral nerve injury by promoting astrocyte proliferation and secretion of proinflammatory cytokines. Mol Med Rep. 2017;15(1):8996.

    • Search Google Scholar
    • Export Citation
  • 39

    Bolleboom A, de Ruiter GCW, Coert JH, Novel experimental surgical strategy to prevent traumatic neuroma formation by combining a 3D-printed Y-tube with an autograft. J Neurosurg. 2018;130(1):184196.

    • Search Google Scholar
    • Export Citation
  • 40

    Yan H, Zhang F, Kolkin J, Mechanisms of nerve capping technique in prevention of painful neuroma formation. PLoS One. 2014;9(4):e93973.

  • 41

    Snow DM, Letourneau PC. Neurite outgrowth on a step gradient of chondroitin sulfate proteoglycan (CS-PG). J Neurobiol. 1992;23(3):322336.

    • Search Google Scholar
    • Export Citation
  • 42

    Rolls A, Shechter R, London A, Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 2008;5(8):e171.

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 337 337 153
Full Text Views 36 36 18
PDF Downloads 29 29 10
EPUB Downloads 0 0 0