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Semin Plast Surg 2021; 35(03): 204-210
DOI: 10.1055/s-0041-1731630
Review Article

Peripheral Nerve Healing: So Near and Yet So Far

Aslan Baradaran
1   Division of Plastic and Reconstructive Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
,
Hassan El-Hawary
1   Division of Plastic and Reconstructive Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
,
Johnny Ionut Efanov
2   Division of Plastic and Reconstructive Surgery, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
,
Liqin Xu
1   Division of Plastic and Reconstructive Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
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Abstract

Peripheral nerve injuries represent a considerable portion of chronic disability that especially affects the younger population. Prerequisites of proper peripheral nerve injury treatment include in-depth knowledge of the anatomy, pathophysiology, and options in surgical reconstruction. Our greater appreciation of nerve healing mechanisms and the development of different microsurgical techniques have significantly refined the outcomes in treatment for the past four decades. This work reviews the peripheral nerve regeneration process after an injury, provides an overview of various coaptation methods, and compares other available treatments such as autologous nerve graft, acellular nerve allograft, and synthetic nerve conduits. Furthermore, the formation of neuromas as well as their latest treatment options are discussed.

Keywords

peripheral nerve - injury - repair - review


Publication History

Article published online:
10 September 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Taylor CA, Braza D, Rice JB, Dillingham T. The incidence of peripheral nerve injury in extremity trauma. Am J Phys Med Rehabil 2008; 87 (05) 381-385
    CrossrefPubMedGoogle Scholar
  • 2 Noble J, Munro CA, Prasad VS, Midha R. Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 1998; 45 (01) 116-122
    CrossrefPubMedGoogle Scholar
  • 3 Robinson LR. Traumatic injury to peripheral nerves. Muscle Nerve 2000; 23 (06) 863-873
    CrossrefPubMedGoogle Scholar
  • 4 He B, Zhu Z, Zhu Q. et al. Factors predicting sensory and motor recovery after the repair of upper limb peripheral nerve injuries. Neural Regen Res 2014; 9 (06) 661-672
    CrossrefPubMedGoogle Scholar
  • 5 Thomas P, Holdorff B. Neuropathy due to physical agents. Peripheral Neuropathy. 1993; 2: 1948
    PubMedGoogle Scholar
  • 6 Waller AV. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Philos Trans R Soc Lond 1850; (140) 423-429
    PubMedGoogle Scholar
  • 7 Zochodne DW. Neurobiology of Peripheral Nerve Regeneration. Cambridge University Press; Cambridge, UK: 2008
    CrossrefGoogle Scholar
  • 8 Seddon HJ, Medawar PB, Smith H. Rate of regeneration of peripheral nerves in man. J Physiol 1943; 102 (02) 191-215
    CrossrefPubMedGoogle Scholar
  • 9 Sunderland S. A classification of peripheral nerve injuries producing loss of function. Brain 1951; 74 (04) 491-516
    CrossrefPubMedGoogle Scholar
  • 10 Mackinnon S, Dellon A. Classification of nerve injuries as the basis for treatment. In: Surgery of the Peripheral Nerve. New York: Thieme; 1988: 35-63
    Google Scholar
  • 11 Atkins S, Smith KG, Loescher AR. et al. Scarring impedes regeneration at sites of peripheral nerve repair. Neuroreport 2006; 17 (12) 1245-1249
    CrossrefPubMedGoogle Scholar
  • 12 Chen P, Piao X, Bonaldo P. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathol 2015; 130 (05) 605-618
    CrossrefPubMedGoogle Scholar
  • 13 Carriel V, Garzón I, Alaminos M, Campos A. Evaluation of myelin sheath and collagen reorganization pattern in a model of peripheral nerve regeneration using an integrated histochemical approach. Histochem Cell Biol 2011; 136 (06) 709-717
    CrossrefPubMedGoogle Scholar
  • 14 Napoli I, Noon LA, Ribeiro S. et al. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 2012; 73 (04) 729-742
    CrossrefPubMedGoogle Scholar
  • 15 Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci 1995; 15 (5 Pt 2): 3886-3895
    CrossrefPubMedGoogle Scholar
  • 16 Höke A, Gordon T, Zochodne DW, Sulaiman OA. A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol 2002; 173 (01) 77-85
    CrossrefPubMedGoogle Scholar
  • 17 Chen Z-L, Yu W-M, Strickland S. Peripheral regeneration. Annu Rev Neurosci 2007; 30: 209-233
    CrossrefPubMedGoogle Scholar
  • 18 Rahmatullah M, Schroering A, Rothblum K, Stahl RC, Urban B, Carey DJ. Synergistic regulation of Schwann cell proliferation by heregulin and forskolin. Mol Cell Biol 1998; 18 (11) 6245-6252
    CrossrefPubMedGoogle Scholar
  • 19 Murinson BB, Archer DR, Li Y, Griffin JW. Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. J Neurosci 2005; 25 (05) 1179-1187
    CrossrefPubMedGoogle Scholar
  • 20 Scheib J, Höke A. Advances in peripheral nerve regeneration. Nat Rev Neurol 2013; 9 (12) 668-676
    CrossrefPubMedGoogle Scholar
  • 21 Lu P, Wang Y, Graham L. et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 2012; 150 (06) 1264-1273
    CrossrefPubMedGoogle Scholar
  • 22 Nguyen QT, Sanes JR, Lichtman JW. Pre-existing pathways promote precise projection patterns. Nat Neurosci 2002; 5 (09) 861-867
    CrossrefPubMedGoogle Scholar
  • 23 Cattin AL, Burden JJ, Van Emmenis L. et al. Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell 2015; 162 (05) 1127-1139
    CrossrefPubMedGoogle Scholar
  • 24 Parrinello S, Napoli I, Ribeiro S. et al. EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 2010; 143 (01) 145-155
    CrossrefPubMedGoogle Scholar
  • 25 Lu J, Tapia JC, White OL, Lichtman JW. The interscutularis muscle connectome. PLoS Biol 2009; 7 (02) e32
    PubMedGoogle Scholar
  • 26 Gordon T, de Zepetnek JET. Motor unit and muscle fiber type grouping after peripheral nerve injury in the rat. Exp Neurol 2016; 285 (Pt A) 24-40
    CrossrefPubMedGoogle Scholar
  • 27 Gordon T, Tyreman N. Sprouting capacity of lumbar motoneurons in normal and hemisected spinal cords of the rat. J Physiol 2010; 588 (Pt 15): 2745-2768
    CrossrefPubMedGoogle Scholar
  • 28 Rafuse VF, Gordon T. Self-reinnervated cat medial gastrocnemius muscles. II. analysis of the mechanisms and significance of fiber type grouping in reinnervated muscles. J Neurophysiol 1996; 75 (01) 282-297
    CrossrefPubMedGoogle Scholar
  • 29 Willand MP, Holmes M, Bain JR, de Bruin H, Fahnestock M. Sensory nerve cross-anastomosis and electrical muscle stimulation synergistically enhance functional recovery of chronically denervated muscle. Plast Reconstr Surg 2014; 134 (05) 736e-745e
    CrossrefPubMedGoogle Scholar
  • 30 Elsohemy A, Butler R, Bain JR, Fahnestock M. Sensory protection of rat muscle spindles following peripheral nerve injury and reinnervation. Plast Reconstr Surg 2009; 124 (06) 1860-1868
    CrossrefPubMedGoogle Scholar
  • 31 Schmalbruch H, al-Amood WS, Lewis DM. Morphology of long-term denervated rat soleus muscle and the effect of chronic electrical stimulation. J Physiol 1991; 441: 233-241
    CrossrefPubMedGoogle Scholar
  • 32 Veltri K, Kwiecien JM, Minet W, Fahnestock M, Bain JR. Contribution of the distal nerve sheath to nerve and muscle preservation following denervation and sensory protection. J Reconstr Microsurg 2005; 21 (01) 57-70 , discussion 71–74
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Brushart TM, Mesulam MM. Alteration in connections between muscle and anterior horn motoneurons after peripheral nerve repair. Science 1980; 208 (4444): 603-605
    CrossrefPubMedGoogle Scholar
  • 34 Gillespie MJ, Gordon T, Murphy PR. Motor units and histochemistry in rat lateral gastrocnemius and soleus muscles: evidence for dissociation of physiological and histochemical properties after reinnervation. J Neurophysiol 1987; 57 (04) 921-937
    CrossrefPubMedGoogle Scholar
  • 35 Alant JD, Senjaya F, Ivanovic A, Forden J, Shakhbazau A, Midha R. The impact of motor axon misdirection and attrition on behavioral deficit following experimental nerve injuries. PLoS One 2013; 8 (11) e82546
    CrossrefPubMedGoogle Scholar
  • 36 de Ruiter GC, Spinner RJ, Verhaagen J, Malessy MJ. Misdirection and guidance of regenerating axons after experimental nerve injury and repair. J Neurosurg 2014; 120 (02) 493-501
    CrossrefPubMedGoogle Scholar
  • 37 Htut M, Misra P, Anand P, Birch R, Carlstedt T. Pain phenomena and sensory recovery following brachial plexus avulsion injury and surgical repairs. J Hand Surg [Br] 2006; 31 (06) 596-605
    CrossrefPubMedGoogle Scholar
  • 38 Thomas CK, Stein RB, Gordon T, Lee RG, Elleker MG. Patterns of reinnervation and motor unit recruitment in human hand muscles after complete ulnar and median nerve section and resuture. J Neurol Neurosurg Psychiatry 1987; 50 (03) 259-268
    CrossrefPubMedGoogle Scholar
  • 39 Lee SK, Wolfe SW. Peripheral nerve injury and repair. J Am Acad Orthop Surg 2000; 8 (04) 243-252
    CrossrefPubMedGoogle Scholar
  • 40 Gordon T. The role of neurotrophic factors in nerve regeneration. Neurosurg Focus 2009; 26 (02) E3
    CrossrefPubMedGoogle Scholar
  • 41 Gordon T, Tyreman N, Raji MA. The basis for diminished functional recovery after delayed peripheral nerve repair. J Neurosci 2011; 31 (14) 5325-5334
    CrossrefPubMedGoogle Scholar
  • 42 Anzil AP, Wernig A. Muscle fibre loss and reinnervation after long-term denervation. J Neurocytol 1989; 18 (06) 833-845
    CrossrefPubMedGoogle Scholar
  • 43 Bentolila V, Nizard R, Bizot P, Sedel L. Complete traumatic brachial plexus palsy. Treatment and outcome after repair. J Bone Joint Surg Am 1999; 81 (01) 20-28
    CrossrefPubMedGoogle Scholar
  • 44 Tötösy de Zepetnek JE, Zung HV, Erdebil S, Gordon T. Innervation ratio is an important determinant of force in normal and reinnervated rat tibialis anterior muscles. J Neurophysiol 1992; 67 (05) 1385-1403
    CrossrefPubMedGoogle Scholar
  • 45 Grinsell D, Keating CP. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. BioMed Res Int 2014; 2014: 698256
    CrossrefPubMedGoogle Scholar
  • 46 Moore AM, Novak CB. Advances in nerve transfer surgery. J Hand Ther 2014; 27 (02) 96-104 , quiz 105
    CrossrefPubMedGoogle Scholar
  • 47 Boyd KU, Nimigan AS, Mackinnon SE. Nerve reconstruction in the hand and upper extremity. Clin Plast Surg 2011; 38 (04) 643-660
    CrossrefPubMedGoogle Scholar
  • 48 Gregory J, Cowey A, Jones M, Pickard S, Ford D. The anatomy, investigations and management of adult brachial plexus injuries. Orthop Trauma 2009; 23 (06) 420-432
    CrossrefPubMedGoogle Scholar
  • 49 Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 2004; 16 (05) E1
    CrossrefPubMedGoogle Scholar
  • 50 Novak CB, Mackinnon SE. Distal anterior interosseous nerve transfer to the deep motor branch of the ulnar nerve for reconstruction of high ulnar nerve injuries. J Reconstr Microsurg 2002; 18 (06) 459-464
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Oberlin C, Béal D, Leechavengvongs S, Salon A, Dauge MC, Sarcy JJ. Nerve transfer to biceps muscle using a part of ulnar nerve for C5-C6 avulsion of the brachial plexus: anatomical study and report of four cases. J Hand Surg Am 1994; 19 (02) 232-237
    CrossrefPubMedGoogle Scholar
  • 52 Watchmaker GP, Gumucio CA, Crandall RE, Vannier MA, Weeks PM. Fascicular topography of the median nerve: a computer based study to identify branching patterns. J Hand Surg Am 1991; 16 (01) 53-59
    CrossrefPubMedGoogle Scholar
  • 53 Diao E, Vannuyen T. Techniques for primary nerve repair. Hand Clin 2000; 16 (01) 53-66 , viii viii.
    CrossrefPubMedGoogle Scholar
  • 54 Siemionow M, Tetik C, Ozer K, Ayhan S, Siemionow K, Browne E. Epineural sleeve neurorrhaphy: surgical technique and functional results--a preliminary report. Ann Plast Surg 2002; 48 (03) 281-285
    CrossrefPubMedGoogle Scholar
  • 55 Levinthal R, Brown WJ, Rand RW. Comparison of fascicular, interfascicular and epineural suture techniques in the repair of simple nerve lacerations. J Neurosurg 1977; 47 (05) 744-750
    CrossrefPubMedGoogle Scholar
  • 56 Ornelas L, Padilla L, Di Silvio M. et al. Fibrin glue: an alternative technique for nerve coaptation--Part I. Wave amplitude, conduction velocity, and plantar-length factors. J Reconstr Microsurg 2006; 22 (02) 119-122
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Sames M, Blahos Jr J, Rokyta R, Benes Jr V. Comparison of microsurgical suture with fibrin glue connection of the sciatic nerve in rabbits. Physiol Res 1997; 46 (04) 303-306
    PubMedGoogle Scholar
  • 58 Isaacs JE, McDaniel CO, Owen JR, Wayne JS. Comparative analysis of biomechanical performance of available “nerve glues”. J Hand Surg Am 2008; 33 (06) 893-899
    CrossrefPubMedGoogle Scholar
  • 59 Martins RS, Siqueira MG, Da Silva CF, Plese JP. Overall assessment of regeneration in peripheral nerve lesion repair using fibrin glue, suture, or a combination of the 2 techniques in a rat model. Which is the ideal choice?. Surg Neurol 2005; 64 (Suppl. 01) S1 , 10–16, discussion S1, 16
    PubMedGoogle Scholar
  • 60 Nishimura MT, Mazzer N, Barbieri CH, Moro CA. Mechanical resistance of peripheral nerve repair with biological glue and with conventional suture at different postoperative times. J Reconstr Microsurg 2008; 24 (05) 327-332
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Félix SP, Pereira Lopes FR, Marques SA, Martinez AM. Comparison between suture and fibrin glue on repair by direct coaptation or tubulization of injured mouse sciatic nerve. Microsurgery 2013; 33 (06) 468-477
    CrossrefPubMedGoogle Scholar
  • 62 Colen KL, Choi M, Chiu DTW. Nerve grafts and conduits. Plast Reconstr Surg 2009; 124 (06) e386-e394
    CrossrefPubMedGoogle Scholar
  • 63 Terzis JK, Kostopoulos VK. Vascularized nerve grafts and vascularized fascia for upper extremity nerve reconstruction. Hand (N Y) 2010; 5 (01) 19-30
    CrossrefPubMedGoogle Scholar
  • 64 Cruz NI, Debs N, Fiol RE. Evaluation of fibrin glue in rat sciatic nerve repairs. Plast Reconstr Surg 1986; 78 (03) 369-373
    CrossrefPubMedGoogle Scholar
  • 65 McCall TD, Grant GA, Britz GW, Goodkin R, Kliot M. Treatment of recurrent peripheral nerve entrapment problems: role of scar formation and its possible treatment. Neurosurg Clin N Am 2001; 12 (02) 329-339
    CrossrefPubMedGoogle Scholar
  • 66 Hanwright PJ, Rath JB, von Guionneau N. et al. The effects of a porcine extracellular matrix nerve wrap as an adjunct to primary epineurial repair. J Hand Surg Am 2021; S0363 -5023(20)30741-3
    PubMedGoogle Scholar
  • 67 Kokkalis ZT, Jain S, Sotereanos DG. Vein wrapping at cubital tunnel for ulnar nerve problems. J Shoulder Elbow Surg 2010; 19 (02) 91-97
    CrossrefPubMedGoogle Scholar
  • 68 Thakker A, Sharma SC, Hussain NM, Devani P, Lahiri A. Nerve wrapping for recurrent compression neuropathy: a systematic review. J Plast Reconstr Aesthet Surg 2020
    Google Scholar
  • 69 Jiang X, Lim SH, Mao H-Q, Chew SY. Current applications and future perspectives of artificial nerve conduits. Exp Neurol 2010; 223 (01) 86-101
    CrossrefPubMedGoogle Scholar
  • 70 Siemionow M, Brzezicki G. Chapter 8: Current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol 2009; 87: 141-172
    Google Scholar
  • 71 Thorne CH, Chung KC, Gosain AK. et al. Grabb and Smith's plastic surgery: Seventh edition. Wolters Kluwer Health Adis (ESP)'. 2013
    Google Scholar
  • 72 Nichols CM, Brenner MJ, Fox IK. et al. Effects of motor versus sensory nerve grafts on peripheral nerve regeneration. Exp Neurol 2004; 190 (02) 347-355
    CrossrefPubMedGoogle Scholar
  • 73 Gu X, Ding F, Yang Y, Liu J. Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration. Prog Neurobiol 2011; 93 (02) 204-230
    CrossrefPubMedGoogle Scholar
  • 74 Schmidt CE, Leach JB. Neural tissue engineering: strategies for repair and regeneration. Annu Rev Biomed Eng 2003; 5: 293-347
    CrossrefPubMedGoogle Scholar
  • 75 Pierucci A, de Duek EAR, de Oliveira ALR. Peripheral nerve regeneration through biodegradable conduits prepared using solvent evaporation. Tissue Eng Part A 2008; 14 (05) 595-606
    CrossrefPubMedGoogle Scholar
  • 76 Strauch B, Ferder M, Lovelle-Allen S, Moore K, Kim DJ, Llena J. Determining the maximal length of a vein conduit used as an interposition graft for nerve regeneration. J Reconstr Microsurg 1996; 12 (08) 521-527
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Kehoe S, Zhang XF, Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. Injury 2012; 43 (05) 553-572
    CrossrefPubMedGoogle Scholar
  • 78 Jones LL, Oudega M, Bunge MB, Tuszynski MH. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol 2001; 533 (Pt 1): 83-89
    CrossrefPubMedGoogle Scholar
  • 79 Whitlock EL, Tuffaha SH, Luciano JP. et al. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve 2009; 39 (06) 787-799
    CrossrefPubMedGoogle Scholar
  • 80 Lanier ST, Jordan SW, Ko JH, Dumanian GA. Targeted muscle reinnervation as a solution for nerve pain. Plast Reconstr Surg 2020; 146 (05) 651e-663e
    CrossrefPubMedGoogle Scholar
  • 81 Souza JM, Purnell CA, Cheesborough JE, Kelikian AS, Dumanian GA. Treatment of foot and ankle neuroma pain with processed nerve allografts. Foot Ankle Int 2016; 37 (10) 1098-1105
    CrossrefPubMedGoogle Scholar
  • 82 Poppler LH, Parikh RP, Bichanich MJ. et al. Surgical interventions for the treatment of painful neuroma: a comparative meta-analysis. Pain 2018; 159 (02) 214-223
    CrossrefPubMedGoogle Scholar
  • 83 Ives GC, Kung TA, Nghiem BT. et al. Current state of the surgical treatment of terminal neuromas. Neurosurgery 2018; 83 (03) 354-364
    CrossrefPubMedGoogle Scholar
  • 84 Wolvetang NHA, Lans J, Verhiel SHWL, Notermans BJW, Chen NC, Eberlin KR. Surgery for symptomatic neuroma: anatomic distribution and predictors of secondary surgery. Plast Reconstr Surg 2019; 143 (06) 1762-1771
    CrossrefPubMedGoogle Scholar
  • 85 Terzis JK, Tzafetta K. The “babysitter” procedure: minihypoglossal to facial nerve transfer and cross-facial nerve grafting. Plast Reconstr Surg 2009; 123 (03) 865-876
    CrossrefPubMedGoogle Scholar
  • 86 Al-Majed AA, Neumann CM, Brushart TM, Gordon T. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci 2000; 20 (07) 2602-2608
    CrossrefPubMedGoogle Scholar
  • 87 Elzinga K, Tyreman N, Ladak A, Savaryn B, Olson J, Gordon T. Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats. Exp Neurol 2015; 269: 142-153
    CrossrefPubMedGoogle Scholar
  • 88 Willand MP, Chiang CD, Zhang JJ, Kemp SW, Borschel GH, Gordon T. Daily electrical muscle stimulation enhances functional recovery following nerve transection and repair in rats. Neurorehabil Neural Repair 2015; 29 (07) 690-700
    CrossrefPubMedGoogle Scholar
  • 89 Jiang X, Savchenko O, Li Y. et al. A review of low-intensity pulsed ultrasound for therapeutic applications. IEEE Trans Biomed Eng 2019; 66 (10) 2704-2718
    CrossrefPubMedGoogle Scholar
  • 90 Jiang W, Wang Y, Tang J. et al. Low-intensity pulsed ultrasound treatment improved the rate of autograft peripheral nerve regeneration in rat. Sci Rep 2016; 6 (01) 22773
    CrossrefPubMedGoogle Scholar
  • 91 Tajdaran K, Chan K, Shoichet MS, Gordon T, Borschel GH. Local delivery of FK506 to injured peripheral nerve enhances axon regeneration after surgical nerve repair in rats. Acta Biomater 2019; 96: 211-221
    CrossrefPubMedGoogle Scholar