Download PDF
J Reconstr Microsurg 2023; 39(09): 695-704
DOI: 10.1055/s-0043-1764487
Original Article

Focal Application of Neurotrophic Factors Augments Outcomes of Nerve–Muscle–Endplate Grafting Technique for Limb Muscle Reinnervation

Liancai Mu
1   Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
,
Jingming Chen
1   Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
,
Stanislaw Sobotka
1   Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
,
Jing Li
1   Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
,
Themba Nyirenda
1   Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Background We have developed a novel muscle reinnervation technique called “nerve–muscle–endplate grafting (NMEG) in the native motor zone (NMZ).” This study aimed to augment the outcomes of the NMEG-NMZ (NN) by focal application of exogenous neurotrophic factors (ENFs) for limb reinnervation.

Methods Adult rats were used to conduct NN plus ENF (NN/ENF) and autologous nerve grafting (ANG, technique control). The nerve innervating the left tibialis anterior (TA) muscle was resected and the denervated TA was immediately treated with NN/ENF or ANG. For NN procedure, an NMEG pedicle was taken from the lateral gastrocnemius muscle and transferred to the NMZ of the denervated TA. For ANG, the nerve gap was bridged with sural nerve. Three months after treatment, the extent of functional and neuromuscular recovery was assessed by measuring static toe spread, maximal muscle force, wet muscle weight, regenerated axons, and innervated motor endplates (MEPs).

Results NN/ENF resulted in 90% muscle force recovery of the treated TA, which is far superior to ANG (46%) and NN alone (79%) as reported elsewhere. Toe spread recovered up to 89 and 49% of the control for the NN/ENF and ANG groups, respectively. The average wet muscle weight was 87 and 52% of the control for muscles treated with NN/ENF and ANG, respectively. The mean number of the regenerated axons was 88% of the control for the muscles treated with NN/ENF, which was significantly larger than that for the ANG-repaired muscles (39%). The average percentage of the innervated MEPs in the NN/ENF-treated TA (89%) was higher compared with that in the ANG-repaired TA (48%).

Conclusion ENF enhances nerve regeneration and MEP reinnervation that further augment outcomes of NN. The NN technique could be an alternative option to treat denervated or paralyzed limb muscles caused by traumatic nerve injuries or lesions.

Keywords

nerve–muscle–endplate grafting - exogenous neurotrophic factors - peripheral nerve injury - tibialis anterior - gastrocnemius


Publication History

Received: 06 July 2022

Accepted: 08 January 2023

Article published online:
22 March 2023

© 2023. Thieme. All rights reserved.

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

 

  • References

  • 1 Ecklund JM, Ling GS. From the battlefront: peripheral nerve surgery in modern day warfare. Neurosurg Clin N Am 2009; 20 (01) 107-110 , vii
    CrossrefPubMedGoogle Scholar
  • 2 Rivera JC, Glebus GP, Cho MS. Disability following combat-sustained nerve injury of the upper limb. Bone Joint J 2014; 96-B (02) 254-258
    CrossrefPubMedGoogle Scholar
  • 3 Masini BD, Waterman SM, Wenke JC, Owens BD, Hsu JR, Ficke JR. Resource utilization and disability outcome assessment of combat casualties from Operation Iraqi Freedom and Operation Enduring Freedom. J Orthop Trauma 2009; 23 (04) 261-266
    CrossrefPubMedGoogle Scholar
  • 4 Eser F, Aktekin LA, Bodur H, Atan C. Etiological factors of traumatic peripheral nerve injuries. Neurol India 2009; 57 (04) 434-437
    CrossrefPubMedGoogle Scholar
  • 5 Kretschmer T, Antoniadis G, Braun V, Rath SA, Richter HP. Evaluation of iatrogenic lesions in 722 surgically treated cases of peripheral nerve trauma. J Neurosurg 2001; 94 (06) 905-912
    CrossrefPubMedGoogle Scholar
  • 6 Lundborg G. Richard P. Bunge memorial lecture. Nerve injury and repair--a challenge to the plastic brain. J Peripher Nerv Syst 2003; 8 (04) 209-226
    CrossrefPubMedGoogle Scholar
  • 7 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
  • 8 Siemionow M, Brzezicki G. Chapter 8: current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol 2009; 87: 141-172
    CrossrefPubMedGoogle Scholar
  • 9 Lee SK, Wolfe SW. Peripheral nerve injury and repair. J Am Acad Orthop Surg 2000; 8 (04) 243-252
    CrossrefPubMedGoogle Scholar
  • 10 Sobotka S, Mu L. Force recovery and axonal regeneration of the sternomastoid muscle reinnervated with the end-to-end nerve anastomosis. J Surg Res 2013; 182 (02) e51-e59
    CrossrefPubMedGoogle Scholar
  • 11 Sobotka S, Mu L, Chen J, Li J, Nyirenda T. Reinnervation of paralyzed limb muscle by nerve-muscle-endplate grafting technique. Neurosurgery 2023; 92 (05) 1091-1098
    CrossrefPubMedGoogle Scholar
  • 12 Green DC, Berke GS, Graves MC. A functional evaluation of ansa cervicalis nerve transfer for unilateral vocal cord paralysis: future directions for laryngeal reinnervation. Otolaryngol Head Neck Surg 1991; 104 (04) 453-466
    CrossrefPubMedGoogle Scholar
  • 13 Moneim M, Omer G. Clinical outcome following acute nerve repair. In: Omeg G, Spinner M, Van Beek A. eds. Management of Peripheral Nerve Problems. Philadelphia, PA: Saunders; 1998
    Google Scholar
  • 14 Stanec S, Stanec Z. Reconstruction of upper-extremity peripheral-nerve injuries with ePTFE conduits. J Reconstr Microsurg 1998; 14 (04) 227-232
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Strauch B. Use of nerve conduits in peripheral nerve repair. Hand Clin 2000; 16 (01) 123-130
    CrossrefPubMedGoogle Scholar
  • 16 Lee SK, Wolfe SW. Nerve transfers for the upper extremity: new horizons in nerve reconstruction. J Am Acad Orthop Surg 2012; 20 (08) 506-517
    CrossrefPubMedGoogle Scholar
  • 17 Ma CHE, Omura T, Cobos EJ. et al. Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. J Clin Invest 2011; 121 (11) 4332-4347
    CrossrefPubMedGoogle Scholar
  • 18 Mu L, Sobotka S, Su H. Nerve-muscle-endplate band grafting: a new technique for muscle reinnervation. Neurosurgery 2011; 69 (2, Suppl Operative): discussion ons224 ons208-ons224
    PubMedGoogle Scholar
  • 19 Mu L, Sobotka S, Chen J, Nyirenda T. Reinnervation of denervated muscle by implantation of nerve-muscle-endplate band graft to the native motor zone of the target muscle. Brain Behav 2017; 7 (06) e00668
    CrossrefPubMedGoogle Scholar
  • 20 Zeng L, Worseg A, Redl H, Schlag G. Peripheral nerve repair with nerve growth factor and fibrin matrix. Eur J Plast Surg 1994; 17: 228-232
    CrossrefPubMedGoogle Scholar
  • 21 Jubran M, Widenfalk J. Repair of peripheral nerve transections with fibrin sealant containing neurotrophic factors. Exp Neurol 2003; 181 (02) 204-212
    CrossrefPubMedGoogle Scholar
  • 22 Lee AC, Yu VM, Lowe III JB. et al. Controlled release of nerve growth factor enhances sciatic nerve regeneration. Exp Neurol 2003; 184 (01) 295-303
    CrossrefPubMedGoogle Scholar
  • 23 Aebischer P, Salessiotis AN, Winn SR. Basic fibroblast growth factor released from synthetic guidance channels facilitates peripheral nerve regeneration across long nerve gaps. J Neurosci Res 1989; 23 (03) 282-289
    CrossrefPubMedGoogle Scholar
  • 24 Mu L, Chen J, Li J, Sobotka S, Nyirenda T. Limb muscle reinnervation with the nerve-muscle-endplate grafting technique: an anatomical feasibility study. Neurol Res Int 2021; 2021: 6009342
    PubMedGoogle Scholar
  • 25 Iwata Y, Ozaki N, Hirata H. et al. Fibroblast growth factor-2 enhances functional recovery of reinnervated muscle. Muscle Nerve 2006; 34 (05) 623-630
    CrossrefPubMedGoogle Scholar
  • 26 Mu L, Sobotka S, Chen J, Nyirenda T. Nerve growth factor and basic fibroblast growth factor promote reinnervation by nerve-muscle-endplate grafting. Muscle Nerve 2018; 57 (03) 449-459
    CrossrefPubMedGoogle Scholar
  • 27 Bervar M. Video analysis of standing--an alternative footprint analysis to assess functional loss following injury to the rat sciatic nerve. J Neurosci Methods 2000; 102 (02) 109-116
    CrossrefPubMedGoogle Scholar
  • 28 Smit X, van Neck JW, Ebeli MJ, Hovius SER. Static footprint analysis: a time-saving functional evaluation of nerve repair in rats. Scand J Plast Reconstr Surg Hand Surg 2004; 38 (06) 321-325
    CrossrefPubMedGoogle Scholar
  • 29 Hosseinian MA, Shirian S, Loron AG, Ebrahimy AA, Hayatolah GH. Distal sensory to distal motor nerve anastomosis can protect lower extremity muscle atrophy in a murine model. Eur J Plast Surg 2018; 41: 9-14
    CrossrefPubMedGoogle Scholar
  • 30 Mu L, Sobotka S, Chen J. et al; Arizona Parkinson's Disease Consortium. Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease. J Neuropathol Exp Neurol 2013; 72 (02) 119-129
    CrossrefPubMedGoogle Scholar
  • 31 Cashman NR, Covault J, Wollman RL, Sanes JR. Neural cell adhesion molecule in normal, denervated, and myopathic human muscle. Ann Neurol 1987; 21 (05) 481-489
    CrossrefPubMedGoogle Scholar
  • 32 Derby A, Engleman VW, Frierdich GE, Neises G, Rapp SR, Roufa DG. Nerve growth factor facilitates regeneration across nerve gaps: morphological and behavioral studies in rat sciatic nerve. Exp Neurol 1993; 119 (02) 176-191
    CrossrefPubMedGoogle Scholar
  • 33 Grothe C, Nikkhah G. The role of basic fibroblast growth factor in peripheral nerve regeneration. Anat Embryol (Berl) 2001; 204 (03) 171-177
    CrossrefPubMedGoogle Scholar
  • 34 Wang S, Cai Q, Hou J. et al. Acceleration effect of basic fibroblast growth factor on the regeneration of peripheral nerve through a 15-mm gap. J Biomed Mater Res A 2003; 66 (03) 522-531
    CrossrefPubMedGoogle Scholar
  • 35 Casella GTB, Almeida VW, Grumbles RM, Liu Y, Thomas CK. Neurotrophic factors improve muscle reinnervation from embryonic neurons. Muscle Nerve 2010; 42 (05) 788-797
    CrossrefPubMedGoogle Scholar
  • 36 Lewin SL, Utley DS, Cheng ET, Verity AN, Terris DJ. Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone. Laryngoscope 1997; 107 (07) 992-999
    CrossrefPubMedGoogle Scholar
  • 37 Cheng H, Fraidakis M, Blombäck B, Lapchak P, Hoffer B, Olson L. Characterization of a fibrin glue-GDNF slow-release preparation. Cell Transplant 1998; 7 (01) 53-61
    PubMedGoogle Scholar
  • 38 Tajdaran K, Gordon T, Wood MD, Shoichet MS, Borschel GH. A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts. Acta Biomater 2016; 29: 62-70
    CrossrefPubMedGoogle Scholar
  • 39 Ho PR, Coan GM, Cheng ET. et al. Repair with collagen tubules linked with brain-derived neurotrophic factor and ciliary neurotrophic factor in a rat sciatic nerve injury model. Arch Otolaryngol Head Neck Surg 1998; 124 (07) 761-766
    CrossrefPubMedGoogle Scholar
  • 40 Jonsson S, Wiberg R, McGrath AM. et al. Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery. PLoS One 2013; 8 (02) e56484
    CrossrefPubMedGoogle Scholar
  • 41 Mu L, Chen J, Li J, Nyirenda T, Fowkes M, Sobotka S. Immunohistochemical detection of motor endplates in the long-term denervated muscle. J Reconstr Microsurg 2018; 34 (05) 348-358
    Article in Thieme ConnectPubMedGoogle Scholar