Grace Gasper

Background:  Peripheral nerve injuries that result in significant functional impairment make up 3% of admitted patients to Level I Trauma Centers in the United States.¹ Such injuries cause a disruption in the supply of lipids, carbohydrates, proteins, and more to the distal nerve.² A process known as Wallerian degeneration results, which leads to outcomes such as neuromuscular junction denervation, muscle atrophy, and functional impairment. Current repairs are completed by micro-suturing the proximal and distal nerves together directly or to an intervening conduit such as autogenous vein, collagen, nerve autografts, or decellularized nerve allografts.¹ None of these repairs restore axonal continuity or prevent Wallerian degeneration. Polyethylene glycol (PEG) is a hydrophobic compound that acts as a fusogen by lowering the activation energy of membrane fusion.³ This makes PEG a promising candidate to overcome the shortcomings of current peripheral nerve repair.

Research Objectives: Demonstrate that PEG restores axonal continuity and prevents Wallerian degeneration, which results in improved physiologic and functional results compared to micro-suturing alone.

Methods:  Multiple PubMed searches were completed with the keywords: “PEG nerve”, “polyethylene glycol nerve”, and “peripheral nerve injury”.

Results:  In contrast to micro-suturing alone, PEG fusion is shown to restore axonal continuity by reestablishment of CAPs and CMAPs for the sciatic nerve and tibialis anterior muscle.⁴ Improved fusion of the damage nerve helps prevent Wallerian degeneration as evidenced by conservation of axon diameter (2.69 μm with PEG, 1.90 μm without) and axon counts.^4,5 Neuromuscular junctions are preserved and retained at least 97% 42 days PO for PEG fusion repair, compared to less than 43% innervation for neurorrhaphy alone.⁴ Muscle atrophy is averted and soleus muscle fiber area is better maintained (1780 μm² with PEG, 1140 μm² without).⁴ All these factors contribute to improved behavioral recovery, particularly after 42 PO.⁶ PEG fusion also prevents allograft rejection, eliminating the need for decellularization, tissue matching, or immunosuppression.⁶

Conclusion:  PEG fusion is a novel technique for peripheral nerve repair that restores axonal continuity and prevents Wallerian degeneration. Consequential benefits include preservation of neuromuscular junctions, reduction of muscle atrophy, improved behavioral recovery, and prevention of allograft rejection. These results are promising and have motivated four different clinical trials to test the use of PEG fusion for peripheral nerve repair in humans. Future directions for research include investigation of techniques to improve fascicle realignment before micro-suturing and the application of PEG fusion for attachment of nerves during limb transplantation.

Works Cited:

1. Nuelle JAV, Bozynski C, Stoker A. Innovations in Peripheral Nerve Injury: Current Concepts and Emerging Techniques to Improve Recovery. Mo Med. 2022;119(2):129-135.
2. Gordon T. Peripheral Nerve Regeneration and Muscle Reinnervation. Int J Mol Sci. 2020;21(22):8652. Published 2020 Nov 17. doi:10.3390/ijms21228652
3. Van Nest DS, Kahan DM, Ilyas AM. Polyethylene Glycol Fusion of Nerve Injuries: Review of the Technique and Clinical Applicability. J Hand Microsurg. 2021;13(2):49-54. doi:10.1055/s-0040-1718651
4. Ghergherehchi CL, Hibbard EA, Mikesh M, Bittner GD, Sengelaub DR. Behavioral recovery and spinal motoneuron remodeling after polyethylene glycol fusion repair of singly cut and ablated sciatic nerves. PLoS One. 2019;14(10):e0223443. Published 2019 Oct 4. doi:10.1371/journal.pone.0223443
5. Bamba R, Riley DC, Kim JS, et al. Evaluation of a Nerve Fusion Technique With Polyethylene Glycol in a Delayed Setting After Nerve Injury. J Hand Surg Am. 2018;43(1):82.e1-82.e7. doi:10.1016/j.jhsa.2017.07.014
6. Mikesh M, Ghergherehchi CL, Rahesh S, et al. Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats [published correction appears in J Neurosci Res. 2018 Sep;96(9):1624]. J Neurosci Res. 2018;96(7):1243-1264. doi:10.1002/jnr.24227
7. Ghergherehchi CL, Mikesh M, Sengelaub DR, et al. Polyethylene glycol (PEG) and other bioactive solutions with neurorrhaphy for rapid and dramatic repair of peripheral nerve lesions by PEG-fusion. J Neurosci Methods. 2019;314:1-12. doi:10.1016/j.jneumeth.2018.12.015
8. Brown BL, Asante T, Welch HR, et al. Functional and Anatomical Outcomes of Facial Nerve Injury With Application of Polyethylene Glycol in a Rat Model. JAMA Facial Plast Surg. 2019;21(1):61-68. doi:10.1001/jamafacial.2018.0308
9. Hibbard EA, Sengelaub DR. Intraneural Topography of Rat Sciatic Axons: Implications for Polyethylene Glycol Fusion Peripheral Nerve Repair. Front Cell Neurosci. 2022;16:852933. Published 2022 Mar 30. doi:10.3389/fncel.2022.852933