A novel bioengineered technique to rapidly and permanently repair cut PNS nerves Our long term objective is to performance-optimize to translate for clinical use our novel and innovative technique to produce rapid and permanent repair of acutely and chronically severed mammalian PNS axons to restore the behavioral functions they mediated prior to severance. We apply a well-specified sequence of bioengineered solutions containing polyethylene glycol (PEG) and various anti-oxidizing or oxidizing agents to rapidly and permanently rejoin (PEG-fuse) completely cut-severed ends of rat sciatic axons as a model in vivo system so that PEG-fused axons are physiologically and morphologically intact through the lesion site and their stimulation restores behavioral functions mediated by intact sciatic nerves. Our physiological and morphological measures of axonal continuity are action potential conduction and intraaxonal dye diffusion across the lesion site and EM and immuno-histochemical analyses.. Our measures of behavioral restoration are Foot Fault Asymmetry test and Sciatic Functional Index. We retard Wallerian degeneration by cooling or cyclosporin A and then repair axons chronically severed for up 10 days by PEG-fusion. We performance optimize tissue (biocompatability) responses of acutely or chronically excised sciatic nerve segments that are used as inter- position autografts or allografts to PEG-fuse repair acutely or chronically cut rat sciatic nerves. Nerve severance is a common traumatic injury to PNS axons in humans. Various procedures currently slightly improve the number and specificity of PNS axons that reestablish connections following severance, but not outgrowth rate (~1mm/day) or time (weeks to years) for PNS axons to re-establish those connections. Target tissues may atrophy before re-innervation can occur. Consequently, target tissues are often non-specifically re-innervated and behavioral recovery is often poor. PEG-fusion dramatically improves the speed and efficacy of behavioral recovery following acute cut- or crush-severance of mammalian PNS axons. We can also retard axonal Wallerian degeneration of severed mammalian axons for up to 10 days to increase the time for successful PEG-fusion for up to 10 days post-severance so that nerve injuries do not have to be immediately treated. Our well-specified sequence of bio-engineered solutions and materials needed for PEG-fusion use only FDA-approved chemicals. Hence, our PEG-fusion technique developed on rat sciatic nerves as a model in vivo system should rapidly translate to clinical procedures. The results of our proposed R-01 have high potential for shifting the current emphasis of current research and clinical practice from devising procedures to enhance the results of slow axonal outgrowth to considering rapid repair by our novel PEG-fusion technique.

Public Health Relevance

Severance of PNS nerves is by far the most common clinical nerve injury and their repair has been a largely-unsolved fundamental problem in neuroscience. Behavioral recovery from such injuries typically takes months to years --- and often the recovery is very poor. We propose to further improve the dramatic success of our novel bio-engineering technique that uses polyethylene glycol and other substances to repair severed peripheral nerve axons in rats as a model system so as to rapidly (within days) and permanently restore many behavioral functions evoked prior to injury. Our procedure uses FDA-approved substances and materials and should be rapidly translatable for clinical use. !

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Jakeman, Lyn B
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University of Texas Austin
Schools of Arts and Sciences
United States
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Mikesh, Michelle; Ghergherehchi, Cameron L; Hastings, Robert Louis et al. (2018) Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats. J Neurosci Res 96:1223-1242
Poon, Andrew D; McGill, Sarah H; Bhupanapadu Sunkesula, Solomon Raju et al. (2018) Ca2+/calmodulin-dependent protein kinase II and Dimethyl Sulfoxide affect the sealing frequencies of transected hippocampal neurons. J Neurosci Res 96:1208-1222
Bittner, George D; Sengelaub, Dale R; Ghergherehchi, Cameron L (2018) Conundrums and confusions regarding how polyethylene glycol-fusion produces excellent behavioral recovery after peripheral nerve injuries. Neural Regen Res 13:53-57
Mikesh, Michelle; Ghergherehchi, Cameron L; Rahesh, Sina et al. (2018) Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats. J Neurosci Res 96:1243-1264
Bittner, G D; Sengelaub, D R; Trevino, R C et al. (2017) Robinson and madison have published no data on whether polyethylene glycol fusion repair prevents reinnervation accuracy in rat peripheral nerve. J Neurosci Res 95:863-866
Bittner, George D; Spaeth, Christopher S; Poon, Andrew D et al. (2016) Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells. Neural Regen Res 11:1033-42
McGill, Christopher H; Bhupanapadu Sunkesula, Solomon Raju; Poon, Andrew D et al. (2016) Sealing frequency of B104 cells declines exponentially with decreasing transection distance from the axon hillock. Exp Neurol 279:149-158
Ghergherehchi, Cameron L; Bittner, George D; Hastings, Robert Louis et al. (2016) Effects of extracellular calcium and surgical techniques on restoration of axonal continuity by polyethylene glycol fusion following complete cut or crush severance of rat sciatic nerves. J Neurosci Res 94:231-45
Bittner, G D; Sengelaub, D R; Trevino, R C et al. (2016) The curious ability of polyethylene glycol fusion technologies to restore lost behaviors after nerve severance. J Neurosci Res 94:207-30
Bittner, George D; Mikesh, Michelle; Ghergherehchi, Cameron L (2016) Polyethylene glycol-fusion retards Wallerian degeneration and rapidly restores behaviors lost after nerve severance. Neural Regen Res 11:217-9

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