Mechanisms of Disease: What factors limit the success of peripheral nerve regeneration in humans?

Neuromuscular Division, Department of Neurology at Johns Hopkins Hospital, Baltimore, MD 21287, USA.
Nature Clinical Practice Neurology (Impact Factor: 7.64). 09/2006; 2(8):448-54. DOI: 10.1038/ncpneuro0262
Source: PubMed


Functional recovery after repair of peripheral nerve injury in humans is often suboptimal. Over the past quarter of a century, there have been significant advances in human nerve repair, but most of the developments have been in the optimization of surgical techniques. Despite extensive research, there are no current therapies directed at the molecular mechanisms of nerve regeneration. Multiple interventions have been shown to improve nerve regeneration in small animal models, but have not yet translated into clinical therapies for human nerve injuries. In many rodent models, regeneration occurs over relatively short distances, so the duration of denervation is short. By contrast, in humans, nerves often have to regrow over long distances, and the distal portion of the nerve progressively loses its ability to support regeneration during this process. This can be largely attributed to atrophy of Schwann cells and loss of a Schwann cell basal lamina tube, which results in an extracellular environment that is inhibitory to nerve regeneration. To develop successful molecular therapies for nerve regeneration, we need to generate animal models that can be used to address the following issues: improving the intrinsic ability of neurons to regenerate to increase the speed of axonal outgrowth; preventing loss of basal lamina and chronic denervation changes in the denervated Schwann cells; and overcoming inhibitory cues in the extracellular matrix.

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    • "The decision to carry out a study on sheep and select a crush nerve injury hinged on the fact that long-distance regeneration (Höke, 2006;Luo et al., 2012) and crush injuries are more appropriate to investigate the intrinsic cellular and molecular events taking place in peripheral nerve injuries, and to assess whether these molecular interventions might speed up axon regeneration and, consequently, to further gauge the effectiveness of reinnervation (Rodríguez et al., 2004). The results of the present study showed that PRGF injections and scaffolds enhance peripheral nerve regeneration by improving axonal sprouting and myelination of newly generated axons, a result which correlated with an early positive electrophysiological response at week 8 after the PRGF molecular intervention as a sign of functional recovery. "
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    ABSTRACT: In the present study we evaluated the motor recovery process of peripheral nerve injury (PNI), based on electrophysiological and histomorphometric criteria, after treatment with plasma rich in growth factors (PRGF) injections and scaffolds in an ovine model. Three groups of sheep underwent a nerve crush lesion: the first group (n = 3) was left to recover spontaneously (SR); the second group was administered saline injections (SI; n = 5) and a third group (n = 6) received PRGF injections and scaffolds immediately after the crush injury. At post-intervention week 8, 70% of sheep in the PRGF group were CMAP-positive, with no electrophysiological response in the rest of the groups. Histomorphometric analysis 12 weeks after the surgical intervention revealed that the average axonal density of the SR (1184 ± 864 axons/µm2) and SI (3109 ± 2450 axons/µm2) groups was significantly inferior to the control (8427 ± 2433 axons/µm2) and also inferior to the PRGF group (5276 ± 4148 axons/µm2), showing no significant differences between the control and PRGF groups. The axonal size of the SR and SI groups was significantly smaller compared with the control group (18 ± 4 µm2), whereas the axonal size of the PRGF group (6 ± 5 µm2) did not show statistical differences from the control. Morphometry of the target muscles indicated that the PRGF group had the lowest percentage volume reduction 12 weeks after the crush injury. The PRGF group had larger muscle fibre areas than the SI and SR groups, although the differences did not reach statistical significance. Overall, these data suggest that the PRGF injections and scaffolds hastened functional axon recovery and dampened atrophy of the target muscles in an ovine model. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Sep 2015 · Journal of Tissue Engineering and Regenerative Medicine
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    • "Furthermore, they have long axons rich in mitochondria and are particularly susceptible to any interference in energy metabolism, oxidative stress, and axonal transport [27]. SC are involved in endogenous neuroprotective pathways [28] and the reciprocal interaction with axons is mandatory for the normal functions of nerves. Previous works showed that hyperglycaemia can impair the secretion of SC-derived cytokines and growth factors, and affect axonal growth [8]. "
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    ABSTRACT: The pathogenetic role of vascular endothelial growth factor (VEGF) in long-term retinal and kidney complications of diabetes has been demonstrated. Conversely, little is known in diabetic neuropathy. We examined the modulation of VEGF pathway at mRNA and protein level on dorsal root ganglion (DRG) neurons and Schwann cells (SC) induced by hyperglycaemia. Moreover, we studied the effects of VEGF neutralization on hyperglycemic DRG neurons and streptozotocin-induced diabetic neuropathy. Our findings demonstrated that DRG neurons were not affected by the direct exposition to hyperglycaemia, whereas showed an impairment of neurite outgrowth ability when exposed to the medium of SC cultured in hyperglycaemia. This was mediated by an altered regulation of VEGF and FLT-1 receptors. Hyperglycaemia increased VEGF and FLT-1 mRNA without changing their intracellular protein levels in DRG neurons, decreased intracellular and secreted protein levels without changing mRNA level in SC, while reduced the expression of the soluble receptor sFLT-1 both in DRG neurons and SC. Bevacizumab, a molecule that inhibits VEGF activity preventing the interaction with its receptors, restored neurite outgrowth and normalized FLT-1 mRNA and protein levels in co-cultures. In diabetic rats, it both prevented and restored nerve conduction velocity and nociceptive thresholds. We demonstrated that hyperglycaemia early affected neurite outgrowth through the impairment of SC-derived VEGF/FLT-1 signaling and that the neutralization of SC-secreted VEGF was protective both in vitro and in vivo models of diabetic neuropathy.
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    • "The treatment of distal nerve lesions is commonly protracted due to the fact that axonal regeneration starts from central nerve system sprouting into the periphery with approximately 1–4 mm/day dependent on age, nerve, and species [16, 17, 29]. Furthermore, the distance between a nerve lesion and the spinal cord in humans is far bigger compared to rodents [30], implicating that the main subject is the protection of the target muscle from degeneration until new axons reach the motor end-plate for reinnervation [2, 31, 32]. Here, the muscle spindles remain important to prevent muscular atrophy as one major factor. "
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    ABSTRACT: The babysitter-procedure might offer an alternative when nerve reconstruction is delayed in order to overcome muscular atrophy due to denervation. In this study we aimed to show that a sensomotoric babysitter-procedure after median nerve injury is capable of preserving irreversible muscular atrophy. The median nerve of 20 female Wistar rats was denervated. 10 animals received a sensory protection with the N. cutaneous brachii. After six weeks the median nerve was reconstructed by autologous nerve grafting from the contralateral median nerve in the babysitter and the control groups. Grasping tests measured functional recovery over 15 weeks. At the end of the observation period the weight of the flexor digitorum sublimis muscle was determined. The median nerve was excised for histological examinations. Muscle weight (P < 0.0001) was significantly superior in the babysitter group compared to the control group at the end of the study. The histological evaluation revealed a significantly higher diameter of axons (P = 0.0194), nerve fiber (P = 0.0409), and nerve surface (P = 0.0184) in the babysitter group. We conclude that sensory protection of a motor nerve is capable of preserving muscule weight and we may presume that metabolism of the sensory nerve was sufficient to keep the target muscle's weight and vitality.
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