Chapter 24 Electrical Stimulation for Improving Nerve Regeneration: Where do we Stand?
Introduction
Recovery following peripheral nerve injury, particularly proximal nerve injury, remains a significant clinical problem despite the known capacity for axon regeneration in the peripheral nervous system. Poor functional outcomes following repair of peripheral nerve lesions have been attributed to two main factors impeding axonal regeneration: (1) slow growth across coaptation sites and/or nerve gaps and (2) a relatively short time frame when the injured neurons and the denervated Schwann cells can support regenerating axons following injury. Expedition of regenerating axons across repair sites in order to optimize functional regeneration is a major focus of current research. This review will consider why functional recovery in humans remains an extensive clinical problem and will discuss the developing role of electrical stimulation (ES) as a method of accelerating the outgrowth of axons across a site of nerve repair, both in animals and humans.
Section snippets
Basis for Poor Functional Recovery After Nerve Injury and Repair
Despite the permissive growth environment of the peripheral nervous system, functional recovery after surgical repair of injured peripheral nerves is often suboptimal (Kim et al., 2003, Sunderland, 1978, Terzis and Smith, 1990). This is true particularly when nerves regenerate over long distances and/or long delays occur between injury and target reinnervation. Experimentally, when axon regeneration from the proximal nerve stump and through the distal the nerve stump is delayed in rat
Wallerian Degeneration and Staggered Axon Regeneration into the Distal Nerve Stump
Axons do not regenerate across surgical sites within the time frames predicted by well‐established rates of regeneration of 1–3 mm/day. Using retrograde dyes that are taken up by regenerated axon tips and transported to the cell bodies of motoneurons and sensory neurons, we observed that the regeneration of axons across a site of nerve repair is very slow when compared with the 1–3 mm/day rate of axon regeneration (Fig. 1) (Al‐Majed et al., 2000b, Brushart et al., 2002, Gordon et al., 2008).
Conclusions
Despite continuous advancements in knowledge and technique, regeneration in the peripheral nervous system remains a significant source of morbidity. The recent application of ES to promote axonal sprouting in nerve injury has resulted in promising functional recovery in animal models. With the limitation of ES to 1 h, the translational potential of this modality is significant. To date, one study has made the translation to human trial where post-surgical ES of the median nerve following carpal
Acknowledgments
We appreciate the financial support by the Canadian Institutes for Health Research (CIHR) for operating grants to TG from CIHR and a CIHR group grant that includes Dr. Zochodne, Dr. Sayed, and Dr. Midha from University of Calgary, VMKV from University of Saskatchewan, and Dr. Chan and T.G. from University of Alberta. T.G. is an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Investigator.
References (46)
- et al.
Blocking of up‐regulated ICAM‐1 does not prevent macrophage infiltration during Wallerian degeneration of peripheral nerve
Exp. Neurol.
(2004) - et al.
Differential macrophage responses in the peripheral and central nervous system during wallerian degeneration of axons
Exp. Neurol.
(1995) - et al.
Electrical stimulation restores the specificity of sensory axon regeneration
Exp. Neurol.
(2005) - et al.
Electrical stimulation promotes sensory neuron regeneration and growth‐associated gene expression
Exp. Neurol.
(2007) - et al.
Axonal transport of the cytoskeleton in regenerating motor neurons: Constancy and change
Brain Res.
(1980) - et al.
Expression and possible function of nerve growth factor receptors on Schwann cells
Trends Neurosci.
(1988) - et al.
Electrical stimulation of regenerating nerve and its effect on motor recovery
Brain Res.
(1983) - et al.
Acceleration of peripheral nerve regeneration after crush injury in rat
Neurosci. Lett.
(1985) - et al.
Tropism in nerve regeneration in vivo. Attraction of regenerating axons by diffusible factors derived from cells in distal nerve stumps of transected peripheral nerves
Brain Res.
(1982) - et al.
Temporal and spatial expression of ciliary neurotrophic factor after peripheral nerve injury
Exp Neurol.
(1993)