"Pathway protection" - enhanced motoneuron regeneration by end-to-side coaptation of sensory axons

Abstract

Proximal nerve injuries and delayed nerve repair lead to reduced peripheral nerve regeneration. Poor functional results after nerve injury are clinically a very challenging problem. Experimental studies defined "chronic axotomy" of the neuron and the proximal part of a dissected nerve that are separated from their distal target, as well as "chronic denervation" of the distal nerve stump as an independent factors that reduce regenerative capacity of injured nerves. The denervated distal nerve undergoes changes associated with Wallerian degeneration. Denervated Schwann cells change their phenotype to interact with in-growing axons and increase the expression of growth factors. These changes lead to a pro-regenerative environment in the distal nerve stump. This growth-permissive environment deteriorates with time leading to significantly reduced nerve regeneration. Clinically, delayed nerve repair and long regeneration distances often result in inadequate functional outcomes. Different "pathway protection" techniques were developed to improve nerve regeneration and reduce the chronic denervation of the distal nerve. Most of these "babysitter" procedures used a motor donor nerve which was coapted usually end-to-side to the denervated distal nerve stump. Experimental studies showed that in-growing donor axons increase neurotrophic factor levels and improved reinnervation of distal targets. Motor "babysitter" procedures are, however, associated with a motor donor nerve deficit. In recent years, sensory "pathway protection" was investigated to avoid such motor deficit. Motoneuron regeneration of its axons can, in experimental animal models, be improved by end-to-side coaptation of sensory donor axons to either a denervated distal nerve stump or to a long autologous nerve graft, both of which undergo changes associated with chronic denervation. Sensory "pathway protection" has already been successfully clinically applied, however long-term functional analysis awaits.