Nerve Cross-Bridging to Enhance Nerve Regeneration in a Rat Model of Delayed Nerve Repair

Tessa Gordon,Holliday Cartar,Michael Hendry,Christine A Lafontaine,Gregory H Borschel,Jennifer J Zhang,William D Phillips

doi:10.1371/journal.pone.0127397

Tessa Gordon, Holliday Cartar + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0127397

Copy DOI

Abstract

There are currently no available options to promote nerve regeneration through chronically denervated distal nerve stumps. Here we used a rat model of delayed nerve repair asking of prior insertion of side-to-side cross-bridges between a donor tibial (TIB) nerve and a recipient denervated common peroneal (CP) nerve stump ameliorates poor nerve regeneration. First, numbers of retrogradely-labelled TIB neurons that grew axons into the nerve stump within three months, increased with the size of the perineurial windows opened in the TIB and CP nerves. Equal numbers of donor TIB axons regenerated into CP stumps either side of the cross-bridges, not being affected by target neurotrophic effects, or by removing the perineurium to insert 5-9 cross-bridges. Second, CP nerve stumps were coapted three months after inserting 0-9 cross-bridges and the number of 1) CP neurons that regenerated their axons within three months or 2) CP motor nerves that reinnervated the extensor digitorum longus (EDL) muscle within five months was determined by counting and motor unit number estimation (MUNE), respectively. We found that three but not more cross-bridges promoted the regeneration of axons and reinnervation of EDL muscle by all the CP motoneurons as compared to only 33% regenerating their axons when no cross-bridges were inserted. The same 3-fold increase in sensory nerve regeneration was found. In conclusion, side-to-side cross-bridges ameliorate poor regeneration after delayed nerve repair possibly by sustaining the growth-permissive state of denervated nerve stumps. Such autografts may be used in human repair surgery to improve outcomes after unavoidable delays.

Highlights

Despite optimal management, recovery of function after peripheral nerve injury and surgical repair is rarely complete; it is frequently poor [1,2]
Autologous common peroneal (CP) nerve cross-bridges from the left hindlimb were dissected and placed in a side-to-side fashion via perineurial windows that were opened at equal distances within a 10 mm length of the intact donor tibial (TIB) nerve and the recipient denervated CP nerve stump in the right experimental hindlimb (Fig 1)
The TIB neurons that regenerated their axons into the recipient CP nerve stump were backlabelled with the dye applied to the CP nerve stump but not with dye applied to the donor TIB nerve

Summary

Introduction

Recovery of function after peripheral nerve injury and surgical repair is rarely complete; it is frequently poor [1,2]. Whilst this is usually attributed to fat replacement of atrophic denervated muscles [2], the progressive failure of nerve regeneration over time and distance is accounted for by a progressive decline in the regenerative capacity of the injured neurons and the diminished regenerative support by the chronically. The tibial axons ‘protected’ chronically denervated Schwann cells because the number of motoneurons that regenerated their axons after delayed coaptation of the proximal and distal CP nerve stumps was increased 1.7-fold [12]

Objectives

Methods

Results

Conclusion