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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.

Background: In unilateral facial palsy, cross-face nerve grafts are used for emotional facial reanimation. Facial nerve regeneration through the grafts takes several months, and the functional results are sometimes inadequate. Chronic denervation of the cross-face nerve graft results in incomplete nerve regeneration. The authors hypothesize that donor axons from regional sensory nerves will enhance facial motoneuron regeneration, improve axon regeneration, and improve the amplitude of facial muscle movement., Methods: In the rat model, a 30-mm nerve graft (right common peroneal nerve) was used as a cross-face nerve graft. The graft was coapted to the proximal stump of the transected right buccal branch of the facial nerve and the distal stumps of the transected left buccal and marginal mandibular branches. In one group, sensory occipital nerves were coapted end-to-side to the cross-face nerve graft. Regeneration of green fluorescent protein-positive axons was imaged in vivo in transgenic Thy1-green fluorescent protein rats, in which all neurons express green fluorescence. After 16 weeks, retrograde labeling of regenerated neurons and histomorphometric analysis of myelinated axons was performed. Functional outcomes were assessed with video analysis of whisker motion., Results: "Pathway protection" with sensory axons significantly enhanced motoneuron regeneration, as assessed by retrograde labeling, in vivo fluorescence imaging, and histomorphometry, and significantly improved whisker motion during video analysis., Conclusion: Sensory pathway protection of cross-face nerve grafts counteracts chronic denervation in nerve grafts and improves regeneration and functional outcomes.

Accumulating evidence suggests that neuregulin, a potent Schwann cell mitogen, and its receptor, ErbB2, have an important role in regulating peripheral nerve regeneration. We hypothesized that Herceptin (Trastuzumab), a monoclonal antibody that binds ErbB2, would disrupt ErbB2 signaling, allowing us to evaluate ErbB2's importance in peripheral nerve regeneration. In this study, the extent of peripheral motor and sensory nerve regeneration and distal axonal outgrowth was analyzed two and four weeks after common peroneal (CP) nerve injury in rats. Outcomes analyzed included neuron counts after retrograde labeling, histomorphometry, and protein analysis. The data analysis revealed that there was no impact of Herceptin administration on either the numbers of motor or sensory neurons that regenerated their axons but histomorphometry revealed that Herceptin significantly increased the number of regenerated axons in the distal repaired nerve after 4 weeks. Protein analysis with Western blotting revealed no difference in either expression levels of ErbB2 or the amount of activated, phosphorylated ErbB2 in injured nerves. In conclusion, administration of the ErbB2 receptor inhibitor after nerve transection and surgical repair did not alter the number of regenerating neurons but markedly increased the number of regenerated axons per neuron in the distal nerve stump. Enhanced axon outgrowth in the presence of this ErbB2 inhibitor indicates that ErbB2 signaling may limit the numbers of axons that are emitted from each regenerating neuron., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aim: Recovery following nerve transection declines when target reconnection is delayed for prolonged periods. GDNF has previously been shown to promote motor axon regeneration following delayed nerve repair., Materials & Methods: We constructed delivery systems using fibrin gels containing free GDNF or poly(lactide-co-glycolide) microspheres with GDNF. The delivery systems were implanted with fluorescent fibrinogen surrounding the common fibular (CF; peroneal) nerve in transgenic Thy-1 GFP rats (whose axons express GFP) to track degradation of the system. A delayed nerve repair model was designed by transecting the rat CF nerve, where nerve regeneration was prevented by ligating the two stumps to surrounding muscle for 2 months prior to resuture. At resuture, either a delivery system with GDNF or an additional group consisting of fibrin gels with empty microspheres were implanted surrounding the repair site. In an additional positive control, the CF was transected and repaired immediately without delay., Results: ELISA assays demonstrated GDNF release in vitro for 2 weeks from fibrin gels with GDNF microspheres. Implanted delivery systems, including GDNF microspheres, remained surrounding the nerve for at least 10 days compared with 3 days for free GDNF. Four weeks after repair, histomorphometry of distal nerve cross-sections taken 20 mm from the repair site demonstrated increased fiber diameter and myelin thickness due to release of GDNF from microspheres compared with empty microspheres. Additionally, the number of motoneurons that regenerated their axons to the same site increased to comparable levels as immediate repair due to the extended delivery of GDNF from microspheres., Conclusion: These findings demonstrate that early measures of nerve regeneration after delayed nerve repair is improved by GDNF microspheres implanted at the coaptation site.