Misdirection and guidance of regenerating axons after experimental nerve injury and repair

Misdirection of regenerating axons is one of the factors that can explain the limited results often found after nerve injury and repair. In the repair of mixed nerves innervating different distal targets (skin and muscle), misdirection may, for example, lead to motor axons projecting toward skin, and vice versa-that is, sensory axons projecting toward muscle. In the repair of motor nerves innervating different distal targets, misdirection may result in reinnervation of the wrong target muscle, which might function antagonistically. In sensory nerve repair, misdirection might give an increased perceptual territory. After median nerve repair, for example, this might lead to a dysfunctional hand. Different factors may be involved in the misdirection of regenerating axons, and there may be various mechanisms that can later correct for misdirection. In this review the authors discuss these different factors and mechanisms that act along the pathway of the regenerating axon. The authors review recently developed evaluation methods that can be used to investigate the accuracy of regeneration after nerve injury and repair (including the use of transgenic fluorescent mice, retrograde tracing techniques, and motion analysis). In addition, the authors discuss new strategies that can improve in vivo guidance of regenerating axons (including physical guidance with multichannel nerve tubes and biological guidance accomplished using gene therapy).