Promoting and directing nerve growth and wound healing in vivo. (360G-Wellcome-079518_Z_06_Z)

Understanding how to stimulate and direct nerve regeneration is crucial. Using rat cornea, we showed for the first time that the cues directing nerve growth and wound healing in vivo include wound-generated electrical signals (Song et al, 2002, 2004 & front cover). These signals arise the instant the wound occurs and remain until the wound closes. Direct current electrical fields (DC EF) of the same magnitude stimulate and direct nerve growth and wound healing in vitro (McCaig et al, 2002, 2005). Moreover, in a recent Phase 1 clinical trial to treat spinal cord injuries, patients implanted with long-term electrical stimulators showed return of significant sensory functions and of some motor activity (Shapiro et al, 2005). Nevertheless there is still only limited understanding and acceptance of electrical regulation of nerve guidance and wound healing. Therefore we propose two definitive tests. Using a unique combination of cell biology, biophysics, pharmacology and molecular genetics, we shall apply a DC EF directly to rat corneal wounds in vivo. If wound-directed nerve growth and wound healing are regulated electrically, the polarity and magnitude of the applied EF will determine whether these cell behaviours are enhanced or inhibited. In addition, we shall test the role of the EF in vivo using pharmacological and genetic methods of disrupting the electrical seals formed by the epithelial tight junctions.