Spinal cord repair strategies

Sammanfattning: Regeneration of long fiber tracts does not occur spontaneously in the adult mammalian brain or spinal cord. The present work is an attempt to develop a repair strategy that may overcome this lack of recovery and apply it to spinal cord injury. The strategy is based on bridging the spinal cord gap with multiple peripheral nerve grafts supported by several facilitating additional measures. To be able to reconnect and reroute several descending and ascending spinal cord tracts, multiple nerve implants are needed. Intercostal nerves were found to be a useful alternative, since they were thin, and could be collected in sufficient amount for autologous grafting without causing severe functional deficits. Primate intercostal nerves were also tested for their ability to "deliver" a mixed population of regenerating nerve fibers to a target environment. Grafting intercostal nerve segments to the rat spinal cord was carried out after removal of 5 mm of the cord at T8. Eighteen grafts were placed to specifically initiate regeneration of, and reroute defined fiber tracts from white matter proximal to the gap to corresponding termination areas in gray matter below the gap, and vice versa. Fibrin glue was evaluated as a biodegradable stabilization agent. The glue was shown not to cause any disturbance of brain tissue grafts, and to allow penetration of growing nerve fibers. The fibrin glue was further evaluated as a possible vehicle for slow release of trophic proteins. Both acidic fibroblast growth factor (aFGF) and glial cell line- derived neurotrophic factor (GDNF) could be effectively incorporated into the glue. Acidic FGF, a normal constituent of the spinal cord hypothetized to be of importance in injury, was then included in fibrin glue and such glue infused into the engrafted area of the spinal cord. Several methods for vertebral column stabilization were tested in a vertebral shortening paradigm allowing the cut spinal cord stumps to meet and leading to a degree of proxim- odistal regeneration of descending 5-HT fibers. Based on these tests, a method using com- pressive wiring of spinal processes and securing the monofilament stainless steel wire to the rib cage, was chosen for the repair strategy. Analysis of rats made paraplegic and subjected to the full repair strategy (18 white-to-gray bridges, fibrin glue with aFGF, compressive wiring) demonstrated return of hind limb positioning, followed by return of hindlimb movements and partial weight bearing. None of these changes were noted in any of several different types of paraplegic control animals. Structural analysis using anterograde and retrograde WGA-HRP axonal tracing revealed many regenerated descending fiber tracts, including the corticospinal tract. Detailed analyis of gait demonstrated that the repaired ani- mals were able to use their four limbs in controlled order and patterns similar to those found in normal rats. While the repaired animals remain functionally inferior to normal animals, the data demonstrate that it is possible to regain some hindlimb function after complete spinal cord injury. If this method can be improved, and applied to animals with chronic spinal cord injury, it may have future clinical potential. Keywords: Spinal cord, injury, paraplegia, repair, regeneration, nerve graft, fibrin glue, aFGF, GDNF, gait, axonal tracing Henrich Cheng, 1996 ISBN 91-628-2278-0