Biomaterial bridges enable regeneration and re-entry of corticospinal tract axons into the caudal spinal cord after SCI: Association with recovery of forelimb function

Severed axon tracts fail to exhibit robust or spontaneous regeneration after spinal cord injury (SCI). Regeneration failure reflects a combination of factors, including the growth state of neuronal cell bodies and the regeneration-inhibitory environment of the central nervous system. However, while spared circuitry can be retrained, target reinnervation depends on longitudinally directed regeneration of transected axons. This study describes a biodegradable implant using poly(lactide-co-glycolide) (PLG) bridges as a carrier scaffold to support regeneration after injury. In order to detect regeneration of descending neuronal tracts into the bridge, and beyond into intact caudal parenchyma, we developed a mouse cervical implantation model and employed Crym:GFP transgenic mice. Characterization of Crym:GFP mice revealed that descending tracts, including the corticospinal tract, were labeled by green fluorescent protein (GFP), while ascending sensory neurons and fibers were not. Robust co-localization between GFP and neurofilament-200 (NF-200) as well as GFP and GAP-43 was observed at both the rostral and caudal bridge/tissue interface. No evidence of similar regeneration was observed in mice that received gelfoam at the lesion site as controls. Minimal co-localization between GFP reporter labeling and macrophage markers was observed. Taken together, these data suggest that axons originating from descending fiber tracts regenerated, entered into the PLG bridge at the rostral margin, continued through the bridge site, and exited to re-enter host tissue at the caudal edge of the intact bridge. Finally, regeneration through implanted bridges was associated with a reduction in ipsilateral forelimb errors on a horizontal ladder task.