An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury

Abstract

The failure of long descending pathways to regenerate after spinal cord injury (SCI) is generally attributed to inhibitory proteins associated with the glial scar and myelin, or to the loss of neurons' intrinsic capacity to grow, or both. Here, we describe the use of hydrogels as a novel way to deliver molecules that promote axon growth in the injured CNS of adult rats. This method utilizes an injectable liquid polymer solution that crosslinks into a biodegradable, water-swollen hydrogel when photoactivated under visible light. Neurotrophin-3 (NT-3), a trophic factor known to act on corticospinal tract (CST) projection neurons, was used as a prototypic pro-regenerative molecule. Hydrogel release properties were established in vitro to ensure long-term, sustained NT-3 release over a 2-week period; this avoided the need for multiple injections or minipump implantation. Hydrogel/NT-3-treated animals showed improved recovery in the open-field BBB test and in a horizontal ladder walk test compared to controls implanted with hydrogel alone. At the anatomical level, hydrogel/NT-3-treated animals showed far greater axon growth than controls in two major descending pathways for motor control, the CST and the raphespinal tract. In the case of the CST, much of the NT-3-induced growth represented collateral branching from undamaged ventral CST fibers. These studies demonstrate the effectiveness of hydrogel technology as a clinically feasible delivery system to promote regeneration and enhance functional outcome after spinal cord injury.