The targeted delivery of genes and the transplantation of suitable cell types into the adult nervous system have received considerable interest over the last years. The development of improved vector systems for in vivo gene delivery and the discovery of neural stem cells in the adult nervous system have opened new venues for potential therapeutic intervention in progressive neurodegenerative disease and nervous system injury. Thus, strategies have evolved for the delivery of potentially neuroprotective molecules, such as neurotrophic factors, and the replacement of cells and tissue lost due to CNS injury and degeneration.

Strategies to promote axonal extension through a site of injury, including the provision of nervous system growth factors and supportive substrates, produce growth of axons, that is highly random and does not extend past the lesion site and into the host tissue (Brain Res. Bull 57(6) (2002) 833). Physically guiding the linear growth of axons across a site of injury, in addition to providing neurotrophic and/or cellular support, would help to retain the native organization of regenerating axons across the lesion site and into distal host tissue, and would potentially increase the probability of achieving functional recovery. In the present study, a novel procedure was developed for using freeze-dry processing to create nerve guidance scaffolds made from agarose, with uniaxial linear pores. The hydrated scaffolds were soft and flexible, contained linear guidance pores extending through their full length, were stable under physiological conditions without chemical crosslinking, and could be readily loaded with diffusible growth stimulating proteins. (C) 2004 Elsevier Ltd. All rights reserved.

Previous attempts to promote regeneration after spinal cord injury have succeeded in stimulating axonal growth into or around lesion sites but rarely beyond them. We tested whether a combinatorial approach of stimulating the neuronal cell body with cAMP and the injured axon with neurotrophins would propel axonal growth into and beyond sites of spinal cord injury. A preconditioning stimulus to sensory neuronal cell bodies was delivered by injecting cAMP into the L4 dorsal root ganglion, and a postinjury stimulus to the injured axon was administered by injecting neurotrophin-3 (NT-3) within and beyond a cervical spinal cord lesion site grafted with autologous bone marrow stromal cells. One to 3 months later, long-projecting dorsal-column sensory axons regenerated into and beyond the lesion. Regeneration beyond the lesion did not occur after treatment with cAMP or NT-3 alone. Thus, clear axonal regeneration beyond spinal cord injury sites can be achieved by combinatorial approaches that stimulate both the neuronal soma and the axon, representing a major advance in strategies to enhance spinal cord repair.

Neurogenesis has been described in various regions of the CNS throughout life. We examined the extent of natural cell division and replacement from 7 weeks to 7 months after cervical spinal cord injury in four adult rhesus monkeys. Bromodeoxyuridine ( BrdU) injections revealed an increase of > 80-fold in the number of newly divided cells in the primate spinal cord after injury, with an average of 725,000 BrdU-labeled cells identified per monkey in the immediate injury zone. By 7 months after injury, 15% of these new cells expressed mature markers of oligodendrocytes and 12% expressed mature astrocytic markers. Newly born oligodendrocytes were present in zones of injury-induced demyelination and appeared to ensheath or remyelinate host axons. Thus, cell replacement is an extensive natural compensatory response to injury in the primate spinal cord that contributes to neural repair and is a potential target for therapeutic enhancement.