Nerve regeneration is a complex biological phenomenon. In the peripheral nervous system, nerves can regenerate on their own if injuries are small. Larger injuries must be surgically treated, typically with nerve grafts harvested from elsewhere in the body. Spinal cord injury is more complicated, as there are factors in the body that inhibit repair. Unfortunately, a solution to completely repair spinal cord injury has not been found. Thus, bioengineering strategies for the peripheral nervous system are focused on alternatives to the nerve graft, whereas efforts for spinal cord injury are focused on creating a permissive environment for regeneration. Fortunately, recent advances in neuroscience, cell culture, genetic techniques, and biomaterials provide optimism for new treatments for nerve injuries. This article reviews the nervous system physiology, the factors that are critical for nerve repair, and the current approaches that are being explored to aid peripheral nerve regeneration and spinal cord repair.

Neural tissue engineering: strategies for repair and regeneration.

Translating developmental time across mammalian species.

Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.

/pdf/therapeutic-interventions-after-spinal-cord-injury-319za83fnv.pdf

Therapeutic interventions after spinal cord injury.

Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury

Blindfolded rats were trained to stretch across a gap to palpate rough or smooth surfaces with their mystacial vibrissae. Animals learned to discriminate reliably a smooth surface from a rough surface having shallow (approximately 30 microns) grooves spaced at 90 microns intervals. Field-by-field video analyses confirmed that rats used only their vibrissae to contact the discriminanda. The whiskers swept across the surfaces at 696 degrees/sec during forward movements and 1106 degrees/sec for retracting movements. Mean amplitudes, which were 32 degrees, were considerably smaller than the total arc through which whiskers can move. Rats maintained whisker contact with discriminanda for several hundreds of msec, during which time the animals repetitively swept their vibrissae across the surface at a dominant frequency of 8 Hz. The range extended from 1 to 20 Hz, and the frequencies utilized varied within and among subjects. Whiskers contacted the discriminanda along the hair shaft, not at the whisker tips. The hair shafts were bent continually but to varying degrees as an animal palpated the surface, and more than one of the large caudal whiskers were almost always in contact with it. Thus, whiskers are not used independently as rigid levers. Results indicate that the capacity of the rodent whisker system to distinguish a smooth surface from a rough one is comparable to that of primates using their fingertips and suggest common strategies for active touch in the mammalian somatomotor system.

/pdf/biometric-analyses-of-vibrissal-tactile-discrimination-in-11mvpm7c9r.pdf

Biometric analyses of vibrissal tactile discrimination in the rat

We demonstrated recently that transplantation of olfactory ensheathing cells from the nasal olfactory mucosa can promote axonal regeneration after complete transection of the spinal cord in adult rat. Ten weeks after transection and transplantation there was significant recovery of locomotor behaviour and restoration of descending inhibition of spinal cord reflexes, accompanied by growth of axons across the transection site, including serotonergic axons arising from the brainstem raphe nuclei. The present experiment was undertaken to determine whether olfactory ensheathing cells from the olfactory mucosa are capable of promoting regeneration when transplanted into the spinal cord 4 weeks after transection. Under general anaesthesia, thoracic spinal cord at the T10 level was transected completely in adult rats. Four weeks later, the scar tissue and cavities at the transection site were removed to create a 3-4 mm gap. Into this gap, between the cut surfaces of the spinal cord, pieces of olfactory lamina propria were placed. Ten weeks later, the locomotor activity of these animals was significantly improved compared with control animals, which received implants of either pieces of nasal respiratory lamina propria or collagen (Basso, Beattie, Bresnahan Locomotor Rating Scale scores 4.3 + 0.8, n = 6 versus 1.0 + 0.2, n = 10, respectively; P < 0.001). Ten weeks after transplantation the behavioural recovery was still improving. Regrowth of brainstem raphe axons across the transplant site was shown by the presence of serotonergic axons in the spinal cord caudal to the transection site, and by retrograde labelling of cells in the nucleus raphe magnus after injections of fluorogold into the caudal spinal cord. Neither serotonergic axons nor labelled brainstem cells were observed in the control animals. These results indicate that olfactory ensheathing cells from the nasal olfactory lamina propria have the ability to promote spinal cord regeneration when transplanted 4 weeks after complete transection. Olfactory ensheathing cells are accessible and available in the human nose; the present study further supports clinical use of these cells in repairing the human spinal cord via autologous transplantation.

Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord.

Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord

Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.

The outcome of spinal cord injury depends on the extent of secondary damage produced by a series of cellular and molecular events initiated by the primary trauma. This article reviews the evidence that secondary spinal cord injury involves the apoptotic as well as necrotic death of neurons and glial cells. Also discussed are the major factors that can contribute to cell death, such as glutamatergic excitotoxicity, free radical damage, cytokines, and inflammation. The development of innovative therapeutic strategies to reduce secondary spinal cord injury depends on an increased understanding of secondary injury mechanisms at the molecular and biochemical level. Such therapeutic interventions may include the use of antiapoptotic drugs, free radical scavengers, and anti-inflammatory agents. These could be targeted to block key reactions on cellular and molecular injury cascades, thus reducing secondary tissue damage, minimizing side effects, and improving functional recovery.

Advances in secondary spinal cord injury: role of apoptosis.

This chapter addresses the unique anatomy of the pathway for facial sensations, involving the trigeminal ganglion and its associated nuclei within the brainstem. The innervation of specialized cranial structures such as the teeth, tongue, oral and nasal mucosa, cornea, meninges, and conjunctiva are considered. This chapter will also address trigeminal mechanisms in clinically relevant conditions such as toothache, headache and trigeminal neuralgia including using advances in imaging techniques and resolution. Thus it is now possible to obtain functional MR images (fMRI) of the trigeminal pathway from ganglion to cortex. Magnetoencephalography (MEG) and fMRI techniques have provided more details on cortical organization in facial regions of both S1 and S2, while diffusion tensor imaging has been useful for visualizing trigeminothalamic pathways. Plasticity of the system after injury, its association with pain conditions, and the opportunities that this offers for training and rehabilitation, are further areas of current research that are discussed.

Phil M.E. Waite

Papers

Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord.

Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord

Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.

Advances in secondary spinal cord injury: role of apoptosis.

Trigeminal sensory system.