Currently, there are approximately 200,000-250,000 para- or quadriplegics in the EC, most of whom became disabled in early adulthood as a result of traffic or sporting accidents. Traumatic spinal cord injuries encountered in neurosurgical practice are highly heterogeneous due to a variety of factors : e.g. open or closed nature of injury ; segmental level of injury (ranging from upper cervical to conus level) ; possible association with bone lesions leading to prolonged cord compression ; possible association of root avulsion; possible association with dura mater dilaceration or impaction within the spinal tissue.
Throughout the last century, there has been a consensus of opinion amongst physicians, surgeons and rehabilitation specialists that severed spinal cord injury invariably leads to motor function deficit and severe disability. The doctrine of "abortive sprouting" established by Ramon y Cajal in the early 20th century has only recently been challenged. The work of David and Aguayo (1981) indicated that spinal neurons possess an intrinsic capacity to regenerate provided that they are presented with an environment which is permissive to axon growth.
The last decade has witnessed a surge of intense scientific activity in the field of CNS regeneration. The spinal cord is the model of choice since the clinical syndrome induced by spinal cord injury is very specific. Also, the well known anatomical organisation of the spinal cord as the principal conduit for motor, sensory and autonomic pathways permits correlated anatomical, biochemical and functional studies.
We have two main objectives :
to study the pathophysiological mechanisms at the site of injury and to develop strategies for their management. At the lesion site there are specific problems, such as the disruption of the blood-spinal cord barrier with massive invasion by blood-borne and mesenchymal elements. Additionally, local and long distance circuits are disrupted and there may be substantial tissue loss, the repair of which necessitates physical bridging combined with chemical stimulation of axonal regrowth.
to study the pathophysiological mechanisms remote from the site of injury and to develop strategies for their management.
Unlike any other tissue, the central nervous system is characterized by short and long distance interactions between its elements via axons. Thus, damage to central tissue is likely to be characterized by pathological alterations not only at the site of the lesion, but also in remote areas of the CNS, often at substantial distances from the lesion. This is particularly evident in the spinal cord, where ascending and descending projections connect many regions of the brain with motor/visceral or sensory relays. Thus, it is important to obtain fundamental information about the remote consequences of spinal cord injury so that therapeutic interventions can be formulated to prevent deleterious changes.
To reach these objectives we will employ several experimental models of spinal cord injury, which are currently used in the participating laboratories, and develop a new model which reproduces the type of scarring encountered clinically in nearly 50 % of patients.
These objectives are in complete accordance with area 3 of the Biomed program and in particular with the following :
- Mechanisms of cell growth and plasticity affected in disease.
- Cell degeneration, regeneration, injury and repair.
- Development of therapeutic strategies for damage limitation, regrowth promotion and repair.
This work program will be implemented through the following experiments :
Analysis of several experimental models of spinal cord injury :
Hemisection or complete sections.
Contusion lesions (weight drop model, balloon model).
The design of a combined lesion - transplantation model.
Segmental reactions following injury :
At the site of injury.
Rostral and caudal to the lesion site.
Target neuron behaviour.
Glial cell behaviour.
How to encourage axon growth across the lesion :
Promote directed regeneration.
Re-establish functional circuits.
Remove inhibition of axonal regeneration
* use of a collagen matrix.
* use of transplanted permissive cells: tanycytes.
How to manage the remote consequences of the lesion ?
Stimulation of sprouting of remaining axons.
Prevention of astrogliosis.
Functional substitution of non-specific neuromodulatory spinal inputs : monoaminergic neurons.
Funding SchemeCSC - Cost-sharing contracts
3584 CG Utrecht