Degeneration of peripheral nerve is a common phenomenon both as a consequence of nerve injury and as a complication to systemic disease and results in clinical disability. Recovery is frequently incomplete due to insufficient regeneration and reinnervation. To further the understanding of factors that influence recovery, it is the long-term aim of this proposal to study nerve regeneration and specifically to investigate the effect of the microenvironment of the denervated nerve stump on regeneration. A newly electrophysiological method was used to monitor nerve regeneration quantitatively in in vivo long-term observations in animal models. The method has the advantage that different phases of the regenerative process, (such as retrograde degeneration, delays in regeneration, the rate of elongation, and the level of maturation), can be differentiated. The method is well suited to answer questions regarding factors influencing regeneration. In order to manipulate the denervated nerve stump and study effects on regeneration, three specific questions will be addressed.
The first aim i s to quantify nerve regeneration following nerve lesions causing nerve; focal nerve crush; and section of nerve followed by end-to-end suture of nerve stumps. The lesions will be compared to delineate a focal effect of the lesion from impairment of regeneration throughout the nerve.
The second aim i s to evaluate regeneration across a gap in the nerve trunk. In clinical practice, tissue gaps are reduced by inserting a nerve graft. The feasibility of replacing a graft with a nerve growth guide will be investigated by comparing regeneration through bioresorbable nerve growth tubes with or without a laminin gel (cell adhesion macromolecule) with the after grafting.
The third aim i s to study the role of the metabolic integrity of the distal stump in regeneration. To inhibit Schwann cells, neurotoxic inhibitors (Mitomycin C or Doxorubicin) will be injected into the distal denervated nerve stump. The effect of cell inhibition will be compared with that associated with cell degeneration caused by freezing of the nerve trunk. Regeneration will be monitored using biocompatible electrode-arrays implanted around the nerve. The high resolution from single fiber to whole nerve action potentials and the stable anatomical and functional relationship of the electrodes with the nerve, allow detection of the first regenerating fibers in the nerve, measurements of rate of elongation, and characterization of the caliber of the first regenerating fibers. These characteristics are of importance in following an quantifying various treatment procedures in regeneration and will be of help in providing information about factors controlling regeneration. Quantitative histological measurements will be used to correlate the conduction properties with structural axonal changes. The results of the experiments will further our understanding of basic processes of peripheral nerve regeneration and repair. The method will be useful in the investigation of the role of specific substances in nerve regeneration and the effects of neuronal factors such as slow and fast axoplasmic transport. This may provide further information about the relationship between neural and glial factors and contribute to the treatment of patients with peripheral nerve disorders.
| Fugleholm, K; Schmalbruch, H; Krarup, C (1994) Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat. J Neurosci 14:2659-73 |
