Peripheral nerve disorders vary widely in their origin, but similarly cause significant sensory and motor dysfunction for patients. The peripheral nervous system (PNS) consists of motor and sensory axons within each nerve that extend from the spinal cord to the highly specialized motor endplates in muscle or sensory receptors located in joints,muscle and skin. Each nerve is like a fiber optic cable and contains many thousands of motor and sensory axons. Axons travel for the most part in parallel, each within their own microscopic endoneurial tube.
Acute or chronic repetitive injury disrupts this unique structure either directly or indirectly due to the body’s own inflammatory response. Unlike the central nervous system (CNS), the PNS demonstrates significant regenerative potential. Damaged axons can remyelinate (myelin is the insulated coating around axons that speeds up conduction velocity) and regenerate and reconnect to target organs. The major challenge is to harness the regenerative potential of the PNS, avoid the pitfalls of misguided regeneration and the nonspecific scarring due to the body’s natural wound healing response, and to find ways to maintain the integrity of the specialized target receptors and muscle awaiting the often lengthy time it takes for reinnervation.
The most common disorders affecting the peripheral nervous system are traumatic in nature. Acute traumatic disorders vary from blunt compression and crush injury to sharp partial or complete transection. Chronic disorders vary from repetitive trauma or compressive injury to post traumatic, painful, incomplete regenerative injury. Operative treatment varies and includes decompression of entrapped nerves, resection of scarred nerves and neurorrphaphy (reconnection) or replacement of damaged segments. Similar to recovery following acute injury, after reconstructive surgery motor and sensory recovery is often incomplete due to a myriad of factors. The isolation, understanding of these factors and improvement of each will lead to a more complete return in function.
Our laboratory has looked at the mechanisms by which regenerating nerves choose the correct pathway of regeneration to their correct targets (selective reinnervation).Misguided reinnervation of sensory axons to motor targets or motor axons to sensory targets or sensory and motor axons to wrong topographical targets appears to be minimized by contact cues and diffusible substrates from the target axon tubes and end organs to some degree.We have developed surgical models to assess the accuracy of reinnervation and are developing mutant gene models to isolate specific motor versus sensory axon lures to enhance this accuracy.
Traditional methods of reconstructive surgery utilize a patient’s own intact sensory nerves (autograft) to replace damaged motor nerves as motor function is more of a priority for function. Harvesting these nerves causes numbness and sometimes pain in the donor area and frequently there is not enough expendable nerve available to replace the damaged segments. Our research is focused on finding ways of developing alternative types of nerve grafts.
Cadaveric donor nerve (allograft) peripheral nerve is one type of alternative graft material that has been tried unsuccessfully for over one hundred years. Research that we have performed has made it possible to transplant allograft nerves with systemic immunosuppression. We have looked extensively at methods of storing allograft nerve for extended periods, and have found that the storage process not only makes the nerve less antigenic (less chance for rejection), it allows time for adequate tissue testing and the ability to perform reconstructive procedures on an elective non-emergent basis which is both convenient for the patient and more cost effective.
We believe the future of nerve transplantation will be the development of nontoxic, more specific immunosuppressive agents and better graft storage and preparation to render it nonimmunogenic. A totally synthetic or bioengineered nerve graft that allows for accurate and accelerated regeneration is the ultimate goal. Our laboratory is currently working on these models.
