Nerve injuries to the upper and lower extremities are very common in the United States, occurring in over 700,000 cases annually. In the military, there is a greater than 90% chance of survival from a battlefield injury. Unfortunately, the increasing rate of survival means that more wounded warriors are living the rest of their lives with injured arms and legs or amputations. Most of these injuries involve damage to nerves. Repair after nerve injury is completely dependent upon the success of nerve regrowth. Nerves grow very slowly - at a rate of about 1 inch per month. Damaged nerves near the shoulder must grow a long distance to reach arm and hand muscles. In fact, such nerve injuries consistently heal so poorly that amputations are common for these patients.

Polyethylene glycol and methylene blue are components within solutions used commonly in medical practice today. In animal studies, polyethylene glycol improves the healing of nerve injury sites by immediate fusion of the cut nerve ends while methylene blue lessens the spread of oxidative injury. We have used these solutions in our lab to demonstrate that we can improve nerve function after injury in rats. Our breakthrough treatment is a single dose that is easily applied during the surgical repair. This study will help develop the best ways to apply the solutions by developing a tube that will both bring the cut nerve ends together and allow for the fusion solutions to be applied. This strategy has been shown to rapidly restore nerve function, even when the nerves are completely cut or when large segments have been cut away.

Overall Objective: This study is designed to develop a safe simple delivery device to allow polyethylene glycol-based nerve repair with nerve grafts to treat nerve injuries. Our hypothesis is that by simplifying the technique, nerve repairs will be more successful and this technique could lead to increased function for patients with severe nerve injuries.

Specific Objectives:

(1) Development of a prototype nerve cuff delivery system.

(2) Determine the effectiveness of the prototype delivery system in our rat sciatic nerve injury model.

(3) Prepare production methods for producing clinical grade investigational product.

Risks: Our technology applies polyethylene glycol and methylene blue in solution form to the site of nerve repair. These medications are already being used in humans and have demonstrated safety and the nerve cuff the delivery system is based on is also currently applied in people. In animal studies, these solutions applied in the intended manner caused no harm. For these reasons we feel the eventual risk to people that would undergo this therapy is minimal; however, the goal of this proposal is to demonstrate efficacy in animals prior to translation to people.

Benefits: Traditional nerve repair techniques rely on axons (i.e., neurons) growing from the site of injury to the organs to be innervated, and this distance can be up to a meter in humans. This is a very slow process and may take, literally, years to occur while muscle atrophies resulting in permanent loss of function. Polyethylene glycol-based cell fusion repair of axons relies on a fundamentally different mechanism. With this technique the severed proximal and distal stumps of axons are literally rejoined to recreate, almost immediately, a functional nerve. This is analogous to soldering a cut wire back together rather than relaying an entirely new cable. No other method is known to cause an immediate fusion of cut nerves and a resulting near-immediate recovery in patients. We have shown the surgical repair of nerves, when supplemented with this solution, shows immediate restoration of nerve conduction and, in the weeks that follow, leads to observable improvement of functional outcomes in treated animals. If this technique can be successfully applied clinically, this new protocol will fundamentally change the way nerve injury is treated. We expect this novel technique will dramatically improve the rate and extent of recovery after nerve injury. This technique will fundamentally change the way nerves are repaired; this work will allow the technique to be broadly and consistently implemented to provide the best clinical results possible to our injured civilians and wounded warriors. We anticipate that in the future this technique will be broadly useful wherever patients have a nerve injury in need of surgical repair. The technique utilizes substances that are already used in people, so if the technique demonstrates benefit, it is readily translatable to people.