|Program and Abstracts
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Development of a Medical Device for Clinical Translation of a Novel PEG Fusion Method for Immediate Physiological Recovery after Peripheral Nerve Injury
David C. Riley, BS1, Curt A. Deister, PhD2, Richard B. Boyer, BS1, Charlie L. Rodriguez-Feo, BS1, Tu-Anh N. Ha, BS1, Bruce R. Shack, MD1, Wesley P. Thayer, MD/PhD1.
1Vanderbilt University Medical Center, Nashville, TN, USA, 2Axogen, Gainesville, FL, USA.
In the United States, 360,000 people suffer peripheral nerve injuries on an annual basis. Many of these traumatic injuries result in life-long disabilities. Functional recovery of the effected muscles depends on proximal axonal outgrowth, which occurs at a rate of approximately 1 mm/day. Presently, there is no clinical treatment to immediately restore behavioral function and prevent Wallerian degeneration of the distal stump. Polyethylene glycol (PEG) has been shown to improve functional outcomes immediately following nerve transection in animal models. This project aims to enable the broad clinical application of peripheral nerve repair using the aforementioned PEG-based method. We hypothesize that the results of PEG-based repair using a novel PEG application device will be superior to that of a non-PEG repair. The application device will provide a controlled and stable delivery of PEG into the center of the coaptation site. After completion of the testing using a small-animal model we plan to prepare this technology for transition into clinical trials.
Female Spraque-Dawley rats were anesthetized with 2% isoflurane. The left sciatic nerve was exposed following a sharp 2 cm dissection through the biceps femoris. Baseline compound action potentials were then recorded. The nerve was transected and repaired in an end-to-end fashion using standard microsurgical techniques. PEG was delivered to the neurorrhaphy using a novel application device. Post-repair compound action potentials were immediately recorded following repair. Experimental animals were treated with a combination of solutions including Plasmalyte A (calcium free saline), 1% methylene blue, PEG, and Lactated Ringers (calcium containing saline); control animals received all solutions except for PEG. Animals underwent behavioral assessments at 3 days and 1 week post-operatively using the foot fault asymmetry and sciatic functional index tests. At 1 week post-operatively, animals were perfused and fixed for histological analysis.
The PEG application device rapidly restores axonal continuity as measured by action potential conduction (p<0.05) and diffusion of intracellular retrograde tracer (p<0.05) across the injury. Axonal counts were obtained from cross sections proximal and distal to the coaptation site. PEG treated animals are associated with a statistically significant increase (p<0.01) in the number of motor and sensory axons distal to the injury site (Fig. 1). Additionally, behavioral function is significantly restored within 3 days as measured by the foot fault asymmetry (p<0.05) and sciatic functional index (p<0.05) tests in PEG animals.
The aforementioned data suggests that PEG significantly improves behavioral function and axonal survival distal to the injury site. Furthermore, the use of the application device for delivery of PEG at the coaptation site increases the consistency of success for PEG-based repair of severed peripheral nerves.
Fig. 1: Motor (A,B) and sensory (D,E) myelinated axons in paraffin-embedded cross section of sciatic nerve at 20x for negative control (A,D) and PEG-fused (B,E) distal to repair-site. Total motor and sensory axon counts were completed at 1 week post-operatively (C,F).
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