Peripheral nerve damage is a consequence of blast injury to the extremities of soldiers and a secondary outcome following cervical spinal cord injury. Functional recovery from peripheral nerve damage is often poor, resulting in impaired motor function, sensory loss, and pain. Clinical complexity and prognosis for recovery is further compounded for Veterans, whose injuries are surgically repaired or revised following separation from the armed forces. This timeline results in a chronic nerve injury, which results in a fundamentally different clinical scenario from acute injury, and one for which therapeutic and rehabilitative strategies are lacking. The significance of strategies for enhancing function of chronically denervated nerves for a Veteran's population is highlighted by the prioritization of nerve regeneration and spinal cord rehabilitation by the VA RR&D Spinal Cord Injury and Regenerative Medicine Program. We have developed an innovative strategy for nerve regeneration that takes advantage of the inherent capacity of intact proximal nerve stumps to grow in response to tensile deformation (stretch). Our novel, modular internal-fixator device lengthens the proximal stump towards the distal stump in a controlled manner, and will facilitate reconnectivity of nerve stumps more rapidly than other strategies, including gold- standard autologous grafts. Importantly, this acceleration of nerve regeneration will also enable more distal connectivity, which is particularly crucial to bypass large swaths of the distal stump of chronically injured nerves, which severely inhibits regeneration. We hypothesize that more rapid and more distal reconnectivity will, in turn, enhance motor and sensory functional recovery. Towards these goals, we will use an integrative, cross-disciplinary approach to address two specific aims.
In Aim 1, we will examine the impact of moderate levels of tensile loading on nerve regeneration and functional recovery in moderate 10mm rat sciatic defects, following acute injury and chronic denervation. In this animal model, which allows us to efficiently and practically test our proposed concept, we hypothesize that in both acute and chronic injury groups, moderate levels of continuous nerve strain imposed on the proximal nerve stump will accelerate nerve regeneration as well as sensory and motor functional recovery compared to autologous grafts. Efficacy will be evaluated statistically by comparing a comprehensive battery of biological, structural, and functional outcomes.
In Aim 2, we will examine the impact of moderate levels of tensile loading on nerve regeneration and functional recovery in massive 20mm rabbit sciatic nerve defects, following chronic denervation. The longer length scale in a rabbit model creates a more clinically relevant regenerative challenge, and also enables direct measurement of nerve conduction velocity across the injury site. Based on comparison of biological, structural, and functional outcomes, we predict that lengthened nerves will display dramatically enhanced regeneration and functional recovery across a 20mm gap following chronic denervation, compared to gaps repaired with autologous grafts. Successful completion of our proposed aims will demonstrate the feasibility and efficacy of nerve lengthening as a novel strategy for regeneration of previously irreparable injured peripheral nerves. We anticipate that these efforts will contribute to improved motor and sensory recovery for injured Veterans.

Public Health Relevance

Peripheral nerve damage can result from traumatic injury to the limbs of soldiers or as a secondary effect of spinal cord injury. For Veterans, nerve repair is often initiated or surgically revised after separation from the armed forces. This timeline creates a variety of complexities associated with chronic nerve injury. This clinical scenario is understudied, lacks effective therapeutic strategies, and results in impaired motor function, sensory loss, and chronic pain. Our novel nerve regeneration strategy incorporates a new modular nerve-lengthening device, which exploits the natural capacity for nerves to grow in response to stretch. This strategy will enable more rapid and more distal connectivity of regenerating proximal stumps to degenerating distal nerve stumps, which will reduce the extent and duration of neuronal outgrowth through a highly non-permissive regenerative environment. Comprehensive biological, structural, and functional testing will evaluate the efficacy of our strategy in rat and rabbit nerve injury models as important steps towards clinical translation.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Translational Rehab (Basic) (RRD0)
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VA San Diego Healthcare System
San Diego
United States
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Love, James M; Bober, Brian G; Orozco, Elisabeth et al. (2017) mTOR regulates peripheral nerve response to tensile strain. J Neurophysiol 117:2075-2084