Progressive Lengthening for Nerve Repair

PROJECT SUMMARY Peripheral nerve injuries are a common consequence of traumatic injury or collateral damage during surgery. Consequences of nerve injury are motor impairment, sensory loss, and pain, resulting in profound and chronic reductions in function, independence, and quality of life. Functional recovery is often incomplete, and clinical outcomes are especially poor for transections resulting in a large nerve gap. Though direct end-to-end repair of transected nerves results in superior functional outcomes compared to graft-based repair, the risk of ruptured repair due to tension at the site of reattachment has seen an increased reliance on grafts and guidance scaffolds during nerve reconstruction. Graft-based strategies have yielded some positive results for smaller gaps, but despite technological advances, outcomes remain poor for larger nerve gaps. Autografts remain the current gold- standard, but suffer several limitations, including inferior outcomes compared to end-to-end repair. We propose that gradual lengthening of the proximal nerve stump provides a solution that enables the benefits of an end-to-end repair while avoiding drawbacks of graft-based approaches. We have developed a novel strategy in which a device grips the proximal stump of a severed nerve and progressively lengthens it towards the distal stump, at rates exceeding traditional axonal outgrowth. After this stretch-mediated growth, the device is explanted and a standard end-to-end, graft-free repair is performed. Compelling preliminary data in rat and rabbit models demonstrate that combined nerve lengthening and end-to-end repair results in superior structural and functional neuromuscular outcomes compared to autografts. These outcomes support our specific hypothesis to be tested in this proposal, that rate-controlled nerve lengthening of a transected nerve and subsequent end-to-end repair most effectively recapitulates native structure-mechanics-function relationships by upregulating protein synthesis and reducing inflammation, as compared to current standards of care. In this proposed study, we propose to explore the extent to which stretch-growth restores nerve architecture and biomechanical capabilities, which ultimately dictate neuronal function, and how the rate of lengthening affects these properties. Further, we will investigate the underlying biological pathways responsible for stretch- activated growth. Addressing these questions has direct implications for determining the rates, limits, and quality of regeneration, towards enhanced functional recovery. Our Specific Aims are to: 1) Test the influence of nerve lengthening rate and end-to-end repair on neuromuscular architecture, nerve biomechanics and functional recovery in tension-based repairs. 2) Evaluate the influence of nerve lengthening rate and end-to-end repair on markers of protein synthesis and inflammation. 3) Establish that nerve lengthening before end-to-end repair enhances regenerative outcomes for large nerve gap injuries in two non-rodent animal models. By addressing these aims, we will be poised to systematically deploy tension-based strategies to a broader set of nerve reconstruction scenarios, towards enhanced and sustained neuromuscular recovery.