American Society for Peripheral Nerve

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Tissue Engineered Grafts Accelerate Peripheral Nerve Repair by Direct Axon-Induced Axon Regeneration
D. Kacy Cullen, PhD1, Laura A. Struzyna1, Mindy I. Ezra, PhD1, Joseph P. Morand1, Harry C. Ledebur, PhD2 and Douglas H. Smith, MD1
1Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 2Axonia Medical, Inc, Kalamazoo, MI

Peripheral nerve injury (PNI) repair has not progressed past nerve guidance tubes (NGTs) to bridge small gaps or autografts for larger defects. To address these challenges, we are developing living tissue engineered nerve grafts (TENGs) to enable repair following major PNI. TENGs are lab-grown nervous tissue comprised of long axon tracts spanning two populations of neurons. TENGs are generated based on axon "stretch growth", a natural axon growth mechanism that we replicate in custom mechano-bioreactors to generate axons of unprecedented lengths in a short time frame (5-10 cm in 14-21 days). For transplant, living axons are embedded in an extracellular matrix and placed in a NGT. We previously demonstrated in the rat sciatic nerve model that allogeneic TENGs survived chronically (absent immunosuppression) and facilitated robust host axon regeneration and functional recovery. To advance these promising findings, we found that TENGs accelerated acute axonal regeneration compared to NGTs alone (>3-fold increase, p<0.001) at levels statistically equivalent to autografts (p=0.59) for repair of 1.0 cm sciatic nerve lesions in rats. Importantly, host axons closely intertwined with TENG axons, indicating that TENGs serve as a living scaffold to accelerate and direct host axon regeneration. Schwann cells also directly migrated and organized along TENG axons, resulting in accelerated Schwann cell infiltration across the graft compared to NGTs alone (p<0.001). In addition, at both acute and chronic time points, we found robust graft axon penetration into the distal nerve sheath. This corresponded with distal host Schwann cells maintaining a pro-regenerative alignment and phenotype over extended time periods compared to NGT-only controls. Moreover, following repair of 2.0 cm lesions, TENGs led to rapid and robust functional restoration based on recovery of compound nerve action potential, compound muscle action potential, and muscle force generation. Collectively, these data suggest that our unique tissue engineering strategy may address critical challenges in PNI repair by accelerating axon regeneration across the graft via axon-induced axon growth as well as prolonging the pro-regenerative environment of the distal nerve structure, necessary to enable host axons to reach long-distance targets and accelerate functional recovery. Taken together, these attributes differentiate TENGs from existing PNI repair strategies - including the autograft - potentially enabling target reinnervation and functional recovery following currently untreatable PNI. In ongoing efforts, we are using a porcine model to evaluate the efficacy of these living TENGs to facilitate regeneration following clinically relevant, major PNI.


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