Tissue Engineered Nerve Grafts Facilitate Muscle Reinnervation Following Long Gap Facial Nerve Injury in Swine
Zarina S Ali, MD, MS1, Justin C Burrell, MS1,2, Dmitriy Petrov, MD1,2, Kevin Browne, BA1,2, Franco A. Laimo, BS1,2, Kritika Katiyar, PhD1,2,3, Suradip Das, PhD1,2 and Daniel Kacy Cullen, PhD1,2, (1)University of Pennsylvania, Philadelphia, PA, (2)CMC VA Medical Center, Philadelphia, PA, (3)Axonova Medical, Philadelphia, PA
Tissue-Engineered Nerve Grafts Facilitate Muscle Reinnervation Following Long-Gap Facial Nerve Injury in Swine
Introduction: Nerve injury resulting in disconnection requires surgery to reconnect proximal and distal nerve stumps by direct anastomosis, nerve guidance tube (NGT), or biological/synthetic grafts. Functional outcomes following nerve repair are generally unsatisfactory due to limited recovery. We have demonstrated tissue-engineered nerve grafts (TENGs), consisting of stretch-grown axons from dorsal root ganglia (DRG), can facilitate regeneration in rat and porcine models of nerve injury based on the newfound mechanism of axon-facilitated axon regeneration. However, axonal modality (e.g., sensory, motor, mixed sensory-motor) might be important for axon pathfinding; for instance, motor axons preferentially grow along existing motor axons and sensory axons extend along both motor and sensory axons during neurodevelopment. Previously, we generated modality-specific TENGs consisting of stretch-grown populations of DRGs (sensory TENGs), motor neurons (MNs; motor TENGs), or mixed sensory-motor TENGs (mixed TENGs) using rat neurons. Here, we evaluated the effect of modality-specific TENGs generated from porcine neurons in a facial nerve (FN), a predominantly motor nerve, injury model in pigs.
Materials and Methods: Sensory, motor, and mixed TENGs were fabricated using DRGs and spinal MNs isolated from E-40 fetal pigs. MNs were force-aggregated by centrifugation and, along with DRGs, plated in mechanobioreactors for 7 days to allow for axonal network formation. Axons were stretched to 1 or 4cm, embedded in collagen and rolled into a NGT for transplantation in Yucatan minipigs. Regeneration was evaluated at 2 weeks following a 1cm FN repair using modality-specific TENGs, autografts, or NGT. Electrophysiological recovery and nerve morphometry was assessed at 16 weeks following a 4cm FN repair.
Results: Porcine-derived, modality-specific TENGs were generated for 1 or 4cm FN repairs to evaluate preferential motor axon growth along a specific type of TENG axon. Axonal outgrowth was visualized at 2 weeks post-repair of 1cm lesions, with regenerating host axons preferentially growing along TENG axons. At 16 weeks, compound muscle and nerve action potentials were recorded following stimulation of the 4cm repaired nerves, indicating functional reinnervation and connectivity. Additionally, muscle reinnervation occurred following TENG or autograft repair, but not following NGT repair alone. Moreover, axonal regeneration was found in the distal nerve following TENG or autograft repair, indicating host axons crossed the long-gap nerve injury.
Conclusion: These tissue-engineered living scaffolds have the potential to act as a repair strategy for challenging nerve defects by catering to the modality of the damaged nerve.
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