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Tissue Engineering Strategies to Bridge Segmental Defects and Maintain Distal Target Efficacy Following Major Peripheral Nerve Injury
Zarina S Ali, MD; Justin C Burrell, MS; Suradip Das, PhD; Kritika S. Katiyar, BS; Kevin D Browne, BS; D. Kacy Cullen, PhD; University of Pennsylvania, Department of Neurosurgery, Philadelphia, PA

Peripheral nerve injury (PNI) is a common affliction that affects individuals of all age groups and socioeconomic backgrounds. Even following state-of-the-art surgical reconstruction, patients face a high probability of residual functional deficits especially when axons are tasked with regenerating over long distances that require many months to reach distal targets. To address this need, our research team is pioneering the first dual peripheral nerve repair strategy that provides tissue engineered living "bridges" across missing nerve segments while maintaining the full regenerative pathway and capacity for target muscle reinnervation a phenomenon we refer to as "babysitting". For bridging, we have developed tissue engineered nerve grafts (TENGs), which are lab-grown constructs consisting of aligned axonal tracts that we routinely generate in custom-built mechanobioreactors at densities of >100,000 axons and lengths of ?5cm within 2 weeks through the controlled process of axon "stretch-growth". TENG axons mimic the developmental action of pioneer axons, where targeted axonal outgrowth can be achieved along pre-existing axonal tracts in vivo. Indeed, we have shown that TENGs effectively serve as a bridge across segmental nerve defects by accelerating and directing axonal regeneration in rat and pig models of PNI. In the pig, TENG-based repair of a major gap (5cm) in a critical motor nerve resulted in significant reinnervation of distant end targets (>18cm from lesion). For babysitting, we have implanted separate miniature TENGs comprised of motor and sensory neurons within the otherwise denervated distal nerve sheath, which extend axons to integrate with host Schwann cells and target muscle to thereby maintain pro-regenerative capacity and increase the window for long distance axonal regeneration and reinnervation. Using our established porcine model of major PNI, we are assessing the simultaneous ability of bridging TENGs to accelerate axonal regeneration across the zone of injury while employing separate babysitting TENGs to sustain the regenerative environment of distal Schwann cells and receptiveness of target muscles to enable host axons to reinnervate ultra long-distance targets. This dual regenerative medicine strategy may accelerate axonal regeneration while maintaining the structure and function of denervated muscle and sensory end targets to allow functional reinnervation following currently intractable PNI. This work is supported by the U.S. Dept. of Defense (W81XWH-15-1-0466 & W81XWH-16-1-0796).

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