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Tissue Engineered Nerve Grafts Derived from an FDA-Approved Cell Source Facilitate Muscle Reinnervation following Long-Gap Facial Nerve Injury in a Porcine Model
Zarina S. Ali, MD, MS; Franco A. Laimo, BS; Robert B. Shultz, PhD; Kevin D. Browne, BA; Justin C. Burrell, PhD; Kritika S. Katiyar, PhD; D. Kacy Cullen, PhD
University of Pennsylvania, Philadelphia, PA

Introduction Peripheral nerve injury (PNI) is a common consequence of trauma or surgery. The extent of functional recovery is often unsatisfactory, especially following repair of long segmental defects or proximal nerve injuries that necessitate extremely long regenerative distances to distal targets. Consequently, patients who suffer major PNIs often face functional deficits that impact their quality of life, even following state-of-the-art surgical reconstruction. To address this issue, we have developed an approach using tissue engineered nerve grafts (TENGs). TENGs are three-dimensional nerve constructs that consist of stretch-grown axon tracts spanning discrete neuronal populations. Here, we transplanted 4 cm long TENGs, fabricated from wild-type or an FDA-approved hypoimmunogenic porcine cell source, into a swine facial nerve model of PNI to assess host axon regeneration and functional recovery out to 4 months post-repair.
Materials and Methods TENGs were fabricated from sensory and motor neurons harvested from day 40 swine embryos and cultured in custom mechanobioreactors to “stretch-grow” to 4 cm within 30-35 days. Aligned axon tracts were encapsulated in a collagenous matrix, transferred into a nerve guidance conduit, and then transplanted to bridge a ~4 cm segmental defect in the facial nerve. To assess nerve regeneration, transcutaneous electrophysiological methods were employed to record compound muscle action potentials (CMAPs) from target facial muscles at 12 and 16 weeks post-repair. In addition, at 16 weeks intraoperative CMAPs and compound nerve action potentials (CNAPs) were recorded, after which nerve and muscle tissue was harvested for histological assessment.

Results Axon regeneration, myelination, and neuromuscular junction formation were quantified.At 12 and 16 weeks, CMAPs were recorded from target muscle in animals receiving TENGs or autografts (saphenous nerve), but not in animals receiving acellular nerve guidance conduits (negative control). CMAP amplitudes increased at 16 versus 12 weeks, suggesting ongoing reinnervation and muscle expansion. In addition, intraoperative CNAPs were recorded in animals receiving TENGs or autografts, further demonstrating axon re-growth across the long-gap graft zone.
Conclusion These functional measures suggest reinnervation, and were structurally corroborated with histological evidence of robust axon regeneration, myelination, and reinnervation following both autograft and TENG repairs compared to negative control. This study builds on our previous findings by demonstrating TENGs derived from an FDA-approved xenogeneic cell source may be suitable for clinical repair of long-gap nerve defects.


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