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Micro-Tissue Engineered Nerve Grafts for Maintenance of Distal Nerve and Muscle Following Major PNI
Kritika Katiyar, PhD1; Robert B. Shultz, PhD1; Franco A. Laimo, BS2; Zarina S. Ali, MD, MS2; D. Kacy Cullen, PhD2
1Axonova Medical, Philadelphia, PA; 2University of Pennsylvania, Philadelphia, PA

Introduction Major peripheral nerve injury (PNI) is an injury with a long defect (?3cm) or occurring proximally, requiring long regenerative distances of the host nerve to distal structures (distal nerve, target muscle, etc.). These features result in minimal, if any, functional regeneration as the distal nerve and muscle often degenerate before the host nerve is able to reinnervate these structures due to inherently slow regeneration rates. Since current standard clinical practices delay repairing nerve injuries until the patient (in cases of polytrauma) or the injury site is stabilized, functional recovery is often extremely limited. To maintain the innervation capability of nerves and muscles following injury, we have developed a proxy for these degenerating axons to maintain or “babysit” the distal structures until the host axons are able to reinnervate the distal targets. This product, the micro-tissue engineered nerve graft (?TENG), consists of neurons, with their axon tracts, within a hydrogel column. Notably, the diameter of ?TENGs is designed to be on the scale of micrometers, making them easily implantable to facilitate incorporation into current standard of care practices in the clinic. In pre-clinical rodent studies, implantation of exogenous axons has led to maintenance of a pro-regenerative environment, therefore keeping distal structures more receptive to eventual host axon reinnervation.
Materials & Methods Hydrogel micro-columns were fabricated with an inner diameter of 300?m and wall thickness of 50?m. The lumen was filled with a collagen-laminin extracellular matrix (ECM) to support cell adhesion and growth. Once the ECM polymerizes, sensory dorsal root ganglia and motor neuron aggregates were plated within the column and allowed to extend neurites over days in vitro. These ?TENGs were then plated on a bed of myocytes to determine the effectiveness of forming functional neuromuscular junctions (NMJs) in vitro, as well as implanted into a rat model of PNI.
Results Immunocytochemical labeling of cultures revealed that ?TENG axons and myocytes interact in vitro, forming NMJs (bungarotoxin-positive and phalloidin-positive labeling). In vivo, at 6 weeks post transplantation into a chronic axotomy PNI model, ?TENG axons were seen to interact with otherwise axotomized Schwann cells and muscle. Ongoing studies are exploring the potential of ?TENGs to babysit the distal regenerative pathway and target muscle in a porcine model of long-gap PNI.
Conclusions By maintaining the pro-regenerative environment in distal nerve and muscle, ?TENGs hold promise in transforming the field of nerve repair by significantly increasing the clinical window for PNI repair.


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