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Peripheral nerve matrix hydrogel promotes functional recovery by modulation of macrophage phenotype
Jonathan Cheetham, VetMB, PhD, DACVS1, Megan Bernard, MS, DVM2, Travis Prest, PhD3, Michael Sledziona, BS1, Lorenzo Soletti, Ph.D., MBA, MS4 and Bryan Brown, Ph.D.5, (1)Cornell University, Ithaca, NY, (2)Cornell University College of Veterinary Medicine, Ithaca, NY, (3)University of Pittsburgh, Pittsburgh, PA, (4)Renerva LLC, Pittsburgh, PA, (5)McGowan Institute for Regenerative Medicine, Pittsburgh, PA

Macrophages and Schwann cells play a key role in the orchestration of early events after peripheral nerve injury. One opportunity for functional improvement after nerve reconstruction is manipulation of the microenvironment at the site of nerve repair to promote modulation of the host inflammatory response and promote Schwann cell (SC) migration and axon extension across the repair site. We have recently shown that this is an effective approach. Here we determined the effects of a decellularized peripheral nerve matrix (PNM) hydrogel on macrophage gene expression, phenotype and migration using a combination of FACS, Nanostring technology and immunohistochemistry. We also evaluate effects on SC migration, numbers of motor neurons reaching their target, axon extension, neuromuscular junction formation, compound motor action potential and peak tetanic forceusing a combination of mouse and rat models.

Finally, functional recovery was determined after both sciatic crush injury and common peroneal nerve transection associated with a short gap. Control groups including uninjured animals, exposure of the nerve without injury, transection and ligation without repair and delivery of hydrogel to uninjured nerves were also performed (n=8/group). Animals were followed for 12 weeks and assessed longitudinally using multiple measures of sensory and functional recovery. Metrics included von Frey nociception assay, sciatic functional index, and kinematic analysis. At 12 weeks animals were subjected to electrophysiologic assessment of evoked compound motor action potential prior to euthanasia for tissue collection and subsequent histologic analysis.

Macrophage, particularly M2 (regenerative phenotype), recruitment to the injury site was increased in both mice and rats (2 fold increase, p<0.05). PMN promoted SC migration both in vitro and in vivo (p<0.05). Axon extension determined by extension of GFP+ axons across an 8mm gap was increased in the presence of PNM compared with an empty conduit (>5 fold increase, p<0.05). PNM increased the number of retrograde labelled MN at 12 weeks after injury compared to empty conduit (20%, p<0.05).

The amplitude of Compound Motor Action Potentials across the sciatic transection injury site, demonstrating axonal regrowth to the terminal muscle was increased by 50% compared to control following subepineural delivery of PNM 8 weeks after nerve transection. Peak Tetanic force was also increased by 30% at 4 and 8 week time points.

These results demonstrate that an injectable, peripheral nerve matrix hydrogel derived from porcine sciatic nerve can modulate the response of two key cell types which conduct the early response to nerve injury.


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