Wesley Poon

Introduction. Peripheral nerve injury is a common cause of disability warranting a half million surgical procedures in the United States annually.¹ In a transection of peripheral nerve, suturing (neurorrhaphy) is limited to gaps under 0.5 cm due to tension. For larger gaps, autologous grafting (autografting) typically utilizing a sensory nerve is the gold standard though it incurs damage to the donor site.² An alternative is nerve conduits which are currently clinically only for nerve gaps under 3 cm.³ After injury, Schwann cells produce glial cell derived neurotrophic factor (GDNF) that supports neuronal regeneration.^{3, 4} GDNF interacts with GDNF family receptor α2 (GFR α2) to cause axon outgrowth via inhibition of the RhoA/ROCK pathway.⁴ GDNF supplementation is best provided for 2-3 weeks following injury, which may be related to the increased expression of both GDNF and GFR α2 at 2 weeks after injury.^5-7 However, GDNF given after 3 months of chronic denervation still enhances regeneration.⁸ One possible way then to improve conduits is by eluting growth factors like GDNF from the conduit to support regenerating axons. Methods. Polycaprolactone (PCL) conduits were made with GDNF-eluting microspheres that release maximally at 20 days. Rhesus macaques learned a grasping functional test then had a 5 cm gap made in the median nerve. Repair by the GDNF-releasing conduit (PCL+GDNF) was compared to a conduit without GDNF (empty) or with the inverted nerve section (autograft). Functional testing was assessed for 50 weeks. Electrophysiology was carried out after one year and regenerated nerve was histologically analyzed.³ Results. PCL+GDNF and autograft were not significantly different in functional recovery. Though nerve conduction velocity of PCL+GDNF nerve (31.41 ± 15.34 m/s) was substantially lower than uninjured (70.75 ± 27.19 m/s), performance was significantly better than autograft (25.45 ± 3.96 m/s, P<0.01). Compound muscle action potential of the autograft was six times that of PCL+GDNF. PCL+GDNF nerve exhibited double the Schwann cell area vs. autograft and only 5% less axonal area vs. autograft (P<0.001). Finally, average g-ratio perimeter of PCL+GDNF was lower than autograft with no significant difference vs. native nerve.³ Conclusions. While electrophysiological performance of the GDNF-releasing conduit was somewhat poor, the increased recruitment of Schwann cells, comparable degree of myelination to native nerve, and similar functional recovery and axon diameter compared to autograft suggests that GDNF-releasing conduits could be a promising alternative to autografts for repair of long nerve gaps.

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