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Functional Recovery Following Delayed Nerve Repair is Affected by the Duration of GDNF Release
Matthew D. Wood; Tessa Gordon; Stephen W. P. Kemp; Edward H. Liu; Howard Kim; Molly Shoichet; Gregory H. Borschel
The Hospital for Sick Children, Toronto, ON, Canada
Introduction: Recovery following nerve cut and repair declines precipitously with prolonged denervation and axotomy. Glial cell-line derived neurotrophic factor (GDNF) has previously been shown to promote motor axon regeneration following delayed treatment. However, bioengineering strategies are needed to deliver GDNF to the site of nerve repair. In this work, we determined the optimal duration of GDNF delivery to nerve following a 2 month period of delayed repair that improved both the success of nerve regeneration and functional recovery.
Materials and Methods: We constructed polylactide-glycolic acid (PLGA) microspheres capable of extended GDNF release for 2 or 4 weeks. In vitro protein release assays (ELISA) were used to verify the time course of GDNF release. Rat common fibular (peroneal) nerve was chronically axotomized and denervated for 2 months. Experimental groups underwent delayed repair and treatment with GDNF microspheres in fibrin glue at the repair site or control treatments (empty microspheres, free GDNF without microspheres). Retrograde labeling of regenerating axons distal to the repair site was performed 8 weeks following treatment to quantify regenerating axons from motor and sensory neurons. Contractile muscle force was measured 12 weeks following treatment and nerves were analyzed for histomorphometry. All groups were compared for statistical significance using ANOVA with Bonferroni correction (p<0.05).
Results: Delivery of GDNF from microspheres for both 2 and 4 weeks to regenerating axons resulted in an increase in retrograde labeled motor and sensory neurons regenerating their axons compared to treatments without GDNF. Contractile muscle force production increased in both twitch and tetanic muscle force due to delivery of GDNF from microspheres compared to no GDNF or short-term release of GDNF to nerve following delayed nerve repair. Histomorphometric metrics of nerve cross-section distal to the repair site demonstrated differences in axon counts and fiber diameters due to GDNF microsphere delivery. Metrics of nerve regeneration and functional recovery slightly favored delivery of GDNF from microspheres for only 2 weeks compared to 4 weeks.
Conclusions: Delivery of free GDNF (no microspheres) from fibrin glue had minimal effects on nerve regeneration, whereas extended delivery of GDNF from microspheres for at least 2 weeks significantly improved nerve regeneration following delayed nerve repair. GDNF delivery from microspheres partially reversed the deleterious effects of chronic nerve injury.
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