American Society for Peripheral Nerve

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The Duration of GDNF Release Affects Nerve Regeneration Following Delayed Nerve Repair
Matthew D. Wood, PhD; Howard Kim, PhD; Stephen W. P. Kemp, PhD; Mark Szynkaruk; Christine Weber; Molly Shoichet, PhD; Tessa Gordon, PhD; Gregory H. Borschel, MD
Matt, Toronto, Canada

Purpose: Recovery following nerve cut and repair declines precipitously with prolonged denervation and axotomy. Glial-derived neurotrophic factor (GDNF) has previously been shown to promote motor axon regeneration following delayed treatment. However, excess duration or quantity of GDNF, or the location of the exogenous GDNF may actually impair motor axon regeneration if the axons remain within the region rich in GDNF. Previously, we developed a bioengineering strategy to deliver GDNF to chronically denervated and axotomized nerve. Our previous study tested the effect of 1 week delivery of GDNF on motor regeneration to verify that our delivery system was capable of delivering active growth factor to the regenerating axons. In this work, we determined the optimal duration of GDNF delivery to nerve following a 2 month period of delayed repair.

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 peroneal nerve was either (a) chronically axotomized or (b) both chronically axotomized and denervated for 2 months. Both groups underwent delayed repair and treatment with GDNF microspheres in fibrin glue at the repair site. Retrograde labeling of regenerating axons distal to the repair site was performed 4 weeks following treatment to quantify regenerating axons from motor versus sensory neurons.

Results: Delivery of GDNF from microspheres for 4 weeks resulted in a decrease in retrograde labeled motor neurons 20 mm distal to the repair site compared to treatments without GDNF delivered for this duration, either with (a) chronic axotomy or (b) chronic axotomy with chronic denervation. Delivery of a single dose of GDNF (no microspheres) from fibrin glue did not affect nerve regeneration. Histomorphometric measures distal to the repair site demonstrated differences in axon counts due to the effects of GDNF.

Conclusions: GDNF should only be delivered for a short period to enhance motor nerve regeneration. Excessive delivery decreases motor nerve regeneration.


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