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A Novel Local FK506 Delivery System Results in Excellent Nerve Regeneration in Rats
Kasra Tajdaran, MASc; Molly Shoichet, PhD; Tessa Gordon, PhD; Gregory H Borschel, MD
The Hospital for Sick Children, Toronto, ON, Canada
Purpose: Many challenges exist in improving outcomes following peripheral nerve injuries, specifically in cases with delayed nerve repair and with large nerve defects. This study focused on investigating a new method to improve axon regeneration after surgical repair of a severely injured nerve. FK506, an FDA approved immunosuppressant, promotes functional recovery and reinnervation following peripheral nerve injury. However, FK506 has not been widely adopted for treating nerve injuries because the systemically delivered drug causes undesirable immunosuppression. We investigated a novel local delivery system for FK506 which utilizes fibrin gel as a biodegradable drug reservoir that could be placed at a site of nerve injury and surgical repair.
Methods: FK506 was incorporated into fibrin gel in solubilized, particulated and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. In order to analyze the effectiveness of the delivery systems in enhancing nerve regeneration, a rat nerve transection model was used, where the proximal tibial nerve stump was cross-sutured to the distal stump of a cut common peroneal nerve. Rats in the negative control groups either did not receive any delivery system treatment or received fibrin gel with empty microspheres (without any FK506). The experimental groups included rats treated with fibrin gel loaded with solubilized, particulated, or PLGA microspheres encapsulated FK506. Three weeks after repair, nerve regeneration was assessed using retrograde labeling and collecting nerve samples 7 mm distal to the repair site for histomorphometric analysis.
Results: Rats in experimental groups receiving FK506-loaded microspheres and the particulate form of FK506 doubled the number of motoneurons regenerating their axons after injury and allowing all the tibial motoneurons to regenerate their axons successfully. The numbers of the motor and sensory neurons that regenerated their axons in the FK506 microspheres treated group and the particulated FK506 treated group were significantly higher than the numbers in all the groups, including the solubilized FK506 treated group and negative control groups. Histomorphometric analysis indicated increased number of myelinated axons following particulated FK506 and FK506 microspheres treatment compared to the negative control groups.
Conclusion: The local application of FK506 via our proposed delivery systems resulted in excellent axon regeneration while eliminating the toxicity of systemic FK506 that has prevented clinicians from using FK506 routinely for treating severe cases of peripheral nerve injuries.
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