Local FK506 Delivery Enhances Nerve Regeneration and Functional Recovery Following Chronic Axotomy
Kasra Tajdaran, MASc, PhD1,2; Katelyn Chan, B.Eng BioSci1,2; Molly Shoichet, PhD2; Tessa Gordon, PhD, DSc3; Gregory H. Borschel, MD, FAAP, FACS1,2
1Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, 2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada, 3The Hospital for Sick Children, Toronto, ON, Canada
Purpose: Following delayed peripheral nerve repair and/or nerve regeneration over long distances, chronically axotomized neurons progressively lose their ability to regenerate their axons, resulting in poor recovery. Local application of FK506, an FDA approved immunosuppressant with strong neuroregenerative properties, has the potential to improve nerve regeneration while preventing the site effects that are associated with the systemic administration of the drug. In this study, we determined the effectiveness of localized FK506 administration in improving axon regeneration and functional recovery in a rat chronic axotomy model using a fibrin gel-based drug delivery system.
Methods: FK506 was incorporated into the fibrin gel in a) solubilized, b) particulate, and c) poly(lactic-co-glycolic) acid microsphere-encapsulated forms. A chronic axotomy model was used in which the rat tibial nerve (TIB) was transected and regeneration was prevented by ligation for two months. Thereafter, the chronically axotomized proximal TIB nerve stump was sutured to a freshly cut distal common peroneal (CP) nerve stump. The three experimental groups were implanted with the three forms of the drug delivery system at the repair site. In a positive control group, the proximal TIB nerve stump was coapted to the distal CP nerve stump immediately after transection. Rats in the negative control groups did not receive any delivery system treatment. Four weeks after repair, nerve regeneration was quantitated using retrograde labeling and collecting nerve samples 15 mm distal to the cross-suture site for histomorphometric analysis. Twelve weeks following treatment, tibialis anterior (TA) contractile muscle force and mass were measured.
Results: The local application of FK506 using the particulate FK506 or FK506 microspheres doubled the number of chronically axotomized motor and sensory neurons that regenerated their axons and the number of regenerated myelinated axons as compared to the negative control group without FK506. Importantly, the drug delivery system containing particulate FK506 or FK506 microspheres promoted the recovery of the reinnervated TA muscle force and mass to the levels attained after immediate nerve repair.
Conclusion: Local application of FK506 significantly improves motor and sensory neuron survival, axon regeneration, muscle force, and muscle mass recovery in a standard chronic axotomy model of nerve injury and surgical repair.
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