Local FK506 Drug Delivery Enhances Nerve Regeneration through Fresh, Unprocessed Nerve Allografts in Rats
Kevin Zuo, MD, MASc1, Golsa Shafa, BSc2, Katelyn Chan, B.Eng BioSci3, Jennifer Zhang, B.Sc, MD, PhD4, Kasra Tajdaran, MASc, PhD3, Tessa Gordon, PhD5 and Gregory H. Borschel, MD3, (1)University of Toronto, Toronto, ON, Canada, (2)Hospital for Sick Children, Toronto, ON, Canada, (3)Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, (4)The Hospital for Sick Children, Toronto, ON, Canada, (5)Neurosurgery/Spine Center, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada
Peripheral nerve allografts are a strategy of nerve gap reconstruction with advantages including native nerve microstructure, donor Schwann cells that maintain a pro-regenerative milieu, expendable supply, and avoidance of donor site morbidity. Despite good outcomes, clinical use of unprocessed, fresh nerve allografts (FNAs) is limited due to requirement for transient systemic immunosuppression. To circumvent the systemic effects of FK506, an FDA-approved immunosuppressant, our laboratory developed a local FK506 drug delivery system that provides sustained, targeted drug release over 28 days. The objective of this study was to investigate if local FK506 delivery enhances nerve regeneration in a rodent model of nerve gap defect reconstruction with unprocessed FNAs.
MATERIALS & METHODS
In male Lewis rats, a 10 mm hindlimb common peroneal (CP) nerve gap was reconstructed with 20 mm long nerve isografts from donor Lewis rats or FNAs from donor ACI rats. The latter rats received either systemic FK506 (2 mg/kg/d intraperitoneal injections), local FK506 (420 µg FK506 encapsulated in poly(lactic-co-glycolic acid) microspheres suspended in fibrin hydrogel), or no treatment. After 4 weeks, nerve regeneration was evaluated using retrograde labeling to enumerate motor and sensory neurons that regenerated axons through the graft, quantitative histomorphometry of the midgraft and distal CP nerve, and serum cytokine profile.
Rats with untreated FNAs demonstrated very poor nerve regeneration compared to isografts or FNAs treated with systemic FK506 (p<0.001). Rats with FNAs treated with local FK506 demonstrated robust motor and sensory neuron regeneration significantly better than rats with untreated FNAs (p<0.001) and comparable to rats with nerve isografts and rats with FNAs treated with systemic FK506. These findings were consistent on histomorphometric analysis in the midgraft and in the distal nerve with local FK506-treated FNAs having comparable numbers of myelinated axons as isografts and FNAs treated with systemic FK506. Serum concentrations of the pro-inflammatory cytokine IL-12 were significantly lower 7 days after surgery in rats with FNAs treated with local FK506 (p<0.05) or systemic FK506 (p<0.001); however, rats with local FK506 had undetectable serum levels of FK506.
A local FK506 drug delivery system enhances motor and sensory nerve regeneration through fresh nerve allografts to a level comparable to that with systemic immunosuppression or with nerve isografts. Local FK506 delivery may have clinical application in transplantation of peripheral nerve or vascularized composite allografts. Future directions include evaluating functional outcomes and using an immunodeficient rat to distinguish the neurotrophic and immunosuppressive effects of local FK506.
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