A biodegradable nerve wrap delivering FK506 enhances nerve regeneration in a rat model of acute cut and repair
Simeon C. Daeschler, MD, Dr. med.1, Katelyn Chan, MASc BioSci2, Jennifer Zhang, B.Sc, MD, PhD3, Konstantin Feinberg, PhD4, Tessa Gordon, PhD2 and Gregory H Borschel, MD5, (1)SickKids Research Institute, Toronto, ON, Canada, (2)Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, (3)The Hospital for Sick Children, Toronto, ON, Canada, (4)Hospital for Sick Children, Toronto, ON, Canada, (5)Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Introduction: Proximal peripheral nerve injuries often result in life-long disability with loss of sensation and paralysis. A key issue is the slow axonal regeneration rate and the consequently prolonged axonal deprivation of the distal nerve segment and the nerve's target muscle, creating an increasingly non-permissive environment for the regrowing axons. Adjunct therapies that accelerate axonal regeneration may decrease the denervation time and thereby improve functional recovery but are currently clinically unavailable. We previously demonstrated that the local delivery of the FDA-approved drug FK506 to the nerve repair site increases the rate of axonal regeneration. A convenient, surgeon-friendly delivery system is needed for clinical application. We aimed to develop a reliable and easy-to-use, off-the-shelf product for local drug delivery following nerve surgery.
Materials and Methods: We fabricated a biodegradable, membraniform drug delivery system (DDS) of electrospun, FK506-loaded, polycarbonate-urethane nanofibers to enable a drug release to the nerve repair site for up to 30 days. We tested its microsurgical suitability and therapeutic effectiveness in a rat model by wrapping it around the nerve repair site. Adult female Sprague-Dawley rats (n=20; 220-270 g) underwent unilateral common peroneal nerve transection and immediate epineural repair. Intraoperatively, the rats were randomly allocated to the experimental groups, receiving either a previously developed microsphere-based DDS loaded with 200 µg FK506, or the novel DDS loaded with 200 µg FK506, or a sham-DDS without FK506 or served as non-treated control. After 21 days, the number of motoneurons that regenerated their axons 7 mm distal to the nerve repair site was determined using retrograde labelling. The results for additional outcome metrics are pending at the time of submission due to COVID-19.
Results: The tensile strength and flexibility of the novel DDS enabled precise positioning while withstanding microsurgical manipulation. After 21 days of regeneration, the rats that received the FK506-loaded wrap regenerated significantly more motoneurons (mean±SD: 409±37) compared to the DDS wrap without FK506 (252±44) and control group (272±21; p<0.05), whereas the difference with the microsphere treated group (330±91) was not statistically significant (p=0.25).
Conclusions: This novel, biodegradable drug delivery wrap enables local and sustained neuroregenerative therapy following nerve surgery. The wrap promoted a higher number of regenerating motoneurons following nerve repair, presumably due to accelerated axonal regeneration. Given the surgeon-friendly design of this off-the-shelf product, it may enable local drug therapy in clinical nerve surgery and thereby help to improve functional recovery.
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