A Nerve Wrap for Localized FK506 Delivery to Enhance Peripheral Nerve Regeneration
Katelyn Chan, B.Eng BioSci1,2, Marina Manoraj, .1, Jenny Cheung, .1, Jennifer J Zhang, MD, PhD1, Konstantin Feinberg, PhD3, Tessa Gordon, PhD1 and Gregory H. Borschel, MD, FAAP, FACS1,2,4, (1)Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, (2)Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada, (3)Hospital for Sick Children, Toronto, ON, Canada, (4)Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Canada
Introduction: FK506, an FDA-approved drug, encapsulated in biodegradable microspheres and hydrogel, enhances peripheral nerve regeneration in rats. Though effective, this process is not yet user-friendly enough for human surgical use. We hypothesize that incorporating FK506 within a nerve wrap will be simpler and more clinically-feasible to deliver FK506 locally and improve regeneration following microsurgical repair. We aim 1) to develop an implantable FK506 delivery nerve wrap with properties for clinical application, 2) to sustain bioactive FK506 release, and 3) that the wrap be biocompatible and biodegradable.
Material & Methods: 1) Coaxial electrospinning, a one-step process to create core-shell fibrous mats, was used to fabricate the wrap with the biodegradable synthetic polymer polycarbonate urethane (PCNU) which encapsulated FK506 in the inner shell to protect it from burst release within an outer polymer shell. Scanning electron microscopy determined fiber diameter and porosity. Tensile tests measured the dry elastic modulus. Thermogravimetric analysis and differential scanning calorimetry analyzed thermal properties. 2) In vitro incubation and mass spectrometry determined the encapsulation efficiency of FK506 and the release profile. 3) Nerve wraps were implanted around rat sciatic nerves for 7 and 60 days. Hematoxylin & eosin staining was used to determine the in vivo inflammatory response and to quantify biodegradation and nerve compression.
Results: 1) The fiber diameter and porosity were 320 ± 70 nm and 40 ± 10% (means ± standard deviation) respectively, and the dry elastic modulus was 2.38 ± 1.05 MPa. Physical properties of the nerve wrap indicated a longer degradation rate to prolong FK506 delivery and high tensile strength to withstand surgical forces. Onset of degradation for PCNU-FK506 nerve wraps occurred at 260°C with a melt temperature of 43.16°C, indicating thermal stability at physiological temperature (37°C). FK506 encapsulation efficiency was 92 ± 14%, indicating complete availability of FK506 to encourage nerve regeneration following implantation of the wrap. 2) Burst release was observed within 24 hours, but ~4.8ng FK506 remained after 28 days of incubation, still sufficient to enact a neurotrophic effect. 3) Major inflammation was not observed after 7 and 60 days of implantation and the PCNU-FK506 nerve wraps degraded by 58% over 60 days without causing morphological nerve compression.
Conclusions: The electrospun PCNU and FK506 fibers have the potential to form clinically useful and feasible nerve wraps that enhance peripheral nerve regeneration due to their simplicity, ideal physical properties, high FK506 loading, and general biocompatibility and biodegradability.
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