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Enhancing Functional Recovery With Local FK506 Hydrogel Treatment In Peripheral Nerve Injury
Fuat Baris Bengur, MD, Chiaki Komatsu, MD, Jocelyn S. Baker, BS, Benjamin K. Schilling, PhD, W. Vincent Nerone, BA, Firuz Feturi, PhD, Kacey G. Marra, PhD, Alexander M. Spiess, MD, Mario G. Solari, MD.
University of Pittsburgh, Pittsburgh, PA, USA.

PURPOSE: Peripheral nerve injuries result in loss of function and can be associated with long durations of recovery. Accelerating the nerve regeneration is vital to decrease the time to functional recovery and improve the outcomes. Several pharmacologic agents have been investigated for this purpose. FK506 (tacrolimus) accelerates the recovery and enhances axonal regeneration with its neurotrophic properties. However, systemic effects, such as multiorgan toxicity and global immunosuppression, limit its clinical applications. Drug delivery approaches hold promise for local FK506 delivery without any of the systemic side effects. This study aims to assess functional recovery after systemic and local FK506 therapy with hydrogel.
METHODS: Sciatic nerve transection and repair surgery was performed in all rats. The rats were then divided into four groups as: Negative control, daily systemic FK506, empty hydrogel and FK506-loaded hydrogel application. The hydrogel was a Poloxamer-based gel that was further processed to increase its degradation time. On the hydrogel groups, the gel was applied locally over the repair site (1.5cm) for once at the time of the initial surgery. On the systemic injection group, rats received daily subcutaneous injections of FK506 for the duration of the experiment. All groups were followed 7 weeks with weekly FK506 blood concentration measurements and walking track/gait analysis. Electrophysiology was performed at the endpoint to assess gastrocnemius tetanic force.
RESULTS: Blood FK506 levels in the systemic group were within the therapeutic range throughout the experiment Blood FK506 levels in the local hydrogel-treated group were below detectable levels throughout the experiment, after the mild initial burst following the surgery. The systemic injection group had the highest functional index, followed by the hydrogel treated group. Hydrogel treated group achieved significantly greater functional index than its respective control of empty hydrogel (p<0.001). The gastrocnemii of the hydrogel and systemic groups generated similar forces, and the hydrogel group generated greater force than its respective control (p<0.001).
CONCLUSION: Local FK506 delivery with hydrogel has the potential to improve functional outcomes after nerve injury, while negating systemic side effects. This hydrogel can be easily applied under direct visualization and could be injected under ultrasound guidance. Future studies on molecular mechanisms of nerve regeneration and local drug dosing can help identify the optimal treatment for different nerve injuries.


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