Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Sustained Release of FK506 from a Polymeric Drug Delivery System for the Treatment of Peripheral Nerve Injury
Kasra Tajdaran, MASc1, Matthew D. Wood, PhD2, Molly S. Shoichet, PhD1, Tessa Gordon, PhD1, Gregory H. Borschel, MD, FACS, FAAP1.
1University of Toronto, Toronto, ON, Canada, 2Washington University, St. Louis, MO, USA.

PURPOSE:
Despite substantial improvement of microsurgical techniques for nerve repair, recovery after nerve injury in the peripheral nervous system is usually incomplete. Delays in treatment further compromise recovery because of the diminished capability of neurons to regenerate their axons after chronic axotomy when the axons have not yet connected to their end-organs. This decline is in part due to the reduced neurotrophic factors availability within the neurons and from the progressively denervated Schwann cells in the growth pathway of the distal nerve stump. Exogenous agents can promote neuron survival and axon regeneration under conditions where endogenous supplies of neurotrophic factors decline with time. FK506, an FDA approved immunosuppressant, also promotes functional recovery and reinnervation following peripheral nerve injury. However, FK506 has not been widely adopted for nerve injuries because the systemically delivered drug causes undesirable global immunosuppression. Currently available local delivery strategies, such as implanted mini-osmotic pumps are not clinically ideal, because they are prone to infection and compression of the nerve. We have therefore designed a biodegradable local delivery strategy for FK506 using fibrin gel as the drug reservoir that could be placed at a site of nerve injury.
METHODS:
FK506 was incorporated into fibrin gel in solubilized, particulated and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. The properties of the delivery system were analyzed by determining the drug release profile. The bioactivity of the released FK506 was analyzed in an in vitro dorsal root ganglion (DRG) neurite extension assay.
RESULTS:
Tunable release of FK506 in the fibrin gel was observed with the rate of release being most rapid for the solubilized form and then the particulate form (Fig.1). The most prolonged period of release was seen with the PLGA microsphere-encapsulated form. Typical neurite outgrowth was observed in vitro when DRG’s were cultured with a FK506 release sample as compared to either no FK506 or 100ng/mL stock solution of FK506 (Fig.2A-C). DRGs treated with the released FK506 showed significant increase in neurite extension compared to the control group lacking the drug. The bioactivity of the released FK506 over the four weeks was equivalent to the media supplemented with the stock FK506. Hence the incorporation of FK506 in the delivery system did not alter the bioactivity of the drug (Fig.2D).
CONCLUSION:
We have demonstrated effective and sustained release of a drug from a novel drug delivery system that incorporates the drug into fibrin gel. Incorporation of FK506 in poly(lactic-co-glycolic) acid (PLGA) microspheres was the most effective with constant delivery of the drug during a protracted period of one month. This study has provided promising results for the use of the proposed delivery system for enhancing peripheral nerve regeneration.



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