Nerve injuries caused by trauma or tumors often require the removal of the injured segment of nerve and subsequent repair with an autologous nerve graft or conduit. Autologous nerve is the current gold standard and outperforms conduits. Currently available conduits lack the necessary support cells and structure to allow for nerve regeneration. Despite the advantages of autograft nerve, they still have the problems of donor site morbidity and limited tissue availability. Allografts can overcome these limitations of autografts while maintaining the 3-D scaffold and support cells that are required to enhance nerve regeneration. However, allograft use requires treatment with immunosuppressive drugs, such as tacrolimus, that can have negative side-effects when used systemically. Separately, our group has developed a biodegradable drug delivery conduit that fits concentrically around a nerve graft. This device is made of poly(lactide-co-glycolic acid) (PLGA) and is capable of locally delivering drug in a controlled manner, at the site of nerve graft or direct repair. The gal of this proposal is to combine allograft nerve transplants with our unique drug delivery device that can release tacrolimus locally to the graft to prevent rejection. By delivering the drug locally, we can limit the negative effects of systemic immunosuppressive treatment, while concomitantly preventing graft rejection. Additionally, tacrolimus is known to directly enhance nerve regeneration.
We aim to first optimize the device design, reservoir volume and release kinetics to continuously release tacrolimus from the device for 60 days. The drug delivery device is manufactured with bio-compatible and degradable PLGA. Using a combination of mathematical modeling and rapid prototyping the release kinetics of tacrolimus from the drug delivery device will be designed to achieve consistent daily release of tacrolimus (5-10ng/mL). Next, we will investigate the efficacy of our treatment strategy in a 15mm rat sciatic nerve gap model. Using our drug delivery conduit, prevention of allograft rejection and the extent of nerve regeneration with 60 days of local tacrolimus delivery will be evaluated. Comparison groups will include autograft control, allograft with systemic tacr olimus and untreated allograft. Nerve regeneration and functional recovery will be evaluated at 30 and 90 days using walking track analysis, muscle weight comparisons, motor endplate staining and retrograde labelling. Histologic analysis will be performed to evaluate nerve histomorphometry (number of myelinated fibers, fiber diameter) and degree of rejection using standard stereological techniques. We will also evaluate the effects of early withdrawal of immunosuppression (90 day group) on host nerve regeneration and functional outcomes.
This aim will allow us to determine if transient local tacrolimus delivery can sufficiently prevent rejection and improve nerve regeneration outcomes. If successful our unique delivery approach can transform the way we treat nerve injuries and allow for the expanded use of allograft nerve transplants.

Public Health Relevance

Peripheral nerve injuries such as those that occur with trauma, fractures, or nerve plexus injuries are particularly devastating and often have few treatment options, most of which result in long -term disabilities. While autologous nerve is the 'gold standard' for nerve grafting, it still has the problems of donor site morbidity and limited tissue availability. Allografts can overcome these limitations and when combined with local drug delivery, we can limit the negative effects of systemic immunosuppressive treatment and prevent graft rejection.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (BNVT)
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Jakeman, Lyn B
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University of Utah
Schools of Medicine
Salt Lake City
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Davis, Brett; Wojtalewicz, Susan; Labroo, Pratima et al. (2018) Controlled release of FK506 from micropatterned PLGA films: potential for application in peripheral nerve repair. Neural Regen Res 13:1247-1252
Li, Ching-Wen; Davis, Brett; Shea, Jill et al. (2018) Optimization of micropatterned poly(lactic-co-glycolic acid) films for enhancing dorsal root ganglion cell orientation and extension. Neural Regen Res 13:105-111
Labroo, Pratima; Shea, Jill; Sant, Himanshu et al. (2017) Effect Of combining FK506 and neurotrophins on neurite branching and elongation. Muscle Nerve 55:570-581