Sunday, October 3, 2010
17883

Controlled Neurotrophic Factor Delivery to Promote Functional Peripheral Nerve Regeneration

Matthew D. Wood, PhD1, Matthew R. MacEwan, MSc2, Alexander R. French, BSc2, Amy M. Moore, MD3, Daniel A. Hunter, RA3, Susan E. Mackinnon, MD3, Daniel W. Moran, PhD2, Shelly E. Sakiyama-Elbert, PhD2, and Gregory H. Borschel, MD4. (1) Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave., Room 5549, Toronto, ON M5G 1X8, Canada, (2) Biomedical Engineering, Washington University in Saint Louis, 1 Brookings Drive, St. Louis, MO 63130, (3) Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, (4) Plastic and Reconstructive Surgery, The Hospital for Sick Children / University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada

Purpose:

Despite advances in the treatment of peripheral nerve injury, functional recovery is often suboptimal.  Alternatives to current treatments (autografts) have included nerve guidance conduits.  Glial-derived neurotrophic factor (GDNF) is the most potent motor growth factor to date and may enhance regenerating motor axons.  Therefore, the delivery of this growth factor from a nerve guidance conduit may enhance motor nerve regeneration and functional recovery.  We chose to investigate the use of an affinity-based delivery system (DS) constructed in fibrin (Figure 1) to provide controlled local delivery of growth factor to the injury site to enhance motor nerve regeneration.

Methods:

We evaluated the effect of controlled delivery of GDNF from fibrin-filled nerve guidance conduits on motor nerve regeneration and functional recovery in a 13 mm rat sciatic nerve defect.  Seven experimental groups were evaluated including: GDNF and DS and NGF with DS and control groups including: GDNF without a DS, isograft (positive control), fibrin with growth factors and empty conduits.  Animals were monitored monthly for behavioral recovery, which included sciatic functional index and grid-grip abilities, and analyzed after 12 weeks for muscle contractile force assessment and retrograde labeling of motor neurons.

Results:

Groups with growth factor in the nerve guidance conduit performed similar to or better (GDNF) than the isograft in behavioral tests and had similar spared relative muscle mass (53 – 63%).  Additionally, groups with controlled GDNF delivery had greater extensor digitorum longus contractile force than the isograft (56% compared to 25%, normalized to uninjured muscle).  Motor regeneration assessed by retrograde labeling revealed that controlled GDNF delivery matched the isograft in the number of regenerating normalized ventral horn neurons (~60%) (Figure 2).

Conclusion:

Overall, the controlled delivery of GDNF from a nerve guidance conduit demonstrated improved measures of functional recovery, suggesting GDNF has potential as a treatment for motor nerve injury.

Figure 1 Schematic representation of surgical implantation of nerve guidance conduit containing the affinity-based delivery system (DS) (modified from Wood et al.).

Figure 2 Normalized ventral horn neurons retrograde labeled 12 weeks after injury.

References:

  1. Wood MD, Moore AM, Hunter DA, Tuffaha S, Borschel GH, Mackinnon SE, and Sakiyama-Elbert SE. Affinity-based release of glial-derived neurotrophic factor from fibrin matrices enhances sciatic nerve regeneration. Acta Biomaterialia 5:959-968, 2009.