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PSRC 60th Annual Meeting
Program and Abstracts

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A Critical Analysis of Peripheral Nerve Regeneration in a Chronic Denervation Rat Model Using a Sustained Biomaterial-Based Delivery of GDNF, Chondroitinase, and GDNF+Chondroitinase Growth Factors
Karim A. Sarhane, MD, MSc, Sami H. Tuffaha, MD, Kellin Krick, PhD candidate, Chris Cashman, MD/PhD candidate, Joshua D. Budihardjo, BSc, Justin M. Broyles, MD, Russel Martin, PhD candidate, James Abraham, MA, Zuhaib Ibrahim, MD, Ruifa Mi, MD, PhD, Damon S. Cooney, MD, PhD, Ahmet Hoke, MD, PhD, WP Andrew Lee, MD, Hai-Quan Mao, PhD, Gerald Brandacher, MD.
Johns Hopkins University, Baltimore, MD, USA.

PURPOSE:Functional recovery after nerve injury declines when target reconnection is delayed. Currently, no intervention exists to improve functional outcomes after prolonged denervation. Regeneration can be improved with delivery of growth factors. In this study, we explore the neuroregenerative effects of various growth factors in a preclinical animal model of nerve regeneration
METHODS:A fibrin-based sustained delivery method was optimized in vitro, and then applied in vivo at the nerve repair site to deliver specific growth factors to regenerating nerves in a chronic denervation model that recapitulates the challenges to human nerve regeneration. The model was designed by transecting the rat tibial nerve distal to the sciatic trifurcation; two months later, the peroneal nerve was cut distal to the trifurcation, and the proximal end cross-sutured to the chronically denervated tibial nerve. A delivery system consisting of either GDNF (group 1), chondroitinase (group 2), GDNF+chondroitinase (group 3), or fibrin gel only (group 4) was applied to the distal stump. In an additional positive control, the tibial nerve was transected and repaired immediately without delay (group 5). Endpoints included nerve morphometric analysis, retrograde labeling, and general histology at 5 weeks. Additionally immunofluorescence mechanistic studies were performed 3 days after injection to define the dynamics underlying nerve regeneration in each group
RESULTS:ELISA assays demonstrated adequate release kinetics. Five weeks after repair, histomorphometry demonstrated a significant increase in the number of regenerating myelinated axons in the GDNF+chondroitinase group as compared to GDNF, chondroitinase, and negative control groups. There was no significant difference between the GDNF and chondroitinase groups, but both performed better than negative control. Moreover, GDNF increased preferentially motor neuron regeneration, whereas chondroitinase increased both motor and sensory regeneration. A synergistic effects was observed when combined together (approaching but not reaching statistical significance). Finally, GDNF seems to exert its neuroregenerative effects by upregulating Ki67 in Schwann cells, whereas chondroitinase cleaves inhibitory chondroitin sulfate proteoglycans resulting in enhanced regeneration (Figure)
CONCLUSION:These findings demonstrate that early measures of nerve regeneration after delayed nerve repair are best improved by targeting axonal regrowth (GDNF) and scar tissue breakdown (chondroitinase)


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