Adjuvant neurotrophic factors in peripheral nerve repair with chondroitin sulfate proteoglycan-reduced acellular nerve allografts

• Published in: The Journal of surgical research 2015-02, Vol.193 (2), p.969-977
• Main Authors: Boyer, Richard B., BS, Sexton, Kevin W., MD, Rodriguez-Feo, Charles L., BS, Nookala, Ratnam, MBBS, Pollins, Alonda C., MLI, Cardwell, Nancy L., BS, Tisdale, Keonna Y, Nanney, Lillian B., PhD, Shack, R. Bruce, MD, Thayer, Wesley P., MD, PhD
• Format: Article
• Language: English
• Subjects: Allografts - drug effects; Animals; Axotomy; Chemotherapy, Adjuvant; Chick Embryo; Chondroitin; Chondroitin Sulfate Proteoglycans; Chondroitinase; CSPG; Drug Evaluation, Preclinical; Female; Ganglia, Spinal - drug effects; GDNF; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Glial Cell Line-Derived Neurotrophic Factor - therapeutic use; Nerve Growth Factor - pharmacology; Nerve Growth Factor - therapeutic use; Nerve repair; Neurites - drug effects; Neurotrophic; NGF; P75; Peripheral Nerve Injuries - drug therapy; Peripheral Nerve Injuries - surgery; Rats, Sprague-Dawley; Sciatic; Sciatic Nerve - transplantation; Surgery
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2014.09.023

Abstract Background Acellular nerve allografts are now standard tools in peripheral nerve repair because of decreased donor site morbidity and operative time savings. Preparation of nerve allografts involves several steps of decellularization and modification of extracellular matrix to remove chondroitin sulfate proteoglycans (CSPGs), which have been shown to inhibit neurite outgrowth through a poorly understood mechanism involving RhoA and extracellular matrix-integrin interactions. Chondroitinase ABC (ChABC) is an enzyme that degrades CSPG molecules and has been shown to promote neurite outgrowth after injury of the central and peripheral nervous systems. Variable results after ChABC treatment make it difficult to predict the effects of this drug in human nerve allografts, especially in the presence of native extracellular signaling molecules. Several studies have shown cross-talk between neurotrophic factor and CSPG signaling pathways, but their interaction remains poorly understood. In this study, we examined the adjuvant effects of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on neurite outgrowth postinjury in CSPG-reduced substrates and acellular nerve allografts. Materials and methods E12 chicken DRG explants were cultured in medium containing ChABC, ChABC + NGF, ChABC + GDNF, or control media. Explants were imaged at 3 d and neurite outgrowths measured. The rat sciatic nerve injury model involved a 1-cm sciatic nerve gap that was microsurgically repaired with ChABC-pretreated acellular nerve allografts. Before implantation, nerve allografts were incubated in NGF, GDNF, or sterile water. Nerve histology was evaluated at 5 d and 8 wk postinjury. Results The addition of GDNF in vitro produced significant increase in sensory neurite length at 3 d compared with ChABC alone ( P