GDNF and NGF released by synthetic guidance channels support sciatic nerve regeneration across a long gap

Abstract

The present work was performed to determine the ability of neurotrophic factors to allow axonal regeneration across a 15-mm-long gap in the rat sciatic nerve. Synthetic nerve guidance channels slowly releasing NGF and GDNF were fabricated and sutured to the cut ends of the nerve to bridge the gap. After 7 weeks, nerve cables had formed in nine out of ten channels in both the NGF and GDNF groups, while no neuronal cables were present in the control group. The average number of myelinated axons at the midpoint of the regenerated nerves was significantly greater in the presence of GDNF than NGF (4942 +/-1627 vs. 1199 +/-431, P < or = 0.04). A significantly greater number of neuronal cells in the GDNF group, when compared to the NGF group, retrogradely transported FluoroGold injected distal to the injury site before explantation. The total number of labelled motoneurons observed in the ventral horn of the spinal cord was 98.1 +/-23.4 vs. 20.0 +/-8.5 (P < or = 0.001) in the presence of GDNF and NGF, respectively. In the dorsal root ganglia, 22.7% +/- 4.9% vs. 3.2% +/-1.9% (P +/-0.005) of sensory neurons were labelled retrogradely in the GDNF and NGF treatment groups, respectively. The present study demonstrates that, sustained delivery of GDNF and NGF to the injury site, by synthetic nerve guidance channels, allows regeneration of both sensory and motor axons over long gaps; GDNF leads to better overall regeneration in the sciatic nerve.

Differentially promoted peripheral nerve regeneration by grafted Schwann cells over-expressing different FGF-2 isoforms

“…Several studies using cell free synthetic nerve grafts examined the effects of different growth factors on peripheral nerve repair across long gaps including FGF-2 (Aebischer et al, 1989), BDNF andNT-3 (Xu et al, 1995), and GDNF and NGF (Fine et al, 2002). Short-term studies of our own group showed that a cellular substrate like transplanted genetically modified Schwann cells over-expressing FGF-2 isoforms is a promising tool to promote Fig.…”

“…In addition, nerve fiber regeneration was also enhanced at the proximal coaptation site, but it did not persist across the distal coaptation site of a 20-mm gap (Rovak et al, 2004). Nerve growth factor (NGF) and glia-derived neurotrophic factor (GDNF), respectively, continuously released by synthetic guidance channels bridging a 15-mm gap in rat sciatic nerves showed different effects on the regeneration of myelinated sensory and motor axons as well as unmyelinated axons (Fine et al, 2002). NGF entrapped in microspheres loaded into synthetic nerve guides bridging a 10-mm gap in rat sciatic nerves showed good regeneration of myelinated fibers also, according to fiber diameter, fiber population, and grade of myelination (Xu et al, 2003).…”

“…Enhanced morphological peripheral nerve regeneration has also been seen after treatment with nerve growth factor (NGF) either slowly released from synthetic nerve guides (Fine et al, 2002) or from NGF-containing polymeric microspheres within synthetic nerve guides (Fine et al, 2002;Xu et al, 2003) or to a even better extent after treatment with glial-derived neurotrophic factor also slowly released from synthetic nerve guides (Fine et al, 2002). Furthermore, it has been shown previously that entrapment of the low molecular weight (18-kDa) isoform of fibroblast growth factor-2 (FGF-2) in synthetic nerve guidance channels is able to enhance growth of myelinated and unmyelinated axons across long gaps significantly (Aebischer et al, 1989).…”

Adenoviral gene transfer of bone morphogenetic protein-7 enhances functional recovery after sciatic nerve injury in rats

“…[30][31][32][33] However, there have been major problems in delivering neurotrophic factors into the nervous system, such as the serum half-life of the recombinant protein may be short and the blood-brain barrier limits access to the central nervous system. This study provided evidence for the beneficial effects of BMP7 gene transfer on the regeneration/protection of the injured sciatic nerves in rats and raised the possibility of developing BMP7 gene transfer as a potential neuroprotective agent for peripheral nerve repair applications.…”

Neuregulin 1 Role in Schwann Cell Regulation and Potential Applications to Promote Peripheral Nerve Regeneration

“…More recently, research has been focused mainly on improving the single lumen nerve tube to bridge larger nerve gaps (de Ruiter, Malessy, Yaszemski, Windebank, & Spinner, 2009;de Ruiter, Spinner, Yaszemski, Windebank, & Malessy, 2009). The artificial conduit may be implanted empty, or it may be filled with collagen and laminin-containing gels (Labrador, Buti, & Navarro, 1998;Madison, Da Silva, & Dikkes, 1988;Verdu et al, 2002), internal frameworks (de Ruiter, Spinner et al, 2009;Francel, Francel, Mackinnon, & Hertl, 1997;Lundborg & Kanje, 1996;Meek et al, 2001;Nakamura et al, 2004;Yoshii & Oka, 2001;Yoshii, Oka, Shima, Taniguchi, & Akagi, 2003), supportive cells (Ansselin, Fink, & Davey, 1997;Evans et al, 2002;Guenard, Kleitman, Morrissey, Bunge, & Aebischer, 1992;Kim et al, 1994;Rodriguez, Verdu, Ceballos, & Navarro, 2000;Sinis et al, 2005), growth factors (Derby et al, 1993;Fine, Decosterd, Papaloizos, Zurn, & Aebischer, 2002;Hollowell, Villadiego, & Rich, 1990;Lee et al, 2003;Midha, Munro, Dalton, Tator, & Shoichet, 2003;Sterne, Brown, Green, & Terenghi, 1997), and conductive polymers, but combinations have also already been used (Figure 2). An artificial graft can meet many of the needs of regenerating fibres by concentrating neurotrophic factors, reducing cellular invasion and providing directional neuritis outgrowth to prevent neuroma formation.…”