title: Fibrin gels containing GDNF microspheres increase axonal regeneration after delayed peripheral nerve repair.
abstract: OBJECTIVE
  Recovery following nerve transection declines when target reconnection is delayed for prolonged periods. GDNF has previously been shown to promote motor axon regeneration following delayed nerve repair.
  
  
  METHODS
  We constructed delivery systems using fibrin gels containing free GDNF or poly(lactide-co-glycolide) microspheres with GDNF. The delivery systems were implanted with fluorescent fibrinogen surrounding the common fibular (CF; peroneal) nerve in transgenic Thy-1 GFP rats (whose axons express GFP) to track degradation of the system. A delayed nerve repair model was designed by transecting the rat CF nerve, where nerve regeneration was prevented by ligating the two stumps to surrounding muscle for 2 months prior to resuture. At resuture, either a delivery system with GDNF or an additional group consisting of fibrin gels with empty microspheres were implanted surrounding the repair site. In an additional positive control, the CF was transected and repaired immediately without delay.
  
  
  RESULTS
  ELISA assays demonstrated GDNF release in vitro for 2 weeks from fibrin gels with GDNF microspheres. Implanted delivery systems, including GDNF microspheres, remained surrounding the nerve for at least 10 days compared with 3 days for free GDNF. Four weeks after repair, histomorphometry of distal nerve cross-sections taken 20 mm from the repair site demonstrated increased fiber diameter and myelin thickness due to release of GDNF from microspheres compared with empty microspheres. Additionally, the number of motoneurons that regenerated their axons to the same site increased to comparable levels as immediate repair due to the extended delivery of GDNF from microspheres.
  
  
  CONCLUSIONS
  These findings demonstrate that early measures of nerve regeneration after delayed nerve repair is improved by GDNF microspheres implanted at the coaptation site.
authors.affiliation: Division of Plastic & Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada. matthew.wood@sickkids.ca
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wood
authors.forename: Tessa
authors.initials: T
authors.lastname: Gordon
authors.forename: Howard
authors.initials: H
authors.lastname: Kim
authors.forename: Mark
authors.initials: M
authors.lastname: Szynkaruk
authors.forename: Peter
authors.initials: P
authors.lastname: Phua
authors.forename: Christine
authors.initials: C
authors.lastname: Lafontaine
authors.forename: Stephen Wp
authors.initials: SW
authors.lastname: Kemp
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Borschel
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005337:Fibrin / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005782:Gels / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D006801:Humans; D020007:Implants, Experimental; D008863:Microspheres; D009416:Nerve Regeneration / Q000187:drug effects*; D010543:Peroneal Nerve / Q000473:pathology* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D005782:Gels; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005337:Fibrin