title: Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model.
abstract: The use of growth factors, such as glial cell line-derived neurotrophic factor (GDNF), for the treatment of peripheral nerve injury has been useful in promoting axon survival and regeneration. Unfortunately, finding a method that delivers the appropriate spatial and temporal release profile to promote functional recovery has proven difficult. Some release methods result in burst release profiles too short to remain effective over the regeneration period; however, prolonged exposure to GDNF can result in axonal entrapment at the site of release. Thus, GDNF was delivered in both a spatially and temporally controlled manner using a two-phase system comprised of an affinity-based release system and conditional lentiviral GDNF overexpression from Schwann cells (SCs). Briefly, SCs were transduced with a tetracycline-inducible (Tet-On) GDNF overexpressing lentivirus before transplantation. Three-centimeter acellular nerve allografts (ANAs) were modified by injection of a GDNF-releasing fibrin scaffold under the epineurium and then used to bridge a 3 cm sciatic nerve defect. To encourage growth past the ANA, GDNF-SCs were transplanted into the distal nerve and doxycycline was administered for 4, 6, or 8 weeks to determine the optimal duration of GDNF expression in the distal nerve. Live imaging and histomorphometric analysis determined that 6 weeks of doxycycline treatment resulted in enhanced regeneration compared to 4 or 8 weeks. This enhanced regeneration resulted in increased gastrocnemius and tibialis anterior muscle mass for animals receiving doxycycline for 6 weeks. The results of this study demonstrate that strategies providing spatial and temporal control of delivery can improve axonal regeneration and functional muscle reinnervation.
authors.affiliation: 1 Department of Biomedical Engineering, Washington University in St. Louis , St. Louis, Missouri.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Marquardt
authors.affiliation: 2 Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri.
authors.forename: Xueping
authors.initials: X
authors.lastname: Ee
authors.affiliation: 1 Department of Biomedical Engineering, Washington University in St. Louis , St. Louis, Missouri.
authors.forename: Nisha
authors.initials: N
authors.lastname: Iyer
authors.affiliation: 2 Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hunter
authors.affiliation: 2 Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Mackinnon
authors.affiliation: 2 Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wood
authors.affiliation: 1 Department of Biomedical Engineering, Washington University in St. Louis , St. Louis, Missouri.|2 Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri.
authors.forename: Shelly E
authors.initials: SE
authors.lastname: Sakiyama-Elbert
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis*; D016086:Lentivirus; D008297:Male; D009416:Nerve Regeneration; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D014161:Transduction, Genetic
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor