title: Convection enhanced drug delivery of BDNF through a microcannula in a rodent model to strengthen connectivity of a peripheral motor nerve bridge model to bypass spinal cord injury.
abstract: Models employing peripheral nerve to bypass spinal cord injury (SCI), although highly promising, may benefit from improved nerve regeneration and motor bridge connectivity. Recent studies have demonstrated that neuronal growth factor-induced enhancement of endogenous neurorestoration may improve neuronal connectivity after severe neurologic injury, particularly if delivered intraparenchymally with zero-order kinetics. We sought to investigate the effect of convection-enhanced delivery of brain-derived neurotrophic factor (BDNF), a neuronal growth factor, on the connectivity of a peripheral motor-nerve bridge in a rodent model using electrophysiology and immunohistochemistry (IHC). Spinal cords of 29 female rats were hemisected at the L1 level. Ipsilateral T13 peripheral nerves were dissected from their muscular targets distally, while maintaining their connections with the spinal cord, and inserted caudal to the injury site to establish the nerve bridge. A microcannula attached to a six-week mini-osmotic pump was used to deliver either BDNF (n=12), saline (n=14), or fluorescein dye (n=3) directly into the spinal cord parenchyma between the site of nerve insertion and hemisection to a depth of 2mm into the area of the lateral motor pool. After four weeks, gastrocnemius muscle activation was assessed electromyographically in five animals from each group. Spinal cords were harvested and analyzed with IHC for cannula-associated injury, and nerve regeneration. Strength of motor bridge connection was illustrated by electrophysiology data. Intraspinal BDNF levels were measured using enzyme-linked immunosorbent assay. IHC revealed increased intraparenchymal BDNF concentration at the nerve bridge insertion site with evidence of minimal trauma from cannulation. BDNF infusion resulted in stronger connections between bridge nerves and spinal motor axons. Bridge nerve electrical stimulation in BDNF-treated rats evoked hind leg electromyogram responses of shorter latency and larger amplitudes than saline-infused controls. Thus, direct convection-assisted delivery provides reliable administration of potent growth factors directly into the spinal cord parenchyma. Delivery of BDNF at the peripheral nerve bridge site results in enhanced connectivity of the peripheral motor bridge in a rodent model of SCI.
authors.affiliation: Department of Neurological Surgery, Columbia University Medical Center, Columbia University, 710 West 168th Street, Room 431, New York, NY 10032, USA.
authors.forename: W
authors.initials: W
authors.lastname: Martin Bauknight
authors.forename: Samit
authors.initials: S
authors.lastname: Chakrabarty
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Hwang
authors.forename: Hani R
authors.initials: HR
authors.lastname: Malone
authors.forename: Shailendra
authors.initials: S
authors.lastname: Joshi
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: E
authors.initials: E
authors.lastname: Sander Connolly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winfree
authors.forename: Miles G
authors.initials: MG
authors.lastname: Cunningham
authors.forename: John H
authors.initials: JH
authors.lastname: Martin
authors.forename: Raqeeb
authors.initials: R
authors.lastname: Haque
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D018481:Convection; D016503:Drug Delivery Systems; D004594:Electrophysiology; D005260:Female; D007150:Immunohistochemistry; D009416:Nerve Regeneration / Q000187:drug effects*; D010525:Peripheral Nerves / Q000187:drug effects / Q000637:transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000601:surgery; D013126:Spinal Nerve Roots / Q000187:drug effects* / Q000601:surgery
chemical_list: D019208:Brain-Derived Neurotrophic Factor