title: Stable release of BDNF from the fibroblast cell line NIH3T3 grown on silicone elastomers enhances survival of spiral ganglion cells in vitro and in vivo.
abstract: The treatment of choice for profound sensorineural hearing loss (SNHL) is direct electrical stimulation of spiral ganglion cells (SGC) via a cochlear implant (CI). The number and excitability of SGC seem to be critical for the success that can be achieved via CI treatment. However, SNHL is associated with degeneration of SGC. Long-term drug delivery to the inner ear for improving SGC survival may be achieved by functionalisation of CI electrodes with cells providing growth factors. Therefore, the capacity of brain-derived neurotrophic factor (BDNF)-secreting NIH3T3 cells grown on cylindrically shaped silicone elastomers (SE) to exert local and sustained neuroprotective effects was assessed in vitro and in vivo. An in vitro model to investigate adhesion and cell growth of lentivirally modified NIH3T3 cells synthesising BDNF on SE was established. The bioactivity of BDNF was characterised by co-cultivation of SGC with cell-coated SE. In addition, cell-coated SE were implanted into deafened guinea pigs. The recombinant NIH3T3 cells proliferated on silicone surfaces during 14 days of cultivation and expressed significantly increasing BDNF levels. Enhanced survival rates and neurite outgrowth of SGC demonstrated the bioactivity of BDNF in vitro. Implantation of SE with adhering BDNF-secreting NIH3T3 cells into the cochleae of systemically deafened guinea pigs induced a significant increase in SGC survival in comparison to SE without cell coating. Our data demonstrate a novel approach of cell-based long-term drug delivery to support SGC survival in vitro and in vivo. This therapeutic strategy--once transferred to cells suitable for clinical application--may improve CI performance.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany. warnecke.athanasia@mh-hannover.de
authors.forename: Athanasia
authors.initials: A
authors.lastname: Warnecke
authors.forename: Susanne
authors.initials: S
authors.lastname: Sasse
authors.forename: Gentiana I
authors.initials: GI
authors.lastname: Wenzel
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
authors.forename: Gerrit
authors.initials: G
authors.lastname: Paasche
authors.forename: Verena
authors.initials: V
authors.lastname: Scheper
authors.forename: Uta
authors.initials: U
authors.lastname: Reich
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Esser
authors.forename: Thomas
authors.initials: T
authors.lastname: Lenarz
authors.forename: Timo
authors.initials: T
authors.lastname: Stöver
authors.forename: Kirsten
authors.initials: K
authors.lastname: Wissel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D003638:Deafness / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D004976:Ethacrynic Acid; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006168:Guinea Pigs; D006801:Humans; D007612:Kanamycin; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats; D017207:Rats, Sprague-Dawley; D012826:Silicone Elastomers / Q000737:chemistry*; D013136:Spiral Ganglion / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D013997:Time Factors; D014162:Transfection
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012826:Silicone Elastomers; D049452:Green Fluorescent Proteins; D007612:Kanamycin; D004976:Ethacrynic Acid