Biopolymer-released dexamethasone prevents tumor necrosis factor alpha-induced loss of auditory hair cells in vitro: implications toward the development of a drug-eluting cochlear implant electrode array.
OBJECTIVE
Polymer-eluted dexamethasone (DXM) will retain its ability to protect against tumor necrosis factor alpha (TNFalpha)-induced hair cell (HC) loss.


BACKGROUND
TNFalpha has been shown to be associated with trauma-induced hearing loss. DXM has been demonstrated to protect the cochlea against trauma-induced hearing loss. DXM is currently administered either systemically or locally to treat patients with sudden hearing loss of unknown cause.


METHODS
P-3 organ of Corti explants challenged with an ototoxic level of TNFalpha was the experimental system, and the base form of DXM (DXMb) incorporated into a biorelease polymer (i.e., SIBS) was the otoprotection molecule tested. The efficacy of otoprotection was determined by counts of fluorescein isothiocyanate-phalloidin-stained HCs and changes in gene expression.


RESULTS
HC counts show 1) SIBS alone did not protect HCs from TNFalpha ototoxicity (SIBS versus SIBS + TNFalpha; p < 0.001), and 2) SIBS with DXMb provides a significant level of protection against TNFalpha-induced loss of HCs (TNFalpha + SIBS versus TNFalpha + SIBS/DXMb, 299 mug; p < 0.001). Gene expression results show that polymer-eluted DXMb 1) upregulates antiapoptotic genes (i.e., Bcl-2, Bcl-xl) and downregulates a proapoptotic gene (i.e., Bax) in TNFalpha-challenged explants and 2) downregulates TNFR1 in these explants.


CONCLUSIONS
Polymer-eluted DXMb retains its otoprotection capabilities in our in vitro test system of TNFalpha-challenged organ of Corti explants by altering the pattern of gene expression to favor survival of TNFalpha-exposed HCs. These results, although in vitro, support the application of polymer containing DXMb to electrode arrays for the conservation of hearing during cochlear implantation.
Dinh
Christine
C
Cochlear Implant Research Program, University of Miami Ear Institute, Department of Otolaryngology, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Hoang
Kimberly
K
Haake
Scott
S
Chen
Shibing
S
Angeli
Simon
S
Nong
Eva
E
Eshraghi
Adrien A
AA
Balkany
Thomas J
TJ
Van De Water
Thomas R
TR
D000818:Animals; D000831:Animals, Newborn; D001704:Biopolymers; D003054:Cochlear Implants; D003692:Delayed-Action Preparations / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000502:physiology*; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D009925:Organ of Corti / Q000187:drug effects*; D011474:Prosthesis Design; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*
D001704:Biopolymers; D003692:Delayed-Action Preparations; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone