Growth factor-eluting cochlear implant electrode: impact on residual auditory function, insertional trauma, and fibrosis

Journal of Translational Medicine

Juichi Ito³  Akio Ido⁴  Hirohito Tsubouchi⁴  Yasuhiko Tabata²  Lin Ying¹  Takayuki Nakagawa³  Yayoi S Kikkawa³ 

[1] Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Xi¿an, China;Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan;Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kawaharacho 54, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan;Department of Digestive and Life-style Related Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

关键词: Insertional trauma;    Hearing loss;    Guinea pig;    Hepatocyte growth factor (HGF);    Insulin-like growth factor 1 (IGF1);    Spiral ganglion neuron;    Auditory hair cells;    Gelatin hydrogel;    Drug delivery system;    Cochlear implant;   

Others  :  1147699
DOI  :  10.1186/s12967-014-0280-4

 received in 2014-04-30, accepted in 2014-09-24,  发布年份 2014

【 摘 要 】

Background

A cochlear implant (CI) is an artificial hearing device that can replace a damaged cochlea. The present study examined the use of growth factor-eluting gelatin hydrogel coatings on the electrodes to minimize inner ear trauma during electrode insertion. Insulin-like growth factor 1 (IGF1) and/or hepatocyte growth factor (HGF) were chosen as the agents to be administered.

Methods

Silicone CI electrode analogs were prepared and coated with gelatin hydrogels. Adsorption/release profile of the hydrogel was measured using ¹²⁵I-radiolabeled IGF. Hydrogel-coated electrodes were absorbed with IGF1, HGF, IGF1 plus HGF, or saline (control) and implanted into the basal turns of guinea pig cochleae (n?=?5). Auditory sensitivity was determined pre-operatively, immediately after, and 3, 7, 14, 21, and 28 days post-operatively by using auditory brainstem response (ABR; 4¿16 kHz). In addition, histological analysis was performed and auditory hair cell (HC) survival, spiral ganglion neuron (SGN) densities, and fibrous tissue thickness were measured.

Results

Compared to non-coated arrays, hydrogel-coated electrodes adsorbed significantly greater amounts of IGF1 and continuously released it for 48 h. Residual hearing measured by ABR thresholds after surgery were elevated by 50¿70 dB in all of the electrode-implanted animals, and was maximal immediately after operation. Thresholds were less elevated after hydrogel treatment, and the hearing protection improved when IGF1 or HGF was applied. Histopathologically, hair cell survival, spiral ganglion cell survival, and fibrous tissue thickness were not different between the experimental groups. No serious adverse events were observed during the 4-week observation period.

Conclusions

Our findings provide the first evidence that hydrogel-coated, growth factor-releasing CI electrodes could attenuate insertional trauma and promote recovery from it, suggesting that this combination might be a new drug delivery strategy not only in cochlear implantation but also in treating clinical conditions characterized by inner ear damage.

【 授权许可】

   
2014 Kikkawa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Richardson RT, Wise AK, Thompson BC, Flynn BO, Atkinson PJ, Fretwell NJ, Fallon JB, Wallace GG, Shepherd RK, Clark GM, O'Leary SJ: Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. Biomaterials 2009, 30:2614-2624.
• [2]Choi CH, Oghalai JS: Predicting the effect of post-implant cochlear fibrosis on residual hearing. Hear Res 2005, 205:193-200.
• [3]Huang CQ, Tykocinski M, Stathopoulos D, Cowan R: Effects of steroids and lubricants on electrical impedance and tissue response following cochlear implantation. Cochlear Implants Int 2007, 8:123-147.
• [4]Jia H, Venail F, Piron JP, Batrel C, Pelliccia P, Artieres F, Uziel A, Mondain M: Effect of surgical technique on electrode impedance after cochlear implantation. Ann Otol Rhinol Laryngol 2011, 120:529-534.
• [5]Chang A, Eastwood H, Sly D, James D, Richardson R, O'Leary S: Factors influencing the efficacy of round window dexamethasone protection of residual hearing post-cochlear implant surgery. Hear Res 2009, 255:67-72.
• [6]Bas E, Dinh CT, Garnham C, Polak M, Van de Water TR: Conservation of hearing and protection of hair cells in cochlear implant patients¿ with residual hearing. Anat Rec (Hoboken) 2012, 295:1909-1927.
• [7]Gantz BJ, Turner C, Gfeller KE, Lowder MW: Preservation of hearing in cochlear implant surgery: advantages of combined electrical and acoustical speech processing. Laryngoscope 2005, 115:796-802.
• [8]Gstoettner WK, van de Heyning P, O'Connor AF, Morera C, Sainz M, Vermeire K, McDonald S, Cavalle L, Helbig S, Valdecasas JG, Anderson I, Adunka OF: Electric acoustic stimulation of the auditory system: results of a multi-centre investigation. Acta Otolaryngol 2008, 128:968-975.
• [9]Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR: Local dexamethasone therapy conserves hearing in an animal model of electrode insertion trauma-induced hearing loss. Otol Neurotol 2007, 28:842-849.
• [10]James DP, Eastwood H, Richardson RT, O'Leary SJ: Effects of round window dexamethasone on residual hearing in a Guinea pig model of cochlear implantation. Audiol Neurootol 2008, 13:86-96.
• [11]Meyer H, Stover T, Fouchet F, Bastiat G, Saulnier P, Baumer W, Lenarz T, Scheper V: Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization. Int J Nanomedicine 2012, 7:2449-2464.
• [12]Tabata Y, Yamada K, Miyamoto S, Nagata I, Kikuchi H, Aoyama I, Tamura M, Ikada Y: Bone regeneration by basic fibroblast growth factor complexed with biodegradable hydrogels. Biomaterials 1998, 19:807-815.
• [13]Ozeki M, Tabata Y: Affinity evaluation of gelatin for hepatocyte growth factor of different types to design the release carrier. J Biomater Sci Polym Ed 2006, 17:139-150.
• [14]Lee KY, Nakagawa T, Okano T, Hori R, Ono K, Tabata Y, Lee SH, Ito J: Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel. Otol Neurotol 2007, 28:976-981.
• [15]Inaoka T, Nakagawa T, Kikkawa YS, Tabata Y, Ono K, Yoshida M, Tsubouchi H, Ido A, Ito J: Local application of hepatocyte growth factor using gelatin hydrogels attenuates noise-induced hearing loss in guinea pigs. Acta Otolaryngol 2009, 129:453-457.
• [16]Kikkawa YS, Nakagawa T, Tsubouchi H, Ido A, Inaoka T, Ono K, Ito J: Hepatocyte growth factor protects auditory hair cells from aminoglycosides. Laryngoscope 2009, 1:2027-2031.
• [17]Fujiwara T, Hato N, Nakagawa T, Tabata Y, Yoshida T, Komobuchi H, Takeda S, Hyodo J, Hakuba N, Gyo K: Insulin-like growth factor 1 treatment via hydrogels rescues cochlear hair cells from ischemic injury. Neuroreport 2008, 19:1585-1588.
• [18]Hayashi Y, Yamamoto N, Nakagawa T, Ito J: Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice. Mol Cell Neurosci 2013, 56:29-38.
• [19]Nakagawa T, Sakamoto T, Hiraumi H, Kikkawa YS, Yamamoto N, Hamaguchi K, Ono K, Yamamoto M, Tabata Y, Teramukai S, Tanaka S, Tada H, Onodera R, Yonezawa A, Inui K, Ito J: Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial. BMC Med 2010, 8:76. BioMed Central Full Text
• [20]Tabata Y, Miyao M, Ozeki M, Ikada Y: Controlled release of vascular endothelial growth factor by use of collagen hydrogels. J Biomater Sci Polym Ed 2000, 11:915-930.
• [21]Young S, Wong M, Tabata Y, Mikos AG: Gelatin as a delivery vehicle for the controlled release of bioactive molecules. J Control Release 2005, 109:256-274.
• [22]Kinoshita M, Sakamoto T, Kashio A, Shimizu T, Yamasoba T: Age-related hearing loss in Mn-SOD heterozygous knockout mice. Oxid Med Cell Longev 2013, 2013:325702.
• [23]Ogita H, Nakagawa T, Lee KY, Inaoka T, Okano T, Kikkawa YS, Sakamoto T, Ito J: Surgical invasiveness of cell transplantation into the guinea pig cochlear modiolus. ORL J Otorhinolaryngol Relat Spec 2009, 71:32-39.
• [24]Sly DJ, Hampson AJ, Minter RL, Heffer LF, Li J, Millard RE, Winata L, Niasari A, O'Leary SJ: Brain-derived neurotrophic factor modulates auditory function in the hearing cochlea. J Assoc Res Otolaryngol 2012, 13:1-16.
• [25]Wang H, Murphy R, Taaffe D, Yin S, Xia L, Hauswirth WW, Bance M, Robertson GS, Wang J: Efficient cochlear gene transfection in guinea-pigs with adeno-associated viral vectors by partial digestion of round window membrane. Gene Ther 2012, 19:255-263.
• [26]Iizuka T, Kanzaki S, Mochizuki H, Inoshita A, Narui Y, Furukawa M, Kusunoki T, Saji M, Ogawa K, Ikeda K: Noninvasive in vivo delivery of transgene via adeno-associated virus into supporting cells of the neonatal mouse cochlea. Hum Gene Ther 2008, 19:384-390.
• [27]Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM: Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 1998, 391:285-288.
• [28]Roland JT, Huang TC, Fishman AJ: Cochlear Implant Electrode/History, Choices, and Insertion Techniques. In Cochlear Implants. Edited by Waltzman SB, Roland JT. Thieme Medical Publishers, New York; 2006:124.