The adhesion molecule cadherin 11 is essential for acquisition of normal hearing ability through middle ear development in the mouse.

Cadherin 11 (Cdh11), a member of the cadherin adhesion molecule family, is expressed in various regions of the brain as well as the head and ear. To gain further insights into the roles of Cdh11 in the development of the ear, we performed behavioral tests using Cdh11 knockout (KO) mice. KO mice showed reduced acoustic startle responses and increased thresholds for auditory brainstem responses, indicating moderate hearing loss. The auditory bulla volume and ratio of air-filled to non-air-filled space in the middle ear cavity were reduced in KO mice, potentially causing conductive hearing loss. Furthermore, residual mesenchymal and inflammatory cells were observed in the middle ear cavity of KO mice. Cdh11 was expressed in developing mesenchymal cells just before the start of cavitation, indicating that Cdh11 may be directly involved in middle ear cavitation. Since the auditory bulla is derived from the neural crest, the regulation of neural crest-derived cells by Cdh11 may be responsible for structural development. This mutant mouse may be a promising animal model for elucidating the causes of conductive hearing loss and otitis media.

Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A.

Microtubule-associated protein 1A (MAP1A) is a member of the major non-motor microtubule-binding proteins. It has been suggested that MAP1A tethers NMDA receptors (NRs) to the cytoskeleton by binding with proteins postsynaptic density (PSD)-93 and PSD-95, although the function of MAP1A in vivo remains elusive. The present study demonstrates that mouse MAP1A plays an essential role in maintaining synaptic plasticity through an analysis of MAP1A knock-out mice. The mice exhibited learning disabilities, which correlated with decreased long-term potentiation and long-term depression in the hippocampal neurons, as well as a concomitant reduction in the extent of NR-dependent EPSCs. Surface expression of NR2A and NR2B subunits also decreased. Enhanced activity-dependent degradation of PSD-93 and reduced transport of NR2A/2B in dendrites was likely responsible for altered receptor function in neurons lacking MAP1A. These data suggest that tethering of NR2A/2B with the cytoskeleton through MAP1A is fundamental for synaptic function. SIGNIFICANCE STATEMENT: This work is the first report showing the significance of non-motor microtubule-associated protein in maintaining synaptic plasticity thorough a novel mechanism: anchoring of NMDA receptors to cytoskeleton supports transport of NMDA receptors and stabilizes postsynaptic density scaffolds binding to NMDA receptors. Newly generated mutant mice lacking MAP1A exhibited learning disabilities and reduced synaptic plasticity attributable to disruptions of the anchoring machinery.

Prognostic factors for long-term hearing preservation after canal-tympanoplasty for congenital aural atresia.

The present study aimed to determine favorable prognostic factors for long-term postoperative hearing outcome after canal-tympanoplasty for congenital aural atresia (CAA). We retrospectively reviewed pre and postoperative hearing results and image findings of 51 ears with CAA performed by canal-tympanoplasty for primary repair. Averages of the postoperative air and bone-conduction thresholds, and the air-bone gap (ABG) were calculated from the last pure-tone audiometry. Follow-up duration ranged from 16 to 139 months. A successful hearing result was defined as a postoperative ABG of ≤15 dB, or a postoperative pure-tone average of ≤30 dB. The influence of the following factors on the success of surgery was assessed by multivariate logistic regression analysis: total Jahrsdoerfer grading system score, age at surgery, and dimensions of middle ear including incudostapedial joint angulation, mesotympanic height, mesotympanic width, mesotympanic depth, mesotympanic area, mesotympanic volume, reconstructable external auditory canal (EAC) diameter, and reconstructable EAC height. Successful hearing outcomes were achieved in 24 of 51 ears (47.1%). A multivariate logistic regression analysis showed that an EAC area >72.3 mm(2) was the most significant favorable predictive factor (P = 0.006), followed by mesotympanic depth >5.5 mm (P = 0.013), mesotympanic height >4.6 mm (P = 0.016), and EAC diameter >9.5 mm (P = 0.029). In conclusion, the size of the reconstructable EAC and mesotympanum is important for predicting long-term favorable hearing outcome following canal-tympanoplasty for CAA.

Differences in Postoperative Hearing Outcomes and Vertigo in Patients with Otosclerosis Treated with Laser-Assisted Stapedotomy versus Stapedectomy.

BACKGROUND: Otosclerosis is an abnormal bone growth in the otic capsule that can result in hearing loss. In this study, we compared postoperative hearing outcomes and vestibular symptoms between patients treated with laser-assisted stapedotomy versus stapedectomy. METHODS: The medical charts of 99 ears treated with stapes surgery were retrospectively reviewed. RESULTS: A stapedotomy, partial stapedectomy, or total stapedectomy was conducted in 77, 16, and 56 ears, respectively. The ears treated with partial- and total stapedectomies were unified into one stapedectomy group. The postoperative changes in the air-bone gap after stapedotomies were significantly larger than those after stapedectomies at 1, 2, and 4 kHz. The postoperative changes in the air conduction threshold after stapedotomies were significantly larger than those after stapedectomies at 1, 2, 4, and 8 kHz. The postoperative changes in the bone conduction threshold at 0.5, 1, 2, and 4 kHz did not differ between the groups. The postoperative vertigo duration after stapedotomies was significantly shorter than that after stapedectomies. CONCLUSIONS: Surgery-induced sensorineural hearing losses were similar for stapedotomies and stapedectomies. However, stapedotomies were more effective and atraumatic than stapedectomies because of the better postoperative hearing results at middle and high frequencies and the shorter postoperative vertigo.

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

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 (125)I-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.

Vestibular Imaging and Function in Patients With Inner Ear Malformation Presenting With Profound Hearing Loss.

Objective: Vestibular impairment has been observed in patients with congenital hearing loss, but little is known about the vestibular anatomy and function of those in this group with inner ear malformations. This study aims to investigate the association between vestibulocochlear anatomy and vestibular function test results in children with inner ear malformations. Study Design: Case series with chart review. Setting: Pediatric patients with inner ear malformations presenting with bilateral profound hearing loss at a tertiary hospital from 1999 to 2017. Methods: Ears were classified into subgroups based on anatomic abnormalities seen on computed tomography imaging. Cervical vestibular evoked myogenic potential (cVEMP), rotatory chair, and caloric test results were obtained and collated. Descriptive and inferential statistics were calculated. Results: Of 82 ears, 29.3% had incomplete partition type II malformation, the most common type. The second-most common type was isolated vestibular organ anomaly (20.7%), which is not included in currently accepted categories. Most ears exhibited abnormal vestibular function. Abnormal vestibule volume was associated with a nonreactive cVEMP (P < .001). Radiologically abnormal lateral semicircular canals were associated with abnormal caloric and rotatory chair results (P < .001). Conclusion: With a relatively large number of cases of isolated vestibular organ anomaly not only in our study but also in previous publications, we suggest that this category be added to the subsets of inner ear malformations. Abnormal vestibule volume was significantly associated with a nonreactive cVEMP finding. The majority of patients with hearing loss secondary to inner ear malformations have abnormal vestibular function test results.

Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL. METHODS: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy. RESULTS: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed. CONCLUSIONS: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids.

Acute bilateral vestibulopathy with simultaneous involvement of both superior and inferior vestibular nerves.

We report a case of acute vestibulopathy with the simultaneous involvement of both superior and inferior vestibular nerves on both sides. A 36-year-old female presented with dizziness, oscillopsia and a walking impairment subsequent to a high fever. Vestibular function tests including caloric testing, video head impulse testing (vHIT) and cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were performed. In the first examination, vHIT and caloric testing showed severe impairments in all three semicircular canals in each ear, and both cVEMPs and oVEMPs were absent on both sides. During a 1-year follow-up, the gain of vHIT gradually recovered by more than 0.5 to normal. cVEMPs also recovered to normal on both sides while oVEMPs remained absent on both sides. This is the first reported case of acute bilateral vestibulopathy with simultaneous involvement of both superior and inferior vestibular nerves on both sides. Repeated evaluation of vestibular function using vHIT, cVEMPs and oVEMPs is helpful to assess the time course of recovery in patients with vestibulopathy.

Surgical invasiveness of cell transplantation into the guinea pig cochlear modiolus.

OBJECTIVE: Previous studies have demonstrated the potential of cell transplantation for regeneration of spiral ganglion neurons (SGNs). However, the effect of surgical invasion on host cochleae has yet to be evaluated. The present study investigated the efficiency and invasiveness of our surgical procedure using a fine glass pipette for injections into the cochlear modiolus. METHODS: We examined the survival of transplanted embryonic stem cell-derived neurons in the cochlear modiolus of guinea pigs. Surgical invasiveness was assessed by measurements of electrically evoked auditory brainstem responses (eABRs) and SGN densities after an injection of 5 microl of saline into the cochlear modiolus. RESULTS: All of the transplanted animals exhibited localization of transplanted cells in the cochlear modiolus. No significant alterations in the eABR thresholds or SGN densities were found following surgery. CONCLUSION: These findings indicate that our procedure is a viable method for testing the potential of transplants for SGN replacement.

Alteration of Musashi1 Intra-cellular Distribution During Regeneration Following Gentamicin-Induced Hair Cell Loss in the Guinea Pig Crista Ampullaris.

The mechanism underlying hair cell (HC) regeneration in the mammalian inner ear is still under debate. Understanding what molecules regulate the HC regeneration in mature mammals will be the key to the treatment of the inner ear disorder. Musashi1 (MSI1) is an RNA binding protein associated with asymmetric division and maintenance of stem cell function as a modulator of the Notch-1 signaling pathway. In this study, we investigated the cellular proliferative activity and changes in spatiotemporal pattern of MSI1 expression in the gentamicin (GM)-treated crista ampullaris (CA) in guinea pigs. Although the vestibular HCs in the CA almost disappeared at 14 days after injecting GM in the inner ear, the density of vestibular HCs spontaneously increased by up to 50% relative to controls at 56 days post-GM treatment (PT). The number of the type II HCs was significantly increased at 28 days PT relative to 14 days PT (p < 0.01) while that of type I HCs or supporting cells (SCs) did not change. The number of SCs did not change through the observational period. Administration of bromodeoxyuridine with the same GM treatment showed that the cell proliferation activity was high in SCs between 14 and 28 days PT. The changes in spatiotemporal patterns of MSI1 expression during spontaneous HC regeneration following GM treatment showed that MSI1-immunoreactivity was diffusely spread into the cytoplasm of the SCs during 7-21 days PT whereas the expression of MSI1 was confined to the nucleus of SCs in the other period. The MSI1/MYO7A double-positive cells were observed at 21 days PT. These results suggest that regeneration of vestibular HCs might originate in the asymmetric cell division and differentiation of SCs and that MSI1 might be involved in controlling the process of vestibular HC regeneration.

Aging Is a Risk Factor for Utricular Dysfunction in Idiopathic Benign Paroxysmal Positional Vertigo.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of balance disorders in the elderly. Dislodgement of the otoconia in BPPV might have an association with damage to the otolith organs. The aim of this study was to investigate whether aging is a risk factor for otolith organ dysfunction in idiopathic BPPV. We retrospectively reviewed the medical records of 112 consecutive idiopathic BPPV patients who underwent cervical VEMP testing to air-conducted sound (ACS cVEMP), ocular VEMP testing to bone-conducted vibration (BCV oVEMP), and caloric testing. We performed binomial logistic regression analyses to see whether age, the side affected by BPPV or the canal affected by BPPV have an association with the presence of peripheral vestibular dysfunction in idiopathic BPPV patients. The elderly group (aged ≥65 years) had a significantly positive association with abnormalities in BCV oVEMPs (p = 0.0109), while the side affected by BPPV (p = 0.598) and the canal affected by BPPV (p = 0.576) did not. The odds ratio of the abnormal BCV oVEMPs for the elderly group compared with the non-elderly group (aged < 65 years) was 2.676 (95% confidence interval, 1.254-5.079). The elderly group had no significant association with the abnormalities in ACS cVEMPs (p = 0.0955) or caloric testing (p = 0.488). Dysfunction of the utricle, where the dislodgement of the otoconia mainly occurs, is affected by aging in idiopathic BPPV.

Progression of inner ear pathology in Ames waltzer mice and the role of protocadherin 15 in hair cell development.

The Ames waltzer (av) mouse mutant exhibits auditory and vestibular abnormalities resulting from mutation of protocadherin 15 (Pcdh15). Ames waltzer has been identified as an animal model for inner ear pathology associated with Usher syndrome type 1F. Studies correlating anatomical phenotype with severity of genetic defect in various av alleles are providing better understanding of the role played by Pcdh15 in inner ear development and of sensorineural abnormalities associated with alterations in Pcdh15 protein structure as a result of gene mutation. In this work we present new findings on inner ear pathology in four alleles of av mice with differing mutations of Pcdh15 as well as varying alterations in inner ear morphology. Two alleles with in-frame deletion mutations (Pcdh15 (av-J) and Pcdh15 (av-2J)) and two presumptive functional null alleles (Pcdh15 (av-3J) and Pcdh15 (av-Tg)) were studied. Light and electron microscopic observations demonstrated that the severity of cochlear and vestibular pathology in these animals correlates positively with the extent of mutation in Pcdh15 from embryonic day 18 (E18) up to 12 months. Electron microscopic analysis of immature ears indicated early abnormalities in the arrangement of stereocilia and the inner and outer hair cell cuticular plates, stereocilia rootlets, and the actin meshwork within the cuticular plate. In severe cases, displacement of the kinocilium and alterations in the shape of the cuticular plate was also observed. Mice harboring in-frame deletion mutations showed less disorganization of stereocilia and cuticular plates in the organ of Corti than the presumptive functional null alleles at P0-P10. A slower progression of pathology was also seen via light microscopy in older animals with in-frame deletions, compared to the presumptive functional null mutations. In summary, our results demonstrate that mutation in Pcdh15 affects the initial formation of stereocilia bundles with associated changes in the actin meshwork within the cuticular plate; these effects are more pronounced in the presumed null mutation compared to mutations that only affect the extracellular domain. The positive correlation of severity of effects with extent of mutation can be seen well into adulthood.

Safety, reliability, and operability of cochlear implant electrode arrays coated with biocompatible polymer.

CONCLUSION: Polymer-coated electrodes can reduce surgically-induced trauma associated with the insertion of a cochlear implant (CI) electrode array. OBJECTIVES: To evaluate if insertion trauma in CI surgery can be reduced by using electrode arrays coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer. METHODS: We analyzed characteristics of the Contour Advance electrode arrays coated with MPC polymer. To assess surgical trauma during electrode insertion, polymer-coated or uncoated (n = 5 each) animal electrode arrays were implanted in guinea pig cochleae and operability and electrophysiological and histological changes were assessed. RESULTS: Under light and scanning electron microscopy, polymer-coated electrodes did not appear different from uncoated electrodes, and no change was observed after mechanical stressing of the arrays. Electrode insertion was significantly easier when polymer-coated electrodes were used. Auditory brainstem response (ABR) thresholds did not differ between groups, but p1-n1 amplitudes of the coated group were larger compared with the uncoated group at 32 kHz at 28 days after surgery. The survival of outer hair cells and spiral ganglion cells was significantly greater in the polymer-coated group.

Hydrogen protects auditory hair cells from cisplatin-induced free radicals.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various malignancies. However, its maximum dose is often limited by severe ototoxicity. Cisplatin ototoxicity may require the production of reactive oxygen species (ROS) in the inner ear by activating enzymes specific to the cochlea. Molecular hydrogen was recently established as an antioxidant that selectively reduces ROS, and has been reported to protect the central nervous system, liver, kidney and cochlea from oxidative stress. The purpose of this study was to evaluate the potential of molecular hydrogen to protect cochleae against cisplatin. We cultured mouse cochlear explants in medium containing various concentrations of cisplatin and examined the effects of hydrogen gas dissolved directly into the media. Following 48-h incubation, the presence of intact auditory hair cells was assayed by phalloidin staining. Cisplatin caused hair cell loss in a dose-dependent manner, whereas the addition of hydrogen gas significantly increased the numbers of remaining auditory hair cells. Additionally, hydroxyphenyl fluorescein (HPF) staining of the spiral ganglion showed that formation of hydroxyl radicals was successfully reduced in hydrogen-treated cochleae. These data suggest that molecular hydrogen can protect auditory tissues against cisplatin toxicity, thus providing an additional strategy to protect against drug-induced inner ear damage.

Favorable prognostic factors for long-term postoperative hearing results after canal tympanoplasty for congenital aural stenosis.

OBJECTIVE: We aimed to determine favorable prognostic factors for long-term postoperative hearing results after canal tympanoplasty for congenital aural stenosis (CAS). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Canal tympanoplasty for CAS was performed in 25 ears. INTERVENTION: Primary repair of CAS. MAIN OUTCOME MEASURES: The influences of the following factors on the success of surgery were assessed by univariate and multivariate logistic regression analyses: modified Jahrsdoerfer grading system total score; age at surgery; patterns of presentation (whether sporadic or syndromic); presence of external auditory canal (EAC) cholesteatoma; presence of ossicular fixation, including the malleus bar; presence of a partial atretic plate; exposure of the facial nerve at the tympanic portion; type of tympanoplasty; and each component of the modified Jahrsdoerfer grading system. RESULTS: The univariate analysis revealed that the absence of EAC cholesteatoma (p = 0.029) and the presence of a partial atretic plate (p = 0.040) were significant predictive factors for favorable hearing prognosis, whereas the multivariate logistic regression analysis showed that an absence of EAC cholesteatoma was the most significant favorable predictive factor (p = 0.011), followed by anterolateral position of the malleus/incus complex with respect to the stapes as the second-most favorable factor (p = 0.021). CONCLUSION: The absence of EAC cholesteatoma and anterolateral position of the malleus/incus complex with respect to the stapes are considered useful in predicting long-term favorable hearing results after canal tympanoplasty for CAS.

Mechanical stress-induced reactive gliosis in the auditory nerve and cochlear nucleus.

OBJECT: Hearing levels following microsurgical treatment gradually deteriorate in a number of patients treated for vestibular schwannoma (VS), especially in the subacute postoperative stage. The cause of this late-onset deterioration of hearing is not completely understood. The aim of this study was to investigate the possibility that reactive gliosis is a contributory factor. METHODS: Mechanical damage to nerve tissue is a feature of complex surgical procedures. To explore this aspect of VS treatment, the authors compressed rat auditory nerves with 2 different degrees of injury while monitoring the compound action potentials of the auditory nerve and the auditory brainstem responses. In this experimental model, the axons of the auditory nerve were quantitatively and highly selectively damaged in the cerebellopontine angle without permanent compromise of the blood supply to the cochlea. The temporal bones were processed for immunohistochemical analysis at 1 week and at 8 weeks after compression. RESULTS: Reactive gliosis was induced not only in the auditory nerve but also in the cochlear nucleus following mechanical trauma in which the general shape of the auditory brainstem response was maintained. There was a substantial outgrowth of astrocytic processes from the transitional zone into the peripheral portion of the auditory nerve, leading to an invasion of dense gliotic tissue in the auditory nerve. The elongated astrocytic processes ran in parallel with the residual auditory neurons and entered much further into the cochlea. Confocal images disclosed fragments of neurons scattered in the gliotic tissue. In the cochlear nucleus, hypertrophic astrocytic processes were abundant around the soma of the neurons. The transverse diameter of the auditory nerve at and proximal to the compression site was considerably reduced, indicating atrophy, especially in rats in which the auditory nerve was profoundly compressed. CONCLUSIONS: The authors found for the first time that mechanical stress to the auditory nerve causes substantial reactive gliosis in both the peripheral and central auditory pathways within 1-8 weeks. Progressive reactive gliosis following surgical stress may cause dysfunction in the auditory pathways and may be a primary cause of progressive hearing loss following microsurgical treatment for VS.

Hydrogen protects vestibular hair cells from free radicals.

CONCLUSION: Hydrogen gas effectively protected against the morphological and functional vestibular hair cell damage by reactive oxygen species (ROS). OBJECTIVE: ROS are generally produced by oxidative stress. In the inner ear, ROS levels increase as a result of noise trauma and ototoxic drugs and induce damage. It is thus important to control ROS levels in the inner ear. The protective effects of hydrogen gas in cochlear hair cells have been reported previously. METHODS: This study examined the effects of hydrogen gas on mouse vestibular hair cell damage by ROS using antimycin A. RESULTS: In the group *exposed to hydrogen gas, vestibular hair cells were morphologically well preserved and their mechano-electrical transduction activities were relatively well maintained when compared with controls. Hydroxyphenyl fluorescein (HPF) fluorescence in vestibular tissue was also reduced by hydrogen gas.

Inner ear drug delivery system from the clinical point of view.

CONCLUSION: Three types of inner ear drug delivery systems (DDS) that were ready to be applied in clinics were developed. OBJECTIVES: To develop clinically applicable inner ear DDS for the treatment of inner ear disorders. METHODS: Inner ear DDS using clinically applicable materials were developed and evaluated. RESULTS: The systemic application of stealth-type nanoparticles encapsulating betamethasone provided superior therapeutic results for the treatment of noise-induced hearing loss compared with the systemic application of betamethasone in mice. Microparticles made of biodegradable polymer (poly (lactic/glycolic) acid, PLGA) encapsulating lidocaine were placed on the round window membrane of guinea pigs, and resulted in reasonable concentrations of lidocaine in the cochlea without serious adverse effects. The phase I/IIa clinical trial of the application of insulin-like growth factor-1 (IGF-1) in combination with gelatin hydrogel on the round window membrane was conducted, recruiting patients with acute sensorineural hearing loss after the failure of systemic application of steroids.

Hydrogen protects auditory hair cells from free radicals.

Reactive oxygen species (ROS) play a role in the degeneration of auditory hair cells because of aging, noise trauma, or ototoxic drugs. Hydrogenation is a fundamental reduction/de-oxidation reaction in living organisms. This study thus examined the potential of hydrogen to protect auditory hair cells from ROS-induced damage. To generate ROS, we applied antimycin A to explant cultures of auditory epithelia, and examined the effect of hydrogen on the protection of hair cells against ROS. Incubation with a hydrogen-saturated medium significantly reduced ROS generation and subsequent lipid peroxidation in the auditory epithelia, leading to increased survival of the hair cells. These findings show the potential of hydrogen to protect auditory hair cells from ROS-induced damage.

Hepatocyte growth factor protects auditory hair cells from aminoglycosides.

OBJECTIVES/HYPOTHESIS: To examine the effect of hepatocyte growth factor (HGF) for protection of auditory hair cells against aminoglycosides and its molecular mechanisms. STUDY DESIGN: Experimental study. METHODS: We quantitatively assessed protective effects of HGF on mouse cochlear hair cells against neomycin toxicity using explant culture systems. To understand mechanisms of hair cell protection by HGF, we examined the expression of c-Met, HGF receptor, and 4-hydroxynonenal (a lipid peroxidation marker) in the cochlea by means of immunohistochemistry and Western blotting. RESULTS: The application of HGF to cochlear explant cultures significantly reduced the hair cell loss induced by neomycin. Immunohistochemistry showed c-Met expression in normal auditory hair cells, and its increase in response to neomycin-induced damage. Immunostaining for 4-hydroxynonenal suggested that HGF acted by attenuating the lipid peroxidation of auditory epithelia induced by neomycin. CONCLUSIONS: These findings demonstrate that a functional HGF/c-Met coupling is present in the cochlea, and HGF application exerts protective effects on hair cells, indicating the potential of HGF as a therapeutic agent for sensorineural hearing loss.