Developing the supraparticle technology for round window-mediated drug administration into the cochlea.

The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as '(Chi/Alg)SPs', to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 µg of NT3 loaded per SP that weights ~50 µg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 µg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 µg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss.

Electrophysiological and histomorphological changes of cochlea in miniature pigs after abrasion of round window niches.

Background: In operations of cochlea implantation (CI), many surgeons choose to drill a window on the bone wall of cochlea basic rotation, when more and more patients receive CI with residual hearing, what damage this step would result in is unclear.Objective: To study the effect to inner ear hair cells which is caused by drilling during CI.Methods: 6 miniature pigs are equally divided into two groups, Round window niche of each pig in the experimental group was milled, while the pigs in control group wasn't. After implanting depth of 6.5, 11.5 and 20 mm, round window electrocochleography was recorded to analyze the change of cochlea microphonic (CM) potentials respectively, histomorphological changes was observed.Results: Thresholds of CM in experimental group were higher than that of control group at different depth, amplitudes were smaller. In further group, cilia of inner hair cells (IHC) at bottom rotation were significantly damaged. After operation, ABR hearing threshold of experimental group was higher, differences at low frequency region were more obvious.Conclusions: Damage caused by mulling round window niche may seriously affect the function of the hair cells. Damage of the IHC is greater than OHC. CI through round window may protect residual hearing.

Exploratory tympanotomy in sudden sensorineural hearing loss for the identification of a perilymphatic fistula - retrospective analysis and review of the literature.

OBJECTIVE: The diagnostic value of exploratory tympanotomy in sudden sensorineural hearing loss remains controversial. This study and review were performed to identify the incidence of perilymphatic fistula in patients with sudden sensorineural hearing loss. The effectiveness of tympanotomy for sealing of the cochlear windows in cases with perilymphatic fistula was evaluated. METHODS: A search in common databases was performed. Overall, 5034 studies were retrieved. Further, a retrospective analysis on 90 patients was performed. RESULTS: Eight publications dealing with tympanotomy in patients with sudden sensorineural hearing loss were identified. In 90 patients diagnosed with sudden sensorineural hearing loss and undergoing exploratory tympanotomy, 10 patients (11 per cent) were identified with a perilymphatic fistula, and this corresponds to the results obtained from our review (13.6 per cent). CONCLUSION: There was no significant improvement after exploratory tympanotomy and sealing of the membranes for patients with a definite perilymphatic fistula.

The Forgotten Second Window: A Pictorial Review of Round Window Pathologies.

The round window serves to decompress acoustic energy that enters the cochlea via stapes movement against the oval window. Any inward motion of the oval window via stapes vibration leads to outward motion of the round window. Occlusion of the round window is a cause of conductive hearing loss because it increases the resistance to sound energy and consequently dampens energy propagation. Because the round window niche is not adequately evaluated by otoscopy and may be incompletely exposed during an operation, otologic surgeons may not always correctly identify associated pathology. Thus, radiologists play an essential role in the identification and classification of diseases affecting the round window. The purpose of this review is to highlight the developmental, acquired, neoplastic, and iatrogenic range of pathologies that can be encountered in round window dysfunction.

Influence of middle ear disorder in round-window stimulation using a finite element human ear model.

PURPOSE: The aim of this work was to study the effect of middle ear disorder on round window (RW) stimulation, so as to provide references for the optimal design of RW stimulation type middle ear implants (MEIs). METHODS: A human ear finite-element model was built by reverse engineering technique based on micro-computed tomography scanning images of human temporal bone, and was validated by three sets of comparisons with experimental data. Then, based on this model, typical disorders in otosclerosis and otitis media were simulated. Finally, their influences on the RW stimulation were analyzed by comparison of the displacements of the basilar membrane. RESULTS: For the otosclerosis, the stapedial abnormal bone growth severely deteriorated the equivalent sound pressure of the RW stimulation at higher frequencies, while the hardening of ligaments and tendons prominently decreased the RW stimulation at lower frequencies. Besides, among the hardening of the studied tissues, the influence of the stapedial annular ligament's hardening was much more significant. For the otitis media, the round window membrane (RWM)'s thickening mainly decreased the RW stimulation's performance at lower frequencies. When the elastic modulus' reduction of the RWM was considered at the same time especially for the acute otitis media, it would raise the lower-frequency performance of the RW stimulation. CONCLUSIONS: The influence of the middle ear disorder on the RW stimulation is considerable and variable, it should be considered during the design of the RW stimulation type MEIs.

Influence of ossicular chain malformation on the performance of round-window stimulation: A finite element approach.

As a novel application of implantable middle ear hearing device, round-window stimulation is widely used to treat hearing loss with middle ear disease, such as ossicular chain malformation. To evaluate the influence of ossicular chain malformations on the efficiency of the round-window stimulation, a human ear finite element model, which incorporates cochlear asymmetric structure, was constructed. Five groups of comparison with experimental data confirmed the model's validity. Based on this model, we investigated the influence of three categories of ossicular chain malformations, that is, incudostapedial disconnection, incus and malleus fixation, and fixation of the stapes. These malformations' effects were evaluated by comparing the equivalent sound pressures derived from the basilar membrane displacement. Results show that the studied ossicular chain malformations mainly affected the round-window simulation's performance at low frequencies. In contrast to the fixation of the ossicles, which mainly deteriorates round-window simulation's low-frequency performance, incudostapedial disconnection increases this performance, especially in the absence of incus process and stapes superstructure. Among the studied ossicular chain malformations, the stapes fixation has a much more severe impact on the round-window stimulation's efficiency. Thus, the influence of the patients' ossicular chain malformations should be considered in the design of the round-window stimulation's actuator. The low-frequency output of the round-window simulation's actuator should be enhanced, especially for treating the patients with stapes fixation.

Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use.

Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.

Audiometric Results of Stapedotomy Surgery for Otoscelorsis: Influence of the Radiological Stage.

BACKGROUND: The objective of this study was to identify a correlation between the radiological stage of otosclerosis and the pre- and postoperative audiometric results of patients who underwent a stapedotomy. METHODS: Ninety-three patients with radiologically and surgically confirmed otosclerosis who underwent stapedotomy surgery and CT scanning within 18 months before the operation were included. The CT scans were interpreted by an otologist and a specialised radiologist to determine their radiological stage according to the classification of Veillon and Fraysse. The patients received a pre- and postoperative audiogram in the short and long term. RESULTS: The preoperative bone conduction thresholds were higher in patients who presented with an advanced radiological stage of otosclerosis: 32.7 dB ±â€Š12.4 compared with those who presented with a less advanced radiological stage: 24.3 dB ±â€Š10.0. The preoperative air conduction thresholds were higher in patients who presented with an impairment of the round window: 58.1 dB ±â€Š13.5 compared with those who presented with no impairment of the round window: 48.7 dB ±â€Š14.5. The postoperative improvement in the air-bone gap was significantly higher for the localised foci: 16.9 dB ±â€Š8.6 versus 11.0 dB ±â€Š9.2, but only in the short term. CONCLUSION: There was a clinical radiological correlation with the preoperative results: In BC, there was a correlation with the radiological stage of Veillon and in AC, there was a correlation with impairment of the round window. The link between the radiological stage of otosclerosis and the postoperative audiometric results is less obvious. In the short term, the audiometric improvements in the air-bone gap were greater in patients in the early stages according to the Veillon classification, but this result was not sustained in the long-term.

Effects of Various Trajectories on Tissue Preservation in Cochlear Implant Surgery: A Micro-Computed Tomography and Synchrotron Radiation Phase-Contrast Imaging Study.

OBJECTIVES: The purpose of this study was to evaluate the three-dimensional (3D) anatomy and potential damage to the hook region of the human cochlea following various trajectories at cochlear implantation (CI). The goal was to determine which of the approaches can avoid lesions to the soft tissues, including the basilar membrane and its suspension to the lateral wall. Currently, there is increased emphasis on conservation of inner ear structures, even in nonhearing preservation CI surgery. DESIGN: Micro-computed tomography and various CI approaches were made in an archival collection of macerated and freshly fixed human temporal bones. Furthermore, synchrotron radiation phase-contrast imaging was used to reproduce the soft tissues. The 3D anatomy was investigated using bony and soft tissue algorithms, and influences on inner ear structures were examined. RESULTS: Micro-computed tomography with 3D rendering demonstrated the topography of the round window (RW) and osseous spiral laminae, while synchrotron imaging allowed reproduction of soft tissues such as the basilar membrane and its suspension around the RW membrane. Anterior cochleostomies and anteroinferior cochleostomies invariably damaged the intracochlear soft tissues while inferior cochleostomies sporadically left inner ear structures unaffected. CONCLUSIONS: Results suggest that cochleostomy approaches often traumatize the soft tissues at the hook region at CI surgery. For optimal structural preservation, the RW approach is, therefore, recommended.

"Emergency" Cochlear Implantation in Labyrinthitis Ossificans Secondary to Polyarteritis Nodosa: How to Face a Rare Entity.

Polyarteritis nodosa (PAN) is a systemic vasculitis affecting the small- and medium-sized arteries that may present with hearing impairment. In rare cases, PAN may be associated with progressive labyrinthitis ossificans (LO), an otologic emergency requiring early cochlear implantation (CI) to restore hearing before the complete, irreversible cochlear ossification. We report the first case in the literature of a patient affected by PAN with bilateral sudden sensorineural hearing loss and rapid LO who underwent "emergency" bilateral simultaneous CI. This case report emphasizes the importance of an early audiological evaluation in patients with PAN when LO is suspected. Multidisciplinary approach is mandatory when facing organ-specific manifestations in patients with PAN. Detailed discussion is provided with particular regard to clinical and radiological presentation as well as CI outcomes in such a rare and challenging case.

Cochlear-Internal Canal and Cochlear-Facial Dehiscence: A Novel Entity.

Different types of otic capsule dehiscence restricted to the cochlea have been described. Here we describe the case of a patient with a cochlear-internal auditory canal dehiscence associated with a cochlear-facial dehiscence not reported before. A 53-year-old patient with severe to profound sensorineural hearing loss due to bilateral Meniere's disease underwent a cochlear implant surgery on the right ear. Preoperative brain magnetic resonance imaging findings were reported to be normal; during surgery, a cerebrospinal fluid gusher occurred at the time of round window opening. Postoperative computed tomography imaging showed a bony dehiscence at two levels of the otic capsule.

Sneezing and Perilymphatic Fistula of the Round Window: Case Report and Systematic Review of the Literature.

The goal of the present study was to describe a case of perilymphatic fistula (PLF) of the round window (RW) that occurred after sneezing, along with a review of the literature. We report a case of PLF of RW, which was provoked by sneezing, and its consequent medical and surgical treatments. With respect to the review of the literature, articles were initially selected based on their titles or abstracts, followed by methodological evaluation. The patient underwent an explorative tympanotomy (ET) with packaging of RW with the pericondrium, following which the patient's complaints regarding vertigo and imbalance disappeared, but the severe sensorineural hearing loss persisted. For the literature review, five references were selected. These studies showed a great variety in the clinical presentation and healing of symptoms. Sneezing represents a rare but well-recognized cause of PLF, as reported in our case. The correct selection of patients who should undergo ET and an early surgical repair of PLF are mandatory for better outcomes, especially in case of hearing.

[The fistula of the round window of the cochlea]. / Fistula okna ulitki.

This article presents the data on the frequency, diagnostics, and variants of the surgical treatment of the fistula of the round window of the cochlea. A case of this pathology is reported with the special emphasis placed on the approaches to the diagnostics and surgical management of this condition.

Morphological changes in the round window membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla.

OBJECTIVE: The round window membrane (RWM) encloses the round window, the opening into the scala tympani (ST) from the middle ear. During the course of acute otitis media (AOM), structural changes of the RWM can occur that potentially affect sound transmission into and out of the cochlea. The relationship between such structural changes and conductive hearing loss during AOM has remained unclear. The focus of the current study was to compare the thickness distribution across the RWM surface between normal ears and those with AOM in the chinchilla. We assessed the occurrence of AOM-associated histological changes in this membrane compared to uninfected control animals after AOM of two relatively short durations. MATERIAL AND METHODS: AOM was induced by transbullar injection of the nontypeable Haemophilus influenzae strain 86-028NP into two groups of adult chinchillas (n = 3 each). Bullae were obtained from the two infected groups, at 4 days or 8 days post challenge. Structures and thickness of these RWMs were compared between the two infected treatment groups and to RWMs from uninfected control animals (n = 3) at seven different RWM locations. RESULTS: RWM thickness in infected chinchillas increased significantly at locations along the central line on the 4th day post bacterial challenge compared to values found for uninfected control animals. Lymphocyte infiltration and edema were the primary contributors to these thickness increases. No significant further increases in RWM thickness were observed when RWMs from chinchillas ears infected for 4 and 8 days were compared. Thickness and structural changes at the RWM lateral and medial areas were less visually obvious and not statistically significant among the three treatment groups. These latter RWM regions clearly were less affected during AOM than the central areas. CONCLUSIONS: This histological study establishes that H. influenzae-induced AOM causes significant acute changes in chinchilla RWM structure that are characterized by region-specific increases in thickness. Our new morphological findings comparing normal and diseased chinchilla RWMs identify yet another biomechanical mechanism by which nontypeable H. influenzae may contribute to hearing loss in AOM.

The Effect of Round Window Sealants on Delayed Hearing Loss in a Guinea Pig Model of Cochlear Implantation.

AIM: To determine whether the type of material used to seal the cochlea after round window cochlear implantation influences delayed hearing loss. BACKGROUND: Cochlear implants are now prescribed to patients with residual, low-frequency hearing. This hearing-which provides perceptual benefits for the implanted ear-is frequently lost for unknown reasons weeks to months after surgery in a proportion of patients. A post-surgical change in cochlear mechanics, related to the material used to seal the cochlea after round window implantation, may contribute to this loss. METHODS: An electrode array was implanted in guinea pigs via the round window, which was then sealed with muscle, periosteum, or fibrin glue. Auditory brainstem responses (ABRs) to pure tones (2, 8, 16, 24, and 32 kHz) were recorded before surgery and 1, 4, and 12 weeks after surgery, with subjects then euthanized and their cochleae harvested for histological analysis. RESULTS: Muscle and periosteum, but not fibrin glue, exhibited delayed threshold rises at 2 kHz. Twelve weeks after implantation, 2 kHz threshold shifts differed significantly between muscle (mean, 27.1 dB) and fibrin glue (9.3 dB), but not between these groups and periosteum (19.3 dB). Muscle was sometimes associated with much greater tissue reactions than the other sealants. Most cochleae had injuries to the basilar membrane and/or osseous spiral lamina, regardless of sealant. Hair cell counts did not differ significantly among sealants. CONCLUSION: Delayed, low-frequency hearing loss was observed when cochleae were sealed with muscle or periosteum, but not when cochleae were sealed with fibrin glue.

Pathologic Findings of the Cochlea in Labyrinthitis Ossificans Associated with the Round Window Membrane.

OBJECTIVE: To quantitatively demonstrate and classify the histopathologic changes in the cochlea of the human temporal bones with labyrinthitis ossificans (LO). STUDY DESIGN: Comparative human temporal bone study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: We compared 23 temporal bone specimens from 19 deceased donors with LO associated with the round window membrane (RWM) and 27 age-matched specimens from 20 deceased donors without any otologic diseases. We focused on the location of LO in the inner ear, the intensity of endolymphatic hydrops, the number of spiral ganglion cells and cochlear hair cells, and the areas of the stria vascularis and spiral ligament. In addition, we created a new pathologic grading system for temporal bone specimens from deceased donors with LO associated with the RWM. RESULTS: We most often observed LO in the scala tympani of the basal cochlear turn. In the LO group (as compared with the control group), the intensity of endolymphatic hydrops was significantly increased; the number of spiral ganglion cells was significantly decreased in all segments; the loss of outer and inner hair cells was significantly increased in all turns of the cochlea; the atrophy of the stria vascularis was significantly greater in all turns of the cochlea; and atrophy of the spiral ligament was significantly greater in the basal and middle cochlear turn. CONCLUSION: LO was associated with significant cochlear damage (to the spiral ganglion cells, cochlear hair cells, stria vascularis, and spiral ligament) and with increased intensity of endolymphatic hydrops.

Evaluation of Round Window Stimulation Performance in Otosclerosis Using Finite Element Modeling.

Round window (RW) stimulation is a new type of middle ear implant's application for treating patients with middle ear disease, such as otosclerosis. However, clinical outcomes show a substantial degree of variability. One source of variability is the variation in the material properties of the ear components caused by the disease. To investigate the influence of the otosclerosis on the performance of the RW stimulation, a human ear finite element model including middle ear and cochlea was established based on a set of microcomputerized tomography section images of a human temporal bone. Three characteristic changes of the otosclerosis in the auditory system were simulated in the FE model: stapedial annular ligament stiffness enlargement, stapedial abnormal bone growth, and partial fixation of the malleus. The FE model was verified by comparing the model-predicted results with published experimental measurements. The equivalent sound pressure (ESP) of RW stimulation was calculated via comparing the differential intracochlear pressure produced by the RW stimulation and the normal eardrum sound stimulation. The results show that the increase of stapedial annular ligament and partial fixation of the malleus decreases RW stimulation's ESP prominently at lower frequencies. In contrast, the stapedial abnormal bone growth deteriorates RW stimulation's ESP severely at higher frequencies.

Serrated needle design facilitates precise round window membrane perforation.

The round window membrane (RWM) has become the preferred route, over cochleostomy, for the introduction of cochlear implant electrodes as it minimizes inner ear trauma. However, in the absence of a tool designed for creating precise perforation, current practices lead to tearing of the RWM and significant intracochlear pressure fluctuations. On the basis of RWM mechanical properties, we have designed a multi-serrated needle to create consistent holes without membrane tearing or damaging inner ear structures. Four and eight-serrated needles were designed and produced with wire electrical discharge machining (EDM). The needle's ability to create RWM perforations was tested in deidentified, commercially acquired temporal bones with the assistance of a micromanipulator. Subsequently, specimens were imaged under light and scanning electron microscopy (SEM). The needles created consistent, appropriately sized holes in the membrane with minimal tearing. While a four-serrated crown needle made rectangular/trapezoid perforations, the octagonal crown formed smooth oval holes within the membrane. Though designed for single use, the needle tolerated repeated use without significant damage. The serrated needles formed precise perforations in the RWM while minimizing damage during cochlear implantation. The octagonal needle design created the preferred oval perforation better than the quad needle. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1633-1637, 2016.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

Air, bone and soft tissue excitation of the cochlea in the presence of severe impediments to ossicle and window mobility.

Clinical conditions have been described in which one of the two cochlear windows is immobile (otosclerosis) or absent (round window atresia), but nevertheless bone conduction (BC) thresholds are relatively unaffected. To clarify this apparent paradox, experimental manipulations which would severely impede several of the classical osseous mechanisms of BC were induced in fat sand rats, including discontinuity or immobilization of the ossicular chain, coupled with window fixation. Effects of these manipulations were assessed by recording auditory nerve brainstem evoked response (ABR) thresholds to stimulation by air conduction (AC), by osseous BC and by non-osseous BC (also called soft tissue conduction-STC) in which the BC bone vibrator is applied to skin sites. Following the immobilization, discontinuity and window fixation, auditory stimulation was also delivered to cerebro-spinal fluid (CSF) and to saline applied to the middle ear cavity. While the manipulations (immobilization, discontinuity, window fixation) led to an elevation of AC thresholds, nevertheless, there was no change in osseous and non-osseous BC thresholds. On the other hand, ABR could be elicited in response to fluid pressure stimulation to CSF and middle ear saline, even in the presence of the severe restriction of ossicular chain and window mobility. The results of these experiments in which osseous and non-osseous BC thresholds remained unchanged in the presence of severe restriction of the classical middle ear mechanisms and in the absence of an efficient release window, while ABR could be recorded in response to fluid pressure auditory stimulation to fluid sites, indicate that it is possible that the inner ear may be activated at low sound intensities by fast fluid pressure stimulation. At higher sound intensities, a slower passive basilar membrane traveling wave may serve to excite the inner ear.