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Cochlear implantation leads to many structural changes within the cochlea which can impair residual hearing. In patients with preserved low-frequency hearing, a delayed hearing loss can occur weeks-to-years post-implantation. We explore whether stiffening of the basilar membrane (BM) may be a contributory factor in an animal model. Our objective is to map changes in morphology and Young's modulus of basal and apical areas of the BM after cochlear implantation, using quantitative nanomechanical atomic force microscopy (QNM-AFM) after cochlear implant surgery. Cochlear implantation was undertaken in the guinea pig, and the BM was harvested at four time-points: 1 day, 14 days, 28 days and 84 days post-implantation for QNM-AFM analysis. Auditory brainstem response thresholds were determined prior to implantation and termination. BM tissue showed altered morphology and a progressive increase in Young's modulus, mainly in the apex, over time after implantation. BM tissue from the cochlear base demonstrated areas of extreme stiffness which are likely due to micro-calcification on the BM. In conclusion, stiffening of the BM after cochlear implantation occurs over time, even at sites far apical to a cochlear implant., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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.

Introduction: Cochlear implantation (CI) has developed from its origins in the 1980s. Initially, CI was for profound bilateral hearing impairment. However, candidacy for CI have become more widespread in recent years with unilateral implantation and an emphasis on hearing preservation. Evidence supports full electrode insertion in an atraumatic fashion into the scala tympani (ST) provides optimal hearing outcomes. The main aim of this systematic review was to elucidate the degree of trauma associated with CI insertion., Methods: A systematic literature search was undertaken using PubMed Medline. A grading system described by Eshraghi was used to classify cochlear trauma. Both radiological and histological studies were included., Results: Twenty one papers were identified which were relevant to our search. In total, 653 implants were inserted and 115 (17.6%) showed evidence of trauma. The cochleas with trauma had basilar membrane elevation in 5.2%, ruptured in 5.2%, the electrode passed from the ST to the SV in 84.4% and there was grade 4 trauma in 5.2%. The studies used a variety of histological and radiological methods to assess for evidence of trauma in both cadaveric temporal bones and live recipients., Conclusions: Minimizing cochlear trauma during implant insertion is important to preserve residual hearing and optimize audiological performance. An overall 17.6% trauma rate suggests that CI insertion could be improved with more accurate and consistent electrode insertion such as in the form of robotic guidance. The correlation of cochlea trauma with post-operative hearing has yet to be determined.

The aim of the study was to evaluate insertion forces during manual insertion of a straight atraumatic electrode in human temporal bones, and post-implantation histologic evaluation of the samples to determine whether violation of intracochlear structures is related to insertion forces. In order to minimize intracochlear trauma and preserve residual hearing during cochlear implantation, knowledge of the insertion forces is necessary. Ten fresh frozen human temporal bones were prepared with canal wall down mastoidectomy. All samples were mounted on a one-axis force sensor. Insertion of a 16-mm straight atraumatic electrode was performed from different angles to induce "traumatic" insertion. Histologic evaluation was performed in order to evaluate intracochlear trauma. In 4 of 10 samples, dislocation of the electrode into scala vestibuli was observed. The mean insertion force for all 10 procedures was 0.003 ± 0.005 N. Insertion forces measured around the site of dislocation to scala vestibuli in 3 of 4 samples were significantly higher than insertion forces at the same location of the cochleae measured in samples without trauma (p < 0.04). Mean force during the whole insertion process of the straight atraumatic electrode is lower than reported by other studies using longer electrodes. Based on our study, insertion forces leading to basilar membrane trauma may be lower than the previously reported direct rupture forces.

In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status., Competing Interests: The authors declare no conflict of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

More than 100 genes have been associated with deafness. However, SMAD4 is rarely considered a contributor to deafness in humans, except for its well-defined role in cell differentiation and regeneration. Here, we report that a SMAD4 defect in mice can cause auditory neuropathy, which was defined as a mysterious hearing and speech perception disorder in human for which the genetic background remains unclear. Our study showed that a SMAD4 defect induces failed formation of cochlear ribbon synapse during the earlier stage of auditory development in mice. Further investigation found that there are nearly normal morphology of outer hair cells (OHCs) and post-synapse spiral ganglion nerves (SGNs) in SMAD4 conditional knockout mice (cKO); however, a preserved distortion product of otoacoustic emission (DPOAE) and cochlear microphonic (CM) still can be evoked in cKO mice. Moreover, a partial restoration of hearing detected by electric auditory brainstem response (eABR) has been obtained in the cKO mice using electrode stimuli toward auditory nerves. Additionally, the ribbon synapses in retina are not affected by this SMAD4 defect. Thus, our findings suggest that this SMAD4 defect causes auditory neuropathy via specialized disruption of cochlear ribbon synapses.

Cochlear implantation is an effective, established procedure for patients with profound deafness. Although implant electrodes have been considered as biocompatible prostheses, surgical insertion of the electrode induces various changes within the cochlea. Immediate changes include insertional trauma to the cochlea. Delayed changes include a tissue response consisting of inflammation, fibrosis and neo-osteogenesis induced by trauma and an immunologic reaction to a foreign body. The goal of this study was to evaluate the effect of these delayed changes on the word recognition scores achieved post-operatively. Seventeen temporal bones from patients who in life had undergone cochlear implantation were prepared for light microscopy. We digitally calculated the volume of fibrous tissue and new bone within the cochlea using Amira(®) three-dimensional reconstruction software and assessed the correlations of various clinical and histologic factors. The postoperative CNC word score was positively correlated with total spiral ganglion cell count. Fibrous tissue and new bone were found within the cochlea of all seventeen specimens. The postoperative CNC word score was negatively correlated with the % volume of new bone within the scala tympani, scala media/vestibuli and the cochlea, but not with the % volume of fibrous tissue. The % volume of new bone in the scala media/vestibuli was positively correlated with the degree of intracochlear insertional trauma, especially trauma to the basilar membrane. Our results revealed that the % volume of new bone as well as residual total spiral ganglion cell count are important factors influencing post-implant hearing performance. New bone formation may be reduced by limiting insertional trauma and increasing the biocompatibility of the electrodes., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This study aimed to investigate the p19 expression in cisplatin-treated rats and the role of p19 in the degeneration of inner ear cells. It also searched for p19 gene alterations in patients with profound sensorineural deafness. P19ink4d is essential for the postmitotic maintenance of hair cells. It is presumed that a mutation in the functional homolog of p19 or a disturbance in its regulated expression can be the underlying cause of hearing loss. Experiments were conducted on male and female Sprague-Dawley rats (aged 6-7 weeks, 280-320 g) with thresholds of auditory brainstem responses <30 dB in the sound pressure level, and signs of middle ear infection were used for the experiment. For clinical evaluation, 400 children (age less than 13 years) from unrelated families with severe or profound sensorineural hearing loss (SNHL) were recruited at the second Xiangya Hospital of Central South University between 2005 and 2013, and genomic DNA for deafness gene analysis was obtained from peripheral blood samples of the patients and their lineal relatives. It was found that the p19 expression increased over time in the inner ear cells after cisplatin administration, but the p19 mRNA and protein levels significantly decreased in rats with manifested hearing loss induced by cisplatin. However, no mutation existed within the coding exons of p19 in the patients with profound sensorineural deafness. To conclude, the results support the concept that p19 may play an important role in the ototoxic effects of cisplatin and is probably involved in the pathogenesis of hearing loss.

Background: Cochlear implants have been used for almost 30 years as a device for the rehabilitation of individuals with severe-to-profound hearing loss. One of the important aspects of cochlear implantation is the type of electrode selected and proper insertion of the electrode array in scala tympani to minimize cochlear damage. The HiFocus Helix™ electrode is a precurved design aimed at placing the electrode contacts close to the spiral ganglion cells in the modiolus. The prescribed insertion techniques are intended to minimize the likelihood of damage to the basilar membrane or lateral wall of the cochlea., Case Presentation: To describe the first insertion of a HiFocus Helix™ electrode in Brazil exposing surgical particularities and device details in a patient with profound hearing loss, due to Mondini's dysplasia., Conclusion: No problems were encountered during the surgical procedure. The patient experienced improvement in hearing thresholds and speech perception. The HiFocus Helix™ electrode proved easy to insert and provided expected hearing benefits for the patient. This manuscript indicates that the HiResolution™ Bionic Ear System with HiFocus Helix™ electrode comprise a cochlear implant system that is practical and beneficial for the treatment of severe-to-profound hearing loss.

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.

Hypothesis: This study aimed to evaluate whether there is a difference in the degree of intracochlear trauma when the cochlear implant electrode arrays is inserted through different quadrants of the round window membrane., Background: The benefits of residual hearing preservation in cochlear implant recipients have promoted the development of atraumatic surgeries. Minimal trauma during electrode insertion is crucial for residual hearing preservation., Methods: In total, 25 fresh human temporal bones were subjected to mastoidectomy and posterior tympanotomy. The cochlear implant electrode array was inserted through the anterosuperior quadrant of the round window membrane in 50% of the bones and through the anteroinferior quadrant in the remaining 50%. The temporal bones were dehydrated, embedded in epoxy, serially polished, stained, viewed through a stereomicroscope, and photographed with the electrode arrays in situ. The resulting images were analyzed for signs of intracochlear trauma., Results: Histological examinations revealed varying degrees of damage to the intracochlear structures, although the incidence and severity of intracochlear trauma were not influenced by the quadrant of insertion., Conclusions: The incidence and severity of intracochlear trauma were similar in all samples, irrespective of electrode array insertion through the anterosuperior or anteroinferior quadrant of the round window membrane.

A cochlear implant (CI) restores partial hearing to profoundly deaf individuals. CI electrodes are inserted manually in the cochlea and surgeons rely on tactile feedback from the implant to determine when to stop the insertion. This manual insertion method results in a large degree of variability in surgical outcomes and intra-cochlear trauma. Additionally, implants often span only the basal turn. In the present study we report on the development of a new method to assist CI electrode insertion. The design objectives are (1) an automated and standardized insertion technique across patients with (2) more apical insertion than is possible by the contemporary methods, while (3) minimizing insertion trauma. The method relies on a viscous fluid flow through the cochlea to carry the electrode array with it. A small cochleostomy (∼100-150 um in diameter) is made in scala vestibuli (SV) and the round window (RW) membrane is opened. A flow of diluted Sodium Hyaluronate (also known as Hyaluronic Acid, (HA)) is set up from the RW to the SV opening using a perfusion pump that sets up a unidirectional flow. Once the flow is established an implant is dropped into the ongoing flow. Here we present a proof-of-concept study where we used this technique to insert silicone implants all the way to the cochlear apex in rats and gerbils. In light-microscopic histology, the implantation occurred without cochlear trauma. To further assess the ototoxicity of the HA perfusion, we measured compound action potential (CAP) thresholds following the perfusion of HA, and found that the CAP thresholds were substantially elevated. Thus, at this point the method is promising, and requires further development to become clinically viable., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Postoperative imaging plays a growing role in clinical studies concerning prognostic factors in cochlear implantation. Indeed, intracochlear position of the cochlear implant has recently been identified as a contributor in functional outcomes and radiological tools must be accurate enough to determine the final placement of the electrode array. The aim of our study was to validate cone beam computed tomography as a reliable technique for scalar localization of the electrode array. We performed therefore a temporal bone study on ten specimens that were implanted with a perimodiolar implant prototype. Cone beam reconstructions were performed and images were analyzed by two physicians both experienced in cochlear implant imaging, who determined the scalar localization of the implant. Temporal bones then underwent histological control to document this scalar localization and hypothetical intracochlear lesions. In four cases, a dislocation from scala tympani to scala vestibuli was suspected on cone beam reconstructions of the ascending part of the basal turn. In three of these four specimens, dislocation in pars ascendens was confirmed histologically. In the remaining temporal bone, histological analysis revealed an elevation with rupture of the basilar membrane. Histological assessment revealed spiral ligament tearing in another bone. We conclude that cone beam is a reliable tool to assess scalar localization of the selectrode array and may be used in future clinical studies.

A major component of minimally invasive cochlear implantation is atraumatic scala tympani (ST) placement of the electrode array. This work reports on a semiautomatic planning paradigm that uses anatomical landmarks and cochlear surface models for cochleostomy target and insertion trajectory computation. The method was validated in a human whole head cadaver model (n = 10 ears). Cochleostomy targets were generated from an automated script and used for consecutive planning of a direct cochlear access (DCA) drill trajectory from the mastoid surface to the inner ear. An image-guided robotic system was used to perform both, DCA and cochleostomy drilling. Nine of 10 implanted specimens showed complete ST placement. One case of scala vestibuli insertion occurred due to a registration/drilling error of 0.79 mm. The presented approach indicates that a safe cochleostomy target and insertion trajectory can be planned using conventional clinical imaging modalities, which lack sufficient resolution to identify the basilar membrane.

Objective: Although inhibition of histone deacetylases (HDACs) has been shown to protect against cisplatin-induced hearing loss, the underlying mechanism is still poorly understood. In the present study, we aim to investigate the protective effect of trichostatin A (TSA), a specific inhibitor of HDACs, on cisplatin-induced ototoxicity and to determine the differentially expressed genes involved in this process., Methods: The basilar membrane of the cochlea was isolated from 3-day newborn Wistar rats. Organotypic cultures were treated with 150 μM cisplatin or 200 nM TSA. For combination treatment, cells were pre-incubated with TSA for 1h, followed by TSA plus cisplatin treatment. Rhodamine-phalloidin staining was used to label hair cells, and immunocytochemistry with an anti-neurofilament-200 antibody was applied to label spiral ganglion neurons (SGNs). Global expression profile microarray analysis was used to identify differentially expressed genes. Molecular function and signal pathway analysis were performed using a protein analysis through evolutionary relationships (PANTHER) classification system. Real-time quantitative PCR (qPCR) was carried out for data validation., Results: Severe loss of hair cells and SGNs occurred after 48 h of cisplatin incubation, while TSA significantly increased the number of hair cells and SGNs in the combination treatment group (P<0.05). Compared with control, expression of 71 genes were up-regulated and 383 genes were down-regulated upon cisplatin treatment. Addition of TSA induced the up-regulation of 1387 genes and down-regulation of 1226 genes as compared with cisplatin administration alone. After cisplatin treatment, we observed significant down-regulation of mRNA for several genes related to synaptic function genes, including Camk2a, Camk2b, Vglut1, Snap25 and Rab3b, whereas pretreatment with TSA elevated mRNA levels of these genes. TSA greatly decreased expression of genes related to the calcium signaling pathway (Capn1 and Capn2) and apoptosis signaling pathway (Tnfrsf1a and Tp53), while addition of TSA significantly reduced levels of Tnfrsf1a and Tp53 compared with cisplatin alone (P<0.01)., Conclusions: Our results suggested that TSA might protect against cisplatin-induced ototoxicity via mediating expression of genes responsible for regulating apoptosis, intracellular calcium homeostasis, neurotransmitter synthesis and release, and synaptic plasticity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa(EGFP/EGFP)) mouse. In the Otoa(EGFP/EGFP) mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.

Objective: To develop a transmastoid-posterior tympanotomy approach for the implantation of a penetrating auditory prosthesis in the most distal portion of the cochlear nerve., Background: Animal studies suggest that penetrating cochlear nerve implants may overcome limitations of current cochlear implant systems. One step toward human implantation is the development of a suitable surgical approach., Methods: In computer-rendered 3-dimensional (3-D) models (based on micro-CT scans of 10 human temporal bones), we simulated trajectories through the most basal part of the cochlea that gave access to the most distal portion of the cochlear nerve with minimal damage to intracochlear structures. We determined their vectors with respect to the mid-modiolar axis and posterior round window edge and assessed if they intersected the chorda tympani nerve., Results: The typical vector obtained with these 3-D models ran in an anterosuperior direction, through the inferior part of the facial recess and anterior round window edge. In 7 of 10 temporal bones, this trajectory intersected the chorda tympani nerve. Based on the vectors, dummy probes were implanted in 3 of 10 temporal bones, and the need for chorda tympani removal was confirmed in accordance with the 3-D models. Postoperative micro-CT scans revealed that all probes were successfully implanted in the cochlear nerve, whereas the osseous spiral lamina and basilar membrane were preserved., Conclusion: The vector for drilling and implantation found in this study can be used as a guideline for real-life surgery and, therefore, is another step toward the clinical implementation of cochlear nerve implants.

Background: Exposure to intense noise causes the excessive movement of the organ of Corti, stretching the organ and compromising sensory cell functions. We recently revealed changes in the transcriptional expression of multiple adhesion-related genes during the acute phases of cochlear damage, suggesting that the disruption of cell-cell junctions is an early event in the process of cochlear pathogenesis. However, the functional state of cell junctions in the sensory epithelium is not clear. Here, we employed graded dextran-FITC, a macromolecule tracer that is impermeable to the organ of Corti under physiological conditions, to evaluate the barrier function of cell junctions in normal and noise-traumatized cochlear sensory epithelia., Results: Exposure to an impulse noise of 155 dB (peak sound pressure level) caused a site-specific disruption in the intercellular junctions within the sensory epithelium of the chinchilla cochlea. The most vulnerable sites were the junctions among the Hensen cells and between the Hensen and Deiters cells within the outer zone of the sensory epithelium. The junction clefts that formed in the reticular lamina were permeable to 40 and 500 but not 2,000 kDa dextran-FITC macromolecules. Moreover, this study showed that the interruption of junction integrity occurred in the reticular lamina and also in the basilar membrane, a site that had been considered to be resistant to acoustic injury. Finally, our study revealed a general spatial correlation between the site of sensory cell damage and the site of junction disruption. However, the two events lacked a strict one-to-one correlation, suggesting that the disruption of cell-cell junctions is a contributing, but not the sole, factor for initiating acute sensory cell death., Conclusions: Impulse noise causes the functional disruption of intercellular junctions in the sensory epithelium of the chinchilla cochlea. This disruption occurs at an early phase of cochlear damage. Understanding the role of this disruption in cochlear pathogenesis will require future study.

In this study, a three-dimensional finite-element model of the passive human cochlea was created. Dynamic behavior of the basilar membrane caused by the vibration of the stapes footplate was analyzed considering a fluid-structure interaction with the cochlear fluid. Next, the effects of a perilymphatic fistula (PLF) on the vibration of the cochlea were examined by making a small hole on the wall of the cochlea model. Even if a PLF existed in the scala vestibuli, a traveling wave was generated on the basilar membrane. When a PLF existed at the basal end of the cochlea, the shape of the traveling wave envelope showed no remarkable change, but the maximum amplitude became smaller at the entire frequency range from 0.5 to 5kHz and decreased with decreasing frequency. In contrast, when a PLF existed at the second turn of the cochlea, the traveling wave envelope showed a notch at the position of the PLF and the maximum amplitude also became smaller. This model assists in elucidating the mechanisms of hearing loss due to a PLF from the view of dynamics., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Atraumatic and complete insertion of the electrode array is a stated objective of cochlear implant surgery. However, it is known that obstructions within the cochlea such as new bone formation, cochlear otosclerosis, temporal bone fracture, and cochlear anomalies may limit the depth of insertion of the electrode array. In addition, even among patients without obvious clinical or radiographic indicators of obstruction, incomplete insertion may occur. The current study is a histopathologic evaluation of possible sources of resistance to insertion of the electrode array using the temporal bone collection of the Massachusetts Eye and Ear Infirmary., Methods: Forty temporal bones from patients who in life had undergone cochlear implantation were evaluated. Temporal bones were removed at autopsy and fixed and prepared for histologic study by standard techniques. Specimens were then serially sectioned and reconstructed by 2-dimensional methods. Two electrode metrics were determined for each bone: the inserted length (IL: the distance measured from the cochleostomy site to the apical tip of the electrode) and the active electrode length (AEL: the distance between the most basal and most apical electrodes on the electrode array). The ratio of these two metrics (IL/AEL) was used to split the temporal bones into two groups: those with incomplete insertion (n = 27, IL/AEL <1.0) and those with complete insertion (n = 13, IL/AEL ≥ 1.0). Seven possible histopathologic indicators of resistance to insertion of the electrode due to contact with the basilar membrane, osseous spiral lamina and/or spiral ligament were evaluated by analysis of serial sections from the temporal bones along the course of the electrode tracks., Results: Obvious obstruction by abnormal intracochlear bone or soft tissue accounted for only 6 (22%) of the 27 partial insertions. Of the remaining 21 bones with incomplete insertions and 13 bones with complete insertions, dissection of the spiral ligament to the lateral cochlear wall was the only histopathologic indicator of insertion resistance identified with significantly higher frequency in the partial-insertion bones than in the complete-insertion bones (p = 0.003). An observed trend for the percentage of complete insertions to decrease with the number of times the electrode penetrated the basilar membrane did not reach significance. In the bones without an obvious obstruction, the most frequently observed indicator of insertion resistance was dissection of the spiral ligament (with no contact of the lateral cochlear wall) identified in 67% (14/21) of partial-insertion bones and in 92% (12/13) of complete-insertion bones., Conclusion: These results are consistent with the view that (1) electrode contact with cochlear structures resulting in observable trauma to the basilar membrane, osseous spiral lamina and/or spiral ligament does not necessarily impact the likelihood of complete insertion of the electrode array and (2) once contact trauma to the spiral ligament reaches the point of dissection to the cochlear wall, the likelihood of incomplete insertion increases dramatically., (Copyright © 2010 S. Karger AG, Basel.)

Objective: Middle-turn cochleostomies are occasionally used for cochlear implant electrode placement in patients with labyrinthitis ossificans. This study evaluates the anatomic characteristics of the middle-turn cochleostomy and its suitability for placement of implant electrodes., Methods: Ten cadaveric human temporal bones were dissected using a facial recess approach. A middle-turn cochleostomy was drilled 2 mm anterior to the oval window and just inferior to the cochleariform process. The preparations were then stained with osmium tetroxide and microdissections were performed. The location of the cochleostomy on the cochlear spiral and its path through the various cochlear compartments were evaluated in all 10 specimens. A Cochlear Corporation depth gauge was inserted in five of the specimens and insertion trauma, number of contact rings, and depth of insertion were recorded., Results: Eight of the 10 cochleostomies were placed at approximately 360 degrees on the cochlear spiral, near the transition between the basal and middle turns. In one case, the cochleostomy was found to enter the cochlear apex and in another it entered scala vestibuli of the proximal basal turn. The cochleostomy entered scala media in six bones and scala vestibuli in four specimens. A depth gauge was inserted in five specimens. The number of contacts placed within the cochlear lumen ranged from four to nine. There was evidence of insertional trauma to the lateral wall of the cochlear duct, basilar membrane, and Reissner's membrane, but no evidence of fractures to the osseous spiral lamina or modiolus., Conclusion: This study demonstrates that electrodes inserted via a middle-turn cochleostomy are likely to enter scala vestibuli and have access to the middle- and apical-cochlear turns. It is also possible that the electrode could be directed into the descending portion of the basal turn depending on cochleostomy orientation. Middle-turn cochleostomy seems to be a viable alternative for electrode placement when preservation of residual hearing is not a concern.

Objective: To demonstrate and compare polycationic-mediated cochlear gene transfer with linear polyethylenimine (PEI) via cochleostomy and osmotic pump infusion method., Design: A dissociated cochlear culture was used to select the optimum nitrogen to phosphate ratio of PEI/DNA complexes to be used in vivo. The PEI-enhanced green fluorescent protein reporter gene DNA complex was introduced with single inoculation (cochleostomy) or with sustained delivery (osmotic pump method) into guinea pig cochleas and examined for transgene expression., Subjects: Male Albino Hartley guinea pigs (250-350 g)., Results: The relatively low transfection efficiency of PEI limits its potential when compared with viral counterparts; however, sustained release of the vector solution was able to improve PEI's transfection efficiency. The PEI-infused cochleas maintained intact cellular and tissue architecture with absence of inflammation. Transfection confined to the perilymphatic space highlights the need to target the gene vector into the scala media if transfection is targeted at cells within the organ of Corti., Conclusion: These findings indicate that PEI is able to transfect the cochlea in vivo with sustained delivery and present an alternative for nonviral cochlear gene therapy.

Previous experimental studies of insertion of the Nucleus standard straight and the Contour arrays into the scala tympani have reported that the electrode arrays cause damage to various cochlear structures. However, the level of insertion-induced damage by these electrode arrays to cochlear structures (the spiral ligament, the basilar membrane and the osseous spiral lamina) has not been quantified. Although it has been suggested that rotation can overcome this resistance and prevent the basilar membrane from being pierced by the tip of the Nucleus standard straight array, there has not been any attempt to study the relationship between the rotation and the reduction of damage to the basilar membrane. In this study, 3D finite element analyses of insertions of the Nucleus standard straight array and the Contour array into the scala tympani have been undertaken. The perforation of the basilar membrane by the tip of the Nucleus standard straight array at the region of 11-14 mm from the round window appears to be compounded by the geometry of the spiral passage of the scala tympani. Anti-clockwise rotations between 25 degrees and 90 degrees applied at the basal end of the electrode array (for the right cochlea) were shown to significantly reduce the contact stresses exerted by the tip on the basilar membrane which support the practice of applying small rotation partway through insertion of electrode array to minimize damage to the basilar membrane. Although the Contour array (with its stylet intact) is stiffer than the Nucleus standard straight array, a slight withdrawal of the stylet from the Contour array before insertion was found to significantly reduce damage by the electrode array to the spiral ligament and the basilar membrane.

Objective: To assess the effect of cochlear implant (CI) insertion depth and surgical technique on intracochlear trauma., Study Design and Setting: Twenty-one fresh human temporal bones were implanted with CI electrodes and underwent histologic processing and evaluation. Specimens were grouped into 3 categories: 1) soft implantation technique and standard electrode; 2) soft implantation technique and flexible prototype array; 3) forceful implantations and standard electrode. Based on the grading system (1 to 4), 2 numeric values were calculated indicating the overall severity of cochlear damage (trauma indices)., Results: Mean trauma index values were 13.8, 36.3, and 59.2 for group 1, 2, and 3, respectively. Differences in cochlear trauma (trauma index) were nonsignificant between specimens in groups 1 and 2 but were significant between groups 1 and 3., Conclusion: This study gives evidence that intracochlear trauma increases with deep insertions. Thus, in cases where cochlear integrity might be important, limited insertions should be achieved.

Objective: To evaluate the effects of type 2 diabetes mellitus on cochlear elements in humans., Design: Comparative study of the histopathologic characteristics of human temporal bones., Setting: Otopathology laboratory in a tertiary academic medical center., Patients: Temporal bones from 18 patients with type 2 diabetes mellitus were divided into 2 groups according to the method of management of diabetes: insulin in 11 patients (mean age, 51.9 years; age range, 44-65 years) and oral hypoglycemic agents in 7 patients (mean age, 54.4 years; age range, 45-64 years). The diabetic groups and 26 age-matched controls (mean age, 52.9 years) were examined using light microscopy, and the cochlear changes were compared between groups., Main Outcome Measures: Morphometric measurements of vessel wall thickness in the basilar membrane and stria vascularis were made in all turns of the cochlea at the midmodiolar level. Area measurements of the stria vascularis were made in all turns of the cochlea at the midmodiolar level. Cochlear reconstructions and standard cytocochleograms were prepared using an oil immersion objective. The number of spiral ganglion cells was determined for each segment of the cochlea. Comparisons were made in each segment between diabetic and control groups., Results: In the insulin group, walls of the vessels of the basilar membrane and stria vascularis in all turns were significantly thicker than those of controls. Walls of the vessels of the stria vascularis in the basal turn were also significantly thicker in the oral hypoglycemic group than in controls. Atrophy of the stria vascularis in most turns of the insulin group and the lower middle turn of the oral hypoglycemic group was significantly greater than in the controls. Loss of cochlear outer hair cells was significantly greater in the lower and upper basal turns in both diabetic groups. No significant difference was found in the number of spiral ganglion cells or inner hair cells between groups., Conclusion: This study demonstrates that cochlear microangiopathy and degeneration of the stria vascularis and cochlear outer hair cells are found in patients with type 2 diabetes mellitus.

Conclusions: Except for basal cochlear traumatization, all specimens implanted into scala tympani showed atraumatic insertion properties and good perimodiolar electrode positioning. Cochleostomy preparation and placement can have a significant impact on levels of basal cochlear trauma., Objective: In the past, perimodiolar cochlear implant electrodes increased the risk for intracochlear traumatization when compared to free-fitting arrays. Recently, however, clinical evidence for atraumatic perimodiolar implantations with preservation of residual hearing has been described. The aim of this paper was to histologically evaluate a perimodiolar cochlear implant array for its insertion properties in cadaver human temporal bones. Surgical and electrode factors, as well as preparation artifacts influencing intracochlear trauma, were considered in the evaluation., Materials and Methods: Sixteen human temporal bones were harvested up to 24 hours post mortem and implanted immediately with the Nucleus 24 Contour Advance cochlear implant electrode array. Implantations were either performed using a regular caudal approach cochleostomy or through the round window membrane. After implantation, all bones underwent special histological processing, which allowed sectioning of undecalcified bone. Insertion properties were evaluated according to a grading system., Results: Fourteen specimens were implanted into scala tympani and only two exhibited basal trauma attributable to electrode insertion characteristics. Two bones were implanted into scala vestibuli after causing trauma in the region of the cochleostomy. Insertion depths ranged from 180 degrees to 400 degrees. All bones showed good perimodiolar electrode positioning. Basal trauma due to surgical issues and histological artifacts was present in 10 of 16 bones.

Objective: To investigate the correlation between the reticular basement membrane thickness and the airway wall remolding in asthma patients., Methods: Lung tissues were obtained from 5 patients who died from asthma, 3 males and 2 females, aged 45 +/- 16 (fatal asthma group), 5 asthmatics who died of diseases unrelated to asthma, 3 males and 2 females, aged 47 +/- 13, (non-fatal asthma group), and 5 dead patients without asthma, 3 males and 2 females, aged 24 +/- 14 (control group) to select 41, 38, and 43 transverse sections of tracheae respectively. The samples of tracheae were divided into cartilaginous and membranous airways by light microscopy (x100). The thickness of reticular basement membrane and the dimensions of the airway wall, including the smooth muscle area, submucosal gland area, inner and outer wall areas, and lumen area were measured. The correlations of reticular basement membrane thickness with the airway changes were analyzed., Results: The reticular basement membrane was significantly thicker in both cartilaginous and membranous airways in the fatal and non-fatal asthma groups than in the control group (all P < 0.05). The submucosal gland area of the fatal asthma group was significantly larger than those of the non-fatal asthma group and control group (both P < 0.05). The inner wall area of the cartilaginous airway of the fatal asthma group was significantly larger than that of the non-fatal asthma group (P < 0.05); however, the inner wall area of the membranous airway of the fatal asthma group was not significantly different from that of the non-fatal asthma group. The outer wall areas of cartilaginous and membranous airways of the fatal asthma group were both significantly larger than those of the other 2 groups (all P < 0.05). There was no significant difference in the lumen areas of cartilaginous and membranous airways between the fatal and non-fatal asthma groups. The reticular basement membrane thickness was correlated with the smooth muscle area (P < 0.05), submucosal gland area (P < 0.05), and inner wall area (P < 0.01) of the corresponding bronchi in regard to the cartilaginous airway; and was correlated with the smooth muscle area (P < 0.05) and inner wall area (P < 0.01) of the corresponding bronchi in regard to the membranous airway, but was not correlated with the airway size, lumen area, and outer wall area in regard to the 2 kinds of airways., Conclusion: The reticular basement membrane thickness of central airway reflects the airway remolding of the central airway and the changes of smooth muscle and inner wall of the peripheral airway. It is worthwhile to do end bronchial biopsy to measure the reticular basement membrane thickness so as to assess the pathology of the airway and to conduct long-term follow-up among the asthma patients.

Objective: To study the relationship of changes in basement membrane of cerebral micro-vessels and plasminogen activator system after cerebral ischemia/reperfusion (I/R) injury in aged rats., Methods: Middle cerebral artery occlusion (MCAO) was produced by the introduction of a thread. Rats were divided randomly into sham-operation group with young rats (cerebral ischemia 3 hours and I/R 6, 12, 24, 72, 144 hours groups), sham-operation group and I/R groups in aged rats (cerebral ischemia 3 hours and I/R 6, 12, 24, 72, 144 hours groups). Immunohistochemical technique, zymogram analysis, and reverse zymogram analysis were used to study changes in basement membrane structure of cerebral-cortex microvessel, type IV collagen (Col IV) and laminin (LN) contents, and plasminogen activator system in every group., Results: With the increase of age, Col IV and LN contents of the microvessel basement membrane increased. With prolongation of I/R, the contents of Col IV and LN decreased in both young and aged rats, while the contents of tissue plasminogen activator (t-PA), urokinase plasminogen (u-PA) and plasminogen activator inhibitor (PAI-1) expression increased at the beginning and decreased subsequently. Compared with young groups, Col IV (ischemia 3 hours-I/R 12 hours), LN (ischemia 3 hours-I/R 24 hours), t-PA (I/R 6-24 hours) and u-PA (I/R 12-144 hours) expression levels were higher in aged rats, but PAI-1 (I/R 12 and 24 hours) expression was lower. In addition, changes in PAI-1 contents as determined with reverse zymogram analysis method coincided with its immunoexpression., Conclusion: With the increase of age, alterations in constituents of cerebro-microvessel basement membrane (Col IV and LN) increased. Injury to cerebro-microvessel basement membrane resulted in more serious changes in aged rats compared with the young rats. Changes in cerebro-microvessel basement membrane after I/R injury in the aged SD rats is related to change in plasminogen activator system.

Nontuberculous causes of basilar meningitis are rare. This study presents the case of a male who developed fever and meningitis caused by Streptococcus pneumoniae. He developed multiple cranial nerve palsies and imaging findings consistent with basilar meningitis and ventriculitis. Computed tomographic scans of the floor of the anterior fossa were performed after the detection of a cephalocele on magnetic resonance imaging. This imaging revealed a defect in the cribiform plate and fovea ethmoidalis with a large nasoethmoidal cephalocele. There was a second separate defect and cephalocele involving the middle cranial fossa. The association of basilar meningitis with an atypical organism should lead to a careful search for disruption in the floor of the anterior or middle cranial fossa.

Objective: To explore carboplatin-induced injury patterns of inner hair cells (IHCs) in cochlea of chinchilla, namely, when injury of IHCs occurs, what extension injury of IHCs exists at different time after drug administration, where maximal injury of IHCs locates on basal membrane and how long most IHCs lose after drug administration., Method: Carboplatin of moderate concentration (100 mg/kg) was used to inject peritoneally one time and animals were decapitated on schedule, surface preparations were made and cochleograms were obtained to observe injury of IHCs in the cochleae of chinchillas., Result: Loss of outer hair cells was not observed on basal membrane from 24 hours to 3 months after drug administration except one ear. The characteristic of IHCs injury patterns was found to be: (1) IHCs were intact at 24 hours after drug administration. IHCs injury was firstly observed within 3 days. (2) The maximal rate of IHCs injury located around boundary of turn one and turn two on basal membrane from 24 hours to 3 months. (3) IHCs injury began from boundary of turn one and turn two and extended to basal turn and apical turn gradually. Compared to apical turn, IHCs injury on basal turn occurred earlier and more severely. (4) Most IHCs lost in 3 months., Conclusion: Carboplatin of 100 mg/kg unequally destroyed IHCs from different turns. Temporal variance of injury of IHCs from given turn is most likely due to their discrepant sensitivity to carboplatin.

Conclusions: Gentamicin-induced cochlear hair cell loss depends on local middle ear administration kinetics and the total drug dose. Single-dose gentamicin instillation in the middle ear is associated with a high variation in hair cell loss., Objective: To compare the effects of single-dose and continuous round window administration of gentamicin on cochlear hair cell loss in a guinea pig model., Material and Methods: Two methods for drug administration to the inner ear were used. In groups of five animals, a total dose of 0.8 or 3.2 mg of gentamicin was either instilled as a single dose directly into the round window niche or administered continuously over a 1-week period using a pump-catheter system. Continuous administration was achieved by means of a posterior tympanotomy and subcutaneous placement of an osmotic pump fitted with a catheter. The tip of the catheter was fixed in the round window niche. One group of five animals served as controls and received a saline infusion. The animals were sacrificed after 1 week and hair cell loss was determined microscopically after dissection and phalloidin labelling of the basilar membrane and organ of Corti., Results: Quantitation of cochlear hair cell loss revealed a dose-dependent effect of gentamicin. With both treatment modalities the higher dose induced a higher percentage of hair cell loss. There was inner and outer hair cell loss in all four groups that received gentamicin. With the single-dose instillation, hair cell loss was distributed irregularly from the round window membrane towards the cochlear apex, whereas continuous administration induced hair cell loss close to the round window membrane. Single-dose instillation induced greater hair cell loss than continuous administration at the same dose. The inter-individual variation in hair cell loss was highest following single-dose instillation.

The round window membrane is considered the most likely pathway from the middle to the inner ear. Various substances placed in the middle ear have been seen to pass through the round window membrane. Once toxic substances or inflammatory mediators such as cytokines and nitric oxide enter the inner ear, various inner ear sequelae such as labyrinthitis, endolymphatic hydrops, sensorineural hearing loss or more insidious diseases can occur.

Background: The development of intracochlear electrode arrays is aiming at a placement close to the modiolus with an insertion as atraumatic as possible. A new perimodiolar electrode model the Nucleus Contour Advance was to be evaluated regarding the possible intracochlear trauma., Methods: The implantation of the Contour Advance electrode was performed in 11 frozen native temporal bones. Beneath a regular insertion in 5 temporal bones in 6 cases the insertion was carried out using the "advance-off-stylett" technique with a fixed stylett. The temporal bones were embedded in metacrylate based resin for histomorphological evaluation. The evaluation was performed regarding to the intracochlear placement close to the modiolus and the damage to intracochlear fine structures (basilar membrane, osseus spiral lamina)., Results: In 2 out of 11 cases we found a perforation from the scala tympani to the scala vestibuli independent of the insertion-technique. A severe intracochlear trauma was observed in one case with fracture of osseus spiral lamina using the AOS-technique. A close position to the modiolus could be achieved by insertion the scala tympani without perforation of the basilar membrane., Conclusions: The Nucleus Contour Advance electrode array showed minimal trauma in human temporal bones by using a standard insertion technique. By using the freehand AOS-technique a severe cochlear trauma is possible. Therefore further development in electrode design and the use of an insertion-tool is recommended.

Objective: To demonstrate that the amount of basilar membrane displacement toward the scala tympani and its attachment to the bony wall of the scala tympani (i.e., interscalar septum) in hydropic temporal bones is related to the intraosseous endolymphatic sac volume., Study Design: A retrospective analysis of temporal bones from individuals with the histopathologic diagnosis of "endolymphatic hydrops.", Methods: Fifty-two temporal bones, from 38 patients, with the histopathologic findings of "endolymphatic hydrops" were analyzed microscopically. Data were obtained regarding the displacement of the basilar membrane, endolymphatic sac volume, hair cell loss, strial atrophy, ganglion cell loss, and last measured auditory thresholds. The relationships between these variables were examined statistically., Results: Nineteen of the 52 temporal bones (36.5%) with endolymphatic hydrops showed displacement of the basilar membrane toward the scala tympani in the apical and middle segments of the cochlea. A reduced volume of the endolymphatic sac was significantly related to increased severity of basilar membrane deformation (Rho = -.646; P < or = .001). Multiple regression analysis showed that severity of basilar membrane deformation was the single best predictor of low frequency thresholds while loss of hair cells was the best predictor of pure-tone average threshold., Conclusions: The displacement of the basilar membrane in the apical and middle segments that may occur with endolymphatic hydrops, to the extent that it impinges on the interscalar septum, is related to a reduction in the intraosseous endolymphatic sac volume.

Background: The objective of this study was to assess the intracochlear position and the extent of trauma to cochlear structures using the C40(+) M electrode (MED-EL, Innsbruck, Austria), which was especially designed for the combined electric acoustic stimulation., Methods: Five human temporal bones were implanted using a standard cochlear implant procedure featuring mastoidectomy, posterior tympanotomy, and promontory cochleostomy. For the cochleostomy, an inferior approach with preservation of the endosteum of the cochlea was used to contribute to hearing preservation in the in vivo condition., Results: All insertions of the new electrode array were performed into the scala tympani of the cochlea. The average insertion depth was 288 degrees. Apically, 4 of the 5 implantations were completely atraumatic. One bone showed a rupture of the basilar membrane only at the tip of the electrode. However, 4 of the 5 arrays produced severe trauma to basal cochlear structures. Two pathomechanisms, the direct traumatization through drilling of the cochleostomy or the indirect traumatization via buckling of the array could be distinguished., Conclusions: Due to the reduced contact spacing and its flexible body, the C40(+) M electrode is suitable for cochlear implantations with hearing preservation and combined electric and acoustic stimulation of the auditory system. Modifications of the surgical pathway to the cochlea should help to minimize the risk of basal cochlear trauma.

Objective: To determine the histopathologic abnormalities within the cochlea in Alport syndrome., Background: Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen. The proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL., Methods: We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen proportional, variant5 chain gene., Results: By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal., Conclusions: The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.

This is the second communication of a series of publications on Russian studies in the field of optical coherent tomography (OCT), the newest noninvasive highly resolving technology of visualization of the structure of biological tissues. By using the investing tissues as an example, this paper demonstrates the universal types of changes in their optical properties. Optimal images permit differentiate benign and malignant processes with a high degree of diagnostic accuracy. Diverse benign processes occurring in the epithelium are detected on the OCT images as changes in its height, the scattering properties and stroke of a basilar membrane. The absence of any structure on the image is the main OCT criterion for malignancy. The diagnostic efficiency of OCT is high in recognizing neoplasia of various mucous membranes: the sensitivity of the technique is 77-98%; its specificity and diagnostic accuracy are 71-96 and 81-87%, respectively.

Objective: To investigate the characteristics of cell proliferation in chick basilar papilla (BP) following severe acoustic trauma, and the orgin of precursor cell that can generate into new hair cell., Method: Chicks were continuously exposed to a 1.5 kHz pure tone at 120 dB SPL for 48 h, and they were intraperitoneally injected with bromodeoxyuridine (BrdU) at 40 h, 48 h after the onset of exposure. Then, cochlea were immunocytochemically labeled to detect BrdU, and examined the cell proliferative activity in BP., Result: 1. Labeled cells presented in the mid-proximal region of BP where hair cells have been damaged and lost following noise overstimulation; 2. The most cells in S phase were detected at 48 h after the onset of exposure; and 3. Both labeled hair cells and supporting cells can be seen in BP; In addition, the supporting cells may act as precursor cells that can generate into new hair cells., Conclusion: These findings suggest that auditory epithelial cells can be regenerated in chick cochlea after acoustic trauma, even though ongoing production of hair cells don't occur in BP, and supporting cells may be a source of newly generated hair cells under pathological conditions.

Morphological examination of the human temporal bone in the apical region supports the benefits of deep electrode insertion. Initiation of spikes on peripheral processes close to the basilar membrane would provide improved channel selectivity during electrical stimulation but recruiting of nerve fibres requires a higher current. A clinical study was performed on 10 users of the MED-EL COMBI 40 + implant to evaluate the effect of the insertion depth of the cochlear implant electrode on speech perception. All subjects were implanted with the standard COMBI 40 + electrode with an insertion depth of > 30 mm. Acute speech tests were carried out in which stimulation was restricted to the apical, middle and basal regions of the cochlea in turn, and using electrode arrangements in which contacts were either distributed over the whole length of the cochlea or concentrated at the basal end, thus mimicking an insertion depth of approximately 20 mm only. The results showed that stimulation of the apical region of the cochlea supports a significant degree of speech understanding, and that distributing the contacts over the whole length of the cochlea improves speech perception in quiet and in noise.

Hypothesis: Are all glucocorticoids supposed to have the same effect on the round window membrane?, Background: Interest in glucocorticoids for topical treatment of inner ear diseases is increasing. The safety of such treatment should therefore be an important consideration before clinical use., Methods: In this study the authors investigated the morphology of the round window membrane after topical instillation of dexamethasone or hydrocortisone into the middle ear. Twenty Sprague-Dawley rats were used. Five rats received 5 doses, and five rats 10 doses, of 1 microg (20 microl) dexamethasone in the right ear, and five others were given 5 doses, and five rats 10 doses, of 2% (20 microl) hydrocortisone solution, also in the right ear. Membrane morphology was studied in both light microscopy and transmission electron microscopy. The thickness of exposed membranes was measured and compared with that of control membranes., Results: Thickening and microscopically signs of inflammation were observed in hydrocortisone-exposed membranes but not in dexamethasone-exposed membranes, which did not differ morphologically from those in control ears., Conclusion: Although hydrocortisone has anti-inflammatory properties, it seems to provoke inflammation in the round window membrane after topical instillation. Dexamethasone had no such effects, however.

Cochlear gene therapy represents a potential experimental and therapeutic tool to understand and treat deafness. In designing cochlear gene transfer studies, the chosen route of delivery of vector and the choice of gene therapy vector have to be given careful consideration. Several different routes of delivery have been tested in our laboratory including infusion with osmotic minipump, direct microinjection into the cochlea and application of vector-transgene complex-soaked Gelfoam((R)) into the direct contact with the round window membrane. In our experience, the latter is an easy, safe and atraumatic technique to deliver gene into the cochlea. A number of different gene transfer vectors have been investigated in vivo for their efficacy, utility and safety in intracochlear gene transfer. Vectors successfully studied include cationic liposomes, adeno-associated virus, adenovirus, lentivirus, herpes simplex virus and vaccinia virus. While the viral vectors offer clear experimental advantages, human gene therapy in the future will likely utilize nonviral vectors to maximize safety. Finally, safety issues regarding dissemination of gene transfer vectors beyond the target cochlea will need to be adequately addressed., (Copyright 2002 S. Karger AG, Basel)

Background: There are no satisfactory, noninvasive techniques currently available to visualize the cochlear implant (CI) electrode in a dynamic state as it is advanced inside the cochlea., Objective: This study describes a radiologic technique that can be used in temporal bones to monitor the electrode position in real time and to visualize the basilar membrane., Methods: A cochleostomy was performed in accordance with the normal procedure for cochlear implantation in seven fresh cadaveric temporal bones. A special x-ray tube (Microfocus; Focus, Wunstorf, Germany) with a spot size of 1 microm and fluoroscopy were used for continuous videotape imaging of the advancing electrode in the cochlea. Conventional electrodes (MED-EL 40+; MED-EL, Innsbruck, Austria) and prototypes of perimodiolar electrodes (MED-EL), with varying thicknesses and angles of insertion, were used for the study. Finally, contrast liquid (Ultravist; Berlex Imaging, Schering, Germany) was injected into the scala vestibuli through the stapes footplate., Results: The advancing electrode carrier was clearly visible at x20 magnification. With the perimodiolar electrodes, deep insertion was impossible if the guiding wire was too rigid, and retraction occurred if the wire was soft. The intact nature of the basilar membrane could be confirmed by the sequential filling of scala vestibuli and the scala tympani., Conclusion: To our knowledge, this is the first noninvasive study demonstrating continuous visualization with high-resolution and x-ray magnification of CI electrode advancement inside the intact cochlea. Our technique can be used for the development of CI electrodes with optimal design characteristics, especially stiffness. Visualization of the basilar membrane will influence the insertion techniques when CIs are developed for patients with residual hearing.

The histopathologic correlates of presbycusis suggest several categories, including degeneration of sensory cells, neurons, or the stria vascularis. Lack of clear-cut histopathologic changes in some cases has suggested an "indeterminate category"; however, several studies have suggested that a disorder of the basilar membrane (BM) may underlie indeterminate presbycusis. The objective of the present study was to quantify age-related changes in the human BM and correlate them with audiometric patterns. Under high-resolution light microscopy, BM thickness was calculated, and the number of tympanic mesothelial cells (TMCs) lining the BM was counted, at 4 cochlear locations in 92 temporal bones. The control group (n = 80) included subjects from 10 decades of age with normal hearing and/or histopathologic findings. The indeterminate group (n = 12) consisted of elderly patients (ages 64 to 91 years) with hearing loss and no apparent histopathologic changes. Age-related BM thickening was seen in both groups, but only in the most basal cochlear region. The BM thickness in the indeterminate group was not significantly different from that of age-matched controls. Counts of TMCs showed age-related decreases in all cochlear regions in both groups; however, TMC counts in the indeterminate group were not different from those of age-matched controls. The results suggest that BM histopathology is not a common cause of presbycusis. Although age-related BM thickening, seen in both groups, could contribute to hearing loss, the extreme basal region, to which the thickening was confined, is not tested in routine audiometry.

Current research and an overall review of 25 years of round window membrane studies are presented. The approach, rationale and concepts that have evolved from these studies are described. Ultrastructural studies of the round window membrane of humans, monkeys, felines and rodents have disclosed three basic layers: an outer epithelium, a middle core of connective tissue and an inner epithelium. Interspecies variations are mainly in terms of thickness, being thinnest in rodents and thickest in humans. Morphologic evidence suggests that the layers of the round window participate in resorption and secretion of substances to and from the inner ear, and that the membrane could play a role in the defense system of the ear. Different substances, including antibiotics and tracers, when placed in the middle ear side traverse the membrane. Tracers placed in perilymph become incorporated into the membrane by the inner epithelial cells. Permeability is selective and factors affecting permeability include size, concentration, electrical charge, thickness of the membrane and tacilitating agents. Passage of substances through the membrane is by different pathways, the nature of which is seemingly decided at the outer epithelium of the membrane. Round window membrane studies have provided increased knowledge of the anatomy and function of this structure, as well as new insights into pathology and pathogenesis. The concepts that have evolved from these studies are potentially useful for understanding middle and inner ear interactions, and for eventual drug delivery (based on permeability) to the inner ear.

Cholesteatoma epithelium is characterized by a keratinocyte disregulation accompanied by destruction of the ossicles and other bony parts of the temporal bone. Immunohistochemical methods using antibodies to fibronectin, tenascin and metalloproteinases were used to assess the alterations of the instrinsic and extrinsic components of the basement membrane. Spatial orientation of the basement membrane was preserved in histological sections. Collagen type IV, tenascin, fibronectin, basic fibroblastic growth factor (bFGF), and matrix metalloproteinases (MMPs) are related to the matrix, perimatrix of normal or pathological tissues. They were studied immunohistologically in twenty cholesteatomas, eight samples of normal auditory canal skin, and six specimens of normal middle ear mucosa. Cholesteatomas displayed alterations of the basal membrane, with presence of MMPs and a linear immunoreactivity for collagen type IV and laminin, disrupted in areas with intense inflammation. The electronic microscope revealed protrusions, duplications, thickening and disruptions of the lamina densa of the basement membrane. Thus, we conclude, that MMPs and bFGF could play an important role maintaining the proliferative activity and the aggressive behaviour of cholesteatoma in the middle ear.

Cell death has been documented in bird auditory inner ear epithelia after induced damage. This cell death is quickly followed by an increase in supporting cell division and regeneration of the epithelium, thereby suggesting a possible relationship between these two processes. However, aspects of this relationship still need to be better understood. The Belgian Waterslager (BWS) canary is an ideal system in which to study cell death and subsequent cell division. In contrast to mixed breed (MB) canaries, cell division normally occurs in the auditory end organ of the BWS without any external manipulation. In addition, some of the cells in the auditory epithelium may be dying through an apoptotic-like process. In the present study two methods were used to quantify dying cells in the BWS and MB canary auditory epithelia: morphological criteria and TUNEL. Results confirm that some of the abnormal hair cells in the BWS auditory epithelium are apoptotic-like. The presence of both cell death and cell division indicates that these processes act concurrently in the adult end organ. Future studies are needed to determine if cell death is a stimulus for the observed cell division.

Objectives: To evaluate the handling and insertion trauma of the recently developed Nucleus perimodiolar Contour electrode array (Cochlear Ltd., Pty, Lane Cove, New South Wales, Australia) in human temporal bones compared with the Nucleus standard straight electrode array., Study Design: E-perimental control group., Methods: Twenty-nine fresh-frozen bones were implanted with different electrode arrays by an experienced cochlear implant surgeon, and evaluated both radiologically and histologically., Results: Intracochlear insertion of the standard Nucleus straight electrode array was found to be atraumatic, confirming previous findings in the literature. Insertion of the Nucleus Contour electrode array resulted in instances of localized basilar membrane penetration causing the electrode array to move from the scala tympani into the scala vestibuli. However, this trauma did not result in any observable damage to the osseous spiral lamina or the modiolus. Basilar membrane penetration was observed in six of eight cochlear bones when a standard cochleostomy size (approximately 0.8 mm) and site (anterior and superior to the round window) were used. However, when the surgical technique was modified to use a slightly larger cochleostomy ( approximately 1.8 mm) situated closer to the round window and employ a partial stylet withdrawal technique during electrode insertion, the frequency of penetrations was restricted to two of seven bones. This trauma rate is comparable to that observed with other cochlear implants designs., Conclusions: Following our results, the design of the Nucleus Contour electrode appears to fulfill the safety requirements for an intracochlear electrode array, provided that the surgical insertion technique is modified in the manner outlined.

Kainic acid (KA) selectively damages afferent synapses that innervate, in chickens, mainly tall hair cells. To better understand the nature of KA-induced excitotoxic damage to the cochlear afferent neurons, KA, at two different concentrations (0.3 or 5 mM), was injected directly into the inner ear of adult chickens. Pathologic changes in the afferent nerve ending and cell body were evaluated with light and transmission electron microscopy at various time points after KA application. The compound action potential (CAP) and cochlear microphonic (CM) potential were recorded to monitor the physiologic status of the afferent neurons and hair cells, respectively. Hair cell morphology and function were essentially normal after KA treatment. However, afferent synapses beneath tall hair cells were swollen within 30 minutes after KA at both low (KA-L) and high (KA-H) doses. In the KA-L group, the swelling disappeared within 1 day and the morphology of the postsynaptic region returned to near normal condition. In the KA-H group, by contrast, the vacant region beneath tall hair cells remained evident even 20 weeks after KA. The number of cochlear ganglion neurons in the KA-H group decreased progressively from 1 to 8-20 weeks, whereas hair cells in the basilar papilla remained morphologically intact out to 20 weeks after KA. There was no significant change in neuron number in the KA-L group. Temporal changes in the CAP amplitude paralleled the anatomic changes, although the CAP only partially recovered. These results suggest that KA induces partially reversible damage to cochlear afferent neurons with low KA concentration; above this level, KA triggers irreversible, progressive neurodegeneration., (Copyright 2001 Wiley-Liss, Inc.)

Objective: Hearing loss caused by combined rupture of Reissner's membrane and the round window (RW) membrane (the double-membrane rupture) may differ depending on the site of the lesion on Reissner's membrane. The purpose of this experimental study was to reveal the relationship between the hearing impairment and the site of the lesion on Reissner's membrane., Background: According to experimental studies on perilymphatic fistula (PLF), profound hearing loss is not induced by rupture of RW alone, but by the double-membrane rupture. However, the mechanism responsible for hearing loss in the double-membrane rupture remains unclear., Methods: Compound action potentials (CAPs) of the cochlear nerve in response to tone pip stimuli (1, 2, 4, and 8 kHz) were recorded before the lesion, 90 minutes after the Reissner's membrane rupture, and 90 minutes after subsequent laceration of the RW. Reissner's membrane was ruptured at one of the four turns for comparison., Results: The double-membrane rupture caused a more severe increase in CAP thresholds than seen with separate ruptures, when the Reissner's membrane was ruptured at the second turn. Such pronounced increase in threshold was not seen in ears with the rupture at other turns., Conclusions: The double-membrane rupture causes varying degrees of hearing loss depending on the site of the lesion of Reissner's membrane. When the Reissner's membrane was ruptured at the second turn, the most severe hearing loss was detected.