Effect of Return Electrode Placement at Apical Cochleostomy on Current Flow With a Cochlear Implant.

OBJECTIVES: A method for stimulating the cochlear apex using perimodiolar electrode arrays is described. This method involves implanting an electrode (ECE1) into the helioctrema in addition to standard cochlear implant placement. One objective is to verify a suitable approach for implanting ECE1 in the helicotrema. Another is to determine how placement of ECE1 reshapes electric fields. DESIGN: Two cadaveric half-heads were implanted, and electric voltage tomography was measured with ECE1 placed in many positions. RESULTS: An approach for placing ECE1 was identified. Changes in electric fields were only observed when ECE1 was placed into the fluid in the helicotrema. When inside the helicotrema, electric voltage tomography modeling suggests an increased current flow toward the apex. CONCLUSIONS: Placement of ECE1 into the cochlear apex is clinically feasible and has the potential to reshape electric fields to stimulate regions of the cochlea more apical than those represented by the electrode array.

Contribution of macrophages to neural survival and intracochlear tissue remodeling responses following cochlear implantation.

BACKGROUND: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. MAIN TEXT: 10- to 12-week-old CX3CR1 + /GFP Thy1 + /YFP mice on C57BL/6J/B6 background was fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7 days after starting the diet, 3-channel cochlear implants were implanted in the ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28 days post-CI for 5 h/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10, 28 or 56 days post-CI were cryosectioned and labeled with an antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus, and lateral wall for each turn were traced manually to measure region volume. The density of nuclei, CX3CR1 + macrophages, Thy1 + spiral ganglion neuron (SGN) numbers, and the ratio of the α-SMA + volume/scala tympani volume were calculated. Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all time points. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. CONCLUSION: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival.

Contribution of macrophages to intracochlear tissue remodeling responses following cochlear implantation and neural survival.

Introduction: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani; a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. Materials and methods: 10-12-week-old CX3CR1+/GFP Thy1+/YFP mice on C57Bl6 background with normal hearing were fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7-days after starting the diet, 3-channel cochlear implants were implanted ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28- days post-CI for 5 hrs/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10-, 28- or 56-days post-CI were cryosectioned and labeled with antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus and lateral wall for each turn were traced manually to measure region volume. Density of nuclei, CX3CR1+ macrophages, Thy1+ spiral ganglion neuron (SGN) numbers and ratio of volume of α-SMA+ space/volume of scala tympani were calculated. Results: Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea: this response was initially diffuse throughout the cochlea and later localized to the scala tympani of the basal turn by 56-days post-CI. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all timepoints. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. Discussion: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival.

A new paradigm of hearing loss and preservation with cochlear implants: Learnings from fundamental studies and clinical research.

In 2010 Cochlear initiated a coordinated preclinical research program to identify the factors and underlying mechanisms of acoustic hearing loss following cochlear implantation and device use. At its inception the program was structured around several major hypotheses implicated in the loss of acoustic hearing. The understanding of causes evolved over the course of the program, leading to an increased appreciation of the role of the biological response in post-implant hearing loss. A systematic approach was developed which mapped the cochlear implant journey along a timeline that considers all events in an individual's hearing history. By evaluating the available data in this context, rather than by discrete hypothesis testing, causative and associated factors may be more readily detected. This approach presents opportunities for more effective research management and may aid in identifying new prospects for intervention. Many of the outcomes of the research program apply beyond preservation of acoustic hearing to factors important to overall cochlear health and considerations for future therapies.

Cochlear implant imaging in the mouse and guinea pig using light-sheet microscopy.

Postmortem examination of the cochlea with a cochlear implant in the scala tympani presents several challenges. It is technologically difficult to section a cochlea with an implant due to the presence of its wires and metal components that are adjacent to the membranous and bony tissues of the cochlea. These metal components damage traditional steel blades of a microtome in celloidin, paraffin or frozen embedded tissues. However, plastic embedded implanted cochleas have been successfully sectioned using specialized methods (Irving et al., 2013). An alternative non-destructive method is to optically section a chemically cleared cochlea using light-sheet microscopy, which we will describe in this publication. However, since this method uses a light-sheet to section the cochlea the opaque and reflective metal components of the implant results in some artifacts in the 2D optical sections. The best image quality using light-sheet fluorescent microscopy is when the implant is removed prior to imaging.

Animal Models of Hearing Loss after Cochlear Implantation and Electrical Stimulation.

Many hearing-impaired patients may significantly benefit from the Hybrid or electro-acoustic stimulation (EAS) cochlear implant (CI). However, as much as 30-55% of CI recipients lose residual hearing after implantation and the potential for associated benefits of EAS over traditional electric-only stimulation. The cause of this post-implantation hearing loss may be immediate or delayed and result from several factors, including surgical trauma, electric stimulation, and the foreign body response. Clinical and post-mortem studies have helped identify factors effecting EAS performance. Animal CI models are an essential translational tool to further investigate these pertinent issues through histopathological investigation with greater control of biological and stimulation variables as well as other unique research tools not available in clinical and post-mortem research. Additionally, animal CI models may provide useful preclinical data for potential therapeutic strategies aimed at improving EAS outcomes. Here we review the parameters required for rigorous study of mechanisms of post-implantation hearing loss, including selection of animal model, hearing loss model, age and sex considerations, surgical technique, and chronic electrical stimulation.

Therapeutics for hearing preservation and improvement of patient outcomes in cochlear implantation-Progress and possibilities.

The emergence of therapeutics targeted at hearing loss holds great promise in the development of novel treatments for this heterogenous condition. Whilst such therapeutics are largely designed to be efficacious in and of themselves, the possibility of combination with devices, namely cochlear implants, could result in much more effective treatment options. Here, we review the otoprotective molecules currently in clinical development, as well as generic steroids, discussing mechanisms of action and mode of delivery to the perilymph of the cochlea. Presenting both preclinical and clinical data, we explore the challenges these molecules face in reaching the inner ear. Furthermore, we consider the role of the cochlear implant as a drug delivery platform along with the ability of these drugs to preserve residual hearing and improve outcomes in implant recipients.

Cochlear implant material effects on inflammatory cell function and foreign body response.

OBJECTIVES: The objectives of this study were to assess the effects of cochlear implant (CI) biomaterials on the function of macrophages and fibroblasts, two key mediators of the foreign body response (FBR) and to determine how these materials influence fibrous tissue growth and new bone formation within the cochlea. METHODS: Macrophages and fibroblasts were cultured on polydimethylsiloxane (PDMS) and platinum substrates and human CI electrodes in vitro. Cell count, cell proliferation, cytokine production, and cell adhesion were measured. CI electrodes were implanted into murine cochleae for three weeks without electrical stimulation. Implanted cochleae were harvested for 3D X-ray microscopy with the CI left in-situ. The location of new bone growth within the scala tympani (ST) with reference to different portions of the implant (PDMS vs platinum) was quantified. RESULTS: Cell counts of macrophages and fibroblasts were significantly higher on platinum substrates and platinum contacts of CI electrodes. Fibroblast proliferation was greater on platinum relative to PDMS, and cells grown on platinum formed more/larger focal adhesions. 3D X-ray microscopy showed neo-ossification in the peri­implant areas of the ST. Volumetric quantification of neo-ossification showed a trend toward greater bone formation adjacent to the platinum electrodes compared to areas opposite or away from the platinum electrode bearing surfaces. CONCLUSIONS: Fibrotic reactions are biomaterial specific, as demonstrated by the differences in cell adhesion, proliferation, and fibrosis on platinum and PDMS. The inflammatory reaction to platinum contacts on CI electrodes likely contributes to fibrosis to a greater degree than PDMS, and platinum contacts may influence the deposition of new bone, as demonstrated in the in vivo data. This information can potentially be used to influence the design of future generations of neural prostheses.

Chronic cochlear implantation with and without electric stimulation in a mouse model induces robust cochlear influx of CX3CR1+/GFP macrophages.

BACKGROUND: Cochlear implantation is an effective auditory rehabilitation strategy for those with profound hearing loss, including those with residual low frequency hearing through use of hybrid cochlear implantation techniques. Post-mortem studies demonstrate the nearly ubiquitous presence of intracochlear fibrosis and neo-ossification following cochlear implantation. Current evidence suggests post-implantation intracochlear fibrosis is associated with delayed loss of residual acoustic hearing in hybrid cochlear implant (CI) recipients and may also negatively influence outcomes in traditional CI recipients. This study examined the contributions of surgical trauma, foreign body response and electric stimulation to intracochlear fibrosis and the innate immune response to cochlear implantation and the hierarchy of these contributions. METHODS: Normal hearing CX3CR1+/GFP mice underwent either round window opening (sham), acute CI insertion or chronic CI insertion with no, low- or high-level electric stimulation. Electric stimulation levels were based on neural response telemetry (NRT), beginning post-operative day 7 for 5 h per day. Subjects (n=3 per timepoint) were sacrificed at 4 h, 1,4,7,8,11,14 and 21 days. An unoperated group (n=3) served as controls. Cochleae were harvested at each time-point and prepared for immunohistochemistry with confocal imaging. The images were analyzed to obtain CX3CR1+ macrophage cell number and density in the lateral wall (LW), scala tympani (ST) and Rosenthal's canal (RC). RESULTS: A ST peri-implant cellular infiltrate and fibrosis occurred exclusively in the chronically implanted groups starting on day 7 with a concurrent infiltration of CX3CR1+ macrophages not seen in the other groups. CX3CR1+ macrophage infiltration was seen in the LW and RC in all experimental groups within the first week, being most prominent in the 3 chronically implanted groups during the second and third week. CONCLUSIONS: The cochlear immune response was most prominent in the presence of chronic cochlear implantation, regardless of electric stimulation level. Further, the development of intracochlear ST fibrosis was dependent on the presence of the indwelling CI foreign body. An innate immune response was evoked by surgical trauma alone (sham and acute CI groups) to a lesser degree. These data suggest that cochlear inflammation and intrascalar fibrosis after cochlear implantation are largely dependent on the presence of a chronic indwelling foreign body and are not critically dependent on electrical stimulation. Also, these data support a role for surgical trauma in inciting the initial innate immune response.

A mouse model of cochlear implantation with chronic electric stimulation.

OBJECTIVES: Cochlear implants provide an effective treatment option for those with severe hearing loss, including those with preserved low frequency hearing. However, certain issues can reduce implant efficacy including intracochlear tissue response and delayed loss of residual acoustic hearing. We describe a mouse model of cochlear implantation with chronic electric stimulation that can be used to study cochlear implant biology and related pathologies. METHODS: Twelve normal hearing adult CBA/J mice underwent unilateral cochlear implantation and were evenly divided into one group receiving electric stimulation and one not. Serial impedance and neural response telemetry (NRT) measurements were made to assess implant functionality. Functionality was defined as having at least one electrode with an impedance ≤ 35 kOhms. Mouse cochleae were harvested for histology and 3D x-ray microscopy 21 days post-operatively, or, in case the implant was still functional, at a later time point when the implant failed. A separate experiment measured the hearing preservation rate in 7 adult CBA/J mice undergoing unilateral cochlear implantation with serial auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). RESULTS: Implants maintained functionality for a mean of 35 days in the non-stimulated group and 19.8 days in the stimulated group. Reliable NRT and behavioral responses to electric stimulation were recorded. A robust intracochlear peri-implant tissue response with neo-ossification was seen in all cochleae. Six of seven mice maintained intact low frequency hearing up to 6 weeks following cochlear implantation. CONCLUSIONS: We demonstrate the feasibility of cochlear implantation and behaviorally significant electric stimulation in the mouse, with the potential for hearing preservation. This model may be combined with established mouse models of hearing loss and the large genetic and molecular research toolkit unique to the mouse for mechanistic and therapeutic investigations of cochlear implant biology.

Perilymph pharmacokinetics of marker applied through a cochlear implant in guinea pigs.

Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented. We used FITC-labeled dextran as a marker, delivering it into perilymph of guinea pigs at 10 or 100 nL/min though a cannula incorporated into a cochlear implant with the outlet in the mid basal turn. After injections of varying duration (2 hours, 1 day or 7 days) perilymph was collected from the cochlear apex using a sequential sampling technique, allowing dextran levels and gradients along scala tympani to be quantified. Data were interpreted quantitatively using computer simulations of the experiments. For injections of 2 hours duration, dextran levels were critically influenced by the presence or absence of fluid leakage at the cochleostomy site. When the cochleostomy was fluid-tight, substantially higher perilymph levels were achieved at the injection site, with concentration declining along scala tympani towards the apex. Contrary to expectations, large dextran gradients along scala tympani persisted after 24 hours of sustained injection and were still present in some animals after 7 days injection. Functional changes associated with implantation and dextran delivery, and the histological state of the implant and cannula were also documented. The persistent longitudinal gradients of dextan along the ear were not readily explained by computer simulations of the experiments based on prior pharmacokinetic data. One explanation is that inner ear pharmacokinetics are altered in the period after cochlear implantation, possibly by a permeabilization of the blood-labyrinth barrier as part of the immune response to the implant.

Acoustic Hearing After Murine Cochlear Implantation: Effects of Trauma and Implant Type.

OBJECTIVES: To model the contribution of implant material and insertion trauma on loss of acoustic hearing after cochlear implantation in an appropriate animal model. METHODS: Sixty-five C57Bl/6J mice underwent unilateral implantation with implant grade materials: 2 implant grade silicones and a third uncoated platinum wire. A sham surgery group was included as a control. Serial auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were used to discern effects on hearing over 22 weeks. Histologic measurements of damage to the organ of Corti and spiral ganglion were correlated with degree of hearing loss and material type. RESULTS: Organ of Corti damage correlated with rate of hearing loss soon after implantation (0-2 weeks) but not subsequently (2-22 weeks). Organ of Corti damage did not depend on implant type and was present even in sham surgery subjects when hearing was severely damaged. Spiral ganglia appeared unaffected. There was no evidence of an inflammatory or toxic effect of the materials beyond the site of implant insertion. CONCLUSIONS: Hearing loss and cochlear damage appear to be related to insertion trauma, with minimal effect on delayed hearing loss caused by different materials. In the C57Bl/6J mouse model, the sensory epithelium appears to be the location of damage after cochlear implantation.

Radiation therapy in cochlear implant recipients.

HYPOTHESIS: Processes of scattering and attenuation were investigated to determine the consequence on dose distributions by having a cochlear implant in the field of therapeutic radiation. BACKGROUND: Radiation oncology medical accelerator beams of 6- and 18-MV x-ray energy were used. Five cochlear implants were investigated. METHODS: Each implant model was individually studied using computer dose modeling and through exercises in radiation measurement during live delivery. RESULTS: No side scatter was detected, and negligible backscattering was observed for the primary device housing and electrodes. Attenuation consequences were found to be dependent on the model of cochlear implant studied and specifically dependent on the material composition of each device. CONCLUSION: The maximum attenuated dose change for the study was found to be -8.8% for 6 MV and -6.6% for 18 MV. This study presents the first comparison of therapeutic radiation delivery versus computerized treatment simulation involving cochlear implants.