Asymmetric pulses delivered by a cochlear implant allow a reduction in evoked firing rate and in spatial activation in the guinea pig auditory cortex.

Despite that fact that the cochlear implant (CI) is one of the most successful neuro-prosthetic devices which allows hearing restoration, several aspects still need to be improved. Interactions between stimulating electrodes through current spread occurring within the cochlea drastically limit the number of discriminable frequency channels and thus can ultimately result in poor speech perception. One potential solution relies on the use of new pulse shapes, such as asymmetric pulses, which can potentially reduce the current spread within the cochlea. The present study characterized the impact of changing electrical pulse shapes from the standard biphasic symmetric to the asymmetrical shape by quantifying the evoked firing rate and the spatial activation in the guinea pig primary auditory cortex (A1). At a fixed charge, the firing rate and the spatial activation in A1 decreased by 15 to 25 % when asymmetric pulses were used to activate the auditory nerve fibers, suggesting a potential reduction of the spread of excitation inside the cochlea. A strong "polarity-order" effect was found as the reduction was more pronounced when the first phase of the pulse was cathodic with high amplitude. These results suggest that the use of asymmetrical pulse shapes in clinical settings can potentially reduce the channel interactions in CI users.

Hybrid Ear Cubes for local controlled dexamethasone delivery to the inner ear.

A new type of miniaturized implants for local controlled drug delivery to the inner ear is proposed: Hybrid Ear Cubes. They are composed of two main parts: (i) a cylinder, which is placed into a tiny hole (<0.4 mm) drilled into (or close to) the oval (or round) window, and (ii) a cuboid, which is placed into the middle ear. The drug is released at a pre-programmed rate into the perilymph: (i) via the cylindrical part of the implant, which is in direct contact with this liquid, and (ii) via diffusion from the cuboid through the oval/round window. Importantly, the cylindrical part assures a reliable fixation of the drug delivery system at the site of administration. Furthermore, the cuboid provides a relatively "large" drug reservoir, without expulsing perilymph from the cochlea. The required surgery is minimized compared to the placement of an intracochlear implant. In contrast to previously proposed Ear Cubes, which are mono-block systems, Hybrid Ear Cubes consist of two halves, which can: (i) be loaded with different drugs, (ii) be loaded with the same drug at different concentrations, and/or (iii) be based on two different matrix formers. This offers a substantially increased formulation flexibility. Different types of silicone-based Hybrid Ear Cubes were prepared, loaded with 10% dexamethasone in one half and 0-60% dexamethasone in the other half. Importantly, tiny drug crystals were homogeneously distributed throughout the respective implant halves. The observed drug release rates were very low (e.g., <0.5% after 2 months), which can be attributed to the type of drug and silicone as well as to the very small surface area exposed to the release medium. Importantly, no noteworthy implant swelling was observed.

Optimal electrode diameter in relation to volume of the cochlea.

The volume of the cochlea is a key parameter for electrode-array design. Indeed, it constrains the diameter of the electrode-array for low-traumatic positioning in the scala timpani. The present report shows a model of scala timpani volume extraction from temporal bones images in order to estimate a maximum diameter of an electrode-array. Nine temporal bones were used, and passed to high-resolution computed tomography scan. Using image-processing techniques, scala timpani were extracted from images, and cross-section areas were estimated along cochlear turns. Cochlear implant electrode-array was fitted in these cross-sections. Results show that the electrode-array diameter is small enough to fit in the scala timpani, however the diameter is restricted at the apical part.

Ear Cubes for local controlled drug delivery to the inner ear.

A new type of advanced drug delivery systems is proposed: Miniaturized implants, which can be placed into tiny holes drilled into (or close to) the oval window. They consist of two parts: 1) A cylinder, which is inserted into the hole crossing the oval window. The cylinder (being longer than the depth of the hole) is partly located within the inner ear and surrounded by perilymph. This provides direct access to the target site, and at the same time assures implant fixation. 2) A cuboid, which is located in the middle ear, serving as a drug reservoir. One side of the cuboid is in direct contact with the oval window. Drug release into the cochlea occurs by diffusion through the cylindrical part of the Ear Cubes and by diffusion from the cuboid into and through the oval window. High precision molds were used to prepare two differently sized Ear Cubes by injection molding. The miniaturized implants were based on silicone and loaded with different amounts of dexamethasone (10 to 30 % w/w). The systems were thoroughly characterized before and upon exposure to artificial perilymph at 37°C. Importantly, drug release can effectively be controlled and sustained during long time periods (up to several years). Furthermore, the implants did not swell or erode to a noteworthy extent during the observation period. Drug diffusion through the polymeric matrix, together with limited dexamethasone solubility effects, seem to control the resulting drug release kinetics, which can roughly be estimated using mathematical equations derived from Fick's second law. Importantly, the proposed Ear Cubes are likely to provide much more reliable local long term drug delivery to the inner ear compared to liquid or semi-solid dosage forms administered into the middle ear, due to a more secured fixation. Furthermore, they require less invasive surgeries and can accommodate higher drug amounts compared to intracochlear implants. Thus, they offer the potential to open up new horizons for innovative therapeutic strategies to treat inner ear diseases and disorders.

Predictability of drug release from cochlear implants.

A simplified mathematical theory is presented allowing for in silico simulation of the effects of key parameters of miniaturized implants (size and composition) on the resulting drug release kinetics. Such devices offer a great potential, especially for local drug treatments, e.g. of the inner ear. However, the preparation and characterization of these systems is highly challenging, due to the small system dimensions. The presented mathematical theory is based on Fick's second law of diffusion. Importantly, theoretical predictions do not require the knowledge of many system-specific parameters: Only the "apparent" diffusion coefficient of the drug within the implant matrix is needed. This parameter can be easily determined via drug release measurements from thin, macroscopic films. The validity of the theoretical model predictions was evaluated by comparison with experimental results obtained with a cochlear implant. The latter consisted of miniaturized electrodes, which were embedded in a silicone matrix loaded with various amounts of dexamethasone. Importantly, independent experimental results confirmed the theoretical predictions. Thus, the presented simplified theory can help to significantly speed up the optimization of this type of controlled drug delivery systems, especially if long release periods are targeted (e.g., several months or years). Straightforward experiments with thin, macroscopic films and computer simulations can allow for rapid identification of optimal system design.

Understanding the deafened brain: implications for cochlear implant rehabilitation.

The cochlear implant (CI), by enabling oral communication in severely to profoundly deaf subjects, is one of the major medical advances over the last fifty years. Despite the globally very satisfactory results, individual outcomes vary considerably. The objective of this review is to describe the various factors influencing the results of CI rehabilitation with particular emphasis on the better understanding of neurocognitive mechanisms provided by functional brain imaging. The following aspects will be discussed: 1. Peripheral predictors such as the degree of preservation of nerve structures and the positioning of the electrode array. 2. The duration of auditory deprivation whose influence on brain reorganization is now becoming more clearly understood. 3. The age of initiation of hearing rehabilitation in subjects with pre-lingual deafness influencing the possibility of physiological maturation of nerve structures. 4. The concepts of sensitive period, decoupling and cross-modality. 5. In post-lingually deaf adults, brain plasticity can allow adaptation to the disability induced by deafness, subsequently potentiating CI rehabilitation, particularly as a result of audiovisual interactions. 6. Several studies provide concordant evidence that implanted patients present different phonological analysis and primary linguistic capacities. The results of CI rehabilitation are dependent on factors situated between the cochlea and cortical associative areas. The importance of higher cognitive influences on the functional results of cochlear implantation justify adaptation of coding strategies, as well as global cognitive management of deaf patients by utilising brain plasticity capacities.