Cochlear implant with a non-removable magnet: preliminary research at 3-T MRI.

OBJECTIVE: To perform preliminary tests in vitro and with healthy volunteers to determine the 3-T MRI compatibility of a cochlear implant with a non-removable magnet. METHODS: In the in vitro phase, we tested six implants for temperature changes and internal malfunctioning. We measured the demagnetisation of 65 internal magnets with different tilt angles between the implant's magnetic field (bi) and the main magnetic field (b0). In the in vivo phase, we tested 28 operational implants attached to the scalps of volunteers with the head in three different positions. RESULTS: The study did not find significant temperature changes or electronic malfunction in the implants tested in vitro. We found considerable demagnetisation of the cochlear implant magnets in the in vitro and in vivo testing influenced by the position of the magnet in the main magnetic field. We found that if the bi/b0 angle is <90°, there is no demagnetisation; if the bi/b0 angle is >90°, there is demagnetisation in almost 60 % of the cases. When the angle is around 90°, the risk of demagnetisation is low (6.6 %). CONCLUSION: The preliminary results on cochlear implants with non-removable magnets indicate the need to maintain the contraindication of passage through 3-T MRI. KEY POINTS: • Magnetic resonance imaging can affect cochlear implants and vice versa. • Demagnetisation of cochlear implant correlates with the angle between bi and b0. • The position of the head in the MRI influences the demagnetisation. • Three-Tesla MRI for cochlear implants is still contraindicated. • However some future solutions are discussed.

Long term behavior of dexamethasone-loaded cochlear implants: In vitro & in vivo.

The aim of this study was to better understand the long term behavior of silicone-based cochlear implants loaded with dexamethasone: in vitro as well as in vivo (gerbils). This type of local controlled drug delivery systems offers an interesting potential for the treatment of hearing loss. Because very long release periods are targeted (several years/decades), product optimization is highly challenging. Up to now, only little is known on the long term behavior of these systems, including their drug release patterns as well as potential swelling or shrinking upon exposure to aqueous media or living tissue. Different types of cylindrical, cochlear implants were prepared by injection molding, varying their dimensions (being suitable for use in humans or gerbils) and initial drug loading (0, 1 or 10%). Dexamethasone release was monitored in vitro upon exposure to artificial perilymph at 37 °C for >3 years. Optical microscopy, X-ray diffraction and Raman imaging were used to characterize the implants before and after exposure to the release medium in vitro, as well as after 2 years implantation in gerbils. Importantly, in all cases dexamethasone release was reliably controlled during the observation periods. Diffusional mass transport and limited drug solubility effects within the silicone matrices seem to play a major role. Initially, the dexamethasone is homogeneously distributed throughout the polymeric matrices in the form of tiny crystals. Upon exposure to aqueous media or living tissue, limited amounts of water penetrate into the implant, dissolve the drug, which subsequently diffuses out. Surface-near regions are depleted first, resulting in an increase in the apparent drug diffusivity with time. No evidence for noteworthy implant swelling or shrinkage was observed in vitro, nor in vivo. A simplified mathematical model can be used to facilitate drug product optimization, allowing the prediction of the resulting drug release rates during decades as a function of the implant's design.

Dexamethasone-loaded cochlear implants: How to provide a desired "burst release".

Cochlear implants containing iridium platinum electrodes are used to transmit electrical signals into the inner ear of patients suffering from severe or profound deafness without valuable benefit from conventional hearing aids. However, their placement is invasive and can cause trauma as well as local inflammation, harming remaining hair cells or other inner ear cells. As foreign bodies, the implants also induce fibrosis, resulting in a less efficient conduction of the electrical signals and, thus, potentially decreased system performance. To overcome these obstacles, dexamethasone has recently been embedded in this type of implants: into the silicone matrices separating the metal electrodes (to avoid short circuits). It has been shown that the resulting drug release can be controlled over several years. Importantly, the dexamethasone does not only act against the immediate consequences of trauma, inflammation and fibrosis, it can also be expected to be beneficial for remaining hair cells in the long term. However, the reported amounts of drug released at "early" time points (during the first days/weeks) are relatively low and the in vivo efficacy in animal models was reported to be non-optimal. The aim of this study was to increase the initial "burst release" from the implants, adding a freely water-soluble salt of a phosphate ester of dexamethasone. The idea was to facilitate water penetration into the highly hydrophobic system and, thus, to promote drug dissolution and diffusion. This approach was efficient: Adding up to 10% dexamethasone sodium phosphate to the silicone matrices substantially increased the resulting drug release rate at early time points. This can be expected to improve drug action and implant functionality. But at elevated dexamethasone sodium phosphate loadings device swelling became important. Since the cochlea is a tiny and sensitive organ, a potential increase in implant dimensions over time must be limited. Hence, a balance has to be found between drug release and implant swelling.

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.

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.