Implantability of endaurally insertable active vibratory middle-ear implants - an anatomical study.

Background: Hearing loss is often treated with an acoustic hearing aid. However, distortion and insufficient gain may cause problems. Active non-acoustic vibratory middle-ear implants (AMEI) may contribute to solve this problem. We recently developed an AMEI which is to be implanted completely through the patient's external auditory canal. The device uses a light-emitting diode (LED) in the external auditory canal that stimulates a photovoltaic sensor, placed in the middle ear, through the intact tympanic membrane. This results in activation of a vibratory miniaturized piezoelectric displacement transducer (MDT) (actuator) coupled to the auditory organ. Aims/objectives: The aim of this study was to evaluate the anatomical implantability of the novel AMEI using an exclusively endaural approach. Materials and methods: The internal components of our AMEI were implanted into 39 human temporal bones. The surgical procedure and the optimal size and anatomical fitting were systematically evaluated. Results: We can show here that implantation of all components of this novel AMEI into anatomical specimens proves to be a quick and easy procedure, performed using an endaural approach. Conclusions and significance: The anatomical data of this study establish the basis for further technical development of our AMEI and other future implantable hearing systems.

Positioning a Novel Transcutaneous Bone Conduction Hearing Implant: a Systematic Anatomical and Radiological Study to Standardize the Retrosigmoid Approach, Correlating Navigation-guided, and Landmark-based Surgery.

HYPOTHESIS: Anatomical and radiological evaluation improves safety and accuracy of the retrosigmoid approach for positioning a transcutaneous bone conduction implant and provides anatomical reference data for standardized, landmark-based implantation at this alternative site. BACKGROUND: The primary implantation site for the floating mass transducer of a novel bone conduction hearing implant is the mastoid. However, anatomical limitations or previous mastoid surgery may prevent mastoid implantation. Therefore, the retrosigmoid approach has been introduced as an alternative. METHODS: Mastoid and retrosigmoid implantation sites were radiologically identified and evaluated in preoperative computed tomography scans of anatomical head specimens. Navigation-guided implantation was then performed in the retrosigmoid site (n = 20). The optimal retrosigmoid position was determined in relation to both the asterion and the mastoid notch as surgical landmarks in an anatomical coordinate system. RESULTS: Preoperative radiological analysis revealed spatial limitations in the mastoid in 45% of the specimens. Navigation-guided retrosigmoid implantation was possible without affecting the sigmoid sinus in all the specimens. The optimal implantation site was located 1.9 ±â€Š0.1 cm posterior/1.7 ±â€Š0.1 cm inferior to the asterion and 3.3 ±â€Š0.2 cm posterior/2.1 ±â€Š0.1 cm superior to the mastoid notch.Retrosigmoid skull thickness was 6.6 ±â€Š0.4 mm, measured anatomically, 7.0 ±â€Š0.4 mm, measured radiologically and 6.7 ±â€Š0.5 mm, measured with the navigation software. CONCLUSION: The navigation-guided retrosigmoid approach seemed to be a reliable procedure in all the specimens. Measurements of bone thickness revealed the need for spacers in 95% of the specimens. Reference coordinates of the optimal implantation site are provided and can confirm image-guided surgery or facilitate orientation if a navigation system is not available.

Assessing cisplatin-induced ototoxicity and otoprotection in whole organ culture of the mouse inner ear in simulated microgravity.

Cisplatin is a widely used anti-cancer drug. Ototoxicity is a major dose-limiting side-effect. A reproducible mammalian in-vitro model of cisplatin ototoxicity is required to screen and validate otoprotective drug candidates. We utilized a whole organ culture system of the postnatal mouse inner ear in a rotating wall vessel bioreactor under "simulated microgravity" culture conditions. As previously described this system allows whole organ culture of the inner ear and quantitative assessment of ototoxic effects of aminoglycoside induced hair cell loss. Here we demonstrate that this model is also applicable to the assessment of cisplatin induced ototoxicity. In this model cisplatin induced hair cell loss was dose and time dependent. Increasing exposure time of cisplatin led to decreasing EC50 concentrations. Outer hair cells were more susceptible than inner hair cells, and hair cells in the cochlear base were more susceptible than hair cells in the cochlear apex. Initial cisplatin dose determined the final extent of hair cell loss irrespective if the drug was withdrawn or continued. Dose dependant otoprotection was demonstrated by co-administration of the antioxidant agent N-acetyl l-cysteine. The results support the use of this inner ear organ culture system as an in vitro assay and validation platform for inner ear toxicology and the search for otoprotective compounds.

Concept and evaluation of an endaurally insertable middle-ear implant.

A concept for a partially implantable hearing device, for which the power supply and signal transmission are provided by an optical transmission path, is evaluated. The actuator is designed to fit into the round-window niche and to couple directly to the round-window membrane. Implantable hearing aids can be a suitable solution in the case of severe hearing loss, where conventional hearing aids often fail. However, the surgical effort for an implantation is comparatively high. Therefore, the objective of our work was to provide a hearing system which combines reliable coupling to the auditory system with an easy implantation technique. The actuator was designed as a piezoelectric thin-film cantilever. The optical transmission path was realised using an infrared light-emitting diode combined with an active receiver circuit. For a voltage of 1V, the unloaded actuator presents displacement amplitudes of 1µm up to a stimulus frequency of 25kHz and forces up to 0.2mN. Proportionally larger forces can be achieved by stacking single actuators. The overall transmission loss from the electrical input of the light-emitting diode driver to the mechanical output of the unloaded actuator was less than 25dB at 1kHz and maximum output.

Co-localisation of K(ir)4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K(+) recycling routes.

Sensory transduction in the cochlea depends on perilymphatic-endolymphatic potassium (K(+)) recycling. It has been suggested that the epithelial supporting cells (SCs) of the cochlear duct may form the intracellular K(+) recycling pathway. Thus, they must be endowed with molecular mechanisms that facilitate K(+) uptake and release, along with concomitant osmotically driven water movements. As yet, no molecules have been described that would allow for volume-equilibrated transepithelial K(+) fluxes across the SCs. This study describes the subcellular co-localisation of the K(ir)4.1 K(+) channel (K(ir)4.1) and the aquaporin-4 water channel (AQP4) in SCs, on the basis of immunohistochemical double-labelling experiments in rat and human cochleae. The results of this study reveal the expression of K(ir)4.1 in the basal or basolateral membranes of the SCs in the sensory domain of the organ of Corti that are adjacent to hair cells and in the non-sensory domains of the inner and outer sulci that abut large extracellular fluid spaces. The SCs of the inner sulcus (interdental cells, inner sulcus cells) and the outer sulcus (Hensen's cells, outer sulcus cells) display the co-localisation of K(ir)4.1 and AQP4 expression. However, the SCs in the sensory domain of the organ of Corti reveal a gap in the expression of AQP4. The outer pillar cell is devoid of both K(ir)4.1 and AQP4. The subcellular co-localisation of K(ir)4.1 and AQP4 in the SCs of the cochlea described in this study resembles that of the astroglia of the central nervous system and the glial Mueller cells in the retina.

Water channel proteins in the inner ear and their link to hearing impairment and deafness.

The inner ear is a fluid-filled sensory organ that transforms mechanical stimuli into the senses of hearing and balance. These neurosensory functions depend on the strict regulation of the volume of the two major extracellular fluid domains of the inner ear, the perilymph and the endolymph. Water channel proteins, or aquaporins (AQPs), are molecular candidates for the precise regulation of perilymph and endolymph volume. Eight AQP subtypes have been identified in the membranous labyrinth of the inner ear. Similar AQP subtypes are also expressed in the kidney, where they function in whole-body water regulation. In the inner ear, AQP subtypes are ubiquitously expressed in distinct cell types, suggesting that AQPs have an important physiological role in the volume regulation of perilymph and endolymph. Furthermore, disturbed AQP function may have pathophysiological relevance and may turn AQPs into therapeutic targets for the treatment of inner ear diseases. In this review, we present the currently available knowledge regarding the expression and function of AQPs in the inner ear. We give special consideration to AQP subtypes AQP2, AQP4 and AQP5, which have been studied most extensively. The potential functions of AQP2 and AQP5 in the resorption and secretion of endolymph and of AQP4 in the equilibration of cell volume are described. The pathophysiological implications of these AQP subtypes for inner ear diseases, that appear to involve impaired fluid regulation, such as Menière's disease and Sjögren's syndrome, are discussed.

A novel buoyancy technique optimizes simulated microgravity conditions for whole sensory organ culture in rotating bioreactors.

Whole-organ culture of a sensory organ in a rotating wall vessel bioreactor provides a powerful in vitro model for physiological and pathophysiological investigation as previously demonstrated for the postnatal inner ear. The model is of specific relevance as a tool for regeneration research. In the immature inner ear explant, the density was only 1.29 g/cm(3). The high density of 1.68 g/cm(3) of the functionally mature organ resulted in enhanced settling velocity and deviation from its ideal circular orbital path causing enhanced shear stress. The morphometric and physical properties, as well as the dynamic motion patterns of explants, were analyzed and numerically evaluated by an orbital path index. Application of a novel buoyancy bead technique resulted in a 6.5- to 14.8-fold reduction of the settling velocity. The deviation of the explant from its ideal circular orbital path was adjusted as indicated by an optimum value for the orbital path index (-1.0). Shear stress exerted on the inner ear explant was consequently reduced 6.4- to 15.0-fold. The culture conditions for postnatal stages were optimized, and the preconditions for transferring this in vitro model toward mature high-density stages established. This buoyancy technique may also be useful in tissue engineering of other high-density structures.

Enhanced immunogenicity in the murine airway mucosa with an attenuated Salmonella live vaccine expressing OprF-OprI from Pseudomonas aeruginosa.

We constructed an oral live vaccine based on the attenuated aroA mutant Salmonella enterica serovar Typhimurium strain SL3261 expressing outer membrane proteins F and I (OprF-OprI) from Pseudomonas aeruginosa and investigated it in a mouse model. Strains with in vivo inducible protein expression with the PpacC promoter showed good infection rates and immunogenicity but failed to engender detectable antibodies in the lung. However, a systemic booster vaccination following an oral primary immunization yielded high immunoglobulin A (IgA) and IgG antibody levels in both upper and lower airways superior to conventional systemic or mucosal booster vaccination alone. In addition, the proportion of IgG1 and IgG2a antibodies suggested that the systemic booster does not alter the more TH1-like type of response induced by the oral Salmonella primary vaccination. We conclude that an oral primary systemic booster vaccination strategy with an appropriate mucosal vector may be advantageous in diseases with the risk of P. aeruginosa airway infection, such as cystic fibrosis.

Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat.

In vivo monitoring of stem cells after grafting is essential for a better understanding of their migrational dynamics and differentiation processes and of their regeneration potential. Migration of endogenous or grafted stem cells and neurons has been described in vertebrate brain, both under normal conditions from the subventricular zone along the rostral migratory stream and under pathophysiological conditions, such as degeneration or focal cerebral ischemia. Those studies, however, relied on invasive analysis of brain sections in combination with appropriate staining techniques. Here, we demonstrate the observation of cell migration under in vivo conditions, allowing the monitoring of the cell dynamics within individual animals, and for a prolonged time. Embryonic stem (ES) cells, constitutively expressing the GFP, were labeled by a lipofection procedure with a MRI contrast agent and implanted into rat brains. Focal cerebral ischemia had been induced 2 weeks before implantation of ES cells into the healthy, contralateral hemisphere. MRI at 78-microm isotropic spatial resolution permitted the observation of the implanted cells with high contrast against the host tissue, and was confirmed by GFP registration. During 3 weeks, cells migrated along the corpus callosum to the ventricular walls, and massively populated the borderzone of the damaged brain tissue on the hemisphere opposite to the implantation sites. Our results indicate that ES cells have high migrational dynamics, targeted to the cerebral lesion area. The imaging approach is ideally suited for the noninvasive observation of cell migration, engraftment, and morphological differentiation at high spatial and temporal resolution.