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The field of hearing and deafness research is about to enter an era where new cochlear drug delivery methodologies will become more innovative and plentiful. The present report provides a representative review of previous studies where efficacious results have been obtained with animal models, primarily rodents, for protection against acute hearing loss such as acoustic trauma due to noise overexposure, antibiotic use and cancer chemotherapies. These approaches were initiated using systemic injections or oral administrations of otoprotectants. Now, exciting new options for local drug delivery, which opens up the possibilities for utilization of novel otoprotective drugs or compounds that might not be suitable for systemic use, or might interfere with the efficacious actions of chemotherapeutic agents or antibiotics, are being developed. These include interesting use of nanoparticles (with or without magnetic field supplementation), hydrogels, cochlear micropumps, and new transtympanic injectable compounds, sometimes in combination with cochlear implants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The isolated anatomical position and blood-labyrinth barrier hampers systemic drug delivery to the mammalian inner ear. Intratympanic placement of drugs and permeation via the round- and oval window are established methods for local pharmaceutical treatment. Mechanisms of drug uptake and pathways for distribution within the inner ear are hard to predict. The complex microanatomy with fluid-filled spaces separated by tight- and leaky barriers compose various compartments that connect via active and passive transport mechanisms. Here we provide a review on the inner ear architecture at light- and electron microscopy level, relevant for drug delivery. Focus is laid on the human inner ear architecture. Some new data add information on the human inner ear fluid spaces generated with high resolution microcomputed tomography at 15 μm resolution. Perilymphatic spaces are connected with the central modiolus by active transport mechanisms of mesothelial cells that provide access to spiral ganglion neurons. Reports on leaky barriers between scala tympani and the so-called cortilymph compartment likely open the best path for hair cell targeting. The complex barrier system of tight junction proteins such as occludins, claudins and tricellulin isolates the endolymphatic space for most drugs. Comparison of relevant differences of barriers, target cells and cell types involved in drug spread between main animal models and humans shall provide some translational aspects for inner ear drug applications., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Progress in drug delivery to the ear has been achieved over the last few years. This review illustrates the main mechanisms of controlled drug release and the resulting geometry- and size-dependent release kinetics. The potency, physicochemical properties, and stability of the drug molecules are key parameters for designing the most suitable drug delivery system. The most important drug delivery systems for the inner ear include solid foams, hydrogels, and different nanoscale drug delivery systems (e.g., nanoparticles, liposomes, lipid nanocapsules, polymersomes). Their main characteristics (i.e., general structure and materials) are discussed, with special attention given to underlining the link between the physicochemical properties (e.g., surface areas, glass transition temperature, microviscosity, size, and shape) and release kinetics. An appropriate characterization of the drug, the excipients used, and the formulated drug delivery systems is necessary to achieve a deeper understanding of the release process and decrease variability originating from the drug delivery system. This task cannot be solved by otologists alone. The interdisciplinary cooperation between otology/neurotology, pharmaceutics, physics, and other disciplines will result in improved drug delivery systems for the inner ear., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Drug delivery to the inner ear is an ideal method to treat a wide variety of otologic conditions. A broad range of potential applications is just beginning to be explored. New approaches combine principles of inner ear pharmacokinetics with emerging technologies of drug delivery including novel delivery systems, drug-device combinations, and new categories of drugs. Strategies include cell-specific targeting, manipulation of gene expression, local activation following systemic delivery, and use of stem cells, viral vectors, and gene editing systems. Translation of these therapies to the clinic remains challenging given the potential risks of intracochlear and intralabyrinthine trauma, our limited understanding of the etiologies of particular inner ear disorders, and paucity of accurate diagnostic tools at the cellular level. This review provides an overview of future methods, delivery systems, disease targets, and clinical considerations required for translation to clinical medicine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The development of therapies for the inner ear presents unique opportunities and challenges. On the one hand, the ear presents an opportunity for localized drug delivery to avoid systemic side effects. However, we do not understand the pathobiology of many common ear disorders clearly enough to develop rational therapeutic solutions. Further, identification of biomarkers beyond conventional audiometry and balance testing to track disease progress and recovery remain elusive. Because of the comparatively low incidence and prevalence of many inner ear disorders, as well as issues with respect to timing of drug delivery for certain diseases, multi-center, multi-investigator collaborative networks are required to promote effective clinical trial design., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Stem cell research is expanding our understanding of developmental biology as well as promising the development of new therapies for a range of different diseases. Within hearing research, the use of stem cells has focused mainly on cell replacement. Stem cells however have a broad range of other potential applications that are just beginning to be explored in the ear. Mesenchymal stem cells are an adult derived stem cell population that have been shown to produce growth factors, modulate the immune system and can differentiate into a wide variety of tissue types. Potential advantages of mesenchymal/adult stem cells are that they have no ethical constraints on their use. However, appropriate regulatory oversight seems necessary in order to protect patients from side effects. Disadvantages may be the lack of efficacy in many preclinical studies. But if proven safe and efficacious, they are easily translatable to clinical trials. The current review will focus on the potential application on mesenchymal stem cells for the treatment of inner ear disorders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study evaluated the electrocochleographic findings of patients with superior canal dehiscence (SCD) syndrome and determined their diagnostic values and relationships with audiometric parameters. Thirteen symptomatic SCD patients (1 bilateral) confirmed by temporal bone computed tomography (TBCT) and cervical vestibular evoked myogenic potentials (cVEMP) were recruited. SCD sizes were measured on reformatted images in the plane of the superior canal (SC). Results of audiologic tests (audiometry, cVEMP, electrocochleography (ECoG)) for 14 affected and 12 contralateral unaffected ears were evaluated. Relationships between summating potential (SP) to action potential (AP) ratios, as measured by ECoG, and other audiometric parameters were evaluated. Sensitivity analysis of SP/AP ratios was performed by plotting receiver operating characteristic (ROC) curves for SCD syndrome patients and 19 age-matched healthy controls. Mean SP/AP ratio of SCD ears was significantly higher than that of unaffected ears (0.52 versus 0.25, p < 0.001) and SPs were significantly elevated in affected ears (p = 0.011), whereas APs were similar for affected and unaffected ears. SP/AP ratio showed a sensitivity of 92.3% and a specificity of 94.0% for distinguishing SCD syndrome patients given the inclusion criteria applied (symptoms, TBCT, cVEMP threshold) at a cutoff value of 0.34 (p < 0.001). SP/AP ratio was not correlated with SCD size or cVEMP threshold in affected ears. Negative absolute values of bone conduction at low frequency tended to increase with SP/AP ratio. Five out of 13 patients underwent surgical repair experienced symptomatic improvement with normalization of SP/AP ratios. ECoG appears to be a valuable diagnostic adjunct for functional demonstration of the third window in the otic capsule with high sensitivity and specificity, and thus, can support a clinical diagnosis of SCD when used in conjunction with clinical and radiological findings., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.)

A superior semicircular canal dehiscence (SCD) is a break or hole in the bony wall of the superior semicircular canal. Patients with SCD syndrome present with a variety of symptoms: some with vestibular symptoms, others with auditory symptoms (including low-frequency conductive hearing loss) and yet others with both. We are interested in whether or not mechanically altering the superior canal by introducing a dehiscence is sufficient to cause the low-frequency conductive hearing loss associated with SCD syndrome. We evaluated the effect of a surgically introduced dehiscence on auditory responses to air-conducted (AC) stimuli in 11 chinchilla ears. Cochlear potential (CP) was recorded at the round-window before and after a dehiscence was introduced. In each ear, a decrease in CP in response to low frequency (<2 kHz) sound stimuli was observed after the introduction of the dehiscence. The dehiscence was then patched with cyanoacrylate glue leading to a reversal of the dehiscence-induced changes in CP. The reversible decrease in auditory sensitivity observed in chinchilla is consistent with the elevated AC thresholds observed in patients with SCD. According to the 'third-window' hypothesis the SCD shunts sound-induced stapes velocity away from the cochlea, resulting in decreased auditory sensitivity to AC sounds. The data collected in this study are consistent with predictions of this hypothesis.

The Kir4.1 gene (KCNJ10) encodes an inwardly rectifying K(+) channel subunit abundantly expressed in the CNS. Its expression in the mammalian inner ear has been suggested but its function in vivo in the inner ear is unknown. Because diverse human hereditary deafness syndromes are associated with mutations in K(+) channels, we examined auditory function and inner ear structure in mice with a genetically inactivated Kir4.1 K(+) channel subunit. Startle response experiments suggest that Kir4.1-/- mice are profoundly deaf, whereas Kir4.1+/- mice react like wild-type mice to acoustic stimuli. In Kir4.1-/- mice, the Reissner membrane is collapsed, the tectorial membrane is swollen, and type I hair cells and spiral ganglion neurons as well as their central processes degenerate over the first postnatal weeks. In the vestibular ganglia, neuronal cell death with apoptotic features is also observed. Immunostaining reveals that Kir4.1 is strongly expressed in stria vascularis of wild-type but not Kir4.1-/- mice. Within the spiral ganglion, Kir4.1 labeling was detected on satellite cells surrounding spiral ganglion neurons and axons. We conclude that Kir4.1 is crucial for normal development of the cochlea and hearing, via two distinct aspects of extracellular K(+) homeostasis: (1). in stria vascularis, Kir4.1 helps to generate the cochlear endolymph; and (2). in spiral and vestibular ganglia, Kir4.1 in surrounding glial cells helps to support the spiral and vestibular ganglion neurons and their projecting axons.

A substrain of an autoimmune-prone mouse, NZB/kl, was found to show spontaneous elevation of the auditory brainstem response (ABR) threshold with age. Morphological examination of the inner ear in NZB/kl mice with high ABR thresholds revealed pathological changes confined to the stria vascularis, including marked thickening of the capillary basement membrane which contained many foamy structures, and vacuolar degeneration of the intermediate cells. Circular or granular IgM deposits and some IgG deposits were found in the stria vascularis in the mice with high ABR thresholds, suggesting that deposits of immune complexes (mainly IgM antibodies) could cause strial damage that resulted in the ABR threshold elevation. Another substrain of NZB mice, NZB/san, showed lower levels of IgM immune complexes and anti-ss DNA antibodies, and did not develop either inner ear morphological changes or a high ABR threshold. NZB/kl mice may provide a useful animal model for studying the mechanism of autoimmune inner ear disease.

Most current theories regarding the inner ear pathology of Menières disease assume that there is an augmentation of the endolymphatic pressure due to the presence of hydrops. In this study normal hearing pigmented guinea pigs were employed to investigate the effect of increased endolymphatic pressure on the compound action potential (CAP) audiogram. All animals were implanted with an electrode on the round window and the CAP audiogram was determined prior to further surgery. The endolymphatic canal was then visualised by a posterior fossa intra-dural surgical approach. A hole was pierced in the canal and a cannula inserted. The CAP audiogram was again determined before, and at frequent intervals after, the application of hydrostatic pressure (0.5-1 cm Hg). A similar sequence of CAP sensitivity losses was observed within 2 h for 0.5 cm Hg or 15 min for 1 cm Hg. There was at first a very high frequency loss, followed by a very low frequency loss and finally a mid frequency sensitivity loss rendered the audiogram flat and lying around 50 dB sound pressure level. Given that the first characteristic index for experimental hydrops is a low frequency loss the present data suggest that an increase in endolymphatic pressure, as in these experiments, is likely to be a rather late pathological feature of hydrops. Indeed we have shown that a high frequency loss develops at a second phase during the evolution of hydrops.

Pigmented guinea pigs were chronically implanted bilaterally with a platinum electrode on each round window. After recovery the endolymphatic sac was destroyed and the duct blocked on one side only; the other side was employed as a control. The round window response thresholds on both sides were recorded several times per week over a three month period. There were three main results. A sensitivity loss of up to 20 dB was observed for frequencies between 250 Hz and 6.4 kHz within two weeks post-op. At the end of three months the threshold elevation for these frequencies was as much as 50 dB. On the other hand the thresholds for frequencies between 8 and 16 kHz remained within 10 dB of their pre-operative value for at least two months. The thresholds fluctuated with a shift of as much as 25 dB within 24 h. The threshold elevation was associated with a decrease in the latency, at threshold, of the round window AP response which at frequencies between 250 Hz and 6.4 kHz was as short as that for 8 kHz. This observation suggested that it was the base, only, of the cochlea which responded. The present study has indicated that experimentally induced endolymphatic hydrops in the guinea pig mimics well the progressive and fluctuating hearing loss characteristic of Ménière's disease.

Seventeen guinea pigs were unilaterally operated to produce endolymphatic hydrops. After 2 wk (9 animals) or 4 wk (8 animals), extracochlear electrophysiological responses to tone bursts of several frequencies were recorded in both the operated and non-operated ears. In addition, modulation by low-frequency (29 Hz sinusoidal bias) sound of the responses to 8 kHz tonebursts was measured. After the electrophysiological measurements, the animals were killed and examined histologically. Four weeks after the operation, cochlear microphonics in response to a 500 Hz tone burst and to the 29 Hz bias were significantly smaller in the operated ears. The summating potential showed a tendency to be larger in the operated ears. The compound action potential input-output curves for 2 kHz probes showed a small threshold shift accompanied by steep slopes, reminiscent of recruitment. Modulation of summating potentials by the low-frequency bias was smaller on the operated side. In most cochleae an endolymphatic hydrops was observed. Three cochleae showed a collapse of Reissner's membrane.

The response of the endolymphatic sac to a disturbance in endolymph homeostasis was investigated by examining the sac in a mouse mutant, viable dominant spotting, which is known to exhibit primary strial dysfunction and cochleo-saccular degeneration. The function of the vascular stria was assessed by measuring the endocochlear potential and the sacs were then studied by light and transmission electron microscopy. The endolymphatic sac was found to be morphologically abnormal in these mutants, the main abnormality being the presence of granular epithelial cells, which showed clear histological signs of secretory activity. A stainable precipitate, believed to be secreted by the granular cells, was observed in the lumen of the endolymphatic sac in the mutants. The findings strengthen the view that the sac is involved in the regulation of endolymph volume and pressure.

The first author's right ear produces a spontaneous otoacoustic emission (SOAE) at 7529 Hz and 16 dB SPL. An external continuous tone is able to suppress the SOAE. The 3 dB iso-suppression curve is broadly tuned and displaced, relative to the SOAE, toward higher frequencies. An audiogram notch exists at frequencies just below that of the SOAE. We explain the occurrence of both spontaneous and impulsively evoked OAEs in terms of disruption of active feedback mechanisms of the OHCs upon basilar membrane vibration. According to this hypothesis, each segment of the organ of Corti feeds back positively upon its segment of basilar membrane and negatively upon adjacent segments. If a patch of OHC loss exists, adjacent segments of the basilar membrane are released from the negative feedback and respond to an impulsive stimulus with exaggerated oscillations at their resonance frequencies, thus producing OAEs. At particularly sharp transitions between normal and abnormal regions of the organ of Corti SOAEs may be generated.

The dysfunction of the stria vascularis in the viable dominant spotting mutant mouse results in the reduction or the absence of the endocochlear potential. However, these mutants respond to an intense acoustic stimulus with a Preyer reflex (pinna twitch). This study used 14C autoradiography and electromyography to investigate central auditory responses in this mutant. There were three main findings: autoradiography demonstrated an increase in the metabolic rate within each of the central auditory nuclei during noise exposure compared with silence; electromyographic recordings indicated that there was no tensor tympani muscle reflex; the mutants were found to be susceptible to audiogenic seizures. It was concluded that the central auditory pathway of the viable dominant spotting mutant could be activated despite the abnormal strial function. Absence of the tensor tympani muscle reflex, together with auditory deprivation, might contribute to the susceptibility to audiogenic seizures.