Search Results (26)

This study evaluates the protective effects of alpha-lipoic acid (ALA), diltiazem (DIL), and N-acetylcysteine (NAC) as potential adjunctive agents to enhance intratympanic dexamethasone (IT-DEX) therapy in noise-induced hearing loss. A two-phase experiment using C57BL/6J mice was conducted. In phase 1, candidate drugs were screened by perilymph concentration analysis using ultra-high-performance liquid chromatography, auditory brainstem response (ABR) threshold, and organ of Corti (OC) morphology. Western blot analysis evaluated inflammatory markers. Phase 2 investigated the synergistic effects of co-administration of the most promising candidates with DEX. All drugs successfully penetrated the inner ear via IT injection. In the noise-induced hearing loss model, ALA and DIL individually demonstrated significant improvements in ABR thresholds and OC morphology compared to DEX alone, while NAC showed no therapeutic benefit. Western blot analysis revealed that ALA and DIL suppressed inflammatory markers through distinct antioxidant-mediated mechanisms, contrasting with DEX’s anti-inflammatory pathway. However, combination therapy with DEX + ALA or DEX + DIL increased middle ear inflammation and failed to produce synergistic therapeutic effects. While ALA and DIL showed individual therapeutic promise through complementary mechanisms, combination with DEX did not enhance efficacy, suggesting that simple drug combinations may not translate to improved IT therapy outcomes. Full article

Background/Objectives: The vestibular labyrinth is classically viewed as a sensor of low-frequency head motion—linear acceleration for the otoliths and angular velocity/acceleration for the semicircular canals. However, there is now substantial evidence that air-conducted sound (ACS) can also activate vestibular receptors and afferents in mammals and other vertebrates. This sound sensitivity underlies sound-evoked vestibular-evoked myogenic potentials (VEMPs), sound-induced eye movements, and several clinical phenomena in third-window pathologies. The cellular and biophysical mechanisms by which a pressure wave in the cochlear fluids is transformed into a vestibular neural signal remain incompletely integrated into a single framework. This study aimed to provide a narrative synthesis of how ACS activates the vestibular labyrinth, with emphasis on (1) the anatomical and biophysical specializations of the maculae and cristae, (2) the dual-channel organization of vestibular hair cells and afferents, and (3) the encoding of fast, jerk-rich acoustic transients by irregular, striolar/central afferents. Methods: We integrate experimental evidence from single-unit recordings in animals, in vitro hair cell and calyx physiology, anatomical studies of macular structure, and human clinical data on sound-evoked VEMPs and sound-induced eye movements. Key concepts from vestibular cellular neurophysiology and from the physics of sinusoidal motion (displacement, velocity, acceleration, jerk) are combined into a unified interpretative scheme. Results: ACS transmitted through the middle ear generates pressure waves in the perilymph and endolymph not only in the cochlea but also in vestibular compartments. These waves produce local fluid particle motions and pressure gradients that can deflect hair bundles in selected regions of the otolith maculae and canal cristae. Irregular afferents innervating type I hair cells in the striola (maculae) and central zones (cristae) exhibit phase locking to ACS up to at least 1–2 kHz, with much lower thresholds than regular afferents. Cellular and synaptic specializations—transducer adaptation, low-voltage-activated K⁺ conductances (K_LV), fast quantal and non-quantal transmission, and afferent spike-generator properties—implement effective high-pass filtering and phase lead, making these pathways particularly sensitive to rapid changes in acceleration, i.e., mechanical jerk, rather than to slowly varying displacement or acceleration. Clinically, short-rise-time ACS stimuli (clicks and brief tone bursts) elicit robust cervical and ocular VEMPs with clear thresholds and input–output relationships, reflecting the recruitment of these jerk-sensitive utricular and saccular pathways. Sound-induced eye movements and nystagmus in third-window syndromes similarly reflect abnormally enhanced access of ACS-generated pressure waves to canal and otolith receptors. Conclusions: The vestibular labyrinth does not merely “tolerate” air-conducted sound as a spill-over from cochlear mechanics; it contains a dedicated high-frequency, transient-sensitive channel—dominated by type I hair cells and irregular afferents—that is well suited to encoding jerk-rich acoustic events. We propose that ACS-evoked vestibular responses, including VEMPs, are best interpreted within a dual-channel framework in which (1) regular, extrastriolar/peripheral pathways encode sustained head motion and low-frequency acceleration, while (2) irregular, striolar/central pathways encode fast, sound-driven transients distinguished by high jerk, steep onset, and precise spike timing. Full article

Background/Objectives: Migraine is frequently comorbid with Meniere’s disease, which may complicate interpretation of inner ear imaging and clinical diagnosis. While endolymphatic hydrops has been studied in Meniere’s disease and vestibular migraine separately, comparative imaging data for Meniere’s disease patients with and without migraine remain limited. Methods: We retrospectively analyzed 78 patients with definite Meniere’s disease who underwent endolymphatic contrast-enhanced MRI (HYbriD of Reversed image of Positive endolymph signal and native image of positive perilymph signal; or “HYDROPS”). Patients were classified as Meniere’s disease only group (n = 56), or Meniere’s disease with migraine (n = 22). The degree of endolymphatic hydrops (negative, mild, or significant) was assessed separately in the inner ear, the cochlea, and the vestibule. Results: In Meniere’s disease group, the affected ear consistently showed higher rates of significant endolymphatic hydrops compared to the healthy ear across the inner ear, cochlea, and vestibule (p < 0.01). In contrast, Meniere’s disease with migraine group showed no significant interaural differences. Meniere’s disease with migraine group showed a significantly higher frequency of significant endolymphatic hydrops in the healthy cochlea (p < 0.01). Similar patterns were observed in the inner ear (p < 0.025) and vestibule (p = 0.05), although these differences did not reach statistical significance. Bilateral hydrops was significantly more frequent in Meniere’s disease with migraine group than in Meniere’s disease group among all regions investigated (p < 0.05). Conclusions: Meniere’s disease patients with migraine exhibit a distinct endolymphatic hydrops pattern, characterized by bilateral or symmetrical hydrops and involvement of the healthy ear. These findings suggest migraine-related mechanisms may contribute to endolymphatic hydrops, and bilateral endolymphatic hydrops on endolymphatic contrast-enhanced MRI in suspected Meniere’s disease cases should prompt consideration of comorbid migraine, in addition to bilateral Meniere’s disease or asymptomatic hydrops. Full article

Background: Kölliker’s organ (KO), a transient structure in the cochlea, plays a critical role in the auditory maturation of mammals, particularly during embryonic and early postnatal development. This organ is essential for the proper differentiation and function of cochlear cells, acting as a pivotal source of signalling molecules that influence hair cell development and synaptic connectivity. Methods: This study systematically analyses the literature according to the PRISMA statement in order to evaluate the function roles of KO during cochlea development, reporting the molecular mechanisms and signalling pathways involved. Results: From our study, it emerged that KO supporting cells release adenosine triphosphate (ATP) through connexin hemichannels, initiating a cascade of intracellular calcium (Ca²⁺) signalling in adjacent inner hair cells (IHCs). This signalling promotes the release of glutamate, facilitating synaptic excitation of afferent nerve fibres and enhancing auditory neuron maturation prior to the onset of hearing. Additionally, the spontaneous electrical activity generated within KO supports the establishment of essential neural connections in the auditory pathway. The dynamic interplay between ATP release, Ca²⁺ signalling, and morphological changes in KO is crucial for cochlear compartmentalisation and fluid regulation, contributing to the formation of endolymph and perilymph. Furthermore, KO supports cellular plasticity and may provide a reservoir of precursor cells capable of trans-differentiating into hair cells under specific conditions. Conclusions: Dysregulation of KO function or delayed degeneration of its supporting cells has been implicated in auditory disorders, underscoring the importance of this organ in normal cochlear development and auditory function. Despite its identification over a century ago, further investigation is necessary to elucidate the molecular mechanisms underlying KO’s contributions to auditory maturation, particularly in human physiology. Full article

The ability to analyze perilymph could allow inner ear pathologies to be studied. However, today, perilymph sampling is only performed for research purposes because of the risk of negative outcomes such as hearing loss or balance disorders. This paper aims to analyze the current literature on perilymph sampling and propose a method to collect perilymph in clinical settings. The published literature on perilymph sampling and its analyses was screened, and the results were analyzed and discussed in this mini review. Also, articles that discussed microneedle technology were reviewed and included in the analysis of the data. Based on the results of this review, we would like to propose a feasible technique to perform perilymph sampling in clinical settings. A total of eight studies analyzing perilymph were identified; data on proteomic, metabolomic and miRNA features present within human perilymph were collected and described. Two articles describing the use and auditory outcomes post microneedle drug injection into the inner ear were identified. Based on the methods for perilymph sampling described in humans and the recent innovations introduced by the use of microneedles, we suggested a feasible method to collect perilymph in the outpatient setting. The analysis of perilymph undoubtedly represents a valid instrument to fully understand inner ear diseases. A combination of traditional and innovative techniques, such as gaining access to the round window through the transcanalar approach using micro-endoscopes and microneedles to perform sampling, might simplify the sampling procedure and make it practicable in a clinical setting. Full article

The integrity of the blood–labyrinth barrier (BLB) is essential for inner ear homeostasis, regulating the ionic composition of endolymph and perilymph and preventing harmful substance entry. Endothelial hyperpermeability, central in inflammatory and immune responses, is managed through complex intercellular communication and molecular signaling pathways. Recent studies link BLB permeability dysregulation to auditory pathologies like acoustic trauma, autoimmune inner ear diseases, and presbycusis. Polymorphonuclear granulocytes (PMNs), or neutrophils, significantly modulate vascular permeability, impacting endothelial barrier properties. Neutrophil extracellular traps (NETs) are involved in diseases with autoimmune and autoinflammatory bases. The present study evaluated the impact of NETs on a BLB cellular model using a Transwell^® setup. Our findings revealed a concentration-dependent impact of NETs on human inner ear-derived endothelial cells. In particular, endothelial permeability markers increased, as indicated by reduced transepithelial electrical resistance, enhanced dextran permeability, and downregulated junctional gene expression (ZO1, OCL, and CDH5). Changes in cytoskeletal architecture were also observed. These preliminary results pave the way for further research into the potential involvement of NETs in BLB impairment and implications for auditory disorders. Full article

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer’s disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation. Full article

Background: Since the discovery of the perilymphatic fistula (PLF), the diagnosis and treatment remain controversial. If successfully recognized, the PLF is surgically repairable with an obliteration of the fistula site. Successful treatment has a major impact on patient’s quality of life with an improvement in their audiological and vestibular symptoms. Objective: To prospectively investigate patients’ clinical and audiological evolution with PLF suspicion after middle ear exploration and obliteration of the round and oval window. Study Design: Prospective comparative study. Setting: Tertiary care center. Methods: Patients were divided into two groups: Group I consisted of patients where no PLF had been identified intraoperatively at the oval and/or at the round window, and Group II consisted of patients where a fistula had been visualized. Patient assessment was a combination of past medical history, the presence of any risk factors, cochlear and vestibular symptoms, a physical examination, temporal bone imaging, audiograms, and a videonystagmogram (VNG). Results: A total of 98 patients were divided into two groups: 62 in Group I and 36 in Group II. A statistically significant difference regarding gender was observed in Group II (83.3% of males vs. 16.7% of females, p = 0.008). A total of 14 cases (4 and 10 in Groups I and II, respectively) were operated for a recurrent PLF. Fat graft material was used in the majority of their previous surgery; however, no difference was found when comparing fat to other materials. In addition, no statistically significant difference was noted between Groups I and II concerning predisposing factors, imaging, VNG, symptom evolution, or a physical exam before the surgery and at 12 months post-operative. However, both groups showed statistically significant hearing and vestibular improvement. On the other hand, the air conduction (AC) and bone conduction (BC) at each frequency were not statistically different between the two groups before surgery but showed statistically significant improvement at 12 months post-operatively, especially for the BC at the frequencies 250 (p = 0.02), 500 (p = 0.0008), and 1000 Hz (p = 0.04). Conclusions: Whenever you suspect a perilymphatic fistula, do not hesitate to explore middle ear and do window obliterations using a tragal perichondrium material. Our data showed that cochlear and vestibular symptoms improved whether a fistula had been identified or not. Full article

The cochlear aqueduct (CA) connects the scala tympani to the subarachnoid space and is thought to assist in pressure regulation of perilymph in normal ears, however, its role and variation in inner ear pathology, such as in superior canal dehiscence syndrome (SCDS), is unknown. This retrospective radiographic investigation compared CA measurements and classification, as measured on flat-panel computerized tomography, among three groups of ears: controls, n = 64; anatomic superior canal dehiscence without symptoms (SCD), n = 28; and SCDS, n = 64. We found that in a multinomial logistic regression adjusted for age, sex, and BMI, an increase in CA length by 1 mm was associated with a lower odds for being in the SCDS group vs. control (Odds ratio 0.760 p = 0.005). Hierarchical clustering of continuous CA measures revealed a cluster with small CAs and a cluster with large CAs. Another multinomial logistic regression adjusted for the aforementioned clinical covariates showed an odds ratio of 2.97 for SCDS in the small CA cluster as compared to the large (p = 0.004). Further, no significant association was observed between SCDS symptomatology—vestibular and/or auditory symptoms—and CA structure in SCDS ears. The findings of this study lend support to the hypothesis that SCDS has a congenital etiology. Full article

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker^® microbubbles (MBs; VisualSonics—Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 10⁸ MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model. Full article

As noise-induced hearing loss (NIHL) is a leading cause of occupational diseases, there is an urgent need for the development of preventive and therapeutic interventions. To avoid user-compliance-based problems occurring with conventional protection devices, the pharmacological prevention is currently in the focus of hearing research. Noise exposure leads to an increase in reactive oxygen species (ROS) in the cochlea. This way antioxidant agents are a promising option for pharmacological interventions. Previous animal studies reported preventive as well as therapeutic effects of Insulin-like growth factor 1 (IGF-1) in the context of NIHL. Unfortunately, in patients the time point of the noise trauma cannot always be predicted, and additive effects may occur. Therefore, continuous prevention seems to be beneficial. The present study aimed to investigate the preventive potential of continuous administration of low concentrations of IGF-1 to the inner ear in an animal model of NIHL. Guinea pigs were unilaterally implanted with an osmotic minipump. One week after surgery they received noise trauma, inducing a temporary threshold shift. Continuous IGF-1 delivery lasted for seven more days. It did not lead to significantly improved hearing thresholds compared to control animals. Quite the contrary, there is a hint for a higher noise susceptibility. Nevertheless, changes in the perilymph proteome indicate a reduced damage and better repair mechanisms through the IGF-1 treatment. Thus, future studies should investigate delivery methods enabling continuous prevention but reducing the risk of an overdosage. Full article

Noise-induced hearing loss (NIHL) is one of the leading causes of sensorineural hearing loss with global importance. The current treatment of choice for patients with hearing problems is a hearing aid or a cochlear implant. However, there is currently no treatment to restore physiological hearing. The development of preventive drugs is currently the focus of hearing research. In order to test the efficacy of a drug, the active ingredient has to be applied at reliable concentrations over a period of time. Osmotic minipumps can provide local drug delivery into the perilymph. Combined with a cochlear implant or a tube, the implantation of the pumps may lead to increased hearing thresholds. Such surgery-related threshold shifts complicate the examination of other factors, such as noise. The aim of the present study was to develop an animal model for the examination of substances that potentially prevent NIHL. For this purpose, six male guinea pigs were unilaterally implanted with a silicon catheter with a hook-shaped microcannula at its tip, attached to an artificial perilymph containing osmotic minipump. One week after surgery, the animals were exposed to four hours of a musical piece, presented at 120 dB SPL, to induce a threshold shift. The implantation of the hook-delivery device caused a moderate threshold shift that allows to detect an additional noise-induced temporary threshold shift. This method enables to investigate drug effects delivered prior to the noise insult in order to establish a preventive strategy against noise-induced temporary threshold shifts. The established drug delivery approach allows the release of drugs into the inner ear in a known concentration and for a known duration. This provides a scientific tool for basic research on drug effects in normal hearing animals. Full article

Protecting tissues from excessive inflammation by glucocorticoids results in an effective blockade of inflammation; however, it does not instigate processes of inflammatory resolution or tissue repair. Moreover, glucocorticoids have side effects such as a susceptibility to infections. In otolaryngology—specifically, within the inner ear—surgical and non-surgical pathologies include cochlear implantation, stapes surgery, perilymph fistulas and Meniere’s disease. For these, steroids are indicated in order to prevent excessive inflammation that might lead to hearing and vestibular failure. Unless tissue homeostasis is restored, the compromised tissue is at risk of a functional loss. α1-Antitrypsin (AAT) is a circulating inflammation-modulating molecule that rises during the molecular signs of a tissue injury; it manipulates inflammation towards an inflammatory resolution and advances tissue repair. Lifelong infusions of AAT are currently indicated for genetic AAT deficiencies and are safe. In the present review, we discuss the advantages and downfalls of glucocorticoid treatments across several surgical inner ear injuries alongside evidence of the beneficial attributes of treatments with AAT. Collectively, the present knowledge places AAT treatments, wither independent or in combination with glucocorticoids, as adding focus on tissue repair in the context of unmet medical needs in otolaryngology. Full article

Objectives: Precision medicine for inner ear disorders has seen significant advances in recent years. However, unreliable access to the inner ear has impeded diagnostics and therapeutic delivery. The purpose of this review is to describe the development, production, and utility of novel microneedles for intracochlear access. Methods: We summarize the current work on microneedles developed using two-photon polymerization (2PP) lithography for perforation of the round window membrane (RWM). We contextualize our findings with the existing literature in intracochlear diagnostics and delivery. Results: Two-photon polymerization lithography produces microneedles capable of perforating human and guinea pig RWMs without structural or functional damage. Solid microneedles may be used to perforate guinea pig RWMs in vivo with full reconstitution of the membrane in 48–72 h, and hollow microneedles may be used to aspirate perilymph or inject therapeutics into the inner ear. Microneedles produced with two-photon templated electrodeposition (2PTE) have greater strength and biocompatibility and may be used to perforate human RWMs. Conclusions: Microneedles produced with 2PP lithography and 2PTE can safely and reliably perforate the RWM for intracochlear access. This technology is groundbreaking and enabling in the field of inner ear precision medicine. Full article

The pathophysiological mechanisms of noise-induced hearing loss remain unknown. Identifying biomarkers of noise-induced hearing loss may increase the understanding of pathophysiological mechanisms of deafness, allow for a more precise diagnosis, and inform personalized treatment. Emerging techniques such as metabolomics can help to identify these biomarkers. The objective of the present study was to investigate immediate-early changes in the perilymph metabolome following acoustic trauma. Metabolomic analysis was performed using liquid chromatography coupled to mass spectrophotometry to analyze metabolic changes in perilymph associated with noise-induced hearing loss. Sheep (n = 6) were exposed to a noise designed to induce substantial hearing loss. Perilymph was collected before and after acoustic trauma. Data were analyzed using univariate analysis and a supervised multivariate analysis based on partial least squares discriminant analysis. A metabolomic analysis showed an abundance of 213 metabolites. Four metabolites were significantly changed following acoustic trauma (Urocanate (p = 0.004, FC = 0.48), S-(5’-Adenosyl)-L-Homocysteine (p = 0.06, FC = 2.32), Trigonelline (p = 0.06, FC = 0.46) and N-Acetyl-L-Leucine (p = 0.09, FC = 2.02)). The approach allowed for the identification of new metabolites and metabolic pathways involved with acoustic trauma that were associated with auditory impairment (nerve damage, mechanical destruction, and oxidative stress). The results suggest that metabolomics provides a powerful approach to characterize inner ear metabolites which may lead to identification of new therapies and therapeutic targets. Full article