[Facial nerve protection in surgery for rare tumors of the internal auditory canal].

Objective:To explore strategies for preserving facial nerve function during surgeries for rare tumors of the internal auditory canal. Methods:A total of 235 cases of internal auditory canal tumors treated between 2010 and 2023 were included, encompassing vestibular schwannomas, cavernous hemangiomas, meningiomas, and other rare tumors. Various data, including clinical presentations, imaging classifications, and treatment processes, were meticulously analyzed to delineate the characteristics of rare tumors and assess pre-and postoperative facial nerve function. Results:Among all internal auditory canal tumors, vestibular schwannomas accounted for 91.9%. In rare tumors, facial nerve schwannomas constituted 5.3%, cavernous hemangiomas 26.3%, meningiomas 15.8%, and arterial aneurysms 10.5%. Significantly, patients with cavernous hemangiomas displayed pronounced invasion of the facial nerve by the tumor, in contrast to other tumor types where clear boundaries with the facial nerve were maintained. During surgery, individualized approaches and strategies for facial nerve protection were implemented for different tumor types, involving intraoperative dissection, tumor excision, and facial nerve reconstruction. Conclusion:Preservation of the facial nerve is crucial in the surgical management of rare tumors of the internal auditory canal. Accurate preoperative diagnosis, appropriate timing of surgery, selective surgical approaches, and meticulous intraoperative techniques can maximize the protection of facial nerve function. Personalized treatment plans and strategies for facial nerve functional reconstruction are anticipated to enhance surgical success rates, reduce the risk of postoperative facial nerve dysfunction, and ultimately improve the quality of life for patients.

[The value of HRCT in predicting cerebrospinal fluid gusher during cochlear implantation].

Objective:To investigate the predictive value of temporal bone high-resolution CT（HRCT） multiplanar reconstruction（MPR） for cerebrospinal fluid（CSF） gusher during cochlear implantation in patients with inner ear malformation. Methods:The clinical data of 33 patients（36 ears） with inner ear malformation who underwent cochlear implantation were retrospectively analyzed. The predictive value of HRCT for cerebrospinal fluid gusher during cochlear implantation was evaluated. Results:The width of the cochlear foramen（P=0.024, OR=1.735） and the diameter of the inner auditory meatus（P=0.022, OR=6.119） were independent risk factors for CSF gusher during cochlear implantation. The area under the curve（AUC） of cochlear foramen width in predicting intraoperative gusher was 0.851, the sensitivity was 93.33%, and the specificity was 61.90%. The AUC of the upper and lower diameter of the internal auditory canal for predicting intraoperative gusher was 0.848, the sensitivity was 80.00%, and the specificity was 80.95%. The AUC of cochlear foramen width combined with the upper and lower diameters of the internal auditory meatus for predicting intraoperative gusher was 0.930, the sensitivity was 80.00%, and the specificity was 95.24%. Conclusion:Based on temporal bone HRCT, the prediction model of cochlear foramen width combined with the upper and lower diameter of the internal auditory canal has crucial predictive value for the "gusher" during cochlear implantation in patients with inner ear malformation.

[Mechanism of noise induced hidden hearing loss based on proteomics].

Objective: To explore the mechanism of noise-induced hidden hearing loss by proteomics. Methods: In October 2022, 64 SPF male C57BL/6J mice were divided into control group and noise exposure group with 32 mice in each group according to random sampling method. The noise exposure group was exposed to 100 dB sound pressure level, 2000-16000 Hz broadband noise for 2 h, and the mouse hidden hearing loss model was established. Auditory brainstem response (ABR) was used to test the change of hearing threshold of mice on the 7th day after noise exposure, the damage of basal membrane hair cells was observed by immunofluorescence, and the differentially expressed proteins in the inner ear of mice in each group were identified and analyzed by 4D-Label-free quantitative proteomics, and verified by Western blotting. The results were statistically analyzed by ANOVA and t test. Results: On the 7th day after noise exposure, there was no significant difference in hearing threshold between the control group and the noise exposure group at click and 8000 Hz acoustic stimulation (P>0.05) . The hearing threshold in the noise exposure group was significantly higher than that in the control group under 16000 Hz acoustic stimulation (P<0.05) . Confocal immunofluorescence showed that the basal membrane hair cells of cochlear tissue in noise exposure group were arranged neatly, but the relative expression of C-terminal binding protein 2 antibody of presynaptic membrane in middle gyrus and basal gyrus was significantly lower than that in control group (P<0.05) . GO enrichment analysis showed that the functions of differentially expressed proteins were mainly concentrated in membrane potential regulation, ligand-gated channel activity, and ligand-gated ion channel activity. KEGG pathway enrichment analysis showed that differentially expressed proteins were significantly enriched in phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, etc. Western blotting showed that the expression of inositol 1, 4, 5-trisphosphate receptor 3 (Itpr3) was increased and the expression of solute carrier family 38 member 2 (Slc38a2) was decreased in the noise exposure group (P<0.05) . Conclusion: Through proteomic analysis, screening and verification of the differential expression proteins Itpr3 and Slc38a2 in the constructed mouse noise-induced hidden hearing loss model, the glutaminergic synaptic related pathways represented by Itpr3 and Slc38a2 may be involved in the occurrence of hidden hearing loss.

[Research progress in targeted delivery of inner ear using nanocarriers].

Various inner ear diseases such as sensorineural deafness and Meniere's disease bring about problems such as speech communication disorders and decreased work efficiency, which seriously affect the life quality of patients. Due to the special anatomical structure and blood-labyrinth barrier in the inner ear, the current drug administration methods are often unable to achieve satisfactory results. Nanocarriers are the forefront and hot spot of nanotechnology research. In recent years, a lot of research progress has been made in the field of targeted delivery of the inner ear, which is expected to be eventually applied to the treatment of clinical diseases of the inner ear. This review focuses on the advantages, main research achievements and limitations of various nanocarriers in the targeted delivery of the inner ear, hoping to provide new ideas for related research.

Unilateral Multifocal Inner Ear and Internal Auditory Canal or Cerebellopontine Angle Cochleovestibular Schwannomas-Genetic Analysis and Management by Surgical Resection and Cochlear Implantation.

OBJECTIVE: To describe the genetic characteristics and the management of two very rare cases of unilateral multifocal inner ear and internal auditory canal or cerebellopontine angle cochleovestibular schwannomas not being associated to full neurofibromatosis type 2-related schwannomatosis. PATIENTS: In a 29-year-old man and a 55-year-old woman with single-sided deafness multifocal unilateral cochleovestibular schwannomas were surgically resected, and hearing was rehabilitated with a cochlear implant (CI). Unaffected tissue was analyzed using next generation sequencing of the NF2 gene. Tumor tissue was analyzed using a 340-parallel sequencing gene panel. MAIN OUTCOME MEASURES: Mutations in the NF2 gene, word recognition score for monosyllables at 65 dB SPL (WRS 65 ) with CI. RESULTS: No disease-causing mutation was detected in the examined sequences in blood leucokytes. All tumor samples revealed, among others, somatic pathogenic NF2 mutations. While the anatomically separate tumors in case 1 were likely molecular identical, the tumors in case 2 showed different genetic patterns. WRS 65 was 55% at 6 years of follow-up and 60% at 4.5 years of follow-up, respectively. CONCLUSIONS: The occurrence of multifocal unilateral cochleovestibular schwannomas without pathogenic variants in NF2 in non-affected blood leucocytes can be associated with mosaic NF2 -related schwannomatosis (case 1), or with likely sporadic mutations (case 2) and may be overlooked due to their extreme rarity. Although challenging, successful hearing rehabilitation could be achieved through surgical resection of the tumors and cochlear implantation.

A Low Dose of Rapamycin Promotes Hair Cell Differentiation by Enriching SOX2+ Progenitors in the Neonatal Mouse Inner Ear Organoids.

PURPOSE: To investigate the impact of rapamycin on the differentiation of hair cells. METHODS: Murine cochlear organoids were derived from cochlear progenitor cells. Different concentrations of rapamycin were added into the culture medium at different proliferation and differentiation stages. RESULTS: Rapamycin exhibited a concentration-dependent reduction in the proliferation of these inner ear organoids. Nevertheless, organoids subjected to a 10-nM dose of rapamycin demonstrated a markedly increased proportion of hair cells. Furthermore, rapamycin significantly upregulated the expression of markers associated with both hair cells and supporting cells, including ATOH1, MYO7A, and SOX2. Mechanistic studies revealed that rapamycin preferentially suppressed cells without Sox2 expression during the initial proliferation stage, thereby augmenting and refining the population of SOX2+ progenitors. These enriched progenitors were predisposed to differentiate into hair cells during the later stages of organoid development. Conversely, the use of the mTOR activator MHY 1485 demonstrated opposing effects. CONCLUSION: Our findings underscore a practical strategy for enhancing the generation of inner ear organoids with a low dose of rapamycin, achieved by enriching SOX2+ progenitors in an in vitro setting.

Age-related changes in the zebrafish and killifish inner ear and lateral line.

Age-related hearing loss (ARHL) is a debilitating disorder for millions worldwide. While there are multiple underlying causes of ARHL, one common factor is loss of sensory hair cells. In mammals, new hair cells are not produced postnatally and do not regenerate after damage, leading to permanent hearing impairment. By contrast, fish produce hair cells throughout life and robustly regenerate these cells after toxic insult. Despite these regenerative abilities, zebrafish show features of ARHL. Here, we show that aged zebrafish of both sexes exhibited significant hair cell loss and decreased cell proliferation in all inner ear epithelia (saccule, lagena, utricle). Ears from aged zebrafish had increased expression of pro-inflammatory genes and significantly more macrophages than ears from young adult animals. Aged zebrafish also had fewer lateral line hair cells and less cell proliferation than young animals, although lateral line hair cells still robustly regenerated following damage. Unlike zebrafish, African turquoise killifish (an emerging aging model) only showed hair cell loss in the saccule of aged males, but both sexes exhibit age-related changes in the lateral line. Our work demonstrates that zebrafish exhibit key features of auditory aging, including hair cell loss and increased inflammation. Further, our finding that aged zebrafish have fewer lateral line hair cells yet retain regenerative capacity, suggests a decoupling of homeostatic hair cell addition from regeneration following acute trauma. Finally, zebrafish and killifish show species-specific strategies for lateral line homeostasis that may inform further comparative research on aging in mechanosensory systems.

Guinea Pig Round Window Membrane Explantation for Ex Vivo Studies.

Efficient and minimally invasive drug delivery to the inner ear is a significant challenge. The round window membrane (RWM), being one of the few entry points to the inner ear, has become a vital focus of investigation. However, due to the complexities of isolating the RWM, our understanding of its pharmacokinetics remains limited. The RWM comprises three distinct layers: the outer epithelium, the middle connective tissue layer, and the inner epithelial layer, each potentially possessing unique delivery properties. Current models for investigating transport across the RWM utilize in vivo animal models or ex vivo RWM models which rely on cell cultures or membrane fragments. Guinea pigs serve as a validated preclinical model for the investigation of drug pharmacokinetics within the inner ear and are an important animal model for the translational development of delivery vehicles to the cochlea. In this study, we describe an approach for explantation of a guinea pig RWM with surrounding cochlear bone for benchtop drug delivery experiments. This method allows for preservation of native RWM architecture and may provide a more realistic representation of barriers to transport than current benchtop models.

Genetically modified pigs: Emerging animal models for hereditary hearing loss.

Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology, and electrophysiological characteristics, as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models.

A novel radiological software prototype for automatically detecting the inner ear and classifying normal from malformed anatomy.

BACKGROUND: To develop an effective radiological software prototype that could read Digital Imaging and Communications in Medicine (DICOM) files, crop the inner ear automatically based on head computed tomography (CT), and classify normal and inner ear malformation (IEM). METHODS: A retrospective analysis was conducted on 2053 patients from 3 hospitals. We extracted 1200 inner ear CTs for importing, cropping, and training, testing, and validating an artificial intelligence (AI) model. Automated cropping algorithms based on CTs were developed to precisely isolate the inner ear volume. Additionally, a simple graphical user interface (GUI) was implemented for user interaction. Using cropped CTs as input, a deep learning convolutional neural network (DL CNN) with 5-fold cross-validation was used to classify inner ear anatomy as normal or abnormal. Five specific IEM types (cochlear hypoplasia, ossification, incomplete partition types I and III, and common cavity) were included, with data equally distributed between classes. Both the cropping tool and the AI model were extensively validated. RESULTS: The newly developed DICOM viewer/software successfully achieved its objectives: reading CT files, automatically cropping inner ear volumes, and classifying them as normal or malformed. The cropping tool demonstrated an average accuracy of 92.25%. The DL CNN model achieved an area under the curve (AUC) of 0.86 (95% confidence interval: 0.81-0.91). Performance metrics for the AI model were: accuracy (0.812), precision (0.791), recall (0.8), and F1-score (0.766). CONCLUSION: This study successfully developed and validated a fully automated workflow for classifying normal versus abnormal inner ear anatomy using a combination of advanced image processing and deep learning techniques. The tool exhibited good diagnostic accuracy, suggesting its potential application in risk stratification. However, it is crucial to emphasize the need for supervision by qualified medical professionals when utilizing this tool for clinical decision-making.

Probucol-bile acid based nanoparticles protect auditory cells from oxidative stress: an in vitro study.

Aim: Excessive free radicals contribute to oxidative stress and mitochondrial dysfunction in sensorineural hearing loss (SNHL). The antioxidant probucol holds promise, but its limited bioavailability and inner ear barriers hinder effective SNHL treatment. Methodology: We addressed this by developing probucol-loaded nanoparticles with polymers and lithocholic acid and tested them on House Ear Institute-Organ of Corti cells. Results: Probucol-based nanoparticles effectively reduced oxidative stress-induced apoptosis, enhanced cellular viability, improved probucol uptake and promoted mitochondrial function. Additionally, they demonstrated the capacity to reduce reactive oxygen species through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Conclusion: This innovative nanoparticle system holds the potential to prevent oxidative stress-related hearing impairment, providing an effective solution for SNHL.

Hearing loss affects millions of people worldwide, and its prevalence is expected to double by 2050. Current treatments have limitations, pushing researchers to explore new options. Oxidative stress is a key player in hearing loss and is known to damage inner ear hair cells. While antioxidants, known for their protective effects, hold promise, delivering them effectively to the inner ear is challenging. Scientists have been testing nanoparticles loaded with the antioxidant probucol to fight hearing loss. In this study, these particles protected inner ear cells in cell studies, offering potential hope for preventing hearing problems. This research is a significant step toward finding better treatments for hearing loss.

[Endothelial dysfunction as a pathogenetic factor of sensorineural hearing loss]. / Endotelial'naya disfunktsiya kak patogeneticheskii faktor sensonevral'noi tugoukhosti.

Chronic sensorineural hearing loss (SNHL) is a common disease that leads to disability of the population. Despite the many reports devoted to SNHL, the question of the pathogenesis of the disease is still open. Many researchers consider the development of SNHL as a manifestation of microangiopathy. The mechanism of development of microangiopathy in SNHL is multifactorial, but most researchers agree that endothelial dysfunction (ED) triggers a complex of pathological changes in the vessels of the inner ear. OBJECTIVE: Review of the results of scientific research in recent years on the problem of etiopathogenesis of sensorineural hearing loss from the perspective of endothelial dysfunction in the formation of auditory disorders.

Making Recommendations for an Evaluation and Treatment Algorithm for Patients with Ear Fullness and No Objective Abnormalities.

OBJECTIVE: To make recommendations for evaluation, approach to counseling and treatment for patients who present with ear fullness without abnormalities on otomicroscopic examination, standard audiometric studies, or imaging results. METHODS: Retrospective chart review of adult patients in a tertiary referral center presenting with ear fullness and/or otalgia without external, middle, and/or inner ear pathologies. Data collected include demographics (age and gender), laterality and duration of symptoms, co-morbid conditions and final diagnoses of temporomandibular joint (TMJ) dysfunction, intermittent Eustachian tube dysfunction (iETD), migraine disorder, and anxiety. RESULTS: In the span of 8 years of a single neurotologist's practice, 964 patients presented with ear fullness. After excluding all instances where external, middle, and inner ear disorders were identified and where audiometric and radiologic findings were abnormal, 263 patients had ear fullness and no objective causes. Women were more likely than men to complain of ear fullness and/or otalgia and were also more likely to present with no objective abnormalities ( p < 0.05). Patients who reported isolated ear fullness were more likely to be diagnosed with iETD, whereas patients who reported pain were more likely to be diagnosed with TMJ dysfunction (TMJD). Fourteen patients (5.3%) had completely unexplained sensation of ear fullness. CONCLUSIONS: There were 94.7% of the patients presenting with unexplained ear fullness were diagnosed as having a possible contribution of TMJ dysfunction, IETD, migraine disorder, anxiety, or a combination of these conditions to their symptomatology. Directing treatments toward these diagnoses may alleviate symptoms of ear fullness or, if unsuccessful, provide an avenue for counseling in the framework of functional neurologic disorders.

Effect of 2.45 GHz Microwave Radiation on the Inner Ear: A Histopathological Study on 2.45 GHz Microwave Radiation and Cochlea.

BACKGROUND: The present study aims to determine the possible low dose-dependent adverse effects of 2.45 GHz microwave exposure and Wi-Fi frequency on the cochlea. METHODS: Twelve pregnant female rats (n=12) and their male newborns were exposed to Wi-Fi frequencies with varying electric field values of 0.6, 1.9, 5, 10 V/m, and 15 V/m during the 21-day gestation period and 45 days after birth, except for the control group. Auditory brainstem response testing was performed before exposure and sacrification. After removal of the cochlea, histopathological examination was conducted by immunohistochemistry methods using caspase (cysteine-aspartic proteases, cysteine aspartates, or cysteine-dependent aspartate-directed proteases)-3, -9, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Kruskal-Wallis and Wilcoxon tests and multivariate analysis of variance were used. RESULTS: Auditory brainstem response thresholds in postexposure tests increased statistically significantly at 5 V/m and above doses. When the number of apoptotic cells was compared in immunohistochemistry examination, significant differences were found at 10 V/m and 15 V/m doses (F(5,15)=23.203, P=.001; Pillai's trace=1.912, η2=0.637). As the magnitude of the electric field increased, all histopathological indicators of apoptosis increased. The most significant effect was noted on caspase-9 staining (η2 c9=0.996), followed by caspase-3 (η2 c3=0.991), and TUNEL staining (η2 t=0.801). Caspase-3, caspase-9, and TUNEL-stained cell densities increased directly by increasing the electric field and power values. CONCLUSION: Apoptosis and immune activity in the cochlea depend on the electric field and power value. Even at low doses, the electromagnetic field in Wi-Fi frequency damages the inner ear and causes apoptosis.

A silk-based hydrogel containing dexamethasone and lipoic acid microcrystals for local delivery to the inner ear.

Local drug delivery has been exploited recently to treat hearing loss, as this method can both bypass the blood-labyrinth barrier and provide sustained drug release. Combined drug microcrystals (MCs) offer additional advantages for sensorineural hearing loss treatment via intratympanic (IT) injection due to their shape effect and combination strategy. In this study, to endow viscous effects of hydrogels, nonspherical dexamethasone (DEX) and lipoic acid (LA) MCs were incorporated into silk fibroin (SF) hydrogels, which were subsequently administered to the tympanic cavity to investigate their pharmaceutical properties. First, we prepared DEX and LA MCs by a traditional precipitation technique followed by SF hydrogel incorporation (SF+DEX+LA). After characterization of the physicochemical features, including morphology, rheology, and dissolution, both a suspension of combined DEX and LA MCs (DEX+LA) and SF+DEX+LA were administered to guinea pigs by IT injection, after which the pharmacokinetics, biodegradation and biocompatibility were evaluated. To our surprise, compared to the DEX+LA group, the pharmacokinetics of the SF+DEX+LA hydrogel group did not improve significantly, which may be ascribed to their nonspherical shape and deposition effects of the drugs MCs. The cochlear tissue in each group displayed good morphology, with no obvious inflammatory reactions. This combined MC suspension has the clear advantages of no vehicle, easy scale-up preparation, and good biocompatibility and outcomes, which paves the way for practical treatment of hearing loss via local drug delivery.

Cochlear aqueduct revisited: A histological study using human fetuses.

BACKGROUND AND AIM: The cochlear aqueduct (CA) connects between the perilymphatic space of the cochlea and the subarachnoid space in the posterior cranial fossa. The study aimed to examine 1) whether cavitation of the CA occurs on the subarachnoid side or the cochlear side and 2) the growth and/or degeneration of the CA and its concomitant vein. METHODS: We examined paraffin-embedded histological sections from human fetuses: 15 midterm fetuses (crown-rump length or CRL, 39-115 mm) and 12 near-term fetuses (CRL, 225-328 mm). RESULTS: A linear mesenchymal condensation, i.e., a likely candidate of the CA anlage, was observed without the accompanying vein at 9-10 weeks. The vein appeared until 15 weeks, but it was sometimes distant from the CA. At 10-12 weeks, the subarachnoid space (or the epidural space) near the glossopharyngeal nerve rapidly protruded into the CA anlage and reached the scala tympani, in which cavitation was gradually on-going but without epithelial lining. However, CA cavitation did not to occur in the anlage. At the opening to the scala, the epithelial-like lining of the CA lost its meningeal structure. At near-term, the CA was often narrowed and obliterated. CONCLUSION: The CA develops from meningeal tissues when the cavitation of the scala begins. The latter cavitation seemed to reduce tissue stiffness leading, to meningeal protrusion. The so-called anlage of CA might be a phylogenetic remnant of the glossopharyngeal nerve branch. A course of cochlear veins appears to be determined by a rule different from the CA development.

Patterns of Signal Intensity in CISS MRI of the Inner Ear and Eye.

BACKGROUND: Constructive interference in steady state (CISS) is a gradient echo magnetic resonance imaging (MRI) pulse sequence that provides excellent contrast between cerebrospinal fluid and adjacent structures but is prone to banding artifacts due to magnetic field inhomogeneities. We aimed to characterize artifacts in the inner ear and eye. METHODS: In 30 patients (60 ears/eyes) undergoing CISS sequence MRI, nine low-signal intensity regions were identified in the inner ear and compared to temporal bone histopathology. The number and angle of bands across the eye were examined. RESULTS: In the cochlea, all ears had regions of low signal corresponding to anatomy (modiolus (all), spiral lamina (n = 59, 98.3%), and interscalar septa (n = 50, 83.3%)). In the labyrinth, the lateral semicircular canal crista (n = 42, 70%) and utricular macula (n = 47, 78.3%) were seen. Areas of low signal in the vestibule seen in all ears may represent the walls of the membranous utricle. Zero to three banding artifacts were seen in both eyes (right: 96.7%, mean 1.5; left: 93.3%, mean 1.3). CONCLUSION: Low signal regions in the inner ear on CISS sequences are common and have consistent patterns; most in the inner ear represent anatomy, appearing blurred due to partial volume averaging. Banding artifacts in the eye are more variable.

Inner Ear Organoids: Strengths and Limitations.

Inner ear organoids derived from differentiation of human pluripotent stem cells have recently gained momentum as tools to study inner ear development and developmental defects. An additional exciting aspect about this technology is represented by its translational potential, specifically, the use of organoids to validate therapeutics for hearing and balance restoration on human/patient-specific cells. This latter aspect will be briefly discussed here including opportunities and current limitations.