More than 6% of the world\'s population is suffering from hearing loss and balance disorders. The inner ear is the organ that senses sound and balance. Although inner ear disorders are common, there are limited ways to intervene and restore its sensory and balance functions. The development and establishment of biologically therapeutic interventions for auditory disorders require clarification of the basics of signaling pathways that control inner ear development and the establishment of endogenous or exogenous cell-based therapeutic methods. In vitro models of the inner ear, such as organoid systems, can help identify new protective or regenerative drugs, develop new gene therapies, and be considered as potential tools for future clinical applications. Advances in stem cell technology and organoid culture offer unique opportunities for modeling inner ear diseases and developing personalized therapies for hearing loss. Here, we review and discuss the mechanisms for the establishment and the potential applications of inner ear organoids.

Inner ear organoids play a crucial role in hearing research. In comparison to other animal models and 2D cell culture systems, inner ear organoids offer significant advantages for studying the mechanisms of inner ear development and exploring novel approaches to disease treatment. Inner ear organoids derived from human cells are more closely resemble normal human organs in development and function. The 3D culture system of the inner ear organoid enhances cell-cell interactions and mimics the internal environment. In this review, the progress and limitations of organoid culture methods derived from tissue-specific progenitors and pluripotent stem cells (PSCs) are summarized, which may offer new insights into generating organoids that closely resemble the inner ear in terms of morphology and function.

UNASSIGNED: Meniere disease, characterized by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural pressure, is a common cause of vertigo in humans. The pathogenesis of Meniere disease remains unknown. The current study aimed to describe a novel pathological change discovered in the inner ears of patients with Meniere disease who underwent labyrinthectomy.
UNASSIGNED: This retrospective case-control study was conducted with 21 patients with MD who underwent labyrinthectomy. A total of 15 patients diagnosed with acoustic neuroma or glomus jugular tumor were review over the same period of time as control. The clinical information of the patients and the pathological features of the membrane are described.
UNASSIGNED: The new pathological tissue was a morbid membrane structure sealing the round window, characterized by the formation of lymphatic capillaries. Histochemical and immunofluorescent staining was positive for D2-40, LYVE-1, podoplanin, and PROX1, which are the classical markers of the lymphatic vessels. Transmission electron microscopy revealed that the lymph capillaries lacked a typical basement membrane and that their ends were blind, composed of a single layer of endothelial cells with valval connection structures between adjacent capillary epithelial cells.
UNASSIGNED: This is the first report of lymphatic vessels in the human inner ear, and this pathological structure is a completely new discovery. The lymphatic vessels may develop due to inflammation or decompensation of pressure in the inner ear, suggesting that the inner ear can reactively form lymphatic vessels in some inflammation and fluid flow-dependent pathological conditions. The current findings help in improving our understanding of the pathogenesis of Meniere disease.

Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases. However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig\'s inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin. Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe3O4@CUR NPs) could be efficiently delivered into the inner ear. We observed better drug accumulation in the perilymph of the inner ear, resulting in less drug (cisplatin)-induced ototoxicity. Furthermore, physiological, hematological, and histological studies showed that the modulation of the BLB by low-pressure USMB was a safe process without significant adverse effects. We conclude that USMB could become a promising strategy for the systematic delivery of therapeutics in the treatment of inner ear diseases.

Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration.

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.
摘要: 感音神经性聋、梅尼埃病等各种内耳疾病给患者带来言语交流障碍、工作效率下降等问题，严重影响患者生活质量。内耳存在特殊的解剖结构及血-迷路屏障，目前常用的给药方式往往无法取得令人满意的疗效。纳米载体是目前纳米科技研究的前沿和热点，近年在内耳靶向递送领域取得了不少研究进展，有望最终应用于临床内耳疾病的治疗。本文着重介绍各种纳米载体在内耳靶向递送方面的优势、主要研究成果和局限性进行综述，希望为相关研究提供新的思路。.

Objective:To investigate the clinical features of patients with congenitally enlarged bony portions of the Eustachian tube（ET）. Methods:The medical history, physical examination, hearing test, temporal bone high resolution computed tomography（HRCT） of six patients（nine ears） with congenitally enlarged bony portion of the ET were retrospectively analyzed. Results:Four patients were men and two were women. The minimum, maximum, and average ages were 5, 21, and（14.7±6.4） years, respectively. Three malformations were bilateral and three were left-sided. Three ears had conductive hearing loss（average bone and air conduction thresholds were 13.7 dB and 71.3 dB）, three had mixed hearing loss（average bone and air conduction thresholds were 27.7 dB and 83.7 dB）, and one had extremely severe sensorineural hearing loss. The average maximum length and width of the enlarged bony ET on temporal bone HRCT were（22.61±2.94） mm and（6.50±2.33） mm, respectively. The enlargement was combined with an external auditory canal malformation in six ears, narrow tympanic cavity in six, tympanic antrum malformation in five, ossicular chain malformation in seven, cochlear malformation in six, helicotrema malformation in three, vestibule widening in two, semicircular canal malformation in three, vestibular window malformation in six, facial nerve abnormality in five, internal auditory meatus malformation in two, low middle cranial fossa in eight, and severe internal carotid artery malformation in one. Conclusion:Bony ET enlargement is a rare congenital middle ear malformation which could combined with other ear malformations. Patients can have no ET dysfunction but different patterns of hearing loss. The defect is usually found unintentionally during imaging, and the HRCT of temporal bone is significant.
目的：探讨先天性咽鼓管骨部异常扩大畸形的临床特征。 方法：回顾性分析6例（9耳）确诊为先天性咽鼓管骨部异常扩大患者的病史、体格检查、听力检查、颞骨高分辨CT（high-resolution computed tomography，HRCT）检查等结果。 结果：6例先天性咽鼓管骨部异常扩大患者中3例双侧咽鼓管扩大，3例左侧咽鼓管扩大。7耳听力结果提示，3耳为传导性聋，平均骨导13.7 dB，平均气导71.3 dB；3耳为混合性聋，平均骨导27.7 dB，平均气导83.7 dB；1耳为极重度感音神经性聋。颞骨HRCT上骨性咽鼓管异常扩大典型表现为咽鼓管骨部增长、增宽，水平位上测量最大长度和最大宽度分别为（22.61±2.94） mm和（6.50±2.33） mm。此外，合并外耳道畸形6耳，鼓室狭小6耳，鼓窦畸形5耳，听骨链畸形7耳，耳蜗畸形6耳，蜗孔畸形3耳，前庭增宽2耳，半规管畸形3耳，前庭窗畸形6耳，面神经走形异常5耳，内听道畸形2耳，颅中窝低位8耳，颈内动脉畸形1耳。 结论：咽鼓管骨部异常扩大属于罕见的先天性中耳畸形，可以合并外耳、其他中耳结构以及内耳畸形。患者可以无咽鼓管异常开放症状而仅表现为不同程度听力下降，通常在影像学检查时被无意发现，因此颞骨HRCT具有重要提示意义。.

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.
遗传性听力损失是一种影响听觉功能的遗传性疾病，严重影响人类生活质量，并导致社会经济损失。为了研究其病因并评估治疗效果，亟需适当的动物模型。猪作为有价值的大动物模型，已经在生物医学研究中获得广泛使用。在该综述中，我们强调了猪模型在耳部解剖学、内耳形态学和电生理特性方面的优势，以及近期在开发各种遗传修饰的听力损失猪模型方面的进展。此外，我们还讨论了在遗传性听力损失研究中使用猪模型的前景、挑战和建议。总之，该综述为未来使用猪模型进行遗传性听力损失研究提供了洞察和观点。.

OBJECTIVE: 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.
CONCLUSIONS: 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.