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Intrinsic mechanism and pharmacologic treatments of noise-induced hearing loss
Abstract
Noise accounts for one-third of hearing loss worldwide. Regretfully, noise-induced hearing loss (NIHL) is deemed to be irreversible due to the elusive pathogenic mechanisms that have not been fully elucidated. The complex interaction between genetic and environmental factors, which influences numerous downstream molecular and cellular events, contributes to the NIHL. In clinical settings, there are no effective therapeutic drugs other than steroids, which are the only treatment option for patients with NIHL. Therefore, the need for treatment of NIHL that is currently unmet, along with recent progress in our understanding of the underlying regulatory mechanisms, has led to a lot of new literatures focusing on this therapeutic field. The emergence of novel technologies that modify local drug delivery to the inner ear has led to the development of promising therapeutic approaches, which are currently under clinical investigation. In this comprehensive review, we focus on outlining and analyzing the basics and potential therapeutics of NIHL, as well as the application of biomaterials and nanomedicines in inner ear drug delivery. The objective of this review is to provide an incentive for NIHL's fundamental research and future clinical translation.
... Due to the barrier function of the BLB, systemic administration of drugs often results in limited effectiveness for inner ear conditions [136], with studies showing that only~0.000005% of methylprednisolone crosses from the bloodstream to inner ear fluids [137]. Even when drug concentrations in the bloodstream are high following systemic administration, the concentration within the target organs of the inner ear remains low, as evidenced by human studies where dexamethasone concentrations in perilymph after systemic administration were 88-fold lower than those achieved through intratympanic injection [138]. To achieve effective therapeutic concentrations in inner ear tissues, clinicians have to increase the systemic drug dosage, which can lead to off-target effects and adverse reactions. ...
... However, this technique is surgically demanding, carries a high risk of trauma, and is primarily used in animal experiments, with limited clinical applications, particularly in gene therapy [143]. Emerging solutions include osmotic micropumps and reciprocating perfusion systems that enable sustained, low-flow drug delivery while minimizing mechanical trauma to cochlear structures [16,138]. ...
... Furthermore, this method suffers from inconsistent drug diffusion across the round window membrane (RWM) and variable retention rates in the middle ear cavity, leading to unreliable dosage precision and strong basoapical concentration gradients in the cochlea [16,84]. The more direct intracochlear injection approach faces even greater clinical barriers due to its invasive nature that the procedure demands specialized surgical skills to access the cochlea through RWM perforation or cochleostomy, with risks of damaging the fragile sensory epithelium through perilymph volume or pressure changes [138]. ...
The inner ear is a relatively isolated organ, protected by the blood-labyrinth barrier (BLB). This barrier creates a unique lymphatic fluid environment within the inner ear, maintaining a stable physiological state essential for the mechano-electrical transduction process in the inner ear hair cells while simultaneously restricting most drugs from entering the lymphatic fluid. Under pathological conditions, dysfunction of the stria vascularis and disruption in barrier structure can lead to temporary or permanent hearing impairment. This review describes the structure and function of the BLB, along with recent advancements in modeling and protective studies related to the BLB. The review emphasizes some newly developed non-invasive inner ear drug delivery strategies, including ultrasound therapy assisted by microbubbles, inner ear-targeting peptides, sound therapy, and the route of administration of the cerebrospinal fluid conduit. We argue that some intrinsic properties of the BLB can be strategically utilized for effective inner ear drug delivery.
... FDA-approved drugs for its treatment (18,19). Steroids are often used clinically, but their efficacy is not significant. ...
... The prevalence of HFHL in large enterprises, medium-sized enterprises, small enterprises, microenterprises, and enterprises of unknown size was 15.37, 17.60, 26.81, 29.05, and 20.56%, respectively. The prevalence of HFHL among those who never smoked, occasionally smoked, and regularly smoked was 17.96, 19.73, and 24.36%, respectively. The prevalence of HFHL among those who never drank, drank moderately, and drank excessively was 17.27, 22.02, and 40.00%, respectively ( Table 1). ...
Introduction
The aim of the study was to investigate the occupational epidemiological characteristics of hearing loss among noise-exposed workers through a cross-sectional study and to explore the impact of combined noise and dust exposure on workers’ hearing loss through a longitudinal study.
Results
This cross-sectional study revealed that the risk of speech-frequency hearing loss increases with age (OR = 1.096, 95%CI = 1.081–1.111). Independent factors influencing high-frequency hearing loss include sex, age, hazardous factors, industry category, and enterprise size. Scientific research and technical services (OR = 1.607, 95%CI = 1.111–2.324), wholesale and retail (OR = 2.144, 95%CI = 1.479–3.107), manufacturing (OR = 1.907, 95%CI = 1.429–2.545), and other industries (OR = 1.583, 95%CI = 1.002–2.502) are risk factors for high-frequency hearing loss, whereas being female (OR = 0.297, 95%CI = 0.236–0.373) is a protective factor against high-frequency hearing loss. Independent factors influencing occupational noise-induced hearing loss include sex, working age, hazardous factors, industry category, smoking, and drinking, with the risk of occupational noise-induced hearing loss increasing with working age (OR = 1.045, 95%CI = 1.031–1.058). Noise and dust work (OR = 1.271, 95%CI = 1.011–1.597), other work (OR = 0.619, 95%CI = 0.479–0.800), manufacturing (OR = 2.085, 95%CI = 1.336–3.254), other industries (OR = 2.063, 95%CI = 1.060–4.012), occasional smokers (OR = 0.863, 95%CI = 0.652–1.142), regular smokers (OR = 1.216, 95% CI = 0.987–1.497), and excessive drinkers (OR = 2.171, 95%CI = 1.476–3.193) are risk factors for occupational noise-induced hearing loss, whereas being female (OR = 0.496, 95%CI = 0.347–0.709) is a protective factor against occupational noise-induced hearing loss. The longitudinal study revealed differences in pure-tone hearing threshold test results at 500 Hz, 1,000 Hz, 3,000 Hz, 4,000 Hz, and 6,000 Hz in both ears before and after enrollment among noise-exposed workers (p < 0.05). Combined noise and dust exposure (OR = 4.660, 95%CI = 1.584–13.711), 1st year (OR = 1.540, 95%CI = 1.128–2.103), 2nd year (OR = 1.994, 95%CI = 1.409–2.821), and 3rd year (OR = 1.628, 95%CI = 1.170–2.264) were risk factors for high-frequency hearing loss.
Discussion
Combined noise and dust exposure is a risk factor for occupational noise-induced hearing loss. Additionally, occupational noise-induced hearing loss is influenced by gender, working age, enterprise industry category, smoking, and drinking. Employers should enhance occupational health management and improve workers’ occupational health literacy, with a particular focus on older male workers of long working age, and those with unhealthy habits. Combined exposure to noise and dust may have a synergistic effect on causing high-frequency hearing loss, and comprehensive protective measures should be implemented for workers exposed to both.
... In normal auditory function, sound waves travel along the basilar membrane, which comprises three rows of outer hair cells and one row of inner hair cells sitting on top of supporting cells. Outer hair cells serve as amplifiers, while inner hair cells transmit electrical signals to the SGNs [6,12]. Furthermore, the hair cells receive innervation from the auditory nerve, responsible for conveying the electrical signals generated Hearing loss is a complex outcome influenced by various factors such as aging, ototoxic drugs, and noise exposure. ...
... The three primary vulnerable regions to ROS damage in cochlea are the organ of Corti, SGNs, and the stria vascularis [6]. Excessive ROS levels can cause various alterations, including a reduced number of inner and outer hair cells, atrophy of the stria vascularis, and degeneration of spiral ganglion cells [6,15].Outer hair cells, being energetically demanding, are particularly susceptible to ROS damage, especially those located in the basal turn [12]. The base turn of hair cells primarily processes high-frequency sounds, resulting in very high metabolic activity. ...
... However, audiometry is influenced by many factors and these two studies only considered the absence of PAH and audiometry in the process of inclusion and exclusion, while ignoring the factors that affect the results of audiometry (such as cold, abnormal otoscopy and exposure to noise in 24 h, etc.) 43,44 . The studies above only considered the association between single PAH exposure and hearing, while ignoring the possible interaction between PAHs. ...
Polycyclic aromatic hydrocarbons (PAHs) pollution and hearing loss are important issues in the environment and public health. However, current research still lacks data on their association in real-world environments. This study included 658 American adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016. The correlation between single PAH exposure and hearing was estimated by the weighted logistic regression, the overall association between mixed PAHs and hearing was evaluated by Bayesian kernel machine regression and grouped weighted quantile sum regression, and the important chemicals were identified in this study. The results showed that the 1-Hydroxynaphthalene (1-OHNa) was positively correlated with the hearing condition, hearing level and hearing threshold (OR = 1.41, 95% CI 1.08–1.84, P < 0.01; OR = 1.41, 95% CI 1.04–1.87, P < 0.05; OR = 4.34, 95% CI 1.74–10.81, P < 0.01, respectively). And 1-Hydroxypyrene (1-OHP) was positively correlated with the hearing condition and hearing threshold (OR = 1.83, 95% CI 0.99–3.36, P < 0.05; OR = 5.83, 95% CI 1.31–26.03, P < 0.05, respectively) after using covariate correction. The results of BKMR and WQS indicated a positive correlation between overall PAHs exposure and decreased hearing, and the higher the overall exposure to PAHs, the greater the risk of hearing loss. Further analysis revealed that 1-OHP was an important chemical substance related to PAHs and hearing. This result was consistent with the results of the single PAH exposure model. These insights provide a critical new perspective on the association between PAHs and hearing, highlighting the urgent need for strategies to reduce environmental pollution and protect human health.
... Hearing loss is a widespread occupational and environmental health challenge, affecting over 430 million people worldwide, as reported by the World Health Organization [1]. Noise-induced hearing loss (NIHL) is the third most common cause of hearing impairment and is attributed to prolonged exposure to high-intensity noise levels [2]. Traumatic noise exposure leads to cochlear hair cell damage and disrupts connections with the auditory nerve, leading to hair cell dysfunction or death, synaptic loss, and nerve fiber degeneration [3][4][5]. ...
Exposure to traumatic noise triggers cochlear damage and consequently causes permanent sensorineural hearing loss. However, effective treatment strategies for noise-induced hearing loss (NIHL) are lacking. Sirtuin 1 (SIRT1) is a NAD⁺-dependent deacetylase that plays a critical role in multiple physiological and pathological events. However, its role in NIHL pathogenesis remains elusive. This study revealed that SIRT1 expression in the cochlea progressively decreases in a mouse model of NIHL. Hair cell-specific knockout of SIRT1 exacerbates the noise-induced loss of outer and inner hair cell synaptic ribbons, retraction of cochlear nerve terminals, and oxidative stress, leading to more severe NIHL. Conversely, adeno-associated virus (AAV)-mediated SIRT1 overexpression effectively attenuated most noise-induced cochlear damage and alleviated NIHL. Transcriptomic analysis revealed that SIRT1 deficiency impairs glucose metabolism and inhibits antioxidant pathways in the cochlea following exposure to noise. Further investigation revealed that SIRT1 exerts an antioxidant effect, at least in part, through AMPK activation in cultured auditory HEI-OC1 cells exposed to oxidative stress. Collectively, these findings indicate that SIRT1 is essential for the maintenance of redox balance and mitochondrial function in the cochlea after traumatic noise exposure, thus providing a promising therapeutic target for NIHL treatment.
Graphical Abstract
Schematic illustration of SIRT1’s protective role and mechanism in NIHL. Exposure to noise leads to downregulation of SIRT1 and phosphorylated AMPK (p-AMPK) levels, which subsequently triggers OHC loss, synaptopathy, and neurite retraction in the cochlea. This cascade results in mitochondrial dysfunction, which is characterized by reduced ATP production and increased ROS accumulation, with a concomitant decrease in antioxidant capacity. To counteract these adverse effects, AAV-mediated SIRT1 overexpression (AAV-SIRT1) has been explored as a therapeutic strategy to restore SIRT1 levels and protect against NIHL.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-025-02152-9.
... Sensorineural hearing loss was defined as a continuous decline in air and bone conduction thresholds without an air-bone gap. No airbone gaps were detected in the study participants (33). A continuous decline in the curve of air and bone conduction thresholds without an air-bone gap indicated hearing loss in the participants. ...
Background: Occupational noise-induced hearing loss poses a significant health risk especially for military and low enforcement. Unlike steady, prolonged noise, impulse noise, such as gunfire, lead to more immediate and severe hearing impairment. This study explores the link between sensorineural hearing loss and cytokine levels in nasal secretions of male and female military cadets exposed to high-intensity gunfire noise. Methods: 105 cadets (75 males and 30 females, aged 19–25) undergoing regular firearms training were included. Audiometric testing and measurement of IL-1β, TNF-α, GM-CSF, and IL-10 concentrations in nasal secretions were conducted at three-time points: 24 hours before, immediately after and 24 hours following noise exposure. Results: Acute acoustic trauma affected the hearing of 39% of male and 21% of female participants. Among those with audiometric changes, IL-1β levels increased immediately after exposure, while both IL-1β and GM-CSF levels were elevated 24 hours later. Nasal IL-1β and GM-CSF levels significantly changed across all participants, with the most pronounced alterations seen in those with audiogram changes. Male cadets exhibited higher values of pro-inflammatory/anti-inflammatory cytokine ratios compared to female cadets. Conclusions: Acoustic trauma associated with a certain degree of hearing loss due to noise exposure is linked to an increase in nasal pro-inflammatory cytokine levels, and this effect is more pronounced in men than in women.
... Following noise exposure, ROS levels increase, which in turn activates various apoptotic pathways (Xu et al., 2023). To further validate the effect of TCP on HC apoptosis postnoise exposure, we evaluated cleaved caspase-3 levels. ...
JOURNAL/nrgr/04.03/01300535-202505000-00030/figure1/v/2024-07-28T173839Z/r/image-tiff
Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.
... Excessive noise poses a significant risk to the auditory organ known as the cochlea, located within the inner ear. 7 Prolonged exposure to deafening sounds might result in auditory impairment. 6 Prolonged exposure to high levels of noise has the potential to cause harm to the cells and membranes within the cochlea, potentially leading to the destruction of hair cells. ...
Introduction: Noise-induced hearing loss is a condition that develops gradually and often goes unnoticed due to the absence of observable symptoms. Noise-induced hearing loss is usually detected after effects on hearing ability, difficulty understanding speech, and communication disorders. This study aims to determine the prevalence of hearing threshold decline in workers in the clothes convection industry in Klaten, Central Java, Indonesia. Methods: A cross-sectional study, with 21 respondents, was conducted from April to June 2023. Data were collected through interviews, measurement of noise levels in the workplace, otoscopic and audiometric examinations, and research questionnaires. Results: Most study respondents were female (85.7%) and workers who had worked for 11-20 years (66.7%). The main results showed that the prevalence of decreasing hearing threshold among workers in this study was 33.3%. Conclusion: The prevalence of hearing threshold decline was correlated with length of work and use of ear protection equipment.
... Cochlear damage from insults such as acoustic trauma, is a multifaceted degenerative phenomenon caused by a cascade of detrimental responses such as oxidative stress, inflammation, and excitotoxicity, which ultimately result in both necrotic and apoptotic cell death (Bohne et al., 2007;Yang et al., 2016;Kalinec et al., 2017;Arrigali and Serban, 2022;Paik et al., 2022;Xu et al., 2023). Both reactive oxygen species and inflammation have been identified as major contributors to hearing loss . ...
There is a substantial need of effective drugs for the treatment of hearing loss, which affects nearly 500 million individuals globally. Hearing loss can be the result of intense or prolonged noise exposure, ototoxic drugs, infections, and trauma, which trigger inflammatory signaling cascades that lead to irreversible damage to cochlear structures. To address this, we developed and characterized a series of covalent conjugates of anti-inflammatory drugs to hyaluronic acid (HA), for potential use as topical ototherapeutics. These conjugates were tested in in vitro assays designed to mirror physiological processes typically observed with acoustic trauma. Intense noise exposure leads to macrophage recruitment to the cochlea and subsequent inflammatory damage to sensory cells. We therefore first tested our conjugates’ ability to reduce the release of inflammatory cytokines in macrophages. This anti-inflammatory effect on macrophages also translated to increased cochlear cell viability. In our initial screening, one conjugate, ibuprofen-HA, demonstrated significantly higher anti-inflammatory potential than its counterparts. Subsequent cytokine release profiling of ibuprofen-HA further confirmed its ability to reduce a wider range of inflammatory markers, to a greater extent than its equivalent unconjugated drug. The conjugate’s potential as a topical therapeutic was then assessed in previously developed tympanic and round window membrane tissue permeation models. As expected, our data indicate that the conjugate has limited tympanic membrane model permeability; however, it readily permeated the round window membrane model and to a greater extent than the unconjugated drug. Interestingly, our data also revealed that ibuprofen-HA was well tolerated in cellular and tissue cytocompatibility assays, whereas the unconjugated drug displayed significant cytotoxicity at equivalent concentrations. Moreover, our data highlighted the importance of chemical conjugation of ibuprofen to HA; the conjugate had improved anti-inflammatory effects, significantly reduced cytotoxicity, and is more suitable for therapeutic formulation. Overall, this work suggests that ibuprofen-HA could be a promising safe and effective topical ototherapeutic for inflammation-mediated cochlear damage.
Hearing loss (HL) is a significant global health challenge, affecting billions of people and severely impacting quality of life. While traditional interventions such as hearing aids and cochlear implants mitigate symptoms, they fail to address the underlying causes of HL, especially in cases involving severe damage to hair cells or spiral ganglion neurons. Emerging therapeutic strategies, including biomaterials, nanocarrier drug delivery systems, gene therapy, and extracellular vesicle (EV)‐based approaches, have demonstrated significant potential in promoting inner ear regeneration and restoring auditory function. Biomaterials mimic the extracellular matrix to guide inner ear cell regeneration, while nanocarriers and EVs enhance the targeted and sustained delivery of therapeutic agents. Gene therapy offers opportunities to correct genetic mutations, addressing hereditary HL. However, challenges such as the anatomical complexity of the cochlea, the blood‐labyrinth barrier, and limited regenerative capacity persist. Future research must focus on scalable, biocompatible, and clinically safe delivery systems to advance the clinical translation of these innovative therapies. This review underscores the potential of integrating these strategies to develop effective and long‐lasting treatments for HL.
The number of people with hearing loss disorders is enormous, causing great physical and mental stress to patients, as well as a huge social burden. Among these patients, hearing loss caused by inner ear lesions accounts for a large proportion. Therefore, treatment of the inner ear is important. Inner ear drug delivery systems, which can reduce the side effects of systemic drug administration by delivering drugs directly to the inner ear, are important in sensorineural hearing loss. Here, the development of inner ear drug delivery systems is focused, including the complex physiological structure that they face, types of drugs delivered, routes of administration, and forms of drug delivery carrier platforms. Recent studies in this process are presented and it is concluded with a summary and outlook on the problems faced and possible solutions.
Background
The extended high-frequency (EHF; 0.9–16 kHz) region is sensitive to noise exposure and can indicate early noise-induced hearing loss. EHF hearing loss (EHFHL; >20 dB HL for EHF averages) may affect pilots’ noise perception, impacting communication and response in flight. Early identification and monitoring of EHFHL are crucial for pilots’ hearing health and flight safety. However, EHF is not included in routine medical assessments for pilots in China. This study aimed to develop a nomogram to predict EHFHL in pilots with normal audiograms (≤20 dB HL at each standard frequency), providing an early intervention tool.
Methods
A total of 1091 pilots were randomly assigned to the training set (763) and validation set (328). Set characteristics were compared using univariate analysis. In the training set, least absolute shrinkage and selection operator regression identified key predictors, followed by multivariable binary logistic regression to construct a nomogram. The nomogram’s performance was evaluated in both sets, assessing calibration, discrimination and clinical utility.
Results
The nomogram incorporated four factors as follows: left-ear high-frequency audiometry threshold averages (HFAs: 3, 4, 6 and 8 kHz; odds ratio [OR] = 1.144; 95% confidence interval [CI] = 1.083–1.210), right-ear HFAs (OR = 1.186, 95% CI = 1.115–1.263), flight time (OR = 1.001, 95% CI = 1–1.001) and triglyceride (OR = 1.393, 95% CI = 1.038–1.885). The model’s area under the curve was 0.819 (95% CI = 0.790–0.850) and 0.771 (95% CI = 0.712–0.830) during validation. The predictive model was well calibrated (Hosmer–Lemeshow test, χ² = 10.77; P = 0.292). Decision curve analysis showed a net benefit for the training set between 4% and 88%, with similar benefits observed for the validation set from 12% to 100%.
Conclusion
This study developed and validated the first prediction model for EHFHL in Chinese pilots, demonstrating its reliability and clinical utility. The findings support early detection and personalised monitoring, with potential applications in hearing protection strategies and flight safety.
Sensorineural hearing loss (SNHL), the most commonly-occurring form of hearing loss, is caused mainly by injury to or the loss of hair cells and spiral ganglion neurons in the cochlea. Numerous environmental and physiological factors have been shown to cause acquired SNHL, such as ototoxic drugs, noise exposure, aging, infections, and diseases. Several programmed cell death (PCD) pathways have been reported to be involved in SNHL, especially some novel PCD pathways that have only recently been reported, such as ferroptosis, necroptosis, and pyroptosis. Here we summarize these PCD pathways and their roles and mechanisms in SNHL, aiming to provide new insights and potential therapeutic strategies for SNHL by targeting these PCD pathways.
Noise‐induced hearing loss (NIHL) is among the most poorly treated diseases due to irreversible damage to hair cells. Reactive oxygen species contribute to NIHL pathogenesis by injuring the inner ear hair cells. Teriparatide (PTH1‐34) exerts antioxidant properties in the context of osteoporosis. Thus, in the current study, a multifunctional thermosensitive nanodelivery system is developed, based on the unique anatomical structure of the inner ear, to load and sustain the release of PTH1‐34 to alleviate hair cell damage. LR27—a fusion peptide—is assembled from a targeting peptide (A665) and cell‐penetrating peptide (Arg8) to target hair cells and increase the round window membrane permeability. In vitro, the antioxidant and anti‐apoptotic properties of the nanodelivery system are assessed after treating HEI‐OC1 cells and cochlear explants with hydrogen peroxide to simulate the oxidative environment. In vivo, injection of the nanodelivery system into the auditory bulb protects the hearing and hair cells of an NIHL mouse model. These results demonstrate the synergistic effects of multiple peptides in treating NIHL and their potential clinical applications.
Noise‐induced hearing loss (NIHL) results from prolonged exposure to intense noise, causing damage to sensory outer hair cells (OHCs) and spiral ganglion neurons (SGNs). The blood labyrinth barrier (BLB) hinders systemic drug delivery to the inner ear. This study applied a retro‐auricular round window membrane (RWM) method to bypass the BLB, enabling the transport of macromolecular proteins into the inner ear. Pigment epithelium‐derived factor (PEDF), which has anti‐inflammatory and neuroprotective properties, is conjugated to a prestin‐targeting peptide 2 (PrTP2) using N‐succinimidyl‐3‐maleimidopropionate (SMP) to form PrTP2‐SMP/PEDF. This compound specifically targeted Prestin and accumulated around OHCs for sustained release, effectively reducing OHC and SGN loss. Functional and structural tests, including auditory brainstem response (ABR), confocal microscopy, and scanning electron microscopy (SEM), revealed significant hearing restoration and cellular protection. Additionally, the results of enzyme‐linked immunosorbent assay (ELISA), Annexin V and propidium iodide (PI) staining and immunoblotting show that noise exposure may induce pyroptosis in the cochlea by activating the NOD‐like receptor protein 3 (NLRP3)‐apoptosis‐associated speck‐like protein containing a CARD (ASC) – cysteinyl aspartate specific proteinase (Caspase‐1) pathway and PrTP2‐SMP/PEDF alleviates the inflammatory response by inhibiting pyroptosis. Toxicity analysis indicates no adverse effects, suggesting that PrTP2‐SMP/PEDF has a promising therapeutic prospective for NIHL.
The digital era has fundamentally transformed how we interact with sound, making music, entertainment, and communication more accessible than ever before. However, with this revolution comes an escalating public health concern: noise-induced hearing loss (NIHL) and tinnitus, particularly among the younger generation.1 The widespread use of personal listening devices, attendance at loud concerts, and frequent exposure to occupational noise are all contributing factors that subject our ears to harmful sound levels on a near-daily basis. Recent studies have shown that the younger generation is increasingly exposed to recreational noise at hazardous levels, leading to hearing problems that were once considered more common in older populations.2 NIHL is now recognized as one of the most prevalent causes of hearing impairment globally. It occurs when prolonged exposure to loud sound damages the hair cells within the cochlea. Tinnitus often accompanies NIHL and may persist long after the initial noise exposure. According to the World Health Organization (WHO), over 1.1 billion young adults worldwide are at risk of developing NIHL due to unsafe listening practices.3 Historically, NIHL was primarily associated with occupational noise exposure among middle-aged or older adults who had spent decades in noisy workplaces. However, recent data indicate that nearly half of teenagers and young adults in middle- and high-income countries are exposed to unsafe sound levels through personal audio devices.4 This shift in the demographics of NIHL and tinnitus is particularly alarming, as it highlights the growing vulnerability of younger generations to these conditions.
Objectives
We aimed to estimate the global prevalence of hearing loss among adults and to explore its associated factors.
Methods
Our systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement (PRISMA). We retrieved corresponding documents published up to Sep 24, 2021 in PubMed and Web of Science. Random-effects models were used to calculate the pooled prevalence of hearing loss. Subgroup analyses were conducted to explore potential heterogeneity.
Results
The pooled prevalence of any hearing loss across 100 studies was 31.0% (95% CI: 26.9-35.1, P < .001, I ² = 99.9%), and the pooled prevalence of disabling hearing loss across 34 studies was 15.9% (95% CI: 11.1-20.7, P < .001, I ² = 99.9%). The prevalence of hearing loss was higher in the year range of 2000 to 2009, among the elder (≥70) or males, in studies using either ear side of hearing loss definition or in the region of the Americas. Ear disease or surgery, job noise exposure, current smoking, off-work noise exposure, males, cardiovascular disease, past drinking, diabetes mellitus, hypertension, older age, and past smoking are risk factors of hearing loss while education level surpasses high school acts as a protect factor for hearing.
Conclusion
Our results demonstrate high prevalence of hearing loss among adults worldwide and verify several related factors of the disease. Prevention and intervention measures should be implemented.
Noise-induced hidden hearing loss (HHL) is a newly uncovered form of hearing impairment that causes hidden damage to the cochlea. Patients with HHL do not have significant abnormalities in their hearing thresholds, but they experience impaired speech recognition in noisy environments. However, the mechanisms underlying HHL remain unclear. In this study, we developed single-cell transcriptome profiles of the cochlea of mice with HHL, detailing changes in individual cell types. Our study revealed a transient threshold shift, reduced auditory brainstem response wave I amplitude, and decreased number of ribbon synapses in HHL mice. Our findings suggest elevated oxidative stress and GDF15 expression in cochlear hair cells of HHL mice. Notably, the upregulation of GDF15 attenuated oxidative stress and auditory impairment in the cochlea of HHL mice. This suggests that a therapeutic strategy targeting GDF15 may be efficacious against HHL.
Graphical Abstract
HHL mice had a transient threshold shift, reduced ABR wave I amplitude, and decreased number of ribbon synapses.
HHL mice's cochlear hair cells exhibited increased oxidative stress and elevated GDF15 expression.
Upregulation of GDF15 attenuated oxidative stress and auditory damage in the cochlea of HHL mice, implying that GDF15-targeted treatment techniques may be useful for HHL.
Background
Adherens junction in the blood-labyrinth barrier is largely unexplored because it is traditionally thought to be less important than the tight junction. Since increasing evidence indicates that it actually functions upstream of tight junction adherens junction may potentially be a better target for ameliorating the leakage of the blood-labyrinth barrier under pathological conditions such as acoustic trauma.
Aims
This study was conducted to investigate the pathogenesis of the disruption of adherens junction after acoustic trauma and explore potential therapeutic targets.
Methods
Critical targets that regulated the disruption of adherens junction were investigated by techniques such as immunofluorescence and Western blottingin C57BL/6J mice.
Results
Upregulation of Vascular Endothelial Growth Factor (VEGF) and downregulation of Pigment Epithelium-derived Factor (PEDF) coactivated VEGF-PEDF/VEGF receptor 2 (VEGFR2) signaling pathway in the stria vascularis after noise exposure. Downstream effector Src kinase was then activated to degrade VE-cadherin and dissociate adherens junction which led to the leakage of the blood-labyrinth barrier. By inhibiting VEGFR2 or Src kinase VE-cadherin degradation and blood-labyrinth barrier leakage could be attenuated but Src kinase represented a better target to ameliorate blood-labyrinth barrier leakage as inhibiting it would not interfere with vascular endothelium repair neurotrophy and pericytes proliferation mediated by upstream VEGFR2.
Conclusion
Src kinase may represent a promising target to relieve noise-induced disruption of adherens junction and hyperpermeability of the blood-labyrinth barrier.
Objective:
Excessive noise is unpleasant and induces several physiological and psychological effects. Noise pollution is a potential threat to humans, particularly those continuously exposed for extended periods throughout the day over many years. This review aims to examine the various auditory and non-auditory outcomes associated with prolonged exposure to noise pollution.
Materials and methods:
The review utilized a combination of relevant keywords to search the electronic databases. After screening based on the applied selection criteria for title, abstract, and full text, 44 articles were finally selected for critical review.
Results:
We identified and analyzed research findings related to noise-induced hearing loss, tinnitus, and sleep disturbances along with non-auditory issues such as annoyance, cognitive impairments, and mental stress associated with cardiovascular disorders. Furthermore, the existing studies were compared and collated to highlight the unique challenges and significance of noise pollution as a distinctive environmental concern and to explore the ongoing efforts in its research and prevention, including the early detection and potential reversal of noise-induced hearing loss.
Conclusion:
The fundamental health consequences of noise pollution underscore the need for extensive research encompassing emerging noise sources and technologies to establish a health management system tailored to address noise-related health concerns and reduce noise exposure risk among populations. Finally, further research is warranted to ensure improved measurement of noise exposure and related health outcomes, especially in the context of occupational noise.
Objective
This study aimed to explore andrographolide’s mechanism of action and its protective effect on noise-induced hearing loss (NIHL).
Materials and Methods
A mice animal model for NIHL was established through exposure to broadband noise at 120 dB sound pressure level for 4 h. Transcriptomics analysis and pharmacodynamic experiments were carried out.
Results
Andrographolide enters the inner ear and effectively prevents hearing damage following noise exposure in the mice model for permanent hearing loss. Moreover, treatment with andrographolide inhibited the excessive activation of inflammatory factors in the cochleae of noise-exposed mice.
Conclusion
Andrographolide might be a promising candidate for auditory protective drug investigation.
We carried out an acoustic-cued water maze experiment at three sound intensity levels (30 dB, 40 dB, and 50 dB) in 30 mice (10 per group), aiming to determine the sound intensity suitable for an acoustic-cued water maze. The results showed that sound intensities at both 40 dB and 50 dB were effective in terms of the escape latency, the first crossing, the crossing number, and the quadrant time, and the effectiveness of both were about the same. On the other hand, a sound intensity of 30 dB was not as effective because there was no statistically significant improvement in escape latency across training days. Therefore, we consider sound intensities between 40 dB and 50 dB to be suitable for acoustic-cued water maze tests.
Objective
We aimed to investigate the potential environmental risk factors, protective factors, and biomarkers of hearing loss (HL), and establish a hierarchy of evidence.
Data Sources
Embase, PubMed, Cochrane Library, and Web of Science electronic database from inception to June 1, 2023.
Review Methods
We included meta‐analyses of observational studies of associations between HL and environmental risk factors, protective factors, or biomarkers. We calculated summary effect estimates, 95% confidence interval, heterogeneity I ² statistic, 95% prediction interval, small study effects, and excess significance biases.
Results
Of the 9211 articles retrieved, 60 eligible articles were included. The 60 eligible articles identified 47 potential environmental risk and protective factors (N = 4,123,803) and 46 potential biomarkers (N = 173,701). Evidence of association was convincing (class I) for rheumatoid arthritis (RA) and every 1 cm increase in height. Evidence of association was highly suggestive (class II) for human immunodeficiency virus (HIV), diabetes, cumulative noise exposure (CNE), smoking, congenital cytomegalovirus (CMV) infection, combined exposure to organic solvents and noise, non‐Gaussian noise exposure, each 1 kg increase in birth weight, noise exposure, and alopecia areata (AA).
Conclusion
In this umbrella review, RA, every 1 cm increase in height, HIV, diabetes, CNE, smoking, congenital CMV infection, combined exposure to organic solvents and noise, non‐Gaussian noise exposure, each 1 kg increase in birth weight, noise exposure, and AA were strongly associated with HL.
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.
Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.
Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere’s disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.
Damage-associated molecular pattern molecules (DAMPs) play a critical role in mediating cochlear cell death, which leads to noise-induced hearing loss (NIHL). High-mobility group box 1 (HMGB1), a prototypical DAMP released from cells, has been extensively studied in the context of various diseases. However, whether extracellular HMGB1 contributes to cochlear pathogenesis in NIHL and the potential signals initiating HMGB1 release from cochlear cells are not well understood. Here, through the transfection of the adeno-associated virus with HMGB1-HA-tag, we first investigated early cytoplasmic accumulation of HMGB1 in cochlear hair cells after noise exposure. We found that the cochlear administration of HMGB1-neutralizing antibody immediately after noise exposure significantly alleviated hearing loss and outer hair cells (OHCs) death induced by noise exposure. In addition, activation of signal transducer and activators of transcription 1 (STAT1) and cellular hyperacetylation were verified as potential canonical initiators of HMGB1 cytoplasmic accumulation. These findings reveal the adverse effects of extracellular HMGB1 on the cochlea and the potential signaling events mediating HMGB1 release in hair cells, indicating multiple potential pharmacotherapeutic targets for NIHL.
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.
Objective
To investigate whether sound conditioning influences auditory system protection by activating adenylate activated kinase (AMPK), and if such adaption protects ribbon synapses from high-intensity noise exposure.
Materials and methods
CBA mice (12 weeks old) were randomly divided into four groups ( n = 24 mice per group): control, sound conditioning (SC), sound conditioning plus noise exposure (SC+NE), and noise exposure (NE). Hearing thresholds were assessed before testing, after sound conditioning, and 0, 3, 7, and 14 days after 110 dB noise exposure. Amplitudes and latencies of wave I at 90 dB intensity were assessed before test, after conditioning, and at 0 and 14 days after 110 dB noise exposure. One cochlea from each mouse was subjected to immunofluorescence staining to assess synapse numbers and AMPK activation, while the other cochlea was analyzed for phosphorylated adenylate activated kinase (p-AMPK) protein expression by western blot.
Results
There was no significant difference in auditory brainstem response (ABR) threshold between SC and control mice. The degree of hearing loss of animals in the two SC groups was significantly reduced compared to the NE group after 110 dB noise exposure. Animals in the SC group showed faster recovery to normal thresholds, and 65 dB SPL sound conditioning had a stronger auditory protection effect. After sound conditioning, the amplitude of ABR I wave in the SC group was higher than that in the control group. Immediately after noise exposure (D0), the amplitudes of ABR I wave decreased significantly in all groups; the most significant decrease was in the NE group, with amplitude in 65SC+NE group significantly higher than that in the 85SC+NE group. Wave I latency in the SC group was significantly shorter than that in the control group. At D0, latency was prolonged in the NE group compared with the control group. In contrast, there was no significant difference in latency between the 65SC+NE and 85SC+NE groups. Further, at D14, there was no significant difference between the NE and control groups, while latency remained significantly shorter in the 65SC+NE and 85SC+NE groups compared with controls. Number of ribbon synapses in SC mice did not differ significantly from that in controls. After 110 dB noise exposure, there were significantly more ribbon synapses in the SC+NE group than the NE group. Ribbon synapses of all groups were recovered 14 days after the noise exposure, while the SC group had a shorter recovery time than the non-SC groups ( p < 0.05). AMPK was highly activated in the SC group, and p-AMPK expression was detected; however, after 110 dB noise exposure, the strongest protein expression was detected in the NE group, followed by the SC+NE groups, and the lowest protein expression was detected in the control group.
Conclusion
Sound conditioning animals were more noise resistant and recovered hearing faster than non-SC animals. Further, 65 dB SPL SC offered better hearing protection than 85 dB SPL SC. Early AMPK activation may protect hearing by increasing ATP storage and reducing the release of large quantities of p-AMPK, which could help to inhibit synapse damage.
Inflammation is a common complication of many chronic diseases. It includes inflammation of the parenchyma and vascular systems. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, which can directly participate in the suppression of inflammation. It can also regulate the activity of other proteins. Among them, high mobility group box 1 (HMGB1) signaling can be inhibited by deacetylating four lysine residues (55, 88, 90, and 177) in quiescent endothelial cells. HMGB1 is a ubiquitous nuclear protein, once translocated outside the cell, which can interact with various target cell receptors including the receptor for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, and TLR4 and stimulates the release of pro-inflammatory cyto-/chemokines. And SIRT1 has been reported to inhibit the activity of HMGB1. Both are related to the occurrence and development of inflammation and associated diseases but show an antagonistic relationship in controlling inflammation. Therefore, in this review, we introduce how this signaling axis regulates the emergence of inflammation-related responses and tumor occurrence, providing a new experimental perspective for future inflammation research. In addition, it explores diverse upstream regulators and some natural/synthetic activators of SIRT1 as a possible treatment for inflammatory responses and tumor occurrence which may encourage the development of new anti-inflammatory drugs. Meanwhile, this review also introduces the potential molecular mechanism of the SIRT1-HMGB1 pathway to improve inflammation, suggesting that SIRT1 and HMGB1 proteins may be potential targets for treating inflammation.
Oxygen metabolism in the mitochondria is essential for biological activity, and reactive oxygen species (ROS) are produced simultaneously in the cell. Once an imbalance between ROS production and degradation (oxidative stress) occurs, cells are damaged. Sensory organs, especially those for hearing, are constantly exposed during daily life. Therefore, almost all mammalian species are liable to hearing loss depending on their environment. In the auditory pathway, hair cells, spiral ganglion cells, and the stria vascularis, where mitochondria are abundant, are the main targets of ROS. Excessive generation of ROS in auditory sensory organs is widely known to cause sensorineural hearing loss, and mitochondria-targeted antioxidants are candidates for treatment. This review focuses on the relationship between acquired hearing loss and antioxidant use to provide an overview of novel antioxidants, namely medicines, supplemental nutrients, and natural foods, based on clinical, animal, and cultured-cell studies.
Background
Excessive accumulation of reactive oxygen species (ROS) has been documented as the crucial cellular mechanism of cisplatin-induced ototoxicity. However, numerous antioxidants have failed in clinical studies partly due to inefficient drug delivery to the cochlea. A drug delivery system is an attractive strategy to overcome this drawback.
Methods and results
In the present study, we proposed the combination of antioxidant astaxanthin (ATX) and ROS-responsive/consuming nanoparticles (PPS-NP) to combat cisplatin-induced ototoxicity. ATX-PPS-NP were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units, which scavenged ROS and disintegrate to release the encapsulated ATX. The ROS-sensitivity was confirmed by ¹H nuclear magnetic resonance spectroscopy, transmission electron microscopy and an H2O2 ON/OFF stimulated model. Enhanced release profiles stimulated by H2O2 were verified in artificial perilymph, the HEI-OC1 cell line and guinea pigs. In addition, ATX-PPS-NP efficiently inhibited cisplatin-induced HEI-OC1 cell cytotoxicity and apoptosis compared with ATX or PPS-NP alone, suggesting an enhanced effect of the combination of the natural active compound ATX and ROS-consuming PPS-NP. Moreover, ATX-PPS-NP attenuated outer hair cell losses in cultured organ of Corti. In guinea pigs, NiRe-PPS-NP verified a quick penetration across the round window membrane and ATX-PPS-NP showed protective effect on spiral ganglion neurons, which further attenuated cisplatin-induced moderate hearing loss. Further studies revealed that the protective mechanisms involved decreasing excessive ROS generation, reducing inflammatory chemokine (interleukin-6) release, increasing antioxidant glutathione expression and inhibiting the mitochondrial apoptotic pathway.
Conclusions
Thus, this ROS-responsive nanoparticle encapsulating ATX has favorable potential in the prevention of cisplatin-induced hearing loss.
Graphical Abstract
Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.
Background:
The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well.
Purpose:
The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss.
Data collection and analysis:
Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www.
Clinicaltrials:
gov) database identified 61 clinical trials.
Results:
Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss.
Conclusion:
This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field.
The study of drug delivery systems to the inner ear is a crucial but challenging field. The sensory organ (in the inner ear) is protected by the petrous bone labyrinth and the membranous labyrinth, both of which need to be overcome during the drug delivery process. The requirements for such a delivery system include small size, appropriate flexibility and biodegradability. DNA nanostructures, biomaterials that can arrange multiple functional components with nanometer precision, exhibit characteristics that are compatible with the requirements for inner ear drug delivery. Herein, we report the development of a novel inner ear drug delivery system based on epigallocatechin gallate (EGCG)-loaded tetrahedral DNA nanostructures (TDNs, EGCG@TDNs). The TDNs self-assembled via base-pairing of four single-stranded DNA constructs and EGCG was loaded into the TDNs through non-covalent interactions. Cy5-labeled TDNs (Cy5-TDNs) were significantly internalized by the House Ear Institute-Organ of Corti 1 cell line, and this endocytosis was energy-, clathrin-, and micropinocytosis-dependent. Cy5-TDNs penetrated the round window membrane (RWM) rapidly in vivo. Local application of EGCG@TDNs onto the RWM of guinea pigs in a single dose continuously released EGCG over 4 hours. Drug concentrations in the perilymph were significantly elevated compared with the administration of free EGCG at the same dose. EGCG@TDNs were found to have favorable biocompatibility and strongly affected the RSL3-induced down-regulation of GPX4 and the generation of reactive oxygen species, on the basis of 2',7'-dichlorodihydrofluorescein diacetate staining. JC-1 staining suggested that EGCG@TDNs successfully reversed the decrease in mitochondrial membrane potential induced by RSL-3 in vitro and rescued cells from apoptosis, as demonstrated by the analysis of Annexin V-FITC/PI staining. Further functional studies showed that a locally administered single-dose of EGCG@TDNs effectively preserved spiral ganglion cells in C57/BL6 mice after noise-induced hearing loss. Hearing loss at 5.6 and 8 kHz frequencies was significantly attenuated when compared with the control EGCG formulation. Histological analyses indicated that the administration of TDNs and EGCG@TDNs did not induce local inflammatory responses. These favorable histological and functional effects resulting from the delivery of EGCG by TDNs through a local intratympanic injection suggest potential for therapeutic benefit in clinical applications.
Noise-induced hearing loss (NIHL), caused by direct damage to the cochlea, reduces the flow of auditory information to the central nervous system, depriving higher order structures, such as the hippocampus with vital sensory information needed to carry out complex, higher order functions. Although the hippocampus lies outside the classical auditory pathway, it nevertheless receives acoustic information that influence its activity. Here we review recent results that illustrate how NIHL and other types of cochlear hearing loss disrupt hippocampal function. The hippocampus, which continues to generate new neurons (neurogenesis) in adulthood, plays an important role in spatial navigation, memory, and emotion. The hippocampus, which contains place cells that respond when a subject enters a specific location in the environment, integrates information from multiple sensory systems, including the auditory system, to develop cognitive spatial maps to aid in navigation. Acute exposure to intense noise disrupts the place-specific firing patterns of hippocampal neurons, “spatially disorienting” the cells for days. More traumatic sound exposures that result in permanent NIHL chronically suppresses cell proliferation and neurogenesis in the hippocampus; these structural changes are associated with long-term spatial memory deficits. Hippocampal neurons, which contain numerous glucocorticoid hormone receptors, are part of a complex feedback network connected to the hypothalamic-pituitary (HPA) axis. Chronic exposure to intense intermittent noise results in prolonged stress which can cause a persistent increase in corticosterone, a rodent stress hormone known to suppress neurogenesis. In contrast, a single intense noise exposure sufficient to cause permanent hearing loss produces only a transient increase in corticosterone hormone. Although basal corticosterone levels return to normal after the noise exposure, glucocorticoid receptors (GRs) in the hippocampus remain chronically elevated. Thus, NIHL disrupts negative feedback from the hippocampus to the HPA axis which regulates the release of corticosterone. Preclinical studies suggest that the noise-induced changes in hippocampal place cells, neurogenesis, spatial memory, and glucocorticoid receptors may be ameliorated by therapeutic interventions that reduce oxidative stress and inflammation. These experimental results may provide new insights on why hearing loss is a risk factor for cognitive decline and suggest methods for preventing this decline.
Cochlea macrophages regulate cochlea inflammation and may harbors the potentials to protect hearing function from injury, including acoustic overstimulation. Cochlea macrophage numbers increase at 3–7 days after acoustic stimulation. However, the exact timing of macrophage infiltration and maturation from inflammatory monocytes is unclear. Furthermore, neutrophils may also be involved in this process. Therefore, in this study, we investigated time-dependent immune cell infiltration, macrophage transformation, and neutrophil involvement following acoustic stimulation. Flow cytometry and immunofluorescence were conducted in C-X3-C motif chemokine receptor 1 (CX3CR1)+/GFP mice after acoustic overstimulation (at baseline and at 1, 2, 3, and 5 days after exposure to 120 dB for 1 h) to identify inflammatory monocytes in the cochlea. RNA-sequencing and quantitative polymerase chain reaction were performed to identify differentially expressed genes. Inflammatory monocytes infiltrated into the lower portion of the lateral wall within 2 days after acoustic overstimulation (dpn), followed by transformation into macrophages at 3–5 dpn via CX3CR1 upregulation and Ly6C downregulation. In addition, inflammatory monocytes were aggregated inside the collecting venule only at 1 dpn. Neutrophils were not a major type of phagocyte during this response. The gene encoding C-C motif chemokine ligand 2 gene was significantly upregulated as early as 3 h after acoustic overstimulation. Given these results, treatment to control immune response after a noise-induced hearing loss should be applied as soon as possible.
Significance
Ototoxicity is a major side effect of aminoglycoside (AG) antibiotics; however, the mechanism by which this drug enters the cochlea and target hair cells (HCs) is not fully understood. Here, we developed an in vivo cochlear imaging method that enables real-time tracking of ototoxic drug transport into the cochlea in hearing adult mice. The time-lapse monitoring of drugs identified megalin as the major transporter of AG into the endolymph and the mechanotransducer channels as the portal into the HCs. Blocking megalin in vivo prevents AG-induced ototoxicity. Therefore, this study identifies an AG uptake pathway into the cochlea and provides a therapeutic target to eliminate drug-induced hearing loss.
Background
Treatment of many types of hearing instability in humans, including sudden sensorineural hearing loss, Meniere's disease, and autoimmune inner ear disease, rely heavily on the utilization of corticosteroids delivered both by oral and transtympanic routes. Despite this use, there is heterogeneity in the response to treatment with corticosteroids in humans with these diseases. The mechanisms by which corticosteroids exert their effect and the cell types in which they exert their effects in the inner ear remain poorly characterized. In this study, we localize steroid-responsive genes to cochlear cell types using previously published transcriptome datasets from the mammalian cochlea.
Methods
Steroid-responsive genes were localized to specific cochlear cell types using existing transcriptome datasets from wild-type mammalian cochlea exposed to systemic and transtympanic steroids, as well as previously published single-cell and single-nucleus RNA-sequencing datasets from the mammalian cochlea. Gene ontology (GO) analysis of differentially expressed genes (DEGs) was performed using PANTHER to investigate cellular processes implicated in transtympanic vs. systemic steroid action in the cochlea.
Results
Steroid-responsive genes were localized to specific cell types and regions in the cochlea including the stria vascularis, organ of Corti, and spiral ganglion neurons (SGN). Analyses demonstrate differential prevalence of steroid-responsive genes. GO analysis demonstrated steroid-responsive DEGs in the SGN to be associated with angiogenesis, apoptosis, and cytokine-mediated anti-inflammatory pathways.
Conclusions
Single-cell and single-nucleus transcriptome datasets localize steroid-responsive genes to specific regions in the cochlea. Further study of these regionally-specific steroid-responsive genes may provide insight into the mechanisms of and clinical response to corticosteroids in diseases of hearing instability.
Although association between hearing impairment and dementia has been widely documented by epidemiological studies, the role of auditory sensory deprivation in cognitive decline remains to be fully understood. To address this issue we investigated the impact of hearing loss on the onset and time-course of cognitive decline in an animal model of Alzheimer’s disease (AD), that is the 3×Tg-AD mice and the underlying mechanisms. We found that hearing loss induced by noise exposure in the 3×Tg-AD mice before the phenotype is manifested caused persistent synaptic and morphological alterations in the auditory cortex. This was associated with earlier hippocampal dysfunction, increased tau phosphorylation, neuroinflammation, and redox imbalance, along with anticipated memory deficits compared to the expected time-course of the neurodegenerative phenotype. Our data suggest that a mouse model of AD is more vulnerable to central damage induced by hearing loss and shows reduced ability to counteract noise-induced detrimental effects, which accelerates the neurodegenerative disease onset.
Delivery of substances into the inner ear via local routes is increasingly being used in clinical treatment. Studies have focused on methods to increase permeability through the round window membrane (RWM) and enhance drug diffusion into the inner ear. However, the clinical applications of those methods have been unclear and few studies have investigated the efficacy of methods in an inner ear injury model. Here, we employed the medium chain fatty acid caprate, a biologically safe, clinically applicable substance, to modulate tight junctions of the RWM. Intratympanic treatment of sodium caprate (SC) induced transient, but wider, gaps in intercellular spaces of the RWM epithelial layer and enhanced the perilymph and cochlear concentrations/uptake of dexamethasone. Importantly, dexamethasone co–administered with SC led to significantly more rapid recovery from noise-induced hearing loss at 4 and 8 kHz, compared with the dexamethasone-only group. Taken together, our data indicate that junctional modulation of the RWM by SC enhances dexamethasone uptake into the inner ear, thereby hastening the recovery of hearing sensitivity after noise trauma.
The cross-talk between oxidative stress and inflammation seems to play a key role in noise-induced hearing loss. Several studies have addressed the role of PPAR receptors in mediating antioxidant and anti-inflammatory effects and, although its protective activity has been demonstrated in several tissues, less is known about how PPARs could be involved in cochlear dysfunction induced by noise exposure. In this study, we used an in vivo model of noise-induced hearing loss to investigate how oxidative stress and inflammation participate in cochlear dysfunction through PPAR signaling pathways. Specifically, we found a progressive decrease in PPAR expression in the cochlea after acoustic trauma, paralleled by an increase in oxidative stress and inflammation. By comparing an antioxidant (Q-ter) and an anti-inflammatory (Anakinra) treatment, we demonstrated that oxidative stress is the primary element of damage in noise-induced cochlear injury and that increased inflammation can be considered a consequence of PPAR down-regulation induced by ROS production. Indeed, by decreasing oxidative stress, PPARs returned to control values, reactivating the negative control on inflammation in a feedback loop.
The treatment of acute hearing loss is clinically challenging due to the low efficacy of drug delivery into the inner ear. Local intratympanic administration of dexamethasone (D) and insulin-like growth factor 1 (IGF1) has been proposed for treatment, but they do not persist in the middle ear because they are typically delivered in fluid form. We developed a dual-vehicle drug delivery system consisting of cross-linked hyaluronic acid and polylactide-co-glycolide microcapsules. The effect and biocompatibility of the dual vehicle in delivering D and IGF1 were evaluated using an animal model of acute acoustic trauma. The dual vehicle persisted 10.9 times longer (8.7 days) in the middle ear compared with the control (standard-of-care vehicle, 0.8 days). The dual vehicle was able to sustain drug release over up to 1 to 2 months when indocyanine green was loaded as the drug. One-third of the animals experienced an inflammatory adverse reaction. However, it was transient with no sequelae, which was validated by micro CT findings, endoscopic examination, and histological assessment. Hearing restoration after acoustic trauma was satisfactory in both groups, which was further supported by comparable numbers of viable hair cells. Overall, the use of a dual vehicle for intratympanic D and IGF1 delivery may maximize the effect of drug delivery to the target organ because the residence time of the vehicle is prolonged.
Noise-induced hearing loss (NIHL) is a common inner ear disease but has complex pathological mechanisms, one of which is increased oxidative stress in the cochlea. The high-mobility group box 1 (HMGB1) protein acts as an inflammatory mediator and shows different activities with redox modifications linked to the generation of reactive oxygen species (ROS). We aimed to investigate whether manipulation of cochlear HMGB1 during noise exposure could prevent noise-induced oxidative stress and hearing loss. Sixty CBA/CaJ mice were divided into two groups. An intraperitoneal injection of anti-HMGB1 antibodies was administered to the experimental group; the control group was injected with saline. Thirty minutes later, all mice were subjected to white noise exposure. Subsequent cochlear damage, including auditory threshold shifts, hair cell loss, expression of cochlear HMGB1, and free radical activity, was then evaluated. The levels of HMGB1 and 4-hydroxynonenal (4-HNE), as respective markers of reactive nitrogen species (RNS) and ROS formation, showed slight increases on post-exposure day 1 and achieved their highest levels on post-exposure day 4. After noise exposure, the antibody-treated mice showed markedly less ROS formation and lower expression of NADPH oxidase 4 (NOX4), nitrotyrosine, inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) than the saline-treated control mice. A significant amelioration was also observed in the threshold shifts of the auditory brainstem response and the loss of outer hair cells in the antibody-treated versus the saline-treated mice. Our results suggest that inhibition of HMGB1 by neutralization with anti-HMGB1 antibodies prior to noise exposure effectively attenuated oxidative stress and subsequent inflammation. This procedure could therefore have potential as a therapy for NIHL.
Attenuation of noise-induced hair cell loss and noise-induced hearing loss (NIHL) by treatment with FK506 (tacrolimus), a calcineurin (CaN/PP2B) inhibitor used clinically as an immunosuppressant, has been previously reported, but the downstream mechanisms of FK506-attenuated NIHL remain unknown. Here we showed that CaN immunolabeling in outer hair cells (OHCs) and nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) in OHC nuclei are significantly increased after moderate noise exposure in adult CBA/J mice. Consequently, treatment with FK506 significantly reduces moderate-noise-induced loss of OHCs and NIHL. Furthermore, induction of reactive oxygen species (ROS) by moderate noise was significantly diminished by treatment with FK506. In agreement with our previous finding that autophagy marker microtubule-associated protein light chain 3B (LC3B) does not change in OHCs under conditions of moderate-noise-induced permanent threshold shifts, treatment with FK506 increases LC3B immunolabeling in OHCs after exposure to moderate noise. Additionally, prevention of NIHL by treatment with FK506 was partially abolished by pretreatment with LC3B small interfering RNA. Taken together, these results indicate that attenuation of moderate-noise-induced OHC loss and hearing loss by FK506 treatment occurs not only via inhibition of CaN activity but also through inhibition of ROS and activation of autophagy.
Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.
The prevalence of ear disorders has spurred efforts to develop drug delivery systems to treat these conditions. Here, recent advances in drug delivery systems that access the ear through the tympanic membrane (TM) are reviewed. Such methods are either non‐invasive (placed on the surface of the TM), or invasive (placed in the middle ear, ideally on the round window [RW]). The major hurdles to otic drug delivery are identified and highlighted the representative examples of drug delivery systems used for drug delivery across the TM to the middle and (crossing the RW also) inner ear.
We live in a world continuously immersed in noise, an environmental, recreational, and occupational factor present in almost every daily human activity. Exposure to high-level noise could affect the auditory function of individuals at any age, resulting in a condition called noise-induced hearing loss (NIHL). Given that by 2018, more than 400 million people worldwide were suffering from disabling hearing loss and that about one-third involved noise over-exposure, which represents more than 100 million people, this hearing impairment represents a serious health problem. As of today, there are no therapeutic measures available to treat NIHL. Conventional preventive measures, including public awareness and education and physical barriers to noise, do not seem to suffice, as the population is still being affected by damaging noise levels. Therefore, it is necessary to develop or test pharmacological agents that may prevent and/or diminish the impact of noise on hearing. Data availability about the pathophysiological processes involved in triggering NIHL has allowed researchers to use compounds, that could act as effective therapies, by targeting specific mechanisms such as the excess generation of free radicals and blood flow restriction to the cochlea. In this review, we summarize the advantages/disadvantages of these therapeutic agents, providing a critical view of whether they could be effective in the human clinic.
Objective
Artemisinin (ART) is a natural anti-malarial sesquiterpene lactone which has the ability to treat and activate the CLRN1 pathway to play a pivotal role in hearing loss and hair cell function. To investigate the therapeutic effect of ART in hearing loss induced by gentamicin (GM), an ART-loaded poly(ethylene glycol)-b-poly(ε-caprolactone) mPEG-PCL nanoparticle-based photosensitive hydrogel was developed and tested in this study.
Materials and Methods
Artemisinin-loaded mPEG-PCL nanoparticles (mPEG-PCL-ART-NPs) were prepared by a double emulsion method and the formulation was optimized by an orthogonal experimental design. The particle size, zeta potential, morphology and in vitro dissolution of the mPEG-PCL-ART-NPs were well characterized. Biocompatibility of the mPEG-PCL-ART-NPs were tested on HeLa cells with an MTT assay. The photo-crosslinkable biodegradable gelatin methacrylate (GelMA) hydrogel was prepared and its physicochemical properties (such as substitution, photocrosslinking efficiency, cell viability morphology, mechanical and swelling properties) were evaluated. Finally, mPEG-PCL-ART-FITC-NPs, loaded mPEG-PCL-ART-NPs, and loaded mPEG-PCL-ART-NPs-GelMA hydrogels were fabricated and a GM toxicity-induced guinea pig ear damage model was established to determine the effectiveness of the materials on returning auditory function and cochlea pathomorphology.
Results
The zeta potential of the mPEG-PCL-ART-NPs was about −38.64 ± 0.21 mV and the average size was 167.51 ± 1.87 nm with an encapsulation efficacy of 81.7 ± 1.46%. In vitro release studies showed that the mPEG-PCL-ART-NPs possessed a sustained-release effect and the MTT experiments showed good biocompatibility properties of the drug-loaded nanoparticles. The results indicated that the 5% GelMA with MA-4% hydrogel had a better crosslinking density and 3D structure for drug loading and drug delivery than controls. Skin penetration results showed that the mPEG-PCL-ART-NPs increased adhesive capacity and avoided fast diffusion in the skin. Most importantly, auditory brainstem response results indicated that the mPEG-PCL-ART-NPs-GelMA hydrogel alleviated hearing loss induced by GM.
Conclusion
These results suggested that the presently fabricated mPEG-PCL-ART-NPs-GelMA hydrogels are promising formulations for the treatment of hearing loss induced by GM and lay the foundation for further clinical research of inner ear induction therapy.
Cochlear implantation has become known as “the treatment of choice” for adults with severe to profound hearing loss. Wide variability exists, however, in the way hearing loss severity is measured and in the candidacy criteria used to recommend cochlear implantation.
Objectives
This study aimed to provide a descriptive analysis of recent evidence available in the literature in relation to the efficacy of unilateral cochlear implantation in adults, the general findings of these studies, and the populations to which these findings apply. It also aimed to appraise the individual success rate and the magnitude of benefit following implantation.
Design
A scoping review was conducted to identify English-language, peer-reviewed journal articles published between 2000 and 2018 assessing the outcomes of cochlear implantation in adults who received their first cochlear implant from 2000 onwards. To be included, studies had to report speech perception or self-reported measures of listening or quality of life at least three months after implantation. Systematic searches were conducted in Medline, Embase, Web of Science and Google Scholar. A two-stage screening approach was used, with seven reviewers independently screening titles and abstracts against inclusion criteria and three from this group further reviewing full-texts. A data charting form was developed and trialled, with 10% of the study data extracted in duplicate to compare results and further refine the form. Data relevant for efficacy analyses were extracted from studies with sample sizes of at least 10 participants.
Results
A total of 4182 abstracts were screened against inclusion criteria, and of these, 603 full-texts were further screened. After exclusion of non-eligible articles, 201 articles were included in the first part of this scoping review. The majority of these articles were case series or comparative studies without a concurrent group, and had small sample sizes. Data synthesis conducted with the 102 articles with more than 10 participants highlighted that the average word perception ability improved from 8.2% to 53.9% after implantation. Self-reported benefit improved by 21.5 percentage points. At the individual level, 82.0% of adults with postlingual hearing loss and 53.4% of adults with prelingual hearing loss improved their speech perception ability by 15 percentage points or more. A small proportion had poorer ability after implantation or had stopped using the cochlear implant.
Conclusions
Despite broad inconsistencies in measurement, research design, and reporting across articles, it is evident that cochlear implantation is beneficial to the majority of adults of any age who have limited aided speech perception abilities. While many adults with severe-to-profound hearing loss may also have poor speech perception abilities with hearing aids, the validity of using hearing loss severity as a criterion for cochlear implantation has not been demonstrated. Clinical and research recommendations derived from this review are provided.
Significance
Noise can cause excitotoxic trauma to cochlear synapses by triggering excessive release of the neurotransmitter glutamate from the auditory sensory hair cells. We report that a specific class of glutamate receptors, Ca ²⁺ -permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (CP-AMPARs), is largely responsible for this trauma. Because cochlear synapses are heterogenous with respect to glutamate receptors, the observation that a specific class is responsible might explain the variability in susceptibility to noise among synapses. Selective blockade of CP-AMPARs prevents excitotoxicity and noise-induced cochlear synaptopathy, while other glutamate receptors continue to mediate neurotransmission and allow hearing.
Ultrasound-induced microbubble (USMB) cavitation is widely used to promote drug delivery. Our previous study investigated USMB targeting round window membrane by applying the ultrasound transducer to tympanic bulla. In the present study we further extended the use of this technology to enhance drug delivery to inner ear by introducing the ultrasound transducer into external auditory canal (EAC) or applying it to skull. Using a three-dimensional-printed diffusion apparatus mimicking the pathway for ultrasound passing through and reaching middle ear cavity in vitro, both models simulating the transcanal and transcranial approach demonstrated 4.8-fold and 3.7-fold higher delivery efficiencies, respectively. In vivo model of guinea pigs, by filling tympanic bulla with microbubbles and biotin-fluorescein (biotin-FITC), USMB applied transcanally and transcranially induced 2.8-fold and 1.5-fold increases in biotin-FITC delivery efficiencies, respectively. In addition, the gentamicin uptake by cochlear and vestibular hair cells and gentamicin-induced hair cell loss were significantly enhanced following transcanal application of USMB. On the 28th day after transcanal USMB, safety assessment showed no significant changes in the hearing thresholds and the integrity of cochlea. These are the first results to demonstrate the feasibility and support the potential clinical application of applying USMB via EAC to facilitate drug delivery into inner ear.
Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in CX 3 CR1 GFP/+ mice of both sexes led to robust elimination of resident macrophages (∼94%) without significant adverse effects on peripheral leukocytes, cochlear function, and structure. At 1-day after noise exposure of 93 or 90 dB SPL for 2 hours the degree of hearing loss and synapse loss were comparable in presence and absence of macrophages. At 30 days after exposure, damaged synapses appeared repaired in the presence of macrophages. However, in the absence of macrophages such synaptic repair was significantly reduced. Remarkably, upon cessation of PLX5622 treatment, macrophages repopulated the cochlea, leading to enhanced synaptic repair. Elevated auditory brainstem response (ABR) thresholds and reduced ABR peak 1 amplitudes showed limited recovery in the absence of macrophages, but recovered similarly with resident and repopulated macrophages. Cochlear neuron loss was augmented in the absence of macrophages, but showed preservation with resident and repopulated macrophages after noise exposure. While the central auditory effects of PLX5622 treatment and microglia depletion remains to be investigated, these data demonstrate that macrophages do not affect synaptic degeneration but are necessary and sufficient to restore cochlear synapses and function after noise-induced synaptopathy.
SIGNIFICANCE STATEMENT
The synaptic connections between cochlear inner hair cells and spiral ganglion neurons can be lost due to noise over exposure or biological aging. This loss may represent the most common causes of sensorineural hearing loss also known as hidden hearing loss. Synaptic loss results in degradation of auditory information leading to difficulty in listening in noisy environments and other auditory perceptual disorders. We demonstrate that resident macrophages of the cochlea are necessary and sufficient to restore synapses and function following synaptopathic noise exposure. Our work reveals a novel role for innate-immune cells such as macrophages in synaptic repair that could be harnessed to regenerate lost ribbon synapses in noise- or age-linked cochlear synaptopathy, hidden hearing loss and associated perceptual anomalies.
Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t=0) were given mannitol at either t=0, t=6 or t=0,6 hours. Another group of rats was treated with cisplatin with mannitol at 0 hours and NAC/STS with and without mannitol at 6 hours. Concurrent mannitol (t=0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t=6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t=0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t=6) was better than NAC/STS (t=6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t=6 hours reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t=0 hours), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.
It is known that all living organisms are mortal. For many decades, the main interest of researchers has been focused on the investigation of proliferation, differentiation and other fundamental cellular processes, completely ignoring the understanding of the mechanisms of cell elimination. Since the 60s–70s of the last century, a systematic study of cell death began, which is currently one of the most rapidly developing areas of biomedicine. Since this field of research is very wide, in these short notes we tried to discuss the hottest, but not all, topics that are of interest to many of our colleagues.
OBJECTIVE: The purpose of the study is to test the ability of resveratrol to protect the auditory system from reactive oxygen species (ROS)-mediated noise damage. Oxidative stress is mediated by ROS, which are known to cause cellular and molecular damage. Interfering with this process, using ROS inhibitors/scavengers such as antioxidants has shown promise in protecting specific systems from oxidative damage. Among the antioxidants receiving recent attention is resveratrol, an active component in red wine.
STUDY DESIGN AND SETTING: Ten Fischer rats were used for this study. The experimental group (n = 5) received 7 weeks of resveratrol treatment (430/μg/kg/day), by gavage, and the control group (n = 5) received normal saline solution by gavage. Baseline auditory brainstem responses (3, 6, 9, 12 and 18 kHz) were determined for both groups. After 21 days, animals were exposed to noise (105 dB, 4500 to 9000 Hz for 24 hours). Postnoise auditory brainstem responses were assessed at 4 recovery time points: immediate, at 3 days, 7 days, and 4 weeks after noise exposure.
RESULTS: Results demonstrate that the resveratrol group showed reduced threshold shifts compared with the control group after noise exposure. These shifts were significantly different between groups at 6 and 9 kHz ( P < 0.05), corresponding to the region most represented by the frequency of the traumatic noise.
CONCLUSION/SIGNIFICANCE: Initial studies in our laboratory as well as other investigators have shown the importance of specific antioxidant therapy in the prevention of ischemic, noise, and age related hearing loss. The current study demonstrates a protective effect of resveratrol on noise-induced hearing loss.
Local drug delivery has become an effective method for disease therapy in fine organs including ears, eyes, and noses. However, the multiple anatomical and physiological barriers, unique clearance pathways, and sensitive perceptions characterizing these organs have led to suboptimal drug delivery efficiency. Here, we developed dexamethasone sodium phosphate-encapsulated gelatin methacryloyl (Dexsp@GelMA) microgel particles, with finely tunable size through well-designed microfluidics, as otic drug delivery vehicles for hearing loss therapy. The release kinetics, encapsulation efficiency, drug loading efficiency, and cytotoxicity of the GelMA microgels with different degrees of methacryloyl substitution were comprehensively studied to optimize the microgel formulation. Compared to bulk hydrogels, Dexsp@GelMA microgels of certain sizes hardly cause air-conducted hearing loss in vivo. Besides, strong adhesion of the microgels on the round window membrane was demonstrated. Moreover, the Dexsp@GelMA microgels, via intratympanic administration, could ameliorate acoustic noise-induced hearing loss and attenuate hair cell loss and synaptic ribbons damage more effectively than Dexsp alone. Our results strongly support the adhesive and intricate microfluidic-derived GelMA microgels as ideal intratympanic delivery vehicles for inner ear disease therapies, which provides new inspiration for microfluidics in drug delivery to the fine organs.
Declaration of cCompeting iInterestThe authors declare that there is no financial interest in this article.Abstract
Oxidative stress is considered a driving event in the damage to inner hair cell (IHC) synapses. Mitochondrial deacetylase Sirtuin 3 (SIRT3) is an important regulator of reactive oxygen species (ROS) production. However, the effect of SIRT3 on IHC synapses remains elusive. In this study, we treated cochlear basilar membrane (CBM) with hydrogen peroxide (H2O2) to establish an oxidative stress model in vitro. The H2O2-induced CBM exhibited decreased the number of IHC synapses with low levels of ATP and mitochondrial membrane potential. Additionally, H2O2-incuded CBM showed markedly reduced levels of forkhead box protein O 3a (FOXO3a), superoxide dismutase 2 (SOD2), and isocitrate dehydrogenase 2 (IDH2), thereby increasing ROS generation. SIRT3 overexpression via administrating nicotinamide riboside in the H2O2-induced CBM protected IHC synapses against oxidative stress and inhibited hair cell apoptosis. We further demonstrated that SIRT3 overexpression led to upregulation of IDH2, and hypoacetylation of several proteins, such as FOXO3a and SOD2, which in turn reduced the levels of ROS and improved mitochondrial function. Collectively, these findings reveal that SIRT3 may be a potential therapeutic approach for damaged IHC synapses induced by oxidative stress.
Hearing loss is the most common sensory disorder worldwide and may result from age, drugs, or exposure to excessive noise. Crossing the blood-labyrinth barrier to achieve targeted drug delivery to the inner ear is key to the treatment of hearing loss. We designed a nanoparticle (NP)-based system for targeted drug delivery of forskolin (FSK) to the inner ear, driven by the prestin-targeting peptide LS19 ("ligand-receptor type interaction"). In vivo experiments in developing zebrafish embryos (4-96 h past fertilization) and mice confirmed that LS19-FSK specifically targeted and accumulated in zebrafish lateral line neuromasts and mouse outer hair cells (OHCs). LS19 peptide modification enabled LS19-FSK-NPs to rapidly target OHCs with high specificity. Furthermore, the multifunctional LS19-FSK-NPs were successfully delivered to the OHCs via the round window membrane route and exhibited slow-release properties. The sustained release and intracellular accumulation of FSK inhibited apoptosis of OHCs. Compared with LS19-NPs and FSK-NPs, LS19-FSK-NPs provided significantly stronger protection against noise-induced hearing damage, based on auditory brainstem responses at 4, 8, 16, and 32 kHz. Thus, our specially designed targeted nano-delivery system may serve as a basis for future clinical applications and treatment platforms and has the potential to significantly improve the treatment results of many inner ear diseases.
Background
Excessive oxidative stress of the inner ear as a result of high, intense noise exposure is regarded as a major mechanism underlying the development of noise-induced hearing loss (NIHL). The present study was designed to explore the effect and mechanism of activated transcription factor 3 (ATF3) in reduction/oxidation homeostasis of NIHL.
Method
In vitro and in vivo assays were performed to investigate the functional role of ATF3 in the inner ear. Mice hearing was measured using auditory brainstem response audiometry. ATF3 short hairpin RNA (shRNA) was transfected into House Ear Institute-Organ of Corti 1 (HEI-OC1) cells to decrease ATF3 expression. Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) were performed to quantify ATF3, NRF2, HO-1 and NQO1 expression. Glutathione (GSH) assay was performed to detect intracellular GSH levels. ATF3 immunofluorescence analysis was carried out in cochlear cryosectioned samples and HEI-OC1 cells to localize ATF3 expression. Cell counting kit 8 assay and flow cytometry were performed to analyze cell viability.
Result
ATF3 was upregulated in noise-exposed cochleae and HEI-OC1 cells treated with H2O2. NRF2 is a key factor regulated by ATF3. NRF2, HO-1, NQO1, and GSH expression was significantly downregulated in shATF3 HEI-OC1 cells. ATF3 silencing promoted reactive oxygen species accumulation and increased apoptosis and necrosis with H2O2 stimulus.
Conclusion
ATF3 functions as an antioxidative factor by activating the NRF2/HO-1 pathway.
Nitric oxide (NO) is critically involved in the regulation of a wide variety of physiological and pathophysiological processes. However, the role of NO in the pathogenesis of noise-induced hearing loss (NIHL) is complex and remains controversial. Here we reported that treatment of CBA/J mice with l-arginine, a physiological precursor of NO, significantly reduced noise-induced reactive oxygen species (ROS) accumulation in outer hair cells (OHCs), attenuated noise-induced loss of OHCs and NIHL consequently. Conversely, pharmacological inhibition of endothelial nitric oxide synthase exacerbated noise-induced loss of OHCs and aggravated NIHL. In HEI-OC1 cells, NO also showed substantial protection against H2O2-induced oxidative stress and cytotoxicity. Mechanistically, NO increased S-nitrosylation of pyruvate kinase M2 (PKM2) and inhibited its activity, which thus diverted glucose metabolic flux from glycolysis into the pentose phosphate pathway to increase production of reducing equivalents (NADPH and GSH) and eventually prevented H2O2-induced oxidative damage. These findings open new avenues for protection of cochlear hair cells from oxidative stress and prevention of NIHL through NO modulation of PKM2 and glucose metabolism reprogramming.
Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.
Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno associated virus vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF)-gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes SPION tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, ABR wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL.
Noise-induced hearing loss (NIHL) is the second most common cause of acquired hearing loss. Acoustic trauma can cause oxidative damage in the cochlear hair cells (HCs) through apoptotic pathways. Apelin is a newly discovered neuropeptide with neuroprotective effects against the oxidative stress in neurodegenerative disorder. We investigated the preventive effects of apelin-13 on the cochlear HCs and spiral ganglion neurons (SGNs) against acoustic trauma via Sirtuin-1 (Sirt-1) regulation in rats. Animals were assigned to control, control + apelin-13 (50 or 100 µg/kg, ip), and noise exposure groups without any treatment or were administered apelin-13 (50 or 100 µg/kg, ip) and EX-527 (an inhibitor of Sirt-1) prior to each noise session. In the noise groups, 110 dB white noise was applied for 6 hours per 5 days. Pre- and post-exposure distortion product otoacoustic emissions (DPOAE) and cochlear superoxide dismutase (SOD) activity were assessed. Western blot evaluated the cochlear protein expressions of Sirt-1, cleaved-caspase-3, Bax, and Bcl-2. Cell apoptosis was detected through TUNEL staining. Immunofluorescence was used to examine expression of HCs and SGNs specific protein. DPOAE level were significantly improved in the noise exposure group receiving 100 μg/kg apelin-13. At high doses, apelin augmented SOD levels in the rat cochlea subjected to noise. Apelin 100 markedly increased Sirt-1, and decreased cleaved- caspase-3 expression as well as Bax/Bcl-2 ratio in the cochlea tissue of noise-exposed rats. These findings suggest the promising therapeutic potential of apelin-13 for the prevention of noise-induced injury to cochlea and hearing loss.
Achieving sufficient delivery across the blood–brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public–private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood–brain barrier-crossing strategies — with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes — and analyse their potential in the treatment of CNS disorders. The blood–brain barrier is a perennial challenge for the delivery of therapeutics to the central nervous system. In their Review, Terstappen and colleagues discuss non-invasive approaches to brain delivery, particularly for biopharmaceuticals, some of which are now in clinical testing.
Overproduction of reactive oxygen species (ROS) and inflammation are two key pathogeneses of noise-induced hearing loss (NIHL), which leads to outer hair cell (OHC) damage and hearing loss. In this work, we successfully developed ROS-responsive nanoparticles as berberine (BBR) carriers (PL-PPS/BBR) for OHC-targeted therapy of NIHL: Prestin-targeting peptide 2 (PrTP2)-modified nanoparticles (PL-PPS/BBR), which effectively accumulated in OHC areas, and poly(propylene sulfide)120 (PPS120), which scavenged ROS and converted to poly(propylene sulfoxide)120 in a ROS environment to disintegrate and provoke the rapid release of BBR with anti-inflammatory and antioxidant effects. In this study, satisfactory anti-inflammatory and antioxidant effects of PL-PPS/BBR were confirmed. Immunofluorescence and scanning electron microscopy (SEM) images showed that PL-PPS/BBR effectively accumulated in OHCs and protected the morphological integrity of OHCs. The auditory brainstem response (ABR) results demonstrated that PL-PPS/BBR significantly improved hearing in NIHL guinea pigs after noise exposure. This work suggested that PL-PPS/BBR may be a new potential treatment for noise-associated injury with clinical application.
Oxidative stress is the key determinant in the pathogenesis of noise-induced hearing loss (NIHL). Given that cellular defense against oxidative stress is an energy-consuming process, the aim of the present study was to investigate whether increasing energy availability by glucose supplementation protects cochlear hair cells against oxidative stress and attenuates NIHL. Our results revealed that glucose supplementation reduced the noise-induced formation of reactive oxygen species (ROS) and consequently attenuated noise-induced loss of outer hair cells, inner hair cell synaptic ribbons, and NIHL in CBA/J mice. In cochlear explants, glucose supplementation increased the levels of ATP and NADPH, as well as attenuating H2O2-induced ROS production and cytotoxicity. Moreover, pharmacological inhibition of glucose transporter type 1 activity abolished the protective effects of glucose against oxidative stress in HEI-OC1 cells. These findings suggest that energy availability is crucial for oxidative stress resistance and glucose supplementation offers a simple and effective approach for the protection of cochlear hair cells against oxidative stress and NIHL.
To study the effects of drug delivery using solid lipid nanoparticles in the treatment of acute noise exposure-induced cochlea damage. The solid lipid nanoparticles (SLNs) were used as carriers to effectively encapsulate the drug clozapine, improve drug stability in the carrier system, and increase drug bioavailability in vivo. Solid lipid nanoparticles carrying clozapine were produced by ultrasonic technology. The clozapine solution or sulphate SLN was administered though intratympanic or intravenous injection on the first day of noise exposure Guinea pigs were exposed to 110 dB sound pressure level (SPL) noise (2 h per day with center frequencies of 0.25-4.0 kHz for 4 days). After noise exposure, the guinea pigs were subjected to auditory brainstem response (ABR) threshold measurements. Reactive oxygen species (ROS) levels were detected in the cochlea by electron spin resonance (ESR), and outer hair cell counts (OHCs) were obtained using silver nitrate (AgNO₃). SLN particles carrying clozapine exhibited protective effects on the cochlea. The threshold shift and ROS production in treated animals, especially in animals treated with clozapine SLN through intraperitoneal injection, were significantly lower than those in untreated animals.
Introduction
Excessive exposure to noise is a common occurrence that contributes to approximately 50% of the non-genetic hearing loss cases. Researchers need to develop standardized preclinical models and identify molecular targets to effectively develop prevention and curative therapies.
Areas covered
In this review, the authors discuss the many facets of human noise-induced pathology, and the primary experimental models for studying the basic mechanisms of noise-induced damage, making connections and inferences among basic science studies, preclinical proofs of concept and clinical trials.
Expert opinion
Whilst experimental research in animal models has helped to unravel the mechanisms of noise-induced hearing loss, there are often methodological variations and conflicting results between animal and human studies which make it difficult to integrate data and translate basic outcomes to clinical practice. Standardization of exposure paradigms and application of -omic technologies will contribute to improving the effectiveness of transferring newly gained knowledge to clinical practice.
Noise-induced hearing loss (NIHL) is associated both acute and chronic noise exposure. The application of steroid hormones is the first-line treatment for NIHL. However, the application of steroid hormone in the body needs high-dose to keep its efficacy and causes side effects, such as headache and osteoporosis. In this work, we have prepared a zeolitic imidazolate framework (ZIF)-based system for steroid hormone delivery in inner ear. Methylprednisolone (MP), a typical steroid hormone, was encapsulated into ZIF-90 nanoparticles (NPs) in one-pot. The obtained MP@ZIF-90 NPs are negatively charged NPs with 120 nm in size, which show good biocompatibility and good stability at pH 7.4. After intraperitoneal injection, ZIF-90 could efficiently protect drugs during the peripheral blood circulation, enter the inner ear by passing the blood labyrinthine barrier (BLB) and slowly release the drugs. Auditory brainstem response (ABR) tests indicate that MP@ZIF-90 exhibits a better protection of mice from noise than those using free MP and ZIF-8 with encapsulated MP (MP@ZIF-8). More importantly, MP@ZIF-90 shows no defect in inner ear after being treated with noise and low nephrotoxicity during therapy, which demonstrates the biocompatibility of this material. We believe ZIF-90 based delivery system is an efficient delivery system for inner ear therapy of NIHL.
Poloxamers, also called Pluronic, belong to a unique class of synthetic tri-block copolymers containing central hydrophobic chains of poly(propylene oxide) sandwiched between two hydrophilic chains of poly(ethylene oxide). Some chemical characteristics of poloxamers such as temperature-dependent self-assembly and thermo-reversible behavior along with biocompatibility and physiochemical properties make poloxamer-based biomaterials promising candidates for biomedical application such as tissue engineering and drug delivery. The microstructure, bioactivity, and mechanical properties of poloxamers can be tailored to mimic the behavior of various types of tissues. Moreover, their amphiphilic nature and the potential to self-assemble into the micelles make them promising drug carriers with the ability to improve the drug availability to make cancer cells more vulnerable to drugs. Poloxamers are also used for the modification of hydrophobic tissue-engineered constructs. This article collects the recent advances in design and application of poloxamer-based biomaterials in tissue engineering, drug/gene delivery, theranostic devices, and bioinks for 3D printing.
Statement of Significance
Poloxamers, also called Pluronic, belong to a unique class of synthetic tri-block copolymers containing central hydrophobic chains of poly(propylene oxide) sandwiched between two hydrophilic chains of poly(ethylene oxide). The microstructure, bioactivity, and mechanical properties of poloxamers can be tailored to mimic the behavior of various types of tissues. Moreover, their amphiphilic nature and the potential to self-assemble into the micelles make them promising drug carriers with the ability to improve the drug availability to make cancer cells more vulnerable to drugs. However, no reports have systematically reviewed the critical role of poloxamer for biomedical applications. Research on poloxamers is growing today opening new scenarios that expand the potential of these biomaterials from “traditional” treatments to a new era of tissue engineering. To the best of our knowledge, this is the first review article in which such issue is systematically reviewed and critically discussed in the light of the existing literature. Undoubtedly, investigations on the use of poloxamer biomaterials needs further advancement and a lot of critical questions have yet to be answered. Herein, we introduce the salient features, the hurdles that must be overcome, the hopes and practical constraints into further developments.
Biological barriers are the first line of defense against pathogen invasions, but they can also present as critical obstacles to drug delivery. Despite a variety of strategies have been developed recently to overcome them, significant efforts are still needed to achieve safer and more effective drug delivery. Herein, we constructed a metal-free, "slim waist" shaped microshotgun delivery device, which was able to cross the tympanic membrane and round window membrane. The efficient penetration was powered by the gas generating reactions of self-contained chemicals. This device is advantageous in several aspects. First, the device could be prepared using simple procedures, common equipment and affordable materials. Second, the device is deemed biocompatible, revealed by low cytotoxicity, normal blood cell parameters and histological morphology after single/repeated administration. Third, the nanoparticles loaded in the microshotgun were able to actively penetrate the epithelial layer of the membrane after the first acceleration, and can penetrate the endothelial layer of tympanic membrane using external magnetic field as the secondary power to align and accelerate the nanoparticles. In addition, the micro-penetration of membrane induced by microshotgun could recover in a short time as observed in high-resolution scanning electron microscopy. This easy-to-get, efficient and safe micro device provides a new delivery platform for the treatment of diseases in the middle ear and inner ear, and holds potential to overcome the physiologic barrier in the body.