Treatment Of Inner Ear Diseases Research Articles

Reversible opening of the blood-labyrinth barrier by low-pressure pulsed ultrasound and microbubbles for the treatment of inner ear diseases

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

Potential application value of pigment epithelium-derived factor in sensorineural hearing loss.

The inner ear is a complex and precise auditory perception system responsible for receiving and converting sound signals into neural signals, enabling us to perceive and understand sound. However, the occurrence and development of inner ear diseases and auditory disorders, such as sensorineural hearing loss, remain a global problem. In recent years, there has been increasing research on the treatment of inner ear diseases and auditory regeneration. Among these treatments, pigment epithelium-derived factor (PEDF), as a multifunctional secretory protein, exhibits diverse biological activities and functions through various mechanisms, and has shown potential applications in the inner ear. This minireview comprehensively evaluates the performance of PEDF in sensorineural hearing loss in inner ear and its potential targets and therapeutic prospects.

Novel self-degradable prodrug blend thermogel for intratympanic drug delivery to treat inner ear diseases

The use of injectable hydrogel formulations for targeted drug delivery into the inner ear has gained considerable interest. In this study, we introduce a novel self-degradable prodrug blend thermogel system designed to deliver the anti-inflammatory drug, dexamethasone (DEX), in a controlled and safe manner for effective treatment of inner ear diseases. Our approach involves blending a thermogelling polymer, hexanoyl glycol chitosan (HGC), with a polymer prodrug, dexamethasone conjugated glycol chitosan (GC-DEX), to create injectable formulations suitable for intratympanic administration. Through extensive evaluation of the physicochemical and biological properties, we demonstrate that our thermogel formulations exhibit not only excellent thermogelling and injectable characteristics but also controlled release properties, resulting in enhanced drug absorption and prolonged drug concentration in the inner ear. The in vivo T2-weighted MRI Imaging further confirms the long-lasting stability of our thermogel formulations within the tympanic cavity, with a self-degradation period of approximately one month. Notably, guinea pigs treated with the HGC/GC-DEX formulation showed significant hearing recovery merely 7 days after noise exposure, accompanied by a reduction in outer hair cell loss. These promising results indicate the potential of our prodrug blend thermogel as an efficient delivery system for therapeutic agents in the inner ear.

Intratympanic injection for treatment of inner ear diseases

Background: Intratympanic injection has emerged as a novel approach to bypass the blood-labyrinth barrier and effectively deliver drugs into the inner ear. This technique is used for treatment of various inner ear diseases and overcomes the limitations of systemic drug therapy. In this paper, we provide an overview of the application of intratympanic injection using steroids and gentamicin and highlight the major diseases and summarize the reported efficacy of this approach.Current Concepts: Intratympanic steroid injections have been used for treatment of various inner ear diseases, including sudden sensorineural hearing loss, Ménière disease, and tinnitus. Therapeutic effects of steroids include reducing inflammation, modulating the immune response, improving cochlear blood flow, and maintaining ion homeostasis. Intratympanic gentamicin injections are primarily used to minimize hearing loss and control vertigo symptoms in patients with Ménière disease. Gentamicin selectively injures vestibular hair cells with minimal ototoxicity compared with other aminoglycoside antibiotics.Discussion and Conclusion: Intratympanic injections offer several advantages, including targeted drug delivery, minimal systemic adverse effects, and rapid action. Reportedly, intratympanic steroid injections used as primary or salvage treatment are associated with positive outcomes in patients with sudden sensorineural hearing loss. Ménière disease also shows positive outcomes following intratympanic steroid and gentamicin injections. However, studies have reported conflicting results, and further research is required to standardize dosing and administration protocols. Intratympanic injections are a promising therapeutic option, and ongoing research is essential to optimize their efficacy and safety.

Silicone matrices for controlled dexamethasone release: toward a better understanding of the underlying mass transport mechanisms.

Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems, e.g. for the treatment of inner ear diseases or for pacemakers. Generally, very long drug release periods are targeted: several years/decades. This renders the development and optimization of novel drug products cumbersome: experimental feedback on the impact of the device design is obtained very slowly. A better understanding of the underlying mass transport mechanisms can help facilitating research in this field. A variety of silicone films were prepared in this study, loaded with amorphous or crystalline dexamethasone. Different polymorphic drug forms were investigated, the film thickness was altered and the drug optionally partially/completely exchanged by much more water-soluble dexamethasone 'phosphate'. Drug release studies in artificial perilymph, scanning electron microscopy, optical microscopy, differential scanning calorimetry, X-ray diffraction and Raman imaging were used to elucidate the physical states of the drugs and polymer, and of the systems' structure as well as dynamic changes thereof upon exposure to the release medium. Dexamethasone particles were initially homogeneously distributed throughout the systems. The hydrophobicity of the matrix former very much limits the amounts of water penetrating into the system, resulting in only partial drug dissolution. The mobile drug molecules diffuse out into the surrounding environment, due to concentration gradients. Interestingly, Raman imaging revealed that even very thin silicone layers (<20 µm) can effectively trap the drug for prolonged periods of time. The physical state of the drug (amorphous, crystalline) did not affect the resulting drug release kinetics to a noteworthy extent.

Safety and audiological outcome in a case series of tertiary therapy of sudden hearing loss with a biodegradable drug delivery implant for controlled release of dexamethasone to the inner ear.

BackgroundIntratympanic injections of glucocorticoids have become increasingly common in the treatment of idiopathic sudden sensorineural hearing loss (ISSHL). However, due to their fast elimination, sustained applications have been suggested for local drug delivery to the inner ear.Materials and methodsThe study is based on a retrospective chart review of patients treated for ISSHL at a single tertiary (university) referral center. We included patients who were treated with a solid, biodegradable, poly(D,L-lactic-co-glycolic acid) (PLGA)-based drug delivery system providing sustained delivery of dexamethasone extracochlear into the round window niche (n = 15) or intracochlear into scala tympani (n = 2) for tertiary therapy of ISSHL in patients without serviceable hearing after primary systemic and secondary intratympanic glucocorticoid therapy. We evaluated the feasibility and safety through clinical evaluation, histological examination, and functional tests [pure-tone threshold (PTA), word recognition scores (WRS)].ResultsWith adequate surgical preparation of the round window niche, implantation was feasible in all patients. Histologic examination of the material in the round window niche showed signs of resorption without relevant inflammation or foreign body reaction to the implant. In patients where the basal part of scala tympani was assessable during later cochlear implantation, no pathological findings were found. In the patients with extracochlear application, average preoperative PTA was 84.7 dB HL (SD: 20.0) and 76.7 dB HL (SD: 16.7) at follow-up (p = 0.08). The preoperative average maximum WRS was 14.6% (SD: 17.9) and 39.3% (SD: 30.7) at follow-up (p = 0.11). Six patients (40%), however, reached serviceable hearing. The two patients with intracochlear application did not improve.ConclusionThe extracochlear application of the controlled release system in the round window niche and – based on limited observations - intracochlear implantation into scala tympani appears feasible and safe. Due to the uncontrolled study design, conclusions about the efficacy of the treatment are limited. These observations, however, may encourage the initiation of prospective controlled studies using biodegradable controlled release implants as drug delivery systems for the treatment of inner ear diseases.

Nanomaterials for Inner Ear Diseases: Challenges, Limitations and Opportunities.

The inner ear is located deep in the temporal bone and has a complex anatomy. It is difficult to observe and obtain pathological tissues directly. Therefore, the diagnosis and treatment of inner ear diseases have always been a major clinical problem. The onset of inner ear disease can be accompanied by symptoms such as hearing loss, dizziness and tinnitus, which seriously affect people’s lives. Nanoparticles have the characteristics of small size, high bioavailability and strong plasticity. With the development of related research on nanoparticles in inner ear diseases, nanoparticles have gradually become a research hotspot in inner ear diseases. This review briefly summarizes the research progress, opportunities and challenges of the application of nanoparticles in inner ear diseases.

Bioinformatic Analysis of the Perilymph Proteome to Generate a Human Protein Atlas.

The high complexity of the cellular architecture of the human inner ear and the inaccessibility for tissue biopsy hampers cellular and molecular analysis of inner ear disease. Sampling and analysis of perilymph may present an opportunity for improved diagnostics and understanding of human inner ear pathology. Analysis of the perilymph proteome from patients undergoing cochlear implantation was carried out revealing a multitude of proteins and patterns of protein composition that may enable characterisation of patients into subgroups. Based on existing data and databases, single proteins that are not present in the blood circulation were related to cells within the cochlea to allow prediction of which cells contribute to the individual perilymph proteome of the patients. Based on the results, we propose a human atlas of the cochlea. Finally, druggable targets within the perilymph proteome were identified. Understanding and modulating the human perilymph proteome will enable novel avenues to improve diagnosis and treatment of inner ear diseases.

β-Cyclodextrin and Oligoarginine Peptide-Based Dendrimer-Entrapped Gold Nanoparticles for Improving Drug Delivery to the Inner Ear.

Here, we developed a safe and highly effective nanocarrier using β-cyclodextrin (β-CD) and oligoarginine peptide (Arg8)-modified dendrimer-entrapped gold nanoparticles (Au@CD-PAMAM-Arg8), with a diameter of 5 nm, for improved delivery of dexamethasone (Dex) to the inner ear. The properties and in vivo distribution of the Au@CD-PAMAM-Arg8 were assessed in vitro, and a streptomycin (SM) ototoxicity model was used in vivo. Flow cytometry analysis of HEIOC1 cells treated with Au@CD-PAMAM-Arg8 and Au @CD-PAMAM at different time intervals indicated that cell uptake efficiency of the drug delivery carrier Au@CD-PAMAM-Arg8 was higher than that of Au @CD-PAMAM. Au@CD-PAMAM-Arg8 carrying Dex (Au@CD-PAMAM-Arg8/Dex) were mainly distributed in hair cells, the spiral ganglion, lateral wall, and nerve fibers and had stronger protective effects on the inner ear than Dex administration alone. In vivo tracer tests revealed that tympanic injection was significantly more effective than posterior ear injection, muscle injection, and tail vein injection, whereas clinical retro-auricular injection could not increase the efficiency of drug delivery into the ear. Electrocochleography results showed that Au@CD-PAMAM-Arg8/Dex significantly improved hearing in C57/BL6 mice after SM exposure. These findings indicate that Au@CD-PAMAM-Arg8 may be the useful drug carriers for the treatment of inner ear diseases.

Comparison of the Pathway to the Inner Ear Between Postauricular and Intramuscular Injection of Dexamethasone in Guinea Pigs

BackgroundPostauricular injection as a local therapy has been confirmed to be effective for inner ear diseases. However, the mechanism for the drugs entering the inner ears remains unknown. This study aims to compare the distribution of dexamethasone by intramuscular injection with that by postauricular injection, and explore the pathway of the drugs entering the inner ears.MethodsAn in vivo optical imaging system was used to conduct a time course observation to compare the distribution of dexamethasone by intramuscular injection with that by postauricular injection in male guinea pigs. The drug availability in the tympanic mucosa, tympanum, endolymphatic sac, and cochlea was observed by a confocal laser scanning microscope.ResultsThe local fluorescent intensity by postauricular injection was significantly higher in the inner ears, and lower in partial peripheral organs, than that by the intramuscular injection. The drug metabolism by postauricular injection exhibited an obviously sustained release effect in the inner ears. Drugs by postauricular injection might enter the endolymphatic sac through the posterior auricular artery and occipital artery, as well as the connections of the mastoid emissary vein, sigmoid sinus and endolymphatic sac.ConclusionMore drugs concentrated in the inner ear for longer therapeutic time and less systemic delivery implied more effective and less risk of side effects through postauricular injection than intramuscular injection safer for the treatment of inner ear diseases.

Neuron Compatibility and Antioxidant Activity of Barium Titanate and Lithium Niobate Nanoparticles.

The biocompatibility and the antioxidant activity of barium titanate (BaTiO3) and lithium niobate (LiNbO3) were investigated on a neuronal cell line, the PC12, to explore the possibility of using piezoelectric nanoparticles in the treatment of inner ear diseases, avoiding damage to neurons, the most delicate and sensitive human cells. The cytocompatibility of the compounds was verified by analysing cell viability, cell morphology, apoptotic markers, oxidative stress and neurite outgrowth. The results showed that BaTiO3 and LiNbO3 nanoparticles do not affect the viability, morphological features, cytochrome c distribution and production of reactive oxygen species (ROS) by PC12 cells, and stimulate neurite branching. These data suggest the biocompatibility of BaTiO3 and LiNbO3 nanoparticles, and that they could be suitable candidates to improve the efficiency of new implantable hearing devices without damaging the neuronal cells.

Recent Advances and Future Research Directions for Hearing Loss Treatment Based on Nanoparticles

Sensorineural hearing loss is a prevailing health issue worldwide which usually occurs due to sensory inner ear cell destruction. These cells, once damaged, do not regenerate in mammals resulting in permanent hearing loss. Effective treatment of inner ear diseases is strongly correlated with efficient drug delivery to the inner ear. Researchers have made important efforts to deliver drugs locally to the inner ear in a safe and controllable manner. Different strategies and drug delivery systems were used to mitigate the resistance exerted by the multiple anatomical barriers found in the inner ear. Nanoparticles represent an option for sustained drug delivery to the inner ear. Nanocarrier‐based systems can diffuse through the round and oval window membrane allowing for direct delivery into the inner ear components. Certain types of enhanced nanoparticles can focus on specific parts of the inner ear, providing targeted delivery which might represent the future therapy for sensorineural hearing loss. In this article, we will present the latest advances in the treatment of hearing loss based on nanoparticles.

Nanocarriers for Inner Ear Disease Therapy.

Hearing loss is a common disease due to sensory loss caused by the diseases in the inner ear. The development of delivery systems for inner ear disease therapy is important to achieve high efficiency and reduce side effects. Currently, traditional drug delivery systems exhibit the potential to be used for inner ear disease therapy, but there are still some drawbacks. As nanotechnology is developing these years, one of the solutions is to develop nanoparticle-based delivery systems for inner ear disease therapy. Various nanoparticles, such as soft material and inorganic-based nanoparticles, have been designed, tested, and showed controlled delivery of drugs, improved targeting property to specific cells, and reduced systemic side effects. In this review, we summarized recent progress in nanocarriers for inner ear disease therapy. This review provides useful information on developing promising nanocarriers for the efficient treatment of inner ear diseases and for further clinical applications for inner ear disease therapy.

Fused deposition modelling 3D printing proof-of-concept study for personalised inner ear therapy.

There is a requirement within ear therapeutics for a delivery system capable of safely delivering controlled doses to the inner ear. However, the anatomy and sensitivity of the inner ear make current delivery systems problematic and often ineffective. Therefore, a new delivery system is required to overcome these issues and provide a more efficacious system in the treatment of inner ear disease. This study assesses the potential of 3D printing (3DP) as a fabrication method for an implantable drug delivery system (DDS) to the inner ear. Three implantable designs of varying geometry were produced with fused deposition modelling (FDM) 3DP, each loaded with 0.25%, 0.5% and 1% levofloxacin; filaments prepared by hot-melt extrusion. Each implant was effective in providing sustained, therapeutic release of levofloxacin for at least 4 days and as such would be effective in therapeutic treatment of many common inner ear diseases, such as otitis media or Ménière's disease. This proof-of-concept research was successful in utilising FDM as a fabrication method for a DDS capable of providing prolonged release directly to the inner ear and highlights the viability of 3DP in the fabrication of an inner ear DDS.

Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss.

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

Lipid nanoparticles-encapsulated brain-derived neurotrophic factor mRNA delivered through the round window niche in the cochleae of guinea pigs

The treatment of sensorineural hearing loss (SNHL) may be achieved via the application of a cochlear implant (CI) that allows the electrical stimulation of spiral ganglion neurons (SGNs). Nevertheless, the efficacy of CIs is limited by the degeneration of SGNs following SNHL. Although the application of exogenous neurotrophic factors has been reported to decrease SGN degeneration, non-invasive targeted drug delivery systems are required to achieve effective results. In this study, an SS-cleavable proton-activated lipid-like material [ssPalm; a neutral lipid nanoparticle (LNP)], was loaded with mRNA, and the efficacy of this material as a delivery system was investigated. Our results showed that LNPssPalm carrying brain-derived neurotrophic factor (BDNF) mRNA was suitable for the treatment of inner ear diseases, preventing the degeneration of SGNs. In conclusion, this modern nanotechnology-based bioconjugation system, LNPssPalm, is a potential non-invasive targeted therapy allowing the delivering biomaterials to specific structures within the inner ear for the treatment of SHNL.

Design and simulation of the new ultrasonic atomizer using silicon-based with one step resonator

The design and simulation of a new generation Fourier amplifier were investigated in this study. The design and characterization of 500 kHz micro fabricated silicon-based ultrasonic atomization is presented for the concept of uniform and fine droplets. Ultrasonic atomizer nozzle is composed of a silicon-based resonator consisting of the Fourier-Horn., drive section and one step part. The atomization of liquid droplets is verified by using the direct modeling CAD software Space Claim and to construct a single and three Fourier-Horn Amplifier model. At the same time, the multi-section geometric model is completed by the array geometry function of the CAE numerical software COMSOL and the physical characteristics of the Fourier amplifier designed by the finite element analysis module. The simulation study states that the onset amplitude of single Horn ultrasonic atomizer produces to 6.8 μm droplets with a designated frequency of 492 kHz. The types and basic principles of mechanical amplifiers (Horn) and the reason for choosing and the designing of required Fourier amplifiers are explained. The simulation data fit well with experimental data. Micro-droplets are steady and uniformly formed after the liquid feeding rate is optimized. This newly designed ultrasonic atomizer facilitates the development of capillary surface-wave resonance at a designated frequency and easy to form atomization of a liquid drop.There are many uses for uniform and fine droplets, for example, it can be used as a precursor for making micro-sized drops, and can be used as a coating to form extremely fine surfaces; it can increase the surface of droplets, increase evaporation speed and even fuel rate; can be suspended Drugs enter the lungs directly and are absorbed into the blood, treatment of inner ear diseases, nose diseases, and even eye cares can use this single Horn atomizer with a tube.

Recovery of ocular and cervical vestibular evoked myogenic potentials after treatment of inner ear diseases

Purpose: This study aimed to assess the clinical value of ocular vestibular evoked myogenic potential (oVEMP) and cervical vestibular evoked myogenic potential (cVEMP) for monitoring the rehabilitation of vestibular function in patients treated for peripheral vertigo.Materials and methods: Fifteen patients who had been diagnosed with peripheral vertigo and showed no VEMP response on the affected side but exhibited symptom alleviation and VEMP responses after therapies were retrospectively enrolled. We analyzed the restoration and parameters of their VEMP response.Results: After treatment, six patients with sudden sensorineural hearing loss showed VEMP recovery, including two with both oVEMP and cVEMP recovery, three with oVEMP recovery only, and one with cVEMP recovery only. Two patients with Meniere’s disease (MD) showed cVEMP recovery, while the other three MD patients showed oVEMP recovery. Three patients with herpes zoster oticus exhibited cVEMP recovery. One patient with vestibular neuritis exhibited cVEMP recovery. Among the patients with cVEMP and/or oVEMP restoration, most patients presented normal VEMP parameters; however, some patients showed abnormal VEMP parameters after treatment.Conclusion: Combined oVEMP and cVEMP are objective tools for assessing vestibular otolithic end organ function during dynamic functional recovery from vestibular diseases.

Nanomedicine for Inner Ear Diseases: A Review of Recent In Vivo Studies.

Nanoparticles are promising therapeutic options for inner ear disease. In this report, we review in vivo animal studies in the otologic field using nanoparticles over the past 5 years. Many studies have used nanoparticles to deliver drugs, genes, and growth factors, and functional and morphological changes have been observed. The constituents of nanoparticles are also diversifying into various biocompatible materials, including poly(lactic-co-glycolic acid) (PLGA). The safe and effective delivery of drugs or genes in the inner ear will be a breakthrough for the treatment of inner ear diseases, including age-related hearing loss.

Vasopressin induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4 T MRI

From histopathological specimens, endolymphatic hydrops has been demonstrated in association with inner ear disorders. Recent studies have observed findings suggestive of hydrops using MRI in humans. Previous studies suggest that vasopressin may play a critical role in endolymph homeostasis and may be involved in the development of Ménière's disease. In this study we evaluate the effect of vasopressin administration in vivo in longitudinal studies using two mouse strains. High resolution MRI at 9.4 T in combination with intraperitoneally delivered Gadolinium contrast, was performed before and after chronic subcutaneous administration of vasopressin via mini-osmotic pumps in the same mouse. A development of endolymphatic hydrops over time could be demonstrated in C57BL6 mice (5 mice, 2 and 4 weeks of administration) as well as in CBA/J mice (4 mice, 2 weeks of administration; 6 mice, 3 and 4 weeks of administration). In most C57BL6 mice hydrops developed first after more than 2 weeks while CBA/J mice had an earlier response. These results may suggest an in vivo model for studying endolymphatic hydrops and corroborates the future use of MRI as a tool in the diagnosis and treatment of inner ear diseases, such as Ménière's disease. MRI may also be developed as a critical tool in evaluating inner ear homeostasis in genetically modified mice, to augment the understanding of human disease.This article is part of a Special Issue entitled <IEB Kyoto>.