Treatment Of Sensorineural Hearing Loss Research Articles

Randomized Controlled Trial Evaluating Threshold Sound Conditioning in the treatment of Sensorineural Hearing Loss (S26.006)

Randomized Controlled Trial Evaluating Threshold Sound Conditioning in the treatment of Sensorineural Hearing Loss (S26.006)

Exposure to acoustic stimuli promotes the development and differentiation of neural stem cells from the cochlear nuclei through the clusterin pathway.

Stem cell therapy has attracted widespread attention for a number of diseases. Recently, neural stem cells (NSCs) from the cochlear nuclei have been identified, indicating a potential direction for the treatment of sensorineural hearing loss. Acoustic stimuli play an important role in the development of the auditory system. In this study, we aimed to determine whether acoustic stimuli induce NSC development and differentiation through the upregulation of clusterin (CLU) in NSCs isolated from the cochlear nuclei. To further clarify the underlying mechanisms involved in the development and differentiation of NSCs exposed to acoustic stimuli, we successfully constructed animal models in which was CLU silenced by an intraperitoneal injection of shRNA targeting CLI. As expected, the NSCs from rats treated with LV-CLU shRNA exhibited a lower proliferation ratio when exposed to an augmented acoustic environment (AAE). Furthermore, the inhibition of cell apoptosis induced by exposure to AAE was abrogated after silencing the expression of the CLU gene. During the differentiation of acoustic stimuli-exposed stem cells into neurons, the number of astrocytes was significantly reduced, as evidenced by the expression of the cell markers, microtubule associated protein-2 (MAP-2) and glial fibrillary acidic protein (GFAP), which was markedly inhibited when the CLU gene was silenced. Our results indicate that acoustic stimuli may induce the development and differentiation of NSCs from the cochlear nucleus mainly through the CLU pathway. Our study suggests that CLU may be a novel target for the treatment of sensorineural hearing loss.

人工聴覚機器の現状

Remarkable advances have been made in the field of cochlear implantation, especially the new trends of hearing and structure preservation. Electric acoustic stimulation (EAS) is becoming a standard procedure worldwide and has improved the quality of life of patients with a ski-slope type audiogram, while Vibrant Soundbridge (VSB) and Bone Conductive Implant are also becoming available as hearing implants for the hearing-impaired population. We present the current information about hearing implants in Japan. Advances in the development of new atraumatic concepts of electrode design as well as in surgical techniques have enabled structure preservation after cochlear implantation, and EAS is a new trend for patients with residual hearing at lower frequencies, that became eligible for coverage by the national health insurance in Japan in 2014. The VSB is an active middle ear implant that was developed for the treatment of sensorineural hearing loss. Stimulation of the cochlea by coupling the small electromagnetic element called the floating mass transducer (FMT) to the round window membrane was a promising second alternative for the treatment of conductive or mixed hearing loss. A multicenter clinical study for VSB with a round window approach was conducted in Japan in 2014. Bone conductive implants allow direct transmission to the bone of the skull, and Baha is a semi-implantable percutaneous BC hearing device. A multicenter clinical study with 9 participant institutions was conducted in Japan between 2006 and 2009 to compare the efficacy of Baha with that of conventional hearing aids. Baha became eligible for coverage by the national health insurance in 2013. Several types of bone conductive implants have been developed and may be used in Japan in the near future.

The ratio of the subjective audiometry in patients with acoustic trauma and “noisy” production workers.

Introduction: The problem of diagnosis and treatment of sensorineural hearing loss (SHL), including forms developed under the influence of noise, takes one of the leading places in ot­olaryngology. However, there are not many studies on acoustic trauma, although this problem has recently become more and more important. Objective: A comparison of subjective audiometry in patients with sensorineural hearing loss after acute acoustic trauma and chronic noise exposure. Materials and methods. In the work the results of exa­mination of 84 patients with acoustic trauma, 15 healthy as the control group and 15 workers employed on 'noise' occupations as a comparison group are given. Subjective audiometry was fully carried out by clinical audiometer AC-40 «Interacoustics» (Denmark). Hearing indices were investigated in the conventional (0,125-8) kHz and extended (9-16) kHz frequency bands. Results: Subjective audiometry showed a reduction in sound perception in all patients. Ac­cor­ding to the threshold tone audiometry in patients with acoustic trauma hearing thresholds were authentically (P <0,05) increased by 4, 6 and 8 kHz tones of conventional (0,125-8) kHz frequency band and by 14-16 kHz tones of the extended (9-16 kHz) in comparison with the control group, as with workers employed on noise occupations. All the examined patients had deterioration of speech-test audiometry and above-threshold audiometry. Conclusions: According to su­b­jective audiometry, the type similar disorders of auditory function are in patients with acoustic trauma as in patients with long-term noise exposure, but they are more pronounced and develop much faster. The most informative features which show the origin and progression of hearing loss in patients with acoustic trauma are: increasing hearing thresholds by 14 and 16 kHz tones of the extended (9-16 kHz) frequency band and by 4, 6 and 8 kHz tones of con­ven­tional (0,125-8) kHz frequency band plus the reduction of differential thresholds (DT) according to the Lusher’s method at 4 kHz.

Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss.

Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.

Sonic Hedgehog and Retinoic Acid Induce Bone Marrow-Derived Stem Cells to Differentiate into Glutamatergic Neural Cells

Studies have showed that transplanted stem cells in the inner ear won’t regenerate to replace the damaged sensory hair cells. They can spontaneously differentiate into mesenchymal cells and fibrocytes in the damaged inner ear. Only mature sensory cells of MSCs-derived possess the great potency for cell transplantation in the treatment of sensorineural hearing loss. So, we try to establish an efficient generation of the glutamatergic sensory neural phenotype for the cell transplantation of the hearing loss. We isolated MSCs from femoral and tibial bones according to their adherence to culture dishes. After purification, proliferation, and passaged, cells became homogeneous in appearance, showing more uniformity and grew in a monolayer with a typical spindle-shape morphology. The cell surface markers were assessed using FACS to characterize the isolated cells. For neural induction to harvest the glutamatergic sensory neurons, passage 3 MSCs were incubated with preinduced medium for 24 hr, and neural-induced medium for an additional 14 days. The cells exhibit a typical neural shape. RT-PCR analysis indicated that the mRNA levels of the neural cell marker nestin, Tau, MAP-2, β-tubulin III, GluR-3, and GluR-4 were higher compared with primary MSCs. Immunohistochemistry and western-blotting proofed that nestin, MAP-2, β-tubulin III, and GluR-4 proteins indeed exhibit their expression difference in the induced cells compared to the MSCs. We show an efficient protocol by the combined applications of Sonic Hedgehog (Shh) and Retinoic Acid (RA) to induce MSCs to differentiate into the glutamatergic sensory neuron which were identified from the morphological, biochemical, and molecular characteristics.

The Vibrant Soundbridge as an active implant in middle ear surgery

Implantable hearing aids are not only gaining importance for the treatment of sensorineural hearing loss, but also for treatment of mixed hearing loss. The most frequently used active middle ear implant is the Vibrant Soundbridge (VSB) system (Fa. MED-EL, Innsbruck, Österrreich). Following widening of the spectrum of indications for the VBS, various new coupling systems have been established. Based on the literature, available petrosal bone investigations and finite element model (FEM) calculations, this article summarizes the current knowledge concerning mechanical excitation by the VSB. Important concomitant aspects related to coupling, transmission and measurement are also discussed.

PRIEŪMINIO IDIOPATINIO NEUROSENSORINIO KLAUSOS PAŽEIDIMO PROGNOSTINIAI VEIKSNIAI

Objectives. We investigated prognostic factors in sudden sensorineural hearing loss.Patients and methods. Patients were recruited into the trial between August 2011 and June 2013 with complains : an abrupt onset of more than 30 dB hearing loss at three consecutive frequencies during period 72 hours, unilateral. 202 patients were randomized to 1 of 2 groups and administered treatment. Group I : patients were given 12 capsules (60 mg) of prednisolon for 7 days, then 2 less capsule per two days until finished. Group II : patients were given systemic prednisolon and additionally, three times a week were administered a transtympanic injection 1,0 ml - 4 mg/ml dexamethasone solution. Audiograms were performed at first visit and 30 days after treatment. Pure tone averages (PTAs) were measured by taking the 6-frequency average of the threshold value at 250, 500, 1,000, 2,000, 4,000 and 8,000 Hz.Results. Our analysis suggests the presence of the following82prognostic factors for sudden sensorineural hearing loss : method of sudden sensorineural hearing loss treatment (better results in combined treatment group); time delay before start of treatment (better results when treatment started within 2 days of the first symptoms of SSNHL); age; seasonal occurrence of the disease in the winter and spring; stress condition, viral infection and trauma(acoustic) before SSNHL, tinnitus, fullness of the ear.Conclusions. Method of sudden sensorineural hearing loss treatment (better results in combined treatment group); time delay before start of treatment ( better results when treatment started within 2 days of the first symptoms of SSNHL); age; seasonal occurrence of the disease in the winter and spring; stress condition, viral infection and trauma (acoustic) before SSNHL, tinnitus, fullness of the ear are prognostic factors for hearing recovery in SSNHL. Gender, proffesional skills, smoking habits, otological and family history, osteochondrosis are not confirmed as prognostic factors for hearing recovery in SSNHL in our study. Knowing of prognostic factors for hearing recovery in SSNHL leads as predict course of the illness and proper prognosis for hearing improvement.

Improvement in Sensorineural Hearing Loss During Pregnancy

Hearing loss is known to occur in some pregnant women, but improvement in sensorineural thresholds has not been audiometrically characterized. Here, we describe a patient with a history of Ménière's disease and vestibular migraine who experienced temporary recovery of her hearing during pregnancy. Audiograms were obtained from a 31-year-old female over the course of 2 successive pregnancies. Audiograms revealed a substantial improvement in hearing by the third trimester during each pregnancy, with a rapid return to baseline thresholds after delivery. This case is unique in documenting improvements in hearing thresholds during pregnancy and substantiates the effects of hormonal changes on hearing thresholds in humans. It raises the intriguing possibility of hormonal therapy as a treatment for sensorineural hearing loss in specific clinical situations.

Exogenous BDNF and Chondroitinase ABC Consisted Biomimetic Microenvironment Regulates Survival, Migration and Differentiation of Human Neural Progenitor Cells Transplanted into a Rat Auditory Nerve

Current putative regeneration oriented studies express possible role of stem cell based implantation strategy in the restoration of fundamental perception of hearing. The present work utilizes a rat auditory nerve (AN) directed transplantation of human neural progenitor cells (HNPCs) as a cell replacement therapy for impaired auditory function. Groups of b-bungarotoxin induced auditory function compromised female rats were used to transplant HNPCs in the nerve trunk. In the treatment groups, brain derived neurotrophic factor (BDNF), peptide amphiphile nanofiber bioactive gel (Bgel) and Chondroitinase ABC (ChABC), a digestive enzyme that cleaves the core of chondroitin sulphate proteoglycans, were added along with HNPCs while the control groups were with PA inert gel (Igel) and devoid of ChABC. Six weeks post transplantation survival, migration, and differentiation of HNPCs were studied and compared. The groups treated with BDNF and Bgel showed improved survival and differentiation of transplanted HNPCs while the ChABC treated group showed significant migration of HNPCs along the AN and elongation of neuronal fibers along the nerve towards the cochlear nucleus (CN) which was characterized by immunocytochemical markers for human Nuclei (HuN), human mitochondria (HuM) and neuronal β-tubulin (Tuj1). These findings show that addition of BDNF and ChABC consisted Bgel environment facilitated HNPC survival, migration and differentiation along the transplanted rat AN towards the CN. This transplantation strategy provides unique experimental validation for futuristic role of cell based biomaterial consisted neurotrophic factor application in clinically transferable treatment of sensorineural hearing loss (SNHL) along with cochlear implants (CI).

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Sensorineural hearing loss, which is mainly caused by cochlear hair cell damage, is an intractable disease, as cochlear hair cells and supporting cells are unable to proliferate in postnatal mammals. As a novel and potent treatment for sensorineural hearing loss, we have studied IGF-1 and found that it protects cochlear hair cells from the damage caused by noise and ischemic trauma. Through a clinical trial, we have also confirmed that IGF-1 is an effective treatment for idiopathic sudden sensorineural hearing loss. In the current study, we attempted to identify the downstream pathways of the IGF-1 signal and the mechanisms by which IGF-1 protects the neonatal mouse cochlear hair cells that have been damaged by neomycin. IGF-1 activated both the PI3K/Akt and MEK/ERK pathways to maintain the hair cell numbers in the injured cochlea. The PI3K/Akt pathway specifically protected the cochlear inner hair cells through the inhibition of apoptosis. In contrast, the MEK/ERK pathway induced the cell cycle promotion of Hensen's and Claudius' cells, the supporting cells that are located lateral to the outer hair cells of the cochlea. This cell cycle promotion of the supporting cells resulted in the maintenance of the outer hair cell numbers. These results indicate that IGF-1 is a growth factor that efficiently regulates different mechanisms through different downstream cascades, thereby protecting cochlear hair cells.

Stem cell transplantation via the cochlear lateral wall for replacement of degenerated spiral ganglion neurons

Spiral ganglion neurons (SGNs) are poorly regenerated in the mammalian inner ear. Because of this, stem cell transplantation has been used to replace injured SGNs, and several studies have addressed this approach. However, the difficulty of delivering stem cells into the cochlea and encouraging their migration to Rosenthal's canal (RC), where the SGNs are located, severely restricts this therapeutic strategy. In this study, we attempted to establish a new stem cell transplantation route into the cochlea via the cochlear lateral wall (CLW). First, we tested the precision of this route by injecting Fluorogold into the CLW and next assessed its safety by mock surgeries. Then, using a degenerated SGN animal model, we transplanted neural stem cells (NSCs), derived from the olfactory bulb of C57BL/6-green fluorescent protein (GFP) mice, via the CLW route and examined the cells' distribution in the cochlea. We found the CLW transplantation route is precise and safe. In addition, NSCs migrated into RC with a high efficiency and differentiated into neurons in a degenerated SGN rat model after the CLW transplantation. This result revealed that the basilar membrane (BM) may have crevices permitting the migration of NSCs. The result of this study demonstrates a novel route for cell transplantation to the inner ear, which is important for the replacement of degenerated SGNs and may contribute to the treatment of sensorineural hearing loss.

Third-Generation Bisphosphonates for Treatment of Sensorineural Hearing Loss in Otosclerosis

To evaluate hearing outcomes in patients treated with third generation bisphosphonates for otosclerosis-related sensorineural hearing loss (SNHL). Otosclerosis is a disease of abnormal bone remodeling in the otic capsule. In recent years, third generation bisphosphonates, with more powerful anti-resorptive properties and increased bone affinity, have demonstrated effectiveness in the treatment of osteoporosis and other metabolic bone diseases. We hypothesized that newer generation bisphosphonates, such as risedronate and zoledronate, would be effective in slowing the progression of SNHL in patients with otosclerosis. Retrospective review. Tertiary referral center, ambulatory care. Risedronate or zoledronate administration. Bone conduction pure tone threshold averages (PTAs) and word recognition (WR) scores were examined for each ear before and after bisphosphonate treatment. Criteria for significant change were defined as greater than 10 decibels in PTA or between 4% and 18% in WR based on binomial variance. All 10 patients had audiometric progression of SNHL in the pretreatment monitoring interval and 12 ears met criteria for significant progression. All 10 patients (19 ears) showed at least no significant progression of SNHL (i.e., stabilization) at an average follow-up of 13 months. Two patients (3 ears) showed improvement by defined audiometric criteria. There were no major complications. Treatment with zoledronate or risedronate stabilized progressive SNHL related to otosclerosis in this small group of patients. Further evaluation of third-generation bisphosphonate treatments is warranted.

Mining Immune Epitopes in Ménière’s Disease and Sudden Sensorineural Hearing Loss

Objective: Etiologies for Ménière’s disease and sudden sensorineural hearing loss remain unknown. Indirect evidence exists for allergy-mediated or autoimmune process. The purpose of this study is to determine whether immunogenic proteins share similar sequences with inner ear proteins, which may lead to cross-reactivity and immune activation in inner ear disorders. Method: Comprehensive bioinformatic primary sequence analyses of intact and mutated proteins associated with human syndromic and nonsyndromic hearing loss and proteins expressed in the human inner ear was performed. Comparison of sequences to epitopes in the Immune Epitope Database was performed by exact match, BLAST, and BLOSUM62 score computational algorithms. Results: Computational analysis of primary protein sequence for 81 known inner ear proteins, 102 proteins from genes identified in syndromic and non-syndromic hearing loss, and 438 protein sequences with known mutations that contribute to sensorineural hearing loss was compared to 151,086 epitopes previously implicated in allergic, autoimmune, and infectious disorders within the Immune Epitope Database. The exact match and BLAST algorithms identified 1925 and 97 unique epitope matches, respectively. Top BLOSUM62 score algorithm resulted in a single hit for the 47 kDa membrane antigen. Other epitopes included those seen in allergic rhinitis, infectious diseases, and autoimmune disorders. Conclusion: Abnormal immune activation is suspected in Ménière’s disease and SSNHL. Candidate immune epitopes were identified that may contribute to pathogenesis of these disorders. While these epitopes await clinical validation, they present novel targets for diagnosis and treatment of sensorineural hearing loss.

New Route for Stem Cell Transplantation into the Cochlea

Objective: Cell transplantation provides a potential method to replace the irreversible loss of auditory hair cells and neurons. In this study, we will prove the intravenous route of stem cell transplantation to the inner ear and the efficacy of the umbilical cord blood-derived mesenchymal stem cell transplantation in hearing restoration of deaf animal model. Method: About 100,000 umbilical cord blood-derived mesenchymal stem cells which were tagged as PKH26 were infused to deaf guinea pigs intravenously. After 1 week and 3 weeks, auditory brainstem response test was checked and we obtained a guinea pig cochlea. A cryosection of each cochlea every 120 μm was obtained and we calculated stem cells for 3 sections of each animal. Results: No hearing gain was shown after stem cell transplantation, but PKH26 tagging mesenchymal stem cell was found in Modiolus, Rosenthal’s canals and organ of Corti. Cells were not found in scala tympani, scala media, and scala vestibuli. Average number of cells in the inner ear was about 88 cells (59-123 cells/section). Most cells were found in spiral ganglion and migrated into the organ of Corti. Conclusion: In this study, we demonstrated that cord blood-derived mesenchymal stem cells could be delivered into the inner ear with intravenous infusion. Based on these results, intravenous injection of stem cells may be used in the treatment of sensorineural hearing loss, regeneration of the auditory hair cells, and neurons.

When Inner Ear Stem Cell Therapy Becomes a Reality

When Inner Ear Stem Cell Therapy Becomes a Reality

Mapping auditory nerve firing density using high-level compound action potentials and high-pass noise masking

Future implementation of regenerative treatments for sensorineural hearing loss may be hindered by the lack of diagnostic tools that specify the target(s) within the cochlea and auditory nerve for delivery of therapeutic agents. Recent research has indicated that the amplitude of high-level compound action potentials (CAPs) is a good predictor of overall auditory nerve survival, but does not pinpoint the location of neural damage. A location-specific estimate of nerve pathology may be possible by using a masking paradigm and high-level CAPs to map auditory nerve firing density throughout the cochlea. This initial study in gerbil utilized a high-pass masking paradigm to determine normative ranges for CAP-derived neural firing density functions using broadband chirp stimuli and low-frequency tonebursts, and to determine if cochlear outer hair cell (OHC) pathology alters the distribution of neural firing in the cochlea. Neural firing distributions for moderate-intensity (60 dB pSPL) chirps were affected by OHC pathology whereas those derived with high-level (90 dB pSPL) chirps were not. These results suggest that CAP-derived neural firing distributions for high-level chirps may provide an estimate of auditory nerve survival that is independent of OHC pathology.

Neural Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells: Applicability for Inner Ear Therapy

Background and ObjectivesRegeneration or replacement of damaged hair cells and neurons in the cochlea might be an ideal treatment for sensorineural hearing loss (SNHL). The purpose of the present study was to investigate whether mesenchymal stem cells (MSCs), derived from the bone marrow of rats, could differentiate into auditory hair cells and neurons.Materials and MethodsThe centrifuge gradient method was used to isolate MSCs from the bone marrow of rats. To confirm whether bone marrow-derived MSCs can differentiate into neuronal cells, culture medium with glial cell-derived neurotrophic factor, brain-derived neurotrophic factor and neurotrophin-3 for 14 days. In addition, immunofluorescence staining and RT-PCR were performed for characterization of the neurospheres and differentiated cells from 7 and 14 day cultures.ResultsThe results showed that MSCs could differentiate into neuron-positive and hair cell-positive cells, using different compositions of growth factors. And RT-PCR result was identified high or low of gene expression all these differentiated cells.ConclusionsRat bone marrow-derived MSCs differentiated into neuronal progenitor cells. These cells might be useful for the treatment of SNHL.

Profound High-Frequency Sensorineural Hearing Loss Treatment With a Totally Implantable Hearing System

This study seeks to assess the efficacy of the Envoy Esteem totally implantable hearing device in treating profound high-frequency sensorineural hearing loss. Five patients with profound high-frequency hearing loss participating in a prospective, multi-center, nonrandomized Food and Drug Administration clinical trial. Implantation with Esteem totally implantable hearing device and comparison to baseline unaided and aided conditions. Speech reception threshold and word recognition scores (WRS) at 50 dB HL presentation level. Preoperative speech reception threshold improved from an unaided 65 dB and aided 48 dB average to 26 dB with the Esteem at 12 months. WRS at 50 dB scores improved from an unaided 10% and aided 23% average to 78% postoperatively. The Esteem totally implantable middle ear hearing device provides appreciable functional gain and improvement in WRS to rehabilitate hearing in patients with a profound high-frequency sensorineural hearing loss.

Regeneration of Hair Cells: Making Sense of All the Noise.

Hearing loss affects hundreds of millions of people worldwide by dampening or cutting off their auditory connection to the world. Current treatments for sensorineural hearing loss (SNHL) with cochlear implants are not perfect, leaving regenerative medicine as the logical avenue to a perfect cure. Multiple routes to regeneration of damaged hair cells have been proposed and are actively pursued. Each route not only requires a keen understanding of the molecular basis of ear development but also faces the practical limitations of stem cell regulation in the delicate inner ear where topology of cell distribution is essential. Improvements in our molecular understanding of the minimal essential genes necessary for hair cell formation and recent advances in stem cell manipulation, such as seen with inducible pluripotent stem cells (iPSCs) and epidermal neural crest stem cells (EPI-NCSCs), have opened new possibilities to advance research in translational stem cell therapies for individuals with hearing loss. Despite this, more detailed network maps of gene expression are needed, including an appreciation for the roles of microRNAs (miRs), key regulators of transcriptional gene networks. To harness the true potential of stem cells for hair cell regeneration, basic science and clinical medicine must work together to expedite the transition from bench to bedside by elucidating the full mechanisms of inner ear hair cell development, including a focus on the role of miRs, and adapting this knowledge safely and efficiently to stem cell technologies.