Treatment Of Sensorineural Hearing Loss Research Articles

Biotechnology in the Treatment of Sensorineural Hearing Loss: Foundations and Future of Hair Cell Regeneration

To provide an overview of the methodologies involved in the field of hair cell regeneration. First, the author provides a tutorial on the biotechnological foundations of this field to assist the reader in the comprehension and interpretation of the research involved in hair cell regeneration. Next, the author presents a review of stem cell and gene therapy and provides a critical appraisal of their application to hair cell regeneration. The methodologies used in these approaches are highlighted. The author conducted a narrative review of the fields of cellular, molecular, and developmental biology, tissue engineering, and stem cell and gene therapy using the PubMed database. The use of biotechnological approaches to the treatment of hearing loss--approaches such as stem cell and gene therapy-has led to new methods of regenerating cochlear hair cells in mammals. Incredible strides have been made in assembling important pieces of the puzzle that comprise hair cell regeneration. However, mammalian hair cell regeneration using stem cell and gene therapy are years--if not decades--away from being clinically feasible. If the goals of the biological approaches are met, these therapies may represent future treatments for hearing loss.

Stealth-Nanoparticle Strategy for Enhancing The Efficacy of Steroids in Mice with Noise-Induced Hearing Loss

This study aimed to investigate the efficacy of encapsulating steroids, which is a primary choice for the treatment of sensorineural hearing loss, in polyethylene glycol-coated polylactic acid nanoparticles for drug delivery to the cochlea. We prepared polyethylene glycol-coated polylactic acid nanoparticles encapsulating rhodamine or betamethasone phosphate (BP), and administered them systemically to CBA/N mice previously exposed to intense noise. We assessed nanoparticle distribution using rhodamine fluorescence, BP concentrations in tissues, nuclear translocation of glucocorticoid receptors and the function and histology of the mouse cochleae. Polyethylene glycol-coated polylactic acid nanoparticles delivered BP to cochleae over a sustained period, resulting in significant reductions in histological and functional damage to cochleae and indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of BP in acute sensorineural hearing loss.

Strengthen the research on prevention and treatment of sensorineural hearing loss in China

感音神经性聋研究是耳科领域的重中之重。严格意义上，感音神经性聋从病变部位上可划分为感音性和神经性。感音性聋从发生时间可分为先天性和后天获得性两大类。先天性感音性聋又可分为遗传性聋和环境因素致聋（孕期病毒感染等）；后天获得性感音性聋包括突发性聋、噪声性耳聋、老年性耳聋、药物性耳聋等。听神经病属于神经性耳聋范畴。

感音難聴とめまい：病態はどこまで分かったか―蝸牛虚血性障害，音響性障害に対するグルココルチコイド治療―

The effect of glucocorticoids on sensorineural hearing loss of sudden onset remains to be controversial although glucocorticoids have been used for treatment of sudden sensorineural hearing loss. We review recent findings about the effect of glucocorticoids on cochlear ischemic and acoustic injuries obtained from animal experiments. Systemically administered glucocorticoids penetrate the blood-cochlear barrier well. Glucocorticoids ameliorated the cochlear ischemic and acoustic injuries at a relatively wide range of doses, and they protect cochlear hair cells in these types of injury. The therapeutic actions of glucocorticoids in cochlear injuries were considered to be mediated via both genomic and non-genomic pathways. Based on the results obtained in acoustic injury, therapeutic time window of glucocorticoids is considered to be short after the onset of injury. These findings obtained from animal experiments are important in considering clinical usage of glucocorticoids for the treatment of sensorineural hearing loss.

Brain-Derived Nerve Growth Factor in the Treatment of Sensorineural Hearing Loss

Brain-Derived Nerve Growth Factor in the Treatment of Sensorineural Hearing Loss

Potential Novel Drug Carriers for Inner Ear Treatment: Hyperbranched Polylysine and Lipid Nanocapsules

Treatment of sensorineural hearing loss could be advanced using novel drug carriers such as hyperbranched polylysine (HBPL) or lipid nanocapsules (LNCs). This study examined HBPL and LNCs for their cellular uptake and possible toxicity in vitro and in vivo as the first step in developing novel nanosized multifunctional carriers. Having incubated HBPL and LNCs with fibroblasts, nanoparticle uptake and cell viability were determined by confocal laser scanning microscopy, fluorescence measurements and neutral red staining. In vivo, electrophysiology, confocal laser scanning microscopy and cytocochleograms were performed for nanoparticle detection and also toxicity studies after intracochlear application. Both nanoparticles were detectable in the fibroblasts' cytoplasm without causing cytotoxic effects. After in vivo application they were visualized in cochlear cells, which did not lead to a change in hearing threshold or loss of hair cells. Biocompatibility and traceability were demonstrated for HBPL and LNCs. Thus, they comply with the basic requirements for drug carriers for potential application in the inner ear.

Brain‐derived nerve growth factor in the treatment of sensorineural hearing loss

A possible medical treatment for sensorineural hearing loss using brain-derived nerve growth factor (BDNF) was explored. The hypothesis is that direct intracochlear application of BDNF will result in improved hearing. Animal research study. Significant hearing loss was created using cisplatin in 11 guinea pigs. One month later, bilateral cochleostomies were performed placing 0.05 microg of BDNF in one cochlea of each animal prior to plugging with connective tissue. The other cochlea served as a control. Auditory brain-stem response (ABR) testing was then carried out for three months at 6,000, 8,000, 12,000, and 24,000 Hz. ABR thresholds were better in the treated ear for all frequencies. Threshold differences were statistically significantly better two months after treatment (general linear model, repeated measures P = .045). Intracochlear application of BDNF may prevent hearing loss.

Hair Cell Regeneration

Hair Cell Regeneration

Prostaglandin E receptor subtype EP4 agonist protects cochleae against noise-induced trauma

Prostaglandin E 1 is frequently used for the clinical treatment of acute sensorineural hearing loss. However, the mechanisms underlying the effects of prostaglandin E 1 on the inner ear have not yet been elucidated. The physiological effects of prostaglandin E 1 are mediated by the prostanoid receptors prostaglandin I receptor and the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, the respective agonists for which have been purified. In the current study, we examined the efficacy of a local EP4 agonist application for the treatment of sensorineural hearing loss. We examined EP4 expression in the mouse cochlea using the reverse transcription–polymerase chain reaction and immunohistochemistry. The protective effects of local EP4 agonist treatment before or after noise exposure were tested in guinea pigs using measurements of auditory brain-stem responses and histological analysis. The results demonstrated EP4 expression in the cochlea, and showed that pre- and post-treatment with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses, and significant attenuation in the loss of outer hair cells was found in local EP4 agonist treatment before noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E 1 actions on the cochlea, and local EP4 agonist treatment could attenuate acute sensorineural hearing loss.

Teilimplantierbare Hörgeräte bei Schallempfindungsschwerhörigkeit und kombinierter Schwerhörigkeit

In recent years semi-implantable hearing aids have become an established option in the treatment of sensorineural hearing loss. In Germany two semi-implantable systems are available, namely the MedEl Soundbridge system and the Otologics MET system, both of which are active middle ear implants. Since 1996 almost 3,500 Soundbridge systems and 300 MET systems have been implanted world-wide. The majority of patients who have received semi-implantable hearing aids consider them to be superior to conventional hearing aids in many respects. Reported benefits include improved speech intelligibility (especially in noise), better sound quality, a more natural sounding own voice and the general advantages of an open ear canal. Implantable hearing systems can be used for a wider range of indications than conventional hearing aids. They are particularly useful in the treatment of patients with high-frequency hearing loss and patients with combined hearing loss. An analysis of the hearing outcomes that have thus far been reported for all patients with a hearing implant shows an average improvement in the hearing threshold by 15 dB, which corresponds to an improvement in hearing of more than 30%. As a consequence semi-implantable hearing systems are an excellent addition to the existing range of conventional hearing aids.

Development of Ebselen, a Glutathione Peroxidase Mimic, for the Prevention and Treatment of Noise-Induced Hearing Loss

The development of therapeutics for the prevention and treatment of sensorineural hearing loss remains an elusive goal for auditory scientists and clinicians worldwide. While much research has focused on the histopathology associated with exposure to intense noise or ototoxins (i.e., loss of hair cells), the biochemical and genetic mechanisms that evoke or mediate hair cell death and dysfunction are still under investigation and debate. Many have observed an early oxidative burst in the cochlea that leads to an increase in lipoperoxidation and the activation of cell death pathways, ultimately resulting in apoptosis. In support of this hypothesis, many have protected the cochlea and preserved auditory function by injecting high doses of antioxidants or inhibitors of cell death activation prior to intense noise or ototoxin exposure. Here we discuss a compound currently in Phase II clinical testing for the prevention and treatment of noise-induced hearing loss. This article will review the historic background and pertinent preclinical and clinical data available for ebselen, a novel drug that mimics the activity of glutathione peroxidase, a catalytic antioxidant enzyme that is essential for the peripheral auditory system.

Use of intratympanic dexamethasone for the therapy of low frequency hearing loss

The objective was to assess the efficacy of intratympanic dexamethasone in treatment of sensorineural hearing loss at lower frequencies (LFSHL). The design is a prospective study. Eleven female and three male patients with LFSHL were included in this study. They were evaluated with pure-tone audiometry, acoustic admittance, transient evoked otoacoustic emission, and glycerol test. Seven, four, and three patients were seen within the mean of 2.86 +/- 1.35 (1-5), 18.25 +/- 2.36 (15-20), and 750 +/- 700 (60-1,460) days from onset of LFSHL, respectively. They were treated with daily intratympanic dexamethasone (ITD) injection and reviewed with repeated daily audiograms during the intratympanic treatment. As complementary treatment, they were given oral prednisolone 1 mg/kg (maximum 60 mg), with 10 mg decreasing doses for every 3 days. Results were compared with their unaffected ear. The mean +/- SD hearing level at 0.125 up to 1.5 kHz improved from 64.29 +/- 19.18 to 25.93 +/- 13.54 (P < 0.001), pure tone average improved from 62.7 +/- 25.7 to 22.9 +/- 17.8 (P < 0.001), speech reception thresholds improved from 34.6 +/- 29.45 to 17.5 +/- 16.38 (P = 0.028), speech discrimination scores improved from 65.7 +/- 39.8 to 84.6 +/- 24.7% (P = 0.024) with treatment. Complete recovery in 10 of 14 patients, partial recovery in 3 patients, was achieved after therapy; and in one patient the situation was unchanged. The mean hearing level at 0.125 up to 1.5 kHz was elevated from 45.6 +/- 17.5 to 9.1 +/- 10.3 dB (P < 0.001) when compared with unaffected ear. The mean recovery rate was 77.9 +/- 25.3%. ITD is an effective therapy for LFSHL.

Protection, regeneration and replacement of hair cells in the cochlea: implications for the future treatment of sensorineural hearing loss.

In the last few years progress has been made in understanding basic mechanisms involved in damage to the inner ear and various potential therapeutic approaches have been developed. It was shown that hair cell loss mediated by noise or toxic drugs may be prevented by antioxidants, inhibitors of intracellular stress pathways and neurotrophic factors/neurotransmission blockers. Moreover, there is hope that once hair cells are lost, their regeneration can be induced or that stem cells can be used to build up new hair cells. However, although tremendous progress has been made, most of the concepts discussed in this review are still in the "animal stage" and it is difficult to predict which approach will finally enter clinical practice. In my opinion it is highly probable that some concepts of hair cell protection will enter clinical practice first, while others, such as the use of stem cells to restore hearing, are still far from clinical utility.

Protection, regeneration and replacement of hair cells in the cochlea: implications for the future treatment of sensorineural hearing loss.

In the last few years progress has been made in understanding basic mechanisms involved in damage to the inner ear and various potential therapeutic approaches have been developed. It was shown that hair cell loss mediated by noise or toxic drugs may be prevented by antioxidants, inhibitors of intracellular stress pathways and neurotrophic factors/neurotransmission blockers. Moreover, there is hope that once hair cells are lost, their regeneration can be induced or that stem cells can be used to build up new hair cells. However, although tremendous progress has been made, most of the concepts discussed in this review are still in the "animal stage" and it is difficult to predict which approach will finally enter clinical practice. In my opinion it is highly probable that some concepts of hair cell protection will enter clinical practice first, while others, such as the use of stem cells to restore hearing, are still far from clinical utility.

5-HT6/7 Receptor Antagonists Facilitate Dopamine Release in the Cochlea via a GABAergic Disinhibitory Mechanism

In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume superfusion techniques we tested 5-HT(6) and 5-HT(7) receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic conditions using currently available and new 5-HT(6) and 5-HT(7) antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT(7) antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT(6) receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type of receptor. Moreover, the mixed 5-HT(6/7) antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement of an indirect neural mechanism through an inhibitory system. In the presence of the GABA(A) receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic inhibitory tone on dopaminergic nerve endings. The mixed 5-HT(7)/D(4) receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals in the cochlea may have a role in the treatment of sensorineural hearing loss.

Langerhans' cell histiocytosis of the temporal bone: successful treatment of sensorineural hearing loss with low-dose radiotherapy

To present the successful treatment of sensorineural hearing loss secondary to Langerhans' cell histiocytosis with low-dose radiotherapy, and also the disparity between radiological resolution of Langerhans' cell histiocytosis lesions and lack of sensorineural hearing loss improvement, accompanied by a review of the literature on otolaryngological manifestations and management of Langerhans' cell histiocytosis. Langerhans' cell histiocytosis is a multisystem disease which frequently causes osseous lesions in the temporal bones. Hearing loss is usually conductive but may be sensorineural with lesions of the petrous temporal bone. We present a case of sensorineural hearing loss secondary to Langerhans' cell histiocytosis affecting the labyrinth and internal auditory meatus, which resolved following radiotherapy. Contralateral sensorineural hearing loss in the same patient, previously treated with chemotherapy, did not resolve despite radiological resolution of the temporal bone lesions. We suggest that timely radiotherapy for treatment of sensorineural hearing loss secondary to Langerhans' cell histiocytosis is an appropriate treatment option.

Genetic and pharmacological intervention for treatment/prevention of hearing loss

Twenty years ago it was first demonstrated that birds could regenerate their cochlear hair cells following noise damage or aminoglycoside treatment. An understanding of how this structural and functional regeneration occurred might lead to the development of therapies for treatment of sensorineural hearing loss in humans. Recent experiments have demonstrated that noise exposure and aminoglycoside treatment lead to apoptosis of the hair cells. In birds, this programmed cell death induces the adjacent supporting cells to undergo regeneration to replace the lost hair cells. Although hair cells in the mammalian cochlea undergo apoptosis in response to noise damage and ototoxic drug treatment, the supporting cells do not possess the ability to undergo regeneration. However, current experiments on genetic manipulation, gene therapy, and stem cell transplantation suggest that regeneration in the mammalian cochlea may eventually be possible and may 1 day provide a therapeutic tool for hearing loss in humans. Learning outcomes: The reader should be able to: (1) Describe the anatomy of the avian and mammalian cochlea, identify the individual cell types in the organ of Corti, and distinguish major features that participate in hearing function, (2) Demonstrate a knowledge of how sound damage and aminoglycoside poisoning induce apoptosis of hair cells in the cochlea, (3) Define how hair cell loss in the avian cochlea leads to regeneration of new hair cells and distinguish this from the mammalian cochlea where there is no regeneration following damage, and (4) Interpret the potential for new approaches, such as genetic manipulation, gene therapy and stem cell transplantation, could provide a therapeutic approach to hair cell loss in the mammalian cochlea.

Regenerative Medizin in der Therapie der Innenohrschwerhörigkeit

Regenerative medicine offers the prospect of causal treatment of sensorineural hearing loss. In humans, the loss of sensory hair cells is irreversible and results in chronic hearing loss. Other vertebrates, particularly birds, have the capability to spontaneously regenerate lost sensory hair cells and restore hearing. In the bird model, regeneration of hair cells is based on the proliferation of supporting cells. In mammals, supporting cells have lost their proliferative capacity and are terminally differentiated. To gain an understanding about regeneration of hair cells in mammals, cell division of supporting cells has to be controlled. Gene disruption of the cell cycle inhibitor p27(Kip1) allows supporting cell proliferation in the organ of Corti in vivo. Furthermore, in vitro studies indicate that newly generated cells may differentiate into hair cells after p27(Kip1) disruption. Other current methods to induce hair cell regeneration include the gene transfer of Math1 and transplantation of stem cells to the inner ear.

Cochlear implant‐mediated perception of non‐linguistic sounds

Cochlear implants (CI) have provided sound perception to profoundly deaf individuals, revolutionizing the treatment of sensorineural hearing loss. Thus far, the overwhelming majority of test measures to assess implant candidacy, efficacy, and progress are based on speech perception. Non‐linguistic speech (NLS) stimuli, by comparison, have received comparatively little attention, despite the importance of NLS sounds for environmental sound awareness. For the prelingually deafened population, in whom speech perception may never be fully realized, NLS perception is an especially critical area deserving further study. The specific aims of this study were to determine the accuracy with which postlingually deafened CI users perceive NLS, and to determine if there is an association between acoustic characteristics of the NLS and ability to identify these sounds using a CI. We used five main categories of NLS: human vocal non‐linguistic, animal/insect, nature/ambient, mechanical/alerting, and musical to comprise a test battery that was given to 10 postlingually deafened CI users. Results of the pilot study showed overall poor ability of CI users to recognize NLS. Furthermore, an association between speech perception and accuracy of NLS was identified. Our results suggest that NLS is a difficult category of complex sound for CI users to perceive.

Survival and stimulation of neurite outgrowth in a serum-free culture of spiral ganglion neurons from adult mice

We have developed a reliable protocol for the serum-free dissociation and culture of spiral ganglion neurons from adult mice, an important animal model for patients with post-lingual hearing loss. Pilot experiments indicated that the viability of spiral ganglion cells in vitro depended critically on the use of Hibernate medium with B27 supplement. With an optimized protocol, we obtained 2 × 10 3 neurons immediately after dissociation, or about one-fifth of those present in the intact spiral ganglion. After four days in culture, 4% of the seeded neurons survived without any exogenous growth factors other than insulin. This yield was highly reproducible in five independent experiments and enabled us to measure systematically the numbers and lengths of the regenerating neurites. Furthermore, the survival rate compared well to the few published protocols for culturing adult spiral ganglion neurons from other species. Enhanced survival and neurite outgrowth upon the addition of brain-derived neurotrophic factor and leukemia inhibitory factor demonstrated that both are potent stimulants for damaged spiral ganglion neurons in adults. This responsiveness to exogenous growth factors suggested that our culture protocol will facilitate the screening of molecular compounds as potential treatments for sensorineural hearing loss.