Junctional Modulation of Round Window Membrane Enhances Dexamethasone Uptake into the Inner Ear and Recovery after NIHL.

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.

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.

Superparamagnetic Nanoparticle Delivery to the Cochlea Through Round Window by External Magnetic Field: Feasibility and Toxicity.

Introduction. The objective of this study was to evaluate the feasibility and toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) administered into the cochlea through the round window (RW) by an external magnetic field. Materials and Methods. In 5 Wistar rats, the left RW was punctured. SPIONs suspended in hyaluronic gel (5 mg/mL) were applied in the RW niche and covered by a muscle graft. The nanoparticles were mobilized using a rare earth magnet (0.54 T) held in 4 consecutive positions around the head. The right ear served as control. Hearing function was monitored by auditory brainstem responses (4-32 kHz tone bursts). Results. The auditory thresholds remained unchanged 1 month after the administration. The histological study of the cochleae showed that SPIONs were driven into the scala tympani in the basal turn, the second turn, and the apex. Conclusion. Superparamagnetic nanoparticles can be driven inside the cochlea toward the apex with a preserved hearing up to 1 month in rats.

Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use.

Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.

Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients.

Glucocorticoids have direct anti-inflammatory, anti-oxidant and anti-apoptotic effects on cochlear hair cells. Cochlear glucocorticoid therapy has gained particular attention for its ability to enhance the protection of residual hearing following hearing preservation cochlear implantation. Local drug delivery methods achieve high drug concentrations within the inner ear fluids but are reliant upon diffusion across the round window membrane. Diffusion has been shown to demonstrate large individual variability. This study explores the role of "adjuvant agents", which when administered with glucocorticoids, enhance inner ear absorption and distribution. Guinea pig cochleae were administered either dexamethasone alone or in combination with hyaluronic acid, histamine, or combination histamine and hyaluronic acid, targeted at the round window membrane. Control subjects received saline. Perilymph was sampled from the cochlear apex, and basal to apical dexamethasone concentrations recorded with mass spectroscopy. Cochleae were harvested, and immunohistochemistry employed to explore dexamethasone tissue penetration and distribution. Basal to apical gradients were observed along the scala tympani, with higher dexamethasone concentrations observed at the cochlear base. Gradients were more pronounced and uniform when administered on a hyaluronic acid sponge, while histamine increased absolute concentrations reaching the inner ear. Tissue penetration correlated with perilymph concentration. Our results demonstrate that adjuvant agents can be employed to enhance dexamethasone absorption and distribution in the inner ear, thus proposing therapeutic strategies that may enhance steroid facilitated hearing protection.

Intratympanic Dexamethasone via Saturated Gelfoam for Idiopathic Sudden Sensorineural Hearing Loss.

The duration of contact time of intratympanic steroids at the round window is a variable that can potentially affect the ultimate concentration within the cochlea. By placing Gelfoam saturated with dexamethasone directly over the round window, contact time is prolonged and potentially increases the dexamethasone concentration within the cochlea. This technique is simple, readily available with standard instruments and ingredients, and easily done in the office.

Alginate Ototoxicity in the Mouse Model.

Objective To determine whether alginate exposure to the round window of the mouse causes any measurable ototoxicity. Study Design Prospective animal study. Setting Basic science laboratory affiliated with a tertiary care university medical center. Subjects and Methods After Institutional Animal Care and Use Committee approval, 5 adult mice were obtained and underwent bullostomy and round window niche application of alginate. Auditory brainstem response (ABR) tests were completed at baseline prior to the procedure and also 5, 14, and 30 days postprocedure. Results were compared. At termination of procedure, the mice were sacrificed with harvest of the cochleae, which were viewed under histologic section. Results There were no significant increases in ABR thresholds in any of the test animals at all test periods after alginate exposure compared to baseline. There were also no observable behavioral changes after the procedure to indicate vestibular dysfunction. Cochlear sectioning revealed no evidence of histologic damage. Conclusion Exposure of alginate to the round window does not cause any obvious ototoxicity in the mouse model. Further clinical trials will be needed to elucidate the effect of alginate in the human middle ear.

Secondary Degeneration of Auditory Neurons after Topical Aminoglycoside Administration in a Gerbil Model.

Hair cells in the cochlea can be damaged by various causes. Damaged hair cells can lead to additional destruction of parts of the auditory afferent pathway sequentially, which is called secondary degeneration. Recently, researches regarding cochlear implants have been actively carried out for clinical purposes; secondary degeneration in animals is a much more practical model for identifying the prognosis of cochlear implants. However, an appropriate model for this research is not established yet. Thus, we developed a secondary degeneration model using an ototoxic drug. 35 gerbils were separated into four different groups and kanamycin was applied via various approaches. ABR was measured several times after drug administration. SGCs were also counted to identify any secondary degeneration. The results showed that outer and inner HCs were damaged in all kanamycin-treated groups. Twelve weeks after kanamycin treatment, the round window membrane injection group showed severe subject differences in hair cells and SGC damage, whereas the gelfoam group showed consistent and severe damage in hair cells and SGCs. In this study, we successfully induced secondary degeneration in hair cells in a gerbil model. This model can be used for various purposes in the hearing research area either for treatment or for preservation.

Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF.

Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug-delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain-derived neurotrophic factor (BDNF) via this catheter with a mini-osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter - whether dry or when delivering AP or BDNF for 4 weeks - was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

A Comparative Study of Drug Delivery Methods Targeted to the Mouse Inner Ear: Bullostomy Versus Transtympanic Injection.

We present two minimally invasive microsurgical techniques in rodents for specific drug delivery into the middle ear so that it may reach the inner ear. The first procedure consists of perforation of the tympanic bulla, termed bullostomy; the second one is a transtympanic injection. Both emulate human clinical intratympanic procedures. Chitosan-glycerophosphate (CGP) and Ringer´s Lactate buffer (RL) were used as biocompatible vehicles for local drug delivery. CGP is a nontoxic biodegradable polymer widely used in pharmaceutical applications. It is a viscous liquid at RT but it congeals to a semi solid phase at body temperature. RL is an isotonic solution used for intravenous administrations in humans. A small volume of this vehicle is precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The safety profiles of both techniques were studied and compared by using functional and morphological tests. Hearing was evaluated by registering the Auditory Brainstem Response (ABR) before and several times after microsurgery. The cytoarchitecture and preservation level of cochlear structures were studied by conventional histological techniques in paraformaldehyde-fixed and decalcified cochlear samples. In parallel, unfixed cochlear samples were taken and immediately frozen to analyze gene expression profiles of inflammatory markers by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Both procedures are suitable as drug delivery methods into the mouse middle ear, although transtympanic injection proved to be less invasive compared to bullostomy.

The effect of systemic lipoic acid on hearing preservation after cochlear implantation via the round window approach: A guinea pig model.

The present study aimed to evaluate the effects of systemic lipoic acid on hearing preservation after cochlear implantation. Twelve Dunkin-Hartley guinea pigs were randomly divided into two groups: the control group and the lipoic acid group. Animals in the lipoic acid group received lipoic acid intraperitoneally for 4 weeks. A sterilised silicone electrode-dummy was inserted through the round window to a depth of approximately 5 mm. The hearing level was measured using auditory brainstem responses (ABRs) prior to electrode-dummy insertion, and at 4 days and 1, 2, 3 and 4 weeks after electrode-dummy insertion. The threshold shift was defined as the difference between the pre-operative threshold and each of the post-operative thresholds. The cochleae were examined histologically 4 weeks after electrode-dummy insertion. Threshold shifts changed with frequency but not time. At 2kHz, ABR threshold shifts were statistically significantly lower in the lipoic acid group than the control group. At 8, 16 and 32kHz, there was no significant difference in the ABR threshold shift between the two groups. Histologic review revealed less intracochlear fibrosis along the electrode-dummy insertion site in the lipoic acid group than in the control group. The spiral ganglion cell densities of the basal, middle and apical turns were significantly higher in the lipoic acid group compared with the control group. Therefore, systemic lipoic acid administration appears to effectively preserve hearing at low frequencies in patients undergoing cochlear implantation. These effects may be attributed to the protection of spiral ganglion cells and prevention of intracochlear fibrosis.

The effect of local application of insulin-like growth factor for prevention of inner-ear damage caused by electrode trauma.

BACKGROUND: Electrode insertion during cochlear implantation causes cochlear damage and apoptosis. Insulin-like growth factor applied locally was investigated in 21 rats. METHODS: In the sham group, an intracochlear dummy electrode was inserted through the round window. In the control group, after the same insertion procedure, saline-soaked porcine skin gelatine was placed on the round window. In the study group, insulin-like growth factor 1 soaked gelatine was placed on the round window. Auditory brainstem response thresholds were measured and histopathological examination was performed. RESULTS: In the study group, at 2-4 kHz, one rat had deterioration, one showed improvement and the rest had stable thresholds 14 days after intervention. At 6 kHz, four rats showed improvement and the rest remained stable. At 8 kHz, four showed improvement, one had deterioration and two remained stable. In the other groups, hearing loss deteriorated in about half of the rats and remained stable in the rest. The mean post-operative 6 kHz threshold was significantly lower than that immediately after the intervention in the study group, contrary to the other groups. The study group had significantly better mean histopathological grading than the other groups. CONCLUSION: Local insulin-like growth factor 1 application may protect hearing after cochlear implantation.

The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy.

Dexamethasone (Dex)-loaded PHEA-g-C18-Arg8 (PCA) nanoparticles (PCA/Dex) were developed for the delivery of genes to determine the synergistic effect of Dex on gene expression. The cationic PCA nanoparticles were self-assembled to create cationic micelles containing an octadecylamine (C18) core with Dex and an arginine 8 (Arg8) peptide shell for electrostatic complexation with nucleic acids (connexin 26 [Cx26] siRNA, green fluorescent protein [GFP] DNA or brain-derived neurotrophic factor [BDNF] pDNA). The PCA/Dex nanoparticles conjugated with Arg8, a cell-penetrating peptide that enhances permeability through a round window membrane in the inner ear for gene delivery, exhibited high uptake efficiency in HEI-OC1 cells. This potential carrier co-delivering Dex and the gene into inner ear cells has a diameter of 120-140 nm and a zeta potential of 20-25 mV. Different types of genes were complexed with the Dex-loaded PCA nanoparticle (PCA/Dex/gene) for gene expression to induce additional anti-inflammatory effects. PCA/Dex showed mildly increased expression of GFP and lower mRNA expression of inflammatory cytokines (IL1b, IL12, and INFr) than did Dex-free PCA nanoparticles and Lipofectamine® reagent in HEI-OC1 cells. In addition, after loading Cx26 siRNA onto the surface of PCA/Dex, Cx26 gene expression was downregulated according to real-time polymerase chain reaction for 24 h, compared with that using Lipofectamine reagent. After loading BDNF DNA into PCA/Dex, increased expression of BDNF was observed for 30 h, and its signaling pathway resulted in an increase in phosphorylation of Akt, observed by Western blotting. Thus, Dex within PCA/Dex/gene nanoparticles created an anti-inflammatory effect and enhanced gene expression.

[Reduction of permanent hearing loss by local glucocorticoid application : Guinea pigs with acute acoustic trauma. German version]. / Begrenzung chronischer Hörverluste durch lokale Glukokortikoidgabe : Meerschweinchen mit akutem Lärmtrauma.

BACKGROUND: High-intensity noise exposure from impulse and blast noise events often leads to acute hearing loss and may cause irreversible permanent hearing loss as a long-term consequence. Here, a treatment regime was developed to limit permanent damage based on a preclinical animal model of acute noise trauma. AIM: To develop clinical trials for the treatment of acute noise traumas using approved drugs. The otoprotective potential of glucocorticoids applied locally to the inner ear was examined. MATERIALS AND METHODS: A series of experiments with different impulse noise exposures was performed. Permanent hearing loss and hair cell density were assessed 14 days after exposure. Hearing and hair cell preservation were investigated as a function of glucocorticoid dose. RESULTS: After impulse noise exposure, local application of high-dose prednisolone (25 mg/ml) or methylprednisolone (12.5 mg/ml) to the round window of the cochlea resulted in a statistically significant reduction in hearing loss compared to the control group. CONCLUSION: Local application of high doses of the drugs to the round window of the cochlea appears to be an effective treatment for acute noise trauma.

The potential use of low-frequency tones to locate regions of outer hair cell loss.

Current methods used to diagnose cochlear hearing loss are limited in their ability to determine the location and extent of anatomical damage to various cochlear structures. In previous experiments, we have used the electrical potential recorded at the round window -the cochlear response (CR) -to predict the location of damage to outer hair cells in the gerbil. In a follow-up experiment, we applied 10 mM ouabain to the round window niche to reduce neural activity in order to quantify the neural contribution to the CR. We concluded that a significant proportion of the CR to a 762 Hz tone originated from phase-locking activity of basal auditory nerve fibers, which could have contaminated our conclusions regarding outer hair cell health. However, at such high concentrations, ouabain may have also affected the responses from outer hair cells, exaggerating the effect we attributed to the auditory nerve. In this study, we lowered the concentration of ouabain to 1 mM and determined the physiologic effects on outer hair cells using distortion-product otoacoustic emissions. As well as quantifying the effects of 1 mM ouabain on the auditory nerve and outer hair cells, we attempted to reduce the neural contribution to the CR by using near-infrasonic stimulus frequencies of 45 and 85 Hz, and hypothesized that these low-frequency stimuli would generate a cumulative amplitude function (CAF) that could reflect damage to hair cells in the apex more accurately than the 762 stimuli. One hour after application of 1 mM ouabain, CR amplitudes significantly increased, but remained unchanged in the presence of high-pass filtered noise conditions, suggesting that basal auditory nerve fibers have a limited contribution to the CR at such low frequencies.

Applying Neurotrophins to the Round Window Rescues Auditory Function and Reduces Inner Hair Cell Synaptopathy After Noise-induced Hearing Loss.

HYPOTHESIS: Applying neurotrophins to the round window immediately after a single noise exposure will prevent noise-induced hidden hearing loss. BACKGROUND: Loud noise can eliminate neural connections between inner hair cells and their afferent neurons (thereby diminishing sound perception) without causing a detectable change on audiogram. This phenomenon is termed hidden hearing loss. METHODS: Guinea pigs were exposed for 2 hours to 4 to 8 kHz noise at either 95 or 105 dB SPL. Immediately afterward a 4 µl bolus of neurotrophins (brain-derived neurotrophic factor 1 µg/µl, and neurotrophin-3 1 µg/µl) was delivered to the round window of one ear, and saline to the other. Auditory brainstem responses to pure-tone pips were acquired preoperatively, and at 1 and 2 weeks' postexposure. Cochleae were removed and whole mounted for immunohistochemical analysis, with presynaptic ribbons of inner hair cells and associated postsynaptic glutamatergic AMPA receptors identified using CtBP2 and GluA2 antibodies respectively. RESULTS: After exposure to 105 dB noise, threshold did not change, but the amplitude growth of the auditory brainstem response was significantly reduced in control ears in response to 16 and 32 kHz tones. The amplitude growth was also reduced neurotrophin ears, but to a lesser degree and the reduction was not significant. Similar results were obtained from control ears exposed to 95 dB, but amplitude growth recovered in neurotrophin-treated ears, this reaching statistical significance in response to 16 kHz tones. There were significantly more presynaptic ribbons, postsynaptic glutamate receptors, and colocalized ribbons after neurotrophin treatment. CONCLUSION: A single dose of neurotrophins delivered to the round window reduced synaptopathy and recovered high-frequency hearing in ears exposed to 95 dB noise. These findings suggest that hidden hearing loss may be reduced by providing trophic support to the cochlea after injury.

Intracochlear Drug Injections through the Round Window Membrane: Measures to Improve Drug Retention.

The goal of this study was to develop an appropriate methodology to apply drugs quantitatively to the perilymph of the ear. Intratympanic applications of drugs to the inner ear often result in variable drug levels in the perilymph and can only be used for molecules that readily permeate the round window (RW) membrane. Direct intracochlear and intralabyrinthine application procedures for drugs, genes or cell-based therapies bypass the tight boundaries at the RW, oval window, otic capsule and the blood-labyrinth barrier. However, perforations can release inner ear pressure, allowing cerebrospinal fluid (CSF) to enter through the cochlear aqueduct, displacing the injected drug solution into the middle ear. Two markers, fluorescein or fluorescein isothiocyanate-labeled dextran, were used to quantify how much of an injected substance was retained in the cochlear perilymph following an intracochlear injection. We evaluated whether procedures to mitigate fluid leaks improved marker retention in perilymph. Almost all procedures to reduce volume efflux, including the use of gel for internal sealing and glue for external sealing of the injection site, resulted in improved retention of the marker in perilymph. Adhesive on the RW membrane effectively prevented leaks but also influenced fluid exchange between CSF and perilymph. We conclude that drugs can be delivered to the ear in a consistent, quantitative manner using intracochlear injections if care is taken to control the fluid leaks that result from cochlear perforation.

Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea.

PURPOSE: Supplementation of exogenous nerve growth factor (NGF) into the cochlea of deafened animals rescues spiral ganglion cells from degeneration. However, a safe and potent delivery of therapeutic proteins, such as NGF, to spiral ganglion cells remains one of the greatest challenges. This study presents the development of self-assembled cubic lipid-based crystalline nanoparticles to enhance inner ear bioavailability of bioactive NGF via a round window membrane route. METHODS: A novel nanocarrier-entrapped NGF was developed based on phytantriol by a liquid precursor dilution, with Pluronic(®) F127 and propylene glycol as the surfactant and solubilizer, respectively. Upon dilution of the liquid lipid precursors, monodispersed submicron-sized particles with a slight negative charge formed spontaneously. RESULTS: Biological activity of entrapped NGF was assessed using pheochromocytoma cells with NGF-loaded reservoirs to induce significant neuronal outgrowth, similar to that seen in free NGF-treated controls. Finally, a 3.28-fold increase in inner ear bioavailability was observed after administration of phytantriol lipid-based crystalline nanoparticles as compared to free drug, contributing to an enhanced drug permeability of the round window membrane. CONCLUSION: Data presented here demonstrate the potential of lipid-based crystalline nanoparticles to improve the outcomes of patients bearing cochlear implants.

A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration.

This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

Controlled release dexamethasone implants in the round window niche for salvage treatment of idiopathic sudden sensorineural hearing loss.

OBJECTIVE: To evaluate the feasibility and hearing outcome of a biocompatible degradable dexamethasone releasing implant for continuous drug delivery to the round window membrane in patients with idiopathic sudden sensorineural hearing loss (ISSHL) and insufficient recovery after systemic high dose glucocorticoid therapy. PATIENTS: Five patients with profound or moderate-to-severe hearing loss after systemic high-dose prednisolone for ISSHL received local salvage therapy with a controlled release dexamethasone implant in the middle ear. INTERVENTION: Pieces of a sterile rod shaped poly(D,L-lactide-co-glycolide) PLGA polymer matrix containing a total of 0.7 mg dexamethasone, which is approved for intravitreal use were implanted into the round window niche. MAIN OUTCOME MEASURE(S): Intraoperative handling and feasibility and hearing recovery as measured by change in pure tone threshold, final word recognition score, and categories of improvement were evaluated. RESULTS: The implants were surgically placed without major difficulties. The mean hearing threshold significantly improved at follow up by 31 ± 31 dB HL (from 94 ± 27 to 63 ± 36 dB HL; p < 0.05). Two of five patients recovered completely. One patient showed partial hearing recovery with serviceable hearing. CONCLUSION: Although no drugs are currently approved for local therapy of inner ear disorders, there is increasing evidence that intratympanic glucocorticoids are effective as salvage therapy in ISSHL. The present study has shown encouraging results with a biodegradable polymer delivery system, demonstrating the translation of preclinical studies with controlled drug delivery into clinical practice.