Publications by authors named "Athanasia Warnecke"

65 Publications

First-in-human intracochlear application of human stromal cell-derived extracellular vesicles.

J Extracell Vesicles 2021 Jun 4;10(8):e12094. Epub 2021 Jun 4.

Department of Transfusion Medicine University Hospital Salzburger Landeskliniken GesmbH (SALK) and Paracelsus Medical University (PMU) Salzburg Austria.

Extracellular vesicles (EVs) derived from the secretome of human mesenchymal stromal cells (MSC) contain numerous factors that are known to exert anti-inflammatory effects. MSC-EVs may serve as promising cell-based therapeutics for the inner ear to attenuate inflammation-based side effects from cochlear implantation which represents an unmet clinical need. In an individual treatment performed on a 'named patient basis', we intraoperatively applied allogeneic umbilical cord-derived MSC-EVs (UC-MSC-EVs) produced according to good manufacturing practice. A 55-year-old patient suffering from Menière's disease was treated with intracochlear delivery of EVs prior to the insertion of a cochlear implant. This first-in-human use of UC-MSC-EVs demonstrates the feasibility of this novel adjuvant therapeutic approach. The safety and efficacy of intracochlear EV-application to attenuate side effects of cochlea implants have to be determined in controlled clinical trials.
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http://dx.doi.org/10.1002/jev2.12094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178433PMC
June 2021

Evaluating Neurotrophin Signaling Using MicroRNA Perilymph Profiling in Cochlear Implant Patients With and Without Residual Hearing.

Otol Neurotol 2021 May 10. Epub 2021 May 10.

Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas Department of Otolaryngology, Medizinische Hochschule Hannover, Hannover Cluster of Excellence "Hearing4all" of the German Research Foundation (EXC 1077), Germany.

Hypothesis: MicroRNAs predicted to regulate neurotrophin signaling can be found in human perilymph.

Background: Animal and human temporal bone studies suggest that spiral ganglion health can affect cochlear implant (CI) outcomes. Neurotrophins have been identified as a key factor in the maintenance of spiral ganglion health. Changes in miRNAs may regulate neurotrophin signaling and may reflect neurotrophin expression levels.

Methods: Perilymph sampling was carried out in 18 patients undergoing cochlear implantation or stapedotomy. Expression of miRNAs in perilymph was evaluated using an Agilent miRNA gene chip. Using ingenuity pathway analysis (IPA) software, miRNAs targeting neurotrophin signaling pathway genes present in a cochlear cDNA library were annotated. Expression levels of miRNAs in perilymph were correlated to the patients' preoperative pure-tone average.

Results: Expression of mRNAs coding for neurotrophins and their receptors were identified in tissue obtained from normal human cochlea during skull base surgery. We identified miRNAs predicted to regulate these signaling cascades, including miR-1207-5p, miR-4651, miR-103-3p, miR-100-5p, miR-221-3p, miR-200-3p. There was a correlation between poor preoperative hearing and lower expression of miR-1207 (predicted to regulate NTR3) and miR-4651 (predicted to regulate NTR2). Additionally, miR-3960, miR-4481, and miR-675 showed significant differences in expression level when comparing mild and profound hearing loss patients.

Conclusions: Expression of some miRNAs that are predicted to regulate neurotrophin signaling in the perilymph of cochlear implant patients vary with the patient's level of residual hearing. These miRNAs may serve as biomarkers for changes in neurotrophin signaling.
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http://dx.doi.org/10.1097/MAO.0000000000003182DOI Listing
May 2021

Potentiation of Brain-Derived Neurotrophic Factor-Induced Protection of Spiral Ganglion Neurons by C3 Exoenzyme/Rho Inhibitor.

Front Cell Neurosci 2021 11;15:602897. Epub 2021 Mar 11.

Institute of Toxicology, Hannover Medical School, Hannover, Germany.

Preservation of the excitability of spiral ganglion neurons (SGN) may contribute to an improved speech perception after cochlear implantation. Thus, the application of exogenous neurotrophic factors such as the neurotrophin brain-derived neurotrophic factor (BDNF) to increase SGN survival and is a promising pharmacological approach in cochlear implant (CI) research. Due to the difficult pharmacokinetic profile of proteins such as BDNF, there is a quest for small molecules to mediate the survival of SGN or to increase the efficacy of BDNF. The C3 exoenzyme from could be a potential new candidate for the protection and regeneration of SGN. Inhibition of the RhoA GTPase pathway which can be mediated by C3 is described as a promising strategy to enhance axonal regeneration and to exert pro-survival signals in neurons. Nanomolar concentrations of C3, its enzymatically inactive form C3, and a 26mer C-terminal peptide fragment covering amino acid 156-181 (C3) potentiated the neuroprotective effect on SGN mediated by BDNF . The neuroprotective effect of C3/BDNF was reduced to the neuroprotective effect of BDNF alone after the treatment with wortmannin, an inhibitor of the phosphatidylinositol-3-kinase (PI3K).The exoenzyme C3 (wild-type and enzyme-deficient) and the C3 peptide fragment C3 present novel biologically active compounds for the protection of the SGN. The exact underlying intracellular mechanisms that mediate the neuroprotective effect are not clarified yet, but the combination of BDNF (TrkB stimulation) and C3 exoenzyme (RhoA inhibition) can be used to protect SGN .
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http://dx.doi.org/10.3389/fncel.2021.602897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991574PMC
March 2021

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

Otol Neurotol 2021 Feb 22. Epub 2021 Feb 22.

Frequency Therapeutics, Woburn, MA & Farmington, CT Department of Surgery, University of Connecticut School of Medicine, Farmington, CT Department of Otolaryngology, Central Institute for the Deaf, Fay and Carl Simons Center for Hearing and Deafness, Washington University School of Medicine, Saint Louis, MO Department of Otolaryngology and Cluster of Excellence of the German Research Foundation "Hearing4all", Hannover Medical School, Hannover, Germany Ear Medical Group Ear Institute of Texas, San Antonio, TX Alamo ENT Associates, San Antonio, TX Worldwide Clinical Trials, San Antonio, TX Forsythe and Bear LLC, Woodland Hills, CA Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN Department of Otolaryngology, Harvard Medical School and Massachusetts Eye and Ear, Boston Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School Boston MA Harvard-MIT Division of Health Science and Technology Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA Broad Institute of MIT and Harvard, Cambridge, MA.

Objectives: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL.

Study Designs: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial.

Setting: Three private otolaryngology practices in the US.

Patients: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms.

Interventions: Intratympanic FX-322.

Main Outcome Measures: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects.

Results: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71).

Conclusions: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.
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http://dx.doi.org/10.1097/MAO.0000000000003120DOI Listing
February 2021

Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo.

Clin Transl Med 2020 Dec;10(8):e262

GMP Unit, Spinal Cord Injury and Tissue Regeneration Centre Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria.

The lack of approved anti-inflammatory and neuroprotective therapies in otology has been acknowledged in the last decades and recent approaches are heralding a new era in the field. Extracellular vesicles (EVs) derived from human multipotent (mesenchymal) stromal cells (MSC) can be enriched in vesicular secretome fractions, which have been shown to exert effects (eg, neuroprotection and immunomodulation) of their parental cells. Hence, MSC-derived EVs may serve as novel drug candidates for several inner ear diseases. Here, we provide first evidence of a strong neuroprotective potential of human stromal cell-derived EVs on inner ear physiology. In vitro, MSC-EV preparations exerted immunomodulatory activity on T cells and microglial cells. Moreover, local application of MSC-EVs to the inner ear significantly attenuated hearing loss and protected auditory hair cells from noise-induced trauma in vivo. Thus, EVs derived from the vesicular secretome of human MSC may represent a next-generation biological drug that can exert protective therapeutic effects in a complex and nonregenerating organ like the inner ear.
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http://dx.doi.org/10.1002/ctm2.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752163PMC
December 2020

Level of sex hormones and their association with acetylsalicylic acid intolerance and nasal polyposis.

PLoS One 2020 17;15(12):e0243732. Epub 2020 Dec 17.

Department of Otolaryngology, Hannover Medical School, Hannover, Germany.

Background: Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet.

Aim: Examine the relationship between levels of sex hormones and nasal polyposis.

Methods: Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy.

Results: Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01).

Conclusion: Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required.

Significance: Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746182PMC
February 2021

Expression pattern of brain-derived neurotrophic factor and its associated receptors: Implications for exogenous neurotrophin application.

Hear Res 2020 Oct 21:108098. Epub 2020 Oct 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Hannover, Germany; Cluster of Excellence "Hearing4all" of the German Research Foundation (EXC 2177/1).

The application of neurotrophins such as brain-derived neurotrophic factor (BDNF) is a promising pharmacological approach in cochlear implant research. Several in vitro and in vivo studies demonstrated that treatment with neurotrophins support the spiral ganglion neuron (SGN) survival and the synapses. Of the more than 40 companies that are working in the field of inner ear therapeutics, only one company is currently advancing BDNF towards clinical translation. Thus, there are no approved clinical therapies with neurotrophins, their precursors or neurotrophin-like substances. For a better understanding of the mechanisms of BDNF in the inner ear, we analysed the expression of mature BDNF (mBDNF), its pro-form proBDNF and their respective receptors the low affinity p75 neurotrophin receptor (p75NTR) and the neurotrophic receptor tyrosine kinase 2 (NTRK2). In the adult murine inner ear, mBDNF is expressed in the inner and outer hair cells (IHC and OHC) of the organ of Corti and in the spiral ganglion of the Rosenthal's canal, whereas proBDNF is only detected in the supporting cells below the OHC. The corresponding receptors NTRK2 and p75NTR are expressed in the spiral ganglion whereof p75NTR is stronger expressed. For more insights in the effects of mBDNF and proBDNF on inner ear specific cells, we treated primary dissociated SGN with different concentrations of mBDNF and proBDNF alone and in combination. Interestingly, treatment with proBDNF is not toxic for SGN but simultaneously not protective. However, combined treatment of mBDNF and proBDNF maintained and perhaps slightly increased the protective effect of mBDNF. Thus, the mixture of mBDNF and proBDNF could be the new direction for the development of BDNF-based therapeutics in cochlear implantation and could represent more precisely the natural environment.
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http://dx.doi.org/10.1016/j.heares.2020.108098DOI Listing
October 2020

On the Intracochlear Location of Straight Electrode Arrays After Cochlear Implantation: How Lateral Are Lateral Wall Electrodes?

Otol Neurotol 2021 02;42(2):242-250

Department of Otorhinolaryngology.

Objective: Cochlear implants are the gold standard for patients with severe sensorineural hearing loss. A focused electrical stimulation of individual spiral ganglion neurons has not been achieved yet because the scala tympani is a fluid-filled compartment and does not offer a matrix for neuritic outgrowth. Coating of the electrode contacts with swelling hydrogels could fill that gap between the electrode array and the medial wall of the cochlea. Therefore, the exact position of the electrode array within the scala tympani has to be known.

Study Design: Retrospective analysis of patient data sets.

Setting: Tertiary referral center. A total of 95 patients with cochlear implants from one manufacturer were included in this study. The lateral wall, the modiolar wall, and the cochlear implant electrode were segmented using OsiriX MD. For repositioning and reconstructing the respective contours and measuring distances, files were analyzed in MATLAB. The distances from the edge of each electrode contact to the cochlear walls showed no significant differences. But between the different contacts within each patient, there were significant differences. Around 180 degree insertion, electrodes start to get in contact with the lateral wall. The tip of the electrode array was always facing toward the modiolar wall independent of the length of the electrode. We established a method to analyze the position of electrodes within the cochlea.
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http://dx.doi.org/10.1097/MAO.0000000000002880DOI Listing
February 2021

The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants.

J Neurosci 2020 09;40(38):7190-7202

University of Tübingen, Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center, Molecular Physiology of Hearing, 72076 Tübingen, Germany.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous γ oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.
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http://dx.doi.org/10.1523/JNEUROSCI.1314-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534911PMC
September 2020

Impedance Values Do Not Correlate With Speech Understanding in Cochlear Implant Recipients.

Otol Neurotol 2020 09;41(8):e1029-e1034

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School.

Objective: To evaluate a possible correlation between impedance values and speech perception after cochlear implantation.

Study Design: Retrospective chart review.

Setting: Tertiary referral center.

Patients And Intervention: All patients implanted with a MedEl Flex28 device in our department with complete audiometric data (Freiburger monosyllabic testing at 65 dB, Hochmaier-Schulz-Moser testing in quiet and in 10 dB noise) and impedance measurements at the 1-year refitting appointment were enrolled in this study. Further inclusion criteria were age > 17 years, native speakers, and no use of electric-acoustic-stimulation.

Main Outcome Measures: Mean values for impedances were calculated over all electrode contacts and separately for basal, medial, and apical regions. These data were correlated statistically (Pearson's correlation) with speech testing results. Furthermore, groups of patients with extreme values were built and compared against each other and against the rest of the collective.

Results: Impedance values did not correlate significantly with speech performance in any of the audiometric tests neither for all electrode contacts nor for specific clusters of contacts. Patients with the lowest impedances did not perform statistically different than patients with the highest impedances in any condition.

Conclusion: To our knowledge, this is the first data on a possible correlation between impedances and speech perception. The extent of the impedances as a benchmark for a good performance in speech discrimination tests could not be verified. Further prospective studies, possibly with more precise diagnostic tools, should be carried out to define the value of impedance measurements for cochlear implantation provision.
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http://dx.doi.org/10.1097/MAO.0000000000002743DOI Listing
September 2020

MicroRNA Profiling as a Methodology to Diagnose Ménière's Disease: Potential Application of Machine Learning.

Otolaryngol Head Neck Surg 2021 02 14;164(2):399-406. Epub 2020 Jul 14.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Kansas, Kansas City, Kansas, USA.

Objective: Diagnosis and treatment of Ménière's disease remains a significant challenge because of our inability to understand what is occurring on a molecular level. MicroRNA (miRNA) perilymph profiling is a safe methodology and may serve as a "liquid biopsy" equivalent. We used machine learning (ML) to evaluate miRNA expression profiles of various inner ear pathologies to predict diagnosis of Ménière's disease.

Study Design: Prospective cohort study.

Setting: Tertiary academic hospital.

Subjects And Methods: Perilymph was collected during labyrinthectomy (Ménière's disease, n = 5), stapedotomy (otosclerosis, n = 5), and cochlear implantation (sensorineural hearing loss [SNHL], n = 9). miRNA was isolated and analyzed with the Affymetrix miRNA 4.0 array. Various ML classification models were evaluated with an 80/20 train/test split and cross-validation. Permutation feature importance was performed to understand miRNAs that were critical to the classification models.

Results: In terms of miRNA profiles for conductive hearing loss versus Ménière's, 4 models were able to differentiate and identify the 2 disease classes with 100% accuracy. The top-performing models used the same miRNAs in their decision classification model but with different weighted values. All candidate models for SNHL versus Ménière's performed significantly worse, with the best models achieving 66% accuracy. Ménière's models showed unique features distinct from SNHL.

Conclusions: We can use ML to build Ménière's-specific prediction models using miRNA profile alone. However, ML models were less accurate in predicting SNHL from Ménière's, likely from overlap of miRNA biomarkers. The power of this technique is that it identifies biomarkers without knowledge of the pathophysiology, potentially leading to identification of novel biomarkers and diagnostic tests.
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http://dx.doi.org/10.1177/0194599820940649DOI Listing
February 2021

Differential Effects of Low- and High-Dose Dexamethasone on Electrically Induced Damage of the Cultured Organ of Corti.

Neurotox Res 2020 Aug 3;38(2):487-497. Epub 2020 Jun 3.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

An increased number of patients with residual hearing are undergoing cochlear implantation. A subset of these experience delayed hearing loss post-implantation, and the aetiology of this loss is not well understood. Our previous studies suggest that electrical stimulation can induce damage to hair cells in organ of Corti (OC) organotypic cultures. Dexamethasone has the potential to protect residual hearing due to its multiple effects on cells and tissue (e.g., anti-inflammatory, free radical scavenger). We therefore hypothesized that dexamethasone treatment could prevent electrical stimulation induced changes in the OC. Organ of Corti explants from neonatal rats (P2-4) were cultured for 24 h with two different concentrations of dexamethasone. Thereafter, OC were subjected to a charge-balanced biphasic pulsed electrical stimulation (0.44-2 mA) for a further 24 h. Unstimulated dexamethasone-treated OC served as controls. Outcome analysis included immunohistochemical labelling of ribbon synapses, histochemical analysis of free reactive oxygen species and morphological analysis of stereocilia bundles. Overall, the protective effects of dexamethasone on electrically induced damage in cochlear explants were moderate. High-dose dexamethasone protected bundle integrity at higher current levels. Low-dose dexamethasone tended to increase ribbon density in the apical region.
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http://dx.doi.org/10.1007/s12640-020-00228-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334252PMC
August 2020

Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation-1 Year Data.

Front Neurol 2020 15;11:258. Epub 2020 Apr 15.

Department of Otorhinolaryngology, Head and Neck Surgery, Hanover Medical School, Hanover, Germany.

Administration of low-dose steroids via a catheter inserted into the cochlea to apply pharmaceuticals to more apical regions was previously shown not to be sufficient for long-term reduction of electrode impedances. The aim of the present study was to investigate the effect of intra-cochlear high-dose triamcinolone application on impedances in cochlear implant recipients. Patients received low-dose (4 mg/ml; = 5) or high-dose (20 mg/ml; = 5) triamcinolone via a cochlear catheter just prior to the insertion of a Med-El Flex28 electrode. Impedances were measured at defined time points from intra-operatively up to 12 months after first fitting and retrospectively compared with a control group (no steroid application). Patients who received a high-dose application of crystalloid triamcinolone showed significantly reduced impedances in the first fitting measurements compared to the control group. This effect was no longer detectable in patients of the low-dose group at that time. Looking at the different regions of the electrode, the impedance values were lowered significantly only at the basal and medial contacts. At later time points, there were no significant differences between any of the groups. This is the first study to demonstrate a dose-dependent reduction of impedances by deep intra-cochlear injection of triamcinolone in cochlear implant patients. With a high-dose, single application of triamcinolone using a cochlear catheter prior to insertion of a Flex28 electrode, the impedances can be significantly reduced up to and including the first fitting. Although the effect was longer lasting than when compared to low-dose triamcinolone, it was also not permanent.
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http://dx.doi.org/10.3389/fneur.2020.00258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194199PMC
April 2020

Endogenous α1-antitrypsin levels in the perilymphatic fluid correlates with severity of hearing loss.

Clin Otolaryngol 2020 07 26;45(4):495-499. Epub 2020 Apr 26.

Otorhinolaryngology Department, Head and Neck Surgery, Hanover Medical University, Hannover, Germany.

Objectives: To determine the levels of endogenous α1-antitrypsin in the perilymph of patients undergoing cochlear implant (CI), and its reverse association with the severity of hearing loss.

Study Design: Retrospective study.

Setting: Tertiary care university hospital.

Participants: The study includes 38 patients undergoing CI surgery, 11 patients diagnosed with congenital deafness and 27 non-congenital deafness, eight patients diagnosed with moderate hearing loss (N = 8; PTA = 70 dB), severe hearing loss (N = 11; PTA 70-90 dB) and profound hearing loss (N = 19; PTA > 90 dB).

Main Outcome And Measure: 1 to 12 μL perilymphatic fluids were collected by micropipette. α1-antitrypsin levels were determined, and current and historic audiological parameters were obtained.

Results: The congenital and non-congenital group exhibited AAT concentrations of 2.5 ± 1.9 × 10 LFQ and 3.2 ± 1.2 × 10 LFQ, respectively (mean ± SD; P = .38). Mean levels of α1-antitrypsin in the perilymph fluid within the moderate group was 3.64 × 10  ± 2.1 × 10 LFQ vs 3.5 × 10  ± 1.2 × 10 in severe hearing loss (P = .81) and 2.4 × 10  ± 1.1 × 10 LFQ in the profound hearings loss group (P = .06). The difference in levels of AAT in samples from the severe hearings loss group vs the profound hearings loss group reached statistical significance (P = .04).

Conclusion: Insufficiency in α1-antitrypsin levels in the perilymph fluid of the inner ear appears to display a relationship with the severity of hearing loss. The prospect of introducing clinical-grade plasma-purified α1-antitrypsin directly onto the site of cochlear injury deserves thorough investigation.
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http://dx.doi.org/10.1111/coa.13541DOI Listing
July 2020

Relations Between Scalar Shift and Insertion Depth in Human Cochlear Implantation.

Otol Neurotol 2020 02;41(2):178-185

Department of Otorhinolaryngology, Head and Neck Surgery.

Objective: The intracochlear position of an electrode array may influence the outcome after cochlear implantation. The design of the electrode array can increase the risk of trauma causing penetration of the basilar membrane or shift of the electrode array into the scala vestibuli. The aim of the present study was to identify a scalar shift after implantation of two different electrode arrays developed by one manufacturer.

Study Design: Retrospective analysis.

Setting: Tertiary referral center.

Patients And Intervention: Cochlear implant recipients implanted between 2010 and 2014 and receiving either a mid-scala (n = 30) or a perimodiolar (n = 30) electrode array.

Main Outcome Measure: Occurrence of scalar shift in association with the electrode type.

Results: Scalar shift occurred in 26.7% (8 of 30) of the patients implanted with a perimodiolar electrode array and in 6.7% (2 of 30) of the patients implanted with the mid-scala electrode array. The mean insertion depth in the patients experiencing scalar shift after implantation of the mid-scala electrode was much deeper (21.59 ± 0.34 mm) when compared with the mean insertion depth of the patients with scalar shift after implantation with a perimodiolar electrode array (17.85 ± 2.19 mm). There tends to be a correlation between the cochlear length and the occurrence of a scalar shift. However, the number of patients with scalar shift in the mid-scala group is rather small.

Conclusion: Based on the presented data, more patients implanted with a perimodiolar electrode array have a scalar shift when compared with the midscalar electrode array.
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http://dx.doi.org/10.1097/MAO.0000000000002460DOI Listing
February 2020

Computational analysis based on audioprofiles: A new possibility for patient stratification in office-based otology.

Audiol Res 2019 Sep 5;9(2):230. Epub 2019 Nov 5.

Department of Otolaryngology, Hannover Medical School, Hannover.

Genetic contribution to progressive hearing loss in adults is underestimated. Established machine learning-based software could offer a rapid supportive tool to stratify patients with progressive hearing loss. A retrospective longitudinal analysis of 141 adult patients presenting with hearing loss was performed. Hearing threshold was measured at least twice 18 months or more apart. Based on the baseline audiogram, hearing thresholds and age were uploaded to AudioGene v4® (Center for Bioinformatics and Computational Biology at The University of Iowa City, IA, USA) to predict the underlying genetic cause of hearing loss and the likely progression of hearing loss. The progression of hearing loss was validated by comparison with the most recent audiogram data of the patients. The most frequently predicted were DFNA2B, DFNA9 and DFNA2A. The frequency of /genes predicted by AudioGene remains consistent when using the initial or the final audiogram of the patients. In conclusion, machine learning-based software analysis of clinical data might be a useful tool to identify patients at risk for having autosomal dominant hearing loss. With this approach, patients with suspected progressive hearing loss could be subjected to close audiological followup, genetic testing and improved patient counselling.
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http://dx.doi.org/10.4081/audiores.2019.230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843421PMC
September 2019

Dimensions of artefacts caused by cochlear and auditory brainstem implants in magnetic resonance imaging.

Cochlear Implants Int 2020 03 25;21(2):67-74. Epub 2019 Sep 25.

Institute of Neuroradiology, Hannover Medical School, Hannover, Germany.

The aim of the study was to investigate the extent of MRI artefacts due to the magnet of selected auditory implants. Artefacts of the Synchrony cochlear implant at 1.5 T as well as at 3 T MRI devices were examined in cadavers and compared to the artefacts in MRI scans at 1.5 T of 17 patients implanted with CI ( = 12) and auditory brainstem implants (ABI) ( = 5). None of the scanned implants showed any failure after MRI. After removal of the magnet, only a portion of the images in the direct neighbourhood of the implant, especially in the temporal and parietal lobe, contained artefacts. More anatomical substructures were visible without artefacts using the MedEl Synchrony device. Artefacts can be markedly reduced by rotating, self-aligning magnet. Removal of the magnet also results in reduction of artefacts.
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http://dx.doi.org/10.1080/14670100.2019.1668617DOI Listing
March 2020

Microarray-based screening system identifies temperature-controlled activity of Connexin 26 that is distorted by mutations.

Sci Rep 2019 09 19;9(1):13543. Epub 2019 Sep 19.

Gottfried-Wilhelm-Leibniz University of Hannover, BMWZ (Zentrum für Biomolekulare Wirkstoffe), Schneiderberg 38, 30167, Hannover, Germany.

Here, we show that human Connexin 26 (hCx26 or Cx26WT) hemichannel opening rapidly enables the transport of small molecules when triggered by temperature and by compensation of the Ca blockade with EDTA. Point mutations within Cx26 were analysed by a novel optical microarray-based Lucifer Yellow uptake assay or by two electrode voltage clamp (TEVC) on frog oocytes to monitor simultaneous activities of channel proteins. Point mutations L90P, F161S, R184P or K188N influenced the temperature-dependent activity drastically. Since several mutations blocked trafficking, the temperature-dependent activity of the recombinant synthesized and purified wild-type Cx26WT and Cx26K188N hemichannel was tested by liposome flux assay (LFA) and on a microarray-based Lucifer Yellow uptake assay under warm conditions (>30 °C). The data from TEVC measurements and dye flux experiments showed that the mutations gave no or only a weak activity at increased temperature (>30 °C). We conclude that the position K188 in the Cx26WT forms a temperature-sensitive salt bridge with E47 whereas the exchange to K188N destabilizes the network loop- gating filter, which was recently identified as a part of the flexible Ca binding site. We assume that the temperature sensitivity of Cx26 is required to protect cells from uncontrolled release or uptake activities through Cx26 hemichannels.
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http://dx.doi.org/10.1038/s41598-019-49423-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753059PMC
September 2019

Defining the Inflammatory Microenvironment in the Human Cochlea by Perilymph Analysis: Toward Liquid Biopsy of the Cochlea.

Front Neurol 2019 25;10:665. Epub 2019 Jun 25.

Hannover Medical School, Institute of Transplant Immunology, Hanover, Germany.

The molecular pathomechanisms in the majority of patients suffering from acute or progressive sensorineural hearing loss cannot be determined yet. The size and the complex architecture of the cochlea make biopsy and in-depth histological analyses impossible without severe damage of the organ. Thus, histopathology correlated to inner disease is only possible after death. The establishment of a technique for perilymph sampling during cochlear implantation may enable a liquid biopsy and characterization of the cochlear microenvironment. Inflammatory processes may not only participate in disease onset and progression in the inner ear, but may also control performance of the implant. However, little is known about cytokines and chemokines in the human inner ear as predictive markers for cochlear implant performance. First attempts to use multiplex protein arrays for inflammatory markers were successful for the identification of cytokines, chemokines, and endothelial markers present in the human perilymph. Moreover, unsupervised cluster and principal component analyses were used to group patients by lead cytokines and to correlate certain proteins to clinical data. Endothelial and epithelial factors were detected at higher concentrations than typical pro-inflammatory cytokines such as TNF-a or IL-6. Significant differences in VEGF family members have been observed comparing patients with deafness to patients with residual hearing with significantly reduced VEGF-D levels in patients with deafness. In addition, there is a trend toward higher IGFBP-1 levels in these patients. Hence, endothelial and epithelial factors in combination with cytokines may present robust biomarker candidates and will be investigated in future studies in more detail. Thus, multiplex protein arrays are feasible in very small perilymph samples allowing a qualitative and quantitative analysis of inflammatory markers. More results are required to advance this method for elucidating the development and course of specific inner ear diseases or for perioperative characterization of cochlear implant patients.
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http://dx.doi.org/10.3389/fneur.2019.00665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603180PMC
June 2019

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol 2019 06;40(5):559-570

Department of Otolaryngology Head and Neck Surgery, Hannover Medical School, Hannover.

Objective: To provide an overview of biotechnology and pharmaceutical companies active in the field of inner ear and central hearing disorders and their therapeutic approaches.

Methods: Scientific and grey literature was searched using broad search terms to identify companies and their hearing-related therapeutic approaches. For each approach its lead indication, product, therapeutic modality, target, mechanism of action and current phase of clinical development was collated.

Results: A total of 43 biotechnology and pharmaceutical companies have been identified that are developing therapeutics for inner ear and central hearing disorders. Their therapeutics include drug-, cell- and gene-based approaches to prevent hearing loss or its progression, restore hearing, and regenerate the inner ear. Their therapeutic targets and specific mechanisms of action are wide-ranging, reflecting the complexity of the hearing pathways and the diversity of mechanisms underlying inner ear disorders. While none of the novel products under investigation have yet made it to the clinical market, and a large proportion are still at preclinical phase, many therapeutics have already entered clinical testing with more expected to do so in the next few years.

Conclusion: A wide range of novel therapeutics targeting different hearing, balance and tinnitus pathways, and patient populations are approaching the clinical domain. It is important that clinicians involved in the care of patients with hearing loss prepare for what may become a radically different approach to the management of hearing disorders, and develop a true understanding of the new therapies' mechanisms of action, applications, and indications.
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http://dx.doi.org/10.1097/MAO.0000000000002194DOI Listing
June 2019

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss.

Front Neurosci 2019 26;13:214. Epub 2019 Mar 26.

Department of Otolaryngology, Hannover Medical School, Hanover, Germany.

The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients ( = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph ( = 41) obtained from hearing-impaired patients ( = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
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http://dx.doi.org/10.3389/fnins.2019.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445295PMC
March 2019

Correction to: Influence of In Vitro Electrical Stimulation on Survival of Spiral Ganglion Neurons.

Neurotox Res 2019 Jul;36(1):217

Department of Otorhinolaryngology, Head and Neck Surgery Hannover Medical School, Stadtfelddamm 34, 30625, Hannover, Germany.

The first multiplication sign (.) for unit μC cm¯·phase¯ was not placed, which is part of the author's correction. Furthermore, the unit appears anywhere in the article.
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http://dx.doi.org/10.1007/s12640-019-00029-7DOI Listing
July 2019

Influence of In Vitro Electrical Stimulation on Survival of Spiral Ganglion Neurons.

Neurotox Res 2019 Jul 7;36(1):204-216. Epub 2019 Mar 7.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Stadtfelddamm 34, 30625, Hannover, Germany.

Patients scheduled for cochlear implantation often retain residual hearing in the low frequencies. Unfortunately, some patients lose their residual hearing following implantation and the reasons for this are not well understood. Evidence suggests that electrotoxicity could be one of the factors responsible for this late adverse effect. Therefore, the aim of this study was to investigate the survival of spiral ganglion neurons (SGN) subjected to in vitro electrical stimulation (ES). A stimulation setup was developed to provide defined electrical fields at given points of the chamber. SGN isolated from Sprague Dawley rats (P3-4) were dissociated and cultured in the chamber for 24 h prior to biphasic, pulsed electrical field exposure for another 24 h. The current varied in the range of 0 to 2 mA and the pulse width from 10 to 400 μs. Neurite growth and survival were evaluated with respect to the charge density at the position of the cells. Non-exposed SGN cultures served as control. Charge densities below 2.2 μC·cm·phase appeared to have no effect on SGN survival and neurite outgrowth. Charge densities above 4.9 μC·cm·phase were detrimental to almost all cells in culture. After fitting results to a sigmoidal dose response curve, a LD of 2.9 μC·cm·phase was calculated. This screening regarding survival and outgrowth of SGN provides parameters that could be used to further investigate the effect of ES on SGN and to develop possible protection strategies, which could potentially rescue residual hearing in the implanted patients.
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http://dx.doi.org/10.1007/s12640-019-00017-xDOI Listing
July 2019

Single Intravenous High Dose Administration of Prednisolone Has No Influence on Postoperative Impedances in the Majority of Cochlear Implant Patients.

Otol Neurotol 2018 12;39(10):e1002-e1009

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School.

Objective: To evaluate effect of prednisolone on the impedances after cochlear implantation.

Study Design: Retrospective case series.

Setting: Tertiary referral center.

Patients And Intervention: A total of 130 patients underwent cochlear implantation with a Med-El Flex28 synchrony device between 2012 and 2016 and met the inclusion criteria. Only patients with full datasets regarding impedance measurements perioperatively, at first fitting (before and after chronic electric stimulation) and at 3 and 12 months appointments afterward were included. Patients (n = 101) received a single intravenous administration of at least 200 mg prednisolone intraoperatively and control patients (n = 29) did not receive any steroids at all. Patients receiving low dose steroids during surgery were excluded.

Main Outcome Measures: Mean values for impedances were calculated over all electrode contacts and separately for basal, medial, and apical regions.

Results: Impedances increased significantly from perioperative measures to first fitting in both groups. Mainly at the basal region of the electrode array, impedances were slightly lower in the steroid group compared with controls. However, the majority of the patients showed increased impedances whether they received steroid treatment or not.

Conclusion: The present study shows a slight but statistically significant reduction of the mean value of postoperative impedances at the basal electrode contacts in patients receiving a single systemic high dose application of prednisolone. Less than half of the patients showed a decrease in impedances and whether this decrease is clinically relevant remains to be elucidated.
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http://dx.doi.org/10.1097/MAO.0000000000002033DOI Listing
December 2018

Microenvironmental support for cell delivery to the inner ear.

Hear Res 2018 10 21;368:109-122. Epub 2018 Jun 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany; Cluster of Excellence "Hearing4all" of the German Research Foundation, Germany. Electronic address:

Transplantation of mesenchymal stromal cells (MSC) presents a promising approach not only for the replacement of lost or degenerated cells in diseased organs but also for local drug delivery. It can potentially be used to enhance the safety and efficacy of inner ear surgeries such as cochlear implantation. Options for enhancing the effects of MSC therapy include modulating cell behaviour with customized bio-matrixes or modulating their behaviour by ex vivo transfection of the cells with a variety of genes. In this study, we demonstrate that MSC delivered to the inner ear of guinea pigs or to decellularized cochleae preferentially bind to areas of high heparin concentration. This presents an opportunity for modulating cell behaviour ex vivo. We evaluated the effect of carboxymethylglucose sulfate (Cacicol), a heparan sulfate analogue on spiral ganglion cells and MSC and demonstrated support of neuronal survival and support of stem cell proliferation.
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http://dx.doi.org/10.1016/j.heares.2018.06.015DOI Listing
October 2018

Feasibility of microRNA profiling in human inner ear perilymph.

Neuroreport 2018 08;29(11):894-901

Departments of Otolaryngology Head and Neck Surgery.

Hearing loss is common and caused by a wide range of molecular and cellular pathologies. Current diagnosis of hearing loss depends on a combination of physiologic testing, patient history, and in some cases genetic testing. Currently, no biopsy or equivalent procedure exists to diagnose inner ear disorders. MicroRNAs (miRNA) are short ribonucleic acids that regulate a variety of cellular processes. They have been found to be reliable markers for a variety of disease processes. In particular, a variety of miRNAs that are markers for neurodegenerative disease have been identified in cerebrospinal fluid. The aim of this study was to determine whether miRNAs could be identified in human perilymph potentially leading to the development of biomarkers for inner ear disease. Prospective sampling of human perilymph and its analysis were carried out. Patients undergoing surgery in which the inner ear is opened as part of the procedure (cochlear implantation, stapedectomy, labyrinthectomy) were recruited. A total of 2-5 μl of perilymph was collected and analyzed using Affymetrix GeneChip miRNA 4.0 microarrays. MiRNA common to all sampling approaches were selected. Analysis of miRNAs was carried out by evaluating miRNA targets in a cochlear transcriptome library using the Ingenuity Pathway Analysis software package. MiRNAs could be isolated from the perilymph of all patients. Evaluation of miRNAs shows the presence of miRNA populations that are predicted to interact with genes expressed in the inner ear. Additional analysis of miRNA populations shows that perilymph miRNAs could be linked to pathways associated with hearing disorders. Sampling of human perilymph is feasible and can potentially identify miRNAs associated with hearing disorders.
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http://dx.doi.org/10.1097/WNR.0000000000001049DOI Listing
August 2018

Intracochlear administration of steroids with a catheter during human cochlear implantation: a safety and feasibility study.

Drug Deliv Transl Res 2018 10;8(5):1191-1199

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Carl Neuberg-Str. 1, 30625, Hannover, Germany.

Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids. Therefore, new devices are needed to warrant rapid distribution of agents into all parts of the cochlea. Five patients received a deep intracochlear injection of triamcinolone with a specifically designed cochlear catheter during cochlear implantation right before inserting a cochlear implant electrode. As a measure for formation of fibrous tissue around the electrode, electrical impedances were measured in the operation room and over 4 months thereafter. No adverse events were observed peri- and postoperatively. The handling of the device was easy. Severe damage to the microstructure of the cochlea was excluded as far as possible by cone beam computed tomography and vestibular testing. A delayed rise of the impedances was seen in the catheter group compared to controls over all regions of the cochlea. A statistical significance, however, was only obtained at the midregion of the cochlea. Consequently, the cochlear catheter is a safe and feasible device for local drug delivery of pharmaceutical agents into deeper regions of the cochlea.
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http://dx.doi.org/10.1007/s13346-018-0539-zDOI Listing
October 2018

The Noncompetitive Effect of Gambogic Acid Displaces Fluorescence-Labeled ATP but Requires ATP for Binding to Hsp90/HtpG.

Biochemistry 2018 05 24;57(18):2601-2605. Epub 2018 Apr 24.

Institute of Biophysics and Center of Biomolecular Drug Research (BMWZ) , Leibniz Universität Hannover , Schneiderberg 38 , 30167 Hannover , Germany.

The heat shock protein 90 (Hsp90) family plays a critical role in maintaining the homeostasis of the intracellular environment for human and prokaryotic cells. Hsp90 orthologues were identified as important target proteins for cancer and plant disease therapies. It was shown that gambogic acid (GBA) has the potential to inhibit human Hsp90. However, it is unknown whether it is also able to act on the bacterial high-temperature protein (HtpG) analogue. In this work, we screened GBA and nine other novel potential Hsp90 inhibitors using a miniaturized high-throughput protein microarray-based assay and found that GBA shows an inhibitory effect on different Hsp90s after dissimilarity analysis of the protein sequence alignment. The dissociation constant of GBA and HtpG Xanthomonas (XcHtpG) computed from microscale thermophoresis is 682.2 ± 408 μM in the presence of ATP, which is indispensable for the binding of GBA to XcHtpG. Our results demonstrate that GBA is a promising Hsp90/HtpG inhibitor. The work further demonstrates that our assay concept has great potential for finding new potent Hsp/HtpG inhibitors.
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http://dx.doi.org/10.1021/acs.biochem.8b00155DOI Listing
May 2018

Long-term delivery of brain-derived neurotrophic factor (BDNF) from nanoporous silica nanoparticles improves the survival of spiral ganglion neurons in vitro.

PLoS One 2018 27;13(3):e0194778. Epub 2018 Mar 27.

Institut für Anorganische Chemie, Leibniz Universität Hannover, Hannover, Germany.

Sensorineural hearing loss (SNHL) can be overcome by electrical stimulation of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Restricted CI performance results from the spatial gap between the SGNs and the electrode, but the efficacy of CI is also limited by the degeneration of SGNs as one consequence of SHNL. In the healthy cochlea, the survival of SGNs is assured by endogenous neurotrophic support. Several applications of exogenous neurotrophic supply have been shown to reduce SGN degeneration in vitro and in vivo. In the present study, nanoporous silica nanoparticles (NPSNPs), with an approximate diameter of <100 nm, were loaded with the brain-derived neurotrophic factor (BDNF) to test their efficacy as long-term delivery system for neurotrophins. The neurotrophic factor was released constantly from the NPSNPs over a release period of 80 days when the surface of the nanoparticles had been modified with amino groups. Cell culture investigations with NIH3T3 fibroblasts attest a good general cytocompatibility of the NPSNPs. In vitro experiments with SGNs indicate a significantly higher survival rate of SGNs in cell cultures that contained BDNF-loaded nanoparticles compared to the control culture with unloaded NPSNPs (p<0.001). Importantly, also the amounts of BDNF released up to a time period of 39 days increased the survival rate of SGNs. Thus, NPSNPs carrying BDNF are suitable for the treatment of inner ear disease and for the protection and the support of SGNs. Their nanoscale nature and the fact that a direct contact of the nanoparticles and the SGNs is not necessary for neuroprotective effects, should allow for the facile preparation of nanocomposites, e.g., with biocompatible polymers, to install coatings on implants for the realization of implant-based growth factor delivery systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194778PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870973PMC
July 2018

Biological Therapies of the Inner Ear: What Otologists Need to Consider.

Otol Neurotol 2018 02;39(2):135-137

evidENT, Ear Institute, University College London, London, UK Department of Otolaryngology Head and Neck Surgery, Hannover Medical School, Hannover, Cluster of Excellence "Hearing for all," German Research Foundation, Bonn, Germany Department of Otolaryngology Head and Neck Surgery, Columbia University, New York, New York, USA Department of Otolaryngology Head and Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA.

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http://dx.doi.org/10.1097/MAO.0000000000001689DOI Listing
February 2018