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.

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.

Background: The success of cochlear implantation may be further improved by minimizing implantation trauma. The physical trauma of implantation and subsequent immunological sequelae can affect residual hearing and the viability of the spiral ganglion. An ideal electrode should therefore decrease post-implantation trauma and provide support to the residual spiral ganglion population. Combining a flexible electrode with cells producing and releasing protective factors could present a potential means to achieve this. Mononuclear cells obtained from bone marrow (BM-MNC) consist of mesenchymal and hematopoietic progenitor cells. They possess the innate capacity to induce repair of traumatized tissue and to modulate immunological reactions. Methods: Human bone marrow was obtained from the patients that received treatment with biohybrid electrodes. Autologous mononuclear cells were isolated from bone marrow (BM-MNC) by centrifugation using the Regenlab™ THT-centrifugation tubes. Isolated BM-MNC were characterised using flow cytometry. In addition, the release of cytokines was analysed and their biological effect tested on spiral ganglion neurons isolated from neonatal rats. Fibrin adhesive (Tisseal™) was used for the coating of silicone-based cochlear implant electrode arrays for human use in order to generate biohybrid electrodes. Toxicity of the fibrin adhesive and influence on insertion, as well on the cell coating, was investigated. Furthermore, biohybrid electrodes were implanted in three patients. Results: Human BM-MNC release cytokines, chemokines, and growth factors that exert anti-inflammatory and neuroprotective effects. Using fibrin adhesive as a carrier for BM-MNC, a simple and effective cell coating procedure for cochlear implant electrodes was developed that can be utilised on-site in the operating room for the generation of biohybrid electrodes for intracochlear cell-based drug delivery. A safety study demonstrated the feasibility of autologous progenitor cell transplantation in humans as an adjuvant to cochlear implantation for neurosensory restoration. Conclusion: This is the first report of the use of autologous cell transplantation to the human inner ear. Due to the simplicity of this procedure, we hope to initiate its widespread utilization in various fields.

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.

Objective: Biomarkers reflecting the etiology and pathophysiology of inner ear diseases are limited. Evaluation of proteins in the perilymph may improve our understanding of inner ear disease. Heat shock proteins (HSP) belong to a superfamily of stress proteins and promote refolding of denatured proteins. The aim of the study was to analyze HSP in human perilymph and to identify possible correlation with audiological and etiologic data. Methods: Sampling of the perilymph was performed during cochlear implantation and vestibular schwannoma removal. Individual proteins were identified by a shot-gun proteomics approach by orbitrap mass spectrometry. Expression of HSP genes was determined in human cochlear tissue that was obtained during transcochlear surgeries. Results: Ten subgroups of HSP were identified in human perilymph samples. Increased levels of HSP were detected in a higher percentage in the perilymph of patients with residual hearing when compared with patients with no residual hearing in cochlear implantation. In patients with complete preservation of residual hearing, HSP 90 is identified in a lower percentage whereas HSP 70 1A/1B and 6 was identified in all the samples. Constitutive expression of HSP family members was verified in normal cochlear tissue. Conclusion: The 10 HSP variants are not identified in all the perilymph samples, but in a higher proportion in patients with residual hearing compared with patients with no residual hearing. In-depth proteome analysis of perilymph samples in correlation to patients’ audiogram data shows an increased concentration of HSP in patients with residual hearing. An increase in specific HSP in patients with loss of residual hearing after cochlear implantation was not observed.