Biomaterials in cochlear implants

The cochlear implant (CI) represents, for almost 25 years now, the gold standard in the treatment of children born deaf and for postlingually deafened adults. These devices thus constitute the greatest success story in the field of ‘neurobionic’ prostheses. Their (now routine) fitting in adults, and especially in young children and even babies, places exacting demands on these implants, particularly with regard to the biocompatibility of a CI’s surface components. Furthermore, certain parts of the implant face considerable mechanical challenges, such as the need for the electrode array to be flexible and resistant to breakage, and for the implant casing to be able to withstand external forces

Molecular biology of hearing

The inner ear is our most sensitive sensory organ and can be subdivided into three functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound, which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear houses the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In recent years there has been significant progress in research on the molecular basis of hearing. An increasing number of genes and proteins related to hearing are being identified and characterized. The growing knowledge of these genes contributes not only to greater appreciation of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss

The role of recombinant epidermal growth factor and serotonin in the stimulation of tumor growth in a SCCHN xenograft model

One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0 phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0-arresting cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit 562 cells were injected into NMRI-Foxn1nu mice. Treatment was performed with 15 µg murine or human EGF, or 200 µg serotonin. The control mice were treated with Lactated Ringer's solution (5 mice/group). Tumor size was measured on days 4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN tumors

Spiral Ganglion Stem Cells Can Be Propagated and Differentiated Into Neurons and Glia

Abstract The spiral ganglion is an essential functional component of the peripheral auditory system. Most types of hearing loss are associated with spiral ganglion cell degeneration which is irreversible due to the inner ear's lack of regenerative capacity. Recent studies revealed the existence of stem cells in the postnatal spiral ganglion, which gives rise to the hope that these cells might be useful for regenerative inner ear therapies. Here, we provide an in-depth analysis of sphere-forming stem cells isolated from the spiral ganglion of postnatal mice. We show that spiral ganglion spheres have characteristics similar to neurospheres isolated from the brain. Importantly, spiral ganglion sphere cells maintain their major stem cell characteristics after repeated propagation, which enables the culture of spheres for an extended period of time. In this work, we also demonstrate that differentiated sphere-derived cell populations not only adopt the immunophenotype of mature spiral ganglion cells but also develop distinct ultrastructural features of neurons and glial cells. Thus, our work provides further evidence that self-renewing spiral ganglion stem cells might serve as a promising source for the regeneration of lost auditory neurons

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Objective: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve–electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active. Methods: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo. Results: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results. Conclusion: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects

Erste Erfahrungen mit TINNELEC, ein Implantat für die Therapie von chronischem Tinnitus [meeting abstract]

Meeting Abstract : 82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. Freiburg i. Br., 01.-05.06.2011. Ca. 3 Millionen Erwachsene in der Bundesrepublik Deutschland leiden unter Tinnitus, wobei eine bei jedem dieser Patienten zur Heilung führende Therapie bisher noch nicht existiert. Ansatzpunkt einer neuartigen Therapie ist die Wiederherstellung des normalen elektrischen Entladungsmusters im Hörnerv mittels elektrischer Stimulation. Hiermit berichten wir über unsere ersten Erfahrungen mit dem Tinnelec, einem Implantat mit einer einzelnen Stimulations-Elektrode die in der Rundfensternische platziert wird. Zurzeit haben wir 4 einseitig ertaubten Patienten mit Tinnitus auf dem betroffenen Ohr jeweils ein Tinnelec-System implantiert. Die Dauer des Tinnitus betrug mindestens ein Jahr und gängige Tinnitus-Therapien wie z.B. Infusionstherapie waren erfolglos geblieben. Ein psychogener Tinnitus wurde ausgeschlossen. Der durch den Tinnitus verursachte Leidensdruck wurde anhand einer VAS Scala (Visuelle Analog Scala) und eines Tinnitus-Handicap-Inventory (THI) Fragebogens beurteilt. Die Reizapplikation betrug mind. 4 Stunden täglich. Als Stimulationsparameter wurde eine Reizmusterannäherung an den Tinnitus angestrebt. Bei drei Patienten wurde unter der Stimulation der Tinnitus erträglicher, eine zeitweise komplette Unterdrückung des Tinnitus schon innerhalb der ersten Therapie-Wochen wurde jedoch nur in einem der Fälle berichtet. Diese Ergebnisse wurden auch durch das THI und VAS unterstützt. Die Tinnelec-Implantation erscheint für Tinnitus Erfolg versprechend zu sein. Weitere Studien bei Tinnitus-Patienten ohne zusätzliche Hörbeeinträchtigung sind jedoch notwendig bis endgültige Schlussfolgerungen betreffend dieses Implantats gezogen werden können. In jedem Fall bleibt die Option einer Cochlea-Implantation im selben Ohr, nach Explantation des Tinnelec, bestehen

Gene Expression Profiles of the Rat Cochlea, Cochlear Nucleus, and Inferior Colliculus

High-throughput DNA microarray technology allows for the assessment of large numbers of genes and can reveal gene expression in a specific region, differential gene expression between regions, as well as changes in gene expression under changing experimental conditions or with a particular disease. The present study used a gene array to profile normal gene expression in the rat whole cochlea, two subregions of the cochlea (modiolar and sensorineural epithelium), and the cochlear nucleus and inferior colliculus of the auditory brainstem. The hippocampus was also assessed as a well-characterized reference tissue. Approximately 40% of the 588 genes on the array showed expression over background. When the criterion for a signal threshold was set conservatively at twice background, the number of genes above the signal threshold ranged from approximately 20% in the cochlea to 30% in the inferior colliculus. While much of the gene expression pattern was expected based on the literature, gene profiles also revealed expression of genes that had not been reported previously. Many genes were expressed in all regions while others were differentially expressed (defined as greater than a twofold difference in expression between regions). A greater number of differentially expressed genes were found when comparing peripheral (cochlear) and central nervous system regions than when comparing the central auditory regions and the hippocampus. Several families of insulin-like growth factor binding proteins, matrix metalloproteinases, and tissue inhibitor of metalloproteinases were among the genes expressed at much higher levels in the cochlea compared with the central nervous system regions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41378/1/10162_2000_Article_42.pd

Glial cell line-derived neurotrophic factor and chronic electrical stimulation prevent VIII cranial nerve degeneration following denervation

As with other cranial nerves and many CNS neurons, primary auditory neurons degenerate as a consequence of loss of input from their target cells, the inner hair cells (IHCs). Electrical stimulation (ES) of spiral ganglion cells (SGCs) has been shown to enhance their survival. Glial cell line-derived neurotrophic factor (GDNF) has also been shown to increase survival of SGCs following IHC loss. In this study, the combined effects of the GDNF transgene delivered by adenoviral vectors (Ad- GDNF ) and ES were tested on SGCs after first eliminating the IHCs. Animal groups received Ad- GDNF or ES or both. Ad- GDNF was inoculated into the cochlea of guinea pigs after deafening, to overexpress human GDNF . ES-treated animals were implanted with a cochlear implant electrode and chronically stimulated. A third group of animals received both Ad- GDNF and ES (GDNF/ES). Electrically evoked auditory brainstem responses were recorded from ES-treated animals at the start and end of the stimulation period. Animals were sacrificed 43 days after deafening and their ears prepared for evaluation of IHC survival and SGC counts. Treated ears exhibited significantly greater SGC survival than nontreated ears. The GDNF/ES combination provided significantly better preservation of SGC density than either treatment alone. Insofar as ES parameters were optimized for maximal protection (saturated effect), the further augmentation of the protection by GDNF suggests that the mechanisms of GDNF- and ES-mediated SGC protection are, at least in part, independent. We suggest that GDNF/ES combined treatment in cochlear implant recipients will improve auditory perception. These findings may have implications for the prevention and treatment of other neurodegenerative processes. J. Comp. Neurol. 454:350–360, 2002. © 2002 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34465/1/10480_ftp.pd

Development and evaluation of the modiolar research array – multi-centre collaborative study in human temporal bones

OBJECTIVE: Multi-centre collaborative study to develop and refine the design of a prototype thin perimodiolar cochlear implant electrode array and to assess feasibility for use in human subjects. STUDY DESIGN: Multi-centre temporal bone insertion studies. MATERIALS AND METHODS: The modiolar research array (MRA) is a thin pre-curved electrode that is held straight for initial insertion with an external sheath rather than an internal stylet. Between November 2006 and February 2009, six iterations of electrode design were studied in 21 separate insertion studies in which 140 electrode insertions were performed in 85 human temporal bones by 12 surgeons. These studies aimed at addressing four fundamental questions related to the electrode concept, being: (1) Could a sheath result in additional intra-cochlear trauma? (2) Could a sheath accommodate variations in cochlea size and anatomies? (3) Could a sheath be inserted via the round window? and (4) Could a sheath be safely removed once the electrode had been inserted? These questions were investigated within these studies using a number of evaluation techniques, including X-ray and microfluoroscopy, acrylic fixation and temporal bone histologic sectioning, temporal bone microdissection of cochlear structures with electrode visualization, rotational tomography, and insertion force analysis. RESULTS: Frequent examples of electrode rotation and tip fold-over were demonstrated with the initial designs. This was typically caused by excessive curvature of the electrode tip, and also difficulty in handling of the electrode and sheath. The degree of tip curvature was progressively relaxed in subsequent versions with a corresponding reduction in the frequency of tip fold-over. Modifications to the sheath facilitated electrode insertion and sheath removal. Insertion studies with the final MRA design demonstrated minimal trauma, excellent perimodiolar placement, and very small electrode dimensions within scala tympani. Force measurements in temporal bones demonstrated negligible force on cochlear structures with angular insertion depths of between 390 and 450°. CONCLUSION: The MRA is a novel, very thin perimodiolar prototype electrode array that has been developed using a systematic collaborative approach. The different evaluation techniques employed by the investigators contributed to the early identification of issues and generation of solutions. Regarding the four fundamental questions related to the electrode concept, the studies demonstrated that (1) the sheath did not result in additional intra-cochlear trauma; (2) the sheath could accommodate variations in cochlea size and anatomies; (3) the sheath was more successfully inserted via a cochleostomy than via the round window; and (4) the sheath could be safely removed once the electrode had been inserted

Suitable Electrode Choice for Robotic-Assisted Cochlear Implant Surgery: A Systematic Literature Review of Manual Electrode Insertion Adverse Events

BACKGROUND AND OBJECTIVE: The cochlear implant (CI) electrode insertion process is a key step in CI surgery. One of the aims of advances in robotic-assisted CI surgery (RACIS) is to realize better cochlear structure preservation and to precisely control insertion. The aim of this literature review is to gain insight into electrode selection for RACIS by acquiring a thorough knowledge of electrode insertion and related complications from classic CI surgery involving a manual electrode insertion process. METHODS: A systematic electronic search of the literature was carried out using PubMed, Scopus, Cochrane, and Web of Science to find relevant literature on electrode tip fold over (ETFO), electrode scalar deviation (ESD), and electrode migration (EM) from both pre-shaped and straight electrode types. RESULTS: A total of 82 studies that include 8,603 ears implanted with a CI, i.e., pre-shaped (4,869) and straight electrodes (3,734), were evaluated. The rate of ETFO (25 studies, 2,335 ears), ESD (39 studies, 3,073 ears), and EM (18 studies, 3,195 ears) was determined. An incidence rate (±95% CI) of 5.38% (4.4–6.6%) of ETFO, 28.6% (26.6–30.6%) of ESD, and 0.53% (0.2–1.1%) of EM is associated with pre-shaped electrodes, whereas with straight electrodes it was 0.51% (0.1–1.3%), 11% (9.2–13.0%), and 3.2% (2.5–3.95%), respectively. The differences between the pre-shaped and straight electrode types are highly significant (p < 0.001). Laboratory experiments show evidence that robotic insertions of electrodes are less traumatic than manual insertions. The influence of round window (RW) vs. cochleostomy (Coch) was not assessed. CONCLUSION: Considering the current electrode designs available and the reported incidence of insertion complications, the use of straight electrodes in RACIS and conventional CI surgery (and manual insertion) appears to be less traumatic to intracochlear structures compared with pre-shaped electrodes. However, EM of straight electrodes should be anticipated. RACIS has the potential to reduce these complications