Timo Stöver

Publications of Timo Stöver

• A device for patterned electrical stimulation of cultivated cells: preliminary tests with rat auditory neurons.

  Authors: Patrick Wefstaedt, Gerrit Paasche, John Parker, Thomas Lenarz, Timo Stöver

  European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 05/2012;

  The number of surviving spiral ganglion neurons (SGNs) is important for the function of cochlear implants. Electrical stimulation has been discussed controversially regarding its protective effectsThe number of surviving spiral ganglion neurons (SGNs) is important for the function of cochlear implants. Electrical stimulation has been discussed controversially regarding its protective effects on SGNs both in vivo and in vitro. The aim of this study was to develop a device for electrical stimulation of cultured SGNs. The developed device was first evaluated with cultivated fibroblasts at voltages from 10 to 60 V using biphasic rectangular pulses (pulse width: 10 ms, frequency: 50 Hz, stimulus burst: 1 s, interburst interval: 19 s). Possible toxic effects of 48 h patterned electrical stimulation were evaluated by propidium-iodide flow cytometry of the harvested fibroblasts. Second, the effects of 48-h electrical stimulation at voltages of 6 and 30 V on survival of cultivated SGNs were investigated as a single treatment and in the presence of brain-derived neurotrophic factor (BDNF, 100 ngml) in the culture medium. The results demonstrated constant pH and temperature behavior during electrical stimulation. Furthermore, no toxic effects on fibroblasts up to 40 V were found. The electrical stimulation of cultured neurons did not alter the survival rate compared to unstimulated control conditions. While BDNF application alone showed a significant effect on SGN survival, combination with electrical stimulation resulted in a not significantly increased cell survival. As a limitation of the study, the sensitivity of the described experimental setup appears to be low and only one stimulation pattern has been tested. Thus, experiments using different patterns of electrical stimulation and a more sensitive cultivation setup have to be carried out to fully investigate the effects of electrical stimulation on cultured SGNs. In this context, the developed device can be of help as it provides controlled and reproducible electrical stimulation conditions.

• Stable release of BDNF from the fibroblast cell line NIH3T3 grown on silicone elastomers enhances survival of spiral ganglion cells in vitro and in vivo.

  Authors: Athanasia Warnecke, Susanne Sasse, Gentiana I Wenzel, Andrea Hoffmann, Gerhard Gross, Gerrit Paasche, Verena Scheper, Uta Reich, Karl-Heinz Esser, Thomas Lenarz, Timo Stöver, Kirsten Wissel

  Hearing research. 04/2012;

  The treatment of choice for profound sensorineural hearing loss (SNHL) is direct electrical stimulation of spiral ganglion cells (SGC) via a cochlear implant (CI). The number and excitability of SGCThe treatment of choice for profound sensorineural hearing loss (SNHL) is direct electrical stimulation of spiral ganglion cells (SGC) via a cochlear implant (CI). The number and excitability of SGC seem to be critical for the success that can be achieved via CI treatment. However, SNHL is associated with degeneration of SGC. Long-term drug delivery to the inner ear for improving SGC survival may be achieved by functionalisation of CI electrodes with cells providing growth factors. Therefore, the capacity of brain-derived neurotrophic factor (BDNF)-secreting NIH3T3 cells grown on cylindrically shaped silicone elastomers (SE) to exert local and sustained neuroprotective effects was assessed in vitro and in vivo. An in vitro model to investigate adhesion and cell growth of lentivirally modified NIH3T3 cells synthesising BDNF on SE was established. The bioactivity of BDNF was characterised by co-cultivation of SGC with cell-coated SE. In addition, cell-coated SE were implanted into deafened guinea pigs. The recombinant NIH3T3 cells proliferated on silicone surfaces during 14 days of cultivation and expressed significantly increasing BDNF levels. Enhanced survival rates and neurite outgrowth of SGC demonstrated the bioactivity of BDNF in vitro. Implantation of SE with adhering BDNF-secreting NIH3T3 cells into the cochleae of systemically deafened guinea pigs induced a significant increase in SGC survival in comparison to SE without cell coating. Our data demonstrate a novel approach of cell-based long-term drug delivery to support SGC survival in vitro and in vivo. This therapeutic strategy - once transferred to cells suitable for clinical application - may improve CI performance.

• Directing neuronal cell growth on implant material surfaces by microstructuring.

  Authors: Uta Reich, Elena Fadeeva, Athanasia Warnecke, Gerrit Paasche, Peter Müller, Boris Chichkov, Timo Stöver, Thomas Lenarz, Günter Reuter

  Journal of biomedical materials research. Part B, Applied biomaterials. 01/2012;

  For best hearing sensation, electrodes of auditory prosthesis must have an optimal electrical contact to the respective neuronal cells. To improve the electrode-nerve interface, microstructuring ofFor best hearing sensation, electrodes of auditory prosthesis must have an optimal electrical contact to the respective neuronal cells. To improve the electrode-nerve interface, microstructuring of implant surfaces could guide neuronal cells toward the electrode contact. To this end, femtosecond laser ablation was used to generate linear microgrooves on the two currently relevant cochlear implant materials, silicone elastomer and platinum. Silicone surfaces were structured by two different methods, either directly, by laser ablation or indirectly, by imprinting using laser-microstructured molds. The influence of surface structuring on neurite outgrowth was investigated utilizing a neuronal-like cell line and primary auditory neurons. The pheochromocytoma cell line PC-12 and primary spiral ganglion cells were cultured on microstructured auditory implant materials. The orientation of neurite outgrowth relative to the microgrooves was determined. Both cell types showed a preferred orientation in parallel to the microstructures on both, platinum and on molded silicone elastomer. Interestingly, microstructures generated by direct laser ablation of silicone did not influence the orientation of either cell type. This shows that differences in the manufacturing procedures can affect the ability of microstructured implant surfaces to guide the growth of neurites. This is of particular importance for clinical applications, since the molding technique represents a reproducible, economic, and commercially feasible manufacturing procedure for the microstructured silicone surfaces of medical implants. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater , 2012.

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

  Authors: Robert J S Briggs, Michael Tykocinski, Roland Lazsig, Antje Aschendorff, Thomas Lenarz, Timo Stöver, Bernard Fraysse, Mathieu Marx, J Thomas Roland, Peter S Roland, Charles G Wright, Bruce J Gantz, James F Patrick, Frank Risi

  Cochlear implants international. 08/2011; 12(3):129-39.

  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. Multi-centreMulti-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. Multi-centre temporal bone insertion studies. 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. 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°. 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.

• The effect of different lubricants on cochlear implant electrode insertion forces.

  Authors: Georgios Kontorinis, Gerrit Paasche, Thomas Lenarz, Timo Stöver

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 04/2011; 32(7):1050-6.

  Application of different lubricants during the cochlear implant electrode insertion can affect the insertion forces. Parameters related to cochlear trauma, such as insertion forces, gained more andApplication of different lubricants during the cochlear implant electrode insertion can affect the insertion forces. Parameters related to cochlear trauma, such as insertion forces, gained more and more importance, especially in regard to preservation of residual hearing. The impact of lubricants on the insertion forces has not been systematically examined yet. Nucleus 24 Contour Advance electrodes were inserted into an artificial model of the human scala tympani filled with glycerin, sodium hyaluronate (Healon), and water or soap solution of 10% Bathox and 90% distilled water. A specially designed insertion protocol was applied so as any remains of the lubricants in the scala tympani model or on the electrodes' surface could be completely removed. Force measurements were performed by a force measurement system equipped with a 10 N load cell. Average (AF) and maximum (MF) insertion forces were recorded for every lubricant. The highest values were documented with water (AF = 0.139 N, MF = 0.367 N) and the lowest with the soap solution (AF = 0.065 N, MF = 0.148 N). Application of Healon and glycerin resulted in low, comparable values between each other. The application of lubricants affects significantly the electrode insertion forces. As soap solution is not usable, for the time being, in human cochlear implantation, low insertion forces combined with the antiadhesive features of Healon make it a proper lubricant for intracochlear application. Because of the low recorded forces, soap solution represents an ideal experimental model for in vitro electrode-mechanics studies.

• Impact of the insertion speed of cochlear implant electrodes on the insertion forces.

  Authors: Georgios Kontorinis, Thomas Lenarz, Timo Stöver, Gerrit Paasche

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 04/2011; 32(4):565-70.

  Objective of the present experimental research study was to examine the hypothesis that cochlear implant insertion speed can significantly affect the insertion forces. Cochlear implant electrodeObjective of the present experimental research study was to examine the hypothesis that cochlear implant insertion speed can significantly affect the insertion forces. Cochlear implant electrode insertion forces can influence the insertion trauma and the preservation of residual hearing. The effect of the electrode insertion speed on the insertion forces still remains unknown. Force measurements were performed while inserting human electrodes in an artificial scala tympani model at different speeds. For these measurements, an Instron 5542 Force Measurement System with a 10 N load cell and Nucleus 24 Contour Advance electrodes were used. Additionally, the insertion speed was measured through videos of 116 human implantations; these videos were recorded in our theaters and involved different surgeons and electrode types. Progressive increase in insertion speed from 10 to 200 mm/min resulted in significant, proportional increase in the average insertion forces from 0.09 to 0.185 N and in the maximum forces from 0.18 to 0.42 N, respectively. The average insertion speed used in the theaters during human cochlear implantations was 96.5 mm/min (range, 42-165.2 mm/min) and depended on the electrode type and the surgeon. High insertion speeds cause significant increase of the forces. Cochlear implant surgeons should use low and stable speeds during the insertion. Insertion speed close to the average value used in the theaters should be applied on experimental models, to approximate human implantation conditions.

• Evaluation of an electrode prototype for atraumatic cochlear implantation in hearing preservation candidates: preliminary results from a temporal bone study.

  Authors: Silke Helbig, Claudia Settevendemie, Martin Mack, Uwe Baumann, Matthias Helbig, Timo Stöver

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 02/2011; 32(3):419-23.

  This study aimed to evaluate an atraumatic prototype electrode carrier for cochlear implantation, the FLEX electrode. This electrode is designed to preserve hearing and to achieve a 360-degreeThis study aimed to evaluate an atraumatic prototype electrode carrier for cochlear implantation, the FLEX electrode. This electrode is designed to preserve hearing and to achieve a 360-degree insertion. A cross-sectional human temporal bone study was conducted. Preliminarily, the prototype electrode was inserted in a scala tympani model to measure the insertion force. Thirteen human temporal bones were acquired postmortem and implanted with the new device using the round window approach. Three of them were implanted under radiologic control to demonstrate the insertion path. After embedding, the remaining 10 temporal bones were sectioned undecalcified and examined macroscopically and histologically. The insertion force was measured to determine intracochlear resistance peaks. The insertion angle was measured, and the degree of intracochlear trauma was determined. The round window approach caused cochlear trauma in 1 of 10 specimens. An exact 360-degree insertion was achieved in 7 of 10 specimens (mean overall insertion angle, 360 degrees). Radiologic examination and insertion force measurements revealed the smooth and atraumatic insertion. The new prototype electrode carrier is suitable for clinical application. It can be handled easily and allows atraumatic 360-degree insertion of all electrode contacts. Therefore, this electrode concept allows good coverage of the cochlea for electrical and additional acoustic stimulation.

• Heterogeneity of primary site biopsies in head and neck squamous cell carcinoma.

  Authors: Susanne Moertel, Hanns Ackermann, Mehran Baghi, Anne Eckardt, Jens Wagenblast, Timo Stöver, Markus Hambek

  Anticancer research. 02/2011; 31(2):665-9.

  There is no common standard defining how biopsies for translational research purposes should be performed. In our study, the impact of two different biopsy methods on the results ofThere is no common standard defining how biopsies for translational research purposes should be performed. In our study, the impact of two different biopsy methods on the results of immunohistochemical staining of the samples for epidermal growth factor receptor (EGFR) and the proliferation antigen Ki-67 were evaluated. Twenty-four patients who underwent surgical treatment of their HNSCC tumour were included. From each surgically resected tumour, one superficial biopsy and one core-needle biopsy through the cross-section of the tumour were taken. As a positive control, a tissue slide through the primary tumour was made. The analysis showed that neither the superficial nor the core biopsy expression of EGFR correlated significantly with that of the tumour. The analysis showed that the superficial biopsy expression of Ki-67 correlated significantly with that of tumour. Translational research projects based on biopsy tissues should be using whole surgical resection specimens of a tumour.

• Molecular biology of hearing.

  Authors: Timo Stöver, Marc Diensthuber

  GMS current topics in otorhinolaryngology, head and neck surgery. 01/2011; 10:Doc06.

  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 ofTHE 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.

• Cochlear osteoneogenesis after meningitis in cochlear implant patients: a retrospective analysis.

  Authors: Martin Durisin, Soenke Bartling, Christoph Arnoldner, Melanie Ende, Jana Prokein, Anke Lesinski-Schiedat, Heinrich Lanfermann, Thomas Lenarz, Timo Stöver

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 09/2010; 31(7):1072-8.

  Retrospective clinical study. Academic tertiary referral center at the Medical University of Hannover. Computed tomographic findings of 126 patients (95 children and 31 adults) profoundly deafened byRetrospective clinical study. Academic tertiary referral center at the Medical University of Hannover. Computed tomographic findings of 126 patients (95 children and 31 adults) profoundly deafened by meningitis during a period of 20 years were evaluated. Children were defined as up to 12 years old at the onset of meningitis. No patients showed any relevant bilateral auditory brainstem response thresholds at the time of admission to our clinic. Patient histories, surgical findings, and imaging results were analyzed by experienced surgeons/neuroradiologists. Of 95 children, 30 (32%) displayed symptoms of labyrinthitis ossificans, whereas 11 (36%) of 31 adults showed changes of the bony structure of the cochlea. High-resolution computed tomography (HRCT) evaluation indicated that the ossification was detected more frequently if there was a larger time interval between onset of meningitis and high-resolution computed tomographic scan. Bilateral ossification at various stages was observed in 67% of children and 55% of adults with obliteration. In the comparison of cochlear ossification found in computed tomographic scans and intraoperative obliteration, HRCT showed a specificity of 73% and a sensitivity of 88%. The intraoperative evaluation revealed various stages of cochlear obliteration in 44% of children and 39% of adults. In our study, the earliest onset of labyrinthitis ossificans was found in high-resolution computed tomographic scans as early as 4 weeks after the onset of meningitis. In most cases, ossification occurred bilaterally with predominantly asymmetric involvement of both ears. The rate of osteoneogenesis increases significantly over time after meningitis. This leads to the conclusion that cochlear ossification can start very early and increase over time with unpredictable speed. Cochlear ossification typically develops bilaterally. From these results, we conclude that cochlear implantation should be performed bilaterally as soon as possible after meningitis and deafness have been diagnosed. HRCT offers good specificity but only limited sensitivity. Preoperative diagnostics should include magnetic resonance imaging to optimize preparation for cochlear implantation.

• Artemin improves survival of spiral ganglion neurons in vivo and in vitro.

  Authors: Athanasia Warnecke, Verena Scheper, Ines Buhr, Gentiana I Wenzel, Kirsten Wissel, Gerrit Paasche, Nurdanat Berkingali, Jesper Roland Jørgensen, Thomas Lenarz, Timo Stöver

  Neuroreport. 04/2010; 21(7):517-21.

  Artemin and its receptors are upregulated in the auditory nerve of deafened rats as a possible intrinsic protective mechanism against ototoxicity-related apoptosis. Consequently, we examined theArtemin and its receptors are upregulated in the auditory nerve of deafened rats as a possible intrinsic protective mechanism against ototoxicity-related apoptosis. Consequently, we examined the effect of artemin on spiral ganglion neurons in vitro and in vivo. Spiral ganglion neurons were isolated from neonatal rats and cultured in serum-free medium supplemented with artemin and/or brain-derived neurotrophic factor (BDNF). In vitro, the survival rate of spiral ganglion neurons cultivated with artemin or BDNF was significantly improved compared with negative controls. In addition, artemin was delivered to the inner ear of deafened guinea pigs for 28 days. In-vivo artemin was as effective as BDNF in spiral ganglion neuron protection. Therefore, artemin promotes the survival of spiral ganglion neurons in vitro and in vivo.

• Contact endoscopy for the evaluation of the pharyngeal and laryngeal mucosa.

  Authors: Athanasia Warnecke, Thomas Averbeck, Martin Leinung, Bisharah Soudah, Gentiana I Wenzel, Hans-Heinrich Kreipe, Thomas Lenarz, Timo Stöver

  The Laryngoscope. 12/2009;

  OBJECTIVES:: Contact endoscopy is a noninvasive tool that allows in vivo and in situ examination of superficial mucosa. Its use for early diagnosis of cancerous lesions of the oropharynx and larynxOBJECTIVES:: Contact endoscopy is a noninvasive tool that allows in vivo and in situ examination of superficial mucosa. Its use for early diagnosis of cancerous lesions of the oropharynx and larynx has not been evaluated. The aim of the study was to validate contact endoscopy for the examination of pharyngeal and laryngeal mucosa. STUDY DESIGN:: Prospective clinical study. METHODS:: Superficial cells of the mucosa were stained with methylene blue and examined with contact endoscopes. The documented images were assessed by a cytopathologist and by an otolaryngologist independently for each patient. Biopsies for histopathological examination of the area were performed and correlated with contact endoscopic findings of both examiners. RESULTS:: Of the 42 examined specimen, 32 (76.2%) showed benign changes in the histological analysis. Squamous cell carcinoma was revealed in 10 specimen (23.8%). Using contact endoscopy, the cytopathologist accurately identified 90.6% of the benign findings (29 of 32); however, only seven of 10 (70%) carcinomas were correctly categorized. In comparison, the otolaryngologist made a correct diagnosis in 93.75% (30 of 32) of the benign and in 90% (nine of 10) of the malignant cases. Thus, a sensitivity of 90% and a specificity of 93.75% can be achieved by contact endoscopy. CONCLUSIONS:: Contact endoscopy offers valuable support for the evaluation of oropharyngeal, hypopharyngeal, and laryngeal mucosa. Contact endoscopy can be a useful contribution to rapid intraoperative evaluation of mucosal alterations for early diagnosis of tumors and might reduce diagnostic biopsy sampling. Even so, it does not replace biopsy sampling. Laryngoscope, 2010.

• BDNF mRNA expression is significantly upregulated in vestibular schwannomas and correlates with proliferative activity.

  Authors: Frauke Kramer, Timo Stöver, Athanasia Warnecke, Marc Diensthuber, Thomas Lenarz, Kirsten Wissel

  Journal of neuro-oncology. 11/2009;

  The expression of neurotrophic factors, such as artemin, glial cell line-derived neurotrophic factor (GDNF), neurturin, transforming growth factors (TGF)-beta1/beta2 and brain-derived neurotrophicThe expression of neurotrophic factors, such as artemin, glial cell line-derived neurotrophic factor (GDNF), neurturin, transforming growth factors (TGF)-beta1/beta2 and brain-derived neurotrophic factor (BDNF), is enhanced in vestibular schwannomas compared to peripheral nerves. Furthermore, this upregulation may correlate with mitotic activity. Vestibular schwannoma arising from Schwann cells of the vestibular nerve are mostly benign and slow-growing. Most of the pathogenic mechanisms regulating the vestibular schwannoma growth process are unknown. An impaired growth regulation and imbalance between mitosis and apoptosis can be assumed. However, molecular mechanisms interfering with regulation of the vestibular schwannoma growth also modulated by mitogenic factors have to be identified. Neurotrophic factors are involved in regulation of developmental processes in neuronal tissues and regeneration after peripheral nerve trauma and also reveal mitogenic effects on glial cell populations. Gene expression profiles of artemin, BDNF, GDNF, TGF-beta1/beta2 and Ret were determined in the vestibular schwannoma in comparison to the peripheral nerve tissues by using semiquantitative RT-PCR. The expression data were correlated to the proliferation-associated Ki-67 labelling index. A significant higher BDNF expression was observed in the vestibular schwannoma, whereas gene expression of artemin and GDNF was upregulated in peripheral nerves. The correlation between LI and BDNF, TGF-beta1 and Ret was found to be significant in the vestibular schwannoma. Our results demonstrate a coherence between BDNF expression and proliferative activity in the vestibular schwannoma. Based on these results, we propose a pivotal role for BDNF in modulating the vestibular schwannoma growth.

• Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series.

  Authors: Gentiana Wenzel, Athanasia Warnecke, Timo Stöver, Thomas Lenarz

  European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 10/2009;

  Gacyclidine, a non-competitive NMDA receptor antagonist, is a phencyclidine derivative with neuroprotective properties. It has been previously safely administered intravenously to acute traumaticGacyclidine, a non-competitive NMDA receptor antagonist, is a phencyclidine derivative with neuroprotective properties. It has been previously safely administered intravenously to acute traumatic brain-injured patients. Experiments in guinea pigs have shown that local administration of gacyclidine to the cochlea can suppress salicylate-induced tinnitus. Thus, we thought that patients with therapy-resistant sensorineural tinnitus might benefit from a local therapy with gacyclidine. As a compassionate treatment, we administered aqueous gacyclidine solution via a Durect RWmuCath(TM) into the round window niche in six patients with unilateral deafness associated with tinnitus. The response of each patient to the drug treatment was given a numerical value by the use of a visual analogue scale (VAS) on a scale of 0-10 for tinnitus intensity, where 0 represented no tinnitus and 10 represented unbearable tinnitus-intensity or -annoyance (subjective). After constant perfusion of gacyclidine for 40-63 h, four out of six patients experienced a temporary relief from their tinnitus. No serious side effects were recorded in any of the cases. Gacyclidine might present a potent drug for the suppression of sensorineural tinnitus in humans and therefore should be considered for future double-blinded, placebo-controlled clinical trials. For lasting effective treatment, controlled intracochlear and long-term delivery of the drug seems to be necessary. Further studies investigating the toxicological effects of gacyclidine intracochlear perfusion as well as different dosages and therapy durations are under way to ensure the safety of the drug for long-term human use and warrant clinical trials.

• Potential novel drug carriers for inner ear treatment: hyperbranched polylysine and lipid nanocapsules.

  Authors: Verena Cheper, Melanie Wolf, Markus Scholl, Zuzana Kadlecova, Thomas Perrier, Harm-Anton Klok, Patrick Saulnier, Thomas Lenarz, Timo Stöver

  Nanomedicine (London, England). 09/2009; 4(6):623-35.

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

• The Long-Term Effects of Modified Electrode Surfaces and Intracochlear Corticosteroids on Postoperative Impedances in Cochlear Implant Patients.

  Authors: Gerrit Paasche, Claudia Tasche, Timo Stöver, Anke Lesinski-Schiedat, Thomas Lenarz

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 07/2009;

  OBJECTIVE:: The objective of this study was to investigate the long-term effect of intraoperative application of steroid suspension and coating of the electrode contacts with a thin film of iridiumOBJECTIVE:: The objective of this study was to investigate the long-term effect of intraoperative application of steroid suspension and coating of the electrode contacts with a thin film of iridium oxide on the intracochlear impedance development after cochlear implantation and on the impedance difference before and after stimulation. DESIGN:: Time-dependent development of intracochlear impedances was investigated in 4 different groups of adult patients up to 4 years after implantation. Additionally, during rehabilitation period just after first fitting, impedances before and after stimulation were measured as to investigate the influence of electrical stimulation on the impedances. Results from standard Nucleus 24 Contour (control), standard Nucleus 24 Contour with intraoperative application of steroids, iridium-coated Nucleus 24 Contour, and iridium-coated Nucleus 24 Contour with intraoperative application of steroids were compared. RESULTS:: Steroid application reduced impedances significantly throughout the observation period of up to 4 years after implantation. Iridium oxide coating had no effect. Differences between the groups were mainly found on the basal and middle parts of the cochlea, but not close to the tip of the array, also indicating that postoperative fibrous tissue growth is stronger in the basal region of the cochlea. Group mean values of the stimulation effect were not influenced by the different treatments. Nevertheless, only in both steroid-treated groups a correlation between the impedance before stimulation and the stimulation effect was found. CONCLUSION:: Although the differences between control and steroid-treated groups decrease with time, single intraoperative intracochlear steroid deposition was proven to lower postoperative impedances during first 3 to 4 years after implantation probably because of reduction of fibrous tissue growth.

• Hearing conservation surgery using the Hybrid-L electrode. Results from the first clinical trial at the Medical University of Hannover.

  Authors: Thomas Lenarz, Timo Stöver, Andreas Buechner, Anke Lesinski-Schiedat, Jim Patrick, Joerg Pesch

  Audiology & neuro-otology. 01/2009; 14 Suppl 1:22-31.

  Patients with high-frequency deafness and/or substantial residual hearing across frequencies might benefit from combined electro-acoustic stimulation. The Hybrid-L electrode was designed to addressPatients with high-frequency deafness and/or substantial residual hearing across frequencies might benefit from combined electro-acoustic stimulation. The Hybrid-L electrode was designed to address the issues of both hearing conservation and effective electrical stimulation in those recipients. The electrode with 22 contacts should be inserted through the round window membrane, and covers approximately 270 degrees of the basal turn of the cochlear. This insertion length is equivalent to the one seen in many patients using the former Nucleus straight electrode. Twenty-four patients with low-frequency thresholds of 60 dB or better, up to 500 Hz, were implanted with a Hybrid-L device in a clinical trial at the Medical University of Hannover. Another group of 8 recipients with less residual hearing was included under extended inclusion criteria. Residual hearing was conserved in the majority of cases. One patient had a loss of more than 30 dB, but hearing partially recovered after 9 months. The median loss in all patients was 10 dB in both the Hybrid group and the extended group. Patients were able to use the residual hearing postoperatively to the same extent as preoperatively. In the Hybrid mode (cochlear implant + ipsilateral hearing aid), patients showed a significant improvement of 21% (p = 0.002) in speech understanding in quiet using the Freiburger Monosyllabic Word Test compared to the preoperative scores under aided conditions with their hearing aid. The Oldenburg Sentence Test in noise showed a remarkable average improvement of 10.2 dB (p < 0.001) compared to the preoperative hearing aid only mode. An additional improvement could be seen in the combined mode using an additional contralateral hearing aid. Recipients with a shorter duration of high-frequency hearing loss showed a larger benefit than those with a longer duration of hearing loss. Hearing conservation using the Hybrid-L electrode and a given surgical technique is possible with high probability in patients with high-frequency deafness or pantonal hearing loss. The use of the residual acoustic hearing offers specific advantages, especially for understanding speech in noise and for spatial hearing.

• Biomaterials in cochlear implants.

  Authors: Timo Stöver, Thomas Lenarz

  GMS current topics in otorhinolaryngology, head and neck surgery. 01/2009; 8:Doc10.

  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 theThe 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.As these implants are in the immediate vicinity of the middle-ear mucosa and of the junction to the perilymph of the cochlea, the risk exists - at least in principle - that bacteria may spread along the electrode array into the cochlea. The wide-ranging requirements made of the CI in terms of biocompatibility and the electrode mechanism mean that there is still further scope - despite the fact that CIs are already technically highly sophisticated - for ongoing improvements to the properties of these implants and their constituent materials, thus enhancing the effectiveness of these devices.This paper will therefore discuss fundamental material aspects of CIs as well as the potential for their future development.

• Effects of delayed treatment with combined GDNF and continuous electrical stimulation on spiral ganglion cell survival in deafened guinea pigs.

  Authors: Verena Scheper, Gerrit Paasche, Josef M Miller, Athanasia Warnecke, Nurdanat Berkingali, Thomas Lenarz, Timo Stöver

  Journal of neuroscience research. 01/2009;

  Electrical stimulation (ES) of spiral ganglion cells (SGC) via a cochlear implant is the standard treatment for profound sensor neural hearing loss. However, loss of hair cells as the morphologicalElectrical stimulation (ES) of spiral ganglion cells (SGC) via a cochlear implant is the standard treatment for profound sensor neural hearing loss. However, loss of hair cells as the morphological correlate of sensor neural hearing loss leads to deafferentation and death of SGC. Although immediate treatment with ES or glial cell line-derived neurotrophic factor (GDNF) can prevent degeneration of SGC, only few studies address the effectiveness of delayed treatment. We hypothesize that both interventions have a synergistic effect and that even delayed treatment would protect SGC. Therefore, an electrode connected to a pump was implanted into the left cochlea of guinea pigs 3 weeks after deafening. The contralateral untreated cochleae served as deafened intraindividual controls. Four groups were set up. Control animals received intracochlear infusion of artificial perilymph (AP/-). The experimental groups consisted of animals treated with AP in addition to continuous ES (AP/ES) or treated with GDNF alone (GDNF/-) or GDNF combined with continuous ES (GDNF/ES). Acoustically and electrically evoked auditory brain stem responses were recorded. All animals were killed 48 days after deafening; their cochleae were histologically evaluated. Survival of SGC increased significantly in the GDNF/- and AP/ES group compared with the AP/- group. A highly significant increase in SGC density was observed in the GDNF/ES group compared with the control group. Additionally, animals in the GDNF/ES group showed reduced EABR thresholds. Thus, delayed treatment with GDNF and ES can protect SGC from degeneration and may improve the benefits of cochlear implants. (c) 2008 Wiley-Liss, Inc.

• Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin.

  Authors: Nurdanat Berkingali, Athanasia Warnecke, Priya Gomes, Gerrit Paasche, Jan Tack, Thomas Lenarz, Timo Stöver

  Hearing research. 10/2008; 243(1-2):121-6.

  The morphological correlate of deafness is the loss of hair cells with subsequent degeneration of spiral ganglion neurons (SGN). Neurotrophic factors have a neuroprotective effect, and especiallyThe morphological correlate of deafness is the loss of hair cells with subsequent degeneration of spiral ganglion neurons (SGN). Neurotrophic factors have a neuroprotective effect, and especially brain-derived neurotrophic factor (BDNF) has been demonstrated to protect SGN in vitro and after ototoxic trauma in vivo. Erythropoietin (EPO) attenuates hair cell loss in rat cochlea explants that were treated with gentamycin. Recently, it has also been shown that EPO reduces the apoptose rate in hippocampal neurons. Therefore, the aim of the study was to examine the effects of EPO on SGN in vitro. Spiral ganglion cells were isolated from neonatal rats and cultured for 48 h in serum-free medium supplemented with EPO and/or BDNF. Results showed that survival rates of SGN were not significantly improved when cultivated with EPO alone. Also, EPO did not further increase BDNF-induced survival of SGN. However, significant elongation of neurites was determined when SGN were cultivated with EPO alone. Even though a less than additive effect was observed, combined treatment with BDNF and EPO led to a significant elongation of neurites when compared to individual treatment with BDNF or EPO. It can be concluded that EPO induces neurite outgrowth rather than promoting survival. Thus, EPO presents as an interesting candidate to enhance and modulate the regenerative effect of BDNF on SGN.