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  • 1. Brown, Toby D
    et al.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Detta, Nicola
    Skelton, Anthony D
    Hutmacher, Dietmar W
    Dalton, Paul D
    Melt electrospinning of poly(ε-caprolactone) scaffolds: phenomenological observations associated with collection and direct writing.2014In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 45Article in journal (Refereed)
    Abstract [en]

    Melt electrospinning and its additive manufacturing analogue, melt electrospinning writing (MEW), are two processes which can produce porous materials for applications where solvent toxicity and accumulation in solution electrospinning are problematic. This study explores the melt electrospinning of poly(ε-caprolactone) (PCL) scaffolds, specifically for applications in tissue engineering. The research described here aims to inform researchers interested in melt electrospinning about technical aspects of the process. This includes rapid fiber characterization using glass microscope slides, allowing influential processing parameters on fiber morphology to be assessed, as well as observed fiber collection phenomena on different collector substrates. The distribution and alignment of melt electrospun PCL fibers can be controlled to a certain degree using patterned collectors to create large numbers of scaffolds with shaped macroporous architectures. However, the buildup of residual charge in the collected fibers limits the achievable thickness of the porous template through such scaffolds. One challenge identified for MEW is the ability to control charge buildup so that fibers can be placed accurately in close proximity, and in many centimeter heights. The scale and size of scaffolds produced using MEW, however, indicate that this emerging process will fill a technological niche in biofabrication.

  • 2.
    Cai, Yixiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 31, 211-220 p.Article in journal (Refereed)
    Abstract [en]

    Cochlear implants (CI) have been used for several decades to treat patients with profound hearing loss. Nevertheless, results vary between individuals, and fine hearing is generally poor due to the lack of discrete neural stimulation from the individual receptor hair cells. A major problem is the deliverance of independent stimulation signals to individual auditory neurons. Fine hearing requires significantly more stimulation contacts with intimate neuron/electrode interphases from ordered axonal re-growth, something current CI technology cannot provide.

    Here, we demonstrate the potential application of micro-textured nanocrystalline diamond (NCD) surfaces on CI electrode arrays. Such textured NCD surfaces consist of micrometer-sized nail-head-shaped pillars (size 5 5 lm2) made with sequences of micro/nano-fabrication processes, including sputtering, photolithography and plasma etching.

    The results show that human and murine inner-ear ganglion neurites and, potentially, neural progenitor cells can attach to patterned NCD surfaces without an extracellular matrix coating. Microscopic methods revealed adhesion and neural growth, specifically along the nail-head-shaped NCD pillars in an ordered manner, rather than in non-textured areas. This pattern was established when the inter-NCD pillar distance varied between 4 and 9 lm.

    The findings demonstrate that regenerating auditory neurons show a strong affinity to the NCD pillars, and the technique could be used for neural guidance and the creation of new neural networks. Together with the NCD’s unique anti-bacterial and electrical properties, patterned NCD surfaces could provide designed neural/electrode interfaces to create independent electrical stimulation signals in CI electrode arrays for the neural population.

  • 3.
    Cai, Yixiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Ordered auditory neuron growth on micro-structured nanocrystalline diamond surface2015Conference paper (Refereed)
  • 4.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Strategies in Cochlear Nerve Regeneration, Guidance and Protection: Prospects for Future Cochlear Implants2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, it is possible to restore hearing in congenitally deaf children and severely hearing-impaired adults through cochlear implants (CIs). A CI consists of an external sound processor that provides acoustically induced signals to an internal receiver. The receiver feeds information to an electrode array inserted into the fluid-filled cochlea, where it provides direct electrical stimulation to the auditory nerve. Despite its great success, there is still room for improvement, so as to provide the patient with better frequency resolution, pitch information for music and speech perception and overall improved quality of sound.

     A better stimulation mode for the auditory nerves by increasing the number of stimulation points is believed to be a part of the solution. Current technology depends on strong electrical pulses to overcome the anatomical gap between neurons and the CI. The spreading of currents limits the number of stimulation points due to signal overlap and crosstalk.

    Closing the anatomical gap between spiral ganglion neurons and the CI could lower the stimulation thresholds, reduce current spread, and generate a more discrete stimulation of individual neurons. This strategy may depend on the regenerative capacity of auditory neurons, and the ability to attract and guide them to the electrode and bridge the gap.

    Here, we investigated the potential of cultured human and murine neurons from primary inner ear tissue and human neural progenitor cells to traverse this gap through an extracellular matrix gel.

    Furthermore, nanoparticles were used as reservoirs for neural attractants and applied to CI electrode surfaces. The nanoparticles retained growth factors, and inner ear neurons showed affinity for the reservoirs in vitro.

    The potential to obtain a more ordered neural growth on a patterned, electrically conducting nanocrystalline diamond surface was also examined. Successful growth of auditory neurons that attached and grew on the patterned substrate was observed.

    By combining the patterned diamond surfaces with nanoparticle-based reservoirs and nerve-stimulating gels, a novel, high resolution CI may be created. This strategy could potentially enable the use of hundreds of stimulation points compared to the 12 – 22 used today. This could greatly improve the hearing sensation for many CI recipients. 

    List of papers
    1. Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study
    Open this publication in new window or tab >>Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study
    Show others...
    2014 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 5, 441-447 p.Article in journal (Refereed) Published
    Abstract [en]

    Conclusions: Human neural progenitor cells can differentiate into spiral ganglion-like cells when exposed to inner ear-associated growth factors. The phenotype bears resemblance to human sphere-derived neurons. Objective: To establish an in vitro model for the human auditory nerve to replace and complement in vivo animal experiments and ultimately human in vivo transplantation. Methods: Human neural progenitors were differentiated under conditions developed for in vitro survival of human primary spiral ganglion culture with media containing growth factors associated with inner ear development. Differentiation was documented using time-lapse video microscopy. Time-dependent marker expression was evaluated using immunocytochemistry with fluorescence and laser confocal microscopy. Results: Within 14 days of differentiation, neural progenitors adopted neural phenotype and expressed spiral ganglion-associated markers.

    Keyword
    Stem cells, spiral ganglion, inner ear development
    National Category
    Otorhinolaryngology Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-224707 (URN)10.3109/00016489.2013.875220 (DOI)000334403800001 ()
    Available from: 2014-05-23 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
    2. 3-D gel culture and time-lapse video microscopy of the human vestibular nerve
    Open this publication in new window or tab >>3-D gel culture and time-lapse video microscopy of the human vestibular nerve
    Show others...
    2014 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 12, 1211-1218 p.Article in journal (Refereed) Published
    Abstract [en]

    UNLABELLED: Abstract Conclusions: Human inner ear neurons have an innate regenerative capacity and can be cultured in vitro in a 3-D gel. The culture technique is valuable for experimental investigations of human inner ear neuron signaling and regeneration.

    OBJECTIVES: To establish a new in vitro model to study human inner ear nerve signaling and regeneration.

    METHODS: Human superior vestibular ganglion (SVG) was harvested during translabyrinthine surgery for removal of vestibular schwannoma. After dissection tissue explants were embedded and cultured in a laminin-based 3-D matrix (Matrigel™). 3-D growth cone (GC) expansion was analyzed using time-lapse video microscopy (TLVM). Neural marker expression was appraised using immunocytochemistry with fluorescence and laser confocal microscopy.

    RESULTS: Tissue explants from adult human SVG could be cultured in 3-D in a gel, indicating an innate potential for regeneration. Cultured GCs were found to expand dynamically in the gel. Growth cone expansion and axonal Schwann cell alignment were documented using TLVM. Neurons were identified morphologically and through immunohistochemical staining.

    National Category
    Otorhinolaryngology Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-239518 (URN)10.3109/00016489.2014.946536 (DOI)000345214100001 ()25399879 (PubMedID)
    Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
    3. Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface
    Open this publication in new window or tab >>Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface
    Show others...
    2017 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 122, 1-9 p.Article in journal (Refereed) Published
    Abstract [en]

    Cochlear implant (CI) is a successful device to restore hearing. Despite continuous development, frequency discrimination is poor in CI users due to an anatomical gap between the auditory neurons and CI electrode causing current spread and unspecific neural stimulation. One strategy to close this anatomical gap is guiding the growth of neuron dendrites closer to CI electrodes through targeted slow release of neurotrophins. Biodegradable calcium phosphate hollow nanospheres (CPHSs) were produced and their capacity for uptake and release of neurotrophins investigated using I-125-conjugated glia cell line-derived neurotrophic factor (GDNF). The CPHSs were coated onto CI electrodes and loaded with neurotrophins. Axon guidance effect of slow-released neurotrophins from the CPHSs was studied in an in vitro 3D culture model. CPHS coating bound and released GDNF with an association rate constant 6.3 x 10(3) M(-1)s(-1) and dissociation rate 2.6 x 10(-5) s(-1), respectively. Neurites from human vestibulocochlear ganglion explants found and established physical contact with the GDNF-loaded CPHS coating on the CI electrodes placed 0.7 mm away. Our results suggest that neurotrophin delivery through CPHS coating is a plausible way to close the anatomical gap between auditory neurons and electrodes. By overcoming this gap, selective neural activation and the fine hearing for CI users become possible.

    National Category
    Medical and Health Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-276334 (URN)10.1016/j.biomaterials.2016.12.020 (DOI)000394472500001 ()28107660 (PubMedID)
    Funder
    Swedish Research Council, 2013-5419
    Available from: 2016-03-07 Created: 2016-02-11 Last updated: 2017-04-28Bibliographically approved
    4. Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond
    Open this publication in new window or tab >>Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond
    Show others...
    2016 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 31, 211-220 p.Article in journal (Refereed) Published
    Abstract [en]

    Cochlear implants (CI) have been used for several decades to treat patients with profound hearing loss. Nevertheless, results vary between individuals, and fine hearing is generally poor due to the lack of discrete neural stimulation from the individual receptor hair cells. A major problem is the deliverance of independent stimulation signals to individual auditory neurons. Fine hearing requires significantly more stimulation contacts with intimate neuron/electrode interphases from ordered axonal re-growth, something current CI technology cannot provide.

    Here, we demonstrate the potential application of micro-textured nanocrystalline diamond (NCD) surfaces on CI electrode arrays. Such textured NCD surfaces consist of micrometer-sized nail-head-shaped pillars (size 5 5 lm2) made with sequences of micro/nano-fabrication processes, including sputtering, photolithography and plasma etching.

    The results show that human and murine inner-ear ganglion neurites and, potentially, neural progenitor cells can attach to patterned NCD surfaces without an extracellular matrix coating. Microscopic methods revealed adhesion and neural growth, specifically along the nail-head-shaped NCD pillars in an ordered manner, rather than in non-textured areas. This pattern was established when the inter-NCD pillar distance varied between 4 and 9 lm.

    The findings demonstrate that regenerating auditory neurons show a strong affinity to the NCD pillars, and the technique could be used for neural guidance and the creation of new neural networks. Together with the NCD’s unique anti-bacterial and electrical properties, patterned NCD surfaces could provide designed neural/electrode interfaces to create independent electrical stimulation signals in CI electrode arrays for the neural population.

    National Category
    Medical Materials Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-266956 (URN)10.1016/j.actbio.2015.11.021 (DOI)000370086100019 ()26593784 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 603029
    Available from: 2015-11-14 Created: 2015-11-14 Last updated: 2017-12-01Bibliographically approved
  • 5.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 5, 441-447 p.Article in journal (Refereed)
    Abstract [en]

    Conclusions: Human neural progenitor cells can differentiate into spiral ganglion-like cells when exposed to inner ear-associated growth factors. The phenotype bears resemblance to human sphere-derived neurons. Objective: To establish an in vitro model for the human auditory nerve to replace and complement in vivo animal experiments and ultimately human in vivo transplantation. Methods: Human neural progenitors were differentiated under conditions developed for in vitro survival of human primary spiral ganglion culture with media containing growth factors associated with inner ear development. Differentiation was documented using time-lapse video microscopy. Time-dependent marker expression was evaluated using immunocytochemistry with fluorescence and laser confocal microscopy. Results: Within 14 days of differentiation, neural progenitors adopted neural phenotype and expressed spiral ganglion-associated markers.

  • 6.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    3-D gel culture and time-lapse video microscopy of the human vestibular nerve2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 12, 1211-1218 p.Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Abstract Conclusions: Human inner ear neurons have an innate regenerative capacity and can be cultured in vitro in a 3-D gel. The culture technique is valuable for experimental investigations of human inner ear neuron signaling and regeneration.

    OBJECTIVES: To establish a new in vitro model to study human inner ear nerve signaling and regeneration.

    METHODS: Human superior vestibular ganglion (SVG) was harvested during translabyrinthine surgery for removal of vestibular schwannoma. After dissection tissue explants were embedded and cultured in a laminin-based 3-D matrix (Matrigel™). 3-D growth cone (GC) expansion was analyzed using time-lapse video microscopy (TLVM). Neural marker expression was appraised using immunocytochemistry with fluorescence and laser confocal microscopy.

    RESULTS: Tissue explants from adult human SVG could be cultured in 3-D in a gel, indicating an innate potential for regeneration. Cultured GCs were found to expand dynamically in the gel. Growth cone expansion and axonal Schwann cell alignment were documented using TLVM. Neurons were identified morphologically and through immunohistochemical staining.

  • 7.
    Hayashi, Hisamitsu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Gifu Univ, Grad Sch Med, Dept Otolaryngol, 1-1 Yanagido, Gifu 5011194, Japan.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, 195-203 p.Article in journal (Refereed)
    Abstract [en]

    Endogenous electric fields (EFs) are required for the physiological control of the central nervous system development. Application of the direct current EFs to neural stem cells has been studied for the possibility of stem cell transplantation as one of the therapies for brain injury. EFs generated within the nervous system are often associated with action potentials and synaptic activity, apparently resulting in a pulsed current in nature. The aim of this study is to investigate the effect of pulsed EF, which can reduce the cytotoxicity, on the migration of human neural progenitor cells (hNPCs). We applied the mono-directional pulsed EF with a strength of 250mV/mm to hNPCs for 6h. The migration distance of the hNPCs exposed to pulsed EF was significantly greater compared with the control not exposed to the EF. Pulsed EFs, however, had less of an effect on the migration of the differentiated hNPCs. There was no significant change in the survival of hNPCs after exposure to the pulsed EF. To investigate the role of Ca(2+) signaling in electrotactic migration of hNPCs, pharmacological inhibition of Ca(2+) channels in the EF-exposed cells revealed that the electrotactic migration of hNPCs exposed to Ca(2+) channel blockers was significantly lower compared to the control group. The findings suggest that the pulsed EF induced migration of hNPCs is partly influenced by intracellular Ca(2+) signaling.

  • 8.
    Li, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hayashi, Hisamitsu
    Gifu Univ, Dept Otolaryngol, Gifu, Japan.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Danckwardt-Lillieström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface2017In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 122, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    Cochlear implant (CI) is a successful device to restore hearing. Despite continuous development, frequency discrimination is poor in CI users due to an anatomical gap between the auditory neurons and CI electrode causing current spread and unspecific neural stimulation. One strategy to close this anatomical gap is guiding the growth of neuron dendrites closer to CI electrodes through targeted slow release of neurotrophins. Biodegradable calcium phosphate hollow nanospheres (CPHSs) were produced and their capacity for uptake and release of neurotrophins investigated using I-125-conjugated glia cell line-derived neurotrophic factor (GDNF). The CPHSs were coated onto CI electrodes and loaded with neurotrophins. Axon guidance effect of slow-released neurotrophins from the CPHSs was studied in an in vitro 3D culture model. CPHS coating bound and released GDNF with an association rate constant 6.3 x 10(3) M(-1)s(-1) and dissociation rate 2.6 x 10(-5) s(-1), respectively. Neurites from human vestibulocochlear ganglion explants found and established physical contact with the GDNF-loaded CPHS coating on the CI electrodes placed 0.7 mm away. Our results suggest that neurotrophin delivery through CPHS coating is a plausible way to close the anatomical gap between auditory neurons and electrodes. By overcoming this gap, selective neural activation and the fine hearing for CI users become possible.

  • 9.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rieger, G.
    Lowenheim, H.
    Senn, P.
    Blumer, M.
    Schrott-Fischer, A.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glueckert, R.
    The Pre- and Post-Somatic Segments of the Human Type I Spiral Ganglion Neurons - Structural and Functional Considerations Related to Cochlear Implantation2015In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 284, 470-482 p.Article in journal (Refereed)
    Abstract [en]

    Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated. Histopathology and clinical experience imply that human SGNs can persist electrically excitable without dendrites, thus lacking connection to the organ of Corti. The biological background to this phenomenon remains elusive. We analyzed the pre- and post-somatic segments of the type I human SGNs using immunohistochemistry and transmission electron microscopy (TEM) in normal and pathological conditions. These segments were found surrounded by non-myelinated Schwann cells (NMSCs) showing strong intracellular expression of laminin-beta 2/collagen IV. These cells also bordered the perikaryal entry zone and disclosed surface rugosities outlined by a folded basement membrane (BM) expressing laminin-beta 2 and collagen IV. It is presumed that human large SGNs are demarcated by three cell categories: (a) myelinated Schwann cells, (b) NMSCs and (c) satellite glial cells (SGCs). Their BMs express laminin-beta 2/collagen IV and reaches the BM of the sensory epithelium at the habenula perforata. We speculate that the NMSCs protect SGNs from further degeneration following dendrite loss. It may give further explanation why SGNs can persist as electrically excitable monopolar cells even after long-time deafness, a blessing for the deaf treated with cochlear implantation. (C) 2014 The Authors. Published by Elsevier Ltd. on behalf of IBRO. This is an open access article under the CC BY-NC-ND license.

  • 10.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Blom, Hans
    Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Tomtebodavagen 23A, S-17121 Solna, Sweden..
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Santi, Peter A.
    Univ Minnesota, Dept Otolaryngol, 121 Lions Res Bldg,2001 Sixth St SE, Minneapolis, MN 55455 USA..
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man2016In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 365, no 1, 13-27 p.Article in journal (Refereed)
    Abstract [en]

    Globally 360 million people have disabling hearing loss and, of these, 32 million are children. Human hearing relies on 15,000 hair cells that transduce mechanical vibrations to electrical signals in the auditory nerve. The process is powered by the endo-cochlear potential, which is produced by a vascularized epithelium that actively transports ions in conjunction with a gap junction (GJ) system. This "battery" is located "off-site" in the lateral wall of the cochlea. The GJ syncytium contains the GJ protein genes beta 2 (GJB2/connexin26 (Cx26)) and 6 (GJB6/connexin30 (Cx30)), which are commonly involved in hereditary deafness. Because the molecular arrangement of these proteins is obscure, we analyze GJ protein expression (Cx26/30) in human cochleae by using super-resolution structured illumination microscopy. At this resolution, the Cx26 and Cx30 proteins were visible as separate plaques, rather than being co-localized in heterotypic channels, as previously suggested. The Cx26 and Cx30 proteins thus seem not to be co-expressed but to form closely associated assemblies of GJ plaques. These results could assist in the development of strategies to treat genetic hearing loss in the future.

  • 11.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Distribution of pejvakin in human spiral ganglion: an immunohistochemical study2013In: Cochlear Implants International, ISSN 1467-0100, E-ISSN 1754-7628, Vol. 14, no 4, 225-231 p.Article in journal (Refereed)
    Abstract [en]

    Up to 10% of permanent hearing impairments in children originate from lesions in the neuronal auditory pathway. This form of auditory neuron injury called auditory neuropathy features a preservation of outer hair cell integrity but an impaired inner hair cell function and/or neuronal transmission. DFNB59 gene encodes the protein pejvakin (PJVK) and its mutations cause autosomal recessive auditory neuropathy as well as other forms of sensorineural hearing loss. The finding of distinct forms of hearing anomalies was based on studies of consanguineous families from different ethnic groups as well as studies in mice with PJVK gene mutations. In the present immunohistochemical study, the distribution of pejvakin protein in surgically obtained human cochleae was for the first time investigated. The human cochleae had normal hearing thresholds before the operation. The expression of pejvakin was located in the cell bodies of all spiral ganglion neurons rather than the nerve fibers that were labeled with Tuj 1 antibody. As Tuj 1 antibody stained the cytoplasm of Type 1 cells, pejvakin antibody labeled both type 1 and type 2 cells. The nuclei of the neurons were also PJVK-positive. No labeling was seen in the structures within the organ of Corti and the stria vascularis. In the previous study, PJVK had been detected in the hair cells, the spiral ganglion, the cochlear nuclei, the superior olivary nucleus, and the inferior colliculus in mouse. Our study demonstrated for the first time the expression of PJVK in human spiral ganglion neurons. Its functional role in neural signal propagation and synchrony needs further elucidation.

  • 12.
    Natan, Michal
    et al.
    Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel..
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Perkas, Nina
    Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel..
    Yacobi, Gila
    Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel..
    Perelshtein, Ilana
    Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel..
    Segal, Elad
    Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel..
    Homsy, Alexandra
    Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, HES SO, Eplatures Grise 17, CH-2300 La Chaux De Fonds, Switzerland..
    Laux, Edith
    Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, HES SO, Eplatures Grise 17, CH-2300 La Chaux De Fonds, Switzerland..
    Keppner, Herbert
    Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, HES SO, Eplatures Grise 17, CH-2300 La Chaux De Fonds, Switzerland..
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Gedanken, Aharon
    Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel..
    Banin, Ehud
    Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel.;Bar Ilan Univ, Ctr Adv Mat & Nanotechnol, IL-52900 Ramat Gan, Israel..
    Two are Better than One: Combining ZnO and MgF2 Nanoparticles Reduces Streptococcus pneumoniae and Staphylococcus aureus Biofilm Formation on Cochlear Implants2016In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 26, no 15, 2473-2481 p.Article in journal (Refereed)
    Abstract [en]

    Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S.aureus) are considered the most common colonizers of cochlear implants (CI), which have prompted the search for new ways to inhibit their growth and biofilm development. In the current study, CI-based platforms are prepared and sonochemically coated with ZnO or MgF2 nanoparticles (NPs), two agents previously shown to possess antibacterial properties. Additionally, a method is developed for coating both ZnO and MgF2 on the same platform to achieve synergistic activity against both pathogens. Each surface is characterized, and the optimal conditions for the NP homogenous distribution on the surface are determined. The ZnO-MgF2 surface significantly reduces the S. pneumoniae and S. aureus biofilm compared with the surfaces coated with either ZnO or MgF2, even though it contains smaller amounts of each NP type. Importantly, leaching assays show that the NPs remain anchored to the surface for at least 7 d. Finally, biocompatibility studies demonstrate that coating with low concentrations of ZnO-MgF2 results in no toxicity toward primary human fibroblasts from the auditory canal. Taken together, these findings underscore the potential of using NP combinations such as the one presented here to efficiently inhibit bacterial colonization and growth on medical devices such as CIs.

  • 13.
    Nordling, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation2015In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 113, no 6, 1312-1322 p.Article in journal (Refereed)
    Abstract [en]

    Ischaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vas, culature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a Significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.

  • 14.
    Senn, Pascal
    et al.
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland.;Univ Hosp Geneva, Dept Clin Neurosci, Serv ORL & HNS, HUG, Geneva, Switzerland..
    Roccio, Marta
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland..
    Hahnewald, Stefan
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland..
    Frick, Claudia
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Kwiatkowska, Monika
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Ishikawa, Masaaki
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Bako, Peter
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pyykko, Ilmari
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Zou, Jing
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Mannerstrom, Marika
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Keppner, Herbert
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Homsy, Alexandra
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Laux, Edith
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Llera, Miguel
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Lellouche, Jean-Paul
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Ostrovsky, Stella
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Banin, Ehud
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Gedanken, Aharon
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Perkas, Nina
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Wank, Ute
    EMC Microcollect GmbH, Tubingen, Germany..
    Wiesmueller, Karl-Heinz
    EMC Microcollect GmbH, Tubingen, Germany..
    Mistrik, Pavel
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Benav, Heval
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Garnham, Carolyn
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Jolly, Claude
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Gander, Filippo
    SCIPROM Sarl, Rue Ctr 70, St Sulpice, Switzerland..
    Ulrich, Peter
    SCIPROM Sarl, Rue Ctr 70, St Sulpice, Switzerland..
    Mueller, Marcus
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Loewenheim, Hubert
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons2017In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 38, no 8, E224-E231 p.Article in journal (Refereed)
    Abstract [en]

    Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear. As a consequence, current devices are limited through 1) low frequency resolution, hence suboptimal sound quality and 2), large stimulation currents, hence high energy consumption (responsible for significant battery costs and for impeding the development of fully implantable systems). A recently completed, multinational and interdisciplinary project called NANOCI aimed at overcoming current limitations by creating a gapless interface between auditory nerve fibers and the cochlear implant electrode array. This ambitious goal was achieved in vivo by neurotrophin-induced attraction of neurites through an intra-cochlear gel-nanomatrix onto a modified nanoCI electrode array located in the scala tympani of deafened guinea pigs. Functionally, the gapless interface led to lower stimulation thresholds and a larger dynamic range in vivo, and to reduced stimulation energy requirement (up to fivefold) in an in vitro model using auditory neurons cultured on multi-electrode arrays. In conclusion, the NANOCI project yielded proof of concept that a gapless interface between auditory neurons and cochlear implant electrode arrays is feasible. These findings may be of relevance for the development of future CI systems with better sound quality and performance and lower energy consumption. The present overview/review paper summarizes the NANOCI project history and highlights achievements of the individual work packages.

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