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Liu, Wei
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Publications (10 of 43) Show all publications
An, F.-W., Yuan, H., Guo, W., Hou, Z.-H., Cai, J.-M., Luo, C.-C., . . . Yang, S.-M. (2019). Establishment of a Large Animal Model for Eustachian Tube Functional Study in Miniature Pigs. Anatomical Record Part A-discoveries in Molecular Cellular and Evolutionary Biology, 302(6), 1024-1038
Open this publication in new window or tab >>Establishment of a Large Animal Model for Eustachian Tube Functional Study in Miniature Pigs
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2019 (English)In: Anatomical Record Part A-discoveries in Molecular Cellular and Evolutionary Biology, ISSN 1552-4884, E-ISSN 1932-8494, Vol. 302, no 6, p. 1024-1038Article in journal (Refereed) Published
Abstract [en]

This study was performed to investigate whether miniature pigs are a suitable animal model for studies of the Eustachian tube (ET). Sixteen Chinese experimental miniature pigs were used in this investigation. Ten animals were used for anatomical and morphometric analyses to obtain qualitative and quantitative information regarding the ET. Three animals were used for histological analysis to determine the fine structure of ET cross-sections. Three animals were used to investigate the feasibility of balloon dilation of the Eustachian tube (BDET). The anatomical study indicated that the pharyngeal orifice and tympanic orifice of the miniature pig ET are located at the posterior end of the nasal lateral wall and anterior wall of the middle ear cavity, respectively. The cartilaginous tube was seen to pass through the whole length of the ET, the length of the cartilaginous part of the ET and the diameter of the isthmus were similar between humans and miniature pigs. The inclination of the ET in miniature pigs was larger than that in humans. The gross histology seemed to be slightly different between miniature pig and human, but the fine structures were essentially the same in both species. BDET experiments verified that the miniature pig model is suitable as a model for clinical operations. The miniature pig ET corresponds very well to that of humans. In addition, the miniature pig ET is suitable as a model for clinical operations. Therefore, the miniature pig is a valid animal model for ET study. 

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
Eustachian tube (ET), miniature pig, balloon dilation of the Eustachian tube (BDET)
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-385000 (URN)10.1002/ar.24098 (DOI)000467570000017 ()30779320 (PubMedID)
Available from: 2019-06-11 Created: 2019-06-11 Last updated: 2019-06-11Bibliographically approved
Liu, W., Kämpfe Nordström, C., Danckwardt-Lillieström, N. & Rask-Andersen, H. (2019). Human Inner Ear Immune Activity: A Super-Resolution Immunohistochemistry Study. Frontiers in Neurology, 10, Article ID 728.
Open this publication in new window or tab >>Human Inner Ear Immune Activity: A Super-Resolution Immunohistochemistry Study
2019 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 10, article id 728Article in journal (Refereed) Published
Abstract [en]

Background: Like the brain, the human inner ear was long thought to be devoid of immune activity. Only the endolymphatic sac (ES) was known to be endowed with white blood cells that could process antigens and serve as an immunologic defense organ for the entire inner ear. Unexpectedly, the cochlear and vestibular organs, including the eighth cranial nerve, were recently shown to contain macrophages whose functions and implication in ear disease are somewhat undefined. Here, we review recent inner ear findings in man and extend the analyses to the vestibular nerve using super-resolution structured illumination microscopy (SR-SIM).

Materials and Methods: Human ESs and cochleae were collected during surgery to treat patients with vestibular schwannoma and life-threatening petro-clival meningioma compressing the brainstem. The ESs and cochleae were placed in fixative, decalcified, and rapidly frozen and cryostat sectioned. Antibodies against ionized calcium-binding adaptor molecule 1-expressing cells (IBA1 cells), laminin beta 2 and type IV collagen TUJ1, cytokine fractalkine (CX3CL1), toll-like receptor 4 (TLR4), CD68, CD11b, CD4, CD8, the major histocompatibility complex type II (MHCII), and the microglial marker TEME119 were used.

Results: IBA1-positive cells were present in the ESs, the cochlea, central and peripheral axons of the cochlear nerve, and the vestibular nerve trunk. IBA1 cells were found in the cochlear lateral wall, spiral limbus, and spiral ganglion. Notable variants of IBA1 cells adhered to neurons with "synapse-like" specializations and cytoplasmic projections. Slender IBA1 cells occasionally protracted into the basal lamina of the Schwann cells and had intimate contact with surrounding axons.

Discussion: The human eighth nerve may be under the control of a well-developed macrophage cell system. A small number of CD4+ and CD8+ cells were found in the ES and occasionally in the cochlea, mostly located in the peripheral region of Rosenthal's canal. A neuro-immunologic axis may exist in the human inner ear that could play a role in the protection of the auditory nerve. The implication of the macrophage system during disease, surgical interventions, and cell-based transplantation should be further explored.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
human, inner ear, IBA1, macrophages, structured illumination microscopy
National Category
Neurosciences Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-390794 (URN)10.3389/fneur.2019.00728 (DOI)000474785100001 ()31354608 (PubMedID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Di Stazio, M., Collesi, C., Vozzi, D., Liu, W., Myers, M., Morgan, A., . . . Gasparini, P. (2019). TBL1Y: a new gene involved in syndromic hearing loss. European Journal of Human Genetics, 27(3), 466-474
Open this publication in new window or tab >>TBL1Y: a new gene involved in syndromic hearing loss
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 466-474Article in journal (Refereed) Published
Abstract [en]

Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/ total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378630 (URN)10.1038/s41431-018-0282-4 (DOI)000458626500016 ()30341416 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Kämpfe Nordström, C., Danckwardt-Lillieström, N., Laurell, G., Liu, W. & Rask-Andersen, H. (2019). The Human Endolymphatic Sac and Inner Ear Immunity: Macrophage Interaction and Molecular Expression. Frontiers in Immunology, 9, Article ID 3181.
Open this publication in new window or tab >>The Human Endolymphatic Sac and Inner Ear Immunity: Macrophage Interaction and Molecular Expression
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 3181Article in journal (Refereed) Published
Abstract [en]

Background: The endolymphatic sac (ES) is endowed with a multitude of white blood cells that may trap and process antigens that reach the inner ear from nearby infection-prone areas, it thus serves as an immunologic defense organ. The human ES, and unexpectedly the rest of the inner ear, has been recently shown to contain numerous resident macrophages. In this paper, we describe ES macrophages using super-resolution structured fluorescence microscopy (SR-SIM) and speculate on these macrophages' roles in human inner ear defense.

Material and Methods: After ethical permission was obtained, human vestibular aqueducts were collected during trans-labyrinthine surgery for acoustic neuroma removal. Tissues were placed in fixative before being decalcified, rapidly frozen, and cryostat sectioned. Antibodies against IBA1, cytokine fractalkine (CX3CL1), toll-like receptor 4 (TLR4), cluster of differentiation (CD) 68, CD11b, CD4, CD8, and the major histocompatibility complex type II (MHCII) were used for immunohistochemistry.

Results: A large number of IBA1-positive cells with different morphologies were found to reside in the ES; the cells populated surrounding connective tissue and the epithelium. Macrophages interacted with other cells, showed migrant behavior, and expressed immune cell markers, all of which suggest their active role in the innate and adaptive inner ear defense and tolerance.

Discussion: High-resolution immunohistochemistry shows that antigens reaching the ear may be trapped and processed by an immune cell machinery located in the ES. Thereby inflammatory activity may be evaded near the vulnerable inner ear sensory structures. We speculate on the immune defensive link between the ES and the rest of the inner ear.

Keywords
human, cochlea, macrophages, IBA1, structured illumination microscopy
National Category
Otorhinolaryngology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-377333 (URN)10.3389/fimmu.2018.03181 (DOI)000457362000001 ()30774637 (PubMedID)
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Glueckert, R., Chacko, L. J., Rask-Andersen, H., Liu, W., Handschuh, S. & Schrott-Fischer, A. (2018). Anatomical basis of drug delivery to the inner ear. Hearing Research, 368, 10-27
Open this publication in new window or tab >>Anatomical basis of drug delivery to the inner ear
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2018 (English)In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 368, p. 10-27Article, review/survey (Refereed) Published
Abstract [en]

The isolated anatomical position and blood-labyrinth barrier hampers systemic drug delivery to the mammalian inner ear. Intratympanic placement of drugs and permeation via the round-and oval window are established methods for local pharmaceutical treatment. Mechanisms of drug uptake and pathways for distribution within the inner ear are hard to predict. The complex microanatomy with fluid filled spaces separated by tight-and leaky barriers compose various compartments that connect via active and passive transport mechanisms. Here we provide a review on the inner ear architecture at light-and electron microscopy level, relevant for drug delivery. Focus is laid on the human inner ear architecture. Some new data add information on the human inner ear fluid spaces generated with high resolution microcomputed tomography at 15 urn resolution. Perilymphatic spaces are connected with the central modiolus by active transport mechanisms of mesothelial cells that provide access to spiral ganglion neurons. Reports on leaky barriers between scala tympani and the so-called cortilymph compartment likely open the best path for hair cell targeting. The complex barrier system of tight junction proteins such as occludins, claudins and tricellulin isolates the endolymphatic space for most drugs. Comparison of relevant differences of barriers, target cells and cell types involved in drug spread between main animal models and humans shall provide some translational aspects for inner ear drug applications. (C) 2018 The Authors. Published by Elsevier B.V.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-370045 (URN)10.1016/j.heares.2018.06.017 (DOI)000447547100003 ()30442227 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Liu, W., Loewenheim, H., Santi, P. A., Glueckert, R., Schrott-Fischer, A. & Rask-Andersen, H. (2018). Expression of trans-membrane serine protease 3 (TMPRSS3) in the human organ of Corti. Cell and Tissue Research, 372(3), 445-456
Open this publication in new window or tab >>Expression of trans-membrane serine protease 3 (TMPRSS3) in the human organ of Corti
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2018 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 372, no 3, p. 445-456Article in journal (Refereed) Published
Abstract [en]

TMPRSS3 (Trans-membrane Serine Protease 3) is a type II trans-membrane serine protease that has proteolytic activity essential for hearing. Mutations in the gene cause non-syndromic autosomal recessive deafness (DFNB8/10) in humans. Knowledge about its cellular distribution in the human inner ear may increase our understanding of its physiological role and involvement in deafness, ultimately leading to therapeutic interventions. In this study, we used super-resolution structured illumination microscopy for the first time together with transmission electron microscopy to localize the TMPRSS3 protein in the human organ of Corti. Archival human cochleae were dissected out during petroclival meningioma surgery. Microscopy with Zeiss LSM710 microscope achieved a lateral resolution of approximately 80 nm. TMPRSS3 was found to be associated with actin in both inner and outer hair cells. TMPRSS3 was located in cell surface-associated cytoskeletal bodies (surfoskelosomes) in inner and outer pillar cells and Deiters cells and in subcuticular organelles in outer hair cells. Our results suggest that TMPRSS3 proteolysis is linked to hair cell sterociliary mechanics and to the actin/microtubule networks that support cell motility and integrity.

Keywords
Cochlea, Trans-membrane Serine Protease 3 (TMPRSS3), Immunohistochemistry, Super-resolution structured illumination microscopy (SR-SIM), Human
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-356851 (URN)10.1007/s00441-018-2793-2 (DOI)000432109000001 ()29460002 (PubMedID)
Projects
OTOSTEM
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Liu, W., Molnar, M., Garnham, C., Benav, H. & Rask-Andersen, H. (2018). Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super-Resolution Immunohistochemistry. Frontiers in Immunology, 9, Article ID 223.
Open this publication in new window or tab >>Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super-Resolution Immunohistochemistry
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 223Article in journal (Refereed) Published
Abstract [en]

The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with "synapse-like" specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human's auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
human, cochlea, macrophages, ionized calcium-binding adaptor molecule 1, structured illumination microscopy, immunohistochemistry
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-348109 (URN)10.3389/fimmu.2018.00223 (DOI)000424911600001 ()29487598 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, FP7, Seventh Framework Programme, 603029
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Agrawal, S., Schart-Moren, N., Liu, W., Ladak, H. M., Rask-Andersen, H. & Li, H. (2018). The secondary spiral lamina and its relevance in cochlear implant surgery. Upsala Journal of Medical Sciences, 123(1), 9-18
Open this publication in new window or tab >>The secondary spiral lamina and its relevance in cochlear implant surgery
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 9-18Article in journal (Refereed) Published
Abstract [en]

Objective: We used synchrotron radiation phase contrast imaging (SR-PCI) to study the 3D microanatomy of the basilar membrane (BM) and its attachment to the spiral ligament (SL) (with a conceivable secondary spiral lamina [SSL] or secondary spiral plate) at the round window membrane (RWM) in the human cochlea. The conception of this complex anatomy may be essential for accomplishing structural preservation at cochlear implant surgery.

Material and methods: Sixteen freshly fixed human temporal bones were used to reproduce the BM, SL, primary and secondary osseous spiral laminae (OSL), and RWM using volume-rendering software. Confocal microscopy immunohistochemistry (IHC) was performed to analyze the molecular constituents.

Results: SR-PCI reproduced the soft tissues including the RWM, Reissner's membrane (RM), and the BM attachment to the lateral wall (LW) in three dimensions. A variable SR-PCI contrast enhancement was recognized in the caudal part of the SL facing the scala tympani (ST). It seemed to represent a SSL allied to the basilar crest (BC). The SSL extended along the postero-superior margin of the round window (RW) and immunohistochemically expressed type II collagen.

Conclusions: Unlike in several mammalian species, the human SSL is restricted to the most basal portion of the cochlea around the RW. It anchors the BM and may influence its hydro-mechanical properties. It could also help to shield the BM from the RW. The microanatomy should be considered at cochlear implant surgery.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Basilar membrane, cochlea, human, secondary spiral lamina, synchrotron-phase contrast imaging
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-354541 (URN)10.1080/03009734.2018.1443983 (DOI)000428060300002 ()29537931 (PubMedID)
Funder
Swedish Research Council, 2017-03801
Available from: 2018-06-20 Created: 2018-06-20 Last updated: 2018-06-20Bibliographically approved
Liu, W., Li, H., Edin, F., Brännström, J., Glueckert, R., Schrott-Fischer, A., . . . Rask-Andersen, H. (2017). Molecular composition and distribution of gap junctions in the sensory epithelium of the human cochlea a super-resolution structured illumination microscopy (SR-SIM) study. Upsala Journal of Medical Sciences, 122(3), 160-170
Open this publication in new window or tab >>Molecular composition and distribution of gap junctions in the sensory epithelium of the human cochlea a super-resolution structured illumination microscopy (SR-SIM) study
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 160-170Article in journal (Refereed) Published
Abstract [en]

Background: Mutations in the GJB2 gene, which encodes the Connexin26 (Cx26) protein, are the most common cause of childhood hearing loss in American and European populations. The cochlea contains a gap junction (GJ) network in the sensory epithelium and two connective tissue networks in the lateral wall and spiral limbus. The syncytia contain the GJ proteins beta 2 (GJB2/Cx26) and beta 6 (GJB6/Cx30). Our knowledge of their expression in humans is insufficient due to the limited availability of tissue. Here, we sought to establish the molecular arrangement of GJs in the epithelial network of the human cochlea using surgically obtained samples. Methods: We analyzed Cx26 and Cx30 expression in GJ networks in well-preserved adult human auditory sensory epithelium using confocal, electron, and super -resolution structured illumination microscopy (SR-SIM). Results: Cx30 plaques (<5 mu m) dominated, while Cx26 plaques were subtle and appeared as 'mini junctions' (2-300 nm). 3-D volume rendering of Z-stacks and orthogonal projections from single optical sections suggested that the GJs are homomeric/homotypic and consist of assemblies of identical GJs composed of either Cx26 or Cx30. Occasionally, the two protein types were co-expressed, suggesting functional cooperation. Conclusions: Establishing the molecular composition and distribution of the GJ networks in the human cochlea may increase our understanding of the pathophysiology of Cx-related hearing loss. This information may also assist in developing future strategies to treat genetic hearing loss.

Keywords
Cochlea, confocal microscopy, connexin 26/30, human, SR-SIM
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-340976 (URN)10.1080/03009734.2017.1322645 (DOI)000414107800002 ()28513246 (PubMedID)
Available from: 2018-02-12 Created: 2018-02-12 Last updated: 2018-02-12Bibliographically approved
Senn, P., Roccio, M., Hahnewald, S., Frick, C., Kwiatkowska, M., Ishikawa, M., . . . Loewenheim, H. (2017). NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons. Paper presented at 14th International Conference on Cochlear Implants and other Implantable Auditory Technologies, MAY 11-14, 2016, Toronto, CANADA. Otology and Neurotology, 38(8), E224-E231
Open this publication in new window or tab >>NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons
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2017 (English)In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 38, no 8, p. E224-E231Article in journal (Refereed) Published
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.

Keywords
Auditory nerve regeneration, BDNF, Cochlear implant, Gapless interface, Guinea pig, Hearing loss, Hydrogel, Multi-electrode array, Neuron-electrode interface
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-335874 (URN)10.1097/MAO.0000000000001439 (DOI)000411032100003 ()28806330 (PubMedID)
Conference
14th International Conference on Cochlear Implants and other Implantable Auditory Technologies, MAY 11-14, 2016, Toronto, CANADA
Funder
EU, European Research Council, 281056
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2017-12-14Bibliographically approved
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