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  1. Article ; Online: Expression of Brain-Derived Neurotrophic Factor in Human Spiral Ganglia Neurons after Cochlear Implantation.

    Wong, Emily C / Lopez, Ivan A / Ishiyama, Akira / Ishiyama, Gail

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2024  Volume 45, Issue 3, Page(s) 326–333

    Abstract: Background: Brain-derived neurotrophic factor (BDNF) is an important factor in the development and neuroprotection of afferent auditory pathways. In this study, we investigated the expression of BDNF in the afferent auditory pathway after cochlear ... ...

    Abstract Background: Brain-derived neurotrophic factor (BDNF) is an important factor in the development and neuroprotection of afferent auditory pathways. In this study, we investigated the expression of BDNF in the afferent auditory pathway after cochlear implantation (CI), hypothesizing that electrical stimulation after CI stimulates BDNF expression in the afferent auditory pathway.
    Methods: Archival human temporal bones from eight patients with a history of CI and five patients with normal hearing (ages 65-93 years old) were studied. Temporal bone specimens were immunoreacted with rabbit polyclonal antibodies against BDNF and mouse monoclonal antibodies against pan-neurofilaments. In cases of unilateral CI, the BDNF expression was compared with the contralateral unimplanted ear and normal temporal bones without hearing loss.
    Results: BDNF immunoreactivity (IR) localized to the spiral ganglion neurons (SGNs) somata and the surrounding satellite cells. BDNF-IR in the spiral ganglia was similar in the apical, middle, and basal hook regions. Neurofilament IR localized to SGN nerve fibers in both implanted and unimplanted cochleae. BDNF-IR in the SGN and satellite cells was significantly increased in the implanted specimens compared with the unimplanted specimens ( p < 0.05) and the normal hearing specimens ( p < 0.05). BDNF-IR expression was similar in the unimplanted cochlea and in the normal cochlea. BDNF protein expression was increased despite complete loss of the organ of Corti hair cells and supporting cells. Even in the cases of CI with a 6-mm first-generation electrode, BDNF expression was upregulated throughout the cochlea.
    Conclusions: BDNF expression in the SGN appears to be upregulated by the electrical stimulation from CI. This study provides evidence that the electrical stimulation from CI may stimulate the expression of BDNF, playing a neuroprotective role in the rehabilitation of hearing in the deafened ear.
    MeSH term(s) Mice ; Animals ; Humans ; Rabbits ; Aged ; Aged, 80 and over ; Spiral Ganglion/physiology ; Cochlear Implantation ; Brain-Derived Neurotrophic Factor ; Cochlea ; Neurons ; Deafness
    Chemical Substances Brain-Derived Neurotrophic Factor
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000004104
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  2. Article: Archival Human Temporal Bone: Anatomical and Histopathological Studies of Cochlear Implantation.

    Ishiyama, Paul / Ishiyama, Gail / Lopez, Ivan A / Ishiyama, Akira

    Journal of personalized medicine

    2023  Volume 13, Issue 2

    Abstract: Since being FDA approved in 1984, cochlear implantation has been used successfully to restore hearing in those with severe to profound hearing loss with broader applications including single-sided deafness, the use of hybrid electroacoustic stimulation, ... ...

    Abstract Since being FDA approved in 1984, cochlear implantation has been used successfully to restore hearing in those with severe to profound hearing loss with broader applications including single-sided deafness, the use of hybrid electroacoustic stimulation, and implantation at all extremes of age. Cochlear implants have undergone multiple changes in the design aimed at improving the processing technology, while simultaneously minimizing the surgical trauma and foreign body reaction. The following review examines the human temporal bone studies regarding the anatomy of the human cochlea and how the anatomy relates to cochlear implant design, the factors related to complications after implantation, and the predictors of new tissue formation and osteoneogenesis. Histopathological studies are reviewed which aim to understand the potential implications of the effects of new tissue formation and inflammation following implantation.
    Language English
    Publishing date 2023-02-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662248-8
    ISSN 2075-4426
    ISSN 2075-4426
    DOI 10.3390/jpm13020352
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  3. Article ; Online: Morphometric Analysis and Linear Measurements of the Scala Tympani and Implications in Cochlear Implant Electrodes.

    Fujiwara, Rance J T / Ishiyama, Gail / Lopez, Ivan A / Ishiyama, Akira

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2023  Volume 44, Issue 5, Page(s) e343–e349

    Abstract: Hypothesis: The objective of this study was to perform detailed height and cross-sectional area measurements of the scala tympani in histologic sections of nondiseased human temporal bones and correlate them with cochlear implant electrode dimensions.!## ...

    Abstract Hypothesis: The objective of this study was to perform detailed height and cross-sectional area measurements of the scala tympani in histologic sections of nondiseased human temporal bones and correlate them with cochlear implant electrode dimensions.
    Background: Previous investigations in scala tympani dimensions have used microcomputed tomography or casting modalities, which cannot be correlated directly with microanatomy visible on histologic specimens.
    Methods: Three-dimensional reconstructions of 10 archival human temporal bone specimens with no history of middle or inner ear disease were generated using hematoxylin and eosin histopathologic slides. At 90-degree intervals, the heights of the scala tympani at lateral wall, midscala, and perimodiolar locations were measured, along with cross-sectional area.
    Results: The vertical height of the scala tympani at its lateral wall significantly decreased from 1.28 to 0.88 mm from 0 to 180 degrees, and the perimodiolar height decreased from 1.20 to 0.85 mm. The cross-sectional area decreased from 2.29 (standard deviation, 0.60) mm 2 to 1.38 (standard deviation, 0.13) mm 2 from 0 to 180 degrees ( p = 0.001). After 360 degrees, the scala tympani shape transitioned from an ovoid to triangular shape, corresponding with a significantly decreased lateral height relative to perimodiolar height. Wide variability was observed among the cochlear implant electrode sizes relative to scala tympani measurements.
    Conclusion: The present study is the first to conduct detailed measurements of heights and cross-sectional area of the scala tympani and the first to statistically characterize the change in its shape after the basal turn. These measurements have important implications in understanding locations of intracochlear trauma during insertion and electrode design.
    MeSH term(s) Humans ; Scala Tympani/surgery ; Cochlear Implants ; X-Ray Microtomography ; Cochlear Implantation/methods ; Cochlea/surgery ; Electrodes, Implanted ; Temporal Bone/diagnostic imaging ; Temporal Bone/surgery ; Temporal Bone/anatomy & histology
    Language English
    Publishing date 2023-03-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000003848
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  4. Article ; Online: Immunohistochemical localization of glucocorticoid receptors in the human cochlea.

    Matsui, Hirooki / Lopez, Ivan A / Ishiyama, Gail / Ishiyama, Akira

    Brain research

    2023  Volume 1806, Page(s) 148301

    Abstract: In the present study we investigated the localization of glucocorticoid receptors (GCR) in the human inner ear using immunohistochemistry. Celloidin-embedded cochlear sections of patients with normal hearing (n = 5), patients diagnosed with MD (n = 5), ... ...

    Abstract In the present study we investigated the localization of glucocorticoid receptors (GCR) in the human inner ear using immunohistochemistry. Celloidin-embedded cochlear sections of patients with normal hearing (n = 5), patients diagnosed with MD (n = 5), and noise induced hearing loss (n = 5) were immunostained using GCR rabbit affinity-purified polyclonal antibodies and secondary fluorescent or HRP labeled antibodies. Digital fluorescent images were acquired using a light sheet laser confocal microscope. In celloidin-embedded sections GCR-IF was present in the cell nuclei of hair cells and supporting cells of the organ of Corti. GCR-IF was detected in cell nuclei of the Reisner's membrane. GCR-IF was seen in cell nuclei of the stria vascularis and the spiral ligament. GCR-IF was found in the spiral ganglia cell nuclei, however, spiral ganglia neurons showed no GCR-IF. Although GCRs were found in most cell nuclei of the cochlea, the intensity of IF was differential among the different cell types being more intense in supporting cells than in sensory hair cells. The differential expression of GCR receptors found in the human cochlea may help to understand the site of action of glucocorticoids in different ear diseases.
    MeSH term(s) Animals ; Rabbits ; Humans ; Receptors, Glucocorticoid/metabolism ; Collodion/metabolism ; Cochlea/metabolism ; Ear, Inner/metabolism ; Spiral Ganglion/metabolism
    Chemical Substances Receptors, Glucocorticoid ; Collodion (9004-70-0)
    Language English
    Publishing date 2023-03-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2023.148301
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    Zs.A 161: Show issues Location:
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  5. Article ; Online: Temporal bone histopathology in revision cochlear implantation.

    Smith, Alden F / Ishiyama, Gail / Lopez, Ivan A / Ishiyama, Akira

    Cochlear implants international

    2023  , Page(s) 1–5

    Abstract: An increasing number of young infants, as early as six months of age with congenital hearing loss receive cochlear implantation, and it is probable that many of these patients will require revision surgery later in life. The possibility of explantation ... ...

    Abstract An increasing number of young infants, as early as six months of age with congenital hearing loss receive cochlear implantation, and it is probable that many of these patients will require revision surgery later in life. The possibility of explantation of the cochlear electrode and reimplantation may cause damage to the cochlea, compromising the speech perception outcome in revision implant is of concern. There is only one prior temporal bone histopathology study to look at the outcome of revision surgery and no prior study evaluating revision cochlear implantation that used the round window approach. We conducted a histopathological study of four temporal bone specimens from four patients who underwent revision cochlear implantation and when available post-operative speech perception tests were evaluated. In all cases, the reimplanted electrode followed into the same fibrous sheath without evidence of additional intracochlear damage due to revision surgery. The intracochlear damage from the initial cochlear implantation appears to be a more important factor in outcomes rather than changes associated with explantation and reimplantation.
    Language English
    Publishing date 2023-12-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2079515-4
    ISSN 1754-7628 ; 1467-0100
    ISSN (online) 1754-7628
    ISSN 1467-0100
    DOI 10.1080/14670100.2023.2281186
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  6. Article ; Online: Emerging Mechanisms in the Pathogenesis of Menière's Disease: Evidence for the Involvement of Ion Homeostatic or Blood-Labyrinthine Barrier Dysfunction in Human Temporal Bones.

    Johns, J Dixon / Olszewski, Rafal / Strepay, Dillon / Lopez, Ivan A / Ishiyama, Akira / Hoa, Michael

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2023  Volume 44, Issue 10, Page(s) 1057–1065

    Abstract: Hypothesis: Analysis of human temporal bone specimens of patients with Menière's disease (MD) may demonstrate altered expression of gene products related to barrier formation and ionic homeostasis within cochlear structures compared with control ... ...

    Abstract Hypothesis: Analysis of human temporal bone specimens of patients with Menière's disease (MD) may demonstrate altered expression of gene products related to barrier formation and ionic homeostasis within cochlear structures compared with control specimens.
    Background: MD represents a challenging otologic disorder for investigation. Despite attempts to define the pathogenesis of MD, there remain many gaps in our understanding, including differences in protein expression within the inner ear. Understanding these changes may facilitate the identification of more targeted therapies for MD.
    Methods: Human temporal bones from patients with MD (n = 8) and age-matched control patients (n = 8) were processed with immunohistochemistry stains to detect known protein expression related to ionic homeostasis and barrier function in the cochlea, including CLDN11, CLU, KCNJ10, and SLC12A2. Immunofluorescence intensity analysis was performed to quantify protein expression in the stria vascularis, organ of Corti, and spiral ganglion neuron (SGN).
    Results: Expression of KCNJ10 was significantly reduced in all cochlear regions, including the stria vascularis (9.23 vs 17.52, p = 0.011), OC (14.93 vs 29.16, p = 0.014), and SGN (7.69 vs 18.85, p = 0.0048) in human temporal bone specimens from patients with MD compared with control, respectively. CLDN11 (7.40 vs 10.88, p = 0.049) and CLU (7.80 vs 17.51, p = 0.0051) expression was significantly reduced in the SGN.
    Conclusion: The results of this study support that there may be differences in the expression of proteins related to ionic homeostasis and barrier function within the cochlea, potentially supporting the role of targeted therapies to treat MD.
    MeSH term(s) Humans ; Meniere Disease/pathology ; Cochlea/pathology ; Stria Vascularis/pathology ; Temporal Bone/pathology ; Homeostasis ; Solute Carrier Family 12, Member 2
    Chemical Substances SLC12A2 protein, human ; Solute Carrier Family 12, Member 2
    Language English
    Publishing date 2023-09-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000004016
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  7. Article ; Online: Differential Expression of Na/K-ATPase in the Human Saccule of Patients With and Without Otologic Disease.

    Avillion, Michael P / Lopez, Ivan A / Matsui, Hirooki / Ishiyama, Gail / Ishiyama, Akira

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2023  Volume 44, Issue 4, Page(s) e256–e261

    Abstract: Hypothesis: Na + , K + -ATPase (Na/K-ATPase) α1 subunit expression in the saccule of patients diagnosed with otologic disease is different compared with normal controls.: Background: We have recently characterized changes in the expression of Na/K- ... ...

    Abstract Hypothesis: Na + , K + -ATPase (Na/K-ATPase) α1 subunit expression in the saccule of patients diagnosed with otologic disease is different compared with normal controls.
    Background: We have recently characterized changes in the expression of Na/K-ATPase α1 subunit in the normal and pathological cochlea; however, no studies have determined the distribution Na/K-ATPase α1 subunit in the human saccule. The present study uses archival temporal bones to study the expression Na/K-ATPase α1 subunit in the human saccule.
    Methods: Archival celloidin formalin fixed 20-micron thick sections of the vestibule from patients diagnosed with Menière's disease (n = 5), otosclerosis (n = 5), sensorineural hearing loss, and normal hearing and balance (n = 5) were analyzed. Sections containing the saccular macula were immunoreacted with mouse monoclonal antibodies against Na/K-ATPase α1 subunit. Micrographs were acquired using a high-resolution digital camera coupled to a light inverted microscope.
    Results: In the normal human saccule vestibular sensory epithelium, Na/K-ATPase α1 immunoreactivity (IR) was present in nerve fibers and calyces that surround type I vestibular hair cells and nerve terminals. The transition epithelium cells were also Na/K-ATPase α1 immunoreactive. Comparison between normal and pathological specimens showed that there was a significant reduction of Na/K-ATPase α1 IR in the saccule vestibular sensory epithelium from patients with Menière's disease, otosclerosis, and sensorineural hearing loss.
    Conclusions: The decrease of Na/K-ATPase-IR α1 in the saccule vestibular sensory epithelium from patients with otopathologies suggests its critical role in inner ear homeostasis and pathology.
    MeSH term(s) Mice ; Animals ; Humans ; Meniere Disease ; Otosclerosis ; Saccule and Utricle ; Vestibule, Labyrinth ; Sodium-Potassium-Exchanging ATPase/metabolism ; Hearing Loss, Sensorineural
    Chemical Substances Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13)
    Language English
    Publishing date 2023-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000003834
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  8. Article ; Online: Dynamic Molecular Markers of Otosclerosis in the Human Cochlea.

    Hodge, Sarah / Lopez, Ivan A / Cronkite, Alex / House, John / Matsui, Hirooki / Ishiyama, Gail / Ishiyama, Akira

    The Annals of otology, rhinology, and laryngology

    2024  Volume 133, Issue 4, Page(s) 390–399

    Abstract: Objective: To investigate the role and distribution of various molecular markers using immunohistochemistry and immunofluorescence to further elucidate and understand the pathogenesis of otosclerosis.: Methods: Archival celloidin formalin-fixed 20- ... ...

    Abstract Objective: To investigate the role and distribution of various molecular markers using immunohistochemistry and immunofluorescence to further elucidate and understand the pathogenesis of otosclerosis.
    Methods: Archival celloidin formalin-fixed 20-micron thick histologic sections from 7 patients diagnosed with otosclerosis were studied and compared to controls. Sections in the mid-modiolar region were immunoreacted with rabbit polyclonal antibodies against nidogen-1, β2-laminin, collagen-IX, BSP, and monoclonal antibodies against TGF β-1 and ubiquitin. Digital images were acquired using a high-resolution light and laser confocal microscope.
    Results: Nidogen-1, BSP, and collagen-IX were expressed in the otospongiotic regions, and to lesser extent, in the otosclerotic regions, the latter previously believed to be inactive. β2-laminin and ubiquitin were uniformly expressed in both otospongiotic and otosclerotic regions. There was a basal level of expression of all of these markers in the normal hearing and sensorineural hearing loss specimens utilized as control. TGF β -1, however, though present in the otosclerosis bones, was absent in the normal hearing and sensorineural hearing loss controls.
    Conclusions: Our results propose that the activity and function of TGF-1 may play a key role in the development and pathogenesis of otosclerosis. Further studies utilizing a higher number of temporal bone specimens will be helpful for future analysis and to help decipher its role as a potential target in therapeutic interventions.
    MeSH term(s) Humans ; Rabbits ; Animals ; Otosclerosis/pathology ; Cochlea/pathology ; Hearing Loss, Sensorineural/etiology ; Collagen ; Laminin/metabolism ; Ubiquitins/metabolism
    Chemical Substances Collagen (9007-34-5) ; Laminin ; Ubiquitins
    Language English
    Publishing date 2024-01-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 120642-4
    ISSN 1943-572X ; 0003-4894
    ISSN (online) 1943-572X
    ISSN 0003-4894
    DOI 10.1177/00034894231225134
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  9. Article ; Online: Histopathologic Analysis of Temporal Bones With Otosclerosis Following Cochlear Implantation.

    Hodge, Sarah E / Ishiyama, Gail / Lopez, Ivan A / Ishiyama, Akira

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2021  Volume 42, Issue 10, Page(s) 1492–1498

    Abstract: Objective: Analyze changes in osteoneogenesis and fibrosis following cochlear implant (CI) surgery in patients with otosclerosis and compare differences based on insertion technique.: Background: When advanced otosclerotic disease extends to the otic ...

    Abstract Objective: Analyze changes in osteoneogenesis and fibrosis following cochlear implant (CI) surgery in patients with otosclerosis and compare differences based on insertion technique.
    Background: When advanced otosclerotic disease extends to the otic capsule, severe and profound sensorineural hearing loss necessitates consideration of a cochlear implant. Histopathological analysis of the human temporal bone after implantation in the patient with otosclerosis may reveal important variables that predict CI success.
    Methods: Histopathological evaluation of archival human temporal bones from subjects with a history of CI for cochlear otosclerosis. A total of 17 human temporal bones (HTB) were analyzed, 13 implanted, and 4 contralateral non-implanted controls.
    Results: Histopathological studies revealed extensive osteoneogenesis and fibrosis which was more prominent at the cochleostomy insertion site in the basal turn of the cochlea often obliterating the scala tympani in the basal turn, and in some cases extending to the scala media and scala vestibuli. Cochlear hydrops was nearly universal in these cases. This contrasted with the round window insertion, which exhibited minimal osteoneogenesis within the cochlear duct. In addition, in the contralateral, unimplanted control ears, there was otosclerosis at the stapes footplate, fissula ante fenestrum but no osteoneogenesis within the cochlear duct.
    Conclusion: Cochleostomy approach to CI insertion in otosclerosis patients is associated with significant fibrosis, osteoneogenesis, and cochlear hydrops. A round window insertion technique can be utilized to help minimize these histopathologic findings whenever feasible.
    MeSH term(s) Cochlea/pathology ; Cochlea/surgery ; Cochlear Implantation/adverse effects ; Cochlear Implants/adverse effects ; Humans ; Otosclerosis/complications ; Temporal Bone/pathology ; Temporal Bone/surgery
    Language English
    Publishing date 2021-09-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000003327
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  10. Article ; Online: Predictors of Fibrotic and Bone Tissue Formation With 3-D Reconstructions of Post-implantation Human Temporal Bones.

    Danielian, Arman / Ishiyama, Gail / Lopez, Ivan A / Ishiyama, Akira

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

    2021  Volume 42, Issue 7, Page(s) e942–e948

    Abstract: Hypothesis: Years of implantation, surgical insertion approach, and electrode length will impact the volume of new tissue formation secondary to cochlear implantation.: Background: New tissue formation, fibrosis, and osteoneogenesis after cochlear ... ...

    Abstract Hypothesis: Years of implantation, surgical insertion approach, and electrode length will impact the volume of new tissue formation secondary to cochlear implantation.
    Background: New tissue formation, fibrosis, and osteoneogenesis after cochlear implantation have been implicated in increasing impedance and affecting performance of the cochlear implant.
    Methods: 3-D reconstructions of 15 archival human temporal bones from patients with a history of cochlear implantation (CI) were generated from H&E histopathologic slides to study factors which affect volume of tissue formation.
    Results: Years of implantation was a predictor of osteoneogenesis (r = 0.638, p-value = 0.011) and total new tissue formation (r = 0.588, p-value = 0.021), however not of fibrosis (r = 0.235, p-value = 0.399). Median total tissue formation differed between cochleostomy and round window insertions, 25.98 and 10.34%, respectively (Mann-Whitney U = 7, p = 0.018). No correlations were found between electrode length or angular insertion depth and total new tissue (p = 0.192, p = 0.35), osteoneogenesis (p = 0.193, p = 0.27), and fibrosis (p = 0.498, p = 0.83), respectively. However, the type II error for electrode length and angular insertion depth ranged from 0.73 to 0.90, largely due to small numbers of the shorter electrodes.
    Conclusions: With numbers of cochlear implant recipients increasing worldwide, an understanding of how to minimize intracochlear changes from implantation is important. The present study demonstrates that increasing years of implantation and inserting electrodes via a cochleostomy compared with a round window approach are associated with significantly greater degree of new tissue volume formation. While previous studies have demonstrated increased intracochlear damage in the setting of translocation with longer electrodes, length, and angular insertion depth of CI electrodes were not associated with increased tissue formation.
    MeSH term(s) Cochlea/surgery ; Cochlear Implantation ; Cochlear Implants ; Electrodes, Implanted ; Fibrosis ; Humans ; Round Window, Ear/surgery ; Temporal Bone/pathology ; Temporal Bone/surgery
    Language English
    Publishing date 2021-01-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2036790-9
    ISSN 1537-4505 ; 1531-7129
    ISSN (online) 1537-4505
    ISSN 1531-7129
    DOI 10.1097/MAO.0000000000003106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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