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Strategies in Cochlear Nerve Regeneration, Guidance and Protection: Prospects for Future Cochlear Implants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
2016 (English)Doctoral 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. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1193
Keyword [en]
Human vestibular nerve, Scarpa's ganglion, Stem cells, Nanoparticles, Nanocrystalline diamond
National Category
Medical and Health Sciences Basic Medicine
Research subject
Oto-Rhino-Laryngology; Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-276336ISBN: 978-91-554-9503-9 (print)OAI: oai:DiVA.org:uu-276336DiVA: diva2:910246
Public defence
2016-04-28, Skoogsalen, Akademiska Sjukhuset, Ingång 78/79, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-04-07 Created: 2016-02-11 Last updated: 2016-04-12
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
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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
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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
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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
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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

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