uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Edin, Fredrik
Publications (10 of 15) Show all publications
Li, H., Edin, F., Hayashi, H., Gudjonsson, O., Danckwardt-Lillieström, N., Engqvist, H., . . . Xia, W. (2017). Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface. Biomaterials, 122, 1-9
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, p. 1-9Article 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: 2018-02-08Bibliographically 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
Show others...
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
Show others...
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
Edin, F. (2016). Strategies in Cochlear Nerve Regeneration, Guidance and Protection: Prospects for Future Cochlear Implants. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Strategies in Cochlear Nerve Regeneration, Guidance and Protection: Prospects for Future Cochlear Implants
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. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1193
Keywords
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:nbn:se:uu:diva-276336 (URN)978-91-554-9503-9 (ISBN)
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: 2018-01-10
Cai, Y., Edin, F., Jin, Z., Alexsson, A., Gudjonsson, O., Liu, W., . . . Li, H. (2016). Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond. Acta Biomaterialia, 31, 211-220
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, p. 211-220Article 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
Liu, W., Edin, F., Blom, H., Magnusson, P., Schrott-Fischer, A., Glueckert, R., . . . Rask-Andersen, H. (2016). Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man. Cell and Tissue Research, 365(1), 13-27
Open this publication in new window or tab >>Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man
Show others...
2016 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 365, no 1, p. 13-27Article in journal (Refereed) Published
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.

Keywords
Human cochlea, Connexin (as elsewhere) 26/30, Structured illumination microscopy
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-299834 (URN)10.1007/s00441-016-2359-0 (DOI)000378877600003 ()26941236 (PubMedID)
Available from: 2016-07-29 Created: 2016-07-28 Last updated: 2018-05-18Bibliographically approved
Hayashi, H., Edin, F., Li, H., Liu, W. & Rask-Andersen, H. (2016). The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling. Brain Research, 1652, 195-203
Open this publication in new window or tab >>The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling
Show others...
2016 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, p. 195-203Article in journal (Refereed) Published
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.

Keywords
Pulsed electric field, Human neural progenitor cell, Electrotactic migration, Intracellular calcium signaling, Time-lapse video microscopy
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-310911 (URN)10.1016/j.brainres.2016.09.043 (DOI)000388059700023 ()27746154 (PubMedID)
Funder
EU, European Research Council, 281056 603029
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-11-29Bibliographically approved
Natan, M., Edin, F., Perkas, N., Yacobi, G., Perelshtein, I., Segal, E., . . . Banin, E. (2016). Two are Better than One: Combining ZnO and MgF2 Nanoparticles Reduces Streptococcus pneumoniae and Staphylococcus aureus Biofilm Formation on Cochlear Implants. Advanced Functional Materials, 26(15), 2473-2481
Open this publication in new window or tab >>Two are Better than One: Combining ZnO and MgF2 Nanoparticles Reduces Streptococcus pneumoniae and Staphylococcus aureus Biofilm Formation on Cochlear Implants
Show others...
2016 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 26, no 15, p. 2473-2481Article in journal (Refereed) Published
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.

Keywords
antibiofilm, bacteria, cochlear, implants, nanoparticles
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-297365 (URN)10.1002/adfm.201504525 (DOI)000375126400008 ()
Funder
EU, FP7, Seventh Framework Programme
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2017-11-28Bibliographically approved
Cai, Y., Edin, F., Li, H. & Karlsson, M. (2015). Ordered auditory neuron growth on micro-structured nanocrystalline diamond surface. In: : . Paper presented at Proceedings of the society of photo-optical instrumentation engineers (SPIE) 9557, Nanobiosystems: Processing, Characterization, and Applications VIII, August 9-13, 2015, San Diego, CA, USA.
Open this publication in new window or tab >>Ordered auditory neuron growth on micro-structured nanocrystalline diamond surface
2015 (English)Conference paper, Oral presentation with published abstract (Refereed)
National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-284530 (URN)
Conference
Proceedings of the society of photo-optical instrumentation engineers (SPIE) 9557, Nanobiosystems: Processing, Characterization, and Applications VIII, August 9-13, 2015, San Diego, CA, USA
Available from: 2016-04-18 Created: 2016-04-18 Last updated: 2016-04-19
Liu, W., Edin, F., Atturo, F., Rieger, G., Lowenheim, H., Senn, P., . . . Glueckert, R. (2015). The Pre- and Post-Somatic Segments of the Human Type I Spiral Ganglion Neurons - Structural and Functional Considerations Related to Cochlear Implantation. Neuroscience, 284, 470-482
Open this publication in new window or tab >>The Pre- and Post-Somatic Segments of the Human Type I Spiral Ganglion Neurons - Structural and Functional Considerations Related to Cochlear Implantation
Show others...
2015 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 284, p. 470-482Article in journal (Refereed) Published
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.

Keywords
human cochlea, spiral ganglion neurons, non-myelinated Schwann cells, laminin-beta 2, collagen IV, immuno-histochemistry
National Category
Neurosciences Surgery Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-241927 (URN)10.1016/j.neuroscience.2014.09.059 (DOI)000346243100042 ()
Available from: 2015-01-27 Created: 2015-01-19 Last updated: 2018-01-11Bibliographically approved
Organisations

Search in DiVA

Show all publications