USC Stem Cell scientists explore the latent regenerative potential of the inner ear
Advancements in Stem Cell Technology and Organoids for the Restoration of Sensorineural Hearing Loss
Rinri Therapeutics Raises £10 million from Existing Investors and UK Future Fund to Advance its Novel Stem Cell Therapy to Restore Hearing Loss
Rinri Therapeutics Raises £10 million to Advance its Novel Stem Cell Therapy to Reverse Sensorineural Hearing Loss
The proceeds will support the development of the Company’s novel stem cell therapy to reverse sensorineural hearing loss (SNHL).
2021 Jan 31. doi: 10.1002/stem.3346. Online ahead of print.
A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss
PMID: 33522002 DOI: 10.1002/stem.3346
Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art
J Assoc Res Otolaryngol. 2021 Jan 28. doi: 10.1007/s10162-020-00781-0. Online ahead of print.
Progressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.
PMID:33507440 | DOI:10.1007/s10162-020-00781-0
Journal of the Association for Research in Otolaryngology : JARO
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Thu, 28 Jan 2021 06:00:00 -0500
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Hearing Loss Treatment Report, Urgent Research, 2021-01-29T04:57:19+00:00, https://www.hearinglosstreatmentreport.com.
Zebrafish as a Biomedical Model for Stem Cells Research in Hearing Impairment
Salma Hafeez * ORCID logo
Version 1 : Received: 4 January 2021 / Approved: 5 January 2021 / Online: 5 January 2021 (14:23:23 CET)
Therapeutic Application of Mesenchymal Stem Cells for Cochlear Regeneration
In Vivo. 2021 Jan-Feb;35(1):13-22. doi: 10.21873/invivo.12227.
Hearing loss is one of the major worldwide health problems that seriously affects human social and cognitive development. In the auditory system, three components outer ear, middle ear and inner ear are essential for the hearing mechanism. In the inner ear, sensory hair cells and ganglion neuronal cells are the essential supporters for hearing mechanism. Damage to these cells can be caused by long-term exposure of excessive noise, ototoxic drugs (aminoglycosides), ear tumors, infections, heredity and aging. Since mammalian cochlear hair cells do not regenerate naturally, some therapeutic interventions may be required to replace the damaged or lost cells. Cochlear implants and hearing aids are the temporary solutions for people suffering from severe hearing loss. The current discoveries in gene therapy may provide a deeper understanding in essential genes for the inner ear regeneration. Stem cell migration, survival and differentiation to supporting cells, cochlear hair cells and spiral ganglion neurons are the important foundation in understanding stem cell therapy. Moreover, mesenchymal stem cells (MSCs) from different sources (bone marrow, umbilical cord, adipose tissue and placenta) could be used in inner ear therapy. Transplanted MSCs in the inner ear can recruit homing factors at the damaged sites to induce transdifferentiation into inner hair cells and ganglion neurons or regeneration of sensory hair cells, thus enhancing the cochlear function. This review summarizes the potential application of mesenchymal stem cells in hearing restoration and combining stem cell and molecular therapeutic strategies can also be used in the recovery of cochlear function.
PMID:33402445 | DOI:10.21873/invivo.12227
In vivo (Athens, Greece)
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Wed, 06 Jan 2021 06:00:00 -0500
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Hearing Loss Treatment Report, Urgent Research, 2021-01-06T11:28:12+00:00, https://www.hearinglosstreatmentreport.com.
Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research
First published: 30 December 2020 https://doi.org/10.1002/stem.3315
Funding information: Schmieder Bohrisch Foundation; Zürcher Stiftung für das Hören
Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo
Clin Transl Med. 2020 Dec;10(8):e262. doi: 10.1002/ctm2.262.
The lack of approved anti-inflammatory and neuroprotective therapies in otology has been acknowledged in the last decades and recent approaches are heralding a new era in the field. Extracellular vesicles (EVs) derived from human multipotent (mesenchymal) stromal cells (MSC) can be enriched in vesicular secretome fractions, which have been shown to exert effects (eg, neuroprotection and immunomodulation) of their parental cells. Hence, MSC-derived EVs may serve as novel drug candidates for several inner ear diseases. Here, we provide first evidence of a strong neuroprotective potential of human stromal cell-derived EVs on inner ear physiology. In vitro, MSC-EV preparations exerted immunomodulatory activity on T cells and microglial cells. Moreover, local application of MSC-EVs to the inner ear significantly attenuated hearing loss and protected auditory hair cells from noise-induced trauma in vivo. Thus, EVs derived from the vesicular secretome of human MSC may represent a next-generation biological drug that can exert protective therapeutic effects in a complex and nonregenerating organ like the inner ear.
PMID:33377658 | DOI:10.1002/ctm2.262
Clinical and translational medicine
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Wed, 30 Dec 2020 06:00:00 -0500
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Hearing Loss Treatment Report, Urgent Research, 2020-12-30T22:51:39+00:00, https://www.hearinglosstreatmentreport.com.
Building inner ears: recent advances and future challenges for in vitro organoid systems
Wouter H. van der Valk, Matthew R. Steinhart, Jingyuan Zhang & Karl R. Koehler
Cell Death & Differentiation volume 28, pages24–34(2021)Cite this article
Access to the Apical Cochlear Modiolus for Possible Stem Cell-Based and Gene Therapy of the Auditory Nerve
Wrobel, Christian*,†; Bevis, Nicholas F.*; Meyer, Alexander C.*; Beutner, Dirk*Author Information
Otology & Neurotology: November 06, 2020 – Volume Publish Ahead of Print – Issue –
Progenitor cell therapy for acquired pediatric nervous system injury: Traumatic brain injury and acquired sensorineural hearing loss
While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central…
Stem Cells Transl Med. 2020 Oct 9. doi: 10.1002/sctm.20-0026. Online ahead of print.
While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central role in injury response and tissue repair, we here suggest that multipotent stem cell therapies achieve therapeutic effect by altering the immune response to injury, thereby limiting damage due to inflammation and possibly promoting repair. These findings argue for a broader understanding of the mechanisms by which cell therapies can benefit patients.
PMID:33034162 | DOI:10.1002/sctm.20-0026
Stem cells translational medicine
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9 Oct 2020
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Fri, 09 Oct 2020 06:00:00 -0400
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Effects of Growth Factors and the MicroRNA-183 Family on Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells Towards Auditory Neuron-Like Cells
Authors Farnoosh G, Mahmoudian-Sani MR
Published 10 September 2020 Volume 2020:13 Pages 79—89
Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review.
Int J Mol Sci. 2020 Aug 11;21(16):
Authors: Kanzaki S, Toyoda M, Umezawa A, Ogawa K
Inner and middle ear disorders are the leading cause of hearing loss, and are said to be among the greatest risk factors of dementia. The use of regenerative medicine for the treatment of inner ear disorders may offer a potential alternative to cochlear implants for hearing recovery. In this paper, we reviewed recent research and clinical applications in middle and inner ear regeneration and cell therapy. Recently, the mechanism of inner ear regeneration has gradually been elucidated. “Inner ear stem cells,” which may be considered the precursors of various cells in the inner ear, have been discovered in the cochlea and vestibule. Research indicates that cells such as hair cells, neurons, and spiral ligaments may form promising targets for inner ear regenerative therapies by the transplantation of stem cells, including mesenchymal stem cells. In addition, it is necessary to develop tests for the clinical monitoring of cell transplantation. Real-time imaging techniques and hearing rehabilitation techniques are also being investigated, and cell therapy has found clinical application in cochlear implant techniques.
PMID: 32796705 [PubMed – as supplied by publisher]
Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells
Rachel A. Heuer, Kevin T. Nella, Hsiang-Tsun Chang, Kyle S. Coots, Andrew M. Oleksijew, Christian B. Roque, Luisa H.A. Silva, Tammy L. McGuire, Kazuaki Homma, and Akihiro J. Matsuoka
Published Online: 7 Aug 2020 https://doi.org/10.1089/ten.tea.2020.0078
Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2020
View this Special Issue
Review Article | Open Access
Volume 2020 |Article ID 8829660 | 10 pages | https://doi.org/10.1155/2020/8829660
Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals
A simpler way to make sensory hearing cells
July 1, 2020
Keck School of Medicine of USC
Scientists are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as ‘hair cells,’ due to their hair-like protrusions that sense sound waves.
Stem cell-based approaches: Possible route to hearing restoration?
Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells
Pei-Ciao Tang,1 Eri Hashino,1,2 and Rick F. Nelson1,
* 1Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal
Role of Yap/Tead transcription factor complex in maintaining inner ear progenitors during development: new strategies to induce sensory cell regeneration
View ORCID ProfileKsenia Gnedeva, View ORCID ProfileXizi Wang, Melissa M. McGovern, Matthew Barton, Litao Tao, Talon Trecek, View ORCID ProfileTanner O. Monroe, Juan Llamas, Welly Makmura, James F. Martin, Andrew K. Groves, Mark Warchol, and View ORCID ProfileNeil Segil
PNAS June 16, 2020 117 (24) 13552-13561; first published June 1, 2020 https://doi.org/10.1073/pnas.2000175117
Edited by Marianne E. Bronner, California Institute of Technology, Pasadena, CA, and approved April 21, 2020 (received for review January 6, 2020)
While Yap/Tead signaling is well known to influence tissue growth and organ size during development, the molecular outputs of the pathway are tissue- and context-dependent and remain poorly understood. Our work expands the mechanistic understanding of how Yap/Tead signaling controls the precise number of progenitor cells that will be laid down within the developing inner ear to ultimately regulate the final size and function of the sensory organs. We also provide evidence that restoration of hearing and vestibular function may be amenable to YAP-mediated regeneration. Our data show that reactivation of Yap/Tead signaling after hair cell loss induces a proliferative response in vivo—a process thought to be permanently repressed in the mammalian inner ear.
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium—the organ of Corti—progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.
Study charts developmental map of inner ear sound sensor in mice
Data offers valuable resource for developing stem cell-based therapies for hearing loss
Stem Cell Study Offers Clues On How To Potentially Restore Hearing
May 26, 2020
Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells.
Stem Cell Reports. 2020 May 06;:
Authors: Tang PC, Hashino E, Nelson RF
Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant extent in humans. Several protocols have been devised to direct pluripotent stem cells (PSCs) into inner ear hair cells and neurons, which display many properties of their native counterparts. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development. Modeling human diseases in vitro through genetic manipulation of PSCs is already feasible, thereby permitting the elucidation of mechanistic understandings of a wide array of disease etiologies. Early studies on transplantation of PSC-derived otic progenitors have been successful in certain animal models, yet restoration of function and long-term cell survival remain unrealized. Through further research, PSC-based approaches will continue to revolutionize our understanding of inner ear biology and contribute to the development of therapeutic treatments for inner ear disorders.
PMID: 32442531 [PubMed – as supplied by publisher]
Role of microRNA in inner ear stem cells and related research progress.
Am J Stem Cells. 2020;9(2):16-24
Authors: Wu X, Zou S, Wu F, He Z, Kong W
Deafness is one of the major global health problems that seriously affects the quality of human life. At present, there are no successful treatments for deafness caused by cochlear hair cell (HC) damage. The irreversibility of mammalian hearing impairment is that the inner ear’s sensory epithelium cannot repair lost hair cells and neurons through spontaneous regeneration. The goal of stem cell therapy for sensorineural hearing loss is to reconstruct the damaged inner ear structure and achieve functional repair. microRNA (miRNA), as a class of highly conserved endogenous non-coding small RNAs, plays an important role in the development of cochlea and HCs. miRNA also participates in the regulation of stem cell proliferation and differentiation, and plays an important role in the process of regeneration of inner ear HCs, miRNA has a broad application prospect of clinical treatment of hearing loss, which is conducive to solving the medical problem of inner ear HC regeneration.
PMID: 32419976 [PubMed]
Mesenchymal stem cells for sensorineural hearing loss: a systematic review of preclinical studies.
Mol Biol Rep. 2020 Apr 22;:
Authors: Chorath K, Willis M, Morton-Gonzaba N, Moreira A
Sensorineural hearing loss (SNHL) is the most common form of hearing loss that is routinely treated with hearing aids or cochlear implants. Advances in regenerative medicine have now led to animal studies examining the possibility of restoring injured hair cells with mesenchymal stem/stromal cell (MSC) administration. We conducted a systematic review and meta-analysis to collate the existing preclinical literature evaluating MSCs as a treatment for SNHL and quantify the effect of MSCs on functional hearing. Our protocol was published online on CAMARADES. Searches were conducted in four medical databases by two independent investigators. Twelve studies met inclusion and were evaluated for risk of bias using SYRCLE. Rodent models were commonly used (n = 8, 66%), while auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) were the most frequent measures assessing hearing loss. MSCs were derived from multiple tissue sources, including bone marrow, adipose tissue, and umbilical cord blood and the dose ranged from 4 × 103 to 1 × 107 cells. Treatment with MSCs resulted in an improvement in ABR and DPOAE (mean difference-15.22, + 9.10, respectively). Despite high heterogeneity and multiple “unclear” domains in the risk of bias, this review provides evidence that MSCs may have a beneficial effect in hearing function.
PMID: 32323262 [PubMed – as supplied by publisher]
Microenvironment Can Induce Development of Auditory Progenitor Cells from Human Gingival Mesenchymal Stem Cells
Sevda Pouraghaei, Fathollah Moztarzadeh*, Chider Chen, Sahar Ansari, and Alireza Moshaverinia*
Cite this: ACS Biomater. Sci. Eng. 2020, 6, 4, 2263–2273
Publication Date:March 10, 2020
Neuronal Differentiation of Dental Pulp Stem Cells From Human Permanent and Deciduous Teeth Following Coculture With Rat Auditory Brainstem Slices
Sensorineural hearing loss is a common disability found worldwide which is associated with a degeneration of spiral ganglion neurons (SGN). It is a challenge to restore SGN due to the permanent degeneration and viability of SGN is requisite for patients to receive an advantage from hearing aid devices. Human dental pulp stem cells (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) are self-renewing stem cells that originate from the neural crest during development. These stem cells have a high potential for neuronal differentiation. This is primarily due to their multilineage differentiation potential and their relative ease of access. Previously, we have shown the ability of these stem cell types to differentiate into spiral ganglion neuron-like cells. In this study, we induced the cells into neural precursor cells (NPC) and cocultured with auditory brainstem slice (ABS) encompassing cochlear nucleus by the Stoppini method. We also investigated their ability to differentiate after 2 weeks and 4 weeks in coculture. Neuronal differentiation of DPSC-NPC and SHED-NPC was higher expression of specific markers to SGN, TrkB, and Gata3, compared to monoculture. The cells also highly expressed synaptic vesicle protein (SV2A) and exhibited intracellular calcium oscillations. Our findings demonstrated the possibility of using DPSCs and SHEDs as an autologous stem cell-based therapy for sensorineural hearing loss patients.
Forgotten Fibrocytes: A Neglected, Supporting Cell Type of the Cochlea With the Potential to be an Alternative Therapeutic Target in Hearing Loss
Fibrocytes as a Potential Target for Therapy in Hearing Loss and MD
Mesenchymal stem cells for sensorineural hearing loss: protocol for a systematic review of preclinical studies.
Syst Rev. 2019 May 25;8(1):126
Authors: Chorath KT, Willis MJ, Morton-Gonzaba N, Humann WJ, Moreira A
BACKGROUND: Sensorineural hearing loss (SNHL) is the most common form of hearing impairment and is characterized by a loss of receptor hair cells and/or spiral ganglion neurons. Regenerative stem cell therapy could potentially restore normal hearing and slow the progression of hearing loss in patients. Preclinical animal studies have demonstrated that mesenchymal stem cells (MSCs) could be a promising new therapy for this condition. These findings have prompted investigators to begin human clinical trials to assess the safety and efficacy of MSCs for the treatment of SNHL. The objective of the proposed systematic review is to examine the efficacy of MSCs as a therapy for SNHL in animal models.
METHODS: We will include preclinical animal studies of SNHL in which MSCs are administered, and outcomes are compared against MSC-naïve controls. The primary outcome will include audiologic tests that are routinely used in experimental studies of hearing loss, such as auditory brainstem response (ABR) and distortion product otoacoustic emissions testing (DPOAE). Secondary outcomes will include histology, microscopy, gene protein expression, and behavioral responses of animals. Electronic searches of MEDLINE via PubMed, Scopus, ScienceDirect, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be performed. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias and publication bias will be assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool and Funnel Plots/Egger’s regression tests, respectively.
DISCUSSION: This systematic review will provide a summary of the efficacy of MSC therapy in animal models of SNHL, utilizing functional hearing assessment as a primary outcome. Findings from this review are important because they can elucidate research gaps that should be addressed in future preclinical studies and in turn can be translated into clinical studies.
SYSTEMATIC REVIEW REGISTRATION: CAMARADES ( http://www.dcn.ed.ac.uk/camarades/ ).
PMID: 31128597 [PubMed – in process]
Stem-cell therapy for hearing loss: are we there yet?
Stem Cell Based Drug Delivery for Protection of Auditory Neurons in a Guinea Pig Model of Cochlear Implantation.
Front Cell Neurosci. 2019;13:177
Authors: Scheper V, Hoffmann A, Gepp MM, Schulz A, Hamm A, Pannier C, Hubka P, Lenarz T, Schwieger J
Background: The success of a cochlear implant (CI), which is the standard therapy for patients suffering from severe to profound sensorineural hearing loss, depends on the number and excitability of spiral ganglion neurons (SGNs). Brain-derived neurotrophic factor (BDNF) has a protective effect on SGNs but should be applied chronically to guarantee their lifelong survival. Long-term administration of BDNF could be achieved using genetically modified mesenchymal stem cells (MSCs), but these cells should be protected – by ultra-high viscous (UHV-) alginate (‘alginate-MSCs’) – from the recipient immune system and from uncontrolled migration. Methods: Brain-derived neurotrophic factor-producing MSCs were encapsulated in UHV-alginate. Four experimental groups were investigated using guinea pigs as an animal model. Three of them were systemically deafened and (unilaterally) received one of the following: (I) a CI; (II) an alginate-MSC-coated CI; (III) an injection of alginate-embedded MSCs into the scala tympani followed by CI insertion and alginate polymerization. Group IV was normal hearing, with CI insertion in both ears and a unilateral injection of alginate-MSCs. Using acoustically evoked auditory brainstem response measurements, hearing thresholds were determined before implantation and before sacrificing the animals. Electrode impedance was measured weekly. Four weeks after implantation, the animals were sacrificed and the SGN density and degree of fibrosis were evaluated. Results: The MSCs survived being implanted for 4 weeks in vivo. Neither the alginate-MSC injection nor the coating affected electrode impedance or fibrosis. CI insertion with and without previous alginate injection in normal-hearing animals resulted in increased hearing thresholds within the high-frequency range. Low-frequency hearing loss was additionally observed in the alginate-injected and implanted cochleae, but not in those treated only with a CI. In deafened animals, the alginate-MSC coating of the CI significantly prevented SGN from degeneration, but the injection of alginate-MSCs did not. Conclusion: Brain-derived neurotrophic factor-producing MSCs encapsulated in UHV-alginate prevent SGNs from degeneration in the form of coating on the CI surface, but not in the form of an injection. No increase in fibrosis or impedance was detected. Further research and development aimed at verifying long-term mechanical and biological properties of coated electrodes in vitro and in vivo, in combination with chronic electrical stimulation, is needed before the current concept can be tested in clinical trials.
PMID: 31139049 [PubMed]