Cochlear Implant Close-Field Electroporation

Housley, Gary D.; Browne, Cherylea J.; Crawford, Edward N.; Klugmann, Matthias; Lovell, Nigel H.; Pinyon, Jeremy L.

doi:10.1007/978-3-319-26779-1_59-1

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…In contrast to chronic electrical stimulation in neural prostheses where cell or tissue excitability can be related to charge injection and strength-duration curves, hypotheses to explain the novel acute application of bionic array based electric field focusing underlying electroporation based gene delivery (Browne et al, 2016; Housley et al, 2016; Abed et al, 2018) are less established; naked plasmid DNA electrotransfer appears less dependent on membrane pore formation and resealing, than processes of endocytosis (Escoffre et al, 2011). However, both modalities share the premise that efficacy is tied to the strength of the electric field at the target cell or tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Cochlear implants can be considered one of the most clinically successful neuroprostheses, with more than 500,000 devices implanted to aid in the restoration of functional hearing in patients. Electroporation facilitated transfection of neurotrophic factors is a methodology that could allow for improving the efficacy of electrical stimulation in cochlear implants (O’Leary et al, 2009; Pinyon et al, 2014, 2019; Browne et al, 2016; Housley et al, 2016; Abed et al, 2018). Even though the model was developed with electroporation as the primary application in this paper, the inclusion of anatomically realistic geometry and EIS-based electrode-electrolyte model makes it well suited to predict electric potentials and fields generated by shorter pulses typically used in cochlear implants for electrical stimulation of the auditory nerve.…”

Section: Discussionmentioning

confidence: 99%

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Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces

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The neural interface is a critical factor in governing efficient and safe charge transfer between a stimulating electrode and biological tissue. The interface plays a crucial role in the efficacy of electric stimulation in chronic implants and both electromechanical properties and biological properties shape this. In the case of cochlear implants, it has long been recognized that neurotrophins can stimulate growth of the target auditory nerve fibers into a favorable apposition with the electrode array, and recently such arrays have been re-purposed to enable electrotransfer (electroporation)-based neurotrophin gene augmentation to improve the “bionic ear.” For both this acute bionic array-directed electroporation and for chronic conventional cochlear implant arrays, the electric fields generated in target tissue during pulse delivery are central to efficacy, but are challenging to map. We present a computational model for predicting electric fields generated by array-driven DNA electrotransfer in the cochlea. The anatomically realistic model geometry was reconstructed from magnetic resonance images of the guinea pig cochlea and an eight-channel electrode array embedded within this geometry. The model incorporates a description of both Faradaic and non-Faradaic mechanisms occurring at the electrode-electrolyte interface with frequency dependency optimized to match experimental impedance spectrometry measurements. Our simulations predict that a tandem electrode configuration with four ganged cathodes and four ganged anodes produces three to fourfold larger area in target tissue where the electric field is within the range for successful gene transfer compared to an alternate paired anode-cathode electrode configuration. These findings matched in vivo transfection efficacy of a green fluorescent protein (GFP) reporter following array-driven electrotransfer of the reporter-encoding plasmid DNA. This confirms utility of the developed model as a tool to optimize the safety and efficacy of electrotransfer protocols for delivery of neurotrophin growth factors, with the ultimate aim of using gene augmentation approaches to improve the characteristics of the electrode-neural interfaces in chronically implanted neurostimulation devices.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces

et al. 2019

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“…This provides efficient gene electrotransfer at significantly lower voltages than that required for conventional electroporation. In doing so, the production of recombinant neurotrophins by a relatively small group of these mescenchymal cells was shown to stimulate outgrowth of the auditory nerve fibres into close proximity with the cochlear implant electrodes, thereby closing the neural gap and functionally improving the interface with the cochlear implant array as anticipated Housley et al, 2016;Pinyon et al, 2018;Pinyon et al, 2014).…”

Section: Validation Of Badge ® For In Vitro and In Vivo Directed Genementioning

confidence: 99%

Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes

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Dual-Plasmid Bionic Array-Directed Gene Electrotransfer in HEK293 Cells and Cochlear Mesenchymal Cells Probes Transgene Expression and Cell Fate

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Naked plasmid DNA electrotransfer offers advantages over viral-based gene delivery, including being regulatory permissive, but factors influencing expression efficiency and cell fate impact on translational utility. This study compared co-expression of red and green fluorescence reporter plasmids with differing promoters in HEK293 cells and in vivo in guinea pig cochlear mesenchymal cells using Bionic array-Directed Gene Electrotransfer (BaDGE). A functional plasmid copy number of ∼64 was established in HEK293 cells by co-transfecting with separate CMV-actin-globin (CAGp) promoter-driven mCherry and green fluorescent protein (GFP) reporters, where cell division diluted plasmids toward discrete red or green channels from 100% co-expression to 10% over 24 days (∼17 cell cycles). Cross-talk between promoters was identified by interchanging a cytomegalovirus promoter (CMVp)-driven GFP plasmid for the CAGp-GFP plasmid. Here, expression of the CMVp-GFP plasmid dominated, while a dual CAGp-based reporter plasmid cocktail showed persistent co-expression beyond 2 weeks. In contrast, in vivo, cochlear mesenchymal cells co-transduced with CAGp-mCherry and CMVp-GFP plasmids showed stable co-expression at ∼50%, while the total transfectant numbers diminished over 2 weeks. This is consistent with a lack of mitosis in the cochlear mesenchymal cells and shows that cell type is a factor in plasmid interaction.

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Cochlear Implant Close-Field Electroporation

Abstract: Gene electrotransfer • Bionic array • Electric field focusing • Naked DNA • Hearing therapeutics • Neurotrophin • Brain-derived neurotrophic factor • HEK293 cells • Gene therapy

Cited by 4 publications

References 14 publications

Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces

Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces

Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes

Dual-Plasmid Bionic Array-Directed Gene Electrotransfer in HEK293 Cells and Cochlear Mesenchymal Cells Probes Transgene Expression and Cell Fate

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