Browsing by Author "Carter, Paul"

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    Chronic intracochlear electrical stimulation at high charge densities results in platinum dissolution but not neural loss or functional changes in vivo
    (IOP Publishing, 2019-01) Shepherd, Robert; Carter, Paul; Enke, Ya Lang; Wise, Andrew; Fallon, James
    OBJECTIVE: Although there are useful guidelines defining the boundary between damaging and non-damaging electrical stimulation they were derived from acute studies using large surface area electrodes in direct contact with cortical neurons. These parameters are a small subset of the parameters used by neural stimulators. More recently, histological examination of cochleae from patients that were long-term cochlear implant users have shown evidence of particulate platinum (Pt). The pathophysiological effect of Pt within the cochlea is unknown. We examined the response of the cochlea to stimulus levels beyond those regarded as safe, and to evaluate the pathophysiological response of the cochlea following chronic stimulation at charge densities designed to induce Pt corrosion. APPROACH: 19 guinea pigs were systemically deafened and implanted with a cochlear electrode array containing eight Pt electrodes of 0.05 0.075 or 0.2 mm2 area. Animals were electrically stimulated continuously for 28 days using charge balanced current pulses at charge densities of 400, 267 or 100 muC/cm2/phase. Electrically-evoked auditory brainstem responses (EABRs) were recorded to monitor neural function. On completion of stimulation electrodes were examined using scanning electron microscopy (SEM) and cochleae examined histology. Finally, analysis of Pt was measured using Energy Dispersive X-ray Spectroscopy (EDS) and inductively coupled plasma mass spectrometry (ICP-MS). MAIN RESULTS: Compared with unstimulated control electrodes and electrodes stimulated at 100 muC/cm2/phase, stimulation at 267 or 400 muC/cm2/phase resulted in significant Pt corrosion. Cochleae stimulated at these high charge densities contained particulate Pt. The extent of the foreign body response depended on the level of stimulation; cochleae stimulated at 267 or 400 muC/cm2/phase exhibited an extensive tissue response that included a focal region of necrosis close to the electrode. Despite chronic stimulation at high charge densities there was no loss of auditory neurons (ANs) in stimulated cochleae compared with their contralateral controls. Indeed, we report a statistically significant increase in AN density proximal to electrodes stimulated at 267 or 400 muC/cm2/phase. Finally, there was no evidence of a reduction in AN function associated with chronic stimulation at 100, 267 or 400 muC/cm2/phase as evidenced by stable EABR thresholds over the stimulation program. SIGNIFICANCE: Chronic electrical stimulation of Pt electrodes at 267 or 400 muC/cm2/phase evoked a vigorous tissue response and produced Pt corrosion products that were located close to the electrode. Despite these changes at the electrode/tissue interface there was no evidence of neural loss or a reduction in neural function.
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    Comparing Perilymph Proteomes Across Species
    (Wiley, 2018-01) Palmer, Jonathon; Lord, Megan; Pinyon, Jeremy; Wise, Andrew; Lovell, Nigel; Carter, Paul; Enke, Ya Lang; Housley, Gary; Green, Rylie
    OBJECTIVES/HYPOTHESIS: Biological components of perilymph affect the electrical performance of cochlear implants. Understanding the perilymph composition of common animal models will improve the understanding of this impact and improve the interpretation of results from animal studies and how it relates to humans. STUDY DESIGN: Analysis and comparison of the proteomes of human, guinea pig, and cat perilymph. METHODS: Multiple perilymph samples from both guinea pigs and cats were analysed via liquid chromatography with tandem mass spectrometry. Proteins were identified using the Mascot database. Human data were obtained from a published dataset. Proteins identified were refined to form a proteome for each species. RESULTS: Over 200 different proteins were found per species. There were 81, 39, and 64 proteins in the final human, guinea pig, and cat proteomes, respectively. Twenty-one proteins were common to all three species. Fifty-two percent of the cat proteome was found in the human proteome, and 31% of the guinea pig was common to human. The cat proteome had similar complexity to the human proteome in three protein classes, whereas the guinea pig had a similar complexity in two. The presence of albumin was significantly higher in human perilymph than in the other two species. Immunoglobulins were more abundant in the human than in the cat proteome. CONCLUSIONS: Perilymph proteomes were compared across three species. The degree of crossover of proteins of both guinea pig and cat with human indicate that these animals suitable models for the human cochlea, albeit the cat perilymph is a closer match. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E47-E52, 2018.
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    Evaluation of focused multipolar stimulation for cochlear implants: a preclinical safety study
    (IOP Publishing Ltd, 2017-06) Shepherd, Robert; Wise, Andrew; Enke, Ya Lang; Carter, Paul; Fallon, James
    OBJECTIVE: Cochlear implants (CIs) have a limited number of independent stimulation channels due to the highly conductive nature of the fluid-filled cochlea. Attempts to develop highly focused stimulation to improve speech perception in CI users includes the use of simultaneous stimulation via multiple current sources. Focused multipolar (FMP) stimulation is an example of this approach and has been shown to reduce interaction between stimulating channels. However, compared with conventional biphasic current pulses generated from a single current source, FMP is a complex stimulus that includes extended periods of stimulation before charge recovery is achieved, raising questions on whether chronic stimulation with this strategy is safe. The present study evaluated the long-term safety of intracochlear stimulation using FMP in a preclinical animal model of profound deafness. APPROACH: Six cats were bilaterally implanted with scala tympani electrode arrays two months after deafening, and received continuous unilateral FMP stimulation at levels that evoked a behavioural response for periods of up to 182 d. Electrode impedance, electrically-evoked compound action potentials (ECAPs) and auditory brainstem responses (EABRs) were monitored periodically over the course of the stimulation program from both the stimulated and contralateral control cochleae. On completion of the stimulation program cochleae were examined histologically and the electrode arrays were evaluated for evidence of platinum (Pt) corrosion. MAIN RESULTS: There was no significant difference in electrode impedance between control and chronically stimulated electrodes following long-term FMP stimulation. Moreover, there was no significant difference between ECAP and EABR thresholds evoked from control or stimulated cochleae at either the onset of stimulation or at completion of the stimulation program. Chronic FMP stimulation had no effect on spiral ganglion neuron (SGN) survival when compared with unstimulated control cochleae. Long-term implantation typically evoked a mild foreign body reaction proximal to the electrode array; however stimulated cochleae exhibited a small but statistically significant increase in the tissue response. Finally, there was no evidence of Pt corrosion following long-term FMP stimulation; stimulated electrodes exhibited the same surface features as the unstimulated control electrodes. SIGNIFICANCE: Chronic intracochlear FMP stimulation at levels used in the present study did not adversely affect electrically-evoked neural thresholds or SGN survival but evoked a small, benign increase in inflammatory response compared to control ears. Moreover chronic FMP stimulation does not affect the surface of Pt electrodes at suprathreshold stimulus levels. These findings support the safe clinical application of an FMP stimulation strategy.
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    Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes
    (Elsevier, Inc., 2019-07) Pinyon, Jeremy; von Jonquieres, Georg; Crawford, Edward; Duxbury, Mayryl; Al Abed, Amr; Lovell, Nigel; Klugmann, Matthias; Wise, Andrew; Fallon, James; Shepherd, Robert; Birman, Catherine; Lai, Waikong; McAlpine, David; McMahon, Catherine; Carter, Paul; Enke, Ya Lang; Patrick, James; Schilder, Anne; Marie, Corinne; Scherman, Daniel; Housley, Gary
    This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies.
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    Platinum dissolution and tissue response following long-term electrical stimulation at high charge densities
    (IOP Publishing, 2021-02) Shepherd, Robert; Carter, Paul; Dalrymple, Ashley; Enke, Ya Lang; Wise, Andrew; Nguyen, Trung; Firth, James; Thompson, Alex; Fallon, James
    OBJECTIVE: Established guidelines for safe levels of electrical stimulation for neural prostheses are based on a limited range of the stimulus parameters used clinically. Recent studies have reported particulate platinum (Pt) associated with long-term clinical use of these devices, highlighting the need for more carefully defined safety limits. We previously reported no adverse effects of Pt corrosion products in the cochleae of guinea pigs following 4 weeks of electrical stimulation using charge densities far greater than the published safe limits for cochlear implants. The present study examines the histopathological effects of Pt within the cochlea following continuous stimulation at a charge density well above the defined safe limits for periods up to 6 months. APPROACH: Six cats were bilaterally implanted with Pt electrode arrays and unilaterally stimulated using charge balanced current pulses at a charge density of 267 C/cm2/phase using a tripolar electrode configuration. Electrochemical measurements were made throughout the implant duration and evoked potentials recorded at the outset and on completion of the stimulation program. Cochleae were examined histologically for particulate Pt, tissue response, and auditory nerve survival; electrodes were examined for surface corrosion; and cochlea, brain, kidney, and liver tissue analysed for trace levels of Pt. MAIN RESULTS: Chronic stimulation resulted in both a significant increase in tissue response and particulate Pt within the tissue capsule surrounding the electrode array compared with implanted, unstimulated control cochleae. Importantly, there was no stimulus-induced loss of auditory neurons or increase in evoked potential thresholds. Stimulated electrodes were significantly more corroded compared with unstimulated electrodes. Trace analysis revealed Pt in both stimulated and control cochleae although significantly greater levels were detected within stimulated cochleae. There was no evidence of Pt in brain or liver; however, trace levels of Pt were recorded in the kidneys of two animals. Finally, increased charge storage capacity and charge injection limit reflected the more extensive electrode corrosion associated with stimulated electrodes. SIGNIFICANCE: Long-term electrical stimulation of Pt electrodes at a charge density well above existing safety limits and nearly an order of magnitude higher than levels used clinically, does not adversely affect the auditory neuron population or reduce neural function, despite a stimulus-induced tissue response and the accumulation of Pt corrosion product. The mechanism resulting in Pt within the unstimulated cochlea is unclear, while the level of Pt observed systemically following stimulation at these very high charge densities does not appear to be of clinical significance.
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    Shepherd, R. K., P. Carter, Y. L. Enke, A. Thompson, B. Flynn, E. Trang, A. Dalrymple, and J. B. Fallon. 2020. Chronic intracochlear electrical stimulation at high charge densities: Reducing platinum dissolution
    (IOP Publishing, 2020-09) Shepherd, Robert; Carter, Paul; Enke, Ya Lang; Thompson, Alex; Flynn, Brianna; Trang, Ella; Dalrymple, Ashley; Fallon, James
    OBJECTIVE: Cochleae of long-term cochlear implant users have shown evidence of particulate platinum (Pt) corroded from the surface of Pt electrodes. The pathophysiological effect of Pt within the cochlea has not been extensively investigated. We previously evaluated the effects of Pt corrosion at high charge densities and reported negligible pathophysiological impact. The present study extends this work by examining techniques that may reduce Pt corrosion. APPROACH: Deafened guinea pigs were continuously stimulated for 28 days using biphasic current pulses at extreme charge densities using: (i) electrode shorting; (ii) electrode shorting with capacitive coupling (CC); or (iii) electrode shorting with alternating leading phase (AP). On completion of stimulation, cochleae were examined for corrosion product, tissue response, auditory nerve (AN) survival and trace levels of Pt; and electrodes examined for surface corrosion. MAIN RESULTS: Pt corrosion was evident at > 200 μC/cm2/phase; the amount dependent on charge density (p < 0.01) and charge recovery technique (p < 0.01); reduced corrosion was apparent using CC. Tissue response increased with charge density (p < 0.007); cochleae stimulated at > 200 μC/cm2/phase exhibited a vigorous response including a focal region of necrosis and macrophages. Notably, tissue response was not dependent on the charge recovery technique (p = 0.56). Despite stimulation at high charge densities resulting in significant levels of Pt corrosion, there was no stimulus induced loss of ANs. SIGNIFICANCE: Significant increases in tissue response and Pt corrosion were observed following stimulation at high charge densities. Charge recovery using CC, and to a lesser extent AP, reduced the amount of Pt corrosion but not the tissue response. Stimulation at change densities an order of magnitude higher than those used when programming cochlear implant recipients in the clinic, produced a vigorous tissue response and corrosion products without evidence of neural loss.