Graeme Clark Collection
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ItemPromoting neurite outgrowth from spiral ganglion neuron explants using polypyrrole/BDNF-coated electrodes(WILEY, 2009-10)Release of neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF) from hair cells in the cochlea is essential for the survival of spiral ganglion neurons (SGNs). Loss of hair cells associated with a sensorineural hearing loss therefore results in degeneration of SGNs, potentially reducing the performance of a cochlear implant. Exogenous replacement of either or both neurotrophins protects SGNs from degeneration after deafness. We previously incorporated NT3 into the conducting polymer polypyrrole (Ppy) synthesized with para-toluene sulfonate (pTS) to investigate whether Ppy/pTS/NT3-coated cochlear implant electrodes could provide both neurotrophic support and electrical stimulation for SGNs. Enhanced and controlled release of NT3 was achieved when Ppy/pTS/NT3-coated electrodes were subjected to electrical stimulation. Here we describe the release dynamics and biological properties of Ppy/pTS with incorporated BDNF. Release studies demonstrated slow passive diffusion of BDNF from Ppy/pTS/BDNF, with electrical stimulation significantly enhancing BDNF release over 7 days. A 3-day SGN explant assay found that neurite outgrowth from explants was 12.3-fold greater when polymers contained BDNF (p < 0.001), although electrical stimulation did not increase neurite outgrowth further. The versatility of Ppy to store and release neurotrophins, conduct electrical charge, and act as a substrate for nerve-electrode interactions is discussed for specialized applications such as cochlear implants.
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ItemConducting polymers, dual neurotrophins and pulsed electrical stimulation - Dramatic effects on neurite outgrowth(ELSEVIER SCIENCE BV, 2010-01-25)In this study the synergistic effect of delivering two neurotrophins simultaneously to encourage neuron survival and neurite elongation was explored. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were incorporated into polypyrrole (PPy) during electrosynthesis and the amounts incorporated and released were determined using iodine-125 ((125)I) radio-labelled neurotrophins. Neurite outgrowth from cochlear neural explants grown on the conducting polymer was equivalent to that on tissue culture plastic but significantly improved with the incorporation of NT-3 and BDNF. Neurite outgrowth from explants grown on polymers containing both NT-3 and BDNF showed significant improvement over PPy doped only with NT-3, due to the synergistic effect of both neurotrophins. Neurite outgrowth was significantly improved when the polymer containing both neurotrophins was electrically stimulated. It is envisaged that when applied to the cochlear implant, these conducting and novel polymer films will provide a biocompatible substrate for storage and release of neurotrophins to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes.
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ItemNo Preview AvailablePolypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons(ELSEVIER SCI LTD, 2009-05)Sensorineural hearing loss is associated with gradual degeneration of spiral ganglion neurons (SGNs), compromising hearing outcomes with cochlear implant use. Combination of neurotrophin delivery to the cochlea and electrical stimulation from a cochlear implant protects SGNs, prompting research into neurotrophin-eluting polymer electrode coatings. The electrically conducting polypyrrole/para-toluene sulfonate containing neurotrophin-3 (Ppy/pTS/NT3) was applied to 1.7 mm2 cochlear implant electrodes. Ppy/pTS/NT3-coated electrode arrays stored 2 ng NT3 and released 0.1 ng/day with electrical stimulation. Guinea pigs were implanted with Ppy/pTS or Ppy/pTS/NT3 electrode arrays two weeks after deafening via aminoglycosides. The electrodes of a subgroup of these guinea pigs were electrically stimulated for 8 h/day for 2 weeks. There was a loss of SGNs in the implanted cochleae of guinea pigs with Ppy/pTS-coated electrodes indicative of electrode insertion damage. However, guinea pigs implanted with electrically stimulated Ppy/pTS/NT3-coated electrodes had lower electrically-evoked auditory brainstem response thresholds and greater SGN densities in implanted cochleae compared to non-implanted cochleae and compared to animals implanted with Ppy/pTS-coated electrodes (p<0.05). Ppy/pTS/NT3 did not exacerbate fibrous tissue formation and did not affect electrode impedance. Drug-eluting conducting polymer coatings on cochlear implant electrodes present a clinically viable method to promote preservation of SGNs without adversely affecting the function of the cochlear implant.
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ItemThe effect of polypyrrole with incorporated neurotrophin-3 on the promotion of neurite outgrowth from auditory neurons(ELSEVIER SCI LTD, 2007-01)This research aims to improve the nerve-electrode interface of the cochlear implant using polymer technology to encourage neuron survival, elongation and adhesion to the electrodes. Polypyrrole (Ppy) doped with p-toluene sulphonate (pTS) is an electroactive polymer into which neurotrophin-3 (NT3) can be incorporated. Ppy/pTS+/-NT3 was synthesised over gold electrodes and used as a surface for auditory neuron explant culture. Neurite outgrowth from explants grown on Ppy/pTS was equivalent to tissue culture plastic but improved with the incorporation of NT3 (Ppy/pTS/NT3). Electrical stimulation of Ppy/pTS/NT3 with a biphasic current pulse, as used in cochlear implants, significantly improved neurite outgrowth from explants. Using (125)I-NT3, it was shown that low levels of NT3 passively diffused from Ppy/pTS/NT3 during normal incubation and that electrical stimulation enhanced the release of biologically active NT3 in quantities adequate for neuron survival. Furthermore, Ppy/pTS/NT3 and its constituents were not toxic to auditory neurons and the Ppy/pTS/NT3 coating on gold electrodes did not alter impedance. If applied to the cochlear implant, Ppy/pTS/NT3 will provide a biocompatible, low-impedance substrate for storage and release of NT3 to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes.
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ItemDischarge rate-level functions from dorsal cochlear nucleus single units in response to acoustic and electrical stimulation of the auditory nerve( 1995)Discharge rate-level (I/O) functions possessed by dorsal cochlear nucleus (DCN) units were examined, in response to bipolar electrical stimulation of the cochlea of the barbiturate-anesthetized cat. Spontaneously active units usually possessed nonmonotonic functions with a minimum, and spontaneously inactive units usually possessed monotonic functions or nonmonotonic functions with a maximum (NM+). In response to acoustic high-pass filtered noise, the function relating discharge rate and cut off frequency resembled the same unit's I/O function to electrical stimulation. The I/O functions to acoustic characteristic tones were usually monotonic or NM+. These results suggest that in the DCN, a prerequisite for the generation of acoustic-like responses with an electrical stimulus may be the matching of the cochlear place and spatial extent activated by each stimulus.
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ItemModel of discharge rate from auditory nerve fibers responding to electrical stimulation of the cochlea: identification of cues for current and time-interval coding( 1995)A model of the response of auditory nerve fibers to electrical stimulation of the cochlea is presented. Auditory nerve fiber responses are described in terms of cochlear regions activated by the stimulus: region A, in which the discharge rate equals a value of the pulse rate plus spontaneous activity, and region B, in which the discharge rate is less than pulse rate plus spontaneous activity but greater than spontaneous activity. The cues for intensity and time-interval coding provided by regions A and B are discussed.
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ItemNeural processes in the dorsal cochlear nucleus of the anaesthetised cat investigated from unit responses to electrical stimulation of the auditory nerve( 1994)Extracellular responses of dorsal cochlear nucleus single units were recorded in response to biphasic, bipolar electrical stimulation of spiral ganglion cells and their peripheral processes using a banded electrode array in the scala tympani of the barbiturate anaesthetised cat. The DCN responses to this stimulus were the result of excitatory and suppressive (including inhibitory) processes. The excitatory responses from DCN units were usually within a range of 1.8-2.8 ms and these responses were probably the result of monosynaptic input from the auditory nerve. Latencies > 2.8 ms were most likely due to activation of di- and poly-synaptic pathways from auditory nerve fibres, except that latencies between 3.5-4.75 in hearing animals could have arisen from electrophonic mechanisms. Suppression of spontaneous activity was usually long acting, lasting > 70 ms following each pulse of the pulse train, but short acting suppression with a latency of 3.5-4.75 ms and a duration of < 10 ms was occasionally observed. These suppressive responses probably resulted from synaptic inhibitory input, but neural membrane properties may have contributed. In hearing animals, excitatory latencies within the range 1.8-5.2 ms were similar for units with different response area types or different PSTH patterns in response to acoustic CF tones or noise.
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ItemIntracochlear electrical simulation of normal and deaf cats investigated using brainstem response audiometry( 1983)Brainstem response audiometry for intracochlear electrical stimulation of normal-hearing and deafened cats was investigated. In normal cochleas the brainstem response amplitude grew slowly near threshold as a current-amplitude dependent process, identified as electrophonic in origin. This terminated in a rapidly growing charge-dependent process at approximately 20 dB above threshold, identified as direct electrical stimulation of the auditory nerve. Small levels of white noise (25-35 dB SPL) were sufficient to mask most of the electrophonic response, leaving the direct stimulation process essentially unmodified. In cochleas damaged with d.c. currents and loud sounds, only a rapidly growing charge-dependent process was observed which grew similarly to that in normal-hearing cats but occurred at lower currents. This indicates that possibly the electrical properties of the cochlea were altered in the deafening process, suggesting the inadequacy of normal animals as deaf models for electrical stimulation. Using the technique of derived brainstem responses, it was shown that direct electrical stimulus components were localized to the vicinity of the stimulus electrode with electrophonic components distributed more widely. However, at high currents there was some evidence of the stimulus spreading into the internal auditory meatus.