Medical Bionics - Research Publications

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    Hybrid optogenetic and electrical stimulation for greater spatial resolution and temporal fidelity of cochlear activation
    Thompson, AC ; Wise, AK ; Hart, WL ; Needham, K ; Fallon, JB ; Gunewardene, N ; Stoddart, PR ; Richardson, RT (IOP PUBLISHING LTD, 2020-10)
    OBJECTIVE: Compared to electrical stimulation, optogenetic stimulation has the potential to improve the spatial precision of neural activation in neuroprostheses, but it requires intense light and has relatively poor temporal kinetics. We tested the effect of hybrid stimulation, which is the combination of subthreshold optical and electrical stimuli, on spectral and temporal fidelity in the cochlea by recording multiunit activity in the inferior colliculus of channelrhodopsin (H134R variant) transgenic mice. APPROACH: Pulsed light or biphasic electrical pulses were delivered to cochlear spiral ganglion neurons of acutely deafened mice, either as individual stimuli or as hybrid stimuli for which the timing of the electrical pulse had a varied delay relative to the start of the optical pulse. Response thresholds, spread of activation and entrainment data were obtained from multi-unit recordings from the auditory midbrain. MAIN RESULTS: Facilitation occurred when subthreshold electrical stimuli were applied at the end of, or up to 3.75 ms after subthreshold optical pulses. The spread of activation resulting from hybrid stimulation was significantly narrower than electrical-only and optical-only stimulation (p < 0.01), measured at equivalent suprathreshold levels of loudness that are relevant to cochlear implant users. Furthermore, temporal fidelity, measured as maximum following rates to 300 ms pulse trains bursts up to 240 Hz, was 2.4-fold greater than optical-only stimulation (p < 0.05). SIGNIFICANCE: By significantly improving spectral resolution of electrical- and optical-only stimulation and the temporal fidelity of optical-only stimulation, hybrid stimulation has the potential to increase the number of perceptually independent stimulating channels in a cochlear implant.
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    Effects of chronic implantation and long-term stimulation of a cochlear implant in the partial hearing cat model
    Fallon, JB ; Dueck, W ; Trang, EP ; Smyth, D ; Wise, AK (ELSEVIER, 2022-12)
    The expansion of criteria for cochlear implantation has resulted in increasing numbers of cochlear implant subjects having some level of residual hearing. The present study examined the effects of implantation surgery and long-term electrical stimulation on residual hearing in a partially deafened cat model. Eighteen animals were partially deafened, implanted and chronically stimulated. Implantation resulted in a pronounced loss evident 2-weeks post implantation of up to 30-40 dB at 4 & 8 kHz which was statistically significant (2-way RM ANOVA (Time, Frequency): p(Time) = 0.001; p(Frequency) < 0.001; p(Time x Frequency) < 0.001)). Chronic stimulation resulted in a significant (RM ANOVA: p(Time) = 0.030) ongoing hearing loss, with 5 animals (∼30%) exhibiting an increase in threshold of 20 dB or more. Different loss profiles were evident with peripheral and central hearing assessments suggests that changes in 'central gain' may be occurring. Despite significant loss of hair cells and spiral ganglion neurons and distinct fibrous tissue growth in the scala tympani following implantation and long-term electrical stimulation, there were no significant correlations with any histological measures and ongoing hearing loss. The partially deafened, chronically stimulated cat model provides a clinically relevant model in which to further investigate the cause of the delayed hearing loss following cochlear implant surgery and use.
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    Effects of an enhanced acoustic environment on residual hearing following chronic cochlear implantation and electrical stimulation in the partially deafened cat
    Wise, AK ; Atkinson, P ; Fallon, JB (ELSEVIER, 2022-12)
    There is an increasing trend to provide cochlear implants for people with useful residual hearing, typically in the low frequency range (<2 kHz). These recipients typically use both electrical stimulation from their implant and acoustic stimulation that has been amplified with a hearing aid to access their residual hearing, so called electro-acoustic stimulation (EAS). However, a significant problem is the loss of residual hearing following implantation that can occur immediately following surgery or delayed over many months. One potential cause of the loss of residual hearing is the over stimulation of remaining hair cells due to the combination of an amplified acoustic input and direct electrical activation. This paper aims to test this hypothesis. Here, we have used a neonatal aminoglycoside-induced partial hearing cat model that resulted in a high frequency hearing loss (>4 kHz). Two separate cohorts of animals were implanted and received unilateral chronic electrical stimulation using clinical stimulators and speech processors over 5 months. To simulate potential over stimulation via a hearing aid, one cohort of animals were also exposed to an enhanced acoustic environment consisting of 80 dB SPL 4-talker babble presented 14 h per day. Hearing thresholds for both stimulated and unstimulated ears were measured throughout the implantation period. Cochleae were collected for histology to measure spiral ganglion neuron survival, hair cell survival and tissue response to chronic implantation and electrical stimulation. Consistent with clinical observations, cochlear implantation and stimulation resulted in an increase in threshold across the population. There was no significant effect of the enhanced acoustic environment on auditory thresholds or histological measures (hair cell survival, neuronal survival) of hearing, indicating that hair cell overstimulation was not a significant driver of loss of residual hearing.
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    Platinum dissolution and tissue response following long-term electrical stimulation at high charge densities
    Shepherd, RK ; Carter, PM ; Dalrymple, AN ; Enke, YL ; Wise, AK ; Nguyen, T ; Firth, J ; Thompson, A ; Fallon, JB (IOP Publishing Ltd, 2021-04)
    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 267μC cm-2phase-1using 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 (ANs) 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 AN 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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    Pharmacokinetics and biodistribution of supraparticle-delivered neurotrophin 3 in the guinea pig cochlea
    Gunewardene, N ; Lam, P ; Ma, Y ; Caruso, F ; Wagstaff, S ; Richardson, RT ; Wise, AK (ELSEVIER, 2022-02)
    Hearing loss is the most prevalent sensory disorder affecting nearly half a billion people worldwide. Aside from devices to assist hearing, such as hearing aids and cochlear implants, a drug treatment for hearing loss has yet to be developed. The neurotrophin family of growth factors has long been established as a potential therapy, however delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We previously demonstrated that direct delivery of exogenous neurotrophin-3 (NT3) in the guinea pig cochleae via a bolus injection was rapidly cleared from the inner ear, with almost complete elimination 3 days post-treatment. Here, we explored the potential of suprapaticles (SPs) for NT3 delivery to the inner ear to achieve sustained delivery over time. SPs are porous spheroid structures comprised of smaller colloidal silica nanoparticles that provide a platform for long-term controlled release of therapeutics. This study aimed to assess the pharmacokinetics and biodistribution of SP-delivered NT3. We used a radioactive tracer (iodine 125: 125I) to label the NT3 to determine the loading, retention and distribution of NT3 delivered via SPs. Gamma measurements taken from 125I NT3 loaded SPs revealed high drug loading (an average of 5.3 μg of NT3 loaded per SP weighing 50 μg) and elution capacities in vitro (67% cumulative release over one month). Whole cochlear gamma measurements from SP-implanted cochleae harvested at various time points revealed detection of 125I NT3 in the guinea pig cochlea after one month, with 3.6 and 10% of the loaded drug remaining in the intracochlear and round window-implanted cochleae respectively. Autoradiography analysis of cochlear micro-sections revealed widespread 125I NT3 distribution after intracochlear SP delivery, but more restricted distribution with the round window delivery approach. Collectively, drug delivery into the inner ear using SPs support sustained, long-term availability and release of neurotrophins in the inner ear.
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    Viral-mediated transduction of auditory neurons with opsins for optical and hybrid activation
    Richardson, RT ; Thompson, AC ; Wise, AK ; Ajay, EA ; Gunewardene, N ; O'Leary, SJ ; Stoddart, PR ; Fallon, JB (NATURE PORTFOLIO, 2021-05-27)
    Optical stimulation is a paradigm-shifting approach to modulating neural activity that has the potential to overcome the issue of current spread that occurs with electrical stimulation by providing focused stimuli. But optical stimulation either requires high power infrared light or genetic modification of neurons to make them responsive to lower power visible light. This work examines optical activation of auditory neurons following optogenetic modification via AAV injection in two species (mouse and guinea pig). An Anc80 viral vector was used to express the channelrhodopsin variant ChR2-H134R fused to a fluorescent reporter gene under the control of the human synapsin-1 promoter. The AAV was administered directly to the cochlea (n = 33) or posterior semi-circular canal of C57BL/6 mice (n = 4) or to guinea pig cochleae (n = 6). Light (488 nm), electrical stimuli or the combination of these (hybrid stimulation) was delivered to the cochlea via a laser-coupled optical fibre and co-located platinum wire. Activation thresholds, spread of activation and stimulus interactions were obtained from multi-unit recordings from the central nucleus of the inferior colliculus of injected mice, as well as ChR2-H134R transgenic mice (n = 4). Expression of ChR2-H134R was examined by histology. In the mouse, transduction of auditory neurons by the Anc80 viral vector was most successful when injected at a neonatal age with up to 89% of neurons transduced. Auditory neuron transductions were not successful in guinea pigs. Inferior colliculus responses to optical stimuli were detected in a cochleotopic manner in all mice with ChR2-H134R expression. There was a significant correlation between lower activation thresholds in mice and higher proportions of transduced neurons. There was no difference in spread of activation between optical stimulation and electrical stimulation provided by the light/electrical delivery system used here (optical fibre with bonded 25 µm platinum/iridium wire). Hybrid stimulation, comprised of sub-threshold optical stimulation to 'prime' or raise the excitability of the neurons, lowered the threshold for electrical activation in most cases, but the impact on excitation width was more variable compared to transgenic mice. This study demonstrates the impact of opsin expression levels and expression pattern on optical and hybrid stimulation when considering optical or hybrid stimulation techniques for neuromodulation.
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    Percutaneous intrarenal transplantation of differentiated induced pluripotent stem cells into newborn mice.
    Lau, RWK ; Al-Rubaie, A ; Saini, S ; Wise, AF ; Ricardo, SD (Wiley, 2020-10)
    The in vivo engraftment of induced pluripotent stem cell (iPSC)-derived podocytes following allogeneic transplantation into host kidneys remains a challenge. Here we investigate the survival and engraftment of human dermal fibroblasts-derived differentiated iPSCs using a newborn mouse model, which represents a receptive immunoprivileged host environment. iPSCs were generated from skin biopsies of patients using Sendai virus reprogramming. Differentiation of nephrin (NPHS1)-green fluorescent protein (GFP) iPSCs into kidney podocytes (iPSC-PODs) was performed by the addition of Activin A, bone morphogenetic protein 7 (BMP7), and retinoic acid over 10 days of culture. To assess the in vivo incorporation of cells, undifferentiated iPSCs or day 10 iPSC-PODs, were labeled with either carboxyfluorescein succinimidyl ester (CFSE) or Qdot nanocrystals (Q705). Thereafter, 1 × 105 differentiated iPSC-PODs were injected directly into the kidneys of mouse pups at postnatal day one (P1). Using co-expression analysis of glomerular and podocyte-specific markers, Day 10 differentiated iPSC-PODs that were positive for podocin, were detected following direct kidney injection into newborn mice up to 1 week after transplantation. Undifferentiated iPSC-PODs were not detected at the same timepoint. The transplanted cells were viable and located in the outer nephrogenic zone where they were found to colocalize with, or sit adjacent to, cells positive for glomerular-specific markers including podocin, synaptopodin, and Wilms' tumor 1 (WT1). This study provides proof-of-principle that transplanted iPSC-POD can survive in recipient newborn mouse kidneys due to the immature and immunoprivileged nature of the developing postnatal kidneys.
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    Integrated multi-omics framework of the plant response to jasmonic acid
    Zander, M ; Lewsey, MG ; Clark, NM ; Yin, L ; Bartlett, A ; Guzman, JPS ; Hann, E ; Langford, AE ; Jow, B ; Wise, A ; Nery, JR ; Chen, H ; Bar-Joseph, Z ; Walley, JW ; Solano, R ; Ecker, JR (NATURE PUBLISHING GROUP, 2020-03)
    Understanding the systems-level actions of transcriptional responses to hormones provides insight into how the genome is reprogrammed in response to environmental stimuli. Here, we investigated the signalling pathway of the hormone jasmonic acid (JA), which controls a plethora of critically important processes in plants and is orchestrated by the transcription factor MYC2 and its closest relatives in Arabidopsis thaliana. We generated an integrated framework of the response to JA, which spans from the activity of master and secondary regulatory transcription factors, through gene expression outputs and alternative splicing, to protein abundance changes, protein phosphorylation and chromatin remodelling. We integrated time-series transcriptome analysis with (phospho)proteomic data to reconstruct gene regulatory network models. These enabled us to predict previously unknown points of crosstalk of JA to other signalling pathways and to identify new components of the JA regulatory mechanism, which we validated through targeted mutant analysis. These results provide a comprehensive understanding of how a plant hormone remodels cellular functions and plant behaviour, the general principles of which provide a framework for analyses of cross-regulation between other hormone and stress signalling pathways.
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    Optical stimulation of neural tissue
    Richardson, RT ; Ibbotson, MR ; Thompson, AC ; Wise, AK ; Fallon, JB (INST ENGINEERING TECHNOLOGY-IET, 2020-06)
    Electrical stimulation has been used for decades in devices such as pacemakers, cochlear implants and more recently for deep brain and retinal stimulation and electroceutical treatment of disease. However, current spread from the electrodes limits the precision of neural activation, leading to a low quality therapeutic outcome or undesired side-effects. Alternative methods of neural stimulation such as optical stimulation offer the potential to deliver higher spatial resolution of neural activation. Direct optical stimulation is possible with infrared light, while visible light can be used to activate neurons if the neural tissue is genetically modified with a light sensitive ion channel. Experimentally, both methods have resulted in highly precise stimulation with little spread of activation at least in the cochlea, each with advantages and disadvantages. Infrared neural stimulation does not require modification of the neural tissue, but has very high power requirements. Optogenetics can achieve precision of activation with lower power, but only in conjunction with targeted insertion of a light sensitive ion channel into the nervous system via gene therapy. This review will examine the advantages and limitations of optical stimulation of neural tissue, using the cochlea as an exemplary model and recent developments for retinal and deep brain stimulation.