Browsing by Author "Nayagam, David"

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    Biocompatibility of Immobilized Aligned Carbon Nanotubes
    (Wiley, 2011) Nayagam, David; Williams, Richard; Chen, Jun; Magee, Kylie; Irwin, Jennifer; Tan, Justin; Innis, Peter; Leung, Ronald; Finch, Sue; Williams, Chris; Clark, Graeme; Wallace, Gordon
    In vivo host responses to an electrode-like array of aligned carbon nanotubes (ACNTs) embedded within a biopolymer sheet are reported. This biocompatibility study assesses the suitability of immobilized carbon nanotubes for bionic devices. Inflammatory responses and foreign-body histiocytic reactions are not substantially elevated when compared to negative controls following 12 weeks implantation. A fibrous capsule isolates the implanted ACNTs from the surrounding muscle tissue. Filamentous nanotube fragments are engulfed by macrophages, and globular debris is incorporated into the fibrous capsule with no further reaction. Scattered leukocytes are observed, adherent to the ACNT surface. These data indicate that there is a minimal local foreign-body response to immobilized ACNTs, that detached fragments are phagocytosed into an inert material, and that ACNTs do not attract high levels of surface fouling. Collectively, these results suggest that immobilized nanotube structures should be considered for further investigation as bionic components.
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    Broadband Onset Inhibition Can Suppress Spectral Splatter in the Auditory Brainstem
    (2015-05-15) Spencer, Martin; Nayagam, David; Clarey, Janine; Paolini, Antonio; Meffin, Hamish; Burkitt, Anthony; Grayden, David
    In vivo intracellular responses to auditory stimuli revealed that, in a particular population of cells of the ventral nucleus of the lateral lemniscus (VNLL) of rats, fast inhibition occurred before the first action potential. These experimental data were used to constrain a leaky integrate-and-fire (LIF) model of the neurons in this circuit. The post-synaptic potentials of the VNLL cell population were characterized using a method of triggered averaging. Analysis suggested that these inhibited VNLL cells produce action potentials in response to a particular magnitude of the rate of change of their membrane potential. The LIF model was modified to incorporate the VNLL cells’ distinctive action potential production mechanism. The model was used to explore the response of the population of VNLL cells to simple speech-like sounds. These sounds consisted of a simple tone modulated by a saw tooth with exponential decays, similar to glottal pulses that are the repeated impulses seen in vocalizations. It was found that the harmonic component of the sound was enhanced in the VNLL cell population when compared to a population of auditory nerve fibers. This was because the broadband onset noise, also termed spectral splatter, was suppressed by the fast onset inhibition. This mechanism has the potential to greatly improve the clarity of the representation of the harmonic content of certain kinds of natural sounds.
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    Cortical activation following chronic passive implantation of a wide-field suprachoroidal retinal prosthesis
    (IOP Publishing, 2014-06) Villalobos, Joel; Fallon, James; Nayagam, David; Shivdasani, Mohit; Luu, Chi; Allen, Penelope; Shepherd, Robert; Williams, Chris
    OBJECTIVE: The research goal is to develop a wide-field retinal stimulating array for prosthetic vision. This study aimed at evaluating the efficacy of a suprachoroidal electrode array in evoking visual cortex activity after long term implantation. APPROACH: A planar silicone based electrode array (8 mm × 19 mm) was implanted into the suprachoroidal space in cats (ntotal = 10). It consisted of 20 platinum stimulating electrodes (600 μm diameter) and a trans-scleral cable terminated in a subcutaneous connector. Three months after implantation (nchronic = 6), or immediately after implantation (nacute = 4), an electrophysiological study was performed. Electrode total impedance was measured from voltage transients using 500 μs, 1 mA pulses. Electrically evoked potentials (EEPs) and multi-unit activity were recorded from the visual cortex in response to monopolar retinal stimulation. Dynamic range and cortical activation spread were calculated from the multi-unit recordings. MAIN RESULTS: The mean electrode total impedance in vivo following 3 months was 12.5 ± 0.3 kΩ. EEPs were recorded for 98% of the electrodes. The median evoked potential threshold was 150 nC (charge density 53 μC cm(-2)). The lowest stimulation thresholds were found proximal to the area centralis. Mean thresholds from multiunit activity were lower for chronic (181 ± 14 nC) compared to acute (322 ± 20 nC) electrodes (P < 0.001), but there was no difference in dynamic range or cortical activation spread. SIGNIFICANCE: Suprachoroidal stimulation threshold was lower in chronic than acute implantation and was within safe charge limits for platinum. Electrode-tissue impedance following chronic implantation was higher, indicating the need for sufficient compliance voltage (e.g. 12.8 V for mean impedance, threshold and dynamic range). The wide-field suprachoroidal array reliably activated the retina after chronic implantation.
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    Development and Characterization of a Sucrose Microneedle Neural Electrode Delivery System
    (Wiley, 2017-12) Apollo, Nicholas; Jiang, Jonathon; Cheung, Warwick; Baquier, Sebastien; Lai, Alan; Mirebedini, Azadeh; Foroughi, Javad; Wallace, Gordon; Shivdasani, Mohit; Prawer, Steven; Chen, Shou; Williams, Richard; Cook, Mark; Nayagam, David; Garrett, David
    Stable brain–machine interfaces present extraordinary therapeutic and scientific promise. However, the electrode–tissue interface is susceptible to instability and damage during long-term implantation. Soft, flexible electrodes demonstrate improved longevity, but pose a new challenge with regard to simple and accurate surgical implantation. A high aspect ratio water-soluble microneedle is developed based on sucrose which permits straightforward surgical implantation of soft, flexible microelectrodes. Here, a description of the microneedle manufacturing process is presented, along with in vitro and in vivo safety and efficacy assessments. Successful fabrication requires control of the glass transition temperature of aqueous sucrose solutions. The insertion force of 5 different microneedle electrode vehicles is studied in agarose brain phantoms, with the sucrose microneedle eliciting the lowest insertion force and strain energy transfer. Short- and long-term assessments of the pathological response to sucrose microneedle implantations in the brain suggest minimal tissue reactions, comparable to those observed following stainless-steel hypodermic needle punctures. Finally, microelectrodes fabricated from graphene, carbon nanotubes, or platinum are embedded in sucrose microneedles and implanted into an epileptic rat model for 22 d. All electrodes are functional throughout the implantation period, with the graphene electrode exhibiting the largest seizure signal-to-noise ratio and only modest changes in impedance.
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    Development of a Magnetic Attachment Method for Bionic Eye Applications
    (Wiley Periodicals, Inc., 2016) Fox, Kate; Meffin, Hamish; Burns, Owen; Abbott, Carla; Allen, Penelope; Opie, Nicholas; McGowan, Ceara; Yeoh, Jonathon; Ahnood, Arman; Luu, Chi; Cicione, Rosemary; Saudners, Alexia; McPhedran, Michelle; Cardamone, Lisa; Villalobos, Joel; Garrett, David; Nayagam, David; Apollo, Nicholas; Ganesan, Kumaravelu; Shivdasani, Mohit; Stacey, Alastair; Escudie, Mathilde; Lichter, Samantha; Shepherd, Robert; Prawer, Stephen
    Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes.
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    Development of a surgical procedure for implantation of a prototype suprachoroidal retinal prosthesis
    (John Wiley & Sons Inc, 2014-09) Saunders, Alexia; Williams, Chris; Heriot, Wilson; Briggs, Robert; Yeoh, Jonathan; Nayagam, David; McCombe, Mark; Villalobos, Joel; Burns, Owen; Luu, Chi; Ayton, Lauren; McPhedran, Michelle; Opie, Nicholas; McGowan, Ceara; Shepherd, Robert; Guymer, Robyn; Allen, Penelope
    BACKGROUND: Current surgical techniques for retinal prosthetic implantation require long and complicated surgery, which can increase the risk of complications and adverse outcomes. METHOD: The suprachoroidal position is known to be an easier location to access surgically, and so this study aimed to develop a surgical procedure for implanting a prototype suprachoroidal retinal prosthesis. The array implantation procedure was developed in 14 enucleated eyes. A full-thickness scleral incision was made parallel to the intermuscular septum and superotemporal to the lateral rectus muscle. A pocket was created in the suprachoroidal space, and the moulded electrode array was inserted. The scleral incision was closed and scleral anchor point sutured. In 9 of the 14 eyes examined, the device insertion was obstructed by the posterior ciliary neurovascular bundle. Subsequently, the position of this neurovascular bundle in 10 eyes was characterized. Implantation and lead routing procedure was then developed in six human cadavers. The array was tunnelled forward from behind the pinna to the orbit. Next, a lateral canthotomy was made. Lead fixation was established by creating an orbitotomy drilled in the frontal process of the zygomatic bone. The lateral rectus muscle was detached, and implantation was carried out. Finally, pinna to lateral canthus measurements were taken on 61 patients in order to determine optimal lead length. RESULTS: These results identified potential anatomical obstructions and informed the anatomical fitting of the suprachoroidal retinal prosthesis. CONCLUSION: As a result of this work, a straightforward surgical approach for accurate anatomical suprachoroidal array and lead placement was developed for clinical application.
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    The development of neural stimulators: a review of preclinical safety and efficacy studies
    (IOP Publishing, 2018-05) Shepherd, Robert; Villalobos, Joel; Burns, Owen; Nayagam, David
    OBJECTIVE: Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. APPROACH: The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. MAIN RESULTS: Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to develop any specialist surgical tooling required. SIGNIFICANCE: The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator.
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    Effects of deafness and cochlear implant use on temporal response characteristics in cat primary auditory cortex.
    (Elsevier, 2014-09) Fallon, James; Shepherd, Robert; Nayagam, David; Wise, Andrew; Heffer, Leon; Landry, Thomas; Irvine, Dexter
    We have previously shown that neonatal deafness of 7-13 months duration leads to loss of cochleotopy in the primary auditory cortex (AI) that can be reversed by cochlear implant use. Here we describe the effects of a similar duration of deafness and cochlear implant use on temporal processing. Specifically, we compared the temporal resolution of neurons in AI of young adult normal-hearing cats that were acutely deafened and implanted immediately prior to recording with that in three groups of neonatally deafened cats. One group of neonatally deafened cats received no chronic stimulation. The other two groups received up to 8 months of either low- or high-rate (50 or 500 pulses per second per electrode, respectively) stimulation from a clinical cochlear implant, initiated at 10 weeks of age. Deafness of 7-13 months duration had no effect on the duration of post-onset response suppression, latency, latency jitter, or the stimulus repetition rate at which units responded maximally (best repetition rate), but resulted in a statistically significant reduction in the ability of units to respond to every stimulus in a train (maximum following rate). None of the temporal response characteristics of the low-rate group differed from those in acutely deafened controls. In contrast, high-rate stimulation had diverse effects: it resulted in decreased suppression duration, longer latency and greater jitter relative to all other groups, and an increase in best repetition rate and cut-off rate relative to acutely deafened controls. The minimal effects of moderate-duration deafness on temporal processing in the present study are in contrast to its previously-reported pronounced effects on cochleotopy. Much longer periods of deafness have been reported to result in significant changes in temporal processing, in accord with the fact that duration of deafness is a major factor influencing outcome in human cochlear implantees.
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    Electrical stimulation of retinal ganglion cells with diamond and the development of an all diamond retinal prosthesis
    (Elsevier, 2012-08) Hadjinicolaou, Alex; Leung, Ronald; Garrett, David; Ganesan, Kumaravelu; Fox, Kate; Nayagam, David; Shivdasani, Mohit; Meffin, Hamish; Ibbotson, Michael; Prawer, Steven; O'Brien, Brendan
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    A Flexible Wireless System for Preclinical Evaluation of Retinal Prosthesis
    (MYU KK, 2018-01) Thien, Patrick; Millard, Rodney; Epp, Stephanie; Nayagam, David
    In this paper, we present a novel stimulation controller and monitoring system for evaluating the safety and efficacy of implantable neuroprosthetic devices in a preclinical setting. It features a programmable controller designed to be worn in a custom backpack by freely moving feline subjects. A custom controller powered two, modified, 22-channel clinical stimulators simultaneously. The controller and stimulators together weighed 140 g and measured 85 × 70 × 35 mm3. Power was supplied from a 3350 mAh lithium-ion battery. A Bluetooth-enabled laptop-PC base station managed up to six systems and allowed the remote adjustment of the stimulation amplitude and automated collection of stimulator telemetry data. The initial application was for the chronic safety testing of a 44-channel retinal prosthesis. Thirteen feline subjects were implanted with a suprachoroidal electrode array, which was then stimulated or monitored continuously for an average of 54.5 d. Batteries were changed twice weekly and electrode impedances were recorded hourly. This allowed broken electrodes and other issues to be quickly identified and addressed. The ability to remotely control the stimulation amplitude minimised the amount of subject handling that was required, likely reducing subject stress. Existing preclinical evaluation systems are either designed for short-term experiments and have many features but limited battery life, or for long-term static stimulation and are long-lived, but with restricted stimulation parameters and channel counts. Here, we have described a system designed to improve the chronic safety testing of electrode arrays. While it was used here with a suprachoroidal retinal implant, it could be readily adapted for other preclinical models requiring continuous, deterministic stimulation over a prolonged period.
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    Hermetic diamond capsules for biomedical implants enabled by gold active braze alloys
    (Elsevier, Ltd., 2015-03) Lichter, Samantha; Escudie, Mathilde; Stacey, Alastair; Ganesan, Kumaravelu; Fox, Kate; Ahnood, Arman; Apollo, Nicholas; Kua, Dunstan; Lee, Aaron; McGowan, Ceara; Saunders, Alexia; Burns, Owen; Nayagam, David; Williams, Richard; Garrett, David; Meffin, Hamish; Prawer, Stephen
    As the field of biomedical implants matures the functionality of implants is rapidly increasing. In the field of neural prostheses this is particularly apparent as researchers strive to build devices that interact with highly complex neural systems such as vision, hearing, touch and movement. A retinal implant, for example, is a highly complex device and the surgery, training and rehabilitation requirements involved in deploying such devices are extensive. Ideally, such devices will be implanted only once and will continue to function effectively for the lifetime of the patient. The first and most pivotal factor that determines device longevity is the encapsulation that separates the sensitive electronics of the device from the biological environment. This paper describes the realisation of a free standing device encapsulation made from diamond, the most impervious, long lasting and biochemically inert material known. A process of laser micro-machining and brazing is described detailing the fabrication of hermetic electrical feedthroughs and laser weldable seams using a 96.4% gold active braze alloy, another material renowned for biochemical longevity. Accelerated ageing of the braze alloy, feedthroughs and hermetic capsules yielded no evidence of corrosion and no loss of hermeticity. Samples of the gold braze implanted for 15 weeks, in vivo, caused minimal histopathological reaction and results were comparable to those obtained from medical grade silicone controls. The work described represents a first account of a free standing, fully functional hermetic diamond encapsulation for biomedical implants, enabled by gold active alloy brazing and laser micro-machining.
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    In vitro and In vivo comparison of the charge injection capacity of platinum macroelectrodes
    (IEEE, 2015-03) Leung, Ronald; Shivdasani, Mohit; Nayagam, David; Shepherd, Robert
    Platinum (Pt) is the most commonly used metal for stimulating electrodes. This study aims to determine the amount of charge that can be delivered without causing irreversible electrochemical reactions (charge injection capacity, Q inj) of Pt macroelectrodes (geometric surface area >0.001 cm(2)) in vitro and in vivo using voltage transient measurements. Pt macroelectrodes were stimulated with biphasic charge-balanced cathodic-first constant-current pulses in phosphate buffered saline. Potential excursions were measured (versus Ag/AgCl electrode) and used to determine Qinj. The in vitro Qinj were compared to those measured in vivo following: acute and chronic implantation close to the retina; chronic intracochlear implantation; and acute subdural implantation, in the cat. Qinj increased with pulsewidth from 35 to 54 μC/cm(2) for respective pulse widths of 100 to 3200 μs per phase in vitro. Qinj was significantly less in vivo. There was no significant difference in Qinj between acutely (3.84 to 16.6 μC/cm(2) with pulsewidths of 100 to 3200 μs) and chronically (6.99 to 15.8 μC/cm(2) with pulsewidths of 200 to 3200 μs) implanted suprachoroidal electrodes. Intracochlear Qinj was not different to suprachoroidal Qinj, while subdural Qinj was significantly less than the suprachoroidal Q inj (p < 0.05). These results have important implications in providing guidelines on Qinj for the safe use of Pt stimulating macroelectrodes and question the relevance of measuring Qinj in vivo using voltage transients.
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    An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants
    (Mary Ann Liebert Inc Publishers, 2013-03) Nayagam, Bryony; Edge, Albert; Needham, Karina; Hyakumura, Tomoko; Leung, Jessie; Nayagam, David; Dottori, Mirella
    In mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. To successfully replace auditory neurons, stem cell-derived neurons must be electrically active, capable of organized outgrowth of processes, and of making functional connections with appropriate tissues. We have developed an in vitro assay to test these parameters using cocultures of developing cochlear explants together with neural progenitors derived from human embryonic stem cells (hESCs). We found that these neural progenitors are electrically active and extend their neurites toward the sensory hair cells in cochlear explants. Importantly, this neurite extension was found to be signifi- cantly greater when neural progenitors were predifferentiated toward a neural crest-like lineage. When grown in coculture with hair cells only (denervated cochlear explants), stem cell-derived processes were capable of lo- cating and growing along the hair cell rows in an en passant-like manner. Many presynaptic terminals (synapsin 1-positive) were observed between hair cells and stem cell-derived processes in vitro. These results suggest that differentiated hESC-derived neural progenitors may be useful for developing therapies directed at auditory nerve replacement, including complementing emerging hair cell regeneration therapies.This is a copy of an article published in the Stem Cells and Development Journal © 2013 [copyright Mary Ann Liebert, Inc.]; Stem Cells and Development is available online at: http://online.liebertpub.com.
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    In vivo biocompatibility of boron doped and nitrogen included conductive-diamond for use in medical implants
    (John Wiley & Sons Inc, 2015-01) Garrett, David; Saunders, Alexia; McGowan, Ceara; Specks, Joscha; Ganesan, Kumaravelu; Meffin, Hamish; Williams, Richard; Nayagam, David
    Recently, there has been interest in investigating diamond as a material for use in biomedical implants. Diamond can be rendered electrically conducting by doping with boron or nitrogen. This has led to inclusion of boron doped and nitrogen included diamond elements as electrodes and/or feedthroughs for medical implants. As these conductive device elements are not encapsulated, there is a need to establish their clinical safety for use in implants. This article compares the biocompatibility of electrically conducting boron doped diamond (BDD) and nitrogen included diamond films and electrically insulating poly crystalline diamond films against a silicone negative control and a BDD sample treated with stannous octoate as a positive control. Samples were surgically implanted into the back muscle of a guinea pig for a period of 4-15 weeks, excised and the implant site sectioned and submitted for histological analysis. All forms of diamond exhibited a similar or lower thickness of fibrotic tissue encapsulating compared to the silicone negative control samples. All forms of diamond exhibited similar or lower levels of acute, chronic inflammatory, and foreign body responses compared to the silicone negative control indicating that the materials are well tolerated in vivo. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015.
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    In vivo biocompatibility of boron doped and nitrogen included conductive-diamond for use in medical implants
    (Wiley Online Library, 2015-01-21) Garrett, David; Saunders, Alexia; McGowan, Ceara; Specks, Joshua; Ganesan, Kumaravelu; Meffin, Hamish; Williams, Richard; Nayagam, David
    Recently, there has been interest in investigating diamond as a material for use in biomedical implants. Diamond can be rendered electrically conducting by doping with boron or nitrogen. This has led to inclusion of boron doped and nitrogen included diamond elements as electrodes and/or feedthroughs for medical implants. As these conductive device elements are not encapsulated, there is a need to establish their clinical safety for use in implants. This article compares the biocompatibility of electrically conducting boron doped diamond (BDD) and nitrogen included diamond films and electrically insulating poly crystalline diamond films against a silicone negative control and a BDD sample treated with stannous octoate as a positive control. Samples were surgically implanted into the back muscle of a guinea pig for a period of 4-15 weeks, excised and the implant site sectioned and submitted for histological analysis. All forms of diamond exhibited a similar or lower thickness of fibrotic tissue encapsulating compared to the silicone negative control samples. All forms of diamond exhibited similar or lower levels of acute, chronic inflammatory, and foreign body responses compared to the silicone negative control indicating that the materials are well tolerated in vivo.
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    In Vivo Feasibility of Epiretinal Stimulation Using Ultrananocrystalline Diamond 1 Electrodes
    (IOP Publishing, 2020-07) Shivdasani, Mohit; Evans, Mihailo; Burns, Owen; Yeoh, Jonathon; Allen, Penelope; Nayagam, David; Villalobos, Joel; Abbott, Carla; Luu, Chi; Opie, Nicholas; Sabu, Anu; Saunders, Alexia; McPhedran, Michelle; Cardamone, Lisa; McGowan, Ceara; Maxim, Vanessa; Williams, Richard; Fox, Kate; Cicione, Rosemary; Garrett, David; Ahnood, Arman; Ganesan, Kumaravelu; Meffin, Hamish; Burkitt, Anthony; Prawer, Steven; Williams, Chris; Shepherd, Robert
    PURPOSE: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes. METHODS: A prototype implant containing up to twenty-five 120×120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously. RESULTS: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in 8 animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in-situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment. CONCLUSIONS: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.
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    Oculomotor Responses to Dynamic Stimuli in a 44-Channel Suprachoroidal Retinal Prosthesis
    (tvst, 2020-12) Titchener, Samuel; Kvansakul, Jessica; Shivdasani, Mohit; Nayagam, David; Epp, Stephanie; Williams, Chris; Barnes, Nick; Kentler, William; Kolic, Maria; Balin, Elizabeth; Ayton, Lauren; Abbott, Carla; Luu, Chi; Allen, Penelope; Petoe, Matthew
    PURPOSE: To investigate oculomotor behavior in response to dynamic stimuli in retinal implant recipients. METHODS: Three suprachoroidal retinal implant recipients performed a four-alternative forced-choice motion discrimination task over six sessions longitudinally. Stimuli were a single white bar ("moving bar") or a series of white bars ("moving grating") sweeping left, right, up, or down across a 42″ monitor. Performance was compared with normal video processing and scrambled video processing (randomized image-to-electrode mapping to disrupt spatiotemporal structure). Eye and head movement was monitored throughout the task. RESULTS: Two subjects had diminished performance with scrambling, suggesting retinotopic discrimination was used in the normal condition and made smooth pursuit eye movements congruent to the moving bar stimulus direction. These two subjects also made stimulus-related eye movements resembling optokinetic reflex (OKR) for moving grating stimuli, but the movement was incongruent with stimulus direction. The third subject was less adept at the task, appeared primarily reliant on head position cues (head movements were congruent to stimulus direction), and did not exhibit retinotopic discrimination and associated eye movements. CONCLUSIONS: Our observation of smooth pursuit indicates residual functionality of cortical direction-selective circuits and implies a more naturalistic perception of motion than expected. A distorted OKR implies improper functionality of retinal direction-selective circuits, possibly due to retinal remodeling or the non-selective nature of the electrical stimulation. TRANSLATIONAL RELEVANCE: Retinal implant users can make naturalistic eye movements in response to moving stimuli, highlighting the potential for eye tracker feedback to improve perceptual localization and image stabilization in camera-based visual prostheses.
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    Ring and peg electrodes for minimally-Invasive and long-term sub-scalp EEG recordings
    (Elsevier, Ltd., 2017-06) Benovitski, Yuri; Lai, Alan; McGowan, Ceara; Burns, Owen; Maxim, Vanessa; Nayagam, David; Millard, Rodney; Rathbone, Graeme; le Chevoir, M.A.; Williams, R.A.; Grayden, David; May, C.N.; Murphy, M.; D'Souza, Wendyl; Cook, Mark; Williams, Chris
    OBJECTIVE: Minimally-invasive approaches are needed for long-term reliable Electroencephalography (EEG) recordings to assist with epilepsy diagnosis, investigation and more naturalistic monitoring. This study compared three methods for long-term implantation of sub-scalp EEG electrodes. METHODS: Three types of electrodes (disk, ring, and peg) were fabricated from biocompatible materials and implanted under the scalp in five ambulatory ewes for 3months. Disk electrodes were inserted into sub-pericranial pockets. Ring electrodes were tunneled under the scalp. Peg electrodes were inserted into the skull, close to the dura. EEG was continuously monitored wirelessly. High resolution CT imaging, histopathology, and impedance measurements were used to assess the status of the electrodes at the end of the study. RESULTS: EEG amplitude was larger in the peg compared with the disk and ring electrodes (p<0.05). Similarly, chewing artifacts were lower in the peg electrodes (p<0.05). Electrode impedance increased after long-term implantation particularly for those within the bone (p<0.01). Micro-CT scans indicated that all electrodes stayed within the sub-scalp layers. All pegs remained within the burr holes as implanted with no evidence of extrusion. Eight of 10 disks partially eroded into the bone by 1.0mm from the surface of the skull. The ring arrays remained within the sub-scalp layers close to implantation site. Histology revealed that the electrodes were encapsulated in a thin fibrous tissue adjacent to the pericranium. Overlying this was a loose connective layer and scalp. Erosion into the bone occurred under the rim of the sub-pericranial disk electrodes. CONCLUSIONS: The results indicate that the peg electrodes provided high quality EEG, mechanical stability, and lower chewing artifact. Whereas, ring electrode arrays tunneled under the scalp enable minimal surgical techniques to be used for implantation and removal.
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    Safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a feline model
    (John Wiley and Sons, 2015-04) Leung, Ronald; Nayagam, David; Williams, Richard; Allen, Penelope; Salinas-La Rosa, Cesar; Shivdasani, Mohit; Ayton, Lauren; Basa, Meri; Yeoh, Jonathan; Saunders, Alexia; Shepherd, Robert; Williams, Chris
    BACKGROUND: A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. METHODS: Suprachoroidal electrode arrays were unilaterally implanted into 13 adult felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. RESULTS: Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P < 0.03). Staphylomas developed near the scleral wound in five animals after device explantation. Device replacement did not alter the cortical evoked potential threshold. Histopathology showed localized outer nuclear layer thinning, tapetal disruption and pseudo-rosette formation, but the overall retinal morphology was preserved. CONCLUSIONS: It is feasible to remove or replace conformable medical grade silicone electrode arrays implanted suprachoroidally. The scleral wound requires careful closure to minimize the risk of staphylomas.
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    Safety Studies for a 44-Channel Suprachoroidal Retinal Prosthesis: A Chronic Passive Study
    (IOVS, 2018-03) Abbott, Carla; Nayagam, David; Luu, Chi; Epp, Stephanie; Williams, Richard; Salinas-LaRosa, Cesar; Villalobos, Joel; McGowan, Ceara; Shivdasani, Mohit; Burns, Owen; Leavens, Jason; Yeoh, Jonathon; Brandli, Alice; Thien, Patrick; Zhou, Jenny; Feng, Helen; Williams, Chris; Shepherd, Robert; Allen, Penelope
    Abstract Purpose: Following successful clinical outcomes of the prototype suprachoroidal retinal prosthesis, Bionic Vision Australia has developed an upgraded 44-channel suprachoroidal retinal prosthesis to provide a wider field of view and more phosphenes. The aim was to evaluate the preclinical passive safety characteristics of the upgraded electrode array. Methods: Ten normal-sighted felines were unilaterally implanted with an array containing platinum electrodes (44 stimulating and 2 returns) on a silicone carrier near the area centralis. Clinical assessments (color fundus photos, optical coherence tomography, full-field electroretinography, intraocular pressure) were performed under anesthesia prior to surgery, and longitudinally for up to 20 weeks. Histopathology grading of fibrosis and inflammation was performed in two animals at 13 to 15 weeks. Results: Eight animals showed safe electrode array insertion (good retinal health) and good conformability of the array to the retinal curvature. Eight animals demonstrated good mechanical stability of the array with only minor (<2 disc diameters) lateral movement. Four cases of surgical or stability complications occurred due to (1) bulged choroid during surgery, (2) hemorrhage from a systemic bleeding disorder, (3) infection, and (4) partial erosion of thin posterior sclera. There was no change in retinal structure or function (other than that seen at surgery) at endpoint. Histopathology showed a mild foreign body response. Electrodes were intact on electrode array removal. Conclusions: The 44-channel suprachoroidal electrode array has an acceptable passive safety profile to proceed to clinical trial. The safety profile is expected to improve in human studies, as the complications seen are specific to imitations (anatomic differences) with the feline model.