Search

Purpose: The Argus I implant is the first-generation epiretinal prosthesis approved for an investigational clinical trial by the United States Food and Drug Administration. Herein we report testing results obtained from a 10-year follow-up to study the physiologic effects of the bioelectronic visual implant after prolonged chronic electrical stimulation., Design: Case report., Participant: One man, 55 years of age when enrolled in the study, underwent surgical implantation of the Argus I in June 2004, followed by periodic tests from July 2004 through June 2014, spanning a total of 10 years., Methods: The decade-long follow-up consisted of implant system performance tests, subject visual function evaluation, and implant-retina interface analysis., Main Outcome Measures: Changes in electrode impedance and perceptual threshold over the time course; subject's performance on visual function task, orientation, and mobility tests; and optical coherence tomography data, fundus imaging, and fluorescein angiography results for the assessment of subject's implant-retina physical interface., Results: Electrically elicited phosphenes were present 10 years after implantation of an epiretinal stimulator. The test subject not only was able to perceive phosphenes, but also could perform visual tasks at rates well above chance., Conclusions: This decade-long follow-up report provides further support for the use of retinal prostheses as a long-lasting treatment for some types of blindness., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Electrical impedance of the retina is a critical factor in retinal prostheses, determining the intraretinal current flow and potential distribution of electrical stimulation. Previous resistivity measurements in retina were limited to healthy retina, and didn't include mouse models, a common and important animal model in retinal research. This experimental study measured the resistivity profiles of wild-type, rd1, and rd10 mice, providing basis for computational simulations and predictive modeling studies. The peak resistance frequency method has been utilized to measure the resistivity profiles of the retina cross section, and the results show agreement with previous studies in retina of normal rats and embryonic chicks. Retinal degeneration affects the width of the profile, which is in agreement with histological measurements. Degeneration also results in lower peak resistivity. The results indicate that, on the mesoscopic scale, resistivity is dominated by spatial factors, while influence of remodeling on the cellular level is not apparent under such scale.

Neuroimaging studies have shown that the visual cortex of visually impaired humans is active during tactile tasks. We sought to determine if this cross-modal activation in the primary visual cortex is correlated with vision loss in individuals with retinitis pigmentosa (RP), an inherited degenerative photoreceptor disease that progressively diminishes vision later in life. RP and sighted subjects completed three tactile tasks: a symmetry discrimination task, a Braille-dot counting task, and a sandpaper roughness discrimination task. We measured tactile-evoked blood oxygenation level dependent (BOLD) responses using functional magnetic resonance imaging (fMRI). For each subject, we quantified the cortical extent of the tactile-evoked response by the proportion of modulated voxels within the primary visual cortex (V1) and its strength by the mean absolute modulation amplitude of the modulated voxels. We characterized vision loss in terms of visual acuity and the areal proportion of V1 that corresponds to the preserved visual field. Visual acuity and proportion of the preserved visual field both had a highly significant effect on the cortical extent of the V1 BOLD response to tactile stimulation, while visual acuity also had a significant effect on the strength of the V1 response. These effects of vision loss on cross-modal responses were reliable despite high inter-subject variability. Controlling for task-evoked responses in the primary somatosensory cortex (S1) across subjects further strengthened the effects of vision loss on cross-model responses in V1. We propose that such cross-modal responses in V1 and other visual areas may be used as a cortically localized biomarker to account for individual differences in visual performance following sight recovery treatments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Advanced materials and fractal design concepts form the basis of a 3D conformal electronic platform with unique capabilities in cardiac electrotherapies. Fractal geometries, advanced electrode materials, and thin, elastomeric membranes yield a class of device capable of integration with the entire 3D surface of the heart, with unique operational capabilities in low power defibrillation. Co-integrated collections of sensors allow simultaneous monitoring of physiological responses. Animal experiments on Langendorff-perfused rabbit hearts demonstrate the key features of these systems., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Retinitis pigmentosa is a family of inherited retinal diseases identified by the degeneration of photoreceptors, which leads to blindness. In efforts to restore vision lost to retinitis pigmentosa, retinal prostheses have been developed to generate visual percepts by electrically stimulating the surviving retinal bipolar and ganglion cells. The response of retinal ganglion cells to electrical stimulation has been characterized through direct measurement. However, the response of bipolar cells has only been inferred by measuring retinal ganglion cell activity. This investigation reports on a novel tissue preparation technique facilitating bipolar cell patch clamp recordings in wholemount retina. We find that bipolar cells respond to extracellular electrical stimuli with time-locked voltage spike depolarizations, which are likely mediated by voltage-gated calcium channels.

Rectangular pulses applied to disk electrodes result in high current density at the edges of the disk, which can lead to electrode corrosion and tissue damage. We explored a method for reducing current density and corrosion, by varying the leading edge of the current pulse. Finite-element modeling and mathematical analysis were used to predict an optimal waveform that reduces current density at the edge while also maintaining short pulse duration. An approximation of the optimized waveform was implemented experimentally and applied to platinum disk electrodes. Surface analysis using energy-dispersive spectroscopy showed significant reduction of corrosion on the periphery of these electrodes after pulsing, compared to those pulsed with the control rectangular waveform.

This study examines the elastic properties of the human posterior retina, choroid, and sclera. Twenty-four human eyes from 30- to 74-year-old donors were obtained from an eye bank. Vertically and horizontally oriented tissue strips of the retina, choroid, and sclera (ideally n = 12 in each group) were harvested from the posterior eyes. Their thicknesses were estimated optically. The samples were stretched at 1 mm/s in 37°C saline. Stress and strain were obtained from the mechanical tests, and then the transition stress, transition strain, toe modulus, and heel modulus were calculated. Statistical analysis was performed for comparison between groups. Linear regression analyses were used to explore the relationship between the mechanical parameters and age. We found that the stress-strain relationship of the retina, choroid, and sclera were nonlinear. Except for the retinal transition strain (p = 0.0124), no statistical difference was found between the vertical and horizontal meridian in the mechanical parameters (p > 0.05). Furthermore, weak relationship was observed between some of the mechanical parameters and the donors' age. Our results suggest that there is significant anisotropy in the retina, and mechanical properties of each layer may change with age., (© 2013 Wiley Periodicals, Inc.)

Retinal prosthesis has been translated from the laboratory to the clinic over the past two decades. Currently, two devices have regulatory approval for the treatment of retinitis pigmentosa. These devices provide partial sight restoration and patients use this improved vision in their everyday lives. Improved mobility and object detection are some of the more notable findings from the clinical trials. However, significant vision restoration will require both better technology and improved understanding of the interaction between electrical stimulation and the retina. This paper reviews the recent clinical trials and highlights technology breakthroughs that will contribute to next generation of retinal prostheses.

Age-related macular degeneration (AMD) etiology is unknown, but its association to atherosclerotic vascular disease (ASVD) has been observed. Since elastin plays an important role in the atherosclerotic process, to understand ASVD and AMD's relationship we examined retinal elastin existence, elastin amount and vessel properties among normal subjects, mild AMD patients, moderate-to severe AMD patients, and ASVD patients (n = 20). One eye per donor was assigned to enzyme-linked immunosorbent assay for quantifying the retinal elastin amount. The rest were assigned to mechanical test for examining the retinal vessel properties. Additionally, two normal human and two porcine eyes were acquired in immunohistochemistry for locating the retinal elastin. We found that elastin presented in the human and porcine retinal vessels at the basement membranes. 3.73 ± 0.55% of the normal retinal tissues were elastin. Elastin decrease, tissue-weight increase, and vessel hardening and in elasticity (p<0.05) were observed in the retina of patients with ASVD and only moderate-to-severe (i.e., not mild) AMD. Most moderate-to-severe AMD patients also happened to have ASVD. The results suggest that ASVD is unlikely the cause of AMD, but it is perhaps a factor that aggravates the condition through mechanism associated with retinal vessel abnormality.

Objective: Epiretinal prostheses are designed to restore functional vision to the blind by electrically stimulating surviving retinal neurons. These devices have classically employed symmetric biphasic current pulses in order to maintain a balance of charge. Prior electrophysiological and psychophysical studies in peripheral nerve show that adding an interphase gap (IPG) between the two phases makes stimulation more efficient than pulses with no gap. This led us to investigate the effect of IPG duration on retinal stimulation thresholds., Approach: We measured retinal ganglion cell (RGC) electrical thresholds in salamander retina and phosphene perceptual thresholds in epiretinal prosthesis patients during stimulation with different IPG lengths. We also built Hodgkin-Huxley-type models of RGCs to further study how IPG affects thresholds., Main Results: In general, there was a negative exponential correlation between threshold and IPG duration. Durations greater than or equal to ~0.5 ms reduced salamander RGC thresholds by 20-25%. Psychophysical testing in five retinal prosthesis patients indicated that stimulating with IPGs can decrease perceptual thresholds by 10-15%. Results from computational models of RGCs corroborated the observed behavior., Significance: Incorporating interphase gaps can reduce the power consumption of epiretinal prostheses and increase the available dynamic range of phosphene size and brightness.

An epiretinal prosthesis aims to restore functional vision in patients suffering from retinal degeneration caused by diseases such as Retinitis Pigmentosa (RP) and Age-Related Macular Degeneration (AMD). These diseases result in the loss of photoreceptors but bipolar, amacrine and ganglion cells survive at high rates and can be electrically activate to produce the sensation of light. Continuous application of biphasic stimulus pulses results in desensitization of the retina. In humans, this manifests as decreased brightness and increased stimulus thresholds. This study presents an in vivo model of retinal desensitization caused by continuous electrical stimulation and describes a novel stimulation pattern that limit desensitization.

This paper presents a fully intraocular self-calibrating epiretinal prosthesis with 512 independent channels in 65 nm CMOS. A novel digital calibration technique matches the biphasic currents of each channel independently while the calibration circuitry is shared among every 4 channels. Dual-band telemetry for power and data with on-chip rectifier and clock recovery reduces the number of off-chip components. The rectifier utilizes unidirectional switches to prevent reverse conduction loss in the power transistors and achieves an efficiency > 80%. The data telemetry implements a phase-shift keying (PSK) modulation scheme and supports data rates up to 20 Mb/s. The system occupies an area of 4.5 ×3.1 mm². It features a pixel size of 0.0169 mm² and arbitrary waveform generation per channel. In vitro measurements performed on a Pt/Ir concentric bipolar electrode in phosphate buffered saline (PBS) are presented. A statistical measurement over 40 channels from 5 different chips shows a current mismatch with μ = 1.12 μA and σ = 0.53 μA. The chip is integrated with flexible MEMS origami coils and parylene substrate to provide a fully intraocular implant.

The aim of this study is to examine the relationship between vitreous temperature and posterior vitreous detachment (PVD). 30 porcine eyes were hemisected to form eyecups. In 10 eyes, the vitreous was warmed to 37 ± 1°C for 1 min and cooled down to room temperature. In 10 eyes, the vitreous was warmed to 44 ± 1°C for 1 min and cooled down to room temperature. 10 eyes were kept at room temperature. The vitreous was then removed surgically by forceps. In the eyes that were kept at room temperature (n=10), and in the eyes that the vitreous was warmed to 37 ± 1°C (n=10), the vitreous removal caused significant retinal damage, detachment and fold, and choroidal detachment. In the eyes that the vitreous was warmed to 44 ± 1°C (n=10), the vitreous removal did not cause any observable changes in the retina and choroid. Therefore, the vitreous separates from the retina after warming to 44 ± 1°C. The effect is likely irreversible through vitreous liquefaction. Thermal effect might have caused PVD in some patients. Since cell death occurs at above 55-58°C, the effect can potentially be safe and beneficial in surgical separation of the vitreous. Evidence is provided to show that this technique could be safely performed in vivo in humans, and that it would lead to safer removal of the vitreous during vitrectomy with fewer post-operative complications., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Retinal prostheses have restored light perception to people worldwide who have poor or no vision as a consequence of retinal degeneration. To advance the quality of visual stimulation for retinal implant recipients, a higher number of stimulation channels is expected in the next generation retinal prostheses, which poses a great challenge to system design and verification. This paper presents a system verification platform dedicated to the development of retinal prostheses. The system includes primary processing, dual-band power and data telemetry, a high-density stimulator array, and two methods for output verification. End-to-end system validation and individual functional block characterization can be achieved with this platform through visual inspection and software analysis. Custom-built software running on the computers also provides a good way for testing new features before they are realized by the ICs. Real-time visual feedbacks through the video displays make it easy to monitor and debug the system. The characterization of the wireless telemetry and the demonstration of the visual display are reported in this paper using a 256-channel retinal prosthetic IC as an example.

Epiretinal implants for the blind are designed to stimulate surviving retinal neurons, thus bypassing the diseased photoreceptor layer. Single-unit or multielectrode recordings from isolated animal retina are commonly used to inform the design of these implants. However, such electrical recordings provide limited information about the spatial patterns of retinal activation. Calcium imaging overcomes this limitation, as imaging enables high spatial resolution mapping of retinal ganglion cell (RGC) activity as well as simultaneous recording from hundreds of RGCs. Prior experiments in amphibian retina have demonstrated proof of principle, yet experiments in mammalian retina have been hindered by the inability to load calcium indicators into mature mammalian RGCs. Here, we report a method for labeling the majority of ganglion cells in adult rat retina with genetically encoded calcium indicators, specifically GCaMP3 and GCaMP5G. Intravitreal injection of an adeno-associated viral vector targets ∼85% of ganglion cells with high specificity. Because of the large fluorescence signals provided by the GCaMP sensors, we can now for the first time visualize the response of the retina to electrical stimulation in real-time. Imaging transduced retinas mounted on multielectrode arrays reveals how stimulus pulse shape can dramatically affect the spatial extent of RGC activation, which has clear implications in prosthetic applications. Our method can be easily adapted to work with other fluorescent indicator proteins in both wild-type and transgenic mammals.

Purpose: To examine the potential for benzalkonium chloride (BAK) to cause denervation of the orbicularis oculi muscle (OOM) in a rabbit model., Methods: Pigmented rabbits were separated into five groups consisting of five rabbits each. Group 1 was injected with 1 mL of BAK 0.25% in the OOM of the upper eyelid. Group 2 was injected with 1 mL of BAK 0.5%. Group 3 included untreated controls. Groups 4 and 5 underwent surgical severing of the facial nerve (to cause complete paralysis of the OOM). Strength-duration curves for electrical stimulation of muscle twitches were measured for each group and chronaxie values were calculated to determine innervation status. Groups 1 and 4 were stimulated at 1 week postintervention while groups 2 and 5 were stimulated at 4 weeks postintervention. The rabbits were then sacrificed and the eyelids sent for histological analysis., Results: In group 1, all five rabbits demonstrated denervation of the OOM in the injected area. In group 2, one rabbit developed an abscess at the injection site and was sacrificed at 1 week. Of the remaining four rabbits, two showed complete denervation and two showed denervation with evidence of partial reinnervation. The histology demonstrated marked atrophy of the OOM for BAK-treated rabbits when compared with controls. In group 3, all five rabbits showed normal OOM function. In groups 4 and 5, all rabbits showed denervation of the OOM and histological evidence of muscle atrophy similar to groups 1 and 2., Conclusions: BAK causes denervation when injected into the OOM in rabbits. The clinical relevance of this finding may be the onset of lagophthalmos and eyelid retraction in patients with chronic BAK exposure.

The study of the mechanical behavior of soft biological materials presents many challenges due to the materials' time-dependent mechanical response as well as inherent size and shape limitations. In this study, by using agar as a surrogate material for soft tissues, the effects of these limitations upon standardized macroscale dynamic compression protocols are compared to dynamic nanoindentation procedures. Both techniques are then applied to dynamically test porcine sclera tissue, showing a significant difference in recorded loss and storage modulus values between the two methodologies. Additionally, the tissues of the porcine eye wall are characterized with macrocompression in their layered in vivo arrangement. The overall constraints of standardized macroscale tests for dynamic mechanical characterization of thin and soft biological tissues are discussed.

Retinal degenerations trigger the loss of photoreceptors and cause the remaining de-afferented neural retina to undergo remodeling. Concerns over this potential retinal synaptic reorganization following visual loss have raised questions regarding the usefulness of visual restoration via retinal electrical stimulation. We have used quantitative positron emission tomography (PET) and 2-deoxy-2-[18F]fluoro-d-glucose (FDG) to objectively evaluate the connection between the retina and the primary visual cortex under both light and transcorneal electrical stimulation (TcES) in five subjects with retinal degeneration (RD) who have had more than ten years of light-perception-only best visual acuity and five age-matched normal-sighted controls. All subjects underwent quantitative PET with FDG as the metabolic tracer during stimulation of the right eye under both light stimulation condition and transcorneal electrical stimulation (TcES) using ERG-Jet contact lens electrode. Cortical activation maps from each stimulation condition were obtained using statistical parametric mapping. TcES phosphene threshold current and qualitative visual cortex activation from both stimulation conditions were compared between the two subject groups. Average phosphene threshold current was 0.72 ± 0.18 mA for the five normal-sighted controls and 3.08 ± 2.01 mA for the retinal degenerative subjects. Phosphene threshold current was significantly higher in retinal degenerative subjects compared to normal-sighted controls (p < 0.05). We found both light stimulation and TcES resulted in retinotopically mapped primary visual cortex activation in both groups. In addition, the patterns of early visual area activation between the two subject groups are more similar during TcES than light stimulation. Our findings suggest primary visual cortex continues to maintain its retinotopy in RD subjects despite prolonged visual loss.

Background: We previously observed that the stiffness of the porcine retina was significantly higher when deforming at room temperature than at body temperature. The present study further investigates this phenomenon by examining the mechanical properties of the retina in saline at temperature lower than room temperature., Methods: Tensile testing was performed on a total of 15 retinal strips dissected from pig eyes. Equal amount of strips from the dissection were tested at 37.0 ± 0.3°C, 26.1 ± 0.1°C, and 7.8 ± 1.2°C. Their transition modulus, stress, and strain were measured for statistical analysis., Results: The transition modulus, the transition stress, and the transition strain of the retinal strips were found to be 11.12 ± 6.10 kPa, 0.12 ± 0.07 kPa, and 0.016 ± 0.001, respectively, at 37.0°C. These values were 111.25 ± 88.16 kPa, 1.11 ± 0.85 kPa, and 0.016 ± 0.001 at 26.1°C, and 125.13 ± 63.61 kPa, 1.30 ± 0.50 kPa, and 0.017 ± 0.003 at 7.8°C, respectively. The differences of the transition modulus and the transition stress at between 37.0°C and 26.1°C and at between 37.0°C and 7.8°C were statistically significant (P < 0.05). There were no significant differences in these values at between 26.1°C and 7.8°C., Conclusion: These findings suggest that lowering the temperature of the retina from body temperature is potentially useful to decrease retinal damage in posterior eye surgeries by increasing the resistance of the retina to mechanical deformation.

Objective: The objective was to evaluate magnetic resonance imaging (MRI) issues (magnetic field interactions, heating, artifacts and functional alterations) at 1.5 T and 3 T for the Argus II Retinal Prosthesis (Second Sight Medical Products, Sylmar, CA, USA)., Materials and Methods: Standardized protocols were used to assess magnetic field interactions (translational attraction and torque; 3 T, worst case), MRI-related heating (1.5 and 3 T), artifacts (3 T; worst case) and functional changes (1.5 and 3 T) associated with MRI., Results: The magnetic field interactions were acceptable. MRI-related heating, which was studied at a relatively high, MR system-reported whole body averaged specific absorption rates, will not pose a hazard to the patient under the conditions used for testing. While artifacts were "moderate" in relation to the dimensions of the Argus II Retinal Prosthesis, optimization of MRI parameters can reduce the size of the artifacts. Exposures to MRI conditions at 1.5 and 3 T did not damage or alter the functional aspects of the Argus II Retinal Prosthesis., Conclusions: In consideration of the test results, a patient with the Argus II Retinal Prosthesis may undergo MRI at 1.5 T or 3 T when specific guidelines and MRI conditions are followed, including those advised by the manufacturer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Agar is a biological polymer, frequently used in tissue engineering research; due to its consistency, controllable size, and concentration-based properties, it often serves as a representative material for actual biological tissues. In this study, nanoindentation was used to characterize both the time-independent and time-dependent response of agar samples having various concentrations (0.5%-5.0% by weight). Quasi-static indentation was performed at different loads and depths using both open- and closed-loop controls. Reduced modulus (Er) values change with agar concentration, ranging from ∼30 kPa for 0.5% samples to ∼700 kPa for 5.0% samples, which is the same modulus range as usually encountered in soft biological materials. Dynamic indentation was performed to assess the effects of load, dynamic frequency and amplitude. Storage modulus values ranged from approximately 30 to 2300 kPa depending on agar concentration. Loss modulus remained consistently less than 30 kPa at all conditions, indicating a diminished damping response in agar., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: In an effort to restore functional form vision, epiretinal prostheses that elicit percepts by directly stimulating remaining retinal circuitry were implanted in human subjects with advanced retinitis pigmentosa RP). In this study, manipulating pulse train frequency and amplitude had different effects on the size and brightness of phosphene appearance., Methods: Experiments were performed on a single subject with severe RP (implanted with a 16-channel epiretinal prosthesis in 2004) on nine individual electrodes. Psychophysical techniques were used to measure both the brightness and size of phosphenes when the biphasic pulse train was varied by either modulating the current amplitude (with constant frequency) or the stimulating frequency (with constant current amplitude)., Results: Increasing stimulation frequency always increased brightness, while having a smaller effect on the size of elicited phosphenes. In contrast, increasing stimulation amplitude generally increased both the size and brightness of phosphenes. These experimental findings can be explained by using a simple computational model based on previous psychophysical work and the expected spatial spread of current from a disc electrode., Conclusions: Given that amplitude and frequency have separable effects on percept size, these findings suggest that frequency modulation improves the encoding of a wide range of brightness levels without a loss of spatial resolution. Future retinal prosthesis designs could benefit from having the flexibility to manipulate pulse train amplitude and frequency independently (clinicaltrials.gov number, NCT00279500).

Previous studies reveal that the primary distribution of the current density is sharply enhanced at the edge of a disk electrode submerged into a semi-infinite space of conductive solution. The current enhancement will cause the double layer capacitance at the periphery of the electrode to be charged much faster compared to the center, and can also lead to severe corrosion at the edge. While several studies focused on the geometric design of the electrode to reduce this enhancement, we explore the feasibility of achieving similar effect by shaping the edges of the current input. The simulation uses finite element analysis software to solve the system of partial differential equations and results show that the edge enhancement could be greatly reduced without significantly changing the input efficacy of current and/or charge.

The epiretinal prosthesis aims to restore functional vision by stimulating electrically the retinal ganglion cells (RGCs) in patients afflicted with degenerative diseases that affect the photoreceptors, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). As degeneration progresses, photoreceptor death is followed by pronounced remodeling and rewiring of remaining inner retinal cells. Despite the loss of rods and cones, a considerable population of RGCs remain receptive to prosthetic stimulation. To stimulate effectively a localized population of RGCs, an improved understanding of the anatomical and physiological properties of these cells is required. Additionally, possible alterations in electrical excitability, produced by the effects of retinal degeneration, needs to be assessed. This study investigates the effect of RGC soma size on the threshold for action potential generation in normal and rd mice and its implications for the rescue of visual function.

Retinal prostheses for the blind have demonstrated the ability to provide the sensation of light in otherwise blind individuals. However, visual task performance in these patients remains poor relative to someone with normal vision. Computer vision algorithms for navigation and object detection were evaluated for their ability to improve task performance. Blind subjects navigating a mobility course had fewer collisions when using a wearable camera system that guided them on a safe path. Subjects using a retinal prosthesis simulator could locate objects more quickly when an object detection algorithm assisted them. Computer vision algorithms can assist retinal prosthesis patients and low-vision patients in general.

An electrodeposition technique was applied for fabrication of dense platinum-iridium alloy nanowires as interconnect structures in hermetic microelectronic packaging to be used in implantable devices. Vertically aligned arrays of platinum-iridium alloy nanowires with controllable length and a diameter of about 200 nm were fabricated using a cyclic potential technique from a novel electrodeposition bath in nanoporous aluminum oxide templates. Ti/Au thin films were sputter deposited on one side of the alumina membranes to form a base material for electrodeposition. Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS) were used to characterize the morphology and the chemical composition of the nanowires, respectively. SEM micrographs revealed that the electrodeposited nanowires have dense and compact structures. EDS analysis showed a 60:40% platinum-iridium nanowire composition. Deposition rates were estimated by determining nanowire length as a function of deposition time. High Resolution Transmission Electron Microscopy (HRTEM) images revealed that the nanowires have a nanocrystalline structure with grain sizes ranging from 3 nm to 5 nm. Helium leak tests performed using a helium leak detector showed leak rates as low as 1 × 10(-11) mbar L s(-1) indicating that dense nanowires were electrodeposited inside the nanoporous membranes. Comparison of electrical measurements on platinum and platinum-iridium nanowires revealed that platinum-iridium nanowires have improved electrical conductivity.

Precise positioning of a stimulating electrode in the eye is not possible by simple visualization. However, reliable measurement of responses to retinal stimulation requires consistent positioning. The present study focuses on impedance measurement techniques to sense the proximity of the electrode to the retina. A platinum-iridium stimulation electrode was placed inside the rat eye and impedance was recorded at different positions of the stimulating electrode relative to the retina. The presence of robust electrically evoked response in the superior colliculus indicates that the electrode may not have to be in absolute contact in order to elicit a neural response. Optical coherence tomography imaging confirmed the distance-impedance relationship.

Unlabelled: Degenerative diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) primarily affect the photoreceptors, ultimately resulting in significant loss of vision. Retinal prostheses aim to elicit neural activity in the remaining retinal cells by detecting and converting light into electrical stimuli that can then be delivered to the retina. The concept of visual prostheses has existed for more than 50 years and recent progress shows promise, yet much remains to be understood about how the visual system will respond to artificial input after years of blindness that necessitate this type of prosthesis. This review focuses on 3 major areas: the histopathologic features of human retina affected by AMD and RP, current results from clinical trials, and challenges to overcome for continued improvement of retinal prostheses., Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Epiretinal prostheses for the blind bypass diseased photosensitive cells in the retina, directly stimulating retinal neurons electrically and evoking signals that are relayed to the brain. Current clinical implants have few electrodes and provide limited visual acuity. Acuity may be improved by identifying electrode array design features and operational details that enhance or interfere with visual percept formation. We labeled all retinal ganglion cells in whole mount retina with a calcium reporter and then measured the number and pattern of cells responding, over a range of electrode diameters and stimulus durations. Span of the response scaled with electrode diameter for electrodes 60 μm and larger. Short stimulation pulse widths selectively activated cells nearest the electrode. Our measurements in the salamander retina suggest that the spatial resolution is 150 μm, which on a human retina is equivalent to 0.55(°) of human visual field and corresponding Snellen acuity of 20/660. Reading large print could be possible with such a prosthesis., (© 2011 IEEE)

Retinal prostheses aim to provide visual perception through electrical stimulation of the retina. Hence they have to operate between threshold charge density and maximum safe charge density. To date most studies in the retina have concentrated on understanding the threshold, while stimulation safety has predominantly been studied in structures other than the retina. Toward this end, the present study focuses on determining the effect of continuous electrical stimulation of the retina both on retinal morphology and on the electrically evoked responses in the superior colliculus in a rodent model. The results demonstrate that the retina is able to tolerate 1 h long stimulation with only minor changes evident in retinal histology when examined three to 14 days later, even at charge densities (0.68 mC cm(-2)) above the safe limit of platinum delivered at high stimulus frequency (300 Hz). However, this continuous electrical stimulation causes an elevation in the threshold of the electrically evoked response in the superior colliculus, indicating some form of adaptation to continuous stimulation.

Retinal activation via transcorneal electrical stimulation (TcES) in normal humans was investigated by comparing subject perception, model predictions, and brain activation patterns. The preferential location of retinal stimulation was predicted from 3-D admittance modeling. Visual cortex activation was measured using positron emission tomography (PET) and (18)F-fluorodeoxyglucose (FDG). Two different corneal electrodes were investigated: DTL-Plus and ERG-Jet. Modeling results predicted preferential stimulation of the peripheral, inferior, nasal retina during right eye TcES using DTL-Plus, but more extensive activation of peripheral, nasal hemiretina using ERG-Jet. The results from human FDG PET study using both corneal electrodes showed areas of visual cortex activation that consistently corresponded with the reported phosphene percept and modeling predictions. ERG-Jet was able to generate brighter phosphene percept than DTL-Plus and elicited retinotopically mapped primary visual cortex activation. This study demonstrates that admittance modeling and PET imaging consistently predict the perceived location of electrically elicited phosphenes produced during TcES., (© 2010 IEEE)

Purpose: To characterize optic nerve and retinal changes in a patient with end-stage retinitis pigmentosa (RP) with an implanted active epiretinal array., Methods: A 74-year-old man with end-stage X-linked RP underwent implantation of an epiretinal array over the macula in the right eye and subsequent stimulation until his death at 5 years and 3 months after implantation. The optic nerves from this study patient, as well as those from two age-matched normal patients and two age-matched RP patients, were morphometrically analyzed against two different sets of criteria and compared. The retina underlying the array in the study patient was also morphometrically analyzed and compared with corresponding regions of the retina in the age-matched RP patients., Results: Optic nerve total axon counts were significantly lower in the study patient and RP patients than in normal patients. However, there was no significant difference when comparing total axon counts from the optic nerve corresponding to the patient's implanted right eye versus the optic nerves from the RP patients (P = 0.59 and P = 0.61 using the two different criteria). Degenerated axon data quantified damage and did not show increased damage in the optic nerve quadrant that retinotopically corresponded to the site of epiretinal array implantation and stimulation. Except for the tack site, there was no significant difference when comparing the retina underlying the array and the corresponding perimacular regions of two RP patients., Conclusions: Long-term implantation and electrical stimulation with an epiretinal array did not result in damage that could be appreciated in a morphometric analysis of the optic nerve and retina.

Electrical stimulation threshold and retinal ganglion cell density were measured in a rat model of retinal degeneration. We performed in vivo electrophysiology and morphometric analysis on normal and S334ter line 3 (RD) rats (ages 84-782 days). We stimulated the retina in anesthetized animals and recorded evoked responses in the superior colliculus. Current pulses were delivered with a platinum-iridium (Pt-Ir) electrode of 75-μm diameter positioned on the epiretinal surface. In the same animals used for electrophysiology, SMI-32 immunolabeling of the retina enabled ganglion cell counting. An increase in threshold currents positively correlated with age of RD rats. SMI-32-labeled retinal ganglion cell density negatively correlated with age of RD rats. ANOVA shows that RD postnatal day (P)100 and P300 rats have threshold and density similar to normal rats, but RD P500 and P700 rats have threshold and density statistically different from normal rats (P < 0.05). Threshold charge densities were within the safety limits of Pt for all groups and pulse configurations, except at RD P600 and RD P700, where pulses were only safe up to 1- and 0.2-ms duration, respectively. Preservation of ganglion cells may enhance the efficiency and safety of electronic retinal implants.

There is an increasing need to understand the mechanical properties of human orbital fat and its encapsulating connective tissue (OFCT), but such knowledge is not available in the current literature. The purpose of the present study is to examine the mechanical properties of the OFCT. From 5 pairs of 76- to 92-year-old Caucasian human eyes and 33 5- to 7-month-old porcine eyes, 5 human and 11 porcine OFCT samples were dissected at the posterior pole or adjacent to the pole in the vertical, horizontal, and radial directions. Sample dimensions were fixed or measured. Tensile tests were performed on the samples in body-temperature saline. The stress-strain relationship was first approximately linear and then became nonlinear. The linear, the neo-Hookean, and the Mooney-Rivlin constants are reported in Tables 1 and 2. No statistical difference was found among their properties in the different directions in either the human or the porcine samples. Statistical differences were found between the human and the porcine material constants in the horizontal and radial directions. Among our material models, only the Mooney-Rivlin model was able to capture the mechanical properties of the OFCT in large deformation properly. The Mooney-Rivlin model was especially adaptive to the human data. This is the first time the mechanical properties of the human and porcine OFCT have been examined in the literature. We believe our data will provide valuable information to others regarding designing implant biomaterials in orbital treatments and developing computer models to study orbital biomechanics.

High-surface area platinum-iridium alloys were electrodeposited by on Pt and Au microelectrodes using a potential sweep technique. Detailed investigations of the structure and morphology and the electrochemical properties of the electrodeposited Pt-Ir alloy coatings were performed. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) were used for the determination of the surface morphology and the chemical composition of the Pt-Ir coatings, respectively. The elemental analysis by EDS showed a nearly 60-40% Pt-Ir composition of the coatings. The electrochemical properties of the Pt-Ir coatings were evaluated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). CV and EIS measurements revealed that the Pt-Ir coated electrodes exhibit significantly increased charge storage capacity and real surface area compared to uncoated Pt electrodes. Charge injection experiments of the Pt-Ir coated microelectrodes revealed low potential excursions, indicating high charge injection capabilities within safe potential limits.

An epiretinal prosthesis aims to restore functional vision by stimulating electrically the retinal ganglion cells (RGCs) in patients affected by photoreceptor degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). During retinal degeneration, photoreceptor death is followed by pronounced remodeling and rewiring of inner retinal cells. Despite these changes, a considerable population of RGCs remain receptive to prosthetic stimulation. To target selectively a localized subset of RGCs, an improved understanding of the anatomical and physiological properties of these cells is required. Additionally, potential alterations in electrical excitability produced by the retinal degeneration needs to be assessed. This study investigates the effect of RGC soma size on the threshold for action potential (spike) generation and its implications for the rescue of visual function.

The most common electrical stimulation pulse used in retinal implants is a symmetric biphasic current pulse. Prior electrophysiological studies in peripheral nerve have shown that adding an interphase gap (IPG) between the two phases makes stimulation more efficient. We investigated the effect of IPG duration on retinal ganglion cell (RGC) electrical threshold. We used calcium imaging to measure the activity of RGCs in isolated retina in response to electrical stimulation. By varying IPG duration, we were able to examine the effect of duration on threshold. We further studied this effect by simulating RGC behavior with a Hodgkin-Huxley-type model. Our results indicate that the threshold for electrical activation of RGCs can be reduced by increasing the length of the IPG.

The inter-subject variability of visual cortex reorganization was assessed in late-blind subjects suffering from retinitis pigmentosa (RP), a degenerative retinal disease that results in tunnel vision and eventual loss of sight. fMRI BOLD responses were measured as blindfolded RP and blindfolded sighted control groups completed a tactile discrimination task (in which subjects determined the relative roughness of sandpaper discs) during successive scans in a 3T Siemens scanner. Resulting activation patterns were compared between the two groups in a whole-brain analysis. We found that vision deprivation leads to elevated activation of the visual cortex elicited with tactile stimuli, and the degree of activation correlates with the degree of visual field loss: higher visual cortex activation is associated with greater vision loss. The location of vision loss in the visual field also correlates with the location of tactile responses in the visual cortex, with greater peripheral vision loss leading to stronger activation in the peripheral of V1. Visual cortex responses to tactile stimuli may hence be used as a diagnostic marker in determining the extent of an individual's vision loss and tracking sight recovery following treatments.

We studied contribution of blood vessels to the mechanical properties of retina. Previous studies revealed anisotropic and inhomogeneous retinal mechanical characteristics. To examine different vessel types and sizes, 3 strips of retinal samples were dissected in each of 5 pig eyes. One strip contained the superior-temporal vein in the axial direction, one strip contained the superior-temporal artery in the axial direction, and one strip did not contain any visible vessel. To examine different vessel orientations, 2 strips of retinal samples were dissected in each of 5 other pig eyes. One strip contained the superior-temporal vein in the axial direction, and one strip contained the superior-temporal vein in the circumferential direction. Tensile testing was performed on the samples. The venous and arterial samples were found to be significantly stiffer than the no-visible-vessel samples. No significant difference was observed neither between the venous and arterial samples, nor between the venous samples in the axial versus circumferential directions. We therefore conclude that the blood vessels contribute significantly to the stiffness of the retina, and the vessel size is the only determining factor that governs the anisotropic and inhomogeneous characteristics of the retina., (Published by Elsevier Ltd.)

We examine the thickness and mechanical properties of the porcine posterior retina, choroid, and sclera in different environments and surface directions. Vertical and horizontal samples were surgically obtained. Uniaxial experiments were performed in room-temperature air, room-temperature saline, and body-temperature saline. Sample thicknesses were estimated optically. Thickness of all layers was found to vary significantly among the samples; thickness standard deviation of the mean was 24, 19, and 19% for the retina, choroid, and sclera, respectively. Transition stresses and heel moduli of all layers were consistently higher in saline than air. The retinal stress-strain relationship in air was typically linear with significantly lower horizontal transition strain. Transition stresses and moduli of all layers were consistently lower in body than room temperature and the differences in the transition stresses and heel moduli of the retina and sclera were significant. Also, the sclera had significantly lower transition strains in body temperature. These results illustrate the importance of testing the tissues at conditions like those found in the body. In body-temperature saline, all layers behaved nonlinearly, but only the retina exhibited surface anisotropy between the vertical and horizontal directions., (Copyright 2009 Wiley Periodicals, Inc.)

Epiretinal prostheses used to treat degenerative retina diseases apply stimulus via an electrode array fixed to the ganglion cell side of the retina. Mechanical pressure applied by these arrays to the retina, both during initial insertion and throughout chronic use, could cause sufficient retinal damage to reduce the device's effectiveness. In order to understand and minimize potential mechanical damage, we have used finite element analysis to model mechanical interactions between an electrode array and the retina in both acute and chronic loading configurations. Modeling indicates that an acute tacking force distributes stress primarily underneath the tack site and heel edge of the array, while more moderate chronic stresses are distributed more evenly underneath the array. Retinal damage in a canine model chronically implanted with a similar array occurred in correlating locations, and model predictions correlate well with benchtop eyewall compression tests. This model provides retinal prosthesis researchers with a tool to optimize the mechanical electrode array design, but the techniques used here represent a unique effort to combine a modifiable device and soft biological tissues in the same model and those techniques could be extended to other devices that come into mechanical contact with soft neural tissues.

The purpose of this paper is to present a wide field electrode array that may increase the field of vision in patients implanted with a retinal prosthesis. Mobility is often impaired in patients with low vision, particularly in those with peripheral visual loss. Studies on low vision patients as well as simulation studies on normally sighted individuals have indicated a strong correlation between the visual field and mobility. In addition, it has been shown that an increased visual field is associated with a significant improvement in visual acuity and object discrimination. Current electrode arrays implanted in animals or human vary in size; however, the retinal area covered by the electrodes has a maximum projected visual field of about 10 degrees. We have designed wide field electrode arrays that could potentially provide a visual field of 34 degrees, which may significantly improve the mobility. Tests performed on a mechanical eye model showed that it was possible to fix 10 mm wide flexible polyimide dummy electrode arrays onto the retina using a single retinal tack. They also showed that the arrays could conform to the inner curvature of the eye. Surgeries on an enucleated porcine eye model demonstrated feasibility of implantation of 10 mm wide arrays through a 5 mm eye wall incision.

Here we present a retrograde loading technique that makes it possible for the first time to rapidly load a calcium indicator in the majority of retinal ganglion cells (RGCs) in salamander retina, and then to observe physiological activity of these dye-loaded cells. Dextran-conjugated calcium indicator, dissolved in water, was applied to the optic nerve stump. Following dye loading, the isolated retina was mounted on a microelectrode array to demonstrate that electrical activity and calcium activity were preserved, as the retina responded to electrical stimuli.

Purpose: With the long-term goal of restoring functional vision in patients with retinal degenerative diseases, the eyes of blind human subjects were implanted chronically with epiretinal prostheses consisting of two-dimensional electrode arrays that directly stimulated cells of the neural retina., Methods: Psychophysical techniques were used to measure the brightness of electrically generated percepts on single electrodes using a variety of electrical stimulation patterns., Results: It was possible to predict the sensitivity of the human visual system to a wide variety of retinal electrical stimulation patterns using a simple and biologically plausible model., Conclusions: This is the first study to demonstrate that, on the single-electrode level, retinal electrical stimulation in humans can produce visual qualia that are predictable using a quantitative model, a prerequisite for a successful retinal prosthesis. (ClinicalTrials.gov number, NCT00279500.).

To function successfully, a retinal prosthesis needs to provide effective stimulation in a safe manner. To date, most studies have been dedicated to assessing proper stimulation parameters, for example, determining stimulus threshold. Few studies have looked at the effects of prolonged stimulation on retinal morphology. One previous study did show gross morphological changes in the rat retina due to mechanical pressure, with and without electrical stimulation (Colodetti, L., Weiland, J.D., Colodetti, S., Ray, A., Seiler, M.J., Hinton, D.R., Humayun, M.S., 2007). Here, we used immunocytochemistry to investigate the effects of the same experimental conditions on neuronal structure in finer detail. For this purpose, we first defined four experimental groups. In Group 1, the stimulating electrode was near but did not contact the retina, and we did not apply current pulses. In Group 2, the electrode also did not contact the retina, but we applied current pulses of 0.09 microC/phase. In Group 3, the stimulating electrode directly contacted the retina, but we did not apply current pulses. In Group 4, the stimulating electrode directly contacted the retina, and we applied current pulses of 0.09 microC/phase. We found neural damage only in the outer retina, including a disturbance of synaptic vesicle proteins in the photoreceptor terminals and a remodeling of horizontal and rod bipolar cells' processes. These results show that, although gross morphological changes are mainly concentrated around the area of electrode contact, immunocytochemistry can reveal changes in adjacent areas as well.

Retinal prosthesis recipients may still have degraded vision, such that additional information about their surroundings may help them perform certain tasks. We evaluate a system that provides cues that point towards important objects. Using a simulated vision grid of 6 x 10 pixels, subjects perform object location and mobility tasks with and without the help of cues. The velocity of head movement in degrees per second and the time taken by subjects to finish the tasks are recorded. Results show that a cueing system may help to reduce and organize the head movements of the subjects, whereas a time benefit exists in object location but not in mobility tasks.

Simulations of artificial vision suggest that 1000 electrodes may be required to restore vision to individuals with diseases of the outer retina. In order to achieve such an implant, new technology is needed, since the state-of-the-art implantable neural stimulator has at most 22 contacts with neural tissue. A critical component of this system is the multi-channel, stimulating electrode array. This array must meet very challenging, competing requirements for manufacturing, integration, surgical handling, and biocompatibility. Our lab has evaluated 3 polymers as retinal prosthesis substrates: polyimide, parylene, and silicone.

In this paper, the thermal elevation in the human body due to the operation of a dual-unit epiretinal prosthesis to restore partial vision to the blind affected by irreversible retinal degeneration is presented. An accurate computational model of a 60-electrode device dissipating 97 mW power, currently under clinical trials is developed and positioned in a 0.25 mm resolution, heterogeneous model of the human head to resemble actual conditions of operation of the prosthesis. A novel simple finite difference scheme combining the explicit and the alternating-direction implicit (ADI) method has been developed and validated with existing methods. Simulation speed improvement up to 11 times was obtained for the the head model considered in this work with very good accuracy. Using this method, solutions of the bioheat equation were obtained for different placements of the implant. Comparison with in-vivo experimental measurements showed good agreement.