US20220176105A1 - Honeycomb-shaped electro-neural interface for retinal prosthesis - Google Patents

Honeycomb-shaped electro-neural interface for retinal prosthesis Download PDF

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US20220176105A1
US20220176105A1 US17/438,807 US202017438807A US2022176105A1 US 20220176105 A1 US20220176105 A1 US 20220176105A1 US 202017438807 A US202017438807 A US 202017438807A US 2022176105 A1 US2022176105 A1 US 2022176105A1
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cavities
walls
stimulation
electrode
pixel
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Daniel V. Palanker
Thomas Flores
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Leland Stanford Junior University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0543—Retinal electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36046—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of the eye
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/3615—Intensity
    • A61N1/3616—Voltage density or current density

Definitions

  • This invention relates to electrical stimulation of neural cells.
  • Conventional stimulation arrays for visual prostheses have a planar configuration of active and return electrodes. This planar configuration creates severe difficulties in scaling the prostheses to have sufficiently small and densely packed pixels to provide useful visual acuity.
  • the increase of stimulation threshold as pixel size decreases is particularly troublesome, since the required current density becomes biologically unsafe at desirable pixel sizes for retinal implants. Accordingly, it would be an advance in the art to alleviate these limitations of planar stimulation arrays.
  • the pixel cavities have depths between 10 ⁇ m and 100 ⁇ m, and widths between 5 ⁇ m and 100 ⁇ m.
  • the current density at the active central electrodes is preferably between 0.01 A/cm 2 and 1 A/cm 2 .
  • the width of the apparatus as a whole is preferably between 0.5 mm to 5 mm, making it suitable for retinal implantation.
  • the charge injection per pulse on the active electrodes is preferably between 0.1 mC/cm 2 and 10 mC/cm 2 .
  • FIG. 1 schematically shows operation of a planar array for neural cell stimulation.
  • FIG. 2A shows a first embodiment of the invention.
  • FIG. 2B shows a second embodiment of the invention.
  • FIGS. 3A-B are another view of the difference between planar and non-planar stimulation arrays.
  • FIGS. 3C-D show overlay of the implants depicted in FIGS. 3A-B with retinal anatomy.
  • FIGS. 4A-B show images of a fabricated array of cavities.
  • FIG. 4C shows an image of the honeycomb implant under the animal retina.
  • FIG. 5 shows histology of the retina integrated with an implanted honeycomb array.
  • FIG. 6A shows simulated electric potential for planar (top) and honeycomb (bottom) arrays.
  • FIG. 6B shows experimental and simulated threshold current density vs. pixel size for a planar array, compared to the safety limit and compared to simulated threshold current density vs. pixel size for a honeycomb array.
  • Section A describes general principles relating to embodiments of the invention.
  • Section B provides a detailed experimental example.
  • FIG. 1 This is a cross section view of a row of pixels 102 , 104 , 106 .
  • the “ON” pixels ( 102 and 106 , also marked with a check) generate electric current and inject it into the electrolyte through the central active electrode (e.g. 108 of pixel 102 ), which is then collected by the remote return electrode 110 outside the pixels (or between the pixels).
  • Current flow is shown with black arrows.
  • Current flow through the electrolyte creates a gradient of electric potential (shading). Current spreads from the active electrodes in all directions, affecting cells in the neighboring pixels as well.
  • “OFF” pixel 104 marked with an X, will receive parasitic stimulation from neighboring pixels, undesirably resulting in low contrast.
  • FIG. 2A shows a cross section of a first embodiment of the invention.
  • stimulation array 200 includes pixels 202 , 204 , 206 .
  • “ON” pixels 202 and 206 (check mark) generate electric current and inject it into the electrolyte through the central active electrode (e.g., 214 of pixel 202 ).
  • Current flows up through the electrolyte (tissue) and is collected by the return electrode 216 on top of the walls 218 to complete the circuit.
  • Flow through electrolyte creates a gradient of electric potential (shading) primarily in front of the “ON” pixels, allowing for localized stimulation of the retina. Note the reduced shading above pixel 204 on FIG. 2A compared to pixel 104 on FIG. 1 .
  • High-capacitance material 216 deposited on top of the conductive honeycomb wall 218 ensures that a majority of the current through the electrolyte is collected at the top of the walls, and a negligible amount of current is collected through the sides of the conductive walls due to low capacitance of the interface between metal and electrolyte. Such a configuration enables manufacturing of the elevated return electrodes in a honeycomb structure without the need for sidewall passivation or insulation.
  • a first embodiment of the invention is apparatus for electrical stimulation of neural cells including an array of cavities configured to allow migration of neural cells inside the cavities.
  • Each cavity has a floor (e.g., 212 on FIG. 2A ) and electrically conductive walls (e.g., 218 on FIG. 2A ).
  • Each cavity has a first electrode (e.g., 214 on FIG. 2A ) disposed on its floor and has a second electrode (e.g., 216 on FIG. 2A ) disposed on top of its walls and vertically separated from its corresponding floor electrode.
  • an ionic current flows through contents of the cavities.
  • a per-cavity capacitance of the second electrodes is greater than a per-cavity capacitance of the conductive walls, whereby the second electrodes preferentially collect the ionic current relative to sides of the conductive walls.
  • the capacitance per unit area of the second electrodes is at least 100 ⁇ greater than the capacitance per unit area of the conductive walls.
  • FIG. 2B shows a cross-section view of a second embodiment of the invention.
  • stimulation array 250 includes pixels 252 , 254 , 256 .
  • “ON” pixels 252 and 256 (check mark) generate electric current and inject into the electrolyte through the central active electrode (e.g., 214 of pixel 252 ).
  • Current flows up through the honeycomb well surrounded by electrically insulating walls 262 and then is collected by the remote return electrode 264 outside the pixels.
  • Flow through the electrolyte creates a gradient of electric potential (shading) primarily in front of the “ON” pixels, allowing for much better localized stimulation of the retina than would be present without the vertical walls. Note the reduced shading above pixel 254 on FIG. 2B compared to pixel 104 on FIG. 1 .
  • a second embodiment of the invention is apparatus for electrical stimulation of neural cells including an array of cavities configured to allow migration of neural cells inside the cavities.
  • Each cavity has a floor (e.g., 212 on FIG. 2B ) and electrically insulating walls (e.g., 262 on FIG. 2B ).
  • Each cavity has a first electrode (e.g., 214 on FIG. 2B ) disposed on its floor.
  • the apparatus includes a common return electrode (e.g., 264 on FIG. 2B ) disposed outside the array of cavities.
  • an ionic current flows through contents of the cavities.
  • the electrically insulating walls improve stimulation efficiency and reduce cross-talk between neighboring cavities of the apparatus by forcing the ionic current to travel vertically within the cavities.
  • the depth of the cavities is preferably between 10 ⁇ m and 100 ⁇ m.
  • the width of the cavities is preferably between 5 ⁇ m and 100 ⁇ m.
  • the depth of the cavities is preferably greater than the width of the cavities.
  • the array of cavities is preferably periodic, and in this case it is preferred that the cavities be hexagonal.
  • the neural cells are retinal cells.
  • an injected charge density at first electrodes of the cavities is between 0.1 mC/cm 2 and 10 mC/cm 2 in operation.
  • the electrode-tissue separation in subretinal space can be reduced using pillar electrodes.
  • Migration of the retinal cells of the inner nuclear layer (INL) to fill the voids in such a 3-D implant brings the target neurons closer to the stimulating electrodes, thereby reducing the stimulation threshold.
  • such pillar electrodes decreased the stimulation threshold only by a factor of two and did not enable significant reduction of the pixel size below 55
  • the fundamental problem limiting the electrode size is the shape of the electric field expanding from a small electrode and returning to another electrode under the target cells.
  • FIG. 3C shows that planar pixels with circumferential returns generate locally confined electric fields with shallow vertical penetration.
  • Cells in electric field polarize according to the potential difference across their length.
  • Bipolar cell somas and axon terminals reside in the INL (inner nuclear layer) and IPL (inner plexiform layer), respectively.
  • Electric potential is therefore represented with respect to potential in the middle of IPL.
  • FIG. 3D shows that return electrodes on top of insulating walls create a vertical dipole confined to the local pixel volume and thereby maximize the vertical potential drop across the target cell layer.
  • Current magnitude (arrow length) is shown in log scale.
  • Potential difference with respect to the middle of IPL (57 ⁇ m) is shown in gray scale for 68 nA current.
  • FIGS. 4A-C show subretinal honeycomb implants.
  • FIG. 4A shows an image of a 1 mm wide device with 25 ⁇ m deep honeycombs of 40 (*), 30 (**), and 20 ⁇ m (***) pixel pitch.
  • the fourth quadrant contained a 10 ⁇ m pitch structure, which was beyond the processing limit and hence did not develop. We refer to it as the “flat” region due to the absence of walls.
  • FIG. 4B is a higher magnification of the honeycombs with 30 ⁇ m pitch.
  • FIG. 4C is an OCT image of the subretinal implant in RCS rat 6 weeks post-op. Scale bars are 200 ⁇ m for FIG. 4A , 50 ⁇ m for FIG. 4B , and 100 ⁇ m for FIG. 4C .
  • INL cells showing no visible signs of fibrosis or trauma, as shown on FIG. 5 .
  • the retinal structure remains preserved, with clearly defined INL, inner plexiform layer (IPL), and ganglion cell layer (GCL).
  • IPL inner plexiform layer
  • GCL ganglion cell layer
  • Black arrows point at the location of the original walls, which were removed after the sample embedding and refilled with epoxy for sectioning.
  • the scale bar on FIG. 5 is 40 ⁇ m.
  • microglia processes within the IPL indicate the microglial resting state, while microglia below the INL extend their processes through the degenerate outer plexiform layer (OPL).
  • OPL outer plexiform layer
  • microglia in the IPL appear similar to those in the control retina, with extended processes indicating the microglial resting state.
  • a planar implant microglia reside close to the device surface. Presence of the cortical response with these active implants indicates that microglia on a subretinal prosthesis does not prevent electrical stimulation.
  • microglia processes extend primarily along the top of the walls, with minimal extension into the wells.
  • the extent of retinal integration was assessed by analyzing cell density as a function of height from the base in the cavities of each size. An average of 50%, 45% and 54% of the INL cells were found inside the cavities with honeycomb pitch of 40, 30 and 20 ⁇ m, respectively. Since the electric field can extend above the walls ( FIG. 6A ), more cells can be stimulated.
  • FIG. 6B shows experimental thresholds (data points) and calculated thresholds for planar (dashed line) and honeycomb (dotted line) devices in terms of current density on active electrode.
  • the planar models (both binary and linear, as described below) reproduce the trend observed in experimental measurements.
  • Honeycomb arrays significantly reduce the stimulation threshold (dotted line), enabling safe operation of devices with pixels below 40 ⁇ m.
  • the maximum charge injection by SIROF (3 mC/cm 2 for a 10 ms pulse) is shown with a dash-dotted line.
  • SIROF is short for Sputtered IRidium Oxide Film.
  • Any other bio-compatible high-capacitance material can also be used for the high capacitance electrodes, such as IrOx deposited by different means (electroplating, chemical deposition etc.), porous Pt, PEDOT, carbon nanotubes, etc.
  • honeycomb-shaped arrays To assess the benefits of the honeycomb-shaped arrays, we used a model of network-mediated retinal stimulation. To validate this model, we first compared the modeling results with the in-vivo stimulation thresholds measured in rats having planar subretinal photovoltaic implants with various pixel sizes, and then computed the stimulation thresholds for honeycombs of various sizes.
  • Electric field in the retina was calculated using a finite element model of the entire arrays in COMSOL Multiphysics 5.0, using the electrostatics module to solve Maxwell's equations for electric potential, assuming steady-state electric currents. Computed fields were then converted into the retinal response using both the binary and linear models. Each model had only one fitting parameter for relating its retinal output to amplitude of the cortical response. For a binary model, it was the fraction of the INL cells which should be activated to elicit a cortical response, while for a linear model it was the slope of the linear fit. Irradiance is converted into current density based on the pixel geometry and light-to-current conversion efficiency of our 2-diode pixels.
  • planar pixels smaller than 40 require current density greater than the safe charge injection limit of SIROF for a 10 ms pulse (>30 mA/cm 2 or charge density of >3 mC/cm 2 ).
  • Placement of the return electrode on top of the insulating honeycomb walls surrounding the pixel forces the current to flow primarily upward from the active electrode ( FIG. 3D ), thereby greatly increasing the depth at which the electric potential exceeds the stimulation threshold.
  • the stimulation threshold in terms of current density does not depend on the pixel width ( FIG. 6B ), enabling scaling the pixels down to the size limited only by the retinal migration, i.e. by cellular dimensions. Improvements in the stimulation threshold are summarized in Table 1.
  • honeycomb electrodes significantly improve the spatial selectivity of electrical stimulation (i.e. the contrast between adjacent pixels), which is essential for high-acuity vision.
  • electrical stimulation i.e. the contrast between adjacent pixels
  • increasing current density leads to an increase in positive potential above the ON pixels, as well as negative potential above the OFF pixels.
  • Insulating walls of the honeycomb prevent the lateral spread of the electric field and thereby widen the dynamic range of selective activation of the ON pixels.
  • electric field extends above the walls of the honeycomb to stimulate cells up to 40 ⁇ m from the base of the cavity within the safe charge injection limits, allowing for up to 99% activation of the total inner retina without crosstalk.
  • the ratio of the electrode size to pixel width is maintained, smaller pixels will require higher current densities, which are limited by the material properties. With one-dimensional flow of current, however, the situation is different: the current density required for a certain potential drop does not change with the pixel width, and therefore pixels can be made much smaller while retaining the same current density on the electrodes. For photovoltaic pixels it means that the threshold irradiance should remain nearly the same for all pixel sizes, as long as the relative dimensions of electrodes to pixel width do not change.
  • the honeycomb design is uniquely suited for subretinal placement due to the ability of the inner retinal neurons to migrate into voids in the subretinal space.
  • Our study demonstrates that the inner retinal neurons readily migrate into wells as small as 18 ⁇ m in width (20 ⁇ m pixel pitch).
  • Tissue viability after 6 weeks demonstrates that diffusion of oxygen and nutrients from the retinal vasculature located above the implant is sufficient for the cell survival within 25 ⁇ m high walls. Since no lower bound of integration was observed in our study, pixel width may continue to scale down, but certainly not below the cell size of about 10 Determination of the exact minimum within this range will require further experimentation. Even without any further decrease in the pixel size, arrays with 20 ⁇ m pixels should enable spatial resolution matching the natural acuity in rats, and acuity better than 20/100 in humans.
  • the walls can be electroplated from gold, having capacitance on the order of 0.01 mF/cm 2 in saline, while the return electrode on top of the walls can be made of Iridium Oxide, having capacitance of 1-10 mF/cm 2 . Due to conductive nature of the walls made from metal, the IrOx on top of such walls can be electroplated. Alternatively, IrOx can be deposited by sputtering, but conductive walls will connect this coating to the electrical circuit on the surface of the device. Walls can be made from other metals, including platinum, aluminum, molybdenum, and others.
  • Side walls can also be coated with a non-conductive material to prevent any current between the electrolyte and the side walls.
  • oxidation of aluminum or molybdenum makes its surface non-conductive.
  • Walls may also be insulated by additive processes, including, but not limited to, atomic layer deposition or photolithography of non-conductive materials. Alternatively, they can be made of an insulator. In this case, the return electrode deposited on top of such a wall should be connected to the electrical circuit via conductive tracks deposited for this purpose on top of the walls.
  • Pixels in the implant can be photovoltaic, i.e. convert light falling onto them into electric current using photodiodes connected between the active and return electrodes.
  • electric current can be delivered to the electrodes via wired connections.
  • the width of the array should be in the range of 0.5 to 5 mm, and more typically 1-3 mm. At these dimensions, the array does not require the use of flexible materials as previously claimed, however larger arrays may incorporate a flexible substrate to conform to the eye.
  • the depth of the cavities should be such that it allows migration of the cells from the inner nuclear layer, i.e. approximately the thickness of the inner nuclear layer plus the subretinal debris layer, i.e. in the range of 20-70 micrometers. Tissue viability after 6 weeks implantation in-vivo indicates that perforations at the bottom of the wells are not required for additional nutrient flow and for tissue survival.
  • Sidewalls can be designed to enable explanation of the implant while simultaneously improving mechanical stability within the subretinal space.
  • Completely smooth, vertical walls, as shown in this study, should not exert much mechanical force on the tissue when the device is removed from the tissue.
  • tissue migrating into the cavities provides a means to anchor the device laterally with respect to the retina.
  • Additional overhang at the top of the wall can be introduced by electroplating above the trench guiding the electroplating procedure.
  • the cavity opening d o ⁇ d c becomes smaller than its width, and hence the implant stability along the z axis can be further improved. This may, however, may make explanation of the device more traumatic, and so the exact configuration can be decided based upon patient's age and likelihood of the explanation.
  • stimulation thresholds are in the range of 0.01-1 A/cm 2 , with 10 ms pulse duration. Therefore, electrode material should be selected such that it can inject charge density in the range of 0.1-10 mC/cm 2 .
  • Reflective side walls of the honeycombs can help direct the radiation to the light-sensitive area of the implant at the bottom of the wells, if the implant is tilted relative to the incoming light.
  • walls made of metal using electroplating are advantageous due to high reflectivity of metals to visible and infrared light.
  • Other materials and coatings with high reflectivity can also be used for this purpose, especially for light incident at the walls at nearly grazing angles.
  • Passive honeycomb implants were fabricated from crystalline silicon wafers using two mask layers to generate patterns for deep silicon etching.
  • a hexamethyldisilazane (HMDS) primed wafer was spin-coated with 2 ⁇ m of negative photoresist (AZ5214-IR) and processed to define the honeycomb walls. This resist was further treated with UV for 15 min to enhance the selectivity during the subsequent etch. 25 ⁇ m deep cavities were formed in the exposed silicon regions using a Bosch etch process.
  • HMDS hexamethyldisilazane
  • photoresist (7.5% SPR 220-7, 68% MEK, and 24.5% PGMEA) was spray-coated over the wafer to a thickness of 14 ⁇ m and processed to define the releasing trenches around the 1 mm wide arrays.
  • a second Bosch process was applied to create these releasing trenches, after which the photoresist was removed.
  • the wafer was spray-coated with a protective 60 ⁇ m thick photoresist, and subsequently underwent backside grinding (Grinding and Dicing Services, Inc., San Jose, Calif., USA) from 500 to 50 ⁇ m in thickness from the base of the honeycombs.
  • FIGS. 4A-B The resulting structures are shown in FIGS. 4A-B .
  • Cavities are arranged in a hexagonal honeycomb patterns of 40, 30 and 20 ⁇ m pitch, having 25 ⁇ m high walls of 4, 3, and 2 ⁇ m thicknesses, respectively, on a 10 ⁇ m thick base.
  • the fourth quadrant was designed for honeycombs of 10 ⁇ m pitch, but these were beyond the processing limit for our lithography system and did not develop. We refer to this region as the “flat” quadrant in the text.
  • a 50 nm thick oxide was grown on the silicon implant's surface to prevent its dissolution in-vivo.
  • the retina was lifted with an injection of saline solution, and the implant was inserted into the subretinal space.
  • the conjunctiva was sutured with nylon 10-0, and topical antibiotic (bacitracin/polymyxin B) was applied on the eye postoperatively.
  • Surgical success and retinal reattachment were verified using Optical Coherence Tomography (OCT) (HRA2-Spectralis; Heidelberg Engineering, Heidelberg, Germany).
  • OCT Optical Coherence Tomography
  • Triton X-100 (Sigma-Aldrich, CA, USA) in PBS for 3 hours at room temperature.
  • the samples were put in 10% bovine serum albumin (BSA) blocking buffer for 1 hour at room temperature, followed by a 12 hour incubation at room temperature with two primary antibodies; rabbit anti-IBA1 (1:200; Wako Chemicals, VA, USA) and mouse anti-Glutamine Synthetase (GS, 1:100; Novus Biologicals, CO, USA) in 0.5% Triton X-100, 5% BSA in PBS.
  • BSA bovine serum albumin
  • 3-D imaging was performed using a Zeiss LSM 880 Confocal Inverted Microscope with Zeiss ZEN Black software.
  • Image planes were acquired through the total thickness of the retina using a Z-stack, with upper and lower bounds defined at the inner limiting membrane (ILM) and 10 ⁇ m below the base of the honeycomb cavities, respectively.
  • Stacks were acquired in the center of each honeycomb quadrant using a 40 ⁇ oil-immersion objective with acquisition area >225 ⁇ m ⁇ 225 ⁇ m, 360 nm z-step, and 0.55 ⁇ m pinhole.
  • the density of cells in the XY plane defined as the percent of the area occupied by cells, was then computed, taking into account the area occupied by the honeycomb walls.
  • each honeycomb unit was independently analyzed, with the cell density normalized to the maximum within the unit stack. The percent of INL contained within the cavities is calculated as
  • samples were rinsed in a buffer and fixed in 1.25% glutaraldehyde solution for 24 hours at room temperature. They were then post-fixed in osmium tetroxide for 2 hours at room temperature and dehydrated in graded alcohol and propylene oxide. Following overnight infiltration in epoxy (without DMP-30) at room temperature (Electron Microscopy Sciences—Araldite-EMbed, RT13940, Mollenhauer's kit), samples were left in an oven for 36 hours at 70° C. Epoxy blocks were then trimmed until the silicon implants were exposed.
  • the silicon implants were removed using a XeF 2 etch (Xactix e-1, 23° C., 3 Torr). Blocks were then refilled with epoxy and put in a vacuum desiccator for two hours, followed by overnight baking at 70° C. This refilling of the void left after etching of the implant provided structural support during sectioning.
  • the 700 nm thick sections (cut by Reichart UltracutE) were stained with toluidine blue for light microscopy.
  • Electric field in the retina was calculated using a 3-D finite element model of the complete array in COMSOL Multiphysics 5.0, using the electrostatics module to solve Maxwell's equations for electric potential, assuming steady-state electric currents.
  • the modeled arrays are 1 mm in diameter, 30 ⁇ m thick, and are composed of hexagonal pixels of various sizes, listed in Table 2, with return electrodes connected into a single mesh.
  • the modeled prosthesis functions as a closed system, in which all the current injected from active electrodes is collected on the return electrodes. Boundary conditions on electrode surfaces were defined as having a uniform current density, which corresponds to the steady state.
  • FIG. 3A planar with local returns
  • FIG. 3B honeycomb with local returns
  • a common return electrode collects the current generated by all active pixels such that the total collected current is the sum of the injected currents on individual active electrodes.
  • Side walls of the honeycombs are non-conductive.
  • we assessed spatial resolution in-vivo by projecting grating patterns of various spatial frequencies with 100% contrast. The maximum resolution corresponds to activating alternating rows of pixels (ON or OFF rows). To replicate this configuration in simulations, we compute the electric field distribution using an identical activation scheme, and analyze the field at the center of the array, where the cross-talk between neighboring pixels is highest.
  • the total current per pixel was calculated based on the diode area for the 2-diode configuration and measured light-to-current conversion efficiencies: 0.40, 0.31, 0.26, and 0.24 A/W for 140, 70, 55, and 40 ⁇ m pixels, respectively.
  • Retinal stimulation thresholds were evaluated using a model of network-mediated activation.
  • a network-mediated stimulation threshold being defined by a voltage drop across bipolar cells.
  • the intracellular medium becomes equipotential within a microsecond, resulting in hyperpolarization and depolarization of the cell membrane near and far from the anode, respectively.
  • the average resistivity of the retina 1000 ⁇ cm
  • a mean length of bipolar cells estimated as the distance from the middle of INL to the middle of IPL (37 ⁇ m)
  • a potential difference threshold 4.8 mV from soma to axonal terminals for anodic stimulation.
  • the cathodic threshold of ⁇ 21 mV was calculated based on the network-mediated activation curve measured in rat retinas with anodic and cathodic stimulation, which was scaled to match the calculated anodic threshold.
  • the total retinal response is calculated by integrating the cellular responses over the volume of INL with either (1) a binary coefficient, i.e. calculating just the fraction of the INL volume above the stimulation threshold, or (2) with cellular response proportional to its polarization.

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WO2024079699A1 (fr) * 2022-10-13 2024-04-18 Neural Automations Ltd. Réseaux de micro-électrodes pour interfaçage électrique

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