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Review
. 2016 Sep;79(9):096701.
doi: 10.1088/0034-4885/79/9/096701. Epub 2016 Aug 9.

Electronic approaches to restoration of sight

G A Goetz  1 , D V Palanker
Affiliations
Review

Electronic approaches to restoration of sight

G A Goetz et al. Rep Prog Phys. 2016 Sep.

Abstract

Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field.

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Figures

Figure 1
Figure 1. The human visual system
(a) Visual perception begins in the eye, where the cornea and lens (1) project an inverted image of the world onto the retina (2), which converts incident photons into neural action potentials. (b) The retina consists of three layers of cells. The photoreceptors (PR), which are in contact with the retinal pigment epithelium (RPE), convert light into neural signals that propagate to the horizontal (HC), bipolar (BC) and amacrine cells (AC) of the inner nuclear layer. The axons of the retinal ganglion cells (RGCs) form the retinal nerve fiber layer (RNFL). They converge onto the optic disk (3), where they congregate to form the optic nerve (4), which relays neural signals to the brain. (c) Signals from the left and right visual fields of both eyes are combined at the optic chiasm (5). The lateral geniculate nucleus (6) relays the left visual field to the right visual cortex and the right visual field to the left visual cortex through neuron axons called the optic radiation. Higher visual processing finally takes place in the visual cortex (7), and further downstream in the brain.
Figure 2
Figure 2. Implant placement
(a) Simplified wiring diagram of the retina. Signals from the photoreceptors (PR) are processed and relayed by the horizontal (HC), bipolar (BC) and amacrine cells (AC) of the inner nuclear layer (INL) to the retinal ganglion cells (RGC). The axons of the retinal ganglion cells form the retinal nerve fiber layer (RNFL), which relays visual signal to the brain. Photoreceptors are located at the back of the eye, in contact with the retinal pigment epithelium (RPE). (b) Histology cross-section of a healthy rat retina. RNFL: retina nerve fiber layer; OS: photoreceptor outer segments. Scale bar: 50 μm. (c) Epiretinal implants are in contact with the ganglion cell layer of the retina, while subretinal implants approach the retina from the photoreceptor side. Suprachoroidal implants are placed on the other side of the choroid, above the sclera. In a degenerate rat retina, as shown here, subretinal implants are in direct contact with the inner nuclear layer. Scale bar: 50 μm.
Figure 3
Figure 3. Subretinal photovoltaic implant
(a) A single module of a photovoltaic prosthesis, which consists of 70 μm-wide pixels separated by 5 μm trenches arranged in a 1 mm-wide hexagonal pattern. Scale bar: 500 μm bottom left; 65 μm top right. (b) Close-up photograph of an anodic 70 μm-wide pixel. Scale bar: 50 μm. (c) The wiring diagram for a pixel. Each pixel consists of two to three (shown here) photodiodes connected in series between the central active (1) and surrounding return (2) electrode. (d) In the absence of irreversible Faradaic reactions, a light pulse is converted by the implant into a charge-balanced current pulse flowing through the inner retina. Adapted from [48].
Figure 4
Figure 4. Concept of a fully optical photovoltaic retinal prosthesis
A head-mounted camera captures visual scenes, which are processed by a mobile signal-processing unit. High-power near infrared light relays visual information to a photovoltaic subretinal implant through the natural optics of the eye.
Figure 5
Figure 5. Thresholds for electroporation
(a) Chronic retinal damage threshold (blue curve) due to electroporation as a function pulse duration measured with pipettes 0.12 (circles) and 1.0 mm in diameter (squares). Thresholds for stimulation of ganglion cells (red curve, from [74]) are up to two orders of magnitude lower for planar disk electrodes of comparable diameters. (b) Ratio of the damage thresholds to the stimulation thresholds. Adapted from [73].
Figure 6
Figure 6. Local degeneration of the retina caused by a subretinal implant
(a) 5 weeks post implantation, an otherwise healthy rat retina shows highly localized degeneration over the area of the implant. Scale bar: 200 μm. (b) Above the implant, most of the photoreceptors, somas included, are gone. The inner nuclear layer (INL) and ganglion cell layer (GCL) are left intact. Scale bar: 100 μm. (c) At the edge of the implant, the retina looks healthy, and photoreceptors (PR) are present.
Figure 7
Figure 7. Equivalent circuit models of a neuron for intracellular electrical stimulation
(a) Equivalent circuit for the Lapicque strength-duration relationship. (b) Equivalent circuit for the Weiss strength-duration relationship. (c) Qualitative representation of the Lapicque and Weiss strength-duration relationships.
Figure 8
Figure 8. Selective subretinal activation of the retina
(a) RGCs respond to electric activation of the retina with a combination of short (SL), medium (ML) and long latency (LL) action potentials. SL responses come from direct activation of the RGCs, while ML responses originate in the inner nuclear layer, and LL responses likely originate in the photoreceptor layer. (b) Strength-duration relationship for a stimulating electrode placed epiretinally delivering cathodic-first current pulses. Short (<2 ms) pulses can selectively activate the RGCs, while long (>10 ms) pulses can selectively activate the INL. (c) Strength-duration relationship for a stimulating electrode placed in the outer plexiform layer (subretinal positioning) delivering anodic-first current pulses. Long (10 ms) anodic pulses can activate the INL without eliciting activity in the GCL. Data adapted from [11].
Figure 9
Figure 9. Retinal migration with pillar implants
The retina robustly migrates into the voids left by pillar implants in the subretinal space in a few weeks post-implantation. Cells in the inner nuclear layer (INL) are brought in close contact with the top of the pillars. Pillars diameter: 20 μm. Spacing between pillars: 40 μm. Scale bar: 50 μm.
Figure 10
Figure 10. Modulation of RGC and cortical responses by pulse width and irradiance
At the level of the RGCs, the number of elicited action potentials increases with irradiance (a) and with pulse width (b). Error bars, s.e.m. At the cortical level, (c) devices with 70 μm pixels (blue) elicit a VEP response at 0.25 mW/mm2, which increases up to 1 mW/mm2 and saturates beyond that level. The 140 μm pixels (black) have lower thresholds and do not saturate at high irradiance. (d) VEP amplitude increases with pulse duration between 1 and 10 ms, and saturates with longer pulses (with 2 and 4 mW/mm2 irradiance for 140 μm and 70 μm pixel devices, respectively). Error bars, s.d. Adapted from [46, 106].
Figure 11
Figure 11. RGC and cortical adaptation to high frequency stimulation
(a) Average steady-state response of RGCs to pulsed stimulation of varying frequency in arbitrary units (a.u.). Error bards, s.d. (b) Normalized amplitude of the VEP response to visible (WT rats) and NIR (RCS rats) stimulation pulses of increasing frequency. Error bars, s.d. (c) With 20 Hz stimulation repetition rate, RGCs respond transiently to image changes and not to every pulse of electrical current (RCS) or visible light (WT), as illustrated in the single channel voltage recordings shown here. Grey dashed lines indicate the image refresh times. Adapted from [48].
Figure 12
Figure 12. In-vivo evaluation of an implant
(a) Fundus image of a subretinal photovoltaiv prosthesis with 70 μm pixels implanted in a rat eye. (b) Fluorescein angiography of a different RCS retina 1 week after implantation demonstrates normal retinal blood perfusion above the implant with no leakage. The implant is opaque to visible light and masks the choroidal fluorescence in the implanted area. Scale bar, 200 μm. (c) In an implanted RCS retina, OCT shows good preservation of the inner retina, with the inner nuclear layer (INL) located 20 μm above the upper surface of the implant (white line). The implant (30 μm in thickness) appears thicker than it actually is because of its high refractive index. The yellow dashed line illustrates the actual position of the backside of the implant, which is located on top of the retinal pigment epithelium. Horizontal and vertical scale bars, 200 μm each. (d) The in-vivo stimulation and recording system consists of a visible (532 nm) and a NIR (915 nm) laser, which illuminate a digital micromirror device (DMD). In turn, this device generates the images projected onto the retina, as shown in the photograph (inset). Projected patterns are monitored by means of a CCD camera. Adapted from [48].
Figure 13
Figure 13. Classifying retinal ganglion cells without visible light information
(a) Multielectrode arrays record a 2D projection of spatio-temporal action potentials, called electrophysiological images (EIs), and schematically illustrated here for a midget (left) and a parasol (right) RGC. Differences in cell morphology lead to differences in the EIs. (b) Examples of handcrafted filters that can extract discriminative features of EIs, such as amount of rotation, number of radial processes, diameter, velocity of propagation of the axonal action potential in the EI. Classifiers can be trained to recognize cell types using these features. Adapted from [126].
Figure 14
Figure 14. Nonlinear subunits in a receptive field
(a) The receptive field of a RGC can be broken into subunits that correspond to the receptive fields of each bipolar cell connecting to the RGC. (b) A subretinal prosthesis with small enough pixels can activate independent subunits, which then sum up nonlinearly in the retinal ganglion cell.
Figure 15
Figure 15. Gratings stimulation thresholds
(a) Amplitude of the response to grating reversal as a function of the grating stripe width, for one sample neuron stimulated with visible light (blue, WT retina) and two sample neurons stimulated with a subretinal photovoltaic prosthesis (red, RCS retina, triangles and squares). Stimuli were displayed with 20 Hz, 4 ms pulses stroboscopic illumination and 1 Hz grating contrast reversal period. The dashed gray line indicates the stimulation threshold. Peristimulus time histograms show the response of the neurons for alternation of 70 μm-wide gratings. The WT response exhibits frequency doubling, indicative of non-linear interactions in receptive field subunits. Prosthetic responses range from flicker-fused and frequency-doubled (left histogram), to more sustained and linear (right histogram). Error bars, s.e.m. (b) Histograms and kernel density estimates of the stimulation thresholds distributions (0.5 action potential/reversal). The peak in the distribution occurs at 28 μm for visible light stimulation. With photovoltaic stimulation, a first peak occurs at 67 μm. (c) Normalized VEP amplitude for visible gratings (blue) and photovoltaic (prosthetic) stimulation (red) measured as a function of grating stripe widths. The acuity limit, estimated as the crossing point of the parabolic fits with the noise level (dashed lines), corresponds to 27 ± 9 μm/stripe for visible light and 64 ± 11 μm/stripe for prosthetic stimulation. Error bars, s.e.m. NS, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001, one-tailed Welch t-test performed against the lowest grating size group. Adapted from [48].
Figure 16
Figure 16. Mean population responses of RGCs to full-field subretinal contrast steps
(a) WT responses to visible full field light steps can broadly be classified into vON (red), vOFF (blue) and vON-OFF (purple) responses. The black dashed line outlines the stimulation threshold, defined as a 503 probability of eliciting an action potential correlated with the contrast step. On average, ON cells respond to contrast increments greater than 73, while OFF cells respond to contrast decrements as small as 33. (b) Photovoltaic stimulation of p90-140 RCS retina with 70 μm pixel implants requires 673 contrast steps to elicit responses in the RGCs. Maximum amplitude of the response is lower than with visible light in the WT retina. Confidence bands represent the standard error of the mean. Adapted from [121].
Figure 17
Figure 17. The Argus II epiretinal implant
(a) Photograph of the external portion of the Argus II prosthesis system (Second Sight Medical Products, Inc., Sylmar, CA) including glasses-mounted video camera, radio-frequency (RF) coil, and video processing unit (VPU) with rechargeable battery. (b) Photograph of the implanted portion of Argus II prosthesis system including the 610 electrode array, electronics case, and implant RF coil. (c) Fundus photograph of an Argus II array implanted in the macular region. A retinal tack secures the electrode array to the retina. The surgeon uses the white handle to position the device in the eye. Scale bar: 5 mm, corresponding to 16.7° visual angle. Adapted from Humayun et al [33].
Figure 18
Figure 18. The Alpha IMS subretinal implant
(a) The cable from the implanted chip in the eye leads under the temporal muscle to the exit behind the ear, and connects with a wirelessly operated power control unit. (b) Position of the implant under the transparent retina. (c) MPDA photodiodes, amplifiers and electrodes in relation to retinal neurons and pigment epithelium. (d) Patient with wireless control unit attached to a neckband. (e) Route of the polyimide foil (red) and cable (green) in the orbit in a three-dimensional reconstruction of CT scans. (f) Photograph of the tip of the subretinal implant at the posterior eye pole through a patient’s pupil. Scale bar: 3 mm, corresponding to 10° visual angle. Reprinted from Zrenner et al [150] under the Creative Commons Attribution License.
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