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. 2015 May;21(5):476-82.
doi: 10.1038/nm.3851. Epub 2015 Apr 27.

Photovoltaic restoration of sight with high visual acuity

Henri Lorach  1 , Georges Goetz  2 , Richard Smith  3 , Xin Lei  4 , Yossi Mandel  5 , Theodore Kamins  4 , Keith Mathieson  6 , Philip Huie  7 , James Harris  4 , Alexander Sher  3 , Daniel Palanker  7
Affiliations

Photovoltaic restoration of sight with high visual acuity

Henri Lorach et al. Nat Med. 2015 May.

Abstract

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

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Figures

Figure 1
Figure 1. Photovoltaic array and in-vitro experimental setup
(a) The prosthesis is composed of 70 μm pixels separated by 5 μm trenches arranged in a 1 mm-wide hexagonal pattern, with the adjacent rows separated by 65 μm. Scale bar, top right-hand corner: 65 μm; bottom left-hand corner: 500 μm. (b, c) Each pixel consists of two to three (shown here) photodiodes connected in series between the central active (1) and surrounding return electrode (2). Scale bar: 50 μm. (d) Schematic representation of a healthy rat retina sandwiched between a transparent multielectrode array (MEA) and the photovoltaic array (PVA). Visible light stimulates the photoreceptors (PR), while much brighter pulsed NIR (880–915 nm) illumination generates biphasic pulses of current in the photovoltaic pixels, stimulating the cells in the inner nuclear layer (INL).
Figure 2
Figure 2. Natural and prosthetic receptive fields of RGCs
(a) Visible-light receptive field (vRF) of an ON RGC. The red ellipsoid corresponds to the 1 standard deviation (SD) contour of a Gaussian fit. Scale bar: 500 μm. (b) Electric receptive field (eRF) of a different RGC. Gray levels encode the number of spikes in response to stimulation of different pixels: black = 0, white = maximum (2.4 action potentials/light pulse). Estimated position of the soma is indicated by the red dot. Scale bar: 500 μm. (c) eRF with an earlier local and a delayed diffuse response. (d) Distribution of eRF (red, photovoltaic, n = 92 for WT and n = 48 RGCs for RCS animals) and vRF (blue, visible, n = 92 RGCs) diameters in healthy (WT) and degenerate (RCS) retinas. Error bars represent the standard deviation, circles correspond to localized eRFs, triangles to eRFs with a diffuse component. Box plots are Tukey boxplots.
Figure 3
Figure 3. Response of RGCs to alternating gratings
(a) Light is pulsed at 20 Hz, and the grating contrast reversed at 1 Hz, corresponding to a contrast reversal every 500ms, as illustrated by the grey dashed lines. This triggers ganglion cell responses to photovoltaic (red, RCS) and visible light (blue, WT) stimulation. These RGCs do not response to individual light pulses but only to the image change at 1 Hz. (b) Amplitude of the response to grating reversal as a function of the grating stripe width, for one sample neuron stimulated with visible light (blue) and two sample neurons stimulated photovoltaically (red, triangles and squares). Dashes gray line indicates the stimulation threshold. Error bars show SEM. (c) Histograms and kernel density estimates of the stimulation thresholds distributions (0.5 spike/reversal, n = 278 RGCS for WT and n = 109 RGCs for RCS). The peak in the distribution occurs at 28 μm for visible-light stimulation. With photovoltaic stimulation, a first peak occurs at 67 μm, followed by a second peak beyond 100 μm.
Figure 4
Figure 4. RGC responses to alternating gratings
(a) Average steady state response of RGCs to pulsed stimulation of varying frequency (n = 178 RGCs for WT and n = 45 RGCs for RCS). Amplitude of both responses decreases with increasing pulse frequency. However, while with visible-light stimulation, the steady state response at 20 Hz is negligible, a number of neurons maintain a weak response to NIR pulses at 20 Hz in the RCS retina. (b) RGC response to 1 Hz contrast reversal of square gratings projected with visible light onto WT retina. The response is almost imperceptible at 30 μm/stripe and exhibits a clear frequency doubling at 70 μm/stripe. At 140 μm/stripe, frequency doubling is still present, while one of the phases of the grating (60°) starts exhibiting a strong linear (f1) component. With photovoltaic stimulation of RCS retina (20 Hz, 4 ms pulses), responses vary between the RGC that exhibits strong flicker fusion, shown in (c), and RGCs that do not, as shown in (d). (c) In RGCs that exhibit strong flicker fusion, transient frequency-doubled response can be seen for all phases of the grating at 70 μm/stripe. At 140 μm/stripe, the frequency doubling still take place for one phase (120°), while strong linear responses can also be seen for other phases of the grating. (d) An RGC without flicker fusion exhibits a dominant linear response (f1) for 140 μm/stripe gratings, with action potentials time-locked to every pulse delivered to the retina. Response is negligible at 70 μm/stripe.
Figure 5
Figure 5. In-vivo subretinal implantation and stimulation setup
(a) Fluorescein angiography one week after surgery 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. (b) OCT shows good preservation of the inner retina, with the inner nuclear layer (INL) located approximately 20μm above the upper surface of the implant (white line). The 30 μm implant appears thicker due to its high refractive index. The yellow dashed line illustrates the actual position of the back side of the implant on top of the RPE. Scale bar: 200 μm. (c) Stimulation system for VEP recordings. The visible (532 nm) and NIR (915 nm) lasers illuminate the DMD which generates the spatial patterns projected onto the retina, as shown in the photograph insert. The cortical activity (VEP signal) is recorded via transcranial electrodes simultaneously to the corneal potential, which reveals the stimulation pulses from the implant.
Figure 6
Figure 6. In vivo prosthetic stimulation and visual acuity
(a) VEP modulation by irradiance and (b) by pulse duration under full field illumination (n = 9 WT animals and n = 7 RCS animals). (c) Sample VEP traces corresponding to different grating stripe widths. We defined the VEP amplitude as the peak-to-peak variation of the signal during the first 100 ms following grating alternation (gray shaded area) for prosthetic stimulation. Visible light triggered slower and longer-lasting responses and we measured the amplitude during the first 300 ms after alternation. Responses decreased to the noise level with 50 μm stripes. (d) VEP amplitude for visible gratings (blue) and prosthetic stimulation (red) decrease with decreasing width of the stripes. Acuity limit and its associated uncertainty, 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 (n = 7 WT animals with visible light and n = 7 RCS animals with prosthetic stimulation). Error bars show standard error of the mean. NS: not significant; *: P < 0.05; ** : P < 0.01 : ***: P < 0.001, one-tailed Welch t-test.
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