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Assessment of visual function in blind mice and monkeys with subretinally implanted nanowire arrays as artificial photoreceptors

Nature Biomedical Engineering (2023)Cite this article

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Abstract

Retinal prostheses could restore image-forming vision in conditions of photoreceptor degeneration. However, contrast sensitivity and visual acuity are often insufficient. Here we report the performance, in mice and monkeys with induced photoreceptor degeneration, of subretinally implanted gold-nanoparticle-coated titania nanowire arrays providing a spatial resolution of 77.5 μm and a temporal resolution of 3.92 Hz in ex vivo retinas (as determined by patch-clamp recording of retinal ganglion cells). In blind mice, the arrays allowed for the detection of drifting gratings and flashing objects at light-intensity thresholds of 15.70–18.09 μW mm–2, and offered visual acuities of 0.3–0.4 cycles per degree, as determined by recordings of visually evoked potentials and optomotor-response tests. In monkeys, the arrays were stable for 54 weeks, allowed for the detection of a 10-μW mm–2 beam of light (0.5° in beam angle) in visually guided saccade experiments, and induced plastic changes in the primary visual cortex, as indicated by long-term in vivo calcium imaging. Nanomaterials as artificial photoreceptors may ameliorate visual deficits in patients with photoreceptor degeneration.

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Fig. 1: Ex vivo responses of RGCs to light stimulus, and in vivo light localization test.
Fig. 2: Ex vivo responses of RGCs to flashing light, and in vivo flashing detection test.
Fig. 3: Spatial resolution and receptive field in blind mice with the implanted NW arrays.
Fig. 4: Orientation selectivity and in vivo orientation discrimination test.
Fig. 5: Long-term responses to light in V1 neurons of blind mice with the implanted NW arrays.
Fig. 6: Ophthalmological characterization of monkeys A and E with the implanted NW arrays.
Fig. 7: VGS behaviour for monkeys A and E with the implanted NW arrays.

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Data availability

The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. The study using stimuli of natural scenes used 30 natural images from the van Hateren Natural Image Dataset (https://github.com/hunse/vanhateren) and the McGill Calibrated Colour Image Database (http://tabby.vision.mcgill.ca.). Source data are provided with this paper.

Code availability

Custom-written codes used to analyse data from this study are available from the corresponding authors on request.

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Acknowledgements

This work was supported by the MOST of China (2022ZD0208604 and 2022ZD0208605 to J.Z.; 2022ZD0210000 to B.Y.), NSF of China (31771195, 81790640, 81773513 and 820712002 to J.Z.; 32100803 to B.Y.), Shanghai Municipal Science and Technology Major Project (no. 2018SHZDZX01 to J.Z.) and ZJLab, the Key Research and Development Program of Ningxia (no. 2022BEG02046 to J.Z.), Sanming Project of Medicine in Shenzhen (SZSM202011015) to J.Z., Key Scientific Technological Innovation Research Project by Ministry of Education to J.Z., Research and Development Fund of Zhongshan Hospital (2020ZSFZ19 to Y.Y.).

Author information

Author notes

  1. These authors contributed equally: Ruyi Yang, Peng Zhao, Liyang Wang, Chenli Feng, Chen Peng.

Authors and Affiliations

  1. State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China

    Ruyi Yang, Peng Zhao, Zhexuan Wang, Kaiwen Shi, Shijun Weng, Tianyun Zhang, Xingdong Chen, Yiheng Wang, Yuanyuan Luo, Qingyuan Chen, Yuqing Chen, Chengyong Jiang, Xiaofen Mo, Xingtao Zhou, Chunhui Jiang, Biao Yan & Jiayi Zhang

  2. Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China

    Liyang Wang, Chenli Feng, Minqian Shen, Chunqiong Dong & Yuanzhi Yuan

  3. Laboratory of Advanced Materials, Department of Chemistry, Fudan University, Shanghai, P. R. China

    Chen Peng & Gengfeng Zheng

  4. Key Laboratory of Brain Functional Genomics (Ministry of Education), East China Normal University, Shanghai, P. R. China

    Yingying Zhang, Fu Zeng & Aihua Chen

  5. Shanghai Key Lab for Future Computing Hardware and System, School of Microelectronics, Fudan University, Shanghai, P. R. China

    Shuiyuan Wang

  6. School of Computer Science, Institute for Artificial Intelligence, Peking University, Beijing, P.R. China

    Shanshan Jia & Zhaofei Yu

  7. School of Computer Science, University of Birmingham, Birmingham, UK

    Jian Liu

  8. Department of Hand Surgery, the National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, P. R. China

    Fei Wang, Su Jiang & Wendong Xu

  9. Department of Hand and Upper Extremity Surgery, Jing’an District Central Hospital, Fudan University, Shanghai, P.R. China

    Wendong Xu

  10. Center of Brain Sciences, Beijing Institute of Basic Medical Sciences, Beijing, P. R. China

    Liang Li & Gang Wang

  11. Zhongshan Hospital (Xiamen), Fudan University, Xiamen, P.R. China

    Yuanzhi Yuan

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  1. Ruyi Yang
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Contributions

J.Z., B.Y. and Y.Y. conceived the study. J.Z. and B.Y. wrote the paper. R.Y. performed the behavioural experiments of mice and monkeys, performed ex vivo patch-clamp experiments, refined the techniques and analysed the data, with help from P.Z., Z.W, K.S., X.C. and T.Z. C.P. and G.Z. synthesized the AuTiO2-x NW arrays. P.Z., R.Y. and Y.C. developed two-photon microscope setups and chronic calcium imaging. R.Y., X.C., T.Z. and S.W. cut and polished the AuTiO2-x NW arrays. Q.C., L.L., Chengyong J. and G.W. analysed the VEP data. Z.W., Shanshan J., J.L., Z.Y., S.W. and G.W. performed data analysis about patch-clamp experiments. L.W., M.S., C.D., Y.L., X.Z., X.M., Chunhui J. and Y.Y. conducted the surgical procedures for NW array implantation in monkey. C.F., Y.L, Y.W., Y.Z., A.C., F.Z., F.W., Su J. and W.X. worked on monkeys’ eyes examinations. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Chunhui Jiang, Yuanzhi Yuan, Biao Yan or Jiayi Zhang.

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Competing interests

The authors declare no competing interests.

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Nature Biomedical Engineering thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Characterization of the photocurrent in AuTiO2-x NW arrays.

a, Schematic of AuTiO2-x NW arrays photocurrent measurement with UV (375/28 nm, 292.99 μW·mm−2), blue (470/20 nm, 318.47 μW·mm−2) or green (546/12 nm, 420.38 μW·mm−2). The photocurrents were measured by Ag/AgCl electrodes attached to the surface of the NW arrays in normal saline solution. b, Photocurrents generated by illumination of UV, blue, green and red light, receptively with an AuTiO2-x NW arrays. c, UV-visible absorbance spectra of original TiO2 and AuTiO2-x. d, Compared with the published results30, the photocurrent of improved NW arrays increased by 760.08%, 559.48% and 556.80% under UV, blue and green light, receptively. e,f, Example of photocurrent measures obtained with UV light stimulus (DMD, wavelength: 400 nm) at 10 μW·mm−2 (e) and 3 μW·mm−2 (f) for 0.005–1.0 sec pulse duration. g, Photocurrent at 10 μW·mm−2 (top) and 3 μW·mm−2 (bottom) for 1.0, 0.5, 0.2, 0.1, 0.05, 0.025 and 0.005 sec in e and f. h, Representative photocurrent recording with UV stimulus (DMD, wavelength: 400 nm, light intensity: 10 μW·mm−2) at different flicker frequency (Magenta, 1.0 Hz; blue, 2.5 Hz; cyan, 5.0 Hz; green, 10.0 Hz; red, 20 Hz). i, Zoom in photocurrent of gray rectangle in h. Dashed black line indicate the stimuli on. j, Mean latency of NW arrays to light stimulus (n = 31 measurements from 4 NW arrays). Latency was defined as the time difference between the onset of the visual stimuli and the time that photocurrent reaches the peak value. All data are expressed as mean ± SEM.

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Extended Data Fig. 2 Miss rate of training trials and choice-box-based light localization test with flashing light at 20 Hz flicker frequency.

a, Miss rates of normal mice (red, n = 3 mice), blind mice with glass implant (black, n = 3 mice) and blind mice with NW arrays implant (blue, n = 4 mice) during training trials. Green line indicates 50% miss rate. b, Correct rates of normal mice (n = 3 mice), blind mice with glass implant (n = 3 mice) and blind mice with NW arrays-implanted (n = 5 mice) in the choice-box-based behavioural test of light localization with flashing light at 20 Hz flicker frequency (pulse duration: 25 msec). c, Correct rates of normal mice (85.02%, red, n = 3 mice), blind mice with glass implant (15.68%, black, n = 3 mice) and blind mice with NW arrays implant (82.07%, blue, n = 5 mice). The correct rates of blind mice with NW arrays implant had no significant difference between flash light at 20 Hz flicker frequency lasted for 10 sec (filled blue column) and 10-sec-long light (hollow blue column). All data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons in c (flash light), and two-sided unpaired t-test in c (10-sec-long light). NS non-significant. *** P < 0.001.

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Extended Data Fig. 3 Choice-box-based static object discrimination test, light localization test, flashing detection test and moving bar detection test of blind mice with the NW arrays implant.

a, Schematic of static object discrimination test. Black dashed line indicates the range where the object was placed. b, Correct rate of normal mice (red, n = 3 mice), blind mice with glass implant (n = 3 mice) and blind mice with NW arrays implant (n = 5 mice). c, Correct rate of 4-week group and 1-week group in choice-box-based light localization test using a UV LED (375/15 nm, 6.24 μW·mm−2). d, Correct rates of normal mice (n = 3 mice), blind mice with glass implant (n = 3 mice) and blind mice with NW arrays implant for 1 week (n = 4 mice) in the choice-box-based behavioural test using flashing light. e, Correct rates of normal mice (n = 3 mice), blind mice with glass implant (n = 3 mice) and blind mice with NW arrays implant for 1 week (n = 4 mice) in the choice-box-based behavioural test using moving light bars (5.25 degrees, 7.85 degrees/sec, 13.38 μW·mm−2). All data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons in b, two-way RM ANOVA with Tukey’s multiple comparisons in c. * P < 0.05, *** P < 0.001.

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Extended Data Fig. 4 Responses of RGCs to flashing light in the normal retina.

a, Schematic of flashing light stimuli. b, Examples responses of RGC to flashing light stimuli in normal retina (Temporal frequency: 0.50-20.0 Hz).

Extended Data Fig. 5 Responses of RGCs to moving light bars in NW arrays-attached blind retina ex vivo, and choice-box-based behavioural test using moving light bars.

a, Schematics of ex vivo patch-clamp recording with moving light bars stimuli. b-d, Responses of representative RGCs to moving light bars stimulus (DMD, wavelength: 400 nm, light intensity: 10 μW·mm−2, width: 120 μm, speed: 200 μm/sec) in normal, blind and NW-array-attached blind retinas. e, Responses of a representative RGC to moving light bars stimuli with different width (width: 20–180 μm). f-g, Average firing rates and fraction of responses of RGCs in normal (n = 9 RGCs from 6 retinas), blind (n = 10 RGCs from 8 retinas) and NW-array-attached blind retinas (16 RGCs from 10 retinas) using moving light bars with width ranging from 0.64 to 5.76 degrees. h, Schematics of the choice-box-based moving bar detection test using moving and static light bar stimuli. i, Correct rate of normal mice (n = 6 mice), blind mice with glass implant (n = 6 mice) and blind mice with NW arrays implant (n = 8 mice) in moving bar detection test (5.25 degrees in width at 7.85 degrees/sec). j-k, Correct rate of normal mice (n = 3 mice), blind mice with glass implant (n = 3 mice) and blind mice with NW arrays implant (n = 4 mice) in moving bar detection test with moving light bars of different widths and speeds (width: 2.63–7.88 degrees, speed: 5.23–10.47 degrees/sec). All data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons in g and i, two-way RM ANOVA with Tukey’s multiple comparisons in j and k. * indicates a significant difference between blind mice with NW arrays and blind mice with glass implant, # indicates a significant difference between blind mice with NW arrays and normal mice. * and # P < 0.05, ** and ## P < 0.01, *** P < 0.001.

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Extended Data Fig. 6 Long-term light-evoked responses using two-photon calcium imaging in V1 of NW-array-implanted blind mice in vivo.

a, Schematic of the position of the cranial window in V1 and the close-up of a completed cranial window by the day of surgery. b, The number of neurons in imaging site (n = 4 sites from 3 mice) recorded at different time points throughout the experiment. c,e, Grayscale images of recording fields of two blind mice before implantation (c) and 7 days after implantation (e). 14 representative light-responsive neurons were marked by red contours. Scale bars, 50 μm. d,f, The fluorescence changes of neurons in c and e in response to visual stimulations (Blue LED, 465/25 nm, 6.75 μW·mm−2, duration: 1 second). Dashed blue lines indicate the onset time of the visual stimulations.

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Extended Data Fig. 7 Responses to natural scenes in V1 neurons of NW-array-implanted blind mice.

a, Schematics of two-photon calcium imaging with natural scenes, which were presented for 0.5 sec followed by 5 sec inter-image gray periods. b, Examples of natural scenes and heatmaps of cellular responses to the natural scenes in normal mice (left, n = 3 mice), blind mice (middle, n = 4 mice) and blind mice with NW arrays implant (right, n = 4 mice). Each axial column represented responses of 30 neurons to one natural scene, with the strongest response positioned at the core. c, Fraction of neurons that responded to at least one natural scene in normal mice (72.36%, n = 3 mice), blind mice (16.69%, n = 4 mice) and blind mice with NW arrays implant (56.71%, n = 4 mice). d, Average lifetime sparseness of neurons in normal mice (0.61, n = 3 mice) and blind mice with NW arrays implant (0.54, n = 4 mice). All data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons in c, two-sided unpaired t-test in d. NS non-significant, * P < 0.05, ** P < 0.01.

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Extended Data Fig. 8 Biocompatibility and dendritic structural analysis of implants in mice.

a, A three-view diagram showing the 3-D outline of an implanted region and ROIs chosen for quantitative analysis. The shape of the NW arrays was represented by the convex of retina since it didn’t emit detectable fluorescence signals. I: Interface, O: Outskirts. b, Example slices of z-stack images cropped by the ROIs in a, cross-dot markers illustrating identification of cells in these slices from corresponding fluorescence signals. Scale bar, 20 μm. c, 3-D reconstructed models of retinas at the borders of the NW arrays at 3 timepoints. Models were presented in x-y view (upper row) and x-z view with y axis rotated for 40 degrees towards z axis (lower row). The dark areas on the lower right side of the models were the edges of NW arrays. Scale bar, 40 μm. d,e, Quantitative analysis of RGC numbers (d) and RBP numbers (e) at 3 timepoints (n = 5 sites for 2 weeks, n = 3 sites for 4 weeks and 6 months). Cell numbers of RGCs and RBPs in each ROI at the interface were normalized to the average cell numbers of RGCs and RBPs of all ROIs at outskirt regions, respectively. f, Typical late-stage RP affected RBP structure from the intact eye of an implanted mouse. The mouse was implanted with NW arrays in another eye at P60 and was 10 months old upon perfusion. The upper graph showed the locations of two 30 μm × 30 μm ROIs (marked by red dashed squares) in a 200 μm × 200 μm window, generated by the maximum intensity projection of three consecutive slices in a z-stack. Two rows of zoomed-in ROIs showed the dendritic features of RBPs (marked by white dashed circles) in blind mice. Z-distances between two consecutive slices were 2 μm. Scale bars, 30 μm for top panels, 10 μm for bottom panels. g,h, Dendritic structures of interface RBPs from the retina of implanted eyes after 2 weeks (g) and 8 months (h). Subfigures were aligned as in f. Red arrows indicated the dendritic bifurcations. Scale bars, 30 μm for top panels, 10 μm for bottom panels. The experiments in a, b, c, f and g were carried out at least three times. The experiments in h were carried out two times. All data are expressed as mean ± SEM.

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Extended Data Fig. 9 VGS performance in Monkey A.

a, Standard deviation of Monkey A’s horizontal and vertical eye traces during fixation before photocoagulation (n = 64 trials), 2 weeks (n = 5 trials) and 11 months (n = 218 trials) after photocoagulation. b, Schematic of VGS task. The gray area indicates target area. c, Example traces of eye position and velocity in the VGS task. Dashed black lines indicate value of 0. d, Distribution of normalized saccadic endpoints in normal retinal regions (eccentricities: 19 and 21 degrees, polar angles: 40, 50 and 130 degrees) with red LED (642/18 nm) stimulus. e-h, Distribution of normalized saccadic endpoints using red LED in NW-array-implanted region (eccentricities: 19 and 21 degrees, polar angles: 200–250 degrees) before implantation, 5–7 weeks, 10–12 weeks and 14–15 weeks after implantation. i, Distribution of normalized saccadic endpoints in normal retinal regions (eccentricities: 19 and 21 degrees, polar angles: 40, 50 and 130 degrees) with blue (465/25 nm) and UV (360/15 nm) LED stimulus. j, Illustration of mean hit rates in VGS task of Monkey A with blue LED stimuli (0.5°, polar angle: 190 to 270 degrees, eccentricity: 19 and 21 degrees) 14–15 weeks after implantation. k, Example saccadic trace of Monkey A in response to blue stimuli in the target points (polar angle: 190 to 270 degrees, eccentricity: 21 degrees), corresponding to j. l, Mean hit rates of VGS task in d-i. Normal region: n = 40 sessions for Red LED stimuli, n = 23 sessions for Blue LED stimuli. NW arrays implanted region: n = 20 sessions for Before, n = 12 sessions for 5–7 weeks, n = 14 sessions for 10–12 weeks, n = 18 sessions for 14–15 weeks. All data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons in l. *** P < 0.001.

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Extended Data Fig. 10 Saccade latency, hit rate and distance between saccadic endpoint and target point in VGS task.

a, Saccade latency of monkey A (left) and E (right). Left: saccade latency of monkey A to UV LED stimuli in normal regions and NW arrays implanted regions at 14–15 weeks after implantation. Right: saccade latency of monkey E to UV LED stimuli in normal regions and NW arrays implanted regions at 18–20 weeks after implantation. Monkey A: normal, n = 285 trials, implant, n = 68 trials, Monkey E: normal, n = 44 trials, implant, n = 72 trials. b, Saccade latency for 1000 msec and 250 msec illuminations with UV LED stimuli in NW-array-implanted region (left) and red LED stimuli in normal region (right). UV LED stimuli: 360/15 nm, 10.00 μW·mm−2. Red LED stimuli: 642/18 nm, 10.00 μW·mm−2. NW-array-implanted region: 1000 msec, n = 60 trials; 250 msec, n = 60 trials. Normal region: 1000 msec, n = 60 trials; 250 msec, n = 40 trials. Dashed black line indicates 250 msec of saccade latency. c, Hit rate for 1000 msec and 250 msec illuminations with UV LED stimuli in NW-array-implanted region (left) and red LED stimuli in normal region (right). NW-array-implanted region: 1000 msec, n = 19 sessions; 250 msec, n = 13 sessions. Normal region: 1000 msec, n = 14 sessions; 250 msec, n = 13 sessions. d, Distance between saccadic endpoint and target point for 1000 msec and 250 msec illuminations with UV LED stimuli in NW-array-implanted region (left) and red LED stimuli in normal region (right). NW-array-implanted region: 1000 msec, n = 60 trials; 250 msec, n = 60 trials. Normal region: 1000 msec, n = 60 trials; 250 msec, n = 40 trials. All data are expressed as mean ± SEM. Statistical significance was determined using two-sided unpaired t-test in b, c and d. NS non-significant.

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Supplementary information

Supplementary Information

Supplementary figures, tables and video captions.

Reporting Summary

Supplementary Video 1

Choice-box-based light localization test with green-LED-light stimulus.

Supplementary Video 2

Choice-box-based static-object-discrimination test.

Supplementary Video 3

Choice-box-based static-flashing-detection test.

Supplementary Video 4

Visual-acuity and contrast-sensitivity tests.

Supplementary Video 5

Choice-box-based orientation-discrimination test.

Supplementary Video 6

Choice-box-based moving-bar-detection test.

Supplementary Video 7

Light-evoked responses in V1 neurons through two-photon calcium-imaging recording.

Supplementary Video 8

VGS task with red LED stimulus.

Supplementary Video 9

VGS task with blue LED stimulus.

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Yang, R., Zhao, P., Wang, L. et al. Assessment of visual function in blind mice and monkeys with subretinally implanted nanowire arrays as artificial photoreceptors. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01137-8

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