Bingyi Wang
Postdoctoral Scholar, Bioengineering
Stanford Advisors
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Josh Makower, Postdoctoral Faculty Sponsor
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Dan Elison Azagury, Postdoctoral Research Mentor
All Publications
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3D electronic implants in subretinal space: Long-term follow-up in rodents.
Biomaterials
2024; 311: 122674
Abstract
Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 μm pixel size. Since scaling the pixels below 75 μm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 32-36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12-16 weeks. With 25 μm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 μm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 μm-wide wells, and stimulation threshold increased over 12-16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.
View details for DOI 10.1016/j.biomaterials.2024.122674
View details for PubMedID 38897028
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On selectivity of neural stimulation with subretinal photovoltaic implants
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024
View details for Web of Science ID 001313316205328
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Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.
Journal of neural engineering
2024
Abstract
High-resolution retinal prosthetics offer partial sight restoration to patients blinded by retinal degenerative diseases through electrical stimulation of remaining neurons. Decreasing pixel size enables increasing prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigated 3-dimensional structures on top of photovoltaic arrays for enhanced penetration of the electric field, permitting higher resolution implants. Approach. 3D COMSOL models of subretinal photovoltaic arrays were developed to accurately quantify the electrodynamics during stimulation and verified through comparison to flat photovoltaic arrays. Models were applied to optimize the design of 3D electrode structures (pillars and honeycombs). Return electrodes on honeycomb walls vertically align the electric field with bipolar cells for optimal stimulation. Pillars elevate the active electrode improving proximity to target neurons. The optimized 3D structures were electroplated onto existing flat subretinal prostheses based on modelling results. Main results. Simulations demonstrate that despite exposed conductive sidewalls, charge mostly flows via high-capacitance sputtered Iridium Oxide films topping the 3D structures. The 24 µm height of honeycomb structures was optimized for integration with the inner nuclear layers cells in the rat retina, whilst 35 µm tall pillars were optimized for penetrating the debris layer in human patients. Implantation of released 3D arrays demonstrates mechanical robustness with histology demonstrating successful integration of 3D structures with the rat retina in-vivo. Significance. Electroplated 3D honeycomb structures produce vertically oriented electric fields, providing low stimulation thresholds, high spatial resolution, and contrast for pixel sizes down to 20 µm. Pillar electrodes offer alternatives for extending past debris layers. Electroplating of 3D structures is compatible with the fabrication process of flat photovoltaic arrays, enabling much more efficient stimulation. .
View details for DOI 10.1088/1741-2552/ad2a37
View details for PubMedID 38364290
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Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.
bioRxiv : the preprint server for biology
2023
Abstract
Objective: High-resolution retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables an increase in prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigate 3-dimensional structures on top of the photovoltaic arrays for enhanced penetration of electric field to permit higher-resolution implants.Approach: We developed 3D COMSOL models of subretinal photovoltaic arrays that accurately quantify the device electrodynamics during stimulation and verified it experimentally through comparison with the standard (flat) photovoltaic arrays. The models were then applied to optimise the design of 3D electrode structures (pillars and honeycombs) to efficiently stimulate the inner retinal neurons. The return electrodes elevated on top of the honeycomb walls surrounding each pixel orient the electric field inside the cavities vertically, aligning it with bipolar cells for optimal stimulation. Alternatively, pillars elevate the active electrode into the inner nuclear layer, improving proximity to the target neurons. Modelling results informed a microfabrication process of electroplating the 3D electrode structures on top of the existing flat subretinal prosthesis.Main results: Simulations demonstrate that despite the conductive sidewalls of the 3D electrodes being exposed to electrolyte, most of the charge flows via the high-capacitance sputtered Iridium Oxide film that caps the top of the 3D structures. The 24 m height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 m height of the pillars was optimized for penetrating the debris layer in human patients. Release from the wafer and implantation of the 3D arrays demonstrated that they are mechanically robust to withstand the associated forces. Histology demonstrated successful integration of the 3D structures with the rat retina in-vivo.Significance: Electroplated 3D honeycomb structures produce a vertically oriented electric field that offers low stimulation threshold, high spatial resolution and high contrast for the retinal implants with pixel sizes down to 20m in width. Pillar electrodes offer an alternative configuration for extending the stimulation past the debris layers. Electroplating of the 3D structures is compatible with the fabrication process of the flat photovoltaic arrays, thereby enabling much more efficient stimulation than in their original flat configuration.
View details for DOI 10.1101/2023.11.09.566003
View details for PubMedID 38014082
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Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.
Proceedings of the National Academy of Sciences of the United States of America
2023; 120 (42): e2307380120
Abstract
In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 μm and reaches the 27 μm limit of natural resolution in rats with 20 μm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.
View details for DOI 10.1073/pnas.2307380120
View details for PubMedID 37831740
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3D electronic implants in subretinal space: long-term follow-up in rodents.
bioRxiv : the preprint server for biology
2023
Abstract
Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 μm pixel size. Since decreasing the pixel size below 75 μm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.
View details for DOI 10.1101/2023.07.25.550561
View details for PubMedID 37546971
View details for PubMedCentralID PMC10402070
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Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats.
Nature communications
2022; 13 (1): 6627
Abstract
Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55mum. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40mum pixels matches the pixel pitch, while with 20mum pixels, it reaches the 28mum limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.
View details for DOI 10.1038/s41467-022-34353-y
View details for PubMedID 36333326
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Photovoltaic implant simulator reveals resolution limits in subretinal prosthesis.
Journal of neural engineering
2022
Abstract
OBJECTIVE: PRIMA, the photovoltaic subretinal prosthesis, restores central vision in patients blinded by atrophic age-related macular degeneration (AMD), with a resolution closely matching the 100mum pixel size of the implant. Improvement in resolution requires smaller pixels, but the resultant electric field may not provide sufficient stimulation strength in the inner nuclear layer (INL) or may lead to excessive crosstalk between neighboring electrodes, resulting in low contrast stimulation patterns. We study the approaches to electric field shaping in the retina for prosthetic vision with higher resolution and improved contrast.APPROACH: We present a new computational framework, RPSim, that efficiently computes the electric field in the retina generated by a photovoltaic implant with thousands of electrodes. Leveraging the PRIMA clinical results as a benchmark, we use RPSim to predict the stimulus strength and contrast of the electric field in the retina with various pixel designs and stimulation patterns.MAIN RESULTS: We demonstrate that by utilizing monopolar pixels as both anodes and cathodes to suppress crosstalk, most patients may achieve resolution no worse than 48mum. Closer proximity between the electrodes and the INL, achieved with pillar electrodes, enhances the stimulus strength and contrast and may enable 24mum resolution with 20mum pixels, at least in some patients.SIGNIFICANCE: A resolution of 24mum on the retina corresponds to a visual acuity of 20/100, which is over 4 times higher than the current best prosthetic acuity of 20/438, promising a significant improvement of central vision for many AMD patients.
View details for DOI 10.1088/1741-2552/ac8ed8
View details for PubMedID 36055219
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Pixel size limit of the PRIMA implants: from humans to rodents and back.
Journal of neural engineering
2022
Abstract
Retinal prostheses aim at restoring sight in patients with retinal degeneration by electrically stimulating the inner retinal neurons. Clinical trials with patients blinded by atrophic Age-related Macular Degeneration (AMD) using the PRIMA subretinal implant, a 2x2 mm array of 100µm-wide photovoltaic pixels, have demonstrated a prosthetic visual acuity closely matching the pixel size. Further improvement in resolution requires smaller pixels, which, with the current bipolar design, necessitates more intense stimulation.We examine the lower limit of the pixel size for PRIMA implants by modeling the electric field, leveraging the clinical benchmarks, and using animal data to assess the stimulation strength and contrast of various patterns. Visually evoked potentials measured in RCS rats with photovoltaic implants composed of 100µm and 75µm pixels were compared to clinical thresholds with 100µm pixels. Electrical stimulation model calibrated by the clinical and rodent data was used to predict the performance of the implant with smaller pixels.PRIMA implants with 75µm bipolar pixels under the maximum safe near-infrared (880nm) illumination of 8mW/mm2 with 30% duty cycle (10ms pulses at 30Hz) should provide a similar perceptual brightness as with 100µm pixels under 3mW/mm2 irradiance, used in the current clinical trials. Contrast of the Landolt C pattern scaled down to 75µm pixels is also similar under such illumination to that with 100µm pixels, increasing the maximum acuity from 20/420 to 20/315.Computational modelling defines the minimum pixel size of the PRIMA implants as 75µm. Increasing the implant width from 2 to 3 mm and reducing the pixel size from 100 to 75µm will nearly quadrupole the number of pixels, which should be very beneficial for patients. Smaller pixels of the same bipolar flat geometry would require excessively intense illumination, and therefore a different pixel design should be considered for further improvement in resolution.
View details for DOI 10.1088/1741-2552/ac8e31
View details for PubMedID 36044878
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Retinal integration with a subretinal honeycomb-shaped prosthesis
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021
View details for Web of Science ID 000690761600452
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Subretinal monopolar photovoltaic arrays provide pixel size-independent stimulation threshold and 40 mu m resolution under spatiotemporal modulation
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021
View details for Web of Science ID 000690761600405
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Optically configurable confinement of electric field with photovoltaic retinal prosthesis
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021
View details for Web of Science ID 000690761600406
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Vertical-junction photodiodes for smaller pixels in retinal prostheses.
Journal of neural engineering
2021
Abstract
Objective.To restore central vision in patients with atrophic age-related macular degeneration, we replace the lost photoreceptors with photovoltaic pixels, which convert light into current and stimulate the secondary retinal neurons. Clinical trials demonstrated prosthetic acuity closely matching the sampling limit of the 100 μm pixels, and hence smaller pixels are required for improving visual acuity. However, with smaller flat bipolar pixels, the electric field penetration depth and the photodiode responsivity significantly decrease, making the device inefficient. Smaller pixels may be enabled by (1) increasing the diode responsivity using vertical p-n junctions and (2) directing the electric field in tissue vertically. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field.Approach.Arrays of silicon photodiodes of 55, 40, 30, and 20 μm in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically using a common return electrode at the edge of the devices. Optical and electronic performance of the diodes was characterized in-vitro, and retinal stimulation threshold measured by recording the visually evoked potentials (VEPs) in rats with retinal degeneration.Main results.The photodiodes exhibited sufficiently low dark current (<10 pA) and responsivity at 880 nm wavelength as high as 0.51 A/W, with 85% internal quantum efficiency, independent of pixel size. Field mapping in saline demonstrated uniformity of the pixel performance in the array. The full-field stimulation threshold was as low as 0.057±0.029 mW/mm2with 10 ms pulses, independent of pixel size.Significance.Photodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20 μm. Vertically-oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of scaling down the photovoltaic pixels for subretinal stimulation.
View details for DOI 10.1088/1741-2552/abe6b8
View details for PubMedID 33592588
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Harmonic-balance circuit analysis for electro-neural interfaces.
Journal of neural engineering
2020
Abstract
Objective. Avoidance of the adverse electrochemical reactions at the electrode-electrolyte interface defines the voltage safety window and limits the charge injection capacity (CIC) of an electrode material. For an electrode that is not ideally capacitive, the CIC depends on the waveform of the stimulus. We study the modeling of the charge injection dynamics to optimize the waveforms for efficient neural stimulation within the electrochemical safety limits.Approach. The charge injection dynamics at the electrode-electrolyte interface is typically characterized by the electrochemical impedance spectrum, and is often approximated by discrete-element circuit models. We compare the modeling of the complete circuit, including a non-linear driver such as a photodiode, based on the harmonic-balance (HB) analysis with the analysis based on various discrete element approximations. To validate the modeling results, we performed experiments with iridium-oxide electrodes driven by a current source with diodes in parallel, which mimics a photovoltaic circuit.Main results. Application of HB analysis based on a full impedance spectrum eliminates the complication of finding the discrete-element circuit model in traditional approaches. HB-based results agree with the experimental data better than the discrete-element circuit. HB technique can be applied not only to demonstrate the circuit response to periodic stimulation, but also to describe the initial transient behavior when a burst waveform is applied.Significance. HB-based circuit analysis accurately describes the dynamics of electrode-electrolyte interfaces and driving circuits for all pulsing schemes. This allows optimizing the stimulus waveform to maximize the CIC, based on the impedance spectrum alone.
View details for DOI 10.1088/1741-2552/ab89fd
View details for PubMedID 32299074