Biology subjects

Chen, Z. C.

Publications and source records attributed to Chen, Z. C..

10 recordsLinked to original sources

bioRxiv2026

Retinal Resistivity Mapped by Electrical Resistance Tomography

Retinal resistivity is a key parameter for modeling both the electric field in tissue and the resulting neural response - a crucial step in designing retinal prostheses, especially since both depend on resistivity nonlinearly. Previous studies using penetrating microelectrodes reported vastly different values, varying by as much as two orders of magnitude, likely due to parasitic capacitance in microelectrodes, compression of tissue and its rupture by the inserted probe, allowing the conductive medium to seep in and alter the measurement. To measure retinal resistivity without compression or rupture, we applied electrical resistance tomography using a planar multielectrode array with a 30 m pitch. Voltage waveforms generated in response to current injected from one electrode were measured on other electrodes in the array, at distances ranging from 30 to 600 m. Data from wild-type and degenerated rat retinas were analyzed using two methods: a commercial inversion software, Res2DInv, and a custom machine learning-based decoder, with healthy retina approximated as a 4-layer structure and degenerated retina - as a 3-layer one.

biophysics↗

bioRxiv2024

Accelerated Simulation of Multi-Electrode Arrays Using Sparse and Low-Rank Matrix Techniques

ObjectiveModeling of Multi-Electrode Arrays used in neural stimulation can be computationally challenging since it may involve incredibly dense circuits with millions of intercon-nected resistors, representing current pathways in an electrolyte (resistance matrix), coupled to nonlinear circuits of the stimulating pixels themselves. Here, we present a method for accelerating the modeling of such circuits with minimal error by using a sparse plus low-rank approximation of the resistance matrix. MethodsWe prove that thresholding of the resistance matrix elements enables its sparsification with minimized error. This is accomplished with a sorting algorithm, implying efficient O (N log (N)) complexity. The eigenvalue-based low-rank compensation then helps achieve greater accuracy without significantly increasing the problem size. Results: Utilizing these matrix techniques, we reduced the computation time of the simulation of multi-electrode arrays by about 10-fold, while maintaining an average error of less than 0.3% in the current injected from each electrode. We also show a case where acceleration reaches at least 133 times with additional error in the range of 4%, demonstrating the ability of this algorithm to perform under extreme conditions. ConclusionCritical improvements in the efficiency of simulations of the electric field generated by multi-electrode arrays presented here enable the computational modeling of high-fidelity neural implants with thousands of pixels, previously impossible. Significance: Computational acceleration techniques described in this manuscript were developed for simulation of high-resolution photovoltaic retinal prostheses, but they are also immediately applicable to any circuits involving dense connections between nodes, and, with modifications, more generally to any systems involving non-sparse matrices.

bioengineering↗

bioRxiv2023

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses

ObjectiveHigh-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. ApproachWe 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 resultsSimulations 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 {micro}m height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 {micro}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. SignificanceElectroplated 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 20{micro}m 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.

neuroscience↗

bioRxiv2023

3D electronic implants in subretinal space: long-term follow-up in rodents

Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 m pixel size. Since decreasing the pixel size below 75 m 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 m 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 m-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 m-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.

neuroscience↗

bioRxiv2022

Cellular integration with a subretinal honeycomb-shaped prosthesis

In patients blinded by geographic atrophy, subretinal photovoltaic implant with 100{micro}m pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75{micro}m, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional electrodes. In particular, elevating the return electrode on top of 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 the majority of the inner retinal neurons migrate into 25{micro}m deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This is important for selective stimulation of the second-order neurons to preserve the retinal 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.

neuroscience↗

bioRxiv2022

Pixel size limit of the PRIMA implants: from humans to rodents and back

ObjectiveRetinal 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 100m-wide photovoltaic pixels, have demonstrated a prosthetic visual acuity closely matching the pixel size. Further improvement in resolution requires smaller pixels, which necessitates more intense stimulation. ApproachHere, we examine the lower limit of the pixel size for PRIMA implants by modeling the electric field, leveraging the clinical benchmarks, as well as using a preclinical animal data to assess the stimulation strength and contrast of various patterns. Visually evoked potentials were measured in RCS rats with photovoltaic implants of 100 and 75m pixels and compared to clinical thresholds with 100 m pixels. Electrical stimulation model calibrated by these clinical and rodent data was used to predict the performance of the implant with smaller pixels. Main ResultsWe found that PRIMA implants with 75m pixels under the maximum safe near-infrared (880nm) illumination of 8 mW/mm2 with 30% duty cycle (10ms pulses at 30Hz) should provide a similar perceptual brightness as with 100 m pixels under 3 mW/mm2 irradiance, used in the current clinical trials. Contrast of the Landolt C pattern scaled down to 75m pixels is also similar under such illumination to that with 100m pixels in clinical settings, increasing the maximum acuity from 20/420 to 20/300. SignificanceComputational model of the photovoltaic subretinal prosthesis defines the minimum pixel size of the PRIMA implants as 75m. Increasing the implant width from 2 to 3 mm and reducing the pixel size from 100 to 75m will nearly quadrupole the number of pixels and thereby should significantly improve the visual performance. 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.

bioengineering↗

bioRxiv2022

Photovoltaic Implant Simulator Reveals the Resolution Limits in Subretinal Prosthesis

ObjectiveThe photovoltaic subretinal prosthesis, PRIMA, restores central vision in patients blinded by atrophic age-related macular degeneration (AMD), with a resolution closely matching the 100 {micro}m 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, giving low contrast stimulation patterns. We study approaches to shaping the electric field in the retina for prosthetic vision with higher resolution and improved contrast. ApproachWe 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 resultsWe demonstrate that by utilizing monopolar pixels as both, anodes and cathodes to suppress crosstalk, most patients may achieve resolution no worse than 48 {micro}m. Closer proximity between the electrodes and the INL, achieved with pillar electrodes, enhances the stimulus strength and contrast and may enable 24 {micro}m resolution with 20 {micro}m pixels, at least in some patients. SignificanceA resolution of 24 {micro}m 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.

bioengineering↗

bioRxiv2021

Electronic "photoreceptors" enable prosthetic vision with acuity matching the natural resolution in rats

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal cross-talk from neighboring electrodes. Local return electrodes within each pixel limit crosstalk, but can over-constrain the electric field, thus precluding efficient stimulation with subretinal pixels smaller than 50 m. Here we demonstrate 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 computational modeling of the field confinement in such an optically-controlled circuit by ex-vivo and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 m pixels matches the pixel pitch, while with 20 m pixels, it reaches the 28 m 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 prosthetic vision with acuity as high as 20/80 in atrophic macular degeneration.

bioengineering↗

bioRxiv2020

Vertical-junction Photodiodes for High-resolution Retinal Prostheses

ObjectiveTo 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 m 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 (1) by increasing the diode responsivity using vertical p-n junctions and (2) by directing the electric field vertically using 3-D electrodes. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field. ApproachArrays of silicon photodiodes of 55, 40, 30, and 20 m in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically by 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 resultsThe 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/mm2 with 10 ms pulses, independent of pixel size. SignificancePhotodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20 m. Vertically-oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of the feasibility of scaling down the photovoltaic pixels for subretinal stimulation.

bioengineering↗

bioRxiv2020

On mechanisms of light-induced deformations in photoreceptors

Photoreceptors in the retina convert light into electrical signals through a phototransduction cycle that consists of multiple electrical and biochemical events. Phase-resolved optical coherence tomography (pOCT) measurements of the optical path length (OPL) change in the cone photoreceptor outer segments after a light stimulus (optoretinogram) reveal a fast, ms-scale contraction by tens of nm, followed by a slow (hundreds of ms) elongation reaching hundreds of nm. Ultrafast measurements with a line-scan pOCT system show that the contractile response amplitude increases logarithmically with the number of incident photons, and its peak shifts earlier at higher stimulus intensities. We present a model that accounts for these features of the contractile response. Conformational changes in opsins after photoisomerization result in the fractional shift of charge across the disk membrane, leading to a transmembrane voltage change, known as the early receptor potential (ERP). Lateral repulsion of the ions on both sides of the membrane affects its surface tension and leads to its lateral expansion. Since the volume of the disks does not change much on a ms time scale, their lateral expansion leads to an axial contraction of the outer segment. With increasing stimulus intensity and resulting tension, the area expansion coefficient of the disk membrane also increases as thermally-induced fluctuations are pulled flat, resisting further expansion. This results in a logarithmic saturation of the deformation and a peak shift to earlier with brighter stimuli. Slow expansion of the photoreceptors is explained by the influx of water due to osmotic changes during phototransduction. Both effects closely match measurements in healthy human volunteers.

biophysics↗