Biology subjects

Butt, E.

Publications and source records attributed to Butt, E..

10 recordsLinked to original sources

bioRxiv2026

Electrodeposited Biocompatible Coatings for 3D Electrodes on Retinal Prostheses

Photovoltaic subretinal prosthesis, PRIMA, provides central vision to patients blinded by age-related macular degeneration, with acuity matching the 100 m pixel size. Further miniaturization requires pillar electrodes to position the stimulating surfaces closer to the inner retinal neurons. While such structures can be electroplated in gold and coated on their tops with SIROF, the exposed gold sidewalls are not biocompatible. Sputtering or atomic layer deposition of protective coatings are unsuitable for selectively passivating the pillar structures without also coating the photosensitive regions and return electrodes of the implant. Here, we present a strategy for biocompatible coating of pillar sidewalls while preserving surrounding implant functionality. The approach combines non-critical photoresist lithography to protect planar return electrodes with electrodeposition of TiO2; or Pt onto gold pillar sidewalls. In-vivo studies demonstrated that both TiO2 and Pt coatings are biocompatible and prevent adverse reactions of the retinal tissue to gold. Since specific capacitance of electroplated TiO2 (25 F/cm2) is much lower than that of Pt (240 F/cm2), the former better limits the current from the side walls and ensures that charge injection occurs predominantly through the pillar tops coated with SIROF (~6 mF/cm2). Electrodeposition, combined with noncritical photolithography provides a scalable wafer-level solution for fabrication of biocompatible three-dimensional electro-neural interfaces, addressing a critical bottleneck in bioelectronics.

bioengineering↗

bioRxiv2026

Titanium and platinum coatings reduce inflammation induced by gold on subretinal prosthesis

Subretinal photovoltaic implants provide central vision to patients blinded by atrophic age-related macular degeneration, with acuity limited by their 100-{micro}m pixels. Higher resolution requires smaller pixels incorporating three-dimensional electrodes, which can be fabricated by gold electroplating. However, the retinal response to exposed gold remains poorly characterized. Here, we evaluated gold biocompatibility on subretinal implants in Royal College of Surgeons rats and compared it with platinum- and titanium-coated surfaces. Although in-vivo optical coherence tomography revealed no overt structural disruption, gold implants induced cellular-scale anomalies, including abnormal morphology of rod bipolar cells, microglial accumulation near the implant, and increased cell death within days after implantation. These effects occurred across flat, pillar, and honeycomb geometries, indicating a material-rather than geometry-dependent response. By contrast, platinum- and titanium-coated implants showed substantially lower loss and morphological disruption of rod bipolar cells, together with markedly reduced microglial activation. These findings indicate that exposed gold surfaces can induce acute retinal inflammation and neuronal loss, whereas conformal platinum or titanium coatings substantially improve biocompatibility. Such coatings enable the development of three-dimensional subretinal prostheses with smaller pixels for improved visual resolution.

bioengineering↗

bioRxiv2025

Amorphous silicon resistors enable smaller pixels in photovoltaic retinal prosthesis

ObjectiveClinical trials of the photovoltaic subretinal prosthesis PRIMA demonstrated feasibility of prosthetic central vision with resolution matching its 100{micro}m pixel size. To improve prosthetic acuity further, pixel size should be decreased. However, there are multiple challenges, one of which is related to accommodating a compact shunt resistor within each pixel that discharges the electrodes between stimulation pulses and helps increase the contrast of the electric field pattern. Unfortunately, standard materials used in integrated circuit resistors do not match the resistivity required for small photovoltaic pixels. Therefore, we used a novel material - doped amorphous silicon (a-Si) and integrated it into photovoltaic arrays with pixel sizes down to 20{micro}m. ApproachTo fit within a few {micro}m2 area of the pixels and provide resistance in the M{Omega} range, the material should have sheet resistance of a few hundred k{Omega}/sq, which translates to resistivity of a few {Omega}*cm. The a-Si layer was deposited by low-pressure chemical vapor deposition (LPCVD) and its resistivity was adjusted by PH3 doping before encapsulating the resistors between SiO2 and SiC for stability in-vivo. Main ResultsHigh-resolution retinal implants with integrated shunt resistors were fabricated with values ranging from 0.75 to 4 M{Omega} on top of the photovoltaic pixels of 55, 40, 30 and 20 {micro}m in size. Photoresponsivity with all pixel sizes was approximately 0.53 A/W, as high as in the arrays with no shunt resistor. The shunts shortened electrodes discharge time, with the average electric potential in electrolyte decreasing by only 21-31% when repetition rate increased from 2 to 30 Hz, as opposed to a 54-55% decrease without a shunt. Similarly, contrast of a Landolt C pattern increased from 16-22% with no shunt to 22-34% with a shunt. Further improvement in contrast is expected with pillar electrodes and local returns within each pixel. SignificanceMiniature shunt resistors in a MOhm range can be fabricated from doped a-Si in a process compatible with manufacturing of photovoltaic arrays. The shunt resistors improved current injection and spatial contrast at video frame rates, without compromising the photoresponsivity. These advances are critical for scaling pixel sizes below 100 {micro}m to improve visual acuity of prosthetic vision.

neuroscience↗

bioRxiv2025

Chronically implantable μLED arrays for optogenetic cortical surface stimulation in mice

Cortical implants are a proven clinical neurotechnology with the potential to transform our understanding of cognitive processes. These processes rely on complex neuronal networks that are difficult to selectively probe or stimulate. Optogenetics offers cell-type specificity, but achieving the density and coverage required for chronic, high-resolution modulation remains a challenge. Here we present a 100-element {micro}LED array (200 {micro}m pixel pitch, 2 x 2 mm2 footprint) coupled into a miniaturised, flexible system suitable for chronic implantation and optogenetic stimulation of the surface of the mouse cortex. The {micro}LEDs can remain stable for over 300 hours continuous operation time in-vivo, allowing for months-long chronic experiments. Simultaneous electrophysiology recordings confirmed robust neuronal responses corresponding to low {micro}LED drive currents (<5 mA), minimising thermal effects and supporting future wireless operation. The spatial resolution of neuronal responses was consistent with a simulated model of light scattering in the cortical layers, enabling device optimisation. Behavioural experiments with chronically implanted mice demonstrated robust learning during discrimination tasks using spatially distinct optogenetic stimulation patterns.

neuroscience↗

bioRxiv2024

Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100m pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22m pixels increased the grating acuity from the 100m capability of PRIMA implants to 28m, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

neuroscience↗

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↗

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↗

bioRxiv2022

U1 snRNP-dependent suppression of miRNA biogenesis by alternative intronic polyadenylation in melanoma

Activation of intronic polyadenylation signals results in premature cleavage and polyadenylation (PCPA). The majority of mammalian miRNAs are also located within intronic regions of protein-coding genes and are transcriptionally co-expressed with their host genes. Here we show that U1-dependent PCPA by telescripting dysregulates miRNA biogenesis. When U1 is reduced, miR-211 levels are decreased as a direct consequence of activation of a newly identified alternative intronic polyadenylation signal located upstream of miR-211 within its host gene TRPM1. Various melanoma cell lines revealed decreased U1 levels and a shift from full-length to truncated TRPM1 isoforms with concomitant decreased miR-211 expression. Modulation of TRPM1 alternative polyadenylation (APA) by morpholino oligonucleotides inhibits and potentially restores miR-211 expression to endogenous levels. This mechanism of intronic PCPA and its effects on miRNA biogenesis represents a previously unrecognized layer of gene expression regulation suitable for therapeutic modulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/479622v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@169c2f1org.highwire.dtl.DTLVardef@7d8f34org.highwire.dtl.DTLVardef@144b9d8org.highwire.dtl.DTLVardef@10523f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

cGMP signaling: probing antagonistic cyclic nucleotide platelet signals by modeling and experiment

BackgroundThe cyclic nucleotides cAMP and cGMP inhibit platelet activation. ResultsWe extended an older model and systematically integrated drugs as external stimuli. Data driven modeling allowed us to design models that provide a quantitative output for quantitative input information. This relies on condensed information about involved regulation and modeling of pharmacological interventions by systematic optimization methods. By multi-experiment fitting, we validated our model optimizing the parameters of the model. In addition, we show how the output of the developed cGMP model can be used as input for a modular model of VASP phosphorylation and for the activity of cAMP and cGMP pathways in platelets. ConclusionsWe present a model for cGMP signaling and VASP phosphorylation, that allows to estimate drug action on any of the inhibitory cyclic nucleotide pathways (cGMP, cAMP) and has been validated by experimental data.

systems biology↗

bioRxiv2018

Functional genomics identifies AMPD2 as a new prognostic marker for undifferentiated pleomorphic sarcoma

Soft-tissue sarcomas are rare, heterogeneous and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, in part because biomarkers that can reliably identify high-risk patients are lacking. Studies on sarcomas often are limited by small sample sizes rendering the identification of novel biomarkers difficult when focusing only on individual cohorts. However, the increasing number of publicly available omics data opens inroads to overcome this obstacle.\n\nHere, we combine high-throughput transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse patient outcome in undifferentiated pleomorphic sarcoma (UPS). Publicly available gene expression and survival data for UPS from two independent studies, The Cancer Genome Atlas (TCGA) and the CINSARC reference dataset, were subjected to survival association testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts (overall and metastasis-free survival), were considered as prognostic marker candidates. The best candidate, AMPD2, was validated on protein level in an independent tissue microarray. Analysis of DNA copy-number and matched gene expression data indicated that high AMPD2 expression is significantly correlated with copy-number gains at the AMPD2 locus. Gene-set enrichment analyses of AMPD2 co-expressed genes in both UPS gene expression datasets suggested that highly AMPD2 expressing tumors are enriched in gene signatures involved in tumorigenesis. Consistent with this prediction in primary tumors, knockdown of AMPD2 by RNA interference with pooled siRNAs or a doxycycline-inducible shRNA construct in the UPS cell line FPS-1 markedly inhibited proliferation in vitro and tumorigenicity in vivo.\n\nCollectively, these results provide evidence that AMPD2 may serve as a novel biomarker for outcome prediction in UPS. Our study exemplifies how the integration of available omics data, immunohistochemical analyses, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers.

pathology↗