In the era of the Internet of Things and edge intelligence, conventional always-on machine vision systems suffer from severe energy bottlenecks because they continuously process massively redundant spatiotemporal data. Inspired by the dual-pathway strategy of the human retina, we propose a bioinspired "Sentinel-Expert" synergetic vision system enabled by polarization-reconfigurable organic ferroelectric phototransistors based on P(VDF-TrFE). By manipulating the ferroelectric polarization states, a single device is reconfigured into three functional modes: (i) a magnocellular pathway-inspired Sentinel mode under negative polarization that exhibits short-term plasticity and fading-memory dynamics for physical reservoir computing and ultralow-power motion event detection; (ii) a parvocellular pathway-inspired Expert mode under positive polarization that provides long-term potentiation-like retention for in-sensor contrast enhancement and high-fidelity static recognition; and (iii) a Programming mode that serves as a unified hardware backend for synaptic weight updates. The system achieves 98.46% recognition accuracy in the Sentinel mode and 97.45% accuracy in the Expert mode. Notably, by exploiting the high spatiotemporal sparsity of valid events in real-world scenarios to activate the Expert mode only upon wake-up events, this event-driven strategy reduces the computational cost by ∼50× at a 1% duty cycle compared with the conventional always-on strategy.

We generated a comparative spatial proteomic atlas of the human and mouse retina using a highly multiplexed immunohistochemistry technique called iterative bleaching extends multiplexity (IBEX). We refined the IBEX workflow by integrating an antibody dissociation option alongside chemical bleaching. This dual strategy enabled removal of the entire antibody complex, permitting the flexible use of antibodies from the same host species across iterative cycles. We coupled this workflow with super-resolution imaging via deconvolution and applied it to the retina of healthy humans and WT mice and the Crb1rd8 mouse model. We successfully imaged over 25 protein markers on human and mouse tissue sections, generating spatial atlases of the major retinal cell populations. Cross-species protein expression was compared to scRNA-seq datasets to identify protein and transcript disparities. Super-resolution IBEX delineated the ultrastructural features of the outer limiting membrane (OLM), identifying CD44 as a core structural component tightly colocalized with a highly organized F-actin belt within Müller glial endfeet. Using the Crb1rd8 mouse model, disruption of this complex was spatially associated with rosette formation and OLM structural failure. In summary, spatial proteomic atlases of the human and mouse retina were used to reveal insights into the arrangement of major retinal cell populations and OLM structure.

The human THRB thyroid hormone receptor gene and the puzzle of retinal disease phenotypes.

Neurons are basic units for information processing in biological systems. Inspired by the information-processing efficiency of biological systems, artificial neural networks (ANNs) have been studied for decades. However, it remains challenging today to realize single physical artificial neurons so that an ANN can be constructed in a bottom-up manner. Herein, we show that by using an innovative light-detecting semiconductor nanowire structure, neuronal features much closer to single, physical artificial neurons can be emulated, including excitation and inhibition, threshold, refractory period, and temporal summation. The analogy between the presented neuron-like nanowire photodetectors and neurons in the human retina system is also discussed. This study lays the cornerstone for the bottom-up construction of a physical ANN.

PurposeTo evaluate whether extending the postmortem interval (PMI) from 12 to 18 hours affects transcript and protein abundances in the human retina.MethodsDonor eyes were recovered from postmortem donors (n = 7 pairs) and stored at 2°C–8°C. Only donor eyes with ocular cooling within eight hours of death were examined. The OD retina was preserved at 12 hours and the OS retina at 18 hours postmortem. Retinas were flash frozen with liquid nitrogen. The macular region superior to the fovea was used for RNA sequencing (RNA-seq), whereas the inferior region was processed for tandem mass tag (TMT) quantitative proteomics. RNA library preparations were performed simultaneously, and the sequencing of all samples were conducted on the same chip. Proteins were isolated and labeled with 16-plex TMTPro isobaric tags, and all samples were analyzed in a 20-fraction TMT-mass spectrometry experiment. RNA-seq data were processed using DESeq2 (Bioconductor) and proteomic data were analyzed using the previously published PAW pipeline.ResultsRNA-seq identified 22,446 transcripts, with only five transcripts showing significant differential expression (adjusted P < 0.1 and a Log2FoldChange > 1) between 12 and 18 hours. No enriched pathways were associated with these changes. Proteomic analysis identified 6,109 proteins, with no significant differences in abundance (all adjusted P > 0.05). Retinal cell-type specific markers and markers relevant for disease research, such as age-related macular degeneration and glaucoma, remained stable across both time points.ConclusionsExtending the PMI cutoff from 12 to 18 hours did not significantly impact transcriptomic or proteomic integrity in human donor retinas. This PMI extension greatly increases the availability of donor eyes for biomedical research.

The human retina capable of extracting key feature information is a crucial sensory element in the visual system. Constructing bionic devices with multitype feedback to emulate the retina behaviors in complex environments has been a persistent pursuit to broaden the visual range. However, the definition and regulation of synaptic weights persist as a bottleneck problem in the terahertz (THz) devices to achieve neuromorphic function. Here, we have proposed bismuth-based THz photonic neuromorphic devices with picosecond short-term plasticity and constructed the THz-optical neural network (THz-ONN) to imitate retina function. Crucially, the weight embodied by THz photoresponse can be precisely regulated via incremental optical pulses, delivering an incredibly simple yet powerful approach that heralds systems with a continuously variable plasticity. Further development of diverse neuromorphic devices for various scenarios could be realized through the combination of band alignment engineering and substrate effects to control photocarrier transport. The corresponding neuromorphic computing based on THz-ONN indicates the high recognition accuracy of hardware. The present study provides an exciting paradigm for the realization of THz neuromorphic devices and opens an avenue for mimicking biological sensory system.

A genome-wide in vivo CRISPR screen identifies neuroprotective strategies in the mouse and human retina.

Age-related macular degeneration (AMD) is a common, complex disease affecting older individuals that can lead to severe vision loss. It is characterized by early anatomical changes in the retina, retinal pigment epithelium (RPE), and choroid, especially in the central (macular) region. AMD can progress to severe atrophy and/or pathologic angiogenesis that leads to visual decline. Over 30 genetic loci have been identified as contributing to AMD risk; however, the mechanisms by which genetic variants affect pathology has not been thoroughly explored. In this report we examined single-nucleus gene expression in the retina, RPE and choroid of 88 individuals categorized by AMD stage, as well as 37 previously published samples. Genotyping was performed on 1.8 million SNPs, with additional SNPs imputed, on each donor to identify expression quantitative trait loci (eQTLs). We found that two AMD-risk loci (PILRB and ARMS2/HTRA1) affected the expression of PILRB and HTRA1, respectively. The risk allele of PILRB was associated with increased PILRB RNA in cones, fibroblasts, choroidal macrophages, and RPE, whereas the HTRA1 risk locus was associated with decreased HTRA1 RNA in the RPE. We also identified an age-related decrease in complement inhibitors in the choriocapillaris, a tissue susceptible to complement mediated damage in AMD.

A timeline of structural and functional consequences to ipRGCs in a mouse model of Alzheimer's disease.

PurposePhotoreceptors are highly polarized sensory neurons containing a modified cilium known as the outer segment. This cilium has a rootlet that spans the length of the metabolically active inner segment and anchors the outer segment to the remainder of the photoreceptor. The full function and reasons for such a long rootlet in photoreceptors are not well understood. To gain deeper insight, we characterized the membrane associated with the rootlet.MethodsProteomic analysis was performed on immunopurified wild-type (WT) and P23H rhodopsin knock-in mouse retina. Images of mouse and human retina were acquired by transmission electron microscopy and electron tomography and protein localization in mouse retina determined by immunofluorescence and immunoelectron microscopy.ResultsIn homozygous P23H knock-in mouse retinas, misfolded rhodopsin retained in the endoplasmic reticulum (ER) prior to degradation was found to be closely associated with rootletin and mitochondrial proteins. This observation helped reveal that the ER forms extensive interactions with the rootlet, running alongside it throughout the inner segment. Furthermore, the ER branches from the rootlet to make contact with mitochondria, Golgi, and the plasma membrane. Human rod photoreceptors had similar rootlet:ER interactions within the proximal inner segment, but differed from mouse, as the rootlet within the distal inner segment mainly interacted with mitochondria.ConclusionsThese findings suggest that the rootlet plays a critical role in organizing intracellular architecture by serving as a kind of “scaffold” that supports ER positioning and allowing it to branch and form membrane contact sites with other cellular membranes.

As a type of promising hardware for next-generation artificial visual systems with extended perceptual and anti-interference capabilities, circular-polarization-resolved retinomorphic sensors are underexplored due to the lack of suitable chiral materials that enable highly dissymmetric circular-polarization responses and multiple biomimetic functions. Here, we demonstrate a self-assembly heterogeneous microstructure consisting of chiral-deficient grains and chiral-rich grain boundaries in chiral perovskites that simultaneously facilitate spin selectivity and optoelectronic properties for highly dissymmetric and multifunctional circular-polarization-resolved retinomorphic sensors. Our sensors not only exhibit a photocurrent dissymmetry factor as high as 1.98 and a panchromatic circular-polarization-resolved response, but also possess multiple biomimetic functions that simulate human retinas, including synaptic behaviors, light adaptation, and color recognition. As a proof-of-concept, we respectively demonstrate their applications using a sensor array that resolves a single circular-polarization handedness for information encryption, as well as binocular sensor arrays that resolve the opposite circular-polarization handedness for virtual stereoscopic reconstruction.

Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell‐type‐specific roles in the human retina remain incompletely characterized. We analyzed the single‐cell RNA sequencing dataset E‐MTAB‐7316 to profile genes from the KEGG steroid hormone biosynthesis and oestrogen signalling pathways. Functional relevance of local oestrogen synthesis was tested in mouse retinal explants treated with the aromatase inhibitor letrozole (20 μM). Over 50% of steroid hormone metabolism genes were expressed in retinal cells, with cell‐type specificity. COMT, HSD17B12, and HSD11B1L were broadly distributed, while LRTOMT, HSD17B7, and SRD5A1 were enriched in rod photoreceptors. Among oestrogen signalling genes, 114/139 were detected, with HSP90AA1 as the most abundant. When oestrogen synthesis was blocked with letrozole, retinal explants showed increased cell death, particularly in the outer nuclear layer, without inducing macrogliosis but with significant microglial activation (IBA1+). Our data indicate that the human retina expresses multiple components of steroid hormone metabolism and oestrogen signalling. The results are consistent with a potential role of locally synthesized oestrogens in photoreceptor maintenance and immune regulation, which may warrant further investigation as a possible avenue for retinal protection.

Magnetophosphenes, flickering visual percepts induced by extremely low-frequency magnetic fields (ELF-MF), represent the most sensitive and reproducible human response to induced electric fields and form a cornerstone of international exposure guidelines. Transcranial Alternating Magnetic Stimulation (tAMS), a recent non-invasive stimulation method, can elicit magnetophosphenes without scalp sensations, but its reliability and underlying mechanisms require replication for further validation. This replication study quantified magnetophosphene perception thresholds in 62 healthy participants exposed to sinusoidal magnetic fields (0-50 mT) at 20, 50, and 60Hz. Three stimulation configurations were tested: retinal (RET), global head (GLO), and occipital (OCC). Perception probability was modeled using mixed-effects logistic regressions based on rate of change of magnetic flux density over time (dB/dt) as the primary metric. tAMS robustly induced magnetophosphenes, reproducing the threshold patterns reported by Legros et al. (2024). RET and GLO exposures produced steep dose-response curves and low thresholds, whereas OCC stimulation yielded minimal effects. Thresholds were strongly frequency-dependent, with highest sensitivity at 20Hz. Regression slopes from the original and replication datasets showed high concordance (r = 0.965), confirming reproducibility. The spatial and frequency profiles consistently support a retinal, rod-mediated origin of magnetophosphenes. This replication study validates tAMS as a reliable method for eliciting magnetophosphenes and confirms their retinal origin across exposure conditions. These results strengthen the use of magnetophosphene thresholds as a benchmark for ELF-MF safety standards and underscore the potential of tAMS as a precise, comfortable, and confound-free neuromodulation tool for future diagnostic and therapeutic applications.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and can lead to severe visual impairment. Based on disease severity, DR is classified into no clinically apparent diabetic retinopathy (NDR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Although nearly all retinal cell types are involved in DR progression, the dominant cell populations and their pathophysiological changes at each stage remain unclear. By integrating bulk and single-cell transcriptomic data from human and mouse retinas, this study revealed the following: (1) In the NDR stage, photoreceptors exhibit significant changes in ribosomal pathways. (2) In the NPDR stage, endothelial cells and pericytes show marked transcriptional alterations, accompanied by enhanced LAMININ signaling in cell-cell communication. (3) At the PDR stage, neural and glial cells are extensively involved in disease progression, with notable changes in ANGPTL signaling. Additionally, this study observed DR-specific subtypes of endothelial cells and pericytes and potentially identifies gene signatures in macroglia cells that correlate with disease duration. The altered expression of several key genes in early diabetic retina was confirmed by qPCR. These findings may offer a comprehensive view of the cellular and molecular landscape underlying DR and may suggest potential targets.

Degenerative eye diseases are major causes of irreversible vision loss worldwide, but effective treatments remain limited, partly due to the lack of effective human models. Retinal organoids derived from stem cells can recapitulate key structural and physiological features of the human retina, offering powerful tools to study disease mechanisms and develop new therapies. Here, we review recent progress in engineering retinal organoids and eye-on-a-chip models for modeling degenerative eye diseases, with a focus on engineering innovations. We first describe conventional methods for organoid differentiation and characterization along with current outstanding challenges. To better engineer retinal organoids, new strategies that leverage microfluidics and biomaterials have emerged to regulate dynamic and physiologically relevant environments for organoid differentiation. Moreover, the integration of artificial intelligence, multimodal sensing, and data analytics improves the monitoring and prediction of retinal function and therapeutic outcomes. Finally, we discuss future directions in innovating next-generation retinal organoid and eye-on-a-chip models for disease modeling, drug discovery, and vision restoration, highlighting their potential for precision ophthalmology.

Multifocal Electroretinogram (mfERG) applies a fast flicker-based stimulation on the human retina and is considered a valuable tool in studying the cone photoreceptor functional pathways. At the same time, the global flash paradigm of the mfERG (MOFO mfERG) is found to be advantageous in the simultaneous evaluation of retinal responses arising from outer (direct component, DC) and inner (induced component, IC) retinal levels. Incorporating a silent substitution stimulus to the MOFO mfERG remains unexplored yet has broad potential utility. The present study aimed to develop an L- and M-cone directed global flash mfERG. A silent substitution stimulus was created appropriate for the commercially available LED monitor. Using the conventional 96% contrast MOFO mfERG as a reference, L- and M-cone directed MOFO mfERG with 19-hexagon stimulation was created and tested in 36 Chinese adults with normal colour vision. Experimental validation was conducted using high-intensity red and green light adaptation to simulate colour vision deficiency. Mathematical validation was performed by calculating and ensuring that proper cone quantal catches are achieved at both targeted and non-targeted cone photoreceptors. The cone response amplitude from participants with simulated protanopia and deuteranopia showed a reduction of up to 50% (p < 0.05) following pigment bleach due to light adaptation. The mean L/M cone amplitude ratio for the Chinese adults concerning the DC and IC was 0.84 ± 0.29 and 0.77 ± 0.32, respectively, for all rings combined. The M-cone amplitudes were higher than that of the L-cone. The M-cone responses were phase-advanced or faster compared to the L-cone responses (p < 0.001). The L- and M-cone-directed global flash mfERG protocols may provide valuable details on the specific cone-related outer and inner retinal responses and hold extensive utility in cone-related diseases and the evaluation of colour vision.

2D ferroelectric materials have recently emerged as a promising class of atomically thin semiconductors capable of integrating sensing, memory, and computation within a single device. Their unique combination of spontaneous switchable polarization, strong light-matter coupling, and van der Waals (vdW) interface compatibility provides an ideal platform for next-generation optoelectronic vision sensors. Coupling ferroelectric polarization with photoresponse, 2D ferroelectric materials such as α-In2Se3, CuInP2S6 (CIPS), SnS, and WTe3 enable non-volatile modulation of photocarrier transport, facilitating adaptive visual perception analogous to the human retina. These 2D ferroelectric photonic devices demonstrate synaptic plasticity, short-term and long-term memory, and optical potentiation and depression characteristics under visible and near-infrared excitation. Integrating ferroelectricity into optoelectronic architectures addresses the von-Neumann bottleneck by enabling in-sensor computing, where data are sensed, stored, and processed locally, minimizing latency and energy consumption. This review provides a comprehensive overview of 2D ferroelectric materials and their device architectures in the memristive and memtransistors devices structures for optoelectronic vision sensors, highlighting their polarization mechanism, light-driven conductance modulation, and neuromorphic functionalities. Additionally, current challenges, such as scalability, polarization fatigue, and interface engineering, have also been extensively discussed together with heterostructure design and hybrid ferroelectric-semiconductor integration toward energy-efficient bio-inspired vision systems.

Early detection of retinal molecular biomarkers is crucial for addressing the unmet clinical need to prevent irreversible neural tissue damage in ophthalmic and neurodegenerative diseases. Among emerging molecular sensing techniques, non-resonant Raman spectroscopy stands out as a naturally label-free and noninvasive method, offering rich biochemical information. However, in vivo detection of non-resonant Raman spectra from retinal tissue has proven to be challenging so far. Previous studies have reported conflicting results, likely due to overwhelming pigment autofluorescence. In this study, we identified the optic nerve head as the optimal retinal location for acquiring non-resonant Raman spectra in the molecular fingerprint region. Through longitudinal intra-subject measurements, we revealed dynamic changes in the molecular composition. Furthermore, a comparative study across age groups enabled the identification of molecular alterations associated with aging. These findings establish a critical foundation for utilizing non-resonant Raman spectroscopy as an early diagnostic tool for the detection of molecular biomarkers associated with ophthalmic and neurodegenerative diseases.

Human retinas have unique anatomical structures called the macula and an associated characteristic vascular pattern. Despite its clinical importance, the mechanism underlying the human-specific vascular pattern remains unknown because of limitations in experimental approaches using primate samples. This study aimed to elucidate such vascular formation process. We first examined the effects of four hypothetical factors contributing to foveal avascular zone (FAZ) formation: inhibitory molecule secretion, chemoattractant depletion, tissue deformation (towing), and tip cell migration restriction. None reproduced the features of the human retinal vascular structure. Next, we developed a mathematical model of human retinal vascular development by considering endothelial cells and astrocytes. We assumed that retinal vessels form via angiogenesis according to the gradient of vascular endothelial growth factor and that astrocytes dynamically expand while avoiding the fovea, providing scaffolds for angiogenesis. Our astrocyte-coupling model recapitulated various features of the human retinal vascular pattern, including a radially outward vascular pattern from the optic disc, inferior and superior temporal arcades, FAZ formation, a radially inward vascular pattern around FAZ, and a vertically facing pattern toward the horizontal vascular borderline in the temporal region of FAZ. Other models did not support the other four hypotheses. Our model explained human-specific retinal vascular formation as the combination of angiogenesis and vascular growth restriction by retinal astrocytes. These results also suggest the importance of astrocyte dynamics, particularly their timing of spreading. Our modeling framework can be extended to abnormal vascular patterns observed in diseases, including retinopathy of prematurity.

Over 500 genes have been linked to various forms of inherited retinal diseases (IRDs), a class of Mendelian conditions that affect the survival and function of rod and cone photoreceptors and, in most instances, lead to progressive visual loss. Yet some affected individuals still lack a clear genetic diagnosis, suggesting that more disease-associated genes remain to be discovered. Following the genetic analysis of extended cohorts of individuals diagnosed with late-onset recessive retinal dystrophy, we identified bi-allelic combinations of six predicted null variants in MDM1 (now renamed SAXO6, stabilizer of axonemal microtubules 6) in six subjects from five families. Iterative ultrastructure expansion microscopy coupled with immuno-gold transmission electron microscopy revealed co-localization of SAXO6 with distinct ciliary microtubules from the immotile cilium present in rod and cone photoreceptors in human retina, as well as from the motile cilia present in lung epithelial cells. Cross-linking mass spectrometry uncovered an interaction between SAXO6 and α-tubulin, supporting its classification as a microtubule inner protein (MIP). These results link SAXO proteins to Mendelian conditions, highlighting the fundamental role for MIPs in the preservation of long-term retinal function.