Abstract Retinal remodeling occurs in both retinitis pigmentosa and age-related macular degeneration. However, it is still unknown whether spared retinal circuits are also functionally altered. Functional changes have been observed in animal models of retinitis pigmentosa, including the emergence of bursting oscillatory activity in retinal ganglion cells. Yet, comparable oscillatory activity, or other functional alterations, has not been demonstrated in patients. To address this gap, here we report a non-invasive corneal neurotechnology measuring in-vivo resting-state electroretinography and analyzing its frequency content and temporal characteristics to identify biomarkers of functional remodeling. We document that retinal remodeling induces bursting oscillatory activity in-vivo in retinitis pigmentosa mouse models and translate these results to patients. Moreover, we showed in mice that bursting oscillatory activity can be pharmacologically modulated in-vivo. Furthermore, reducing this oscillatory activity increases retinal excitability to electrical stimulation. These results are crucial for a better understanding of retinal degeneration and contribute to sight restoration efforts.

Nanowires have served as a transformative platform for advanced neural and tissue interfaces. While their photovoltaic properties hold exceptional promise for neural modulation, existing photostimulation approaches predominantly rely on visible light-activated photoelectrochemical mechanisms. Here, we present a solution-processed photovoltaic nanoassembly comprising a ZnO nanowire array sensitized with AgBiS2 nanocrystals that enables efficient near-infrared (NIR) neural stimulation through capacitive photocurrents. By optimizing nanowire morphology and nanocrystal interdigitation, the platform achieves high charge injection densities (tens of microcoulombs per square centimeter) at low NIR intensities (<1 milliwatt per square millimeter). The nanoassembly was subretinally placed in an ex vivo blind rat retina, where it elicited repeatable and robust responses in retinal ganglion cells under NIR pulses. Notably, these responses were achieved at light intensities substantially below established ocular safety limits. The nexus of neuronal systems and nanoassemblies offers potential for enabling unconventional visual prosthetics and advanced neuromodulation therapies.

ABSTRACT Cell replacement represents a potential treatment modality for retinal disorders characterized by photoreceptor loss. However, photoreceptor replacement approaches have not been clinically established. To take this forward, the main goal of this study was to systematically compare human photoreceptors of different ages and identify those that enable functional integration into the degenerative retina. Donor cells were isolated from iPSC-derived retinal organoids generated by a GMP-compliant protocol at differentiation days 120, 150, or 200 and transplanted subretinally into cone photoreceptor function loss 1 (Cpfl1) recipients, an inherited mouse model of cone degeneration. While younger photoreceptors showed slightly improved transplantation outcomes, donor photoreceptors of all culture stages displayed long-term survival, cone identity, structural integration into the host retina, and tight interactions with host Müller glia, including formation of a continuous outer limiting membrane. Transplanted photoreceptors showed signs of advanced maturation, including correct polarization with generation of apical inner- and outer segments, while basal synapses were formed with host bipolar cells. Electrophysiological assessment of host retinal ganglion cells revealed light-evoked responses in transplant-containing regions, providing evidence for functional incorporation of human photoreceptors into the mouse neuro-retinal circuitry. Thus, GMP-compliant human iPSC-derived photoreceptors are stable over a wide range of differentiation stages and constitute a robust cell source for retinal transplantation and functional repair. The findings provide important prerequisites for the development of standardized procedures towards clinical translation of photoreceptor replacement in the retina. Significant statement Cell transplantation represents a potential therapy for retinal dystrophies. However, conditions allowing stable functional integration and maturation of donor photoreceptors have not been defined. We systematically compared GMP-compliant iPSC-derived photoreceptors of different culture times after transplantation into a retinal degeneration mouse model. Photoreceptors of all ages showed structural integration and advanced maturation in close interaction with host Müller glia and bipolar cells, allowing restoration of light-driven responses. Thus human photoreceptors isolated from retinal organoids represent a robust source for clinical development of cell replacement in the diseased retina.

Microelectrode arrays (MEAs) are essential tools for recording and stimulating electrogenic tissues, but their fabrication typically depends on complex, costly, and mask-based cleanroom processes. While inkjet-printed MEAs have increasingly been explored as low-cost alternatives, most demonstrations have focused on cardiac cell recordings, with only a limited number of studies showing neuronal recordings. Furthermore, no work to date has demonstrated neuronal interfacing, combining single-unit recording with electrical stimulation, using inkjet-printed MEAs. Here, we investigate whether inkjet-printed MEAs enable both extracellular single-unit neuronal recording and reliable electrical stimulation. We fabricated gold microelectrodes on flexible foils via maskless inkjet-printing, insulated them with printed SU-8 (an epoxy-based dielectric), and characterized their morphology using scanning electron microscopy, atomic force microscopy, and profilometry, and their electrochemical behavior using impedance spectroscopy and cyclic voltammetry. The printed gold formed a rough nanoparticle-based morphology, resulting in an increased effective electrochemical surface area. This morphology enabled low electrode impedances and high charge injection during voltage-controlled stimulation. We assessed functional performance in ex vivo retinal tissue. The inkjet-printed MEAs enabled reliable single-unit recordings with signal-to-noise ratios comparable to cleanroom-fabricated commercial devices and cell activation upon electrical stimulation with biphasic pulses. The electrodes were reusable and noncytotoxic, verified via a standard cell viability assay. These results establish the first inkjet-printed microelectrodes capable of neuronal interfacing, demonstrating that printed MEAs can match the functional performance of conventional microfabricated devices. This work positions inkjet-printing as a scalable, easily adaptable, low-cost manufacturing technique for flexible MEAs with rough gold electrodes suitable for neurotechnology applications.

Organic semiconductors are emerging as a promising class of photovoltaic materials for neural interfaces, offering high power conversion, mechanical flexibility, biocompatibility, and tunable optoelectronic properties. In this study, the application of a D18:Y6-based organic photovoltaic (OPV) electrode is investigated for subretinal stimulation in a model of retinal degeneration. It is demonstrated that OPV devices can be engineered to electrically stimulate the retina via network-mediated pathways, in a manner comparable to established neurostimulation approaches. The presented OPV electrodes reliably activate retinal ganglion cells, eliciting consistent spike responses to light pulses within the near-infrared range. The stimulation onset, spike latency, and response profiles suggest effective faradaic charge injection as a key mechanism for neuronal activation, particularly for longer pulse durations. Moreover, it is shown that both light intensity and pulse duration can be used to finely tune the neural response, offering a high degree of control over retinal ganglion cell activation. Finally, it is proven that D18:Y6 blend is biocompatible in vitro when in direct contact with human induced pluripotent stem cell (iPSC)-derived retinal organoids and mouse explants. These results validate the photo-electrical performance and biocompatibility of D18:Y6 OPVs and position them as a viable candidate for next-generation, minimally invasive retinal prosthetics.

An optoelectronic biointerface incorporating AgBiS2 nanocrystals and ZnO nanowires was nanoengineered for infrared neural modulation. The biointerface exhibits high photostability and efficient charge injection, enabling ex-vivo retina photostimulation.