Corrigendum: Localization of hyperpolarization-activated cyclic nucleotide-gated channels in the vertebrate retinas across species and their physiological roles.

[This corrects the article DOI: 10.3389/fnana.2024.1385932.].

Corrigendum: Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation.

[This corrects the article DOI: 10.3389/fncel.2023.1115703.].

Localization of hyperpolarization-activated cyclic nucleotide-gated channels in the vertebrate retinas across species and their physiological roles.

Transmembrane proteins known as hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control the movement of Na+ and K+ ions across cellular membranes. HCN channels are known to be involved in crucial physiological functions in regulating neuronal excitability and rhythmicity, and pacemaker activity in the heart. Although HCN channels have been relatively well investigated in the brain, their distribution and function in the retina have received less attention, remaining their physiological roles to be comprehensively understood. Also, because recent studies reported HCN channels have been somewhat linked with the dysfunction of photoreceptors which are affected by retinal diseases, investigating HCN channels in the retina may offer valuable insights into disease mechanisms and potentially contribute to identifying novel therapeutic targets for retinal degenerative disorders. This paper endeavors to summarize the existing literature on the distribution and function of HCN channels reported in the vertebrate retinas of various species and discuss the potential implications for the treatment of retinal diseases. Then, we recapitulate current knowledge regarding the function and regulation of HCN channels, as well as their relevance to various neurological disorders.

Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration.

Retinitis pigmentosa (RP) is an outer retinal degenerative disease that can lead to photoreceptor cell death and profound vision loss. Although effective regulation of intraretinal inflammation can slow down the progression of the disease, an efficient anti-inflammatory treatment strategy is still lacking. This study reports the fabrication of a hyaluronic acid-based inflammation-responsive hydrogel (IRH) and its epigenetic regulation effects on retinal degeneration. The injectable IRH was designed to respond to cathepsin overexpression in an inflammatory environment. The epigenetic drug, the enhancer of zeste homolog 2 (EZH2) inhibitors, was loaded into the hydrogel to attenuate inflammatory factors. On-demand anti-inflammatory effects of microglia cells via the drug-loaded IRH were verified in vitro and in vivo retinal degeneration 10 (rd10) mice model. Therefore, our IRH not only reduced intraretinal inflammation but also protected photoreceptors morphologically and functionally. Our results suggest the IRH reported here can be used to considerably delay vision loss caused by RP.

Effects on Retinal Stimulation of the Geometry and the Insertion Location of Penetrating Electrodes.

Retinal implants have been developed and implanted to restore vision from outer retinal degeneration, but their performance is still limited due to the poor spatial resolution. To improve the localization of stimulation, microelectrodes in various three-dimensional (3D) shapes have been investigated. In particular, computational simulation is crucial for optimizing the performance of a novel microelectrode design before actual fabrication. However, most previous studies have assumed a uniform conductivity for the entire retina without testing the effect of electrodes placement in different layers. In this study, we used the finite element method to simulate electric fields created by 3D microelectrodes of three different designs in a retina model with a stratified conductivity profile. The three electrode designs included two conventional shapes - a conical electrode (CE) and a pillar electrode (PE); we also proposed a novel structure of pillar electrode with an insulating wall (PEIW). A quantitative comparison of these designs shows the PEIW generates a stronger and more confined electric field with the same current injection, which is preferred for high-resolution retinal prostheses. Moreover, our results demonstrate both the magnitude and the shape of potential distribution generated by a penetrating electrode depend not only on the geometry, but also substantially on the insertion depth of the electrode. Although epiretinal insertions are mainly discussed, we also compared results for subretinal insertions. The results provide valuable insights for improving the spatial resolution of retinal implants using 3D penetrating microelectrodes and highlight the importance of considering the heterogeneity of conductivities in the retina.

Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation.

Background: Microelectronic prostheses for artificial vision stimulate neurons surviving outer retinal neurodegeneration such as retinitis pigmentosa (RP). Yet, the quality of prosthetic vision substantially varies across subjects, maybe due to different levels of retinal degeneration and/or distinct genotypes. Although the RP genotypes are remarkably diverse, prosthetic studies have primarily used retinal degeneration (rd) 1 and 10 mice, which both have Pde6b gene mutation. Here, we report the electric responses arising in retinal ganglion cells (RGCs) of the rd8 mouse model which has Crb1 mutation. Methods: We first investigated age-dependent histological changes of wild-type (wt), rd8, and rd10 mice retinas by H&E staining. Then, we used cell-attached patch clamping to record spiking responses of ON, OFF and direction selective (DS) types of RGCs to a 4-ms-long electric pulse. The electric responses of rd8 RGCs were analyzed in comparison with those of wt RGCs in terms of individual RGC spiking patterns, populational characteristics, and spiking consistency across trials. Results: In the histological examination, the rd8 mice showed partial retinal foldings, but the outer nuclear layer thicknesses remained comparable to those of the wt mice, indicating the early-stage of RP. Although spiking patterns of each RGC type seemed similar to those of the wt retinas, correlation levels between electric vs. light response features were different across the two mouse models. For example, in comparisons between light vs. electric response magnitudes, ON/OFF RGCs of the rd8 mice showed the same/opposite correlation polarity with those of wt mice, respectively. Also, the electric response spike counts of DS RGCs in the rd8 retinas showed a positive correlation with their direction selectivity indices (r = 0.40), while those of the wt retinas were negatively correlated (r = -0.90). Lastly, the spiking timing consistencies of late responses were largely decreased in both ON and OFF RGCs in the rd8 than the wt retinas, whereas no significant difference was found across DS RGCs of the two models. Conclusion: Our results indicate the electric response features are altered depending on RGC types even from the early-stage RP caused by Crb1 mutation. Given the various degeneration patterns depending on mutation genes, our study suggests the importance of both genotype- and RGC type-dependent analyses for retinal prosthetic research.

Short pulses of epiretinal prostheses evoke network-mediated responses in retinal ganglion cells by stimulating presynaptic neurons.

Objective. Microelectronic retinal implant aims to restore functional vision with electric stimulation. Short pulses are generally known to directly activate retinal ganglion cells (RGCs) with a notion of one or two spike(s) per pulse. In the present work, we systematically explore network-mediated responses that arise from various short pulses in both normal and degenerate retinas.Approach. Cell-attached patch clamping was used to record spiking responses of RGCs in wild-type (C57BL/6J) and retinal degeneration (rd10) mice. Alpha RGCs of the mouse retinas were targeted by their large soma sizes and classified by their responses to spot flashes. Then, RGCs were electrically stimulated by various conditions such as duration (100-460µs), count (1-10), amplitude (100-400µA), and repeating frequency (10-40 Hz) of short pulses. Also, their responses were compared with each own response to a single 4 ms long pulse which is known to evoke strong indirect responses.Main results. Short pulses evoked strong network-mediated responses not only in both ON and OFF types of RGCs in the healthy retinas but also in RGCs of the severely degenerate retina. However, the spike timing consistency across repeats not decreased significantly in therd10 RGCs compared to the healthy ON and OFF RGCs. Network-mediated responses of ON RGCs were highly dependent on the current amplitude of stimuli but much less on the pulse count and the repetition frequency. In contrast, responses of OFF RGCs were more influenced by the number of stimuli than the current amplitude.Significance. Our results demonstrate that short pulses also elicit indirect responses by activating presynaptic neurons. In the case of the commercial retinal prostheses using repeating short pulses, there is a possibility that the performance of clinical devices is highly related to the preserved retinal circuits. Therefore, examination of surviving retinal neurons in patients would be necessary to improve the efficacy of retinal prostheses.

Ultrasound stimulation for non-invasive visual prostheses.

Globally, it is estimated there are more than 2.2 billion visually impaired people. Visual diseases such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and optic neuritis can cause irreversible profound vision loss. Many groups have investigated different approaches such as microelectronic prostheses, optogenetics, stem cell therapy, and gene therapy to restore vision. However, these methods have some limitations such as invasive implantation surgery and unknown long-term risk of genetic manipulation. In addition to the safety of ultrasound as a medical imaging modality, ultrasound stimulation can be a viable non-invasive alternative approach for the sight restoration because of its ability to non-invasively control neuronal activities. Indeed, recent studies have demonstrated ultrasound stimulation can successfully modulate retinal/brain neuronal activities without causing any damage to the nerve cells. Superior penetration depth and high spatial resolution of focused ultrasound can open a new avenue in neuromodulation researches. This review summarizes the latest research results about neural responses to ultrasound stimulation. Also, this work provides an overview of technical viewpoints in the future design of a miniaturized ultrasound transducer for a non-invasive acoustic visual prosthesis for non-surgical and painless restoration of vision.

Artificial Visual Information Produced by Retinal Prostheses.

Numerous retinal prosthetic systems have demonstrated somewhat useful vision can be restored to individuals who had lost their sight due to outer retinal degenerative diseases. Earlier prosthetic studies have mostly focused on the confinement of electrical stimulation for improved spatial resolution and/or the biased stimulation of specific retinal ganglion cell (RGC) types for selective activation of retinal ON/OFF pathway for enhanced visual percepts. To better replicate normal vision, it would be also crucial to consider information transmission by spiking activities arising in the RGC population since an incredible amount of visual information is transferred from the eye to the brain. In previous studies, however, it has not been well explored how much artificial visual information is created in response to electrical stimuli delivered by microelectrodes. In the present work, we discuss the importance of the neural information for high-quality artificial vision. First, we summarize the previous literatures which have computed information transmission rates from spiking activities of RGCs in response to visual stimuli. Second, we exemplify a couple of studies which computed the neural information from electrically evoked responses. Third, we briefly introduce how information rates can be computed in the representative two ways - direct method and reconstruction method. Fourth, we introduce in silico approaches modeling artificial retinal neural networks to explore the relationship between amount of information and the spiking patterns. Lastly, we conclude our review with clinical implications to emphasize the necessity of considering visual information transmission for further improvement of retinal prosthetics.

Fabrication of High-Density Out-of-Plane Microneedle Arrays with Various Heights and Diverse Cross-Sectional Shapes.

Out-of-plane microneedle structures are widely used in various applications such as transcutaneous drug delivery and neural signal recording for brain machine interface. This work presents a novel but simple method to fabricate high-density silicon (Si) microneedle arrays with various heights and diverse cross-sectional shapes depending on photomask pattern designs. The proposed fabrication method is composed of a single photolithography and two subsequent deep reactive ion etching (DRIE) steps. First, a photoresist layer was patterned on a Si substrate to define areas to be etched, which will eventually determine the final location and shape of each individual microneedle. Then, the 1st DRIE step created deep trenches with a highly anisotropic etching of the Si substrate. Subsequently, the photoresist was removed for more isotropic etching; the 2nd DRIE isolated and sharpened microneedles from the predefined trench structures. Depending on diverse photomask designs, the 2nd DRIE formed arrays of microneedles that have various height distributions, as well as diverse cross-sectional shapes across the substrate. With these simple steps, high-aspect ratio microneedles were created in the high density of up to 625 microneedles mm-2 on a Si wafer. Insertion tests showed a small force as low as ~ 172 µN/microneedle is required for microneedle arrays to penetrate the dura mater of a mouse brain. To demonstrate a feasibility of drug delivery application, we also implemented silk microneedle arrays using molding processes. The fabrication method of the present study is expected to be broadly applicable to create microneedle structures for drug delivery, neuroprosthetic devices, and so on.

Spiking Characteristics of Network-Mediated Responses Arising in Direction-Selective Ganglion Cells of Rabbit and Mouse Retinas to Electric Stimulation for Retinal Prostheses.

To restore the sight of individuals blinded by outer retinal degeneration, numerous retinal prostheses have been developed. However, the performance of those implants is still hampered by some factors including the lack of comprehensive understanding of the electrically-evoked responses arising in various retinal ganglion cell (RGC) types. In this study, we characterized the electrically-evoked network-mediated responses (hereafter referred to as electric responses) of ON-OFF direction-selective (DS) RGCs in rabbit and mouse retinas for the first time. Interestingly, both species in common demonstrated strong negative correlations between spike counts of electric responses and direction selective indices (DSIs), suggesting electric stimulation activates inhibitory presynaptic neurons that suppress null direction responses for high direction tuning in their light responses. The DS cells of the two species showed several differences including different numbers of bursts. Also, spiking patterns were more heterogeneous across DS RGCs of rabbits than those of mice. The electric response magnitudes of rabbit DS cells showed positive and negative correlations with ON and OFF light response magnitudes to preferred direction motion, respectively. But the mouse DS cells showed positive correlations in both comparisons. Our Fano Factor (FF) and spike time tiling coefficient (STTC) analyses revealed that spiking consistencies across repeats were reduced in late electric responses in both species. Moreover, the response consistencies of DS RGCs were lower than those of non-DS RGCs. Our results indicate the species-dependent retinal circuits may result in different electric response features and therefore suggest a proper animal model may be crucial in prosthetic researches.

A 4.49nW/Pixel Light-to-Stimulus Duration Converter-Based Retinal Prosthesis Chip.

This paper presents a 288-pixel retinal prosthesis (RP) chip implemented in a 0.18 µm CMOS process. The proposed light-to-stimulus duration converter (LSDC) and biphasic stimulator generate a wide range of retinal stimuli proportional to the incident light intensity at a low supply voltage of 1V. The implemented chip shows 25.5 dB dynamic stimulation range and the state-of-the art low power consumption of 4.49 nW/pixel. Ex-vivo experiments were performed with a mouse retina and patch-clamp recording. The electrical artifact recorded by the patch electrode demonstrates that the proposed chip can generate electrical stimuli that have different pulse durations depending on the light intensity. Correspondingly, the spike counts in a retinal ganglion cell (RGC) were successfully modulated by the brightness of the light stimuli.

Air-gap embedded triboelectric nanogenerator via surface modification of non-contact layer using sandpapers.

With the increased number of small electronics and demand for their energy source, renewable energy sources have received much attention. Above all, a triboelectric nanogenerator (TENG) based on the combination of contact electrification and electrostatic induction has been researched as a method of converting mechanical energy into electricity. In order to increase the electrical output of TENGs with raising the surface charge density, a lot of researchers have focused on the fabrication methods to employ micro-/nano-structures onto a contact surface of the TENG, but have been facing several issues regarding the degradation of the output performance from the iterative operation process. Hence, it is highly required to introduce an approach to enhancing the performance of TENG, while minimally degrading the output power during the long-term operation. In this paper, an air-gap embedded TENG (AE-TENG), which contains a microstructure on the non-contact surface by means of a sandpaper, is proposed. These small air-gaps between the spin-coated polydimethylsiloxane and the non-contact surface can significantly boost the total surface charge density of the dielectric layer. Thus, the electrical output performance of the AE-TENG is enhanced without any surface engineering on the contact surface. Furthermore, the effect of the air-gap induced surface charges on the electric potential is systematically analyzed by not only experimentally electrical outputs, but theoretical and computational modeling based on the V-Q-x relationship and simulation software tool. This air-gap induced triboelectric effect opens a new perspective of the development of electrical outputs by providing a structural/theoretical understanding for TENGs.

Omnidirectional Triboelectric Nanogenerator Operated by Weak Wind Towards a Self-Powered Anemoscope.

Wind is a great sustainable energy source for harvesting due to its abundant characteristic. Typically, large space, loud noise, and heavy equipment are essential for a general wind power plant and it is solely operated by big-scale wind. However, wind energy can be efficiently harvested by utilizing the triboelectric nanogenerator due to its abundance, ubiquity, and environmentally friendliness. Furthermore, a few previously reported wind-driven triboelectric nanogenerators, which have the bulk fluttering layer by wind, still show difficulty in generating electricity under the conditions of weak wind because of the static friction arisen from the inherent structure. In this case, the output performance is deteriorated as well as the generator cannot operate completely. In this work, a wind-driven triboelectric nanogenerator (wind-TENG) based on the fluttering of the PTFE strips is proposed to solve the aforementioned problems. At the minimum operating wind pressure of 0.05 MPa, this wind-driven TENG delivers the open-circuit voltage of 3.5 V, short-circuit current of 300 nA, and the associated output power density of 0.64 mW/m2 at the external load resistance of 5 MΩ. Such conditions can be used to light up seven LEDs. Moreover, this wind-TENG has been utilized as a direction sensor which can sense the direction at which the wind is applied. This work thus provides the potential application of the wind-TENG as both self-driven electronics and a self-powered sensor system for detecting the direction under environmental wind.

Dynamic Analysis to Enhance the Performance of a Rotating-Disk-Based Triboelectric Nanogenerator by Injected Gas.

A rotating-disk-based triboelectric nanogenerator (TENG) generating electrical energy from wind usually includes a propeller. TENGs are widely used because their high frequency of rotation allows them to generate a relatively high output current. Deep analysis of the gas flow in a TENG is essential to improve its energy conversion efficiency. However, previous studies have isolated the propeller and the TENG as separate entities that harvest wind energy and generate electrical energy, respectively. Most studies focused on each entity because considering both the dynamics and the TENG operation together is an intricate process. This paper introduces a dynamic analysis of the gas flow by dividing it into four vertical and horizontal directions and carrying out a COMSOL simulation to verify the pressure on the propeller and the flow of the gas. The electrical outputs are measured while varying the height and angle of the inlet and the number of wings on the propeller. After optimization, the P-TENG generated a high output power density of 283.95 mW/m2, which can light up 205 light-emitting diodes and drive a commercial small electronic appliance. In addition, optimizing the P-TENG through a variety of analyses allowed it to provide sustainable power to a self-powered wireless sensor system.

Self-Power Dynamic Sensor Based on Triboelectrification for Tilt of Direction and Angle.

With the great development of the Internet of Things (IoT), the use of sensors have increased rapidly because of the importance in the connection between machines and people. A huge number of IoT sensors consume vast amounts of electrical power for stable operation and they are also used for a wide range of applications. Therefore, sensors need to operate independently, sustainably, and wirelessly to improve their capabilities. In this paper, we propose an orientation and the tilt triboelectric sensor (OT-TES) as a self-powered active sensor, which can simultaneously sense the tilting direction and angle by using the two classical principles of triboelectrification and electrostatic induction. The OT-TES device consists of a rectangular acrylic box containing polytetrafluoroethylene (PTFE) balls moved by gravity. The output voltage and current were 2 V and 20 nA, respectively, with a PTFE ball and Al electrode. The multi-channel system was adopted for measuring the degree and direction of tilt by integrating the results of measured electrical signals from the eight electrodes. This OT-TES can be attached on the equipment for drones or divers to measure their stability. As a result, this proposed device is expected to expand the field of TES, as a sensor for sky and the underwater.