Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.

The transcorneal electrical stimulation as a novel therapeutic strategy against retinal and optic neuropathy: a review of experimental and clinical trials

Transcorneal electrical stimulation （TES） is a novel therapeutic approach to activate the retina and related downstream structures. TES has multiple advantages over traditional treatments, such as being minimally invasive and readily applicable in a routine manner. Series of animal experiments have shown that TES protects the retinal neuron from traumatic or genetic induced degeneration. These laboratory evidences support its utilization in ophthalmological therapies against various retinal and optical diseases including retinitis pigmentosa （RP）, traumatic optic neuropathy, anterior ischemic optic neuropathy （AION）, and retinal artery occlusions （RAOs）. Several pioneering explorations sought to clarify the functional mechanism underlying the neuroprotective effects of TES. It seems that the neuroprotective effects should not be attributed to a solitary pathway, on the contrary, multiple mechanisms might contribute collectively to maintain cellular homeostasis and promote cell survival in the retina. More precise evaluations y/a functional and morphological techniques would determine the exact mechanism underlying the remarkable neuroprotective effect of TES. Further studies to determine the optimal parameters and the long-term stability of TES are crucial to justify the clinical significance and to establish TES as a popularized therapeutic modality against retinal and optic neuropathy.

The effect of transcorneal electrical stimulation in visual acuity: Retinitis pigmentosa

Transcorneal Electrical Stimulation (TES) was applied to a group of volunteer patients suffering from Retinitis Pigmentosa (RP), in order to investigate the effect of TES in Visual Acuity (VA). 28 partial blind patients with diagnosis of classic RP, Usher syndrome I and/or II were stimulated transcornealy, during a period of 52 weeks using a non conventional waveform, only in the lowest visually capable eye. The proposed waveform has been modeled from the natural response of human retina and delivered by means of an adaptive generator designed and built for tissue stimulation. Statistical results show the improvement of average VA or at least the contention of the disease natural progress. Categorized analysis of results indicates the same effect that if the age of patients, time since diagnosis and genetic disorder variation (classic RP, Usher syndrome I and/or II) are considered, in this case clinical and electrophysiological follow-up parameters were statistically analyzed in order to know the effect of TES. General results yield an improvement of 48.15% in the average of VA for stimulated eyes against an average degreasing of -8.06% in the same scale, with respect to their basal condition before the start of the experiment.

Flexible Polyimide Microelectrodes Array for Transcorneal Electrical Stimulation

The relationship between the parameters of Transcorneal Electrical Stimulation (TES) and its neuro-protective effect of TES on axotomised Retinal Ganglion Cells (RGCs) is still unclear. This work discusses the design strategy of a new non conventional TES stimulator, the micro fabrication processes and characterization of an array of MEMS microelectrodes over a flexible polymer layer substrate to stimulate the human cornea. The micro-array of electrodes, over a flexible smooth biocompatible polyimide substrate, fine tunes the curvature of the cornea. This tool can help researchers to define the optimal electric stimulation parameters required in TES.