Simulation of epiretinal prostheses - evaluation of geometrical factors affecting stimulation thresholds.

BACKGROUND: An accurate understanding of the electrical interaction between retinal prostheses and retinal tissue is important to design effective devices. Previous studies have used modelling approaches to simulate electric fields generated by epiretinal prostheses in saline and to simulate retinal ganglion cell (RGC) activation using passive or/and active biophysical models of the retina. These models have limited scope for studying an implanted human retinal prosthesis as they often do not account for real geometry and composition of the prosthesis-retina interface. This interface consists of real dimensions and location of stimulation and ground electrodes that are separated by the retinal tissue and surrounded by physiological fluids. METHODS: In this study, we combined the prosthesis-retina interface elements into a framework to evaluate the geometrical factors affecting stimulation thresholds for epiretinal prostheses used in clinical human trials, as described by Balthasar et al. in their Investigative Ophthalmology and Visual Science (IOVS) paper published in 2008 using the Argus I epiretinal implants. Finite element method (FEM) based computations were used to estimate threshold currents based on a threshold criterion employing a passive electric model of the retina. RESULTS: Threshold currents and impedances were estimated for different electrode-retina distances. The profiles and the values for thresholds and impedances obtained from our simulation framework are within the range of measured values in the only elaborate published clinical trial until now using Argus I epiretinal implants. An estimation of resolution for the electrodes used in these trials was provided. Our results reiterate the importance of close proximity between electrodes and retina for safe and efficient retinal stimulation. CONCLUSIONS: The validation of our simulation framework being relevant for epiretinal prosthesis research is derived from the good agreement of the computed trends and values of the current study with measurements demonstrated in existing clinical trials on humans (Argus I). The proposed simulation framework could be used to generate the relationship between threshold and impedance for any electrode geometry and consequently be an effective tool for design engineers, surgeons and electrophysiologists.

Distinguishing drug-induced minor morphological changes from major cellular damage via label-free impedimetric toxicity screening.

We present a novel perfusion-based microfluidic platform for label-free drug toxicity screening which can single out non-lethal morphological changes from cellular death using electrical impedance spectroscopy. Minor cellular changes such as cell-cell contacts and major cell injury were identified via impedance phase angle analysis and follow-up of impedance magnitude at different frequencies. Having exposed HepG2/C3A cells to acetaminophen (AP), we showed that continuous drug perfusion caused a time and concentration-dependent impedance decrease. Moreover, perfusion of repeated doses revealed altered dielectric properties of the cell culture after recovery from AP exposure. This study highlights the possibility to sense cellular changes long before cellular death takes place, pointing out the remarkable sensitivity advantage of this technique over standard endpoint viability tests and its interest for toxicology.

Simulations to study spatial extent of stimulation and effect of electrode-tissue gap in subretinal implants.

We present a finite element based simulation and analysis method to describe the spatial extent of stimulation and the effects of electrode-tissue interactions in subretinal prostheses. In particular, we estimate the threshold stimulation current needed to depolarise and evoke action potentials in the ganglion cells to be stimulated at a particular distance from the electrode. This is achieved through the application of a threshold electric field to a spherical neuronal soma model of a retinal ganglion cell under consideration. Threshold stimulation currents and the lateral extent of the stimulation zone were computed for disc microelectrodes in subretinal stimulation mode. Recent evidence indicates a decrease in threshold charge with time following subretinal implantation. Consequently, to explain the variation in threshold stimulation currents, we propose a hypothesis based on an electrode-tissue gap. Threshold stimulation currents and impedances for different electrode-tissue gaps were computed. We validate the hypothesis with our simulation results that the changes in impedance observed with time in vivo can be mainly attributed to the varying distance of the ganglion cells from electrodes due to changes in electrode-tissue gap. Our simulation framework proposes a convenient and practical method applicable for studying different electrode geometries used for retinal stimulation.