Development of very large electrode arrays for epiretinal stimulation (VLARS)
© Waschkowski et al.; licensee BioMed Central Ltd. 2014
Received: 20 August 2013
Accepted: 29 January 2014
Published: 6 February 2014
Retinal implants have been developed to treat blindness causing retinal degenerations such as Retinitis pigmentosa (RP). The retinal stimulators are covering only a small portion of the retina usually in its center. To restore not only central vision but also a useful visual field retinal stimulators need to cover a larger area of the retina. However, large area retinal stimulators are much more difficult to implant into an eye. Some basic questions concerning this challenge should be answered in a series of experiments.
Large area retinal stimulators were fabricated as flexible multielectrode arrays (MEAs) using silicon technology with polyimide as the basic material for the substrate. Electrodes were made of gold covered with reactively sputtered iridium oxide. Several prototype designs were considered and implanted into enucleated porcine eyes. The prototype MEAs were also used as recording devices.
Large area retinal stimulator MEAs were fabricated with a diameter of 12 mm covering a visual angle of 37.6° in a normal sighted human eye. The structures were flexible enough to be implanted in a folded state through an insertion nozzle. The implants could be positioned onto the retinal surface and fixated here using a retinal tack. Recording of spontaneous activity of retinal neurons was possible in vitro using these devices.
Large flexible MEAs covering a wider area of the retina as current devices could be fabricated using silicon technology with polyimide as a base material. Principal surgical techniques were established to insert such large devices into an eye and the devices could also be used for recording of retinal neural activity.
Overview on known sizes (width/height/thickness) of electrode arrays used in retina implants with direct retinal contact and their respective number of electrodes
# of electrodes
Dimensions (w/h/t in mm)
Retinal implant AG
Argus II second sight
Simulation of material characteristics
To get an idea of the behavior of a polyimide foil within an eye, we created a very simple model for Comsol, a common finite element simulation software. The model consists of an incompressible spherical shell made of steel with an inner diameter of 22 mm and a polyimide foil with a thickness of 100 μm, a disc shape and a circular hole in the center of the structure. Then the foil was vertically moved into the shell until both parts came into contact. The Young’s modulus of the polyimide PI2611 we used in this simulation was 8.5 GPa and was taken from the material data sheet, the poisson ratio of 0.23 was taken from Patel et al. . The friction between the polyimide foil and the shell was disregarded.
Simulation of the surgical approach
The surgical approach was simulated by performing the procedure in enucleated porcine eyes. The setting was the same as in real surgery. Operations were performed by experienced retinal surgeons using a surgical microscope. Removal of the lens was done by phacoemulsification and removal of the vitreous by vitrectomy using a 20 gauge 3 port approach. Visualization was achieved with endoillumination and a 130° contact lens placed on the corneal surface. Insertion of the device was done either by a scleral incision or by corneal incisions of 6 mm. Insertion of the device was facilitated by using a plastic nozzle.
In Vitro test on stimulation and recording capabilities
Healthy Wistar rats were dark adapted for one hour and decapitated in deep anaesthesia. Retinas were taken from the eye under dim red light. The electrodes of the VLARS MEA were connected to a multichannel recording and stimulating device (MEA2100-System, Multi Channel Systems GmbH, Reutlingen, Germany). The isolated retina was placed onto the VLARS MEA with the ganglion cell side adjacent to the electrodes. The retina was permanently superfused for at least 45 minutes with Carbogene (95% O2; 5% CO2) saturated Ames Medium (Sigma-Aldrich, St. Louis, MO, USA). For electrical stimulation a biphasic 40 μA current pulse with a cathodal and anodal phase duration of 500 μs was chosen. Light stimulation was done using a 1 second white light flash. The stimulation and recording was done with the MEA-Software MC_Rack (Multi Channel Systems GmbH, Reutlingen, Germany). For spike detection raw data sets of 3-5 minutes continuous recording were analyzed with a 300 Hz high-pass filter and a 3000 Hz low-pass filter and an amplification gain factor of two. The data sampling rate was 25 kHz/channel. To distinguish spike waveforms on one electrode spikes were sorted computer based and manually with spike sorting software Offline SorterTM (Plexon Inc, Dallas, Tx, USA) before response analysis was done (NeuroExplorerTM, Nex Technologies, Madison, AL, USA).
All animal experiments were done in accordance with the ARVO statement for the use of animals in ophthalmic and visual research [http://www.arvo.org/About_ARVO/Policies/Statement_for_the_Use_of_Animals_in_Ophthalmic_and_Visual_Research/] and in accordance to the German Law for Animal Protection after approval obtained from the local government.
Concept and assumptions
The VLARS stimulation array is based on the fabrication process of the EPI-RET III implant, which uses the epiretinal concept, i.e. the electrode array is placed on the inner surface of the retina . During implantation the device must be inserted into the eyeball through a small corneal incision. After removal of the lens and of the vitreous body the device can be pushed through the anterior chamber into the vitreous chamber of the eye. From this position it can be further moved to the retinal surface where it can be placed onto the posterior pole. Stable fixation is provided with a retinal tack. We designed a VLARS stimulator with a diameter of 12 mm covering an area of about 110 mm2. A retinal stimulator of that size covers a visual angle of 37.6° in an eye of normal size (axial length 22.8 mm) representing a visual field of 18.8°. With our technology, more than 250 electrodes can be realized on such a base structure for a larger field of percepts and to improve the spatial resolution in the center of the device compared to current available epiretinal technology.
We integrated the MEA into the polyimide PI2611 (HD MicrosystemsTM GmbH, Neu-Isenburg, Germany) foil. The advantage of this material is its relatively low moisture uptake of 0.5%, which helps to prolong the durability of the system embedded metallization layers in the prevailing wet conditions. Furthermore polyimide is characterized by a low relative dielectric constant of about 2.9, which also provides an excellent electric isolation of the feed lines of the electrodes. The low intrinsic stress of PI2611 makes it suitable as a base material for stimulators as the intended one. Additionally, polyimide can be easily structured via photolithographic techniques as it is soluble in the developer of standard photoresists. The Parylene C encapsulation serves as an additional moisture barrier due to its hydrophobic behavior. Additionally Parylene C is moldable under the influence of elevated temperatures. This opens the possibility of creating curved structures .
Shape selection and design modification
The star-like shape (D3) was designed because of its theoretical very good unfolding potential. During insertion (surgery) the arms were properly (nicely) bent back and regained their original shape inside the eye without damage of the device structure. Also it fits well to the curvature of the eyeball. The globe design (D4) is based on the principle of an interrupted cylindrical projection of a spherical structure on a flat surface.
All first generation designs D1-4 had a central hole for tack fixation. Additional holes were provided in the periphery of the structure to be used if necessary to support the primary fixation and keep the electrodes in contact with the retina.
Preliminary test on recording capabilities
Stimulators covering a large area of the retinal surface needed to be fitted to the retinal surface topography. The inner surface of the eye is different from an ideal spherical curvature and moreover due to different axial sizes of eyes the inner curvature also differs within individuals. Despite the fact that, individually designed and fabricated stimulators would be great to ensure a perfect fit with the individual surface topography, but the first step in the development of large arrays is the fabrication of a general design which fits for many sizes of eyes as a proof of concept device. Larger variations are considerably increasing the complexity of the fabrication process and are currently not regarded as useful since e.g. very small eyes such as in young children are not considered to be implanted with retinal implants. Implant structures specially designed for animal experiments covering an extreme variety of eye sizes from mouse to pigs were not planned to be fabricated within this project.
In the foveal region the image size on the retina is nearly proportional to the visual angle. An image covering three millimeters in length on the retina corresponds to a visual angle of approximately 10 degrees . Moreover, it has been shown that there is a strong correlation between the position of the stimulating electrode on the retinal surface and the response within the visual cortex and the visual field, respectively [20, 21].
Retinal stimulator MEAs can be placed either underneath the retina as subretinal devices or onto the retinal surface as epiretinal devices –. Both approaches have in common that current prototypes are designed for stimulation of the foveal region which may allow a visual angle of about 10° – 18° or 5° – 9° of visual field, respectively.
The VLARS project was started to develop a stimulator MEA covering a larger visual field. We built a device with a diameter of 12 millimeters covering a retinal area of about 110 mm2. A retinal stimulator of that size could restore a visual field of about 18.8° covering a corresponding visual angle of 37.6° when implanted in a human eye of normal size. Additionally, more than 250 electrodes can be placed on such a device with current available technology.
Large stimulators were also suggested by Villalobos et al. and the Bionic Vision Australia Group: They described a MEA which can be placed in the suprachoroidal space with dimensions of 8 × 13 mm, providing a visual angle in the human eye of about 27.14 × 39.8° or a visual field of 13.6 × 19.9°. MEA systems not in direct contact with the retina seemed to be limited in terms of spatial resolution because of the distance between the active electrodes and the target neurons. The advantage of suprachoroidal implants however might be the low risk profile of the surgery [22, 23].
Studies on the safety of the EPIRET III device, which was also based on polyimide and contained similar materials and the same encapsulation as the VLARS prototypes confirmed a good biocompatibility and function of the implants –. For epiretinal fixation of the device retinal tacks have been shown to provide direct contact of the electrode array to the retinal surface-a prerequisite for successful retinal ganglion cell stimulation (re-detected and re-established) –. While the fixation of small stimulators requires up to two retinal tacks [7, 8] it requires further experiments to determine if larger devices will need more elements for fixation. For this reason our next step will be the implantation in animal experiments to prove the biocompatibility of the device and during follow-up examinations to quantify the number of necessary tacks. As optical coherence tomography (OCT) has been successfully used to demonstrate the contact of epiretinal stimulators with the retinal surface , this examination procedure will be used for the upcoming experiments. Moreover, stimulating tests will be performed to determine and to evaluate stimulation thresholds of different electrodes in regard to the retinal contact of each part of the stimulator. Alternative approaches to avoid mechanical fixation tools have been described in animal experiments but were not used clinically: Thermosensitive glues and biochemical adhesion provided by immobilized peptide chains have been used in experimental settings [32, 33]. In the future these approaches may help to reduce the amount of retinal tacks for fixation of large epiretinal stimulators.
The main concern for large stimulators is the possibility of intra- or postoperative complications. The larger incision necessary to implant such devices into an eye could cause a higher risk of infection, high astigmatism, leakage, and proliferative tissue reactions. Therefore, a flexible device is desirable which can be inserted through a smaller incision. Our experiments on enucleated pig and rabbit eyes showed that when using a nozzle the folded device could be inserted through an incision of 5-6 mm, which seems to be reasonable in terms of risk profile. Stimulation tests and impedance measurements on implanted devices are necessary to demonstrate that stimulators endure the implantation without any damage.
Currently available epiretinal implants have certain drawbacks not only concerning their stimulator size but also concerning electrode size and material, and stimulation algorithms. To yield better spatial resolution a higher density of electrodes is desirable although that usually means to design smaller electrodes with a greater risk of adverse electrochemical reactions at their surface. Such electrochemical reactions have to be avoided by proper selection of the electrode surface material. Stimulation algorithms usually do not take into account that not only ganglion cells may be stimulated but also other excitable cells like amacrine cells or even bipolar cells . The activation of possibly inhibiting local neural networks in the degenerated retina may prevent useful ganglion cell activity. Furthermore, high current or voltage stimulation could evoke action potentials in axons whose somatas are far away from the stimulation site. This may induce percepts coming from a retinal region unrelated to the position of the electrode [35, 36]. These factors have to be taken also into account when future implant concepts are discussed. However, the enlargement of the stimulator area may be one step towards a larger visual field in otherwise blind subjects.
We were able to demonstrate in a preliminary experiment, that the device is useful for electrical stimulation of the retina and that it also has the potential to record neural network activity. The latter allows the realization of bidirectional implants capable to record from the target tissue and to stimulate the tissue. The recordings could probably be used to automatically modify and optimize the stimulation pattern, which is usually based on image characteristics and fixed assumptions on the functional state of the retina.
The successful fabrication of VLARS prototypes and the promising observations concerning surgical handling, stimulation and recording represent first steps in the realization of a large stimulating array for wide-field direct epiretinal stimulation to generate artificial vision with enlarged visual fields. Further experiments are necessary to demonstrate its long-term biocompatibility in-vivo and also its stimulation properties.
This work was supported by a grant of the Jackstädt Foundation “VLARS”.
SH was supported by DFG grants WA 1472/6-1, TH 603/15-1, MU 3036/3-1.
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