Ординатура / Офтальмология / Английские материалы / Artificial Sight Basic Research, Biomedical Engineering, and Clinical Advances_Humayun, Weiland, Chader_2007
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The IMI Retinal Implant System
Ralf Hornig1, Thomas Zehnder2, Michaela Velikay-Parel3,
Thomas Laube4, Matthias Feucht5 and Gisbert Richard5
1IMI Intelligent Medical Implants GmbH, Bonn, Germany
2IMI Intelligent Medical Implants AG, Zug, Switzerland
3Division of Ophthalmology, University Hospital Graz
4Division of Ophthalmology, University Hospital Essen, Essen, Germany
5Division of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Introduction
The IMI Retinal Implant System currently under development is a new therapeutic approach for restoring vision in patients with retinal degeneration displaying a diverse pathogenesis such as retinitis pigmentosa (RP) and agerelated macular degeneration (AMD).
It is known that, in most cases of retinal degeneration, the photoreceptors degenerate while a large number of the other nerve cells in the retina remain intact [1–4]. This is also true for the ganglion cells which form the output cells of the retina. If the output cells of the retina are intact and can be stimulated electrically, artificial excitation of visual sensations is possible. Electrical stimulation has been extensively investigated since the time of Galvani and Volta. Today functional electrical stimulation is performed by several other medical devices, e.g. cochlear implants and pacemakers.
The activities of Intelligent Medical Implants (IMI) go back to 1998, when the company Intelligent Implants GmbH was established. The goal of Intelligent Implants was to bundle the available know-how on retinal implants in order to develop the first commercially available device that could be used by blind patients. Information technology for the preprocessing of image and stimulation signals is an area of special focus at IMI. Computer-aided learning processes are used to adapt the retinal implant to the needs of individual patients.
IMI is currently developing an epiretinal Learning Retinal Implant. Its operation is based on the transformation of image signals from an extraocular camera into sequences of current pulses applied by implanted microelectrodes. The microelectrodes are placed epiretinally in the area of the macula. The images from the camera are processed by a signal processor into stimulation signals that are conveyed via wireless transmission to the implanted Retina Stimulator.
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Functional models of the Retina Implant system have now been developed and the first tests have been performed with animals and humans. The safety of acute electrical stimulation has been demonstrated in a preclinical study. Following these tests, IMI performed an acute human trial involving 20 subjects suffering from RP.
Retinal Implant Technology
Overview
The aim of the Learning Retinal Implant System is to restore vision in blind people. This is accomplished by capturing images of the environment with a digital camera, processing these images into electronic data signals, and then sending them by wireless transmission to a receiver implanted in the eye. This receiver translates these data signals into electric stimulation currents which are applied through microelectrodes to the epiretinal side of the eye. This leads to an activation of the underlying nerve cells that eventually elicits visual perceptions in the brain.
The Retinal Implant device consists of three main components: the Retina Stimulator, the Visual Interface, and the Pocket Processor. Only the Retina Stimulator is implanted in the eye. The Visual Interface and the Pocket Processor are external components. Additionally, a special software running on a standard PC is provided. The software allows the user to tune certain parameters to meet the needs of individual patients.
External Components
The Visual Interface consists of several electronic components (camera, data, and energy transmitter) mounted in the frame of eyeglasses; it serves to record visual information and to send data and energy to the implanted Retina Stimulator. The Visual Interface is connected via a cable to a Pocket Processor that can be carried on a waist belt or a strap and is responsible for image processing and power supply.
The Visual Interface (Figure 6.1) carries the digital camera; it records images of the environment and sends the data via cable to the Pocket Processor. The processed data is transmitted back to the Visual Interface via the same cable. The Visual Interface contains a wireless communication unit that transmits data and energy to the Retina Stimulator (Figure 6.2). For this energy transmission an electromagnetic approach is preferred. For the transmission of data an optical channel is possible. The transmission of both energy and data has, as far as possible, to be independent of eye movement.
The camera in the Visual Interface features a dynamic range which allows for vision both indoor and outdoor without additional light sources.
The Pocket Processor contains proprietary software that processes the camera images and translates this information into data signals for the Retina Stimulator.
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Figure 6.1. Retinal Implant System.
Figure 6.2. Visual Processor components of the Learning Retinal Implant System.
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In addition, the Pocket Processor contains a rechargeable battery providing an energy supply for the entire system and has connections for a battery charger and a PC. It also has control keys and is able to send acoustic signals. The battery pack for the Pocket Processor is connected to a metal coil, located in the frame of the eyeglasses, which creates a high-frequency alternating electromagnetic field. This allows wireless transmission of the energy to the implant in the eye.
The processed visual information is sent from the Pocket Processor to an infrared (IR) data transmitter inside the Visual Interface, located in front of the eye, which delivers the entire data stream for retinal stimulation to the IR receiver on the implant in the eye via IR light-emitting diodes.
The Visual Interface and the Pocket Processor are connected via a cable that is placed behind the ear and possibly under the clothes (see Figure 6.2).
Retina Encoder
In a healthy retina, image processing is performed by several types of cells. The photoreceptor layer with its rods and cones constitutes the functional input layer. The representation of the visual information at the level of the photoreceptors is comparable to that of a photosensor array in a technical image-processing system. In the natural retina, the image information is processed with the network of horizontal, bipolar, amacrine, and ganglion cells. Photoreceptors, horizontal cells, and bipolar cells process the information with electrotonic potentials. Ganglion cells have a spiking information process whereby the information is coded in the pulse frequency and timing of the action potentials. Amacrine cells process information in both ways, electrotonic and spiking. Retinal implants with epiretinal electrodes stimulate surviving nerve cells at the output of the retinal network. The information processing of the degenerated input network has to be simulated. Information processing in the primate retina has been the subject of extensive investigation [5–7]. The Retina Encoder algorithm can be developed on the basis of these measurements [8, 9]. The first implementation of the Retina Encoder simulated the ganglion cell output of single ganglion cells. However, single cell activation with non penetrating electrodes appeared to be unrealistic since different cells lay close together and the stimulation electrodes have to be relatively large to provide the necessary current. It has to be assumed that microelectrodes in the order of 100 m and larger stimulate up to several hundreds of cells. Therefore the Retina Encoder has to adapt its algorithm to a summary of the information processes in all the stimulated cells. It is possible that one information processing type is dominant in the stimulated cell group.
It is known that the degeneration of the light-sensitive photoreceptor layer triggers a pathological process [10, 11]. As a result of this process, the structure of the retina is irreversibly altered. Consequently, the Retina Encoder has to be even more flexible than is assumed in the literature on the retinal information process.
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The Retina Encoder can be implemented as a set of spatiotemporal filters (Figure 6.3). Every filter has a spatial input area within the input images. For temporal processing a series of input images is taken into account. The output of each filter constitutes the stimulation commands for individual electrodes.
The Retina Encoder has a large number of intrinsic parameters. The effect of some parameters, such as the size and location of receptive fields, can be easily understood. Some other parameters (e.g. parameters of spatial or temporal filters) are more complex and their impact on the resulting image quality is not obvious. In addition, the parameters of the encoder are often not independent of each other.
For the tuning of the Retina Encoder, algorithms are developed that permit efficient parameter optimization. This tuning procedure will be carried out during a rehabilitation period subsequent to the implantation of the Retina Simulator.
Figure 6.4 shows the procedure used to tune the Retina Encoder. This data is processed via simulation using subjects with normal vision [12, 13]. Therefore, the Retina Encoder output was translated back into an image using an inverter module. This inverter module has the inverse function of the Retina Encoder. The inverter module is valid for a certain set of Retina Encoder parameters. Subsequently, the Retina Encoder parameters were untuned. The input image of the Retina Encoder and the output image of the inverter module are shown on a screen. Simple geometric moving figures (e.g. moving circles) were used as the input images. A test subject looking at a screen can see the input image (on the left in Figure 6.4) and the output image (one of the images on the right in Figure 6.4). The output image is distorted because the Retina Encoder has been untuned. During the tuning process, the Retina Encoder parameters have to be adjusted so that the output image matches the input image. At the beginning of the tuning process the system randomly generates several sets of parameters for the Retina Encoder. The test subject has to choose the sets that result in output images which are most comparable with the input image. Once the test subject has made his or her choice, the system generates new sets of parameters
Figure 6.3. Retina Encoder information processing.
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Figure 6.4. Learning procedure (input image, output image after 0, 20, 45, 67 iterations).
for the Retina Encoder. While doing this, the system takes consideration of the previously chosen parameter sets. Afterward, the test subject appraises the new parameters in the same way as the first. This procedure is repeated until the parameters are good enough to perceive the original image at the output of the inverter module. The experiments carried out in the laboratory showed that this is possible after fewer than 100 iterations (see Figure 6.4).
Retina Stimulator
The implantable Retina Stimulator consists of a flexible plastic carrier onto which the various microelectronic components are mounted. The electronic components are used on the one hand to receive data and energy and on the other hand to electrically stimulate the retina with microelectrodes. The Retina Stimulator is implanted into one eye only and has no wire connection to the other parts of the system. The Retina Stimulator has no batteries or energy storage capabilities.
Figure 6.5 shows a functional model with 49 electrodes which has been implemented for animal tests. The carrier of the Retina Stimulator is a flexible circuit board made of polyimide with built-in conducting paths in gold. For long-term hermeticity an additional encapsulation is planned.
The Retina Stimulator has an extraocular part that consists of the transceiver unit containing a high-frequency receiver coil that receives the electromagnetic field from the external sending coil and provides the energy required for the entire stimulation electronics. The extraocular part is fixed with sutures at the sclera. It is connected via a flexible film with the intraocular part.
The intraocular part contains an IR receiver which receives data containing visual information from the external transmitter via an IR optical link permitting high data transmission rates. The IR receiver translates the optical signals into electrical impulses and sends them to the stimulator electronics. Eyelid closing will cause an interruption of data transfer and thereby prevent sight – exactly as would happen in individuals with normal vision.
The stimulator electronics processes data and controls the stimulation currents for the electrode array placed on the retina. The electrode array is composed of stimulation electrodes and is positioned at the epiretinal side of the retina in
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Figure 6.5. Functional model of the Retina Stimulator with 49 electrodes.
the area of the macula. The electrodes are in direct contact with the retina and activate the retinal nerve cells via electrical currents.
To provide a reference potential, a common electrode is positioned at some distance to the electrode array.
The Retina Stimulator can be fastened to the retina by driving one or several surgical retina tacks into the posterior part of the Retina Stimulator [14–16].
The application of electric current is performed by the small electrodes of the microcontact array. To attain stimulation with a good selectivity – which means that only a few cells are selectively stimulated – the electrodes should be as small as possible. With small electrodes, however, only low charges can be applied because the electrodes have limited charge capacities that are a function of the electrode materials.
The charge capacity of an electrode material is the maximum amount of charge per unit area that can be passed in a biphasic pulse without causing electrode damage. Robblee and Rose [17] give a good overview of electrode materials for microelectrodes. The charges that can be safely applied are proportional to the surface of the electrode. IrOx, which has a large charge capacity, is a useful electrode material [28]. Figure 6.6 shows electrode test structures coated with IrOx. The electrode surface is electroplated with IrOx and is electrically activated.
For patients with high thresholds, the stimulation charges have to be increased significantly over 100 nC [3, 18, 19]. Consequently, the electrodes have to be relatively large even though small electrodes have a better selectivity. The optimal electrode size can be defined as the one that is able to apply stimulation charges above the threshold value in nearly all patients. To identify the optimal size a clinical study was performed; this study is described in the Section “Clinical Study”.
Figure 6.6 shows two test structures with IrOx electrodes that have been designed for preclinical and clinical acute trials. The electrode arrangement and the outer geometry will be different in a later chronic retinal implant. The
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Figure 6.6. Microcontact films for electrical stimulation of the retina.
electrodes of film A have the diameters 50 and 100 m. Film B has segmented electrodes with effective electrode diameters of 50, 200 and 360 m.
The electrodes of the microcontact film were tested by impedance spectroscopy at frequencies ranging from 1 to 100 kHz. Figure 6.7 shows the impedance plot of a single 360 m electrode. The impedance at 1 kHz is 4 k .
Figure 6.7. Impedance plot of a single 360 m electrode in a 0.9% NaCl solution. The impedance magnitude is shown in black and the phase angle in gray.
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Preclinical Studies
The safety and biocompatibility of electrical stimulation of the retina was tested in a preclinical study performed with Göttinger mini pigs [20, 21]. An electrode array, as shown in Figure 6.6, connected via a cable to an external current source was temporarily implanted into the eyes of 12 mini pigs. A three-port vitrectomy was carried out under general anesthesia; the microcontact film was inserted through a scleral port and fixed epiretinally in the area of the macula with perfluorodecaline (PFCL). The mini pigs were randomly assigned to four groups. Group 1 was a control group with no stimulation. In groups 2, 3, and 4, continuous stimulation was performed for 4 hours with charge densities of 0.5, 1, and 4 mC/cm2, respectively. After the planned stimulation, the electrode array was removed and the eyes were examined by indirect ophthalmoscopy. The surgical openings were then closed and the animals were followed for an additional 2-week period, after which they were sacrificed for histological examination of the retina.
The following results were obtained: immediately after stimulation, the eyes of two animals in group 4 (stimulation with 4 mC/cm2) developed severe edema in the stimulated area. In groups 1, 2, and 3, no changes were observed. Two weeks after stimulation, the retinas of the animals in groups 1, 2, and 3 exhibited sporadic pigment coating; in two animals belonging to group 4, the retinas showed pale areas locally. Histological evaluation revealed no structural changes in groups 1, 2, and 3. One animal in group 4 displayed a curved structure in the retina which correlated with the observed edema. Based on these results, we concluded that stimulation of the retina with charge densities of up to 1 mC/cm2 for 4 hours is safe and does not induce any tissue damage.
Materials that are in direct contact with the human body can be tested according to a detailed set of standards to determine their biocompatibility (ISO 10993-1 ff). For implantable devices which stay in contact with tissue or bone for > 30 days, the following tests are required.
•Cytotoxicity
•Sensitization
•Irritation
•Acute Toxicity
•Subchronic Toxicity
•Genotoxicity
•Implantation
•Chronic Toxicity
•Carcinogenicity.
In view of the acute human trial planned by the IMI, the processed polyimide films, including gold paths and pads, have already passed the biocompatibility tests for cytotoxicity, sensitization, and irritation.