EP3325089A1

EP3325089A1 - Active retina implant

Info

Publication number: EP3325089A1
Application number: EP17710266.2A
Authority: EP
Inventors: Günther Zeck; Thoralf Herrmann; Florian Jetter; Alfred Stett
Original assignee: NMI Naturwissenschaftliches und Medizinisches Institut
Current assignee: NMI Naturwissenschaftliches und Medizinisches Institut
Priority date: 2016-03-21
Filing date: 2017-03-13
Publication date: 2018-05-30
Also published as: WO2017162458A1; DE102016105174A1; CN109152919A; US20190022376A1; IL261891A

Abstract

The invention relates to an active retina implant for implantation in an eye, comprising an array of stimulation electrodes (17) which emit stimulation signals to cells of the retina. At least one signal generator (31) is provided which generates at least one continuous sinusoidal stimulation signal that has at least one adjustable signal parameter, and the at least one signal generator (31) is electrically connected to at least one stimulation electrode (17).

Description

Active retina implant

The present invention relates to an active retina implant for implantation in an eye, comprising an array of stimulation electrodes that deliver stimulation signals to cells of the retina.

Such a retina implant is known for example from WO 2005/000395 A1.

The known retina implant serves to counteract loss of vision due to retinal degeneration. The basic idea is to implant a microelectronic stimulation chip into a patient's eye, which replaces the lost vision with electrical stimulation of nerve cells.

There are two different approaches to how such retinal prostheses can be designed.

The subretinal approach described in the aforementioned WO 2005/000395 A1 and also, for example, in EP 0 460 320 A2 uses a stimulation chip implanted in the subretinal space between the outer retina and the pigment epithelium of the retina, which responds to an integrated array in the stimulation chip Photodiodes conspicuous environmental converts light into electrical stimulation signals for nerve cells. These stimulation signals drive an array of stimulation electrodes that stimulate the neurons of the retina with spatially resolved electrical stimulation signals that correspond to the image information "seen" by the array of photodiodes.

This retina implant thus stimulates the remaining, intact neurons of the degenerated retina, ie horizontal cells, bipolar cells, amacrine cells and possibly also ganglion cells. The visual image impinging on the array of photodiodes or more complex elements is converted to an electrical stimulation pattern on the stimulation chip. This stimulation pattern then leads to the electrical stimulation of neurons, from which the stimulation is then directed to the ganglion cells of the inner retina and from there via the optic nerve into the visual cortex.

In other words, the subretinal approach exploits the natural interconnection of the formerly present and now at least partially degenerated or lost photoreceptors with the ganglion cells, in order to supply the visual cortex in the usual way with nerve impulses corresponding to the image seen. The known implant is therefore a substitute for the lost photoreceptors; it converts image information into electrical stimulation patterns.

In contrast, the epiretinal approach uses a device consisting of an extra-ocular and an intra-ocular part, which communicate with each other in an appropriate manner. The extra-ocular part comprises a type of camera and a microelectronic circuit to encode captured light, ie the image information, and to transmit it as a stimulation pattern to the intra-ocular part. The intra-ocular part contains an array of stimulation electrodes, which contacts neurons of the inner retina and thus directly electrically stimulates the ganglion cells located there.

From many publications it is known that the transmission of the electrical stimulation signals required by these implants from the stimulation electrodes to the contacted cells requires special attention. The coupling between a stimulation electrode and the contacted tissue is largely of a capacitive nature, so that only transient signals can be used for electrical stimulation. This capacitive coupling is based on the fact that a capacitance (Helmholtz double layer) forms at the interface between the electrode and the electrolyte in the eye as a result of the electrode polarization.

Against this background, in known retinal implants, the stimulation signals are transmitted as rectangular monophasic or biphasic signal pulses which have a specific repetition frequency, amplitude and pulse duration.

In the subretinal implant according to the aforementioned WO 2005/000395, the incident light is converted, for example, into voltage pulses with a pulse length of about 500 microseconds and a pulse interval of preferably 50 milliseconds, so that a repetition frequency of 20 Hz results which is sufficient for flicker-free vision. The pulse spacing is also sufficient to completely return the electrode polarization. It is mentioned that 20 Hz corresponds to the physiological flicker frequency at low ambient brightness.

Humayun et al., "Pattern Electrical Stimulation of the Human Retina", Vision Research 39 (1999) 2569-2576 report experiments with epiretinal stimulation using biphasic pulses comprising a cathodic phase, an intermediate phase and an anodic phase of each have 2 milliseconds. At a pacing rate between 40 and 50 Hz, well above the physiological flicker frequency, a flicker-free perception was observed in two patients.

Jensen and Rizzo, "Responses of ganglion cells to repetitive electrical stimulation of the retina", Journal Neural Eng 4 (2007), S1-S6, report subretinal stimulation experiments on an isolated rabbit retina with biphasic current pulses of different length and repetition rate. Even at a pulse interval of less than 400 milliseconds, they observed a decrease in stimulated activity for the following pulse. WO 2007/128404 A1 deals with the question of how the perception can be further improved by a suitable choice of pulse length and repetition frequency of the electrical stimulation signals.

The inventors report experiments in which the retina of a blind patient was subretinally stimulated with an electrode having biphasic, anodic starting pulses of up to 4 milliseconds duration. When using different repetition frequencies, that is to say with an excitation with a continuous sequence of "flashes" of a certain frequency, the following observation emerged:

At higher frequencies, such as above 10 Hz, the patient only felt flashes for a short time, after which the perception of the flashes disappeared subjectively. However, with electrical stimulation at a mean rate below 10 Hz, the stimulus pulses were perceived as separate flashes for at least a few seconds. At frequencies of a few Hz and below, however, each flash was perceived as a single flash, the sensation remains stable for minutes.

Based on these experimental findings with implanted subretinal

Implants WO 2007/128404 A1 proposes to subdivide the plurality of stimulation electrodes into at least two groups of stimulation electrodes, which are actuated successively in time for the delivery of stimulation signals.

The image seen is therefore not imaged as a whole with a high repetition frequency on the stimulation electrodes, but rather the image is decomposed, so to speak, into at least two partial images, which are alternately "switched through" to the stimulation electrodes with a lower repetition frequency.

If, for example, four partial images each with a repetition frequency of 5 Hz are emitted as stimulation signals of a quarter of the stimulation electrodes, a new (partial) image in the form of stimulation signals, ie pulses, from the stimulation electrodes to the Cells of the retina delivered. Thus, the local resolution may be somewhat reduced, but the refresh rate of 20 Hz required for physiologically flicker-free vision is achieved.

Depending on the number and local "density" of the stimulation electrodes, it is possible to use a larger number of sub-images, provided that the desired spatial resolution is achieved. In the case of a higher number of partial images, the repetition frequency of the individual partial image can then be reduced even further, whereby a new partial image in the form of a pattern of stimulation pulses is output every 50 milliseconds, that is to say with a refresh rate of 20 Hz.

Im and Fried, "Temporal properties of network-mediated responses to repetitive stimuli are depended on retinal ganglion cell type", Journal Neural Eng 13 (2016), 1-12, report on epiretinal stimulation experiments on an isolated rabbit retina with five each other following monophasic sinusoidal, cathodal stimulation pulses of 4 milliseconds in length and rest intervals of 10 to 1000 milliseconds. Their results confirm the user-reported optimal repetition rate of 5 to 7 Hz.

Weitz et al., Science Translational Medicine 7 (318), 318ra203, 16 December 2015, report that epiretinal pacing has a pulse duration of 25 milliseconds compared to shorter pulse durations allows the patient higher-resolution image recognition. They mention that sinusoidal stimulation pulses of 20 Hz stimulate bipolar cells in blind ex vivo retina more effectively than rectangular pulses of the same frequency.

Twyford and Fried, "The Retinal Response to Sinusoidal Electrical Stimulation," IEEE Transactions on Neural Systems and Rehabilitation Engineering, TNSRE-2014-00035. R2, discuss that in retinal implants and many other neural implants, rectangular pulse shapes are used for the stimulation signals. They report on epiretinal experiments on seeing ex vivo retina with sinusoidal stimulation pulses of 5, 10, 25 and 100 Hz, which were applied continuously for 5 seconds each and resulted in measurable results. However, the authors conclude that that the use of low-frequency sinusoidal stimulation signals in retinal prostheses should not make sense, since pharmacological experiments indicate that the stimulation takes place via photoreceptors, which are just no longer present in a blind retina.

US 2012/0083861 A1 describes the use of low-frequency

sinusoidal stimulation signals (LFSS) to selectively stimulate ganglion cells. For the excitation frequencies values below 100 Hz and below 25 Hz, for example 25 Hz and 5 Hz are mentioned. In the experiments, a stimulation electrode was positioned epiretinally. The authors discuss that the use of LFSS places less demand on the positioning of the stimulation electrode. You therefore see further advantages for the subretinal arrangement. The authors further speculate that by appropriate selection of the frequencies by means of LFSS, certain subgroups of ganglion cells or bipolar cells could be selectively activated.

Generally, therefore, the stimulation electrodes of the retinal electrical implant are placed in epi- or subretinal contact with the tissue to be stimulated in order to deliver the stimulation signals. The stimulation signals should be selected so that the patient as possible a flicker-free vision with a correspondingly high time resolution is possible so that he not only quasi-static environment (orientation viewing) but also can detect rapidly changing environmental impressions.

To stimulate the nerve cells in the vicinity of the electrodes, in the known implants are short (about 0.1 to 10 milliseconds long) so far usually rectangular electrical voltage or current pulses with a specific repetition frequency (about 5 to 100 Hz) applied to the electrodes. Between the individual stimulation pulses, rest breaks of about 10 to 200 milliseconds occur.

Chance of sinusoidal stimulation pulses have been proposed.

However, with such retinal stimulation, fading is observed, meaning that the stimulated neurons are not stimulated by each pulse Problem attempts the above-mentioned WO 2007/128404 A1 to solve by the described sub-picture overlay, in which each field, so each associated area of neurons is stimulated with a repetition frequency of 5 Hz.

This is already an orientation vision possible, which is a great step forward for blind patients. However, the aim is also to enable the patient to record high-resolution images which may be changing rapidly, for example during running or television viewing, which is not yet satisfactorily possible with the currently used retina implants.

In the known implants voltage amplitudes greater than 1 volt are also applied to reliably stimulate the neurons. This voltage value can lead to electrode damage since it is located outside of the so-called "water window", in which no or very little chemical surface reactions take place. Voltage values of 1.6 volts (with monophasic stimulation) can also lead to cell electroporation, that is to say damage to the surface stimulated cell membrane.

Another problem with the known retina implants is the energy supply of the stimulation chip.

The energy for generating the electrical stimulation signals can not be obtained from the incident useful light even in subretinal implants, so that additional external energy is needed. In this case, this external energy is either obtained from additional non-visible light which is injected into the eye, externally coupled in inductively via a coil, for example, or passed through a cable guided into the eye.

The implant known from WO 2005/000395 A1 is supplied with electrical energy wirelessly via irradiated IR light or inductively coupled RF energy, wherein information about the control of the implant can be contained in this externally supplied external energy. However, because wireless retinal implants are not yet available to patients with satisfactory quality for human applications, not only epiretinal but also subretinal implants are currently being used, which receive the required external energy via cables.

WO 2007/121901 A1 describes, for example, a subretinal retina implant, in which the external energy and control signals are conducted by cable to the stimulation chip implanted in the eye. The cable is applied to the sclera of the eye and fixed in order to avoid forces on the implant.

Since on the implants usually integrated circuits are present, which are operated with DC voltage, and on the other hand, on the implants itself little space available, most of the known implants are directly supplied with DC voltage. In the case of a supply of alternating voltage, the rectifiers required on the implant would require too much space, in particular because of the required smoothing capacitors, or could not be implemented in integrated circuits in a technically meaningful manner.

However, the wired transmission of DC voltage leads in the long term to electrolytic decomposition processes in the tissue surrounding the cables, so that this type of supply of implants with external energy is unsatisfactory.

WO 2008/037362 A2 therefore proposes to implant the implant with at least one im

Substantially rectangular electrical AC voltage to provision, which is at least almost DC-free with respect to the tissue mass on average over time. In this case, the potential position can be selected such that the supply voltage is at least almost DC-free over the time average. In this way, the disturbing electrolytic decomposition processes are at least largely avoided.

Despite the above-described, promising approaches to solving the major technological problems associated with epi- and most importantly subretinal retinal implants, the currently available retinal implants may not yet meet all the requirements for a comprehensive and satisfactory patient care.

It remains to be investigated whether the epi- or subretinal approach applies to all

Suitable for patients suffering from visual impairment due to loss of natural photoreceptors, such as retinitis pigmentosa or age-related macular degeneration.

A further requirement for retinal implants is that a robust neural activity is triggered with the lowest possible stimulation intensity (voltage or current amplitude). Robust, reliable stimulation is the ability of the stimulated neuronal tissue to generate an electrical response every time the stimulus is presented.

The stated goal of all electrical implants is further to reduce the voltage required for the robust activation of the cells. This can e.g. can be achieved by using low impedance materials while still having to verify the long term stability of these materials.

Against this background, the object of the present invention is to provide a retina implant which takes these observations into account and avoids or reduces disadvantages of the prior art.

According to the invention, this object is achieved in that the above-mentioned active retina implant has at least one signal generator that generates at least one continuous sinusoidal stimulation signal that comprises at least one adjustable signal parameter, and that the at least one signal generator is electrically connected to at least one stimulation electrode, he leads the stimulation signal, wherein preferably the signal parameter is selected from frequency, amplitude, phase, offset and / or waveform. According to the invention, the stimulation is thus carried out with an array of stimulation electrodes, which are supplied with sinusoidal signals. These originate, for example, from at least one continuously operated sinusoidal signal generator. The amplitude, frequency, offset or phase relationship of the sinusoidal signals applied to the individual stimulation electrodes can be adjusted individually and in a time-variable manner for each stimulation electrode or for groups of stimulation electrodes. These signal parameters are adjusted according to the intensity of the light incident on the retina and measured by photodiodes. An increased incidence of light is converted into an increased stimulation amplitude or increased stimulation frequency. Suppression of the activity as it occurs when the field of view is obscured is achieved by a decreased stimulation amplitude or a phase-shifted stimulation. A shift in the voltage zero line, that is to say an offset, can likewise be used to take account of increased or reduced incidence of light.

The stimulation parameter of the delivered stimulation signal can be the

Result of a mathematical calculation is, whereby the calculation takes place either analog or digitally.

Under a "sinusoidal stimulation signal" is used in the present

Invention understood both a "pure" sinusoidal signal following the trigonometric formulas and a continuous, for example mathematically derived signal from a pure sinusoidal signal, with respect to the aspect ratio and / or time component of the positive and negative half wave and / or ratio between the slopes of the positive and negative edges is asymmetric.

The stimulation signal delivered to adjacent stimulation electrodes may have an adjustable phase relationship, wherein the capacitance of the stimulation electrodes may contribute to adjusting the phase of the stimulation signal.

After implantation and commissioning of a retina implant, the

Stimulation frequency of the sinusoidal stimulation signals individually adjusted so that the patient reports stable visual impressions. The stimulation electrodes used can be either metal-based or based on a capacitive material. When capacitive electrodes are used, sinusoidal stimulation results in a phase shift.

According to the invention, a reduction of the voltage required for a robust activation of the cells is thus not achieved by the use of previously untried materials with low impedance, but by a new stimulation protocol that allows the use of already established materials.

The new implant has at least one signal generator, which in the simplest case comprises a sinusoidal signal generator with specific signal parameters, which can be changed via external control parameters. The implant may, however, also have a plurality of sinusoidal signal generators or a complex signal generator in which current sources, digital / analog converters, microcontrollers etc. are provided in order to generate stimulation signals of any desired waveform, frequency, amplitude and phase relationship.

The systems described in the two publications discussed below may be used with appropriate adaptation for carrying out the present invention.

US Pat. No. 6,591,138 B1 describes a control device which can be implanted in the brain of a patient and metrologically detects the electrical activity of the brain and transmits sinusoidal stimulation signals, which have a fundamental frequency below 10 Hz, via implanted electrodes in the case of certain measurement signals. The stimulation signals may vary in terms of frequency, phase, waveform, duration and amplitude from electrode to electrode. In this way, unwanted neurological conditions should be prevented or terminated.

Ghovanloo and Najafi, "A wireless implantable multichannel microstimulating system-on-a-chip with modular architecture", IEEE Transactions on Neural Systems and Rehabilitation Engineering, vol. 15, No. 3, September 2007, describe a microsystem conceived, inter alia, as an epiretinal implant, which can last up to 64, in a further development up to 2048 Stimulation points mono- or biphasic stimulation pulses can deliver. The implant is constructed monolithically as an ASIC and allows the generation of arbitrary waveforms for the stimulation pulses as well as an extensive adjustment of the parameters of the individual stimulation signals.

Stimulation with an array of pacing electrodes individually applied with a sinusoidal pacing signal allows the stimulation voltage needed for stable pacing to be reduced. This protects both the stimulation electrodes and the stimulated tissue.

Furthermore, an increase in the stimulation frequency over the previously optimal range of 5 - 7 Hz is possible. The "fading" described by patients, ie the decay of the stimulated electrical activity, is alleviated or completely eliminated by increasing the stimulation frequency to at least 10 Hz.

The application of stimulation signals with different frequency and

Phase relationship to each other may allow site specific stimulation.

According to the invention, the stimulation is carried out with small current or voltage amplitudes, the maximum voltage amplitude of each half-wave can now be less than 1 volt, it is preferably in a range of 50 mV to 300 mV.

With a voltage amplitude of, for example, 100 mV per half-wave, the stimulation signal thus has a total voltage swing of 200 mV, which may be symmetrical to a zero line, or may also have an offset if the zero line has been shifted.

Furthermore, a continuous stimulation with a frequency greater than 10 Hz, preferably in the range of 10 - 100 Hz is possible. At this pacing rate, the desired pacing effect occurs permanently with each repetition of a pacing sequence. With subretinal stimulation there is thus no fading.

The invention also provides the ability to apply complex spatiotemporal stimulation patterns to individually maximize the physiological effect.

The object underlying the invention is completely solved in this way.

It is preferred if the signal parameter is individually adjustable for each stimulation electrode, wherein more preferably the signal generator has a separate sinusoidal signal generator for each stimulation electrode.

In a development, it is preferred if an image receiver is provided which converts incident ambient light into electrical signals which are fed to the at least one signal generator in order to influence the at least one signal parameter.

These electrical signals thus contain spatially resolved the required image information, with which the signal generator is then driven so that it emits a pattern of electrical stimulation signals with adjusted signal parameters for the individual stimulation electrodes, so that the stimulation signals stimulate the neurons so that the patient from the Image receiver can see "received" image.

In this case, it is preferred if the image receiver has an array of image cells, each image cell is assigned to a stimulation electrode, and the electrical signal generated by a image cell is used to set the signal parameters of the stimulation signal which is fed to the associated stimulation electrode.

Each image cell thus influences the signal parameters of the stimulation signal that is fed to the associated stimulation electrode. The image receiver can be designed as an external image receiver, which is arranged outside the eye.

The externally recorded and processed image information is transmitted as in the known epiretinal implants in the form of electrical signals via cable or wirelessly to the implant. There, these signals are possibly further processed and then used as an "internal image" to control the signal generator (s) so that the signal parameters of the stimulation signals are changed such that the neurons are then stimulated via the stimulation electrodes so that the viewed image is recognized ,

Of the known epiretinal implants, the design details of the external image receiver, the processing electronics and the "data transmission" in the eye - possibly with appropriate adaptation - can be taken over.

Alternatively, the image receptor may also be formed as an implantable image receptor, which is also implanted in the eye.

There is a significant advantage associated with this alternative.

In the case of an image receiver attached to the outside of the eye, the

Eye movement can not be used, which fulfills an important function in object finding. The patient would therefore always see the same picture despite different eye positions, as long as he keeps his head still. This is confusing for him and, according to the inventors, would reduce the benefit of the implant. Although it has already been proposed to use a so-called eye-tracking control for externally mounted image receivers, with which the eye movement is to be detected and used. However, this approach proves to be very time-consuming, although there is still no experience as to whether this will be possible with sufficient accuracy. However, if the image receptor is also implanted in the eye, the patient may use natural eye movement and head movement in the usual manner to view images and scan for objects.

Of the above-mentioned subretinal implants can be the constructive

Details of the implanted arrays of photodiodes, the control and processing electronics and the energy transfer into the eye - possibly with appropriate adjustment - are taken, so the disclosure of the above-mentioned property rights is hereby incorporated by reference to the subject of the present application.

The new implant can thus be used sub- or epiretinally.

It is preferred if the image receiver and the signal generator (s)

integrated in a chip are arranged.

Here it is advantageous that the new chip can be implanted easier than an implant of two chips or components.

In general, it is preferred if the implant comprises a shutdown device, which in

Depending on external control signals at least the one or more signal generators on and off.

Here, it is advantageous that the effect of the

Closing the eyelids can be achieved.

Further advantages will become apparent from the description and the accompanying drawings.

It is understood that the above and the still to

explanatory features are usable not only in the combination given, but also in other combinations or alone, without departing from the scope of the present invention. An embodiment of the invention is illustrated in the drawing and will be explained in more detail in the following description. Show it:

Fig. 1 is a schematic representation of a first embodiment of the new

Retinal implants not to scale;

FIG. 2 shows a schematic illustration of a second exemplary embodiment of the new retina implant in a representation which is not true to scale; FIG.

3 shows a schematic representation of a human eye into which the retina implant according to FIG. 2 is inserted, likewise not to scale;

Fig. 4 is a schematic representation of a third embodiment of the new

Retinal implants not to scale;

5 shows a schematic representation of a signal generator as used in the implants of FIGS. 1 to 4 in order to generate the sinusoidal stimulation signals with corresponding signal parameters from the received image signals;

FIG. 6 shows a sinusoidal waveform with asymmetrical aspect ratio that can be used for the stimulation signals; FIG.

FIG. 7 shows a further sinusoidal waveform with asymmetrical slopes that can be used for the stimulation signals; FIG.

Fig. 8 is a summary of the results of a 5-minute

subretinal continuous wave stimulation of a blind ex vivo retina with a sinusoidal excitation signal of 25 Hz; Figure 9 is a summary of the results of a 5 minute continuous subretinal stimulation of a blind ex vivo retina with a 40 Hz sinusoidal excitation signal;

Fig. 10 is a summary of the results of a 5-minute

subretinal continuous wave stimulation of a blind ex vivo retina with an asymmetric excitation signal of 120 ms period; and

Fig. 1 1 is a summary of the results of a 5-minute

epiretinal continuous wave stimulation of a blind ex vivo retina, alternating with a sinusoidal excitation signal of 10 Hz and with a sinusoidal excitation signal of 25 Hz.

1 shows a schematic representation of a first exemplary embodiment of an active retina implant 10, wherein the dimensions are not shown to scale.

The retina implant 10 is connected via a cable 11 to a supply unit 12 and to an implantable image receiver 13, on which an array 14 of image cells 15 is arranged, which are formed, for example, as photodiodes. On the retina implant 10, an array 16 of stimulation electrodes 17 for the delivery of electrical stimulation signals is arranged.

The supply unit 12 supplies the retina implant 10 via the cable 1 1 with electrical energy and possibly with control signals via which various functions of the retina implant can be influenced or adjusted.

The image receiver 13 converts via its image cells 14 incident ambient light into spatially resolved electrical signals, which are passed to the retina implant 10 and there - optionally after further processing - delivered via the stimulation electrodes 17 as electrical stimulation signals to cells of the retina to these stimulate.

The retina implant 10 can be used epi- or subretinally. On the cable 1 1 mounting tabs 18 are provided with which the cable 1 1 can be attached to the sclera of the eye of the person, who is implanted the retina implant 10. In this way it is avoided that forces are exerted on the retina implant 10, which could lead to a mechanical load and / or displacement of the retina implant 10.

In the retina implant 10 of FIG. 1, the image receiver 13 is arranged outside the eye, for example in a pair of glasses which the patient wears. The retina implant 10 is then epiretinal implanted, for example, wherein the transmission of energy, control signals and image information can also be wireless, as is known as such from various publications.

In preferred embodiments, however, the image receptor 13 is implantable such that it is implanted into the eye, such as the retina implant 10 itself. This arrangement is shown in Fig. 2, where the image receptor 13 is disposed adjacent to the retina implant 10, to which it is connected in the embodiment shown via a cable 19.

Because this subretinal implant also implants the image receptor in the eye, the patient can use natural eye movement and head movement in the usual way to view images and scan for objects.

Of the above-mentioned subretinal implants, the design details of the implanted arrays of photodiodes, the control and processing electronics and the energy transfer into the eye - possibly with appropriate adjustment - can be adopted.

The retinal implant 10 and the image receptor 13 of FIG. 2 are intended to be implanted in a human eye 20, which is shown very schematically in FIG. For the sake of simplicity, only the lens 21 and the retina 22 into which the implant 10 and the image receptor 13 have been implanted are shown. Retina implant 10 and image receptor 13 are preferably in the so

introduced subretinal space which forms between the pigment epithelium and the photoreceptive layer. If the photoreceptor layer is degenerate or lost, the subretinal space forms between the pigment epithelium and the bipolar and horizontal cell layer. The retina implant 10 is placed in such a way that the stimulation electrodes 17 shown in FIG. 2 can deliver the electrical stimulation signals to cells in the retina 22.

A visible light indicated by an arrow 23, the beam path of which can be seen at 24, is transmitted via the lens 21 to the image receiver 13, where the visible light (see arrow 23) is converted into electrical signals which are directed to the retina implant 10 where they are converted into electrical stimulation signals.

Retinal implant 10 and implantable image receptor 13 can be arranged side by side, as shown in FIG. 2, whereby they can be embodied as separate units in, for example, different technologies. Both implants 10, 13 can also be arranged side by side or one above the other on a common foil or integrated into a microchip.

The array 14 of image cells 15 is shown in FIG. 3 as a black area.

The stimulation electrodes 17 are provided in a defined geometric arrangement and have a distance of 50 μηη each other, which is designated in Fig. 2 with a.

This arrangement can be matrix-shaped with rows and columns - as in FIGS. 1 and 2

can be arranged - or beamformed - to create different patterns that provide optimal detection.

In Fig. 3 can still be seen that the cable 1 1 led out laterally out of the eye and out there on the sclera with the mounting tabs 18 is attached before the cable continues to the external supply unit 12. The supply unit 12 is then fastened in a manner not shown in detail outside the eye, for example on the skull of the patient. Via the supply unit 12, electrical energy is sent to the implant 10 and the image receiver 13, wherein at the same time control signals can be transmitted which influence the functioning of the implant as described, for example, in the aforementioned WO 2005/000395 A1, the content thereof is hereby made the subject of the present application.

In this case, the energy supply can take place via substantially rectangular electrical alternating voltage voltages, which are virtually DC-free with respect to the tissue mass over a period of time, as described in the aforementioned WO

2008/037362, the content of which is hereby also made the subject of the present application

It should be noted that the dimensions of the retina implant 10, the image receiver 13, the fastening tabs 18 and the external supply unit 12 in FIGS. 1, 2 and 3 are shown neither to scale nor in correct size relation to one another.

Image receiver 13 and retina implant 10 can alternatively also be integrated in a chip 26, as shown schematically in FIG. The chip 26 is easier to implant than an implant of two chips or components. Furthermore, then the location of the image information (by the image receiver 13) and the location of the delivery of the electrical stimulation signals are very close together, so that the patient perceives no or almost no prism errors. The chip 26 has a carrier 27, on which an input stage 28 can be seen, which is supplied via the cable 1 1 external external energy and possibly control signals. The input stage 28 is connected to a unit 29, which in this case has a multiplicity of image cells 15 which convert incident visible light into electrical signals which are then emitted via the stimulation electrodes 17 indicated next to the respective image cells 15 as electrical excitation patterns to nerve cells of the retina become. The processing of the electrical signals generated by the image cells 15 takes place in a signal generator 31, which generates sinusoidal stimulation signals with individual signal parameters for the various stimulation electrodes 17, which are then fed back to the stimulation electrodes 17.

In this context, it should be pointed out that FIG. 4 is merely a schematic, logical representation of the chip 26, the actual geometric arrangement of the individual components may result, for example, in the immediate vicinity of each image cell 15 having a signal generator 31.

The chip 26 is connected via an indicated at 32 external mass with the tissue into which the implant is introduced. Furthermore, an internal electrical ground 33 is indicated, which is not connected to the external ground 32 in the embodiment shown.

As an alternative to the wired power supply described so far, the chip 26 can also be inductively supplied with HF energy via an external transmitting coil which is received by a receiving coil in / on the eye and then rectified in order to supply the chip 26 with the required DC voltage. like this eg in WO 2009 / 090047A1.

The chip can also be supplied with energy via infrared radiation, as described in detail in WO 2004/067088 A1, the content of which is hereby likewise made the subject of the present application. FIG. 5 shows, by way of example, a signal generator 31 to which a retina 22 and, subsequently, neuronal tissue 33, which is connected via nerve tracts 34 to the visual cortex (not shown), are indicated very schematically. With the retina 22 intact, incident light (see arrow 23) is converted by the retina 22 into electrical signals and delivered to cells of the neuronal tissue 33, which then relay the electrical signals via the nerve tracts 34 to the visual cortex. The object of the patient in question here is not or no longer fully functional retina 22 takes over the inventive retina implant 10th

The signal generator 31 has for each stimulation electrode 17 a sinusoidal signal generator 35 which generates a sinusoidal stimulation signal with adjustable signal parameters.

Each sinusoidal signal generator 35 is associated with an adjusting device 36, which via

Lines 37 are supplied from the image cells 15 output electrical signals representing the viewed image.

The electrical signals of the image cells 15 affect frequency, amplitude, relative

(relative to stimulation signals for adjacent stimulation electrodes) phase and / or relative (again referring to stimulation signals for adjacent stimulation electrodes) offset of the stimulation signal generated in each case, which is then passed via lines 38 to the stimulation electrodes 17.

The signal generator 31 can be a function of the individual, by the electrical

Signals on the lines 37 certain signal parameters that generate stimulation signals with the help of current sources, analog-to-digital converters, microprocessors, etc.

The lines 37, 38 are also shown in Fig. 4, where indicated by double-dashed lines, that in each case a plurality of lines 37 and 38 are provided.

The patient may, for example, the retinal implant 10 via control signals on the

Activate and deactivate cable 1 1 in order to obtain an effect (dark state) during rest or during sleep as with the closing of the eyelids. The continuous delivery of sinusoidal stimulation signals to the stimulation electrodes 17 otherwise provides the patient with a permanent "basic image", which does not disappear even when the eyelids close. The shut-off device 39 provided for this purpose is indicated in FIG. 4 by a rectangle in the input stage 28. The shutdown function can be implemented as a hardware component or as a software component.

In use, the frequencies of the stimulation signals, the individual

Stimulation electrodes 17 or groups of stimulation electrodes 17 are fed individually adjusted so that the patient perceives an even over the entire stimulated image visual impression.

According to findings of the inventors, this individual frequency setting allows the physiologically different conditions of the individual patients to be taken into account so that all the stimulation electrodes 17 deliver their stimulation signals to the respectively assigned cells of the neuronal tissue 33.

Without being limited to this, an explanation currently being made for this effect is that by altering the sinusoidal frequency of the stimulation signal, the cells of the neuronal tissue 33 addressed by the stimulation signal can be selected.

Instead of purely trigonometric sinusoidal signals, stimulation signals deviating from the pure sinusoidal form may also be used, as shown by way of example in FIGS. 6 and 7.

FIG. 6 shows a sinusoidal signal 41 having an amplitude deviation 40 with asymmetrical aspect ratio, in which the anodic component 42 has a different amplitude, here greater, than the cathodic component 43.

This takes into account the fact that with epi- and subretinal stimulation anodic signal components can have a different stimulation threshold than cathodic signal components. Without having to increase the amplitude stroke 40, a more effective stimulation can take place.

7 shows a sinusoidal signal 44 with asymmetrical slopes, in which the falling edge 45 has a different, here greater slope than the rising edge 46th

This takes into account the fact that in the case of epi- and subretinal stimulation, the stimulated activity - possibly in dependence on the stimulation frequency - is primarily associated with one of the two flanks.

In terms of aspect ratio and / or slope slope asymmetric sinusoidal

Signals can be generated by simple mathematical operations from pure trigonometric sinusoidal signals.

Measurements by the present inventors have revealed that blind

Retinas with sinusoidal electrical voltages can be stimulated via subretinal and via epiretinally positioned electrodes. The experiments involved recording ganglion cell activity and recording the total current flowing during stimulation to later determine the charge transferred per stimulation phase. For comparison with stimulation parameters used in the clinical setting, retinas were stimulated with biphasic stimulation pulses of the same duration as well as with short, pulse-shaped anodic stimulation pulses of the same frequency.

As a model system retina served a blind mouse line (about 1, 8 weeks old, reference:

Charles River) applied to a microelectrode array (MEA) in subretinal or epiretinal configuration. During the measurements, the retina was perfused with fumed (carbogen) Arnes medium (Sigma). The temperature in the bath was kept at 37 ° C.

Two different types of MEA with iridium oxide electrodes were used: (i)

Standard MEAs with 200μηι electrode spacing and 30μηι electrode diameter and (ii) HD-MEAs (electrode gap 30μη "ΐ, electrode diameter Ι Ομηη) Simultaneous stimulation with 8 electrodes stimulated an electrode field of either 430 μηη × 430 μηη or 70 μηη × 70 μηη were generated by a STG 2004 (Multi Channel Systems MCS GmbH) In sine excitation, a voltage divider was switched between STG 2004 and the MEA adapter in order to achieve the highest possible resolution An external Ag / AgCl was positioned in the bath as counterelectrode.

The electrostimulated cell responses were measured for subretinal stimulation using a flexible microelectrode array (Flex MEA). The stimulation current was determined by a resistor (10 ohms) between Ag / AgCl electrode and system ground.

Sinusoidal stimulation signals with frequencies of 10 and 25 Hz were included

Signal amplitudes of 15, 50, 100, 150 and 200 mV tested. For both frequencies a stimulation of the retina with amplitudes of 200 mV was measurable.

Thereafter, it was estimated how stable the stimulated activity would be over the duration of the stimulation of 5 minutes, that is, whether the activity triggered by the first pulses is comparable to the activity triggered by the last pulses. When comparing the first 18 and the last 18 seconds of the 5 minute stimulation with 200 mV amplitude and 25 Hz, no difference in stimulated activity is seen, i. there is no fading here, as e.g. has been reported for pulse-shaped stimulation.

From the results obtained it could be concluded that sinusoidal

Steady pacing generates stable responses in which 70% (and often 100%) of pacing cycles generate at least one retinal action potential over 5 minutes.

In comparison to stimuli with rectangular stimulation pulses of the same frequency, it was found that the sinusoidal stimulation at 200 mV excitation amplitude excited a significantly higher activity in the stimulated ganglion cells. It could be shown that with subretinally applied sinusoidal

Voltages of the amplitude 200 mV the blind Retina can be reliably stimulated. On average, at a pacing rate of 10 Hz (25 Hz), 80% (70%) of all stimuli have at least 1 action potential / spike in the measured cell.

The stability of the induced response is higher than in the case of biphasic

Rectangular stimuli or after anodic, short pulses. With sinusoidal voltages, more action potentials can be triggered per stimulation than via the control stimuli.

Further experiments showed that even after 60 minutes of stimulation in both the epiretinal and in the subretinal approach no decrease in the measured stimulation response was.

It has also been shown that changes in pacing rate and pacing amplitude are directly reflected in the pacing response.

In Fig. 8 are exemplified the results of a 5-minute subretinal

Cyst stimulation of a blind ex vivo retina is shown. Each stroke in the upper figure corresponds to a measured action potential. Shown are the measurement results for the first and last twenty sinusoids.

The lower figure shows the timing of the excitation signal, which was a pure sine wave with a frequency of 25 Hz and a total stroke of 400 mV.

FIG. 8 shows that the stimulation is robust, and even after 5 minutes of continuous stimulation the action potentials are still stimulated in a reproducible manner, fading is not recognizable.

Furthermore, it can be seen in FIG. 8 that here the action potentials are triggered predominantly in the anodic stimulation portion. This result can be taken into account, for example, in that the waveform of the stimulation signals is asymmetrical is designed, for example, with a shorter cathodic portion and / or steeper negative edge.

Fig. 9 shows in a representation as in Fig. 8, the results of a 5-minute

subretinal continuous wave stimulation of a blind ex vivo retina but for an excitation signal that was a pure sine with a frequency of 40 Hz and a total stroke of 400 mV.

It can be seen from FIG. 9 that the stimulation is robust even with excitation with 40 Hz sinus, here too the action potentials are stimulated in a reproducible manner after 5 minutes of continuous stimulation, whereby even here a fading can not be recognized.

Fig. 10 below shows an asymmetric excitation signal of 120 ms period and with steeply rising sinusoidal edge and flat falling edge; see also Fig. 7. Above in Fig. 10, the cell response is shown, which is stimulated by the beginning of the falling edge of the excitation signal.

FIG. 11 shows in a representation as in FIG. 8 that the retinal network follows a change of the frequency from 10 Hz to 25 Hz and back to 10 Hz. By increasing and subsequently reducing the excitation frequency, the cell responses shift reproducibly in the time axis. The number of triggered cell responses per second also changes, which represents a possibility for the conversion of the incident light signal into cell responses.

The results shown in FIG. 11 prove that the cell response can be modulated within a few milliseconds via a change in the stimulation frequency. The experimental set-up as well as the measurement evaluation for the results shown in Figs. 8 and 9 corresponded to the setting discussed above in the forefront of the discussion of Fig. 8. The experiments for Figs. 8 and 9 were performed with subretinal, those for Figs. 10 and 11 with epiretinal stimulation. The experimental set-up and the measurement evaluation for the results shown in Fig. 10 1 1 were obtained with a commercial CMOS-based microelectrode array "CMOS MEA 5000" (Multi Channel System MCS GmbH) The stimulation current was 500 nA Titanium nitride isolated with a 25 nm thin titanium oxide layer.

The cellular responses elicited by electrostimulation with CMOS MEA were measured for epiretinal stimulation using a sensor electrode of the CMOS MEA 5000 system. The stimulation current was determined by a resistor (10 ohms) between Ag / AgCl electrode and system ground.

Claims

claims

1 . Active retina implant for implantation in an eye (20), with an array (16) of stimulation electrodes (17) which deliver stimulation signals to cells of the retina (22), characterized in that at least one signal generator (31) is provided generates at least one continuous sinusoidal stimulation signal, which comprises at least one adjustable signal parameter, and that the at least one signal generator (31) is electrically connected to at least one stimulation electrode (17).

2. retina implant according to claim 1, characterized in that the signal parameter is selected from frequency, amplitude, phase, offset and / or waveform.

3. retina implant according to claim 1 or 2, characterized in that the signal parameter is individually adjustable for each stimulation electrode.

4. retina implant according to one of claims 1 to 3, characterized in that the signal generator (31) for each stimulation electrode (17) has its own sinusoidal signal generator (35).

5. retina implant according to one of claims 1 to 4, characterized in that the at least one sinusoidal signal has a frequency greater than 10 Hz.

6. retina implant according to claim 5, characterized in that the at least one sinusoidal signal has a frequency in the range of 10 Hz to 100 Hz.

7. retina implant according to one of claims 1 to 4, characterized in that the at least one sinusoidal signal in each half-wave has an amplitude less than 1 volt.

8. retina implant according to claim 7, characterized in that the at least one sinusoidal signal in each half wave has an amplitude in the range of 50mV to 300 mV.

9. retina implant according to one of claims 1 to 8, characterized in that an image receiver (13) is provided, which converts incident ambient light into electrical signals, which are the at least one signal generator (31) supplied to the at least one signal parameter influence.

10. Retinal implant according to claim 9, characterized in that the image receiver (13) has an array (14) of image cells (15), each image cell (15) is assigned to a stimulation electrode (17), and that of a image cell (15 ) is used to adjust the signal parameters of the stimulation signal that is supplied to the associated stimulation electrode (17).

1 1. Retinal implant according to claim 9 or 10, characterized in that the image receiver (13) as an external image receiver (13) is formed, which is arranged outside of the eye (20).

12. retina implant according to one of claims 9 to 1 1, characterized in that the image receiver (13) is designed as an implantable image receptor (13).

13. Retinal implant according to one of claims 9 to 12, characterized in that the image receiver (13) and the one or more signal generators (31) integrated in a chip (26) are arranged.

14. retina implant according to one of claims 1 to 13, characterized in that it comprises a shut-off device (39) which switches on and off in response to external control signals at least one or more signal generators (31).