Patent Description:
Electrical apparatus such as visual prostheses have been developed to restore vision within blind or partially blind patients. A visual prosthesis such as a retinal prosthesis commonly includes an implantable component having an electrode array, situated on or in a substrate, for placement in the eye on or near retinal nerve cells. Electrical signals are transmitted via the electrodes to the retinal nerve cells, triggering a perception of light within the patient's brain. The prosthesis can therefore provide the perception of vision to patients, e.g. whose retinal photoreceptors have become dysfunctional or lost.

Commonly, a visual prosthesis is used in conjunction with a video camera. A stream of images detected by the camera is converted into digital signals by an image processor and electrical signals are applied to the electrodes in accordance with the digital signals.

<CIT> discloses a prosthesis comprising a substrate having a distal end and a proximal end; and a plurality of electrodes located at or adjacent the distal end of the substrate. The distal end of the substrate is configured for insertion, via an incision, between first and second tissue layers, such as the sclera and choroid in the eye. The prosthesis tapers in thickness towards the distal end and has a substantially curved provide profile at least on one surface so that the prosthesis can be inserted into position without needing a guide and without causing damage to the tissue or the prosthesis. The prosthesis can include an electrode interface unit located at or adjacent the proximal end of the substrate which locates between the tissue layers. An anchor portion can be provided that extends from the substrate into the incision.

<CIT> discloses a visual prosthesis apparatus including an implantable device having a substrate and a plurality of electrodes located in or on the substrate, the substrate adapted to be implanted at least partially in an eye of a patient. A first inductor is included in the implantable device, for example by encapsulating an inductor coil in the substrate or on an associated lead or anchor device. In some instances, the electrodes in the substrate may partially provide the first inductor. A second inductor is adapted to locate externally to the eye and inductively couple with the first inductor. A processor is adapted to determine a direction of movement of the eye based on changes in electrical current induced in one of the first and second inductors due to relative movement of the first and second inductors.

<CIT> discloses a method for treating an ocular disease in a subject comprising the steps consisting of i) delivering a pharmaceutical composition formulated with a therapeutic nucleic acid of interest into the suprachoroidal space of the diseased eye and ii) exposing the region where the pharmaceutical composition was delivered to an electrical field.

<CIT> discloses an electrode device having an insertion part adapted to be inserted into the suprachoroidal space of an eye so as to reach a service position, and an handling part for manipulation of the electrode device. The electrode device comprises a support having a distal part; a set of wires supported by said support and mobile between a retracted position in which said wires substantially extend along the support, and a deployed position in which respective parts of said wires, called "outside parts", project from said distal part of the support; an electrically conductive element forming at least a portion of a said outside part or supported by a said outside part; an electrical conductor enabling, in said deployed position, an electrical connection between said electrically conductive element and an electrical generator; and an actuator adapted for an operator to move the set of wires from said retracted position to said deployed position in said service position.

Shaun L Cloherty et al discusses suprachoroidal positioning of an electrode array for the purposes of restoring sight to the blind. The array is described as being advanced a distance of approximately <NUM> to the posterior pole of the eye wherein an opposite end is fixed to the eye exterior.

<CIT> discloses a biological implantable functional device comprising a casing having a space for accommodating an electronic device and formed with an opening; a bendable flexible wiring substrate in which a wiring is formed in a predetermined pattern so as to correspond to an device-side terminal of the electronic device; a casing inner connecting terminal to be connected to an electric substrate provided outside the casing; and a bump to be electrically connected with the flexible wiring substrate and the casing inner connecting terminal; and a cover for sealing the opening of the casing to hermetically seal the electronic device.

Wong Y T et al discusses electrical stimulation using a suprachoroidally implanted prosthesis with the goal of eliciting responses from neurons in the visual cortex.

Aspects, embodiments and examples of the present disclosure which do not fall under the scope of the appended claims do not form part of the invention and are merely provided for illustrative purposes.

By way of example only, embodiments of the present disclosure are now described with reference to the accompanying Figures in which:.

Embodiments of the present disclosure relate to electrical apparatus for applying therapeutic electrical stimulation to any eye of a patient and/or monitoring the eye of the patient.

<FIG> shows a top view of electrical apparatus according to an embodiment of the present disclosure, the apparatus including an implantable device <NUM>, an anchor device <NUM> and a lead <NUM>.

The implantable device has a flexible substrate <NUM> with a distal end <NUM>, a proximal end <NUM>, a first side <NUM>, and a second side <NUM>. The substrate <NUM>, when viewed from above, is substantially rectangular, with curved corners to minimise surgical trauma. The longitudinal direction (length) of the substrate extends between the distal and proximal ends <NUM>, <NUM> and the transverse direction (width) of the substrate extends between the first and second sides <NUM>, <NUM>. The substrate <NUM> includes first and second opposite surfaces <NUM>, <NUM> that each extend between the distal and proximal ends <NUM>, <NUM> and between the first and second sides <NUM>, <NUM> (see also <FIG>). Electrodes <NUM> are partially embedded in the substrate, which electrodes <NUM> are used to apply electrical current to tissue of the eye for the purposes of therapeutic electrical stimulation and/or are used to monitor properties of the eye by receiving electrical current from tissue of the eye. In this embodiment, four electrodes <NUM> are provided, the electrodes being arranged in a staggered pattern with electrodes <NUM> aligned in rows extending in the longitudinal direction of the substrate but offset in the transverse direction of the substrate. The electrodes <NUM> are exposed at the second surface <NUM> of the substrate.

The length of the substrate <NUM> is between about <NUM> and <NUM>, e.g. about <NUM>, although other lengths are possible. The width of the substrate <NUM> is between about <NUM> and <NUM>, e.g. about <NUM>, although other widths are possible. The electrodes <NUM> are disc-shaped electrodes with circular peripheries, although other shapes are possible. The diameters of the electrodes <NUM> are between about <NUM> and <NUM>, e.g., about <NUM> and have an area of between about <NUM><NUM> and about <NUM><NUM>, e.g., about <NUM><NUM>. However, as discussed in more detail below, a lip <NUM> surrounds the electrodes <NUM> such that only a portion of each electrode, having a diameter of about <NUM> (and an area of about <NUM><NUM>), is exposed from the substrate, although other diameters are possible.

In addition to covering a relatively large area of the substrate <NUM>, the electrodes <NUM> are sized and distributed to retain flexibility of the implantable device <NUM>. The electrodes <NUM> are positioned substantially at either side of a longitudinal centre line <NUM> of the substrate <NUM>. No major part of any electrode <NUM> is this embodiment is positioned across the longitudinal centre line <NUM> of the substrate <NUM>. Thus, the substrate <NUM> can easily flex at the longitudinal centre line <NUM>, without being substantially hindered by any electrode stiffness. So that it possible to avoid positioning the electrodes <NUM> across the longitudinal centre line <NUM> of the substrate <NUM>, electrodes <NUM> are provided each having a diameter that is less than half the width of the substrate <NUM>. Each electrode also has an impedance that is less than <NUM> kΩ, providing for safe low charge density stimulation as well as diagnostic monitoring stability. However, electrode impedances may be used in the range of ~<NUM>-<NUM> kΩ, for example.

Each electrode <NUM> is connected to one or more separate electrical conductors <NUM>, e.g., a biocompatible metal wires such as a platinum wires. The conductors <NUM> extend through the substrate, and extend out of the substrate and through the lead <NUM>. Although only a basic representation of the conductors <NUM> is provided in <FIG>, in practice the conductors <NUM> may be configured in a curved and/or helical configuration, enabling the conductors to adjust to flexing of the implantable device <NUM> and/or lead <NUM>.

The substrate <NUM> of the implantable device includes one or more navigation markers <NUM>, <NUM> to assist in the implantation of the implantable device <NUM>. The navigation markers <NUM>, <NUM> can serve as an indicator of the depth of insertion of the implantable device <NUM> through an incision in the eye and/or as an indicator of the orientation of the implantable device <NUM> relative to the incision. In this embodiment, at least two navigation markers <NUM>, <NUM> are provided, each on the first (rear) surface <NUM> of the substrate <NUM>. In this embodiment, the navigation markers <NUM>, <NUM> are provided in the form of lines. The lines are printed on the rear surface <NUM> of the substrate <NUM>, although in alternative embodiments they may be etched or moulded into the substrate, for example. The lines <NUM> are straight lines that extend in a transverse (width) direction of the substrate <NUM>, perpendicularly to the longitudinal (length) direction of the substrate <NUM>.

A first one of the navigation markers <NUM> is provided to mark the position at which the implantable device <NUM>, when fully implanted, is to align with the incision in the eye. The first marker <NUM> when positioned at the incision not only indicates that the implantable device <NUM> has been inserted to the full implantation depth through the incision, but also provides a means of ensuring that the implantable device <NUM> is oriented appropriately relative to the incision at the full implantation depth. In this embodiment, appropriate orientation at the full implantation depth is achieved when the first marker is positioned directly underneath and extends parallel to the incision. Notably, the first marker is positioned slightly distally of the proximal end of the substrate <NUM>, since the implantable device <NUM>, when fully implanted, is configured to extend either side of the incision. A major portion (distal side) of the implantable device <NUM> is to be located to one side of the incision with a remaining minor portion (proximal side) of the implantable device <NUM> being tucked to the opposite side of the incision (see e.g. <FIG>). The lead <NUM> extends from the implantable device <NUM> at a position that is aligned with the first marker <NUM>, since it is arranged to extend from the implantable device <NUM> immediately through the incision.

A second one of the navigation markers <NUM>, which is located distally of the first navigation marker, provides an intermediate marker. It provides an indication, for example, that the implantable device <NUM> has been inserted to a predetermined intermediate implantation depth through the incision, e.g. at least half of the full implantation depth. Moreover, it provides an indication that the implantable device <NUM> is being inserted at the appropriate orientation relative to the incision at the intermediate implantation depth. In this embodiment, appropriate orientation is achieved at the intermediate implantation depth when the second marker <NUM> is positioned directly underneath and extends parallel to the incision. Additional markers, e.g. lines, may be provided to provide additional indications of the depth of insertion of the implantable device and/or to ensure suitable orientation of the implantable device <NUM> at those different depths.

An example method of implanting the implantable device <NUM> in an eye <NUM> is now discussed with respect to <FIG>. An incision <NUM> is made in the sclera <NUM> of the eye <NUM> with a scalpel <NUM>, the incision <NUM> being slightly wider than the width of the substrate <NUM> of the implantable device <NUM>. For example, the incision may have a width of about <NUM>. The incision <NUM> is made between the inferior rectus muscle <NUM> and the lateral rectus muscle <NUM> of the eye <NUM>. The incision is positioned about <NUM> to <NUM> posterior from the intramuscular septum. The distal end <NUM> of the substrate <NUM> is pushed into the incision <NUM>, using soft-tipped forceps <NUM>, through the sclera <NUM> and into a pocket between the sclera <NUM> and the choroid <NUM> (See <FIG>). During the insertion process, the first and second markers <NUM>, <NUM> provide indications of insertion depth. During the insertion process, a check is made to ensure that the second marker <NUM> is aligned with the incision <NUM> as it passes through the incision and a correction of the orientation is made if necessary. Once the implantable device is fully inserted at the correct orientation, which is confirmed by alignment of the first marker <NUM> with the incision <NUM>, the opening of the incision <NUM> is closed using sutures. When implanted, the implantable device <NUM> of the present embodiment is located entirely between the inferior and lateral rectus muscles <NUM>, <NUM> of the eye <NUM>, in an inferior anterior temporal position of the eye (e.g., in the inferior anterior temporal octant of the eye). In alternative embodiments, a part of the implantable device may be located between the inferior and lateral rectus muscles of the eye and a part of the implantable device may be located under one or both of the inferior and lateral rectus muscles of the eye. In alternative embodiments, the incision and/or all or part of the implantable device may be located under the lateral rectus muscle.

Therapeutic stimulation provided by the implanted device <NUM>, through delivery of electrical current from its electrodes <NUM> to surrounding tissue of the eye, can provide for improvement of the visual function of the eye and/or prevent or slow degradation of the visual function of the eye. Improvement of visual function can provide, for example, improvements in the patient's perception of any one or more of: brightness, contrast, resolution, colours, shapes, movement and size of visual field. Similarly, the prevention or slowing down of degradation of the visual function can prevent or slow down degradation of, for example, the patient's perception of any one or more of: brightness, contrast, resolution, colours, shapes, movement and size of visual field.

In general, this therapeutic stimulation can contrast with stimulation that is intended solely to restore visual function through eliciting the perception of light as a direct result of the stimulation. The therapeutic stimulation may provide an improvement in visual function of the eye and/or prevent or slowing degradation of the visual function of the eye without eliciting a perception of light to the patient, or without eliciting a perception of light to that patient that is visually useful or intended to be visually useful. Additionally or alternatively, the therapeutic stimulation can provide an improvement in visual function of the eye and/or prevent or slowing degradation of the visual function of the eye at a portion of the eye that is not in contact with the electrodes delivering the electrical stimulation.

The therapeutic stimulation may protect against retinal cell loss in degenerative conditions, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD) and glaucoma or otherwise, including vascular and other conditions. The therapy may arrest retinal degeneration in the early stages of diseases, e.g. before a patient loses useful vision, or during intermediate or later stages of diseases. Chronic electrical stimulation can have a neuroprotective effect on retinal cells.

By implanting the implantable device <NUM> suprachoroidally and at an inferior anterior temporal position of the eye (e.g., in the inferior anterior temporal octant of the eye) or elsewhere, efficacious stimulation and/or monitoring of tissue of the eye can be achieved. Positioning of the implantable device <NUM> suprachoroidally can provide an approach that is safe and stable and requires minimally-invasive surgery. Moreover, the positioning of the implantable device <NUM> in the inferior anterior temporal octant can ensure that appropriate space is left in the eye for implantation of a further implantable device, such as a device configured to restore visual function through eliciting the perception of light as a direct result of the stimulation, e.g. a standard "bionic eye" device. In this regard, the implantable device may be kept away from a central retinal region where the bionic eye device may be located. Moreover, the positioning of the implantable device can correspond to a superior visual field mapping area of the retina. Thus, to the extent that it provides stimulation above a threshold level such as to elicits light perception, the stimulation may be less relevant to sight and less obtrusive. Still further, the positioning of the implantable device in the inferior part of the eye can ensure that any bleeding associated with surgery would drain downwards, away from the central retina, and not flow over the central retina.

In addition or as an alternative to providing therapeutic electrical stimulation, the implantable device <NUM> may be used to monitor properties, such as voltages, impedances or otherwise, of the eye. In one embodiment, the implantable device <NUM> is used to perform electroretinography monitoring (ERG).

In addition to the positioning of the implantable device <NUM> in the eye, safety, stability and the need for only minimally invasive surgery is provided in part through the shaping of the substrate <NUM> of the implantable device. A side view, an end view and an oblique view of the substrate <NUM> are provided in <FIG>, respectively. As can be seen, the first surface <NUM> of the substrate is curved. When positioned suprachoroidally, the first surface <NUM> is designed to rest against the inner surface of the sclera <NUM>, as illustrated in <FIG>.

With reference to <FIG>, the degree of curvature of the first surface <NUM> increases in the longitudinal direction from a central region <NUM> of the first surface <NUM> of the substrate <NUM> towards the distal end <NUM> of the substrate <NUM>. The curvature of the first surface <NUM> also increases in the longitudinal direction from the central region <NUM> towards the proximal end <NUM> of the substrate <NUM>. Similarly, with reference to <FIG>, the degree of curvature of the first surface <NUM> increases in the transverse direction from the central region <NUM> of the first surface <NUM> of the substrate <NUM> towards the first side <NUM> the substrate <NUM>. The curvature the first surface <NUM> also increases in the longitudinal direction from the central region <NUM> towards the second side <NUM> of the substrate <NUM>. The curvature of the first substrate <NUM> of the substrate <NUM> is such that the substrate <NUM> tapers in thickness from a central region of the substrate <NUM> towards the ends and sides of the substrate <NUM>.

The degree of curvature of the first surface <NUM> changes in steps in this embodiment, although a continuous change may be provided in alternative embodiments. By increasing in steps, the first surface <NUM> has discrete regions, each region having a constant radius of curvature, but with the radius of curvature changing from one region to the next. In particular, at least three curved regions are provided in the present embodiment, the central region <NUM>, a first outer region <NUM> and a second outer region <NUM>, wherein the first outer region <NUM> is located between the central region <NUM> and the second outer region <NUM>. The central region <NUM> has a first radius of curvature R1, the first outer region <NUM> has a second radius of curvature R2 and the second outer region <NUM> has a third radius of curvature R3, where R1>R2>R3.

The curvature of any one or more of the curved regions <NUM>, <NUM>, <NUM> can be part-spherical. In this embodiment, the curvature at the central region <NUM> is part-spherical and substantially follows the spherical curvature of the eye. The first surface <NUM> is configured to lie against the inside of the scleral. The relatively low, part-spherical curvature of at least the central region <NUM> of the first surface <NUM> reduces the amount of static pressure exerted against the sclera when the implantable device <NUM> is in the implantation position between the sclera and choroid. Nevertheless, the relatively high curvature of the outer regions <NUM>, <NUM> of the first surface can assist in the insertion of the substrate <NUM> between the tissue layers of the eye. The substrate <NUM> can be pushed into place between the tissue layers, causing separation of the tissue layers. The relatively high curvature can assist in separating the tissue layers, essentially opening up a pocket in which the implantable device locates. The curvature of the substrate <NUM> may ease surgical placement and forces. Moreover, the curvature may help support the incision <NUM> in the eye <NUM> through which the implantable device <NUM> is implanted in the eye <NUM>.

With reference to <FIG>, the lead <NUM> is arranged to extend from the implantable device <NUM>, through the incision in the sclera <NUM> of the eye <NUM>, from the eye <NUM> to the adjacent orbital bone <NUM>, around the orbital bone <NUM> and along the side of the patient's skull <NUM> to an electronics unit <NUM>, which electronics unit <NUM> may comprise one or more of: an electrical stimulator for delivering electrical signals to the electrodes, an electrical amplifier for amplifier electrical signals received from the electrodes and a communications interface, for example. Components of the electronics unit <NUM> may be provided in a housing or 'can'. The housing may be a biocompatible metal housing, such as a titanium can. A return electrode <NUM> is connected to the electronics unit <NUM>. The communications interface can allow for connection between the implantable device and an external electrical component such as a signal generator, signal processing device, a controller or otherwise.

Referring also to <FIG>, the lead <NUM> includes first and second lead sections <NUM>, <NUM> that locate externally to the eye when the implantable device <NUM> is implanted in position. The second lead section <NUM> is configured to extend around the orbital bone <NUM> and the first lead section <NUM> is configured to locate between the implantable device <NUM> and the second lead section <NUM>. The first lead section <NUM> has a pre-formed bend and specifically a pre-formed U-shaped bend, in this embodiment. The pre-formed bend provides a change in direction of the lead at the first lead section of about <NUM> degrees, although other angles may be utilised. The pre-formed bend has a radius of about <NUM> to <NUM>, although other radii may be utilised. Moreover, more than one pre-formed bend may be provided at the first lead section <NUM>.

The pre-formed bend of the first lead section <NUM> bends in a posterior direction when the implantable device is implanted in the eye, as shown in <FIG>. Thus, ends <NUM>, <NUM> of the U-shaped bend locate anteriorly of a middle-section <NUM> of the U-shape.

The first lead section <NUM> is flexible and has a length that is greater than the distance between the eye <NUM> and the orbital bone <NUM> and, more specifically, a length that is greater than the distance between the incision <NUM> of the eye <NUM> at which the lead <NUM> exits the eye, when the eye is in a forward-facing position, and a point on the orbital bone <NUM> to which the lead <NUM> makes contact as it extends around the orbital bone <NUM>.

During use of the electrical apparatus, the eye <NUM> can rotate. To allow relatively unhindered rotation of the eye <NUM> when the implantable device <NUM> is implanted in the eye <NUM>, the lead flexes and moves. Without the flexing and moving of the lead <NUM>, the lead <NUM> would hinder or prevent movement of the eye <NUM> in one or more rotational directions. Essentially it might fix the position of the eye <NUM> relative to the orbital bone <NUM>. By providing a first lead section <NUM> that is flexible and that has a length that is greater than the distance between the eye <NUM> and the orbital bone <NUM>, the eye can move substantially in all rotational directions. As the eye rotates, depending on the direction of rotation, regions of the first lead section <NUM> collect together (concertina) or extend apart (straighten). By providing the first lead section <NUM> with the pre-formed bend, the amount of force required to cause the first lead section <NUM> to concertina or straighten is significantly lower, reducing discomfort to the patient and/or potential eye damage.

The pre-formed bend of the first lead section <NUM> in the present embodiment is formed subsequent to moulding of the first lead section <NUM>. The first lead section <NUM> comprises the conductors <NUM> embedded in a surrounding cladding layer. The cladding layer is formed of silicone or other polymeric material, such as polyurethane, that is cured during the moulding process. The pre-formed bend is formed using a post-curing technique and specifically by rolling or holding the first lead section about a curved or angled surface while subjecting the first lead section to heating for a period of time. The curved or angled surface is at least part-cylindrical surface and has a radius of curvature of about <NUM> to <NUM> in this embodiment. The heating is conducted at a temperature of about <NUM> for a period of time of about <NUM> minutes, although other curvatures, temperatures and timings can be employed.

In the present embodiment, the second lead section <NUM> includes a reinforcement device <NUM> that provides for a thickening of the second lead section. The reinforcement device <NUM> directs the lead around the orbital bone <NUM> of the eye socket, as shown in <FIG>, and provides protection for the lead and its conductors <NUM> against high stresses at this region. The reinforcement device <NUM> has a bend region <NUM>, a first section <NUM> on the implantable device side of the bend region <NUM>, and a second section <NUM> on the communications interface side of the bend region <NUM>.

The reinforcement device <NUM> is arranged to be attached to the orbital bone <NUM>. For example, the reinforcement device can be located in a notch formed in the orbital bone <NUM> to assist with attachment to the orbital bone <NUM>. The notch can include a recessed groove to receive the reinforcement device <NUM> and an access opening through which the reinforcement device <NUM> is locatable in the recessed groove. The access opening may be narrower than the recessed groove. The reinforcement device may be squeezed through the access opening into the recessed groove where it remains substantially trapped in position at the orbital bone. The point at which the lead extends around the orbital bone <NUM>, at which the notch is located, is lower than a transverse plane extending through the centre of the eye. In a posterior direction, the groove of the notch is angled inferiorly, by about <NUM> degrees.

The reinforcement device <NUM> is formed integrally with the second lead section <NUM> in this embodiment, e.g. by a moulding technique or otherwise, but may be a discrete component in alternative embodiment. For example, in alternative embodiments, the reinforcement device may be clipped to and/or glued in position at the second lead section <NUM>.

The second lead section <NUM> and the reinforcement device <NUM> at the second lead section <NUM> has at least one pre-formed bend configured to conform to the angle of the orbital bone <NUM> such as to navigate the second lead section <NUM> around the orbital bone <NUM>. The pre-formed bend at the second lead section <NUM> is formed through a post-curing technique, e.g., in the same manner that the pre-formed bend of the first lead section <NUM> is formed.

The pre-formed bend of the second lead section <NUM> has a sharper angle than the pre-formed bend of the first lead section <NUM>. In particular, the pre-formed bend of the second lead section <NUM> is a V-shaped bend. In combination, the bends at the first and second lead sections <NUM>, <NUM> provide the lead <NUM> with an S-shaped configuration or more specifically a <NUM>-shaped configuration (i.e. a configuration shaped substantially like the number <NUM>). The bends at the first and second lead sections bend in opposite directions. The bend at the first lead section <NUM> bends in a posterior direction as described above and the bend at the second lead section <NUM> bends in an anterior direction.

With reference to <FIG>, the lead <NUM> has one or more stripes <NUM>, <NUM> extending along the lead <NUM>. The one or more stripes <NUM>, <NUM> assist with placement of the lead <NUM> during implantation of the implantable device <NUM>. Specifically, the stripes <NUM> provide a visual indication to the surgeon implanting the device regarding whether or not the lead <NUM> is twisted. The one or more strips <NUM>, <NUM> extend along at least the first lead section as shown in <FIG>, although they may extend along the entire length of the lead <NUM>. The stripes <NUM>, <NUM> can be formed from a layer of titanium dioxide or other material that has a contrasting colour to adjacent parts of the lead. Two of the stripes <NUM>, <NUM> can be provided, each stripe <NUM>, <NUM> being located at substantially opposite sides of the lead <NUM>.

As indicated above, the electrical apparatus includes an anchor device <NUM>. The anchor device <NUM> is provided to anchor the lead <NUM> at the outer surface of the eye <NUM>, at or adjacent the incision <NUM> in the eye <NUM> through which the lead <NUM> extends, and to route the lead <NUM> away from the eye. The anchor device <NUM> is flexible and formed of polymeric material such a medical grade silicone or polyurethane with a stiffening element embedded at one or more portions therein, such as a mesh, e.g. polyethylene terephthalate mesh (DacronTM mesh). The anchor device <NUM> is in the form of a patch or flap with a preformed shape, e.g. channel <NUM>, that is adapted to receive a portion of the lead <NUM> when it secures the lead <NUM> to the outer surface of the eye <NUM>.

The anchor device <NUM> includes a proximal end portion <NUM> fixed to the lead <NUM> and a distal end portion <NUM> connected to the proximal end portion. Prior to implantation of the implantable device <NUM>, e.g. during the manufacturing process, the anchor device <NUM> is releasably secured in a folded configuration in which the distal end portion <NUM> projects towards the proximal end portion <NUM>, as illustrated in <FIG>. The releasable securing of the anchor device <NUM> in the folded configuration is achieved by providing at least one suture <NUM> to suture the distal end portion <NUM> to the proximal end portion <NUM>, although other releasable fixation means may be employed such as adhesive.

While the anchor device <NUM> is in the folded configuration, the proximal end portion <NUM> may be secured to the outer surface of the eye <NUM>, e.g., using one or more sutures <NUM>.

By releasably securing the anchor device <NUM> in the folded configuration, the distal end portion <NUM> of the anchor device <NUM> can be temporarily held away from the incision <NUM> in the outer surface of the eye <NUM> through which the lead <NUM> exits the eye. Accordingly, the distal end portion <NUM> does not block or obstruct access to the incision <NUM> in the outer surface of the eye <NUM>. By maintaining such access to the incision <NUM> , sutures <NUM> can be applied more easily at the incision <NUM> in the outer surface of the eye <NUM>, e.g. to close up the incision <NUM> (see <FIG>), and/or other treatment can be more easily applied at or adjacent the incision. Once such steps have been completed, the suture <NUM> securing the distal end portion <NUM> to the proximal end portion <NUM> can be released, whereupon the distal end portion <NUM> automatically, or through manipulation, projects away from the proximal end portion <NUM> (see <FIG>). The distal end portion <NUM> can then at least partly cover the incision <NUM> in the outer surface of the eye <NUM>. In general, the anchor device <NUM> can extend over the lead <NUM> and cover at least part or all of the incision <NUM> in the outer surface of the eye <NUM>.

The proximal and/or distal end portions <NUM>, <NUM> of the anchor device <NUM> can be secured to the outer surface of the eye <NUM> using one or more sutures <NUM>, <NUM> or other fixation means. In some embodiments, alternatively or additionally, one or more side portions of the anchor device <NUM> may be securable to the outer surface of the eye <NUM> using one or more sutures or other fixation means.

With reference to <FIG>, any anchor device <NUM>', <NUM>" according to the present disclosure, whether it is folded or otherwise, may include one or more recesses <NUM>', <NUM>", each configured to receive a respective suture knot <NUM>', <NUM>" of sutures <NUM>', <NUM>" used to secure the device to the surface of an eye <NUM>. The recesses <NUM>', <NUM>" may be discrete recesses as shown in the Figures, or otherwise connected together. In the embodiment of <FIG>, for example, the recesses <NUM>' are each provided as depressed portions on the top surface of the anchor device <NUM>', e.g. at side portions of the anchor device <NUM>'. In an alternative embodiment, shown in <FIG>, the recesses <NUM>"are provided on the underside of the anchor device <NUM>", e.g. at side portions of the anchor device <NUM>", to create pockets between the anchor device <NUM>" and the outer surface of the eye <NUM>. In use, once each suture <NUM>', <NUM>" has been tied off, the suture may be rotated to position the suture knot <NUM>', <NUM>" in the respective recess <NUM>', <NUM>". In the embodiment of <FIG>, the suture knot <NUM>' may be pulled through the material of the anchor device to access the pocket.

In general, when secured to the outer surface of the eye <NUM>, the anchor device <NUM>, <NUM>', <NUM>" provide supports and stabilisation for the lead as it extends out of the incision <NUM> in the outer surface of the eye <NUM>. Furthermore, the anchor device shields the incision <NUM> in the outer surface of the eye <NUM>. The anchor device <NUM> also serves to route the lead <NUM> in an appropriate direction away from the anchor device <NUM> and the eye <NUM>, e.g., past extraocular muscles of the eye and towards the lateral orbital rim <NUM>. To achieve this routing, the lead <NUM> at the anchor device follows a bent path.

As discussed above, the implantable device <NUM> according to the present disclosure includes a substrate <NUM> and electrodes <NUM> partially embedded in the substrate <NUM>. The substrate <NUM> is formed primarily of a first, non-conductive material; and the electrodes are formed of a second, conductive material. As will now be described with reference to <FIG>, each electrode <NUM> includes apertures <NUM> through which the first material of the substrate <NUM> at least partially extends to anchor the electrode <NUM> to the substrate <NUM>.

Each electrode <NUM> is substantially flat and with a first surface <NUM> and an opposite second surface. Each electrode <NUM> has a circular disk shape. The first surface <NUM> of the electrode faces away from the substrate <NUM> and is partially exposed from the substrate <NUM> to enable electrical contact with tissue of the eye <NUM>. The second surface of the electrode <NUM> is buried within the substrate <NUM> and specifically the first, non-conductive material of the substrate <NUM>. Each aperture <NUM> of the electrode <NUM> has open ends at the first and second surfaces of the electrode <NUM>.

In this embodiment, a plurality of the apertures <NUM> are provided in each electrode <NUM>, adjacent a peripheral edge of the electrode <NUM>. The apertures <NUM> are uniformly spaced and positioned in a ring pattern adjacent the peripheral edge of the electrode <NUM> and positioned within the outer <NUM> or <NUM>% of the diameter of the electrode <NUM>. Each aperture <NUM> has a diameter that is less than <NUM>% of the diameter of the electrode <NUM>. For example, each aperture may have a diameter of between <NUM> and <NUM>. Each aperture may be circular, although other aperture shapes can be used.

The first, non-conductive material is a flowable polymeric material such as a silicone elastomer or polyurethane that is set during the manufacturing process to form the substrate <NUM>. While in the flowable state, and prior to setting, the first material can flow into each aperture <NUM> to fill the aperture, generally as represented by arrows <NUM> in <FIG>. The first material can extend out of the aperture <NUM> via the open ends of the aperture <NUM>, whereupon the first material can extend transversely to the aperture <NUM> across surfaces of the electrode <NUM>. The first material can form a continuous loop that extends through each aperture <NUM> and around a periphery of the electrode <NUM> and through other apertures <NUM>. Thus, each electrode <NUM> is trapped between portions of the first material, assisting in the anchoring of the electrode <NUM> to the substrate <NUM>.

As shown in <FIG>, the substrate <NUM> provides a lip <NUM> of the first material that extends around the periphery of the first surface <NUM> of each of the electrodes <NUM> to assist with anchoring the electrodes <NUM> to the substrate, while leaving a central region <NUM> of the first surface <NUM> of each electrode <NUM> exposed. In this embodiment, the first material extends through the apertures <NUM> underneath the lip <NUM>. Thus, the apertures <NUM> enhance the function of the lip <NUM> as a means of assisting anchoring of the electrode <NUM> to the substrate <NUM>.

In addition to or as an alternative to providing apertures <NUM> that extend between the first and second opposite surfaces of the electrode <NUM>, at least one aperture may be defined by a projection on the second surface of the electrode. For example, with reference to <FIG>, the second surface <NUM> of an electrode <NUM> can include a projection such a loop, handle and/or hoop <NUM>, the centre of which provides the aperture <NUM> through which first material of the substrate <NUM> extends. The second surface <NUM> of the electrode <NUM> is buried within the substrate. By providing the projection <NUM> at the second surface that defines the aperture <NUM>, the first material of the substrate can extend through the aperture <NUM> when the second surface is buried within the substrate during manufacturing of the device, e.g., while the first material of the substrate is in a flowable state as discussed above. In some embodiments, as illustrated in <FIG>, a plurality of the projections <NUM> can be provided, each defining at least one aperture <NUM>.

The implantable devices of the present disclosure include a plurality of electrodes that can be used to electrically stimulate the eye. In some embodiments, electrical current may be applied to a plurality of the electrodes simultaneously. For example, two or more of the electrodes <NUM>, shown in <FIG>, for example, can be electrically grouped. Electrical current can be applied simultaneously to electrodes of the group. The electrodes of the group can be electrically addressed in parallel or can be ganged together. The simultaneous addressing of the electrodes <NUM> can provide an increased penetration of the electric field into tissue, leading to better efficacy. Moreover, reduced power consumption may be achieved as a result of lower impedances and lower charge required per electrode.

In an alternative embodiment, as shown in <FIG>, an implantable device <NUM> is provided having a flexible substrate <NUM> with a distal end <NUM>, a proximal end <NUM>, a first side <NUM> and a second side <NUM>. The substrate <NUM>, when viewed from above, is substantially rectangular, with curved corners to minimise surgical trauma. The longitudinal direction (length) of the substrate extends between the distal and proximal ends <NUM>, <NUM> and the transverse direction (width) of the substrate extends between the first and second sides <NUM>, <NUM>. The substrate <NUM> includes first and second opposite surfaces <NUM>, <NUM> that each extend between the distal and proximal ends <NUM>, <NUM> and between the first and second sides <NUM>, <NUM>.

Electrodes <NUM> are partially embedded in the substrate, which electrodes <NUM> are used to apply electrical current to tissue of the eye for the purposes of therapeutic stimulation and/or are used to monitor properties of the eye by receiving electrical current from tissue of the eye. In this embodiment, five electrodes <NUM> are provided although other numbers of electrodes may be used. The electrodes <NUM> are exposed at the second surface <NUM> of the substrate. The five electrodes <NUM> are clustered towards the distal end <NUM> of the substrate <NUM> such that, when implanted, the electrodes <NUM> are positioned substantially under the retina. In this embodiment, in the length direction of the substrate, the electrodes are all located in the distal half of the substrate, there being no electrodes located in the proximal half of the substrate.

The length of the substrate <NUM> is between about <NUM> and <NUM>, e.g. about <NUM>, although other lengths are possible. The width of the substrate <NUM> is between about <NUM> and <NUM>, e.g. about <NUM>, although other widths are possible. The electrodes <NUM> are disc-shaped electrodes with circular peripheries, although other shapes are possible. The diameters of the electrodes <NUM> are between about <NUM> and <NUM>, e.g., about <NUM> or <NUM>. The areas of the electrodes are correspondingly between about <NUM><NUM> and <NUM><NUM>, e.g., about <NUM><NUM> or <NUM><NUM>. However, as for the electrodes <NUM> described above, a lip surrounds the electrodes <NUM> such that only a portion of each electrode is exposed from the substrate.

In this embodiment, electrodes of different sizes are provided. A first group of electrodes have a smaller diameter (about <NUM>) than a second group of electrodes (about <NUM>). The first group of electrodes are located distally of the second group of electrodes. The electrodes of the first group may be used as active electrodes and the electrodes of the second group may be used as inactive (return) electrodes. Alternatively, however, all electrodes may be used as active electrodes, and one or more return electrodes may be located elsewhere, including as implanted electrodes or non-implanted electrodes (e.g. electrode needles contacted to skin on the back of the head or neck).

By providing multiple active electrodes and/or inactive electrodes a number of advantages may be achieved. For example, different combinations of active electrodes and/or inactive electrodes may be selected to enable the monitoring or application of electrical signals in different directions (different current vectors). Further, multiple electrodes may be ganged together to increase their effective area while having reduced impedances. Moreover, having additional electrodes allows for redundancy, e.g. in case of failure of one or more of the electrodes or associated electrical components.

In some embodiments, the implantable device may be configured such that at least the first group of electrodes is positioned beneath the retina and close to the central retina without infringing on the central retina. The distance between the first group of electrodes (or the distal-most electrode or electrodes of the first group of electrodes) and the proximal end of the substrate may be configured accordingly to facilitate this positioning. In one example, the length of the substrate <NUM> is <NUM>, the distal-most pair of the first group of electrodes is positioned about <NUM> (e.g. <NUM> in one example) from the distal end of the substrate. The point at which the lead separates from the substrate (indicated for example by dashed line <NUM> in <FIG>), is positioned about <NUM> from the proximal end <NUM> of the device. In this embodiment, the device is configured to be implanted such that the proximal end of the device is positioned about <NUM> from the limbus, thereby to position the distal-most pair of electrodes close to the central retina. The point at which the lead separates from the substrate may be substantially aligned with the incision point.

With reference to <FIG>, in one embodiment of the present disclosure there is provided electroretinography (ERG) apparatus <NUM> for monitoring an eye of a patient and in particular to measure electrical responses of the retina of the eye to a stimulus such as electrical or light stimulation. The apparatus includes implanted components, including an implantable device <NUM> that is implanted between the sclera and choroid layers of the eye and includes one or more electrodes, and an electronics unit <NUM>. The implantable device <NUM> and electronics unit <NUM> may be configured in accordance with, for example, the implantable devices <NUM>, <NUM> and electronics unit <NUM> of any one of the preceding embodiments or otherwise.

The electronics unit <NUM> is configured to amplify low level electrical signals sensed by the one or more electrodes in response to the stimulus (electrical or light stimulation), before transfer of the signals to an external processing device <NUM> of the apparatus. The external processing device <NUM> may be worn by the patient, e.g., on the side of the patient's head, aligned with the electronics unit <NUM>. In this regard, the device <NUM> may be a wearable device. Transfer of the electrical signals to the external processing device <NUM> may be via a wireless connection, e.g. an RF connection, inductive link, or otherwise, which transfers signals through tissue layers at the side of the patient's head or elsewhere, although alternatively a wired or direct connection may be provided. The electronics unit <NUM> may include an implanted inactive (return) electrode. In alternative embodiments, one or more electrodes of the implantable device <NUM> may be employed as inactive electrodes.

The processing device <NUM> may deliver the electrical signals, e.g., by first converting them from a digital to an analogue form, to an ERG system that may be connected via wire or wirelessly to the processing device <NUM>. The ERG system may be a clinical ERG system <NUM> that may be a system that is known in the art, but which is typically intended to receive electrical signals from one or more electrodes located on a surface of the eye, rather than being implanted in the eye. Alternatively, the ERG system may be a system made for specific use with the implantable and wearable components <NUM>, <NUM>, <NUM> of the present disclosure. The ERG system <NUM> may be configured to control a stimulus to the implanted eye, e.g. an electrical or light stimulus. For example, the ERG system may include a controller to control a light, in order to provide for calibrated delivery of flashes in the field of view of the implanted eye. The controller may also control, e.g. trigger, the recording of ERG signals using the implanted components <NUM>, <NUM> through communication with the processing device <NUM>.

The system <NUM> may communicate with a database such as a cloud database <NUM>, which may be include secure access for clinicians 85a and/or secure access for engineers 85b, to enable ERG results to be accessed remotely, e.g. for the purpose of tracking of disease progress or system performance. The ERG system <NUM> may include processing components and may generally be configured to present electroretinograms and/or associated data to a user such as a clinician. The ERG system <NUM> may include a display to display results of ERG testing.

In use, the patient may be seated and eye drops may be applied to the patient's implanted eye to dilate the eye. The patient may be dark-adapted, e.g. for <NUM> minutes, in a dark room. Before or after this process, the processing device <NUM> of the apparatus may be connected to the clinical ERG system <NUM>. Optionally, an electrode is contacted with the patient, e.g. on the forehead skin, if an external inactive electrode is to be used in place of the implanted inactive electrodes described above. The clinical ERG system <NUM> is then used to control electroretinography testing by controlling delivery of light flashes and controlling the recording of ERG signals using the implanted components <NUM>, <NUM> and processing device <NUM>, and receive and present the results of testing. The clinical system may upload raw and processed data to the cloud database <NUM>, e.g. via the internet. A server may be associated with the cloud database that performs further processing of the uploaded data. Clinicians and engineers may access the patient ERG data via the server.

With reference to <FIG>, an electroretinography apparatus <NUM>' for monitoring an eye of a patient and in particular to measure electrical responses of the retina of the eye to stimulus (electrical or light stimulation) is provided, the apparatus being generally in accordance with the apparatus <NUM> described above with reference to <FIG>, and employing components designed specifically for use with the implantable electronic array and electronics unit according to the present disclosure.

With reference to <FIG>, in another embodiment of the present disclosure there is provided electroretinography apparatus <NUM> that is similar to the electroretinography apparatus <NUM> of the embodiment of <FIG>, including the same or similar implanted device <NUM>, electronics unit <NUM>, processing device <NUM>, database <NUM> and clinician and engineer database access points 85a, 85b, but in which the ERG system <NUM> (e.g. the clinical ERG system) is replaced with a mobile ERG system <NUM>.

The mobile ERG system <NUM> includes eyewear <NUM> such as goggles. The eyewear <NUM> is adapted to be worn over the eyes of the patient <NUM> to cover the eyes (and part of the face) of the patient <NUM>, as illustrated in <FIG>, placing the eyes in complete or almost complete darkness. When worn, the eyewear <NUM> defines a dark inner chamber, located between inner walls of the eyewear and the patient's face and eyes. Accordingly, the eyewear <NUM> can enable a patient to be dark-adapted without necessarily requiring the patient to be located in a dark room.

In this embodiment, the processing device <NUM> is configured to locate at the side of the head of the patient <NUM> in order to align with the implanted electronics unit <NUM>. The processing device <NUM> may, for example, be conveniently positioned on a headband <NUM> of the eyewear <NUM> to achieve the alignment.

In this embodiment, the eyewear <NUM> include a light <NUM>, e.g. an LED, and a controller <NUM> adapted to control flashing of the light <NUM>. The light <NUM> is located in or adjacent to the internal chamber of the eyewear <NUM> so that flashes of the light are presented within the internal chamber and therefore within the field of view of the patient's implanted eye.

In this embodiment, the controller <NUM> is also adapted to control, e.g. trigger, the recording of ERG signals using implanted components <NUM>, <NUM> and processing device <NUM>. The controller <NUM> is also adapted to communicate, e.g. wirelessly, with a mobile computing device <NUM>, e.g. an app-based computing device such as a Smartphone or tablet. In alternative embodiments, the controller <NUM> may be comprised at least partially in the mobile computing device <NUM>. The mobile computing device <NUM> may generally be configured to present electroretinograms and/or associated data, to a user such as a clinician. The mobile computing device may include a display to display results of ERG testing.

In use, the patient may be seated and eye drops may be applied to the patient's implanted eye to dilate the eye. The patient may don the eyewear and be dark-adapted, using the eyewear, e.g. for <NUM> minutes. The eyewear may include a speaker or headphones <NUM> that play music or other audio recordings to the patient while the patient is dark-adapted. Additionally or alternatively, the speaker or headphones <NUM> may be used to provide instructions for use of the apparatus <NUM>.

Once dark-adapted, the patient or clinician may start the ERG recording process, e.g. by pressing a button <NUM> or interacting with another interface on the eyewear <NUM>, or pressing a button or interacting with another an interface of the mobile computing device <NUM>. The mobile ERG system <NUM> is then used to control electroretinography testing by controlling delivery of light flashes using the light <NUM> and controlling the recording of ERG signals using the implanted components <NUM>, <NUM> and processing device <NUM>. The results of testing are provided, e.g. wirelessly, to the mobile computing device <NUM>, which can present electroretinograms and/or associated data to a user. The mobile computing device <NUM> may upload raw and processed data to the cloud database <NUM>, e.g. via the internet. A server <NUM> may be associated with the cloud database that performs further processing of the uploaded data. Clinicians or engineer may access the patient ERG data via the server <NUM>.

ERG systems according to embodiments of the present disclosure, such as the mobile ERG system, may be particularly suited, for example, to home use or in clinics that do not have access to conventional, typically larger, ERG systems. This is made possible in part by use of electrodes that are pre-implanted in the eye, and do not need to be applied to the eye at the time of ERG testing. Therefore, lower-skilled clinicians may be employed to carry out the testing. Moreover, because the electrodes are implanted, the eyewear may be applied around the eyes of the patient without risk of disturbing the electrodes.

With reference to the sixth example study below, ERG apparatus according to embodiments of the present disclosure (e.g. as discussed above with reference to <FIG>) may take advantage of an occurrence identified herein, that the polarity of ERG response signals, e.g. the polarity of ERG waveforms, that are recorded using the one or more implanted electrodes, can change depending on the location of the electrodes.

For example, apparatus <NUM>, <NUM>'or <NUM>' having an implantable device with one or more electrodes as described above or otherwise may be used to: deliver stimulus to the patient's eye; measure an ERG response signal received at the one or more implanted electrodes resulting from the stimulus; and determine the location, or a change in location, of the one or more electrodes based on the polarity of the ERG response signal. For example, in some embodiments, a location of the electrode may be determined by: positioning the one or more electrodes at different locations in the eye; at each of the different locations, delivering stimulus to the patient's eye and measuring an ERG response signal received at the one or more electrodes resulting from the stimulus; identifying the polarities of the ERG response signals received at the different locations; identifying a difference between the polarities of the ERG response signals identified at two of the different locations; and determining a location of the one or more electrodes based on the difference in polarity occurring between the two of the different locations.

As evident from the sixth example study, the location where the polarity changes may be determined as a location beneath the retina of the patient's eye. In this regard, electrode locations to a side of the retina (e.g., beneath or anterior of the pars plana of the eye) may give rise to an ERG response signal having a first polarity, but when moved to an electrode location beneath the retina this may give rise to an opposite polarity of the ERG response signal.

In some embodiments, a change in location of the electrode may be determined by: delivering a first stimulus to the patient's eye; measuring a first ERG response signal received at the one or more electrodes resulting from the first stimulus; optionally delivering a second stimulus to the patient's eye; measuring a second ERG response signal received at the one or more electrodes resulting from the first stimulus (or second stimulus if used); comparing the polarities of the first and second ERG response signals; and determining a change in location of the one or more electrodes if the identified polarity of the first ERG response signal is different from the identified polarity of the second ERG response signal.

In some embodiments, the change in the location of the one or more electrodes may be identified as a change from the one or more electrodes being located beneath the retina of the patient's eye to the one or more electrodes being located to a side of the retina (e.g., beneath or anterior of the pars plana of the eye), or vice-versa.

In some embodiments, the determining of the location or change in location of the electrodes may be used to determine the location or change in location of the implantable device that comprises the electrodes.

In some embodiments, the apparatus may provide an indication of the determined location or change in location, of the one or more electrodes (and/or of an implantable device that includes the one or more electrodes), to a user, e.g. through display of corresponding information on a display screen.

In all embodiments described herein, because electrodes are implanted, anaesthesia may not be required during use. Still further, increased amplitude ERG recordings may be obtained due to the suprachoroidal positioning closer to the retina. Moreover, the suprachoroidal position may be particularly stable and biocompatible, without being prone to causing sub conjunctive erosion, for example.

Any controller or processing device used in the present disclosure may comprise one or more processors and data storage devices (computer readable media). The one or more processors may each comprise one or more processing modules and the one or more storage devices may each comprise one or more storage elements. The modules and storage elements may be at one site, e.g. in a single clinical ERG system, a single mobile computing device, etc., or distributed across multiple sites and interconnected by a communications network such as the internet.

The processing modules can be implemented by a computer program or program code comprising program instructions. The computer program instructions can include source code, object code, machine code or any other stored data that is operable to cause a processor to perform the methods described. The computer program can be written in any form of programming language, including compiled or interpreted languages and can be deployed in any form, including as a stand-alone program or as a module, component, subroutine or other unit suitable for use in a computing environment. The data storage devices may include suitable computer readable media such as volatile (e.g. RAM) and/or non-volatile (e.g. ROM, disk) memory or otherwise.

Suprachoroidal therapeutic stimulation was tested using a genetically modified rat model of retinal degeneration (P23H-<NUM> retinal degeneration rats), which very closely mimics the human condition. The rats were divided into <NUM> groups of control (n = <NUM>), passive (n = <NUM>) and active stimulation (n = <NUM>). Animals in the passive and active stimulation groups had a platinum electrode implanted in one eye of each animal at <NUM> weeks of age. Animals in the passive group did not receive the stimulation. Animals in the active stimulation group received <NUM> hour of chronic micro-electrical stimulation (100µA, <NUM> (pulse per second)) twice per week for <NUM> weeks (equating to roughly <NUM> human years). Full-field electroretinography (ERG) was performed at <NUM>- (baseline) and <NUM>- (post-treatment) weeks of age as a surrogate measure of photoreceptor survival. The ERG responses of the <NUM> study groups were compared to determine the effect of electrical stimulation on photoreceptor survival.

With reference to <FIG>, the control (non-stimulated) eyes lost significant retinal function. However, retinal function was preserved in the active (stimulated) eyes. Retinal function was also lost in passive (sham) treated eyes.

With reference to <FIG>, histological analysis of outer nuclear layer (ONL) thickness revealed that photoreceptors were preserved in the stimulated eyes, the ONL containing cell bodies of the photoreceptors. The ONL was thicker in the stimulated eye compared to the non-stimulated eye, suggesting that suprachoroidal electrical stimulation preserves photoreceptor survival.

In the active stimulation group, it was further found that the ERG a-wave response amplitude at <NUM> weeks of age was slightly reduced in the stimulated eyes (<NUM> ± <NUM>, p=<NUM>) but markedly reduced in the non-stimulated fellow eyes (<NUM> ± <NUM>, p<<NUM>), compared to the baseline value at <NUM> weeks of age (<NUM> ± <NUM>). The ERG a-wave amplitude of both eyes in the control and passive groups were markedly reduced at <NUM> weeks of age compared to the baseline value (p<<NUM>). Furthermore, the magnitude of ERG a-wave amplitude reduction in the control and passive groups was similar to that of the non-stimulated fellow eyes of the active stimulation.

Overall, chronic low-level electrical stimulation using a fully implanted electrode in the P23H-<NUM> rat model of retinal degeneration preserved photoreceptor function, including when micro-electrical stimulation was applied suprachoroidally at a 'dosage' of about twice per week for <NUM> weeks.

Suprachoroidal therapeutic stimulation was tested using a genetically modified rat model of retinal degeneration (P23H-<NUM> retinal degeneration rats), which very closely mimics the human condition. The rats were divided into <NUM> groups of control (n = <NUM>), passive (n = <NUM>) and active stimulation (n = <NUM>). Animals in the passive and active stimulation groups had a platinum electrode implanted in the right eye of each animal at <NUM> weeks of age. Animals in the passive group did not receive the stimulation. Animals in the active stimulation group received <NUM> hour of chronic micro-electrical stimulation (95µA, <NUM> (pulse per second), five times per week for <NUM> weeks. Full-field electroretinography (ERG) was performed at <NUM>, <NUM>, <NUM>, <NUM> and <NUM> weeks of age as a surrogate measure of photoreceptor survival. The ERG responses of the <NUM> study groups were compared to determine the effect of electrical stimulation on photoreceptor survival.

ERG data from the control animals showed, as expected, a gradual decline in photoreceptor function (decreased ERG a-wave amplitude) over the course of the study (<FIG>). On average, there was approximately <NUM>% reduction in ERG response after a period of <NUM> weeks.

The ERG a-wave amplitudes of the eye at various time points for the <NUM> study groups are shown in <FIG>. In the control group, the ERG a-wave response gradually declined over time. In the passive group, the ERG response was reduced at <NUM> weeks from the baseline and then remained relatively unchanged thereafter. At the end of the study (<NUM> weeks from baseline) the ERG a-wave response of the passive group was similar to that of the control. In the active group, there was a significant reduction (P<<NUM>) in the ERG response at <NUM> weeks from the baseline and a further reduction in ERG response at weeks <NUM> and <NUM>. The ERG responses at weeks <NUM> and <NUM> were significantly smaller than that of the control and passive groups (P<<NUM>).

The ERG response of the fellow (left) eye at various time points for the <NUM> study groups are shown in <FIG>. A marked reduction in the ERG a-wave amplitude at <NUM> weeks was noted in the passive and more so in the active group. However, the rate of change in the ERG a-wave amplitude for the control and active groups was similar after <NUM> weeks from the baseline. There was an increase in the ERG a-wave amplitude in the passive group at weeks <NUM> and <NUM>. Inspection of the individual response from this group indicated that this increase in ERG a-wave response was driven by the data from the <NUM> animals. When these data were removed the average ERG a-wave amplitude of the passive group was similar to that of the control and active groups. This suggests that the apparent increase in the ERG a-wave response in the passive group at weeks <NUM> and <NUM> is likely to be outliers.

To further examine the safety and efficacy of <NUM> treatment sessions per week on photoreceptor function the ERG data were analysed by eye for each study group (<FIG>). In the control group, the ERG responses of the <NUM> eyes were similar, except for the <NUM> week time point. In the passive group, the ERG responses of the right eye were similar to that of the control. The response from the left eye was generally greater than that of the right eye. The increase in the ERG response at weeks <NUM> and <NUM> were driven by the data from the <NUM> animals. When these data were excluded the average ERG response of the left eye at weeks <NUM> and <NUM> were similar to that of the right eye. In the active group, the ERG response of the right eye was significantly (p<<NUM>) smaller than that of the fellow (left) eye, particularly at weeks <NUM>, <NUM> and <NUM>. The ERG response of the right eye in the active group was also significantly (p<<NUM>) smaller than that of the other groups at ERG a-wave amplitude (µV).

The study indicated that stimulation treatment <NUM> times per week was associated with a small but significant reduction in the ERG a-wave response comparable to sham and naive controls. This initially indicated that the treatment regime of <NUM> hour per day, <NUM> days a week does not slow the photoreceptor degeneration in the P23His-<NUM> model and that, in consideration of the previous study, treatment of less than <NUM> times a week, e.g. between about <NUM> and about <NUM> times a week, or between about <NUM> and <NUM> times a week could have been preferable. However, it has subsequently been identified that retinal trauma caused by the rat-specific nature of the experimental implant and surgery may have led to premature retinal degeneration and therefore a conclusion regarding maximum dosage interval cannot be drawn based on this particular study.

Suprachoroidal therapeutic stimulation was tested on multiple human subjects using an implanted device including multiple implanted electrodes. After implantation, testing was carried out following a one-month period of recovery. Different combinations of electrodes positioned substantially beneath the retina, at the periphery of the retina, were tested to determine average charge activation thresholds where a visual percept was elicited in the patient, upon gradually increasing the charge levels. Thresholds were detected in a range of: charge: ~<NUM>-150nC per electrode (or ~300nC per pair of electrodes); charge density: ~<NUM> - <NUM>µC. cm<NUM> (platinum electrodes); rate: <NUM> pulses per second. Equivalent energy levels for different pulse rates can be inferred. The lower end of the charge range took into account the likelihood that early stage Retinitis Pigmentosa patients will have lower thresholds for activating their retinae.

An upper limit to charge levels was considered based on a normal-sighted cat model. With reference to <FIG>, histopathology based indicators of stimulus-based injury and tissue reaction were considered for different electrical stimuli delivered to pairs of active electrodes as set forth in Table <NUM> below.

From this study, stimulus of: charge: ~<NUM> nC per electrode (or 500nC per pair of electrodes); charge density: ~<NUM>µC. cm2 (platinum electrodes); and rate: <NUM> Pulses per pulses per second, can be determined as representing an example stimulation "limit", above which a risk of an acute or chronic inflammatory response, histiocytic changes or morphological changes, to the eye, resulting from the stimulation, becomes unacceptable. Equivalent energy levels for different pulse rates can be inferred.

Electrodes were suprachoroidally implanted in an eye to record full field flash evoked ERG responses. A comparison of this ("TEST") was made simultaneously with conventional ERG recordings employing corneal electrodes. With reference to <FIG>, the implanted electrodes provided stable recordings over time, the recordings being longitudinally robust and less variable than conventional ERG.

Normally-sighted adult cats (felis catus) were surgically implanted with an implantable device comprising electrodes, and percutaneous cable, in their left suprachoroidal location. The implantable device included <NUM> platinum disc electrodes and was generally configured in accordance with the implantable device <NUM> described above with reference to <FIG>, the electrodes being partially embedded within a flexible silicone substrate.

After wound healing, the subjects were assessed with clinical electroretinography (ERG). Recording of full-field ERG was performed using an Espion E2 system (Diagnosys LLC, Lowell, MA, USA) after <NUM> minutes of dark adaptation. ERG was recorded simultaneously from the implanted eye using (a) the implanted electrodes as the active input and (b) conventional, corneal-contact lens electrodes as the active input. A stainless-steel needle (Terumo <NUM>) at the neck was used as the negative electrode for both the implanted and conventional set-ups and another grounding needle in the subject's flank.

The retinal responses to scotopic (dim) and photopic (bright) light flash luminance levels (<NUM> - <NUM> cd. m-<NUM>) were recorded; however, only the combined rod-cone maximal ERG response (<NUM> cd. m-<NUM>) is reported here as this ERG response provides information on the functional integrity of both the outer retina photoreceptors (a-wave) and mid retina bipolar cells (b-wave). The responses from both the implanted and conventional set-ups were cleaned and plotted according to ISCEV standards: international society for clinical electrophysiology of vision.

Referring to <FIG>, which show raw data traces, use of the suprachoroidally implanted electrode apparatus according to the present disclosure provided increased (magnitude) amplitude for both the negative A-wave and the positive B-wave, in comparison to conventional corneal-contact lens electrode apparatus. The timing did not appear to be any different; this was expected as the location of the electrodes should not affect the signal latency based on the very small signal transmission distances.

<FIG>, which show cleaned amplitude and latency, also indicate that use of the apparatus according to the present disclosure provides increased (magnitude) amplitudes for both the negative A-wave and the positive B-wave, in comparison to the conventional apparatus. In addition, with the exception of one potential outlier in <FIG> and two potential outliers in <FIG>, it appears that the spread of responses along the amplitude dimension is lower for apparatus according to the present disclosure than for conventional apparatus.

<FIG> and <FIG>, which show A-wave latency (implicit time) and B-wave latency (implicit time), respectively, again indicate that use of the apparatus according to the present disclosure has no effect on timing of signals in comparison to the conventional apparatus.

<FIG>, which compare the means and <NUM>% confidence intervals, of A-wave amplitude and B-wave amplitude measurements respectively, support the hypothesis that use of the apparatus according to the present disclosure provides no significant difference in signal latency.

<FIG>, which compare the means and <NUM>% confidence intervals of A-wave latency (implicit time) and B-wave latency (implicit time) measurements respectively, support the hypothesis that use of from electroretinograms obtained using conventional ERG apparatus and using electrical apparatus according to the present disclosure.

The study indicated that the use of suprachoroidally implanted electrode apparatus provided for stronger ERG data than conventional corneal electrode apparatus, without affecting signal latency.

ERG recordings were made using three different test variants: variant "A" in which a commercial ERG (Espion™) system was used, that employed a conventional contact lens electrode and conventional signal and delivery recording apparatus; variant "B" in which a suprachoroidally implanted electrode device according to the present disclosure was used (similar to the device illustrated in <FIG>) in combination with the conventional (Espion™) signal and delivery recording apparatus; and variant "C" in which a suprachoroidally implanted electrode device according to the present disclosure was used (similar to the device illustrated in <FIG>) in combination with signal and delivery recording apparatus according to the present disclosure (similar to the apparatus illustrated in <FIG>).

ERG waveforms recorded under variant C and variant A are illustrated in the graphs of <FIG>, respectively. Under each variant, waveforms were recorded at different flash intensities (measured as average flash intensity in units of cd. The polarity of certain waveforms for variant C were inverted to enable comparison. The graphs show that there is generally increased waveform amplitude and decreased latency in peak signals at higher flash intensities. Moreover, this study shows that suprachoroidally implanted electrode apparatus provides for strong ERG data as per the conventional electrode apparatus, without affecting signal latency.

ERG waveforms recorded under variant A, B and C are illustrated in the graph of <FIG>. For each variant, waveforms were recorded at the same flash intensity. The polarity of waveforms for variants B and C were inverted to enable comparison. In this instance, while there is a difference in amplitude between the waveforms, it was considered attributable to filter settings of the recording apparatus used.

<FIG> show, respectively, A-wave amplitudes from ERG recordings obtained using the commercially available system (variant A; <FIG>) and using apparatus according to the present disclosure (variant B; <FIG>). Recordings were taken after successive <NUM>-month periods and from seven different subjects.

Under variant B, subjects <NUM> and <NUM> (S1, S5) were implanted with a relatively short implantable device ("short device"; approximately <NUM> long), with three ganged active electrodes of the implantable device being positioned at a distance of about <NUM> distally from the proximal end of the implantable device and about <NUM>. <NUM> from the limbus. Under variant B, subjects <NUM>, <NUM>, <NUM>, <NUM> and <NUM> (S2, S3, S4, S6, S7) were implanted with a relatively long implantable device ("mid device", approximately <NUM> long), with three ganged active electrodes of the implantable device being positioned at a distance of about <NUM> distally from the proximal end of the implantable device and about <NUM> from the limbus. As a result, the active electrodes for subjects <NUM>, <NUM>, <NUM>, <NUM> and <NUM> were located at the periphery of the retina, and closer to the central retina (beneath the retina without infringing on the central retina) in comparison to the active electrodes for subjects <NUM> and <NUM>.

The graphs of <FIG> indicate that, following an initial settling period, ERG recordings used apparatus according to the present disclosure (variant B) are more consistent than those made with conventional contact lens electrodes (variant A). Notably, the recordings were all made in normal-sighted subjects with no expected photoreceptor deterioration.

The graph of <FIG> also indicates that different locations of the implanted electrodes give rise to different polarities in the ERG recordings, including the A-wave peaks. This was also evident from the inversions required to ERG waveforms present in graphs as discussed above. For the subjects implanted with the "mid device", having electrodes beneath the retina, more positive A-wave amplitudes are seen while, for the subjects implanted with the "short device", having electrodes spaced further from the retina, more negative A-wave amplitudes are seen.

For subject <NUM> (S2), there was some initial array movement during the settling period (when the active electrodes were located closer to the incision). However, for subject <NUM>, the ERG amplitude became negative at subsequent <NUM>-month periods. This is consistent with the hypothesis that there is a relationship between the Anterior-Posterior location of the tip of the implantable device and the waveform polarity. Post <NUM>-month implantation, in the ultimate resting location of subject <NUM>'s implantable device, the electrodes would have been close to the threshold position of polarity inversion and thus the resulting vector-summation of the A-wave amplitude was closer to zero. The ERG waveform is the summation of the retina's neural activity. The polarity of the waveform shifts from the "normal" state (that which is obtained using a conventional corneal contact lens recording electrode as the positive terminal) to an "inverted" state as the recording site is advanced posteriorly (behind the retina). A "normal" polarity waveform is characterised by an A-wave with a negative amplitude. As indicated, the "short devices" returned "normal" polarity waveforms, but the "mid devices" returned "inverted polarity" waveforms.

In view of the Example <NUM> study it is identified herein that apparatus according to the present disclosure may assist in a surgical procedure, e.g. to assist in identifying when one or more implanted electrodes have reached a desired location in the eye relative to the retina, e.g. when they have reached a positioned behind the retina, which may be a desirable position to monitor ERG recordings and/or deliver stimulation to the retina or otherwise. In some embodiments, the location of the one or more electrodes may be determined substantially in real time during a surgical procedure. Additionally or alternatively, in some embodiments the apparatus may be used to identify if the one or more electrodes have moved, e.g. undesirably, from an intended implantable location relative to the retina, e.g. moved away from a position behind the retina. Such movement may occur over a period of time after initial surgical implantation and the apparatus according to the present disclosure may therefore provide a means for detection of such movement.

In some embodiments, the determining of the location, or a change in location, of the one or more electrodes relative to the retina of the eye may also be based on amplitude of the ERG signal. When the amplitude is identified as relatively low or lower than amplitudes of other ERG signals, for example, it may be determined that the one or more electrodes are located at a position close to or closer to a threshold location for polarity inversion (the lower amplitude resulting from a vector-summation of different polarity amplitudes).

Claim 1:
An electrical stimulation apparatus for delivering therapeutic electrical stimulation to an eye of a patient, the apparatus comprising:
an implantable device (<NUM>, <NUM>, <NUM>) comprising:
an elongate substrate (<NUM>) having a distal end (<NUM>) , and a proximal end (<NUM>) ; and
one or more electrodes (<NUM>, <NUM>) located in or on the substrate; and
a lead (<NUM>, <NUM>, <NUM>) through which conductors ( <NUM>, <NUM>) extend from the implantable device, the conductors being connected to the one or more electrodes, the lead being configured to extend from the substrate at a point at or adjacent to the proximal end of the substrate and through an incision in the surface of the eye,
wherein the implantable device is configured for implanting in a suprachoroidal space between the sclera (<NUM>) and choroid (<NUM>) layers of the eye, wherein the substrate is configured for insertion, distal end (<NUM>) first, via the incision in the eye (<NUM>) to a stimulation position between the sclera and choroid layers of the eye, wherein, at the stimulation position, the one or more electrodes (<NUM>, <NUM>) are configured for delivering electrical stimulation to the eye;
characterized in that:
a length of the substrate of the implantable device is configured so that, when implanted at the stimulation position, one or more distal-most electrodes of the one or more electrodes (<NUM>, <NUM>) is located at a position beneath the retina of the eye, the substrate (<NUM>) is not positioned beneath, and the one or more electrodes (<NUM>, <NUM>) do not infringe on, the central retina of the eye, the length of the substrate (<NUM>), in a longitudinal direction of the substrate extending between the distal (<NUM>) and proximal (<NUM>) ends of the substrate, is between <NUM> and <NUM>.