Device for treatment of degenerative retinal disease via electrical stimulation of surface stuctures of the eyeball

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SPANISH OFFICE OF

PATENTS AND TRADEMARKS

SPAIN lllllllllllllllllllllllllllllllllllllllllll © Publication number: 2 385 809 © Int. Cl .:

A61N 1/36 (2006.01) © TRANSLATION OF A MODIFIED EUROPEAN PATENT T5

AFTER OPPOSITION @ Date of submission and number of the international application: 10.06.2004 PCT / US2004 / 018606 © Date and number of international publication: 20.01.2005 W005004985 (je) Date of submission and number of the European application: 10.06.2004 E 04755009 (0) © Date and publication number of the European concession modified after opposition: 02.20.2019 EP 1635906 © Title: Device for treating degenerative diseases of the retina by electrical stimulation of superficial structures of the eyeball © Priority:

24.06.2003 US 606117

09.06.2004 US 863519 © Date of publication and mention in BOPI of the translation of the modified patent: 09.10.2019 © Owner / s:

PIXIUM VISION SA (100.0%)

Institut de la Visión, 13, rue Moreau 75012 Paris, FR © Inventor / es:

CHOW, ALAN Y.

@ Agent / Representative:

AZNÁREZ URBIETA, Pablo

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DESCRIPTION

Device for treating degenerative diseases of the retina by electrical stimulation of superficial structures of the eyeball

FIELD OF THE INVENTION

The present invention relates to the treatment of degenerative diseases of the retina and, in particular, to apparatus for treating them based on external electrical stimulation.

BACKGROUND

Many diseases of the human retina cause loss of vision due to partial or complete destruction of the vascular layers of the eye, including the choroid and choriocapillary, which nourish both the external anatomical retina and a part of the internal anatomical retina of the eye.

Many other retinal diseases cause loss of vision due to a partial or complete degeneration of one or both anatomical retinal layers directly, due to abnormalities inherent in these layers. Components of the retinal layers include Bruch's membrane and retinal pigment epithelium, which consist of the external anatomical retinal layer, as well as the external and internal photosensitive segments and the external nuclear, external plexiform, internal nuclear, internal plexiform layers , of amacrine cells, ganglion cells and nerve fibers, which consist of the internal anatomical retinal layer, also known as the neuroretin. The external part of the neuroretin consists of the external and internal photosensitive segments and the external nuclear layer (cell bodies of the photoreceptors) and is also known as the external retina, which must be distinguished from the external anatomical retinal layer as defined above. . The loss of function of the external retina is generally the result of a dysfunction of the external anatomical retinal layer, which provides nutrition to the external retina, and / or directly from defects of the external resin itself. However, the final common result is dysfunction of the external retina that contains the light-sensitive cells, the photoreceptors. Some of these external retinal diseases include age-related macular degeneration, pigmentary retinitis, choroidal disease, late retinal detachment, diabetic retinopathies, Stargardt's disease, choroideremia, Best's disease and The choroid rupture. However, it is common for the internal part of the neuroretin to remain quite intact from the functional and anatomical point of view and can be activated by appropriate stimuli.

Although some researchers have reported attempts to restore visual function in humans by transplanting various retinal cells and retinal donor layers into the subretinal recipient space, the medical community has not widely recognized any continuous visual improvement in such receptors.

Multiple methods and devices for producing a prosthetic artificial vision based on the structured electrical stimulation of the neuroretin in contact with, or very close to, the source of electrical stimulation are already known. As a general rule, these devices employ series of stimulation electrodes powered by photodiodes or microfotodiodes arranged on the epiretinal side (the surface of the retina that faces the vitreous cavity) on the subretinal side (the lower side) of the neuroretin. For example, Chow et al. described various designs for implants to be inserted into the subretinal space, that is, the space created between the internal and external retinal layers, in US Pat. No. 5,016,633; 5,024,223; 5,397,350; 5,556,423; 5,895,415; 6,230,057; 6,389,317 and 6,427,087. As a general rule, the implants described in these patents are brought into contact with the photosensitive layer of the internal retina so that the electrodes in the implants can supply stimulation currents, derived from the photovoltaic conversion of the incident light, to the internal retina. In several of these patents, for example US patents No. 5,016,633; 5,024,223 and 6,389,317, techniques and devices for inserting such implants into the subretinal space are further described.

US 2003/0014089 A1 describes methods to improve damaged cellular functions where a retinal stimulation device is disposed that includes a plurality of electrodes in the subtinean space of the eye or is implanted between the conjunctiva and the sclera surface.

WO 99/45870 A1 describes a visual prosthesis that includes an electrode arrangement and a decoder and demultiplexer circuitry, where the electrode arrangement is disposed on the retina and the circuitry is disposed on an outer surface of the sclera.

WO 01/83026 A1 describes an artificial retinal device with stimulation and ground return electrodes arranged on opposite sides of the neuroretin, where a ground return electrode may be disposed on the sclera surface on the outside of an eye.

Cellular electrical signals also play an important developmental role, allowing nerve cells to develop and function properly. For example, nerve cells undergo constant remodeling or arborization related to electrical signals during development. First a network is formed

ES 2 385 809 T5 extensive preliminary, which is then pruned and refined by mechanisms including cell death, selective growth, loss of neurites (axonal and dendritic extensions) and stabilization and elimination of synapses (Neely and Nicholls , nineteen ninety five). If a transduction of normal electrical activity during arborization has been inhibited or is no longer present in a neuron, axons no longer retract branches that have grown to inappropriate positions.

It is known that the application of electrical currents to organ systems other than the eye promotes and maintains certain cellular functions, including bone growth, spinal cord growth and preservation of cochlear spiral ganglion cells (Acheson et al., 1991; Dooley et al., 1978; Evans et al., 2001; Kane, 1988; Koyama et al., 1997; Lagey et al., 1986; Leake et al., 1991; Leake et al., 1999; Politis and Zanakis, 1988a; Politis and Zanakis, 1988b; Politis and Zanakis, 1989; Politis et al., 1988a; Politis et al., 1988b).

Other studies found that the application of growth factors and neurotrophic type promotes and maintains certain retinal cell functions. For example it has been shown that the neurotrophic factor obtained from the brain (BDNF), neurotrophin-4 (NT-4), neurotrophin-5 (NT-5), fibroblast growth factor (FGF) and the neurotrophic factor obtained from The glial cell line (GDNF) improves the neuritic extension of retinal ganglion cells and increases their survival in cell cultures. It has been shown that GDNF preserves cane photoreceptors in the rd / rd mouse, an animal model of retinal degeneration. Nerve growth factor (NGF) injected into the intraocular area of ​​the C3H mouse, also a model of retinal degeneration, results in a significant increase in surviving photosensitive cells compared to controls (Bosco and Linden, 1999; Caleo et al ., 1999; Carmignoto et al., 1989; Cui et al., 1998; Frasson et al., 1999; Lambíase and Aloe, 1996; Reh et al., 1996). However, no methods or devices are known to improve the overall inherent visual function of damaged retinal cells distant from a source of electrical stimulation, through the use of chronic electrical stimulation applied to the neuroretin, either from within the eye or indirectly, to through contact with superficial structures of the eye.

Other examples of known devices for the treatment of degenerative diseases of the retina are described in US Patent No. 5,109,846 A and US Patent Application Publication No. 2003/014089 A1. Other similar devices are described in European Patent Application Publication No. EP 1 723 984 and International Patent Application Publication No. WO 2004/067088, both of which are published after this application.

BRIEF SUMMARY OF THE INVENTION

The present invention provides devices for the preventive or therapeutic treatment of degenerative diseases of the retina by the application of electrical stimulation. In particular, the present invention affects the use for such treatment of electrical stimulation applied to surface structures of an eyeball, the surface structures being disposed subsequently to the bulbar conjunctiva and comprising the various sheets starting with the sclera as the innermost surface structure and Its overlapping structures. In general, this is achieved with a device comprising a source of an electrical stimulation signal coupled to a first electrode, configured for contact with a first internal surface structure of an eyeball, and a second electrode configured for contact with a second superficial structure of the eyeball, said second external or internal surface structure being able to be. The superficial structures of the eyeball can be classified either as external surface structures (for example the conjunctiva and the cornea) or as internal surface structures (for example the sclera, the episclera, the intramuscular septum, the Tenon capsule, the muscles or tendons extraocular, etc.) The source of the electrical stimulation signal can be implemented internally in a patient's body, externally to the body or by a combined internal / external approach. The source comprises an internal source component that has a subcutaneously implanted receiver induction coil and also comprises an external source component that has a transmission coil configured to transmit data and power. According to various embodiments of the present invention, the electrodes may be arranged in one or more annular formations, including interleaved electrodes. The electrodes are preferably arranged so that a circuit formed by the source, the electrodes and the intermediate biological tissue provides a transretinal electrical stimulation in order to effect the treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a cross-sectional top view of a human eye.

FIGURE 2 is a cross section through a human eye, according to the detail of Figure 1, in which the layers of the external and internal anatomical retina are indicated.

FIGURE 3 is a schematic block diagram of a prior state of the art for indirect electrical stimulation.

FIGURE 4 is a schematic block diagram of another prior state of the art for indirect electrical stimulation.

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FIGURE 5 is a schematic block diagram of another prior state of the art for indirect electrical stimulation.

FIGURE 6 is a schematic block diagram of a technique for indirect electrical stimulation according to the present invention.

FIGURE 7 is a schematic block diagram of another technique for indirect electrical stimulation in accordance with the present invention.

FIGURE 8 is a partial cross-sectional side view of a human eye and surrounding structures.

FIGURE 9 is an enlarged partial cross-sectional view of an area of ​​the eye illustrated in FIGURE 8.

FIGURE 10 is a side view of a human eye, illustrating the application of a corneal electrode in accordance with an embodiment of the present invention.

FIGURE 11 is a side view of a human eye, illustrating the application of an epiconjunctival electrode according to an embodiment of the present invention.

FIGURE 12 is a side view of a human eye, illustrating the application of a fiber electrode in a conjunctival fornix according to an embodiment of the present invention.

FIGURE 13 is a side view of a human eye, illustrating the application of a plurality of series of electrodes applied to an internal surface structure according to an embodiment of the present invention.

FIGURE 14 is a side view of a human eye, illustrating the application of a series of electrodes to an internal surface structure according to an embodiment of the present invention.

FIGURE 15 is a schematic block diagram of an internal surface structure / internal surface structure technique for indirect electrical stimulation in accordance with the present invention.

FIGURE 16 is a schematic block diagram of an internal surface structure / external surface structure technique for indirect electrical stimulation in accordance with the present invention.

FIGURE 17 is a top view of a human eye, illustrating an example of implementation of the embodiment of FIGURE 15.

FIGURE 18 is a top view of a human eye, illustrating a first example of implementation of the embodiment of FIGURE 16 that is not part of the invention.

FIGURE 19 is a top view of a human eye, illustrating a second implementation of the embodiment of FIGURE 16, which is not part of the invention.

DETAILED DESCRIPTION OF THE CURRENTLY PREFERRED EMBODIMENTS

In the course of some trials concerning the safety and efficacy of retinal implants in blind humans as a result of pigmentary retinitis, something unexpected and surprising was observed: although the implants were placed in a specific place in the subretinal space (functioning as a prosthesis ), vision improved not only in these specific places, as expected, but also in places distant from the retina. Thus, chronic electrical stimulation in specific places improved retinal cell function throughout the eye. This halo effect can be used to improve vision in individuals suffering from diseases, conditions and trauma that have damaged the external retinal layer leaving the internal retinal layer at least partially intact. Although prosthetic electrical devices designed to replace damaged or absent retinal cells have been used to treat vision loss caused by degeneration of the external retina, electrical stimulation aimed at improving large areas of retinal cell visual function is new. As a non-limiting explanation, the promotion of enhanced retinal cell visual function through chronic electrical stimulation can be explained by the stimulation of the production and release of growth factors, more specifically neurotrophic growth factors, by stimulated retinas. The synthesis and / or secretion of neurotrophic factors would then improve retinal cell function and survival in conditions in which these activities would be lost.

Accordingly, the present invention discloses new devices for electrical stimulation of the retina in order to improve large areas of retinal visual function and to protect the retina against degeneration. As described below in greater detail, the devices disclosed herein can be broadly classified as indirect. Direct techniques involve the stimulation of a retina in which the stimulus crosses essentially non-intermediate biological structures. Conversely, indirect techniques include stimulation of a retina in which the stimulus must pass through one or more intermediate biological structures.

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Subject / patient

A subject (patient) can be a human being or a non-human animal, but preferably a human being. Normally, the individual has suffered some type of retinal damage and / or retinal degeneration that results in some degree of visual loss and / or has a condition that will result in retinal damage and / or retinal degeneration. . A normal (healthy) subject has no condition that will result in retinal damage and / or retinal degeneration, nor has it suffered any damage to the retina and / or any degeneration of the retina.

Visual function enhancement

The improvement of the visual function refers to the improvement of an objective function of the eye, selected by the professional, and includes the improvement of some or all of the following capacities of the eye, the retina and the visual system: perception of luminosity in the presence of light, perception of darkness in the absence of light, perceptions of contrast, color, shape, resolution, movement and size of the visual field.

Primary visual degradation means a loss of visual function due to a malfunction, damage or degeneration of structures located in the eye. Secondary visual degradation means a loss of visual function due to secondary damage, usually due to the lack of use of brain parts associated with vision. Improving visual function means improving the visual function of primary visual degradation, secondary visual degradation or both.

Eye / eyeball

The eye (or eyeball) has the usual definition in the art. The term eye includes all interior and exterior surfaces, components, contents and cavities of the eye. The term eye does not include the eyelid or optic nerve.

The retina of the eye can be divided into sectors, as is commonly accepted in the art. Such sectors are described by the use of the terms temporal, nasal, upper, lower, by designation of clock time, and by the number of degrees of separation from the macula. For example, the temporal sector of the retina is the temporal retina with respect to a perpendicular plane that passes through the retina from the 12 o'clock position to the 6 o'clock position and through the macula. In another example, the upper sector is the upper retina with respect to a perpendicular plane that passes through the 9 o'clock position to the 3 o'clock position and through the macula. In another example, the upper-temporal sector is the intersection of these two sectors, a pie-shaped area drawn from the 9 o'clock position of the peripheral retina clock to the macula and then clockwise. from the clock to the 12 o'clock position. More specific places of the retina can be indicated by the degrees of separation with respect to the macula and the place as a clock time: for example 20 degrees of separation with respect to the macula and the 3 o'clock position (nasal) . The number of degrees of separation with respect to the macula is in degrees of optical axes. These axes all pass through the lens.

The fields of the visual field correspond opposite to the sectors of the retina, as is commonly understood in the art. For example, the temporal-superior sector of the retina corresponds to the nasal-inferior part of the visual field.

Peripheral

Being peripheral with respect to an object, device or other reference point includes all surrounding parts, but not the object, device or reference point, that is to say that the object, device or reference point and the peripheral part together constitute the whole .

Light

The term light not only refers to the electromagnetic spectrum that humans can perceive visually easily (approximately 400 nm to 750 nm), but also includes ultraviolet light (&lt;400 nm wavelength), as well as infrared light ( &gt; 750 nm wavelength).

Indications

The invention can be used to improve visual function in subjects in whom the retina is damaged by a disease, degeneration, condition or trauma and / or to delay or stop the progression of damage due to disease, degeneration, condition or trauma. Common diseases, conditions, degenerations or trauma particularly susceptible to being cured by this treatment include age-related macular degeneration, pigmentary retinitis, Leber's congenital amaurosis, Stargardt's disease, Best's disease, retinopathy Diabetic, late retinal detachment and choroidal damage.

Eye structure

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Referring to the drawings, FIGURE 1 illustrates a section through the eyeball. Neuroretin 150 comprises multiple layers of cells and structures (see FIGURE 2). The photosensitive components of the retina are located inside the neuroretin that covers the inner posterior cavity of the eye, ending earlier in the ora serrata 167. The ciliary body 168 and iris 162 are covered by extensions of the retina that lack components photosensitive The outermost layers of the eye consist of the sclera 164 and the cornea 158. The sclera is crossed by the emerging optic nerve 166. The lens 160 and the vitreous cavity 154 are also indicated. The macula 169 of the retina is generally an oval region. 3 mm by 5 mm, in the center of which is the fovea 170.

FIGURE 2 shows the following eye layers on the posterior pole from the inside to the outside: internal limiting membrane 40, nerve fiber layer 42, ganglion cell layer 44, internal plexiform 46, internal nuclear layer 48, external plexiform 50, external nuclear cell layer 52 and external and internal photosensitive segment layer 54, all of them composing the internal anatomical retinal layer, also known as neuroretin 56. The retinal pigmentary epithelium 58 and the Bruch membrane 60 make up the external retinal layer 62. The choriocapillary 64 and the choroid 66 constitute the choroidal vasculature 68. The outer layer of the eye is the sclera 70. Light 156 enters the retina as it is sample.

Indirect stimulation

In previous applications, embodiments were disclosed that had the common characteristic that the electrical stimulus was supplied directly to the neuroretin, that is to say that there were essentially no intermediate biological structures. In accordance with the present invention, the electrical stimulus can be applied to the neuroretin in an indirect manner, that is to say through one or more intermediate biological structures.

Various methods for indirect stimulation are already known, as this term is defined here. FIGURES 35 are schematic illustrations of such prior art states. FIGURE 3 illustrates a technique (described in US Pat. No. 5,147,284, granted to Fedorov et al .; in what follows Fedorov) in which electrical stimulation is applied to an eye 204 of a patient 202 through a pair of electrodes 210, 212, surgically implanted, applied to surfaces of the eye 204 and the optic nerve 206. A Electrical stimulation source 208 coupled to the pair of electrodes 210, 212. In practice, source 208 comprises an induction coil that supplies electric currents as a result of magnetic fields applied to the patient's temporal region 202. Although Fedorov reports improved vision in patients, the circumstances in which patients received the Treatment are not known or appear to have undergone a peer review. In addition, it will be perfectly apparent to the average technician that the implantation of an electrode very close to the optic nerve 206 requires a highly invasive and complicated surgery.

FIGURE 4 illustrates a more recent technique proposed by Chow in US Patent No. 6,427,087. Specifically, electrode 210 'is brought into contact with eye tissues 204, while another electrode 212' is placed within the vitreous cavity 205 which may be in contact with the internal limiting membrane (see also vitreous cavity 154 shown in FIGURE 1). It is believed that transretinal stimulation resulting from this configuration will result in more effective stimulation.

Another approach is shown in FIGURE 5, in which, the stimulation and return electrodes 210, instead of being in direct contact with the eye 204, are placed on external tissues 214, 216. In US Pat. 5,522,864 to Wallace et al. and in US Patent Nos. 6,035,236 and 6,275,735 to Jarding et al. Examples of this approach (sometimes called microcurrent stimulation) are offered, particularly in order to treat degenerative diseases of the retina, such as macular degeneration and retinitis pigmentosa. As a rule, the stimulation electrode 210 '' is coupled to an external tissue very close to the eye 204, for example the eyelid, and the return electrode 212 is coupled to distal external tissues, such as the occipital lobe or the arm of the patient 202. Although anecdotal evidence of efficacy has been reported sporadically, it is known that there have been no controlled human studies evaluated by peers and, in addition, The American Academy of Ophtalmology's Task Force on Complementary Therapies concluded in September 2000 that no evidence of weight has been found to demonstrate the efficacy of microcurrent stimulation treatment of [age-related macular degeneration] compared to standard therapies.

In contrast to the prior art states described above, the present invention encompasses indirect stimulation techniques based on the application of one or more electrodes to surface structures of the eye rather than peripheral structures such as the optic nerve or eyelids. As used herein, the surface structures of the eye can be divided into two classes: internal surface structures and external surface structures, as described below in greater detail. In general, the surface structures of the eye can be defined as any of several sheets (starting internally with the sclera in the case of internal surface structures) that form and surround the eye, depending on the specific region of the eye taken into consideration.

FIGURE 6 shows a schematic illustration of an embodiment of indirect stimulation according to the present invention. In this embodiment, at least one active or stimulation electrode 226 is applied to a surface structure of an eye 220. The active electrode (s) 226 are configured for chronic contact with the surface structure of the eye 220. As used herein. , the chronic term covers not only continuous periods of time, but

ES 2 385 809 T5 also repeated and / or periodic time intervals. For example, the active electrode (s) 226 may be subject or otherwise coupled to the surface structure in an essentially permanent manner, or they may be configured to allow repeated contact with the surface structure over a period of time established by a course of treatment and a subsequent repeated of said contact. At least one return or ground electrode 228 is configured for application to tissues 222 of an external surface structure of the eyeball, or an internal surface structure of the eyeball, which is an external surface of the patient's sclera. Additionally, the return electrode (s) 228 may be configured for chronic or temporary application to tissue 222. For example, the return electrode (s) 228 may comprise one or more implantable electrodes permanently coupled to tissue 222 or may comprise one or more temporary skin electrodes secured with an adhesive and electrically connected by the use of a suitable conductive gel. . Placed in this way, and given the relatively low resistance of the vitreous relative to the surface structures and surrounding tissues of the eye, the active and return ground electrodes establish a transretinal circuit such that the application of an electrical stimulation signal to the electrode active will result in beneficial transretinal currents.

In addition to electrodes 226, 228, the system illustrated in FIGURE 6 also comprises a source of the electrical stimulation signal. The specific configuration of the source depends on the implementation internally or externally in relation to the patient. For example, in the case where only the active electrode 226 is configured to be removably in contact with external surface structures of the eye and the return electrode 228 is configured for temporary skin contact, the source may comprise one or more terminals input 224 for the application of the electrical stimulation signal to the electrodes. In this case, the electrical stimulation signal is supplied by an extraocular signal source 224 '.

According to an embodiment not of the invention, which is not part of the invention, the source 224 'is entirely internal with respect to the patient 202', as in the case of an implantable battery and, optionally, a signal generating circuitry (not shown). In this case it is assumed that the return electrode (s) 228 are also chronically implanted in the patient 202 ', thus eliminating any need for input terminals 224.

The source is implemented as a combination of internal components 224 'and external 224 (relative to the patient). The internal component of the source 224 'has a receiver induction coil implanted subcutaneously and the external component of the source 224 has a transmitter coil, which can be exactly aligned with the receiver induction coil. As is known in the art, such transmitter / receiver coil pairs can be used to transmit energy and data, which can be used to deliver the electrical stimulation signal.

In practice, the electrical stimulation signal supplied by the source can comprise virtually any type of waveform that shows a beneficial effect. For example, the electrical stimulation signal may consist of an anodic or cathodic direct current signal or a time-varying waveform, such as a square, sinusoidal, triangular, sawtooth signal or any other similar waveform. . The electrical stimulation signal preferably comprises a biphasic waveform that is compensated in the sense that a zero net charge is applied to the retina over a period of time. By way of non-exhaustive examples, this can be achieved through the use of a signal comprising a continuous train of biphasic pulses of equal duration; biphasic impulses of equal duration separated by periods of inactivity; two-phase compensated load impulses of varying duration and amplitude; combinations of the above, etc. The frequencies of the pulses can have any value between 10 KHz and 0.001 Hz or, in an extreme case, even a continuous single-phase waveform, that is to say 0 Hz. The person skilled in the art will understand that the specific type of stimulation signal Electric used is a matter of design choice and is selected so that it has the maximum beneficial effect.

A schematic illustration of another embodiment of indirect stimulation according to the present invention is shown in FIGURE 7. In this embodiment, the active electrode (s) 226 are applied to a first surface structure of the eye 220 and the return electrode (s) 228 are applied to a second surface structure of the eye 220. In practice, the first and second surface structure may be the same or be different surface structures, the surface structures comprising the various sheets starting with the sclera as the innermost surface structure and its overlapping structures. In this embodiment, the source 224, 224 ', 224 of the electrical stimulation signal may consist of any of the alternatives described above in relation to Figure 6. It is expected that performing the indirect stimulation illustrated in FIGURE 7 provides a high stimulation of the retina, given the relative proximity of the electrodes to the retina. The various surface structures applicable to the present invention are described below with reference to FIGURES 8 and 9.

Referring now to FIGURE 8, an eye and the surrounding structures are shown. The ocular orbit is defined by bone structures 230, 231. Within the orbit, a layer of extraconal fat 233 and intraconal fat 235 surrounds the eyeball. The fat layers 233, 235 are separated from each other by a cone defined by the upper extraocular muscles 236, lower 238 and lateral 240, as well as by an intermuscular septum 242 connecting the muscles. The optic nerve 166 exits the orbit from the back, while the anterior part of the eyeball is formed by a part of the sclera and the cornea 158. The so-called Tenon capsule 244 (partially shown) separates the globe eye of the orbital fat and forms a basin within which the eyeball moves. The upper and lower eyelids 246, 247 enclose and protect the anterior part of the eyeball. The conjunctiva comprises the bulbar conjunctiva 159 ', which covers the anterior part of the sclera, and the palpebral conjunctiva 159, which covers the inner surface

ES 2 385 809 T5 of the upper and lower eyelids 246, 247. The fold between the bulbar conjunctiva 159 'and the palpebral conjunctiva 159 gives rise to a conjunctival fornix 250. In the context of the present invention, the external surface structures comprise the surface structures that are accessible through the eyelid groove defined by the eyelids, that is the cornea 158 and the conjunctiva 159. The internal surface structures are defined as the surface structures posterior to the bulbar conjunctiva 159 'and comprise the various sheets that begin with the sclera and the structures that cover it, the latter depending on the specific region of the eyeball taken into consideration.

FIGURE 9 schematically illustrates the various surface structures present in the region indicated by way of example in FIGURE 8. The dimensions shown are not to scale. The sclera 164 forms the innermost surface structure. Continuing outward from the sclera 164, episclera 260 is a thin, loose layer of connective tissue that forms the outer surface of the sclera 164. Above episclera 260 is the intermuscular septum 242 and above the intermuscular septum 242 is the Tenon capsule 244. For the purposes of the present invention, each of the layers shown in FIGURE 14 comprises a surface structure separated from the that an electrode can be applied. The person skilled in the art will understand that other regions of the eyeball may have layers of different surface structure than those shown in FIGURE 9.

Various examples of implementation of the embodiments of FIGURES 6 and 7 are schematically shown in FIGURES 10-14. By way of reference, each of FIGURES 10-12 shows the upper extraocular muscles 236, lower 238 and lateral 240 , the upper and lower eyelids 246, 247 and the cornea 158. FIGURE 10 illustrates an embodiment in which a contact lens body 265 carries one or more corneal electrodes 266. The person skilled in the art already knows various materials for manufacturing the support body 265 and the corneal electrode (s) 266. The corneal electrode 266 is used as a return electrode (this is also valid for the other embodiments illustrated in FIGURES 11 and 12). The corneal electrode (s) 266 may comprise a plurality of separate electrodes arranged, for example, in an annular formation held near the periphery of the support body 265, or they may comprise a single annular electrode equally attached to the support body 265. Alternatively , the corneal electrode (s) 266 may be arranged closer to the central region of the cornea. It should be noted that, for greater clarity, none of FIGURES 10-12 shows the complementary electrode nor FIGURES 10-14 show the electrical connections between the electrodes and the source of the electrical stimulation signal, the average technician being able to matter easily conceive such connections, this being a matter of design choice.

FIGURE 11 illustrates another embodiment in which an annular support body 270 provides support for at least one epiconjunctival electrode 271. Once again, the person skilled in the art already knows various materials for manufacturing the support body 270 and the or epiconjunctival electrodes 271. As in the embodiment of FIGURE 10, the epiconjunctival electrode (s) 271 may comprise a plurality of individually selectable electrodes or a single annular electrode, this being a matter of design choice. In the example shown in FIGURE 11, the epiconjunctival electrode (s) 271 are in contact with the bulbar conjunctiva 159 'very close to the cornea 158. However, additionally or as an alternative, the epiconjunctival electrode (s) 271 may be placed in a more distal position with respect to the cornea 158, while still being in contact with the bulbar conjunctiva 159 '.

FIGURE 12 illustrates yet another embodiment in which an electrode 275 is placed in epiconjunctival contact within the conjunctival fornix 250. In practice, electrode 275 may comprise a fibrous or filamentous electrode, such as a DTL electrode. DTL electrodes are particularly advantageous, because it is known that patients tolerate them well given their relatively thin dimensions. Although a single electrode is shown in the lower conjunctival fornix 250, it is also possible that there is an electrode placed in the upper conjunctival fornix as an alternative or in addition to the lower electrode. In addition, more than one electrode can be placed at any time in any of the fornices.

All FIGURES 10-12 illustrate embodiments in which a few second electrodes are placed in contact with external surface structures of the eye. FIGURE 13 schematically illustrates an embodiment in which the electrodes are applied to internal surface structures. In particular, one or more support rings 281-283 are implanted in contact with internal surface structures. It should be noted that, although the third ring 283 is placed in contact with an essentially anterior part of the eye, it is implanted below the bulbar conjunctiva 159 '. However, a hybrid technique of internal / external surface structure would be possible if the third ring 283 were placed on top of the bulbar conjunctiva 159 ', similar to that shown in FIGURE 11 (such hybrid arrangements are described below in more detail detailed with reference to FIGURES 16, 18 and 19). Techniques for introducing such rings into the orbit and attaching them to the eye are already known in the state of the art, in particular by the use of so-called scleral buckles. For example, each ring can be sutured in position according to such techniques. It should be noted that the first and second ring 281, 282 are preferably placed under the extraocular muscles 236, 238, 240 according to known techniques.

Each ring comprises at least one electrode 285 and in a preferred embodiment each ring comprises a plurality of electrodes. The person skilled in the art already knows suitable materials for manufacturing the support rings and electrodes. It is preferable that each electrode can be selected individually. Additionally, each individual electrode can be electrically configured to act as an active electrode or a return electrode. In this way, each ring 281-283 can comprise both active electrodes and return electrodes. In such an embodiment, it may be preferable to insert active and return electrodes and, in addition, arrange the active and return electrodes so that they are opposite each other. The arrangement of electrodes opposite each other will give

It is 2 385 809 T5 a transretinal path of the current essentially perpendicular to the retinal surface. In addition, by being individually selected, each electrode of a pair of electrodes opposite each other can be periodically switched between active and return operation. And in addition, the electrodes between rings could be activated as stimulation pairs, for example an electrode of a first ring 281 could be operated as an active electrode and an electrode of a second ring 282 operated as a return electrode, and vice versa. Although a specific number of support rings 281-283 placed in essentially vertical orientations is shown in FIGURE 13, it is understood that it is possible to employ a greater or lesser number of such rings and, furthermore, that the orientation of such rings does not have why limit yourself to an essentially vertical orientation. Taken to the end, support rings 281-283 could be removed, each electrode 285 being able to comprise an independent and separate support element in its place such that it is possible to implant individual electrodes at specific locations of specific internal surface structures.

Another embodiment is shown in FIGURE 14 that provides contact with internal surface structures. In this embodiment, one or more support wraps 290 comprising a plurality of electrodes 292 are placed and fixed in contact with internal surface structures of the eye. The above explained with respect to the individually selected and opposite electrodes in relation to FIGURE 13 is equally applicable to the arrangement of FIGURE 14. To accommodate the presence of various ocular structures, such as the connections between the various muscles 236, 238, 240 and the sclera, openings 294 may be provided. In the example illustrated in FIGURE 14, a plurality of wraps 290 are provided in such a manner. that each envelope 290 covers the surfaces between adjacent muscles, thus forming the openings 294 by being adjacent to the envelopes 290 when implanted. If a single envelope 290 surrounds at least one of the muscles, the anterior part of the opening 294 can be manufactured in such a way that a unitary body (shown with dotted lines) is created, while the opening of the posterior part of the opening 294 allows wrapping envelope 290 to be placed under the muscle. And in addition, instead of trying to maneuver the envelopes 290 around the muscles, holes could be provided within the otherwise continuous envelopes 290. In this case, it would be necessary to first cut the muscles to allow the placement of the wraps and then fix them again in positions corresponding to the holes. Whatever the specific configuration, the embodiment illustrated in FIGURE 14 allows the placement of multiple electrodes in contact with internal surface structures of the eye to facilitate indirect retinal stimulation.

The embodiments of FIGURES 13 and 14 are concrete examples of the scheme shown in FIGURE 15. Similar to the schemes shown in FIGURES 6 and 7, the scheme of FIGURE 15 comprises a source 224, 224 ', 224 coupled to electrodes 226, 228 in contact with an eye 220. However, in this scheme the electrodes are both in contact with internal surface structures 300, 302 of the eye. In a presently preferred embodiment, electrodes 226, 228, configured for contact with internal surface structures, are preferably configured for chronic implantation, for example compounds of materials that have a very good biodurability, biocompatibility, etc.

Another scheme is shown in FIGURE 16 (which generalizes the above-mentioned hybrid embodiment in relation to FIGURE 13). The scheme of FIGURE 16 differs from that of FIGURE 15 in that a second electrode 228 is configured for contact with an external surface structure 304, while the other electrode 226 is configured for contact with an internal surface structure 300. Again, electrodes 226 configured for contact with internal surface structures are preferably configured for chronic implantation. Instead, the second electrodes 228, configured for contact with external surface structures, may be configured for chronic or acute (i.e., removable) contact. In the embodiments illustrated in FIGURES 15 and 16, as well as in all the above embodiments, electrodes 226, 228 may each consist of a plurality of separately selectable electrodes, each of which may alternate between the electrode functionality of stimulation and return electrode. FIGURES 17-19 show specific embodiments of the diagrams of FIGURES 15 and 16. By way of reference, each of FIGURES 17-19 shows a top view of an eyeball comprising a cornea 158, a conjunctiva 159, a sclera 164 and, in hidden view, a neuroretin 150, a macula 169 and a optic nerve 166.

Referring now to FIGURE 17, an exemplary embodiment of the scheme of FIGURE 15 is shown. In particular, FIGURE 17 illustrates the placement of a first electrode 310 (in this case a plurality of electrodes) placed in a first internal surface structure and a second electrode 320 disposed in a second internal surface structure. Connections with an electrical source 324 are shown schematically. In this embodiment, the first and second internal surface structure may comprise, for example, separate regions of scleral tissue. As can be seen, the plurality of electrodes 310 constituting the first electrode are supported by a body element 322 in the form of a scleral tape or ring, as described above in relation to FIGURE 13. Although shown as an electrode unique, the second electrode 320 may comprise a plurality of electrodes. In any case, the second electrode 320 may include a supporting body element (not shown) to facilitate placement and fixation of the second electrode. The application of an electrical stimulation signal through the first and second electrodes will result in transretinal currents that stimulate the retina. To maximize the effects of the transretinal current, the second electrode 320 is preferably configured for an internal surface structure corresponding to (ie aligned with) the macula 169 of the eye and placed thereon.

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Referring now to FIGURES 18 and 19, embodiments are shown that are not part of the invention. FIGURE 18 illustrates the placement of a second electrode 320 (as described above in relation to FIGURE 17) on an internal surface structure of the eye. However, in this embodiment, the first electrode 330 is configured for an epiconjunctival placement, that is to say in contact with an external surface structure. As can be seen, the first electrode may comprise a supporting body element 332, as described above in relation to FIGURE 11. FIGURE 19 illustrates yet another embodiment of internal / external surface structure, which combines the implementation of a scleral annular electrode 310 and the implementation of an epiconjunctival electrode 330.

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