Abstract:
A method for treating or preventing retinal pathology or injury. The method locates and secures a retinal stimulating substance in the eye between the internal limiting membrane and the retina, which is the target site for the substance. The substance may be an implant that provides electrical stimulation to adjacent ganglion and neurofiber cells. Alternatively, the substance may be a pharmaceutical substance to stimulate the retina. In addition to providing direct contact of the substance with its target, the method obviates the need for artificial structures such as tacks or adhesives which may cause retinal bleeding or traction.

Description:
FIELD OF THE INVENTION  
         [0001]    The invention relates to methods for providing a device or composition to a retina.  
         BACKGROUND OF THE INVENTION  
         [0002]    The retina is the innermost layer of the wall of the eyeball located in the posterior segment of the eye. Developed as an outgrowth from the brain, the retina contains nervous tissue, specifically, light-sensitive cells (photoreceptors) and complex neural networks. These networks provide visual information and send impulses through the optic nerve to the brain.  
           [0003]    Degenerative diseases of the retina, such as retinitis pigmentosa, age-related macular degeneration, and hereditary retinal degenerations cause degeneration and death of the photoreceptor cells, resulting in decreased visual function. Fortunately, even in end-stage disease, numerous neuronal cells in the inner retina survive. However, because of loss of the photoreceptors, light stimulation does not occur and the neuronal cells must be artificially stimulated to restore some degree of visual function.  
           [0004]    The neuronal cells may be stimulated, either from the outer surface of the retina or from the so-called subretinal space. One technique for subretinal stimulation uses semiconductor microphotodiode arrays (SMA) as described in Peyman et al.,  Ophthalmic Surgery and Lasers,  1998, vol. 29, p. 234, which is expressly incorporated by reference herein in its entirety. These arrays are fabricated by standard photomask and etch techniques, and can be produced with thicknesses ranging from about 10-200 μm and sizes varying from about 0.5-5 mm in diameter. The arrays are separated into subunits, which create a pixel density of over 1000 subunits/mm 2 . The subunits have no electrical connection; they are powered by incident light having a wavelength between 500-1100 mm. Another technique for retinal stimulation uses an electrode array to electrically stimulate the neurofiber layer of the retina. The array has 25 platinum disks arranged in a 5×5 square, as reported by Majji et al.,  Investigative Ophthalmology and Visual Science,  1999, vol. 40, p. 2073. The improved surface of the platinum disk forms a planar array of stimulating electrodes in a silicon matrix that is less than 1 mm thick. Twenty-five wires originating from the disk form a cable which extends from the array and is at least 10 cm long and 600 mm thick. To implant the array into the eye, the surface of the implant (3×5 mm) is placed over and is fixed to the retina either by mechanical fasteners such as pins or tacks, or by bioadhesives.  
           [0005]    There are, however, several disadvantages of implanting the aforementioned types of arrays into the subretinal space. One disadvantage is that the implant may interfere with nutrition of the retina, since nutrients come partially from the choroid (the back of the retina). Fenestrations, or small openings in the array, can help to maintain nutrient accessibility to the retina. Implanting the electrode type of array over the surface of the retina has additional drawbacks. One drawback is that fixing the array over the retina is very difficult. If pins or other mechanical fasteners are used, they should penetrate the entire retina and reach the scleral wall in order to secure the array, but this increases the risk of hemorrhage from the retinal and choroidal circulation. The increased fibrous proliferation around both the fasteners and the array also causes localized scarring and traction on the retina. Another disadvantage is that electrical stimulation in the subretinal space may not adequately excite the ganglion cells and the neurofiber layer, which are located in the outer portion of the retina.  
           [0006]    Drugs such as gancyclovir or various steroids can also be administered to the patient to attempt to prevent, halt, or alleviate the pathological process. Ocular drugs may be administered systemically, parenterally, or topically. Alternatively or additionally, the drugs may be administered in a slow release formulation.  
           [0007]    While current methods exist for treating patients experiencing a loss in visual function due to retinal pathology, several problems still remain. Thus, additional methods to improve visual function, while decreasing or eliminating these problems, are desirable.  
         SUMMARY OF THE INVENTION  
         [0008]    The invention relates to a method to provide an interventional or therapeutic substance to patients who have experienced decreased visual function due to retinal pathology or injury. The invention is also directed to a method for treating or preventing retinal pathology or injury in a mammal by surgically affixing a therapeutic or preventive substance under an internal limiting membrane in the eye to contact and stimulate the retina.  
           [0009]    The inventive method provides the retinal stimulator substance to a mammalian eye by visualizing the internal limiting membrane of the eye, locating the retinal stimulator between the internal limiting membrane and the retina, and securing the substance under the internal limiting membrane. The method thus locates, contains, and secures a retinal stimulator substance in proximity to the retina, all by using a space provided by the internal limiting membrane in the eye.  
           [0010]    In one embodiment, the substance is an array that is photostimulated to excite the retina. In another embodiment, the substance is an array that is electrically stimulated to excite the retina. In yet another embodiment, the substance is a drug that directly or indirectly stimulates the retina, for example, a drug that is formulated in a vehicle for slow-release delivery.  
           [0011]    The inventive method takes advantage of the physiological placement of the internal limiting membrane in the eye. Previous surgical implant methods had removed the internal limiting membrane. However, the inventive method not only retains the internal limiting membrane, but also takes advantage of the space between it and the adjacent retinal layers to implant a therapeutic or preventative substance. In this way, non-physiological mechanical or chemical fasteners are not needed to locate and secure the implanted substance in place. Thus, there are no devices or compositions which may cause bleeding from the choroid or which may promote retinal traction originating from the cells migrating from the choroid through the mechanical pins, both of which are problems in current methods.  
           [0012]    Another improvement using the inventive method is that the substance implanted is in direct contact with the neurofiber layer and ganglion cells of the retina. This advantageously enhances their stimulation, since the distance between the substance and its target is decreased. For example, when electrical arrays are implanted, there is enhanced qualitative and quantitative cell stimulation because the stimulus is close enough to reach ganglion cells and the neurofiber layer that is located a distance of about 10-50 μm away.  
           [0013]    Still anther improvement is that the inventive method eliminates the need for external stimulation, as is used with currently available diode arrays.  
           [0014]    These and other advantages will be apparent from the following figures and detailed description. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0015]    [0015]FIG. 1 is a schematic cross-sectional view of a mammalian eye.  
         [0016]    [0016]FIG. 2 is an enlarged diagrammatic illustration of the circled area  2  of FIG. 1 showing detailed retinal and choroid structures and placement of a substance using the inventive method. 
     
    
     DETAILED DESCRIPTION  
       [0017]    With reference to FIG. 1, a mammalian eye  10  is shown. The locations of the vitreous cavity  8 , posterior chamber  9 , anterior chamber  11 , cornea  12 , conjunctiva  13 , iris  14 , optic nerve  15 , sclera  16 , macula lutea  17 , lens  18 , retina  20 , ora serrata  21 , and choroid  22  are illustrated.  
         [0018]    The most sensitive portion of the retina  20  is the macula lutea  17 , which is located in the center of the posterior part of the retina  20 . The inner surface of the retina  20 , near the border of the optic nerve  15 , has a shallow round depression, the fovea  41 . The fovea  41  is surrounded by the central area, distinguished by the great number of ganglion cells and by the general refinement and even distribution of the structural elements, especially the rod cells and the cone cells. About one-tenth inch inside the fovea  41  is the point of entrance of the optic nerve  15  and its central artery. At this point, the retina  20  is incomplete and forms the blind spot.  
         [0019]    With reference to FIG. 2, the retina  20  forms the innermost layer of the posterior portion of the eye and is the photoreceptor organ. The retina  20  has an optical portion that lines the inner surface of the choroid  22  and extends from the papilla of the optic nerve  15  to the ora serrata  21  anteriorly. At the papilla, where the retina  20  continues into the tissue of the nerve  15 , and at the ora serrata  21 , the retina  20  is firmly connected with the choroid  22 . The retina  20  has ten parallel layers which are, from outside to inside, as follows: the pigment epithelium  101 , photoreceptor cells (rod cells and cone cells)  102 , the outer limiting membrane  103 , the outer nuclear layer  104 , the outer plexiform layer  105 , the inner nuclear layer  106 , the inner plexiform layer  107 , the layer of ganglion cells  108 , the layer of optic nerve fibers or neurofiber layer  109 , and the so-called inner limiting membrane  110 . The inner limiting membrane  110  is very thin (less than 5 μm), and normally adheres with the neurofiber layer  109  of the ganglion cells  108 .  
         [0020]    The inventive method takes advantage of the adjacent positions of the neurofiber layer  109  and ganglion cells  108  with the inner limiting membrane  110  to provide a space  120  into which a substance  130  for treating the retina  20 , such as an array for electrostimulation of the retina, can be implanted and secured. The potential for and use of this space  120  in implanting an array or any other material has heretofore been unrecognized and unappreciated.  
         [0021]    In the method, the patient is prepared for surgery, typically by providing a topical anesthesia to the eye and dilating the pupil. The eyeball is exposed and the vitreous is removed from the vitreous cavity  8  by standard techniques known to one skilled in this art. The internal limiting membrane  110  is then rendered visible to the surgeon, typically by staining. Any water soluble stain which stains the basement membrane of the internal limiting membrane  110  can be used, for example, indocyanine green, trypan blue, methylene blue, etc. The stain, for example one or two drops, is placed into the eye to allow visualization of the internal limiting membrane  110 . A small incision, typically less than about 0.5 mm in diameter, is made into the internal limiting membrane  110  in the area of the macula lutea  17 .  
         [0022]    In current methods for treating a macular hole, the internal limiting membrane  110  is separated and removed using forceps.  
         [0023]    To create a space where an array can be placed under the internal limiting membrane  110 , the internal limiting membrane  110  can be separated from the retina  20  by a blunt-tipped spatula or a cannula for injection of a liquid.  
         [0024]    In the inventive method, however, instead of cutting and removing the internal limiting membrane  110  as is routinely done, the internal limiting membrane  110  is left in place and is, in fact, used to locate the implanted substance  130 . A small incision  132  is made in the internal limiting membrane  110 , and the membrane  110  is then separated from the adjacent neurofiber layer  109 . The substance  130  is implanted, and because the incision used for separation of the internal limiting membrane is small, the substance  130  is inserted in a secure fit. The internal limiting membrane is then repositioned over the substance  130 . Furthermore, the repositioned internal limiting membrane  110  also secures the implanted substance  130  to the neurofiber layer  109  and ganglion cells  108 . After the substance  130  is located and secured under the internal limiting membrane  110 , the vitreous cavity  8  can be re-filled with fluid, for example, air. This fluid is subsequently absorbed and is replaced by body fluids.  
         [0025]    In the inventive method, positioning and replacement of the internal limiting membrane  110  over the implanted substance  130  either eliminates the need for an adhesive, or allows a smaller quantity of adhesive to be used than if the internal limiting membrane was removed. If desired, however, an adhesive can also be applied to close the incision, but is not placed between the substance  130  and the retina  20 . The adhesive can be, for example, a commercial fibrin sealant, autologous fibrin, Cell-Tak, photocurable glues, polyethylene glycol hydrogels, as described in Margalit et al.,  Retina,  2000, vol. 20, p. 469, which is expressly incorporated by reference herein in its entirety.  
         [0026]    If the substance  130  implanted is an array, it may be with or without external connections. For example, an array with electrode connectors having a length of about 50 μm to about 100 μm may be implanted. An array can be of any type as is know to one of skill in this art, such as the semiconductor microphotodiode array that is described by Peyman et al.,  Ophthalmic Surgery and Lasers,  1998, vol. 29, p. 234, which is expressly incorporated by reference herein in its entirety. An array as small as 10 μm can be implanted. Alternatively, multiple small arrays, with a total size of up to about 8 mm, may be implanted. Their position can subsequently be organized and oriented magnetically. The array can be fabricated to be fenestrated, or it can be without fenestrations. The individual array can be positive-intrinsic layer-negative (PiN), mixed, negative-intrinsic layer-positive (NiP), or uniform. In the array, light absorption occurs in the front and the electricity runs to the side or the back. If electrode arrays are used, the technology described by Majii et al. is utilized, with connectors to penetrate the neurofiber layer  109  of the retina  20 .  
         [0027]    The retinal stimulator substance  130  may also be a drug. As one example, the drug may be an α-adrenergic agonist or a β-adrenergic agonist, as disclosed in U.S. Pat. No. 6,066,675 which is expressly incorporated by reference herein in its entirety. As other examples, the drug may be one or more antiinflammatory agents and/or antiproliferative agents, as is known to one skilled in the art. The drug may be implanted either alone or may be incorporated into a drug delivery system, such as a slow-release system or formulation. Examples of such systems are known to one of skill in this art and include, but are not limited to, a capsule, a bead, a liposome, a sphere, and/or a dissolvable biocompatible polymer sheet.  
         [0028]    The inventive method provides several advantages. It eliminates the need for surgical removal of the internal limiting membrane  110 . Furthermore, the inventive method takes advantage of the presence of the internal limiting membrane  110  to provide a “pocket” or space  120  for implanting the substance  130 . If the substance  130  is an array, the approximation of the array to the ganglion cells  108  and the neurofiber layer  109  can better amplify the stimulation of these structures. The array thus placed requires less electrical power than is required with arrays implanted by previously known methods such as using adhesives. The signal generated, being located directly adjacent its retinal target site, is less likely to be attenuated and hence will be more efficacious. The array  130  is also securely maintained in the space  120  without the need for either mechanical fixatives, such as retinal tacks, or chemical fixatives, such as adhesives. This eliminates the problems of bleeding and/or tearing that are known to occur when mechanical fasteners such as tacks or pins are used. The inventive method also eliminates the problems associated with the use of adhesives, namely, that adhesives come off and the substance becomes dislodged from its original site of implantation, and that adhesives serve as insulators and hence interfere with transmission of an electrical signal from an array to the retina  20 .  
         [0029]    It should be understood that the embodiments of the present invention shown and described in the specification are only preferred embodiments of the inventor who is skilled in the art and are not limiting in any way. Therefore, various changes, modifications or alterations to these embodiments may be made or resorted to without departing from the spirit of the invention and the scope of the following claims.