HK1085113A - Devices and methods for improving vision - Google Patents

Description

Apparatus and method for improving vision

Cross reference to related applications

This application claims priority from U.S. provisional application No. 60/464,590 filed on day 21/4/2003, U.S. provisional application No. 60/464,004 filed on day 18/4/2003, and U.S. provisional application No. 60/410,837 filed on day 13/9/2002, the contents of which are incorporated herein by reference.

Background

1. Field of the invention

The present invention relates to devices and methods for improving vision in a patient. In particular, the present invention relates to a method of improving a patient's vision by placing a corrective ocular device between the epithelium of the patient's eye and the stroma of the patient's cornea. The corrective ocular device may be a lens, including a corneal onlay. The corrective ocular device may have a pre-formed epithelial cell layer secured to the device when placed on the eye of a patient. The pre-formed epithelial cell layer can be synthesized in vitro, or the pre-formed epithelial cell layer can comprise at least a portion of the corneal epithelium of the patient.

2. Description of the related Art

The cornea of the human eye provides approximately 60-70% of the eye's focusing power. As is known in the art, a lens may be placed near the cornea to enhance the focusing power of the eye. Examples of vision correcting lenses include corneal inlays implanted in the cornea, corneal onlays placed on the cornea after removal of the epithelium, and contact lenses placed on the corneal epithelium. Corneal onlays differ from contact lenses in that corneal onlays are covered by an epithelial cell layer, and contact lenses are placed over the corneal epithelium.

Since the corneal onlay is placed over the de-epithelialized cornea, the epithelium must be replaced over the onlay to avoid damage and infection of the eye. Epithelial cells develop from the limbus and migrate across the surface of the eye. Unfortunately, many of the materials used to produce existing corneal onlays are not effective in promoting epithelial cell growth and migration across the onlay.

Certain attempts have been made to prepare corneal onlays that attempt to improve the migration of epithelial cells over the onlay. For example, U.S. patent No. 5,171,318 discloses the use of fibronectin placed on the surface of a cover to promote cell migration on and attachment to the cover. U.S. patent No. 5,713,957 discloses a non-biodegradable, non-hydrogel corneal onlay having large pores in the peripheral portion of the onlay that serve to promote fixation of the onlay to the eye by allowing cells to grow through the pores. Us patent No. 5,836,313 discloses a composite hydrogel corneal onlay which includes a layer of corneal tissue or collagen to improve cell migration on the corneal onlay. U.S. patent No. 5,994,133 discloses corneal onlays produced with various polymers that allow epithelial cells to migrate over the onlay. U.S. patent publication No. US 2001/0047203a1 discloses corneal onlays having surface grooves that support the attachment and migration of epithelial cells on the onlay. PCT publication No. WO 02/06883 discloses a corneal onlay derived from donor corneal tissue. In addition, WO 02/06883 appears to disclose the use of an epithelial cell layer placed on the covering; the epithelial cell layer may be obtained from donor tissue, such as fetal or embryonic tissue, or biopsies of autologous tissue of corneal epithelial cells. Corneal coverings that require epithelial cells to migrate across the surface of the covering do not provide satisfactory coverage of the covering by the epithelium. For example, when it is desired that epithelial cells migrate over the corneal onlay, the epithelial cells may not be fully differentiated. In addition, with the migration of the epithelial cells, there is a tendency for the epithelium to grow underneath the corneal onlay placed in the eye and cause the onlay to slough or coat. In addition, the recovery time for the epithelial cells to grow and migrate on the covering is inhibited and leads to non-idealities of the method.

Although WO 02/06883 discloses the use of cultured epithelial cells to produce an epithelial layer which is used to cover the corneal onlay, this application does not disclose the use of cultured stem cells to prepare the epithelial layer. In fact, the culture of stem cells for the preparation of corneal epithelium has only recently been explored (see, for example, Han et al, "fibrin-type bioengineered ocular surfaces with human corneal epithelial stem cells", Cornea, 21 (5): 505-. The above references disclose culturing corneal epithelial stem cells to repair injured ocular surfaces. Although complications may seem less apparent for correction of injured ocular surfaces, it was found that the use of cultured stem cells with corrective lenses can be problematic.

Summary of The Invention

The present invention relates to a corneal appliance or ocular device configured to improve a patient's vision, and a method of improving or correcting a patient's vision. The corneal appliance has a lens or lenticule and an epithelial cell layer disposed over the lens.

In one aspect, the epithelial cells can be derived from autologous stem cells, or in other words, stem cells obtained from the patient receiving the corneal appliance.

In another aspect, the epithelial cells may comprise at least a portion of the patient's corneal epithelium and/or stroma of the patient's cornea that has been separated from the pre-elastic layer.

Corneal orthotics that address the problems associated with existing corneal onlays have been discovered, as well as the use of epithelial cells in combination with onlays. Additionally, a method of correcting a patient's vision has been invented that includes inserting a corrective ocular device beneath the corneal epithelium of the patient.

The corneal appliance is configured for placement over an epithelialized eye, including a lens and an epithelial cell layer fixedly disposed over the lens. The epithelial cells of the appliance may be derived from stem cells grown in culture, or may be epithelial cells of the patient receiving the corneal appliance. The stem cells used may include limbal stem cells, or may be solely limbal stem cells.

As disclosed herein, the corneal appliance may be produced by a method comprising the steps of: culturing stem cells until at least a portion of the stem cells have differentiated into corneal epithelial cells; and placing a plurality of cells obtained from the culture on an anterior surface of a lens to form an epithelial cell layer that has been immobilized on the lens prior to placing the lens on the eye.

In addition, the corneal appliance may be obtained by a method comprising: a lens is inserted beneath the ocular epithelium substantially without exposing or revealing the underlying corneal surface, and the epithelium is secured to the lens.

The lens of the corneal appliance may comprise collagen, including reconstituted collagen. The lens may be a synthetic matrix having the desired power, or the lens may be made of a hydrogel or non-hydrogel material suitable for use in a vision correcting lens. The lens is configured to promote attachment of the cell to the lens, for example, by forming a groove in the lens. Alternatively or additionally, the appliance may include a cell attachment member disposed between the lens and the epithelial cell.

The cells of the appliance may be from cultured stem cells that are grown in vivo or ex vivo. For example, the cells may be cultured in a petri dish and then transferred to the lens. The cells can be transferred as a suspension or cell layer. The cells may be cultured on the surface of the lens. For example, the cells may be cultured on a lens placed in a lens mold adapted to provide conditions suitable for culturing the cells. Alternatively, the cells may be cultured on the lens under conditions that place the lens in the eye. The cells placed on the lens may be stem cells, a mixture of stem cells and differentiated epithelial cells, or differentiated epithelial cells without stem cells.

The epithelial cells of the corneal appliance may also be part of a layer of corneal epithelium of a patient receiving the appliance. For example, an epithelial layer or flap of a patient may be prepared by separating the epithelium from the cornea of the patient. The epithelial layer may be removed completely from the cornea or may be partially removed to form a flap that remains attached to the remaining epithelium of the patient. The epithelial cell layer or flap can then be placed over the lens of the corneal appliance. In one embodiment, the epithelial cell layer is caused to adhere to the lens by providing a stem cell suspension on the lens. Alternatively, the epithelial cell may be a portion of epithelium separated from the pre-elastic layer, however, it is not part of an epithelial flap. For example, the epithelial cells may be part of an epithelial pocket (pocket), such as part of a pre-formed epithelial layer, that is placed adjacent to where the epithelium begins to separate from the pre-elastic layer or ocular substrate.

Any feature or combination of features disclosed herein is included within the scope of the present invention provided that the features included in any combination described above are not mutually inconsistent as will be understood from the context of the present specification and as will be appreciated by those of ordinary skill in the art. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention.

Other advantages and aspects of the invention will become apparent from the following detailed description.

Brief Description of Drawings

Fig. 1 is a schematic cross-sectional view of a human eye.

Fig. 2 is an enlarged cross-sectional view of the cornea of the human eye of fig. 1.

Figure 3A is a plan elevation view of a corneal appliance as disclosed herein.

Figure 3B is a cross-sectional view of the corneal appliance of figure 3A.

Figure 4A is a plan elevation view of a lens for use on the corneal appliance disclosed herein.

Fig. 4B is a cross-sectional view of the lens shown in fig. 4A.

Figure 5A is an enlarged cross-sectional view of a de-epithelialized cornea.

Figure 5B is a schematic view of the de-epithelialized cornea shown in figure 5A on which a corneal appliance is placed.

Fig. 6A is an illustration of a planar elevation view of an eye in which a flap is formed by a preformed epithelial cell layer.

Fig. 6B is a cross-sectional view of the eye shown in fig. 6A.

Fig. 6C is a cross-sectional view similar to fig. 6B, in which the lens has been placed in a de-epithelialized eye, and the pre-formed epithelial layer has been placed over the lens.

Fig. 7A is an illustration of a planar elevation view of an eye in which a preformed layer of epithelial cells forms a pocket.

Fig. 7B is a cross-sectional view of the eye shown in fig. 7A.

FIG. 7C is a cross-sectional view similar to FIG. 7B, where a lens has been placed on the pocket.

Fig. 8A is an illustration of a planar front view of an eye with a large incision.

Fig. 8B is similar to fig. 8A, with a smaller cut.

Fig. 8C is similar to fig. 8B, with a smaller cut.

Fig. 9A is an illustration of a planar elevation view of an eye having a smaller incision in the epithelium.

FIG. 9B is a front view similar to FIG. 9A, with a fluid injector inserted into an incision in the epithelium to deliver fluid thereunder.

Fig. 9C is a cross-sectional view of the eye shown in fig. 9B, after fluid has been delivered beneath the epithelium.

FIG. 9D is a cross-sectional view similar to FIG. 9C in which a lens has been inserted beneath the pre-formed epithelial cell layer.

Fig. 10A is a front view of an eye having an epithelial flap with an articulating portion located above.

Fig. 10B is a plan elevation view of an eye having a central epithelial incision.

Fig. 10C is a plan elevation view of an eye having an offset epithelial incision.

FIG. 10D is a plan elevation view similar to FIG. 10C, with two offset incisions used to form two epithelial flaps with offset hinge portions.

FIG. 10E is a plan elevation view similar to FIG. 10B, with a central epithelial incision being used to form two epithelial flaps with offset hinge portions.

Fig. 11A is an illustration of a planar elevation view of an eye with an offset epithelial incision.

Fig. 11B is a cross-sectional view of the eye shown in fig. 11A.

Fig. 11C is an illustration of a perspective view of a folded lens configured for insertion into an epithelial incision.

FIG. 11D is an illustration of a perspective view of a folded lens, wherein the lens is folded along its midline.

Figure 12A is an illustration of a planar front view of a corneal cover lens.

Fig. 12B is a cross-sectional view of the lens shown in fig. 12A.

Fig. 12C is an enlarged cross-sectional view of the rim of the cover lens, wherein the rim is rounded.

Fig. 12D is an enlarged cross-sectional view of the rim of the cover lens, wherein the rim includes a rounded anterior portion and an apex at the posterior portion.

Fig. 12E is an enlarged cross-sectional view of the edge of the cover lens, wherein the edge resembles a knife edge.

Figure 13A is an illustration of a planar front view of a cover lens configured to correct astigmatism.

FIG. 13B is a cross-sectional view of a cover lens similar to FIG. 13A, wherein the rear surface of the lens includes a protuberance (torus).

Fig. 13C is a cross-sectional view of a cover lens similar to fig. 13A, wherein the anterior surface of the lens includes a protuberance.

Detailed Description

As shown in FIG. 1, a typical human eye has a lens 12 and an iris 14. Posterior chamber 16 is located posterior to iris 14 and anterior chamber 18 is located anterior to iris 14. As discussed herein, the eye 10 has a cornea 20 with five layers. One layer of the corneal epithelium 22 is flush with the anterior outer surface of the cornea 20. The corneal epithelium 22 is a stratified squamous epithelium that extends transversely to the limbus 32. At the limbus 32, the corneal epithelium 22 thickens and becomes less regular to define the conjunctiva 34.

Fig. 2 shows an enlarged schematic view of the five layers of the cornea 20. Generally, the cornea 20 includes a corneal epithelium 22, a front elastic layer 24, a stroma 26, a back elastic layer 28, and an endothelium 30. The corneal epithelium 22 is typically about 5-6 cell layers thick (about 50 microns thick) and typically regenerates when the cornea is damaged. The corneal epithelium 22 provides a relatively smooth refractive surface and helps prevent ocular infection. The pre-elastic layer 24 is located between the epithelium 22 and the stroma 26 and is believed to protect the cornea from damage. The corneal stroma 26 is a layered structure of collagen that includes cells, such as fibroblasts and corneal cells, dispersed therein. The stroma 26 constitutes approximately 90% of the corneal thickness. The corneal endothelium 30 is typically a single layer of flattened cuboidal or squamous cells that dehydrate the cornea by removing water from the cornea. The thickness of an adult cornea is typically about 500 μm (0.5mm) and is generally free of blood vessels.

In fig. 1, the limbus 32 is shown, which is the transition zone of the cornea into the sclera and sclera. Limbus 32 comprises stem cells, which, as disclosed herein, are capable of differentiating into corneal epithelial cells.

As shown in figure 3A, a corneal appliance 60 has been invented that is configured to be placed over a de-epithelialized eye and generally includes a lens 40 and an epithelial layer 70, or epithelial cell layer, overlying the lens. The corneal appliance 60 is configured to alter the focusing power of the patient's eye and is preferably configured to improve the patient's vision. It is contemplated that the corneal appliance 60 may be placed on a de-epithelialized cornea of an eye, and thus, the corneal appliance 60 may be a corneal onlay. The corneal appliance 60 includes an epithelial layer 70 that reduces the healing time required after a patient's surgery as compared to a corneal onlay, which depends on the regeneration and migration of epithelial cells on the corneal onlay after placement of the corneal onlay on the eye. In addition, the pre-formed epithelial layer 70 provides more uniform epithelial coverage of the cornea than conventional corneal coverings.

As disclosed herein, the epithelial cells placed over the lens may be obtained from the patient receiving the corneal appliance and may be derived from patient stem cells, such as limbal stem cells, which may be cultured in vitro to form the epithelial layer of the appliance. Autologous stem cells result in reduced immunogenicity experienced by patients receiving the appliance as compared to the use of non-autologous derived epithelial cells, such as corneal onlays from fetal or embryonic tissue. In addition, the use of patient-specific stem cells reduces the amount of biopsy tissue required to use corneal coverings of mature or differentiated epithelial cells.

In addition, the epithelial cell layer may be formed by: a portion of the patient's epithelium is separated to form an epithelial flap that can be excised and then placed back over the corneal onlay after placement of the covering over the eye. As discussed herein, the incision around the epithelial flap can be patched over the covering to hold the covering in a desired position on the eye. The pre-formed epithelial cell layer may also be part of the patient's corneal epithelium, which has been separated from the underlying pre-elastic layer or corneal stroma. The pre-formed epithelial layer may be separated from the underlying corneal structure, with or without formation of an epithelial flap, depending on the particular embodiment of the present invention. For example, a cut may be made in the epithelium to provide access to the area between the epithelium and the pre-elastic layer. The epithelium may be separated from the pre-elastic layer by placing a separator in the incision. The separator may be a surgical instrument or may include a substance injectable through the incision. The separator is effective to separate the epithelium from the front resilient layer without significant damage to the front resilient layer. However, the separator may also allow for a smaller incision to be made in the anterior elastic layer without significantly damaging the anterior elastic layer, which facilitates placement of the lens on the substrate and promotes faster or more satisfactory healing of the eye. The corrective ocular device, such as a corneal onlay, may then be inserted between the epithelium and the pre-elastic layer. Preferably, in this embodiment, there is no need to realign the epithelium after insertion of the ocular device and the problem of misalignment of the ocular device is reduced. It is specifically noted that the lens 40 is maintained in a substantially fixed position on the eye relative to the lens, e.g., a substantially identical lens placed on the eye, so that the epithelium must regenerate and migrate over the lens.

The lens 40 used in the corneal appliance 60 may be made of any suitable optically clear material that allows light to be transmitted to the retina of the eye when the corneal appliance 60 is placed on the eye without disrupting the physiology of the eye. As shown in fig. 4A and 4B, lens 40 has an anterior surface 42, a posterior surface 44, and a peripheral edge 46 between anterior surface 42 and posterior surface 44. The anterior surface 42 is generally convex and the posterior surface 44 is generally concave, however, the posterior surface may also include one or more planar portions or surfaces or may be substantially planar. Lens 40 may also include optic zone 48 and peripheral zone 50. Generally, viewing zone 48 is surrounded by peripheral zone 50, or in other words, the viewing zone is generally centered about the optical axis of the lens, such as the central optical axis, with peripheral zone 50 being located between the edge of viewing zone 48 and peripheral edge 46. Other zones and lens configurations may also be provided on the lens, depending on the particular defect experienced by the patient. In addition, the lens may also have no land, such as two or more zones that do not have a land portion that is visible to the naked eye or that is optically detectable. These zones of the lens may be smooth and continuous and the lens may be optically optimized to correct not only refractive errors, but also other ocular abnormalities of the eye and/or optical device, either alone or in combination with correcting refractive errors. As will be appreciated by those skilled in the art, the lens 40 may be configured to correct vision defects including, but not limited to, myopia, hyperopia, astigmatism, and presbyopia. The lenses can correct or ameliorate visual defects by optical or physical means or a combination thereof placed on the ocular substrate. Thus, the lens 40 of the corneal appliance 60 may be a single focus lens or a multi-focus lens, including, but not limited to, a dual focus lens. Additionally or alternatively, the lens 40 may be a toric lens, such as the lenses shown in fig. 13A, 13B, and 13C. For example, lens 40 may include a toric zone 49 that is effective when placed on an eye having astigmatism to correct or reduce the astigmatic effect. Lens 40 may include a toric zone 49a on the posterior surface 44 of lens 40, as shown in fig. 13B, or lens 40 may include a toric zone 49B on the anterior surface 42, as shown in fig. 13C. Advantageously, toric lenses can be used without the need for ballast to maintain the correct orientation of the lens on the eye, as the lens can be held in a relatively fixed position by the epithelium of the orthosis. However, ballast (ballast) may be provided if desired. In certain embodiments, the lens 40 may include ballast, such as prisms, or it may include one or more thin regions, such as one or more lower and/or upper thin regions. On lenses configured to correct for presbyopia, the lens may include one or more designs such as concentric, aspherical (with positive and/or negative-spherical aberration), diffractive, and/or multizone refractive.

In certain embodiments of the corneal appliance 60, the lens may have a power of about-10.00 diopters to about +10.00 diopters, although other powers may be provided and are within the scope of the present invention. Typically, the lens of the corneal appliance has a diameter of about 6mm to about 12 mm. The diameter of the lens is preferably from about 7mm to about 10 mm. The diameter of the optic zone of the lens is generally from about 5 to about 11mm, and preferably from about 6mm to about 8 mm. The optic zone may be provided on the anterior or posterior surface of the lens.

The posterior surface of the lens 40 is specially configured to be substantially aligned with the anterior surface of the de-epithelialized eye. Thus, the posterior surface of the lens 40 may include one or more spherical or aspherical dimensions having a base curve with a diameter of about 5.0mm to about 12.0mm, preferably about 6.0mm to about 9.0mm, more preferably about 7.0mm to about 8.5 mm. The thickness of the lens 40 at or near the center of the lens (i.e., the center thickness) is typically in excess of about 10 microns and less than about 300 microns. The center thickness is preferably from about 30 microns to about 200 microns. Since the maximum thickness is determined by the optical power and refractive index, the exact or specific thickness of the central zone can be determined on a case-by-case basis by one of ordinary skill in the art.

The thickness of the peripheral edge 46 of the lens 40 is typically, but not always, less than the center thickness, as shown in fig. 12A, 12B, 12C, 12D, and 12E. The rim thickness should be thin enough to facilitate epithelial cell growth at the junction between the lens and the anterior elastic layer or stroma of the eye, and may be thin enough to promote additional epithelial cell migration over the rim of the lens. Typically, the edge thickness of the lens is less than about 120 microns. In some embodiments, the thickness of the edge of the lens 40 is less than about 60 microns, and preferably less than about 30 microns. In a preferred embodiment, the thickness of the edge of the lens 40 is about 0 microns (e.g., the thickness of a sharp blade). As shown in fig. 12C, the lens edge may be rounded on the front and back surfaces, as shown in fig. 46A. In addition, the lens edge may include a rounded anterior surface 42 and an apex at or near the posterior surface 44, as shown in FIG. 12D. Alternatively, the lens edge may be knife-edge shaped, as shown at 46B in fig. 12E.

The lens 40 may comprise synthetic or non-synthetic materials and combinations thereof. In this context, the phrase synthetic material means a material that is not obtained from an animal subject, e.g., is not directly obtained from an animal subject. Thus, synthetic materials specifically exclude donor corneal tissue.

In one embodiment, the lens 40 may be made of collagen, such as purified collagen. The collagen may be type I collagen, which forms the bulk of the corneal stroma, or the lens 40 may be made of other types of collagen, including combinations of different types of collagen, such as type III, IV, V, and VII. In certain embodiments, the collagen may be obtained from an animal, including a human. For example, the collagen of the lens 40 may be bovine collagen, porcine collagen, avian collagen, murine collagen, equine collagen, and the like. Many different types of collagen that can be used in the lenses of the invention are publicly available from companies such as Becton Dickenson. In other embodiments, the collagen may be recombinantly synthesized, such as by using recombinant DNA techniques. Preferably, the lens 40 is not obtained from the donor patient, such as from corneal tissue of another individual. Collagen may be obtained by any conventional technique, such as those commonly used in the art. One source of recombinant collagen that is publicly available is FibroGen, Southsan Francisco, Calif. Alternatively or additionally, recombinant collagen may be prepared and obtained by the methods disclosed in PCT publication No. WO 93/07889 or WO 94/16570. The recombinant production techniques disclosed in the above-mentioned PCT publications can be readily modified to produce many different types of collagen, human or non-human. The use of purified collagen simplifies the procedure for preparing corneal onlays, as compared to corneal onlays obtained from donor tissue, as disclosed in PCT publication No. WO 02/06883. For example, the use of purified collagen, including recombinant synthesized collagen, avoids the step of decellularizing the donor corneal tissue. Additionally, the collagen may be fully or partially biodegradable, which may facilitate the attachment of epithelial cells to the covering by allowing the natural collagen produced by the patient receiving the covering to integrate and/or replace the collagen of the corneal appliance. The collagen used to produce the lens 40 may be implanted into cells, such as corneal cells, and then used on the corneal appliance 60. Cells may be added to the collagen, including culturing a corneal cell suspension, and then soaking the lens in corneal cell culture medium, as disclosed in WO 02/06883. Preferably, the cells used to implant the lens do not produce an immune response, or produce a minimal immune response. Thus, the cells may be from an allogeneic source, such as another person, an autologous source, such as the patient receiving the appliance, or may be from a xenogeneic source. As will be appreciated by those of ordinary skill in the art, cells obtained from xenogeneic sources may need to be modified in order to reduce the antigenicity or immunogenicity of the cells when administered to the patient in order to reduce the likelihood of an immune response occurring. Additionally, in embodiments where a lens having one or more openings is placed over the anterior elastic layer, corneal cells from the patient's own stroma can be implanted into the collagen lens, and the integration between the lens and the stroma can facilitate fixation of the lens to the eye.

In addition, the lens 40 may be produced by obtaining and culturing corneal cells, as disclosed in PCT publication No. WO99/37752 and U.S. Pat. No. 5,827,641. A culture of corneal cells is placed in a mold of a lens suitable for vision correction and is capable of producing a collagen matrix similar to the normal matrix in vivo. Thus, the various molds produce a synthetic matrix corneal appliance having the desired power to correct the patient's vision deficiencies.

The lens 40 of the corneal appliance 60 may be made of a polymerized hydrogel, as will be appreciated by those of ordinary skill in the art. Polymeric hydrogels include hydrogel-forming polymers, such as water swellable polymers. The hydrogel itself comprises a polymer that is swellable with water. The polymeric hydrogels useful as corneal appliance lenses, for example, corneal onlays, typically have about 30% to about 80% water by weight, but may have about 20% to about 90% water by weight or about 5% to about 95% water by weight, and a refractive index of about 1.3 to about 1.5, for example about 1.4, similar to that of water and human cornea.

Examples of suitable hydrogel-forming polymeric materials or components of the disclosed lenses include, but are not limited to, poly (2-hydroxyethyl methacrylate) PHEMA, poly (glycerol methacrylate) PGMA, polyelectrolyte materials, polyethylene oxide, polyvinyl alcohol, polydioxaline, poly (acrylic acid), poly (acrylamide), and poly (N-vinyl pyrrolidone), and the like, and mixtures thereof. Many such materials are publicly available. In addition, one or more monomers that are not themselves capable of producing homopolymers (which are not hydrogel-forming polymers), such as Methyl Methacrylate (MMA), other methacrylates, and acrylates, and the like, and mixtures thereof, can also be included in the hydrogel-forming polymer material, so long as the presence of units derived from the monomers does not interfere with the formation of the desired polymeric hydrogel.

Additionally, in certain embodiments, the lens 40 of the corneal appliance 60 may be made of a biocompatible material, a non-hydrogel material or composition, as disclosed in U.S. patent No. 5,713,957. Examples of non-hydrogel materials include, but are not limited to, acrylics, polyolefins, fluoropolymers, silicones, styrenic resins, vinyls, polyesters, polyurethanes, polycarbonates, cellulosic materials, or proteins including collagen-based materials. Additionally, the lens 40 may include a cell growth matrix polymer, such as those disclosed in U.S. patent No. 5,994,133.

Thus, in the illustrated embodiment of the invention, the corneal appliance 60 includes a lens 40 that includes a synthetic material, and more particularly, a non-donor corneal tissue material. In one embodiment, the lens is made entirely of a synthetic material. In certain embodiments, the lens is made from a combination of collagen and synthetic materials, including a combination of bovine collagen and synthetic materials, and a combination of reconstituted collagen and synthetic materials. In another embodiment, the lens may include a poly (N-isopropylacrylamide) (polynipam) component. It has been found that a polynipam composition promotes the adhesion of the lens to the pre-elastic layer and/or the adhesion of the epithelial cell layer to the lens at a temperature of about 37 c. At lower temperatures, such as temperatures of about 32 ℃, the lens can advantageously be separated from the corneal tissue. See, for example, Nishida, k. et al, "novel tissue engineering methods for ocular surface reconstruction, bioengineered corneal epithelial layer grafts using ex vivo expanded limbal stem cells on temperature sensitive cell culture surfaces," ARVO artificial Meeting, Fort Lauderdale, FL, May 4-9, 2003. According to the invention, the polynipam component promotes in vivo attachment of the epithelium to the lens, substantially at normal body temperature, and may assist in the process of removing the lens from the eye by cooling the eye tissue.

The corneal appliance disclosed herein can provide vision correction for a subject in need thereof. In certain embodiments, the corneal appliance lens is designed to correct or reduce wave aberration in the eye of a patient. The wavefront aberration is the three-dimensional shape of the distance between the actual wavefront of the light's center point and a reference surface, e.g., an ideal spherical shaped surface, as shown in FIG. 1 of U.S. Pat. No.6,585,375, and disclosed in Mierdel et al, "DerOphthalcogolome", No.6, 1997. Wave aberration can be understood as the optical path difference between the actual image wavefront and the ideal reference wavefront centered at the image point, which is the optical path difference at any point on the eye pupil. Methods for measuring wave aberration are well known to those of ordinary skill in the art.

Briefly, and as disclosed in the following documents: nader, n., ocularsurry News, "learn new language: understanding the term of wavefront-guided ablation' (February1, 2003), aberrometers (e.g., instruments that measure ocular aberrations) can be used to determine the erroneous images leaving the eye, or can be used to determine the shape of the mesh projected on the retina. For example, while the patient is holding his or her gaze on a vision fixation target, a relatively narrow input laser beam may be directed through the pupil and focused on the retina of the patient's eye to create a point source of light on the retina. The light reflects off the retina back through the pupil and the wavefront of the light passing through the eye passes to the wavefront sensor. As will be appreciated by those of ordinary skill in the art, a wavefront can be defined as a surface connecting all of the field points of an electromagnetic wave that are equidistant from a light source. The light leaves the eye and may pass through an array of lenses, the light deviation being detected by the array. The wavefront is shifted or distorted by non-uniformities in the refractive properties of the ocular media, such as the lens, cornea, aqueous humor, and vitreous. The resulting image is then recorded, for example, by a Charge Coupled Device (CCD) camera.

The wavefront is then generally reconstructed and the deviation is described three-dimensionally by mathematical methods. The calculation of the wavefront deviation can be performed at least in part by analyzing the direction of the light. In general, a parallel beam represents a wavefront with little, if any, aberration, while a non-parallel beam represents a wavefront with aberration that does not produce equidistant focal points.

Typically, Zernike polynomials are used to determine or analyze ocular aberrations. Each Zernike polynomial represents a shape or three-dimensional surface. As understood by those of ordinary skill in the art, Zernike polynomials are an infinite set, but in ophthalmology, Zernike polynomials are typically limited to the first fifteen polynomials. The second order Zernike polynomials represent conventional aberrations such as defocus and astigmatism. Aberrations above the second order aberration are referred to as higher order aberrations. Higher order aberrations are generally not corrected by conventional spherocylindrical lenses. Examples of higher order aberrations include, but are not limited to, coma, spherical aberration, trefoil (with a triple symmetric wavefront), and tetrafoil (with a quadruple symmetric wavefront shape). Many of the higher order aberrations are not symmetric, however, some of the higher order aberrations, such as spherical aberration, may be symmetric.

According to the present invention, the wave aberration of a patient's eye can be determined and analyzed to facilitate the construction of a suitable lens. The lens of the present invention may then be shaped, as disclosed herein, taking into account any wave aberration. Thus, a corneal appliance is obtained having a lens configured to correct the wave aberration of a patient's eye. The wavefront aberration correcting surface may be disposed on the anterior surface, the posterior surface, or both. Thus, in certain embodiments, the lenses of the invention are capable of correcting or reducing higher order wave aberrations. Where the higher order wave aberrations are asymmetric, the lens is configured to substantially maintain a desired orientation to correct the wave aberrations.

The epithelial layer 70 is secured to the lens 40 of the corneal appliance 60. The epithelial layer 70 may include one or more epithelial cell layers. The number of epithelial cell layers is preferably 1-12, more preferably about 5-7. Thus, the number of epithelial cell layers 70 closely matches the number of corneal epithelial layers observed in vivo. The number of epithelial cell layers may also vary over time. For example, a monolayer of epithelial cells may be placed on the lens 40 ex vivo, and the lens may be placed on the eye. Following the procedure of placing the lens on the eye, the epithelial cells may continue to divide to form one or more additional epithelial cell layers. In addition, the epithelial layer 70 may comprise about 5-7 cell layers when it is placed over the lens 40.

The epithelial layer 70 is sized to cover at least a portion of the anterior surface 42 of the lens 40. In the illustrated embodiment of the corneal appliance 60, the epithelial layer 70 extends beyond the peripheral edge 46 of the lens 40. Thus, a flap or a strip of epithelium 70 extends from the edge of the lens 40, which can be used to help secure the corneal appliance 60 to the eye. When the epithelial layer 70 does not extend to or beyond the peripheral edge 46, it is desirable to ensure that epithelial cells of the epithelial layer 70 or of the epithelium of the patient's eye continue to divide and migrate through the exposed portion of the lens. Suitable growth factors or other growth promoting methods may be employed to achieve such results.

As noted herein, the epithelial layer 70 may be derived from stem cells obtained from autologous sources. In the illustrated embodiment of the corneal appliance 60, the epithelial layer is derived from cultured stem cells obtained from the patient receiving the corneal appliance. This is in contrast to the corneal onlays disclosed in WO 02/06883, which utilize epithelial cells from fetal or embryonic tissue, or epithelial cells obtained from a patient receiving the corneal onlay. However, the epithelial cytosol may be derived from any type of stem cell capable of differentiating into corneal epithelial cells, including stem cells from fetal or embryonic tissue.

In one embodiment of the corneal appliance 60, the stem cells obtained from the patient are corneal epithelial limbal stem cells. The corneal epithelial limbal stem cells may be harvested, cultured and prepared as disclosed in the following references: U.S. patent application No. US 2002/0039788a1, and Han et al, "fibrin-type bioengineered ocular surface with human corneal epithelial stem cells", Cornea, 21 (5): 505-510, 2002. Briefly, corneal epithelial stem cells may be cultured on an extracellular matrix, which may include basement membrane components such as laminin, fibronectin, elastin, integrins, and collagen. Cultured epithelial stem cells are expanded on a feeder layer of replication-deficient, but metabolically active fibroblasts (e.g., 3T3 cells). After establishment of epithelial colonies, feeder cells are removed and the epithelial cells are expanded by growth in serum-free, low calcium medium, such as corneal cell growth medium KGM (cascadebiologices, OR). The cultured epithelial cells can then be trypsinized from their culture dishes, suspended in corneal cell growth medium CGM (Cascade biologics), and seeded onto prepared fibrin gels. The fibrin gel is prepared by mixing a solution of fibrinogen in distilled water (human plasminogen-free fibrinogen, Calbiochem, San Diego, Calif.) with calcium chloride, and aprotonin (Sigma) in a buffer, such as Tris buffer at a pH of about 7.0, e.g., 7.2. Cultured corneal fibroblasts and thrombin may be added to the solution, and then the solution is dispersed on a scaffold of gel.

The epithelial layer 70 is attached to the anterior surface 42 of the lens 40 so that the epithelial layer 70 does not move significantly or significantly along the surface of the lens. Thus, when the epithelial layer 70 and the lens 40 are fixedly coupled or connected, they form the corneal appliance 60. The epithelial layer 70 may be attached to the lens 40 by chemical, biological, mechanical, or electrical means.

In certain embodiments, the corneal appliance 60 may further include a cell attachment member positioned between the epithelial layer 70 and the anterior surface 42 of the lens 40. The cell attachment components facilitate stable positioning of the epithelial layer 70 on the lens 40. Although cell attachment members may be desirable when using lenses made of collagen, as disclosed above, most cell attachment members have increasing utility in hydrogel or non-hydrogel lenses. The cell attachment means may comprise physical disturbances of the lens 40, such as grooves provided on the front surface 40, which facilitate cell attachment and do not alter the optical properties of the lens. The recess includes an aperture through the lens extending from the front surface to the back surface of the lens. These grooves may be provided on the entire lens or on a part of said lens. The grooves can also be provided in a specific pattern and size to facilitate the attachment of the epithelial layer to the lens. For example, the grooves can be provided in the form of a plurality of concentric rings emanating from the center of the lens and expanding radially outward. The cell attachment member may also include a polymer that supports adhesion of epithelial cells to the lens. As described above, the lens may be made substantially from a polymer such as that disclosed in U.S. patent No. 5,994,133. In addition, the cell growth matrix polymer may be chemically bonded or otherwise coated on the surface of a hydrogel or collagen-based lens in order to promote cell attachment to the lens. The cell attachment means may also include corneal enhancing molecules, such as corneal enhancing molecules that specifically bind to molecules present on the extracellular surface of epithelial cells. Examples of suitable corneal enhancing molecules include peptides such as tripeptides, RGD, extracellular matrix proteins, corneal growth factors, and ligand-specific corneal enhancing substances such as laminin, fibronectin, substance P, fibronectin adhesion promoting peptide sequences, FAP, insulin-like growth factor-1 (IGF-1), k-laminin, ankyrin, integrin, ankyrin, Fibroblast Growth Factor (FGF), and TGF- β, as disclosed in U.S. patent publication No. US 2002/0007217a 1. The corneal enhancer molecule may include a tether (teter) that enhances the ability of epithelial cells to attach to and migrate over the lens 40.

As described above, the lens 40 of the corneal appliance 60 may be made of collagen to mimic a natural corneal stroma, a hydrogel, or a biocompatible non-hydrogel material. The lens of the corneal appliance 60 may be produced according to standard techniques known in the art. As described above, when a stromal-like lens is desired, a collagen mixture can be formed and include stromal cells. The lens 40 may be molded in a mold of conventional dimensions suitable for a lens, such as a corneal onlay. For example, the lens 40 may be abrasive (etched), molded, spin cast and/or machined, or a combination thereof. However, because epithelial cells may need to be cultured on the lens 40, the molds used to produce the corneal appliance 60 may be configured to allow nutrient, liquid, and gas exchange with the cultured cells. For example, the mould may comprise one or more apertures to allow nutrients and liquids and gases to flow into the cell culture. The mold may be made of any suitable, porous material, including, but not limited to, ceramics, mesh, such as stainless steel mesh, or a membrane made of nylon or cellulose. In one embodiment, the mold may include a concave surface and a convex surface that are shaped to mate with each other. The mold may be placed into a well with culture medium to facilitate the culturing of the cells. The shape of the lens may be determined by a mold designed for cultivation (hereinafter referred to as cultivation mold), or may be molded in a conventional mold. If molded in a conventional mold, the lens may then be placed in a petri dish having a desired shape to maintain the shape of the lens, wherein the petri dish is configured to facilitate culturing of the epithelial cells.

Epithelial cell layer 70 may be prepared substantially as described above. Briefly, fibrin matrix, or other extracellular protein matrix, may be produced from serum, and corneal epithelial stem cells may be seeded into the matrix. The seeded substrate may then be placed on the front surface of the lens. The cells may be applied by dispensing the matrix on the surface of the lens, or the cells may be applied as a relatively flexible layer of cells or a thin film of cells, which is sufficiently flexible to accommodate the curvature of the lens. The thin film of cells may comprise a corneal epithelial stem cell thin film or a developed epithelial cell thin film, which may have one or more layers of thickness, or a combination thereof.

In addition, epithelial cell layers can be obtained by culturing immortalized human corneal epithelial cells, as disclosed in U.S. patent No.6,284,537. Once the corneal appliance is placed on the eye, it is desirable to use this cell line to regulate cell growth. Cell growth may be regulated by any conventional method known to those of ordinary skill in the art.

In another embodiment, the epithelial cell layer can be an epithelial cell layer or flap of a patient that is isolated from a cornea of the patient, as disclosed herein. After the lens is placed on the cornea, the pre-formed epithelial cell layer may be placed on the lens. The lens may or may not be surface treated to aid in the attachment of the epithelial cell layer to the lens. For example, when the lens used is made of a polymeric or composite material that promotes cell attachment, it may not be necessary to include a surface treatment on the lens.

Additionally, one embodiment of the corneal appliance includes providing a suspension of epithelial stem cells on the anterior surface of the lens. As disclosed herein, the suspension may be a fibrin-based suspension. It is believed that the epithelial stem cells provided on the lens may provide nutrients, such as growth promoting factors, which promote the attachment of the epithelial cell layer to the lens. Thus, a suspension of stem cells is provided on the lens and an epithelial flap is placed on the lens, and the stem cells promote attachment and growth of the epithelial flap on the lens. Surprisingly, the stem cells survive long enough after placement on the lens to promote adhesion of the epithelial cell layer to the lens.

In another embodiment, the corneal appliance 60 may be produced by molding a synthetic material, such as reconstituted collagen, in a lens mold having the desired configuration to correct vision defects. The collagen lens may be seeded with stromal corneal cells having low antigenicity or immunogenicity. The surface of the collagen lens may be modified to promote cell attachment of epithelial cells, and then epithelial stem cell cultures may be placed on the collagen lens where they are able to grow and differentiate into an epithelial cell layer.

The corneal appliance 60 may be placed on the eye to provide the desired vision correction. As described above, because the corneal appliance 60 includes an epithelial layer, at least a portion of the epithelium needs to be removed from the eye of the patient receiving the appliance. The de-epithelialized portion should have at least substantially the same dimensions as the corneal appliance. A de-epithelialized cornea is shown in fig. 5A.

The epithelium may be removed by any conventional method. For example, the epithelium may be removed with an abrasive device, sterile cocaine may be applied to the epithelium using a small rotating brush, an alcohol wash, such as an alcohol wash, may be used alone or in combination with an electromagnetic energy source on the epithelium, such as with the LASEK and LASIK methods, which are well known. Alternatively, a portion of the epithelium may be removed with a separator that is capable of separating the epithelium from the pre-elastic layer to form a pre-formed epithelial cell layer. One example of a separator is the sub-epithelial separator developed by doctor ioani smalikaris (greece), such as the separators disclosed in U.S. patent publication nos. 2003/0018347 and 2003/0018348. The separator may include a suction device, or ring, which may deliver suction to the epithelium to cause the epithelium to lift from the cornea. A cutting device, such as a blade, including a microkeratome, which may or may not be part of the separator, may then be used to cut the portion of the epithelium lifted from the cornea to form an epithelial flap, or to completely cut the manipulated portion of the epithelium. Alternatively or additionally, the separator may include a temperature controller that causes a change in temperature of the portion of the device in contact with the epithelium. The separator may be cooled to cause the epithelium to adhere to the cooled region of the separator so that it can lift from the cornea, and then heated, either passively or actively, to release the cut epithelial tissue from the separator. It has been found that the temperature control is capable of manipulating the epithelial cells of the epithelium without unduly damaging and injuring the epithelial cells in the above process. The cooling appears to not only provide a convenient way of attaching the epithelium to the separator, but also, the cooling provides protection for the cells manipulated during the procedure. Where electromagnetic energy is used as the epithelium cutting device, it may be desirable to use an electromagnetic energy source, such as a laser, with reduced, and preferably no, thermal energy to help reduce cell damage in the above process. For example, a fluid such as water or saline may be used in combination with the electromagnetic energy in order to reduce thermal damage caused by the electromagnetic energy. In removing the corneal epithelium, it may be desirable to remove one or more small portions of the anterior elastic layer, as noted herein, in order to facilitate faster healing of the ocular tissue. However, in some instances, the front resilient layer remains intact.

Once the desired amount of epithelium has been removed, the corneal appliance 60 may be placed on the de-epithelialized cornea. When the lens of the appliance is made of collagen, the lens may form a natural bond with the pre-elastic layer, which bond holds the lens to the eye. However, other adhesion mechanisms may be used to facilitate securing the appliance to the eye. For example, glue, preferably biodegradable glue, may be applied to the overlapping edges of the epithelium 70, dissolvable sutures may be used to secure the epithelial edges to the eye, or pressure applied by a bandage may be used to hold the appliance to the eye until the epithelium has been bonded to the rest of the eye. Additionally or alternatively, a fibrin-based stem cell matrix may be used as an adhesive to help maintain the epithelium in place and promote healing and development of the epithelium. Once the procedure is complete, the epithelium of the corneal appliance 60 is mixed with any remaining corneal epithelium remaining on the eye, as shown in fig. 5B. Thus, the corneal appliance 60 has an epithelial layer that adheres more reliably or consistently to the lens than to an epithelium that adheres to a lens obtained from donor tissue, such as the epithelium disclosed in PCT publication No. WO 02/06883.

The corneal appliance 60 may provide significant improvements in the field of vision correction technology. The appliances are devices that provide long-term vision correction that can be restored, as opposed to methods that permanently alter the shape of a patient's cornea, such as the LASEK and LASIK methods. In this regard, the corneal appliance may be conveniently removed from the patient if complications arise or if the patient's vision changes. Thus, the corneal appliance 60 provides long-term, but recoverable, vision correction.

For example, and not by way of limitation, a method of improving a patient's vision may begin with a visit for a visually impaired patient. The physician obtains a sample of corneal epithelial stem cells from the patient and sends the cell sample to a laboratory for culture. As described above, in the laboratory, the cells were seeded onto a fibrin matrix and cultured, and applied onto the anterior surface of the lens. The anterior surface of the lens may be treated or modified to promote cell attachment of the epithelial cells. The surface treatment may comprise physical disturbance, such as roughening the surface of the lens, or may comprise providing the lens with one or more cell attachment members, as discussed above. After about 10-20 days, the cultured cells have developed into an epithelial cell layer covering substantially the entire surface of the lens. The corneal appliance may then be sent to a doctor's office. The patient returns to the doctor's office for an operation that includes removing the epithelium from the patient's cornea and placing the corneal appliance on the de-epithelialized cornea. The epithelium is preferably removed only to the anterior elastic layer and removed so that the diameter of the de-epithelialized portion of the cornea corresponds to the diameter of the epithelial layer of the corneal appliance.

In addition, another method of improving a patient's vision includes forming a slit, incision, or opening in the patient's corneal epithelium that is large enough to enable insertion of the lens described above through the slit and beneath the epithelium, as shown in FIGS. 7A, 7B, and 7C. After forming the slit 72, the epithelium may be separated from the pre-elastic layer using standard blunt dissection techniques or other conventional methods to form the pre-formed epithelial cell layer 70. In addition, as described above, the corneal epithelium may be separated from the cornea with a separator. The epithelium may be separated to form a tissue flap (fig. 6A, 6B, and 6C), or may be separated to form an epithelial pocket, such as pocket 74 shown in fig. 7B, without forming a flap. The lens 40 may or may not be surface treated to promote cell attachment, and may be inserted under an epithelial flap, or into a pocket formed between the epithelium and the pre-elastic layer. After the lens is placed and the epithelial layer is placed over the lens, an adhesive such as a corneal epithelial layer from a stem cell or stem cell suspension as described above may be placed on the patient's epithelium in the region of the slit to promote healing of the incision.

In accordance with the above disclosed method, a method of correcting or improving vision includes the step of inserting a vision correcting ocular device, such as a corrective lens or lenticule, under the epithelium of a patient's cornea without substantially revealing or exposing the anterior surface of the cornea underlying the epithelium, as shown in fig. 7A, 7B, and 7C. The anterior surface of the cornea may be the anterior elastic layer, or it may comprise one or more portions of the corneal stroma. This method is different from the technique of creating an epithelial tissue flap that exposes or reveals the anterior surface of the cornea, as discussed herein, and illustrated in fig. 6A, 6B, and 6C. By inserting the ocular device beneath the epithelium, but at or above the stroma or pre-elastic layer, the ocular device can be effectively substantially fixedly positioned relative to the eye, e.g., by the epithelium, to provide the desired vision correction. In addition, the method provides relatively enhanced healing or reduced healing time and reduced side effects relative to methods of creating epithelial tissue flaps for insertion into ocular devices.

In one aspect of the above method, the lens may be inserted through an incision formed in the epithelium inserting an ocular device. The incision can be made in any desired area around the epithelium, although in preferred embodiments the incision is made in the temporal portion of the epithelium (e.g., the portion of the epithelium located away from the patient's nose), or in the medial portion of the epithelium. The incision is preferably formed to provide an opening in the epithelium, e.g., of a suitable size to accommodate a corrective eye device to be inserted therethrough without forming an epithelial flap. By forming incisions of different sizes, the pre-formed epithelial layer diameter 70D may be varied, as shown in FIGS. 8A, 8B, and 8C. For example, the relatively large incision 72 shown in fig. 8A may provide a smaller preformed epithelial diameter 70D. Additionally or alternatively, the incision size may be varied to accommodate various insertion techniques, such as whether the lens is deformed prior to insertion. Thus, a large notch may be formed when the lens is inserted in a substantially non-deformed state, or a small notch may be formed when the lens is inserted in a deformed state.

In certain embodiments, it is desirable to form a relatively small incision and deform the ocular device prior to insertion through the incision in order to insert the deformed ocular device through the incision and under the epithelium. After placement under the epithelium, the deformed ocular device may assume its native or original shape (e.g., the configuration of the ocular device prior to deformation). For example, as shown in fig. 11A and 11B, an incision 72 may be made in the epithelium of the eye. Thus, the lens 40 may be "rolled" as shown in FIG. 11C, or "folded" as shown in FIG. 11D, so that the lens may be inserted into the incision 72. For example, the lens 40 shown in FIG. 11D is folded along its midline so as to have partial overlap of substantially the same size. The deformed lens may then be inserted into the incision 72, as described herein.

The incision may be made by cutting or ripping the epithelium using a sharp instrument, such as a microkeratome or the like, including the microkeratome disclosed above. Alternatively or additionally, the incision may be made by dissecting epithelial cells using a blunt instrument to create an opening in the epithelium without cutting or ripping the epithelium. Blunt dissection offers the advantage of reduced damage to epithelial cells and/or tissue.

To perform blunt dissection, a blunt instrument is used, the thickness of which reduces the possibility of tearing the epithelium when separating it from the anterior elastic layer and reduces the risk of damaging the anterior elastic layer of the corneal stroma. One suitable blunt dissection device includes a plate, wire or knife having a blunt edge. A tongue depressor is also a suitable blunt dissection device. The blunt dissection device is inserted under the epithelium and gently pressed through the underlying corneal surface to "comb" the epithelium off the anterior elastic layer. The separation appears to be along the path of least resistance to provide substantially complete separation of the epithelium from the pre-elastic layer without substantially damaging the epithelium or underlying cornea. The separation process advances through the corneal surface to achieve a gap size that accommodates a corrective ocular device.

In certain embodiments, only one incision is made in the epithelium. In yet another embodiment, two or more incisions may be made in the epithelium to enable insertion of the ocular device. When a plurality of slits are formed, the slits may be parallel to each other or may be perpendicular to each other. In certain embodiments, two intersecting incisions form four epithelial tissue flaps.

As disclosed herein, the ocular device may be a vision correcting lens, such as a corneal onlay. The ocular device may comprise a synthetic material, including the synthetic polymeric materials discussed above. In certain embodiments, the ocular device can comprise a contact lens configured to be placed between the epithelium and the pre-elastic layer of the cornea.

To insert the ocular device as described above, a portion of the epithelium may be lifted or separated from the cornea. An incision is made in the epithelium after the portion of the epithelium has been lifted or separated. It is preferable to form a cutout at the lifted or raised portion; however, in certain embodiments, it may be formed in the area of the epithelium where: this location is away from, but too close to, the location where the epithelium begins to separate from the anterior elastic layer.

The ocular device may then be inserted through an incision, may be inserted by using forceps, or other similar device. Alternatively, the ocular device may be inserted by using an inserter configured to deform at least a portion of the ocular device so that the device may be inserted through the incision, for example, through a smaller incision, as would be necessary if the ocular device could not be deformed. For example, the ocular device may be folded and rolled or curled to reduce its cross-sectional area while it is inserted under the epithelium, as discussed herein. The corneal onlay insertion device may be a syringe-like device that includes a body having a distal end sized to pass a lens beneath the corneal epithelium of the eye. In some instances, the corneal onlay insertion device may be similar or at least partially similar to intraocular lens inserters that are well known and are obtained as disclosed.

The epithelium may be opened by any suitable technique that will separate the epithelium from the anterior elastic layer, preferably without significantly damaging the anterior elastic layer or the corneal stroma. In certain embodiments, a vacuum is used to raise a portion of the epithelium. The vacuum may be provided by a microkeratome, such as using the separators disclosed in U.S. patent publication Nos. 2003/0018347 and 2003/0018348, or may be provided as a separate instrument. Alternatively or additionally, the epithelium may be raised by delivering fluid under a portion of the epithelium, as shown in fig. 9A, 9B, 9C, and 9D. For example, as shown in FIG. 9A, a small incision 72 may be made in the ocular epithelium. An injection device 80 having a distal end 82 and a fluid 84 located in the body of the injection device may be placed near the eye so that the distal end 82 is capable of delivering the fluid 84 beneath the epithelium of the eye, as shown in fig. 9B. As shown in fig. 9C, the fluid 84 causes the pre-formed epithelial layer 70 to separate from the stroma of the eye. The lens 40 may then be placed under the epithelium 70, and as the volume of fluid 84 decreases, the epithelium 70 is placed over the lens 40 to form the corneal appliance 60, as shown in figure 9D. The delivery of fluid causes the epithelium to swell, forming a bulge of epithelial tissue separated from the pre-elastic layer, as described above. Suitable fluids may include sodium chloride, such as aqueous sodium chloride. Another fluid may include a gel. The gel may be a gel comprising at least one water soluble or water swellable polymeric material, for example, at least one cellulosic component, such as hydroxymethylcellulose and the like, and/or one or more other water soluble or water swellable polymeric materials. In a specific embodiment, the fluid comprises a gel sold under the trademark GENTEAL gel by Ciba Vision, Duluth, GA.

In preparing an epithelium for insertion into an ocular device as disclosed herein, an effective amount of a protective agent may be applied to the epithelium in order to reduce cell damage and death and to maintain the epithelium in a viable state. The protective agent may act as a humectant to keep the epithelium in a moist state. The epithelial-protecting agent may comprise a gel, and in certain embodiments, the epithelial-protecting agent comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof. In other embodiments, the epithelial-protecting agent comprises at least one cellulosic component. In other embodiments, the epithelial protectant agent comprises hydroxymethylcellulose. One suitable epithelial protectant is GENTEAL gel as described above.

In another aspect of the invention, a method of correcting or improving vision includes lifting a portion of an epithelium of a cornea of an eye away from an anterior elastic layer, cutting a portion of the epithelium to form an elongated incision in the epithelium substantially without disrupting the anterior elastic layer, and inserting a corrective ocular device through the incision so that the ocular device is positioned between the epithelium and the anterior elastic layer. As described above, the epithelium may be lifted using a vacuum, liquid, or any other suitable device. The liquid used to lift the epithelium may include sodium chloride and/or other tonicity agents. In certain embodiments, the liquid is a hypertonic aqueous liquid. In one embodiment, the liquid is an aqueous solution containing about 5% (w/v) sodium chloride.

As described above, one or more incisions may be made in the epithelium using a cutting procedure or blunt dissection procedure. In this aspect of the invention, it is important to cut the epithelium without forming an epithelial flap. Additionally, the ocular device is inserted beneath the epithelium without substantially revealing or exposing the anterior surface of the anterior elastic layer. The method may be carried out by applying one or more epithelial-protecting agents to the epithelium. In practicing the methods of the invention, it is preferred to maintain the corneal stroma in a substantially intact or undamaged state.

In another aspect of the invention, a method of correcting or improving vision includes applying a liquid to an epithelium of a cornea of an eye to loosen the epithelium without substantially killing or inactivating epithelial cells, treating the epithelium to provide and/or maintain the epithelium in a moist state, lifting a portion of the loosened epithelium from a corneal surface underlying the epithelium, separating the lifted portion of the epithelium from the corneal surface, forming one or more slits in the lifted portion of the epithelium, and inserting a corrective ocular device beneath the epithelium through the one or more slits.

The method may further include the step of delivering a substance beneath the portion of the epithelium that is lifted prior to forming the incision in the epithelium so as to maintain the separated relationship between the epithelium and the corneal surface.

Suitable liquids for loosening the epithelium without inactivating or killing the epithelial cells include sodium chloride and/or other tonicity adjusting agents, e.g., aqueous solutions. In one embodiment, the liquid is a hypertonic aqueous liquid.

The methods disclosed herein may also be practiced by scraping a portion of the epithelium to form an epithelial defect prior to providing the fluid. The treating step of the above method may comprise applying a gel, such as a gel comprising a water-soluble polymeric material, a water-swellable polymeric material, or a combination or mixture thereof, to the epithelium. One suitable gel includes at least one cellulosic component, such as hydroxymethylcellulose and the like, and mixtures thereof.

Similar to the methods disclosed above, the epithelium may be lifted or elevated with a vacuum or other suitable device and separated using a blunt dissecting device, such as a tongue depressor or wire. The above gel-containing composition may also be delivered under an elevated epithelium to maintain the epithelium in a spaced apart relationship relative to the pre-elastic layer.

In practicing the method, a microkeratome is used to make an incision to cut or rupture one or more portions of the epithelium. In practicing the method, an incision is made in the epithelium to create or form one or more epithelial flaps, which are hinged portions of epithelial tissue that can be folded or rolled, or otherwise positioned so that the underlying corneal surface is exposed. In one embodiment, a single incision is made in the epithelium to form an epithelial flap 70 that includes a hinged portion 76 located at the periphery of the eye, as shown in FIG. 10A, wherein the hinged portion is located in the upper portion of the eye. As shown in fig. 10B, a medial incision 72 may be made and the two petals 70a and 70B may be obtained by a hinge portion 76 that is offset from the medial position of the eye (fig. 10E). In addition, as shown in fig. 10C, an incision 72 may be made in a portion away from the middle of the eye, such as in the temporal portion of the eye. This offset incision can then be used to form two flaps 70a and 70b as shown in fig. 10D, with the hinged portion 70 offset from the middle of the eye. In a preferred embodiment, the incision is made offset from the pupil of the eye in order to lessen the potential for corneal damage over the pupil. In another embodiment, multiple incisions are made in the epithelium to form multiple corneal flaps that can be folded over each other to form the underlying corneal surface. For example, a substantially vertical incision may be made along the midline of the eye, and a substantially horizontal incision may be made that intersects the vertical incision to form four flaps of epithelial tissue.

After the incision is made, an ocular device is inserted over the exposed underlying corneal surface and the tissue flap is placed over the ocular device.

As noted elsewhere herein, the ocular device is preferably a vision correction lens, and in certain embodiments, the ocular device is a contact lens configured to be placed under the epithelium of the cornea of the eye. In another embodiment, the ocular device is a corneal onlay.

In one embodiment, the inventive methods of correcting or improving vision disclosed herein may be performed by scraping the epithelium to form a small, linear 1-2mm defect of the epithelium, similar to a small scratch on the epithelium. An osmolyte ingredient, such as 5% sodium chloride, is then applied to the entire cornea for a period of 10 seconds. The osmolyte regulator component is effective to harden and loosen epithelial cells without killing them. The osmolality adjusting component can then be washed away. The epithelium is kept moist using a wetting agent or an epithelium-protecting agent. Examples of suitable wetting agents or epithelial protectants include water swellable polymers and/or water soluble polymers, as discussed above. An example of a suitable humectant is GENTEAL gel (0.3% hydroxymethyl cellulose; CIBA Vision, Duluth, GA).

The microkeratome suction ring can then be placed over the limbus and centered on the cornea. While increasing pressure on the eye, a spatula or other blunt dissection device (e.g., sold by massel Precision Surgical Instruments, Rapid City, SD) is slipped over the small linear epithelial defect, and epithelial cells, such as epithelial cell layers, are mechanically stripped, using a "spatula scrape" or blunt dissection technique. The suction ring is typically used for less than 30 seconds and no more than 2 times for a given procedure. The epithelium is then filled with a substance to lift the epithelium into a fondant-like shape, separating it from the front resilient layer. One suitable material is GENTEAL gel.

A version of the butterfly LASEK technique may then be implemented, for example, by making an incision in the center of the epithelial "fondant" and pushing the two halves aside. If one incision is insufficient to expose the anterior elastic layer and accommodate the corrective ocular device, one or more other incisions may be made in the epithelial layer to form quadrants (e.g., four) of epithelial tissue. The epithelial tissue flap or quadrant can then be placed over the limbus without interfering with the ocular device being inserted. Prior to insertion of the ocular device, the gel may be wiped off with a moist cellulose sponge, carefully handled so as not to damage the epithelial layer. The epithelial layer may then be folded into position over the corrective ocular device. The epithelium may then be covered and/or may receive one or more healing agents, which may include antimicrobial components, to promote healing of the epithelium.

In practicing the above method, lifting the epithelium and forming one or more slits in the lifted portion, the step of treating the epithelium to provide and/or maintain the epithelium in a moist state may be omitted, and the method may include the step of delivering a substance beneath the lifted portion of the epithelium to maintain a spaced relationship between the epithelium and the corneal surface.

The above method may further comprise the step of applying a healing agent to the epithelium after insertion of the lens to promote faster and more effective healing of the epithelium. In certain embodiments, the healing agent comprises an antimicrobial agent, for example, selected from common and/or well known materials for ophthalmic purposes, in order to reduce possible contamination and infection. The healing agent may be any suitable ophthalmic composition that promotes cell growth, such as epithelial cell growth, and/or reduces cell death.

Additionally, in accordance with the invention disclosed herein, recoverable vision correction procedures have been devised. The method comprises the steps of inserting a corrective ocular device beneath the epithelium of the cornea of the eye, preferably without substantially damaging the anterior elastic layer of the cornea, and removing the corrective ocular device from the eye. In addition, if the patient finds that the corrective ocular device is or becomes insufficient to provide the desired vision correction, or is otherwise unsatisfactory in performance or comfort, the ocular device may be removed and the patient's vision may be restored to its previous state. Thus, the patient may experience vision improvement similar to that provided by existing LASIK and LASEK procedures, but it has the advantage that the patient's vision can be restored if the patient or physician is not fully satisfied with the vision correction.

The method may further comprise the step of inserting another corrective ocular device after removing the first ocular device. For example, if the correction provided by a first ocular device is insufficient to properly improve a patient's vision, a second ocular device having different vision correction characteristics may be inserted to achieve the desired vision correction.

In practicing the above method, the corrective eye device is preferably a vision correction lens, however, other suitable devices that enhance the focusing ability of the eye may be employed. As described above, the ocular device may be inserted by forming one or more corneal flaps, or by forming an incision without forming an epithelial flap. In certain embodiments, a wetting agent or epithelial protectant is used to provide and/or maintain the epithelium in a moist state. The epithelial-protecting agent may be a gel-like composition comprising a water-soluble polymeric material, a water-swellable polymeric material, and/or mixtures thereof, as disclosed above. The incision in the epithelium may be made on the epithelium by using a microkeratome or similar instrument, or by separating the epithelial tissue without inactivating the epithelial tissue, such as by using the blunt dissection device disclosed above.

While the invention has been described in conjunction with specific examples and embodiments, it is to be understood that the invention is not limited to these embodiments, as well as other embodiments, which are within the scope of the invention.

Various publications and patents are cited above. Each of the documents and patents cited are hereby incorporated by reference in their entirety.

Claims (177)

1. A corneal appliance, comprising:

a lens having an anterior surface, a posterior surface, and a peripheral edge at a junction of the anterior and posterior surfaces and configured for placement on a de-epithelialized cornea of a patient's eye; and

epithelial cells from cultured stem cells placed on the anterior surface of a lens are fixed prior to placement of the lens on the de-epithelialized cornea of a patient's eye.

2. The corneal appliance of claim 1, wherein the epithelial cells are derived from cultured stem cells obtained from the patient.

3. The corneal appliance of claim 1, wherein the cultured stem cells are obtained from fetal or embryonic tissue.

4. The corneal appliance of claim 1, wherein the lens is configured to improve the patient's vision.

5. The corneal appliance of claim 1, wherein the lens body comprises an optic zone and a peripheral zone, the optic zone being surrounded by the peripheral zone.

6. The corneal appliance of claim 1, wherein the epithelial cells extend over the anterior surface to the peripheral edge of the lens.

7. The corneal appliance of claim 1, wherein the epithelial cells extend over the anterior surface of the lens and beyond the peripheral edge of the lens.

8. The corneal appliance of claim 1, wherein the cultured stem cells are limbal stem cells.

9. The corneal appliance of claim 1, wherein the epithelial cells are grown in vitro on the anterior surface of the lens body.

10. The corneal appliance of claim 1, wherein the epithelial cells are grown in vitro and applied as a layer of cells on the anterior surface of the lens body.

11. The corneal appliance of claim 1, further comprising a cell attachment member positioned between the anterior surface of the lens body and the epithelial cells.

12. The corneal appliance of claim 11, wherein the cell attachment member comprises a plurality of indentations on the anterior surface of the lens body that facilitate attachment of the epithelial cells to the lens body.

13. The corneal appliance of claim 12, wherein at least one of the plurality of grooves comprises an aperture extending through the lens from its anterior surface to its posterior surface.

14. The corneal appliance of claim 11, wherein the cell attachment member comprises a polymer that supports adhesion of the epithelial cells to the lens body.

15. The corneal appliance of claim 11, wherein the cell attachment member comprises a corneal enhancer moiety.

16. The corneal appliance of claim 15, wherein the corneal enhancer moiety specifically binds to another moiety present on the extracellular surface of an epithelial cell such that the other moiety sufficiently binds the corneal enhancer moiety to prevent the epithelial cell from being dislodged from the surface of the lens body.

17. The corneal appliance of claim 15, wherein the corneal enhancer moiety comprises an extracellular matrix protein.

18. The corneal appliance of claim 1, wherein the epithelial cells are provided in a layer comprising a fibrin matrix.

19. The corneal appliance of claim 1, wherein the corneal appliance is a corneal onlay.

20. The corneal appliance of claim 1, wherein substantially all of the cornea is de-epithelialized.

21. The corneal appliance of claim 1, wherein the lens body comprises collagen.

22. The corneal appliance of claim 21, wherein the collagen is derived from an animal.

23. The corneal appliance of claim 21, wherein the collagen is recombinantly produced.

24. The corneal appliance of claim 1, wherein the lens body is a stroma-like structure.

25. The corneal appliance of claim 24, wherein the lens body is an in vitro grown stroma-like structure.

26. The corneal appliance of claim 1, wherein the lens body is a hydrogel.

27. The corneal appliance of claim 1, wherein the lens body comprises a non-hydrogel material.

28. A corneal appliance produced by a method comprising the steps of:

culturing the stem cells until at least a portion of the stem cells have differentiated into corneal epithelial cells; and

applying a plurality of cells obtained from the stem cell culture onto an anterior surface of a lens to form an epithelial cell layer, the epithelial cell layer being immobilized on the anterior surface of the lens prior to placing the lens on the eye.

29. The corneal appliance of claim 28, wherein the cultured stem cells are obtained from a patient receiving the corneal appliance.

30. The corneal appliance of claim 28, wherein the cultured stem cells are obtained from fetal or embryonic tissue.

31. The corneal appliance of claim 28, wherein the cells administered to the anterior surface of the lens are limbal stem cells.

32. The corneal appliance of claim 28, wherein the plurality of cells applied to the anterior surface of the lens body are epithelial cells that form a layer of cells.

33. The corneal appliance of claim 28, wherein the method further comprises the steps of:

culturing a plurality of cells on the anterior surface of the lens to form a layer of cells across the anterior surface of the lens.

34. The corneal appliance of claim 28, wherein the method further comprises the steps of:

providing a cell attachment member on the anterior surface of the lens to facilitate attachment of the plurality of cells to the surface of the lens.

35. The corneal appliance of claim 28, wherein the lens body comprises collagen.

36. The corneal appliance of claim 28, wherein the lens body comprises a synthetic stroma.

37. A corneal appliance, comprising:

a lens shaped to have a desired refractive power to accommodate a visual deficit of a subject's eye; and

epithelial cells from cultured stem cells are fixed on the anterior surface of the lens prior to placement on the eye.

38. The corneal appliance of claim 37, wherein the cultured stem cells are limbal stem cells from a subject receiving the corneal appliance.

39. The corneal appliance of claim 37, wherein the cultured stem cells are obtained from fetal or embryonic tissue.

40. The corneal appliance of claim 37, wherein the lens body comprises collagen.

41. The corneal appliance of claim 37, wherein the lens body is a synthetic stroma.

42. The corneal appliance of claim 37, further comprising a cell attachment member disposed on the anterior surface of the lens body.

43. The corneal appliance of claim 37, wherein the appliance is configured to improve myopia in the subject.

44. The corneal appliance of claim 37, wherein the appliance is configured to improve hyperopia in a subject.

45. The corneal appliance of claim 37, wherein the appliance is configured to improve presbyopia in the subject.

46. The corneal appliance of claim 37, wherein the appliance is configured to ameliorate astigmatism in the subject.

47. A method of producing a corneal appliance comprising the steps of:

culturing stem cells until a portion of the stem cells have differentiated into corneal epithelial cells; and

the cultured cells are applied to a lens to form a layer of corneal epithelium.

48. The method of claim 47, wherein the stem cells are limbal stem cells.

49. The method of claim 47, wherein the stem cells are stem cells obtained from fetal or embryonic tissue.

50. The method of claim 47, wherein the stem cells are cultured until they form a layer of epithelial cells that can be applied to the lens.

51. The method of claim 47, wherein the stem cells are cultured in a fibrin matrix gel.

52. The method of claim 47, further comprising the step of applying a cell attachment member to the lens to promote attachment between the cultured cells and the lens.

53. A method according to claim 47, comprising the step of forming said lens from collagen in a mould to produce a synthetic matrix-like structure having specific optical properties.

54. The method of claim 47, wherein the lens is a hydrogel and is configured to facilitate attachment of the cell to the lens.

55. A corneal appliance, comprising:

a lens comprising a synthetic lens material sized for placement over a de-epithelialized cornea of a subject's eye; and

a pre-formed epithelial cell layer obtained from a subject receiving the corneal appliance, the pre-formed epithelial cell layer being disposed on an anterior surface of a lens.

56. The corneal appliance of claim 55, wherein the lens body is configured to correct an ametropia selected from the group consisting of: myopia, hyperopia, astigmatism, and presbyopia.

57. The corneal appliance of claim 55, wherein the lens body is configured to correct wave aberration of the eye of the patient.

58. The corneal appliance of claim 55, wherein the lens comprises one of: a multi-focal zone, a toric zone, and two or more zones joined without a junction.

59. The corneal appliance of claim 55, wherein the lens body comprises reconstituted collagen.

60. The corneal appliance of claim 55, wherein the lens body comprises a synthetic polymeric material.

61. The corneal appliance of claim 55, wherein the lens body comprises a combination of a synthetic material and collagen.

62. The corneal appliance of claim 61, wherein the collagen is selected from the group consisting of: bovine collagen, porcine collagen, avian collagen, murine collagen, and equine collagen.

63. The corneal appliance of claim 61, wherein the collagen is recombinant collagen.

64. The corneal appliance of claim 55, wherein the anterior surface of the lens body is treated to promote adhesion of the pre-formed epithelial cell layer.

65. The corneal appliance of claim 55, wherein the pre-formed epithelial cell layer is an epithelial cell layer removed from the eye of the patient.

66. The corneal appliance of claim 55, further comprising stem cells disposed on the anterior surface of the lens body that promote adhesion of the pre-formed epithelial cell layer to the lens body.

67. The corneal appliance of claim 55, wherein the pre-formed epithelial cell layer is an epithelial cell layer that remains attached to an epithelium of the patient's eye when the lens is placed on the cornea.

68. The corneal appliance of claim 55, wherein the temperature of the pre-formed epithelial cell layer is less than the temperature of the epithelial cells on the eye prior to placing the pre-formed epithelial cell layer over the lens.

69. The corneal appliance of claim 55, wherein the pre-formed epithelial cell layer adheres more strongly to the anterior surface of the lens than to an epithelial cell layer derived from donor corneal tissue attached to the lens.

70. A method of producing a corneal appliance, comprising:

a) forming the composite material into a lens having a shape with a desired optical power; and

b) applying the epithelial cells to the anterior surface of the lens such that the epithelial cells adhere to the lens.

71. The method of claim 70, wherein the lens comprises collagen.

72. The method of claim 71, wherein said collagen is recombinant collagen.

73. The method of claim 71, wherein the lens comprises a combination of synthetic material and collagen.

74. The method of claim 70, further comprising the steps of:

modifying the surface of the lens prior to administering the epithelial cells so as to improve the adhesion of the epithelial cells to the lens.

75. The method of claim 70, further comprising the steps of:

stromal corneal cells are added to the lens.

76. The method of claim 70, further comprising the steps of:

culturing stem cells on a first surface of the lens such that the stem cells differentiate into corneal epithelial cells.

77. A method of claim 70, wherein the epithelial cells are provided in a pre-formed epithelial cell layer obtained from a patient receiving the corneal appliance.

78. A method according to claim 77, wherein the pre-formed epithelial cell layer is formed by separating a portion of the patient's corneal epithelium from the anterior elastic layer of the eye to form an epithelial flap that remains attached to the eye.

79. The method of claim 70, further comprising the steps of: an adhesive is applied to facilitate securing the corneal appliance to the eye of the subject.

80. The method of claim 70, wherein the composite material is shaped to have a center thickness of about 10 microns to about 300 microns and an edge thickness of about 0 microns to about 120 microns.

81. A method of correcting vision, comprising:

inserting a vision correcting ocular device beneath an epithelium of a cornea of an eye without substantially revealing an anterior surface of the cornea underlying the epithelium.

82. The method of claim 81, further comprising forming an incision in the epithelium and inserting the ocular device through the incision.

83. The method of claim 82, wherein the step of forming an incision comprises forming an incision in a nasal, temporal, superior, and/or inferior portion of the epithelium.

84. The method of claim 82, wherein the step of forming an incision includes forming an incision in a central portion proximate the epithelium to form a first pocket and a second pocket, each pocket sized to receive a portion of the lens.

85. The method of claim 81, further comprising deforming the ocular device prior to the inserting step.

86. The method of claim 81, further comprising removing the ocular device from the eye and inserting another vision correcting ocular device beneath the epithelium of the eye.

87. The method of claim 81, wherein the ocular device is a vision correcting lens.

88. The method of claim 81, wherein the ocular device is a contact lens configured to fit between the epithelium and the anterior elastic layer of the cornea.

89. The method of claim 81, wherein the ocular device comprises a synthetic material.

90. The method of claim 81, wherein the ocular device comprises a synthetic polymeric material.

91. The method of claim 81, wherein the inserting step is performed without forming an epithelial flap.

92. The method of claim 81, further comprising forming a plurality of incisions in the epithelium.

93. The method of claim 81, wherein the inserting step is performed without substantially damaging a corneal surface underlying the epithelium.

94. The method of claim 93, wherein said inserting step is performed without substantially damaging the anterior elastic layer of the cornea.

95. The method of claim 93, wherein the inserting step is performed without substantially damaging a portion of the corneal stroma.

96. The method of claim 81, further comprising applying a healing agent to the eye in an amount effective to promote healing of the epithelium.

97. The method of claim 81, wherein the inserting step comprises lifting a portion of epithelium from the cornea, forming an incision in the epithelium, and placing the ocular device through the incision.

98. The method of claim 97, wherein the epithelium is raised with a vacuum.

99. The method of claim 97, wherein the epithelium is raised by delivering fluid beneath the epithelium.

100. The method of claim 81, further comprising applying an effective amount of an epithelial preservative to the epithelium.

101. The method of claim 100, wherein the epithelial protectant agent comprises a gel.

102. The method of claim 100, wherein the epithelial protectant agent comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof.

103. The method of claim 100, wherein the epithelial protectant agent comprises at least one cellulosic component.

104. The method of claim 103, wherein the epithelial protectant agent comprises hydroxymethylcellulose.

105. The method of claim 82, wherein the forming step comprises cutting the epithelium with a sharp blade.

106. The method of claim 82, wherein the forming step comprises separating the epithelium using a blunt instrument without substantially severing the epithelium.

107. The method of claim 82, wherein the forming step comprises using a microkeratome.

108. The method of claim 106, wherein the blunt instrument is a tongue depressor or a wire.

109. A method of correcting vision, comprising:

lifting a portion of corneal epithelium from the anterior elastic layer of the cornea;

cutting a portion of the epithelium to form a cut in the epithelium substantially without breaking the pre-elastic layer; and

inserting a corrective ocular device through the incision such that the ocular device is positioned between the epithelium and the pre-elastic layer.

110. The method of claim 109, wherein the step of lifting a portion of the epithelium includes applying a vacuum on the epithelium.

111. The method of claim 109, wherein the step of lifting a portion of the epithelium includes applying a liquid beneath the epithelium.

112. The method of claim 111, wherein the liquid comprises sodium chloride and/or other tonicity adjusting agents.

113. The method of claim 111, wherein the liquid is a hypertonic aqueous liquid.

114. The method of claim 109, wherein the step of cutting a portion of the epithelium includes using a microkeratome.

115. The method of claim 109, wherein the epithelium is cut without forming an epithelial flap.

116. The method of claim 109 wherein the inserting step is performed without substantially revealing the front surface of the front elastomeric layer.

117. The method of claim 109, further comprising applying an epithelial-protecting agent to the epithelium.

118. The method of claim 109, further comprising removing the ocular device from beneath the epithelium and inserting another corrective ocular device beneath the epithelium.

119. The method of claim 109, wherein the corrective ocular device is a vision correcting lens.

120. The method of claim 109, further comprising maintaining the corneal stroma substantially intact or undamaged.

121. A method of correcting vision, comprising:

applying a liquid to the epithelium of the cornea of the eye, the liquid being effective to loosen the epithelium without substantially killing the epithelial cells;

treating the epithelium so as to provide and/or maintain the epithelium in a moist state;

lifting a portion of the loosened, wetted epithelium from the surface of the cornea of the eye below the epithelium;

separating the lifted portion of the epithelium from the surface of the cornea;

forming one or more incisions in the lift-off portion of the epithelium; and

inserting a corrective ocular device under the epithelium through one or more incisions.

122. The method of claim 121, wherein said steps are performed sequentially.

123. The method of claim 121, further comprising delivering a substance beneath the raised portion of the epithelium to maintain the spaced relationship between the epithelium and the corneal surface prior to the forming step.

124. The method of claim 121, wherein the administered fluid comprises sodium chloride and/or other tonicity adjusting agents.

125. The method of claim 121, wherein the applied liquid is a hypertonic aqueous liquid.

126. The method of claim 121, further comprising scraping a portion of the epithelium to form an epithelial defect prior to applying the liquid.

127. The method of claim 121, wherein the treating step comprises applying a gel to the epithelium.

128. The method of claim 127 wherein the gel-containing composition comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof.

129. The method of claim 127, wherein the gel-containing composition comprises at least one cellulosic component.

130. The method of claim 129, wherein the gel-containing composition comprises hydroxymethyl cellulose.

131. The method of claim 121, wherein the step of lifting a portion of the epithelium includes using a vacuum.

132. The method of claim 121, wherein the step of separating the epithelium from the surface of the cornea comprises using a blunt dissection device.

133. The method of claim 132, wherein the blunt dissection device comprises a tongue depressor.

134. The method of claim 121, wherein the substance delivered to the underlying raised portion of the cornea is a gel-containing composition.

135. The method of claim 134, wherein the gel-containing composition comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof.

136. The method of claim 134, wherein the gel-containing composition comprises a cellulosic component

137. The method of claim 134, wherein the gel-containing composition comprises hydroxymethyl cellulose.

138. The method of claim 121, wherein the one or more incisions are formed with a microkeratome.

139. The method of claim 121, wherein the forming step produces one or more epithelial flaps.

140. The method of claim 121, wherein the forming step comprises forming a plurality of cuts in the raised portion of the cornea.

141. The method of claim 140, wherein the forming step produces two or more epithelial flaps.

142. The method of claim 121, wherein the ocular device is a vision correcting lens.

143. The method of claim 142, wherein the ocular device is a contact lens.

144. The method of claim 121, further comprising applying a healing agent to one or more incisions of the cornea.

145. A method of reversible vision correction, comprising:

inserting a corrective ocular device beneath the epithelium of the cornea of the eye without substantially damaging the anterior elastic layer of the cornea; and

removing the corrective ocular device from the eye.

146. The method of claim 145, further comprising inserting another corrective ocular device beneath the corneal epithelium.

147. The method of claim 146, wherein each of the ocular devices is a vision correcting lens.

148. The method of claim 145, wherein the ocular device is inserted beneath the epithelium without forming an epithelial flap.

149. The method of claim 145, further comprising forming an epithelial tissue flap and inserting the ocular device under the epithelial flap.

150. The method of claim 145, comprising applying a humectant to said epithelium, said humectant being effective to provide and/or maintain said epithelium in a moist state.

151. The method of claim 150 wherein the humectant is a gel-containing composition.

152. The method of claim 151, wherein the gel-containing composition comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof.

153. The method of claim 151, wherein the gel-containing composition comprises at least one cellulosic component.

154. The method of claim 153, wherein the gel-containing composition comprises hydroxymethyl cellulose.

155. The method of claim 145, wherein the ocular device is inserted beneath the epithelium through an incision made in the epithelium by a microkeratome.

156. The method of claim 146, wherein an additional ocular device is inserted under the epithelium through the incision formed by the microkeratome.

157. The method of claim 145, further comprising lifting a portion of the epithelium and forming an incision in the epithelium without substantially damaging the anterior elastic layer of the cornea.

158. The method of claim 145, further comprising separating a portion of the epithelium from the anterior elastic layer of the cornea using blunt dissection.

159. The method of claim 145, wherein the ocular device is removed from the eye after a sufficient period of time has elapsed to detect the vision correction provided by the ocular device.

160. A method of correcting vision, comprising:

applying a liquid to the epithelium of the cornea of the eye, the liquid being effective to loosen the epithelium without substantially killing the epithelial cells;

lifting a portion of the loosened epithelium from the corneal surface of the eye below the epithelium;

separating the lift-off portion of the epithelium from the corneal surface;

delivering a substance beneath the lifted portion of the epithelium so as to maintain a spaced relationship between the epithelium and the corneal surface;

forming one or more slits in the opened portion of the epithelium; and

inserting a corrective ocular device under the epithelium through one or more incisions.

161. The method of claim 160, wherein the administered fluid comprises sodium chloride and/or other tonicity adjusting agents.

162. The method of claim 160, wherein the fluid administered is a hypertonic aqueous fluid.

163. The method of claim 160, further comprising scraping a portion of the epithelium to form an epithelial defect prior to applying the liquid.

164. The method of claim 160, wherein the step of lifting a portion of the epithelium includes using a vacuum.

165. The method of claim 160, wherein the step of separating the epithelium from the corneal surface comprises using a blunt dissection device.

166. The method of claim 165, wherein the blunt dissection device comprises a tongue depressor.

167. The method of claim 160, wherein the substance delivered under the raised portion of the cornea is a gel-containing composition.

168. The method of claim 167 wherein the gel-containing composition comprises an ingredient selected from the group consisting of: water-soluble polymeric materials, water-swellable polymeric materials, and mixtures thereof.

169. The method of claim 167 wherein the gel-containing composition comprises at least one cellulosic component.

170. The method of claim 169, wherein the gel-containing composition comprises hydroxymethylcellulose.

171. The method of claim 160, wherein the one or more incisions are formed with a microkeratome.

172. The method of claim 160, wherein the forming step produces one or more epithelial flaps.

173. The method of claim 160, wherein the forming step includes forming a plurality of cuts in the raised portion of the epithelium.

174. The method of claim 173, wherein the forming step produces two or more epithelial flaps.

175. The method of claim 160, wherein the ocular device is a vision correcting lens.

176. The method of claim 175, wherein the ocular device is a contact lens.

177. The method of claim 160, further comprising applying a healing agent to the one or more incisions in the epithelium.