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  • 专利说明
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    • 专利摘要:
    The present invention relates to a lens made of donor corneal tissue suitable for use as a contact lens or implanted lens, a method of making the lens, and a technique for placing the lens over the eye. The lens is made of acellularized donor corneal tissue by removing autologous epithelium and corneal cells. These cells are optionally replaced with human epithelial and corneal cells to form a lens with an anatomical structure similar to the human cornea. Ocular lenses can be used to correct conditions such as astigmatism, myopia, aphagia, and presbyopia.
    公开号:KR20030045779A
    申请号:KR10-2003-7000819
    申请日:2001-07-18
    公开日:2003-06-11
    发明作者:에드워드 페레즈
    申请人:에드워드 페레즈；
    IPC主号:
    专利说明:

    PRE-FABRICATED CORNEAL TISSUE LENS AND METHOD OF CORNEAL OVERLAY TO CORRECT VISION}
    [2] The vision system allows the eye to focus the light beam on a meaningful image. The most common problem encountered by ophthalmologists and optometrists is the formation of images by defocused eyes with perspective control due to spherical refractive errors or improperly shaped eyeballs. The ophthalmologist or optometrist measures the refraction of the eye and corrects the optical error using contact lenses or glasses.
    [3] Many procedures have been developed to correct spherical refractive errors by modifying corneal shape. When light enters, the eye is first focused by the cornea, which has approximately 75% of the eye's total refractive power. Most refractive surgery involves reducing or increasing the forward curvature of the cornea.
    [4] Early corneal refractive surgery procedures, such as interstitial keratoplasty and corneal hypoplastic surgery, were originally developed to correct myopia and involved removing corneal discs from patients using microkeratotomy. The corneal discs that were removed were then frozen prior to reshaping the backside using the freezing shelf. After thawing, the disc was put back in the eye and fixed with sutures.
    [5] Upper corneal lens transplantation described in US Pat. No. 4,662,881 is a process involving the insertion of a precut clipped corneal tissue lens with a slanted edge into the corresponding groove in the recipient cornea. Next, this lens is sealed with the corneal layer. The donor lens is lyophilized and needs to be rehydrated before being placed on the recipient cornea.
    [6] These techniques and their modifications were generally considered unsuccessful due to frequent complications including irregular astigmatism, delayed surgical healing, corneal scars, and instability of refractive results. These problems are due not only to the technical complexity of the process, but also to the distortion of the corneal tissue structure following lens manipulation. For example, in epithelial keratoplasty, epithelial irregularities are caused by lyophilization of donor lenses. In addition, in stromal corneal lens transplantation and corneal hypoplasia, freezing of the lens nuclei causes severe damage to epithelial and parenchymal cells and disrupts the lamellar structure of the cornea.
    [1] The present invention is in the field of ophthalmology. More specifically, the present invention relates to a living lens suitable for use as a contact lens or suitable for subepithelial implants. The lens is made of donor corneal tissue. The present invention includes a method of making this lens and the technique of placing the lens over the eye.
    [21] 1 is a cross-sectional view of the eye.
    [22] 2A is a side view of the focal point of myopia.
    [23] 2B is a side view of the focusing point corrected by flattening the anterior curvature of the cornea.
    [24] 3A is a side cross-sectional view of a pre-fabricated donor lens.
    [25] 3B is a side cross-sectional view of a pre-fabricated donor lens suitable for correcting myopia.
    [26] 3C is a cross-sectional side view of a pre-fabricated donor lens suitable for correcting ataxia.
    [27] 3D is a front view of a pre-fabricated donor lens suitable for bifocal use.
    [28] 3E is a side cross-sectional view of the FIG. 3C lens positioned away from the cornea of the eye.
    [29] 3F is a front view of the lens of the present invention overlaid with an epithelial layer.
    [30] 3G is a side cross-sectional view of the FIG. 3F lens.
    [31] 3H is a side cross-sectional view of the lens of the invention in a carrier.
    [32] 3I is a front view of the annular lens of the present invention.
    [33] 3J is a side cross-sectional view of the FIG. 3I lens.
    [34] 4A is a cross-sectional side view of a de-epithelialized recipient corneal region prepared to receive an optical lens of the present invention.
    [35] 4B is a side cross-sectional view of the donor lens after placement on the recipient cornea.
    [36] 5 shows a series of steps for subcutaneously introducing a lens of the invention.
    [37] details
    [38] The eye is designed to focus light on differentiated receptors in the retina that converts both of the energy of light into neuronal potentials. As shown in FIG. 1, light rays are first transmitted through the cornea 100 of the eye. The cornea is transparent due to the highly organized structure of its collagen fibrils. The edge of the cornea merges with the tough fibrous collagen sclera 102 and is considered the corneal sclera layer.
    [39] Corneal 100 is the portion of the corneal sclera that surrounds the front 1/6 of the eye. The smooth curvature of the cornea is the main force for focusing the image on the retina 104, which provides most of the 60 diopters of converging force of the eye. The cornea is blood vessel-free and persists by diffusion of nutrients and oxygen from the aqueous liquid 106. In addition, some oxygen is derived from the external environment. The avascular nature of the cornea reduces the immunogenicity of the tissue and at the same time increases the rate of growth of the corneal graft.
    [40] The cornea consists of five layers. The outer surface is faced by a stratified squamous epithelium about 5 cells thick. Failure of epithelialization leads to necrosis of the parenchymal cap and potential scarring of the recipient cornea. The epithelium is supported by a differentiated basal membrane known as Bowman's membrane, which provides the cornea with a smooth optical surface. The bulk of the cornea, the parietal parenchyma, is composed of dense collagen connective tissue in a very regular form that forms a thin lamina. Between the laminae are fusiform corneal cells that can be stimulated to synthesize components of connective tissue. The inner surface of the cornea is faced by a layer of flattened epithelial cells supported by Desmet's membrane, a very thick elastic basal membrane.
    [41] As mentioned above, the focusing force of the cornea depends mainly on the radius of curvature of the outer surface of the cornea. In myopia, as shown in FIG. 2A, increased corneal 200 curvature is the cause that the focal point of the light beam 202 does not reach the retina 204.
    [42] Lens structure of the invention
    [43] In a first variant of the lens of the present invention, the physical shape is generally sized and contoured to compensate for curvature of the cornea when installed over the cornea to correct abnormal conditions such as astigmatism, myopia, hyperopia, presbyopia, and aphagia. Has Other modifications of the lens can be placed under the front of the host cornea, or shaped to be used as a source of drug.
    [44] Typically, the lens core is inactivated, for example, to remove autologous corneal cells and epithelium, and to be processed to reduce the chance of tissue rejection, and then at least partially revived, for example in human corneal cells and epithelial layers. It may comprise or consist essentially of acellular donor corneal tissue that has been introduced to at least one and processed to allow and support the continued use of the lens of the invention in place over the eye. It is within the scope of the invention that epithelial cells lie in at least a portion of the front face of the lens of the invention (primarily in the form of separate layers). In some variations of the lens of the invention, the entirety of the front face will be so covered. In one variation discussed below, the epithelial layer will extend past the periphery of the lens core and optionally the lens will be transported in a biodegradable carrier that is used during placement in the eye and later lost.
    [45] The lens of the present invention may be placed on a host eye from which at least most of the native epithelium on the cornea has been removed. Preferably, in this variant of the process of the invention, substantially all of the epithelium is removed from the area where the lens of the invention is to be installed. In addition, the lens may be placed under the epithelial layer lifted from the eye surface, or in other cases below the surface of the host cornea during the process of introducing the lens over the front of the host cornea. The lens of the present invention can be used in various ways to correct refraction (due to shape), or simply to provide a source of drug to be injected into the eye.
    [46] The donor lens nucleus or lens core may be obtained from another human (homologous) or foreign tissue (heterologous) source. Suitable heterologous sources include rabbit, bovine, swine, or guinea pig corneal tissue. The ocular lens core may also come from transgenic corneal tissue or corneal tissue grown in vitro. In many cases, it is desirable that the structure of the corneal layer, the normal corneal tissue matrix, such as connective tissue or parenchyma, in donated corneal tissue is substantially preserved. The "corneal tissue matrix" is made of a thin layer of collagen fibrils. The term "provider corneal tissue" as used herein is meant to include a donor or harvested corneal or corneal tissue containing a "corneal tissue matrix". In addition, in most variations of the present invention, it is highly desirable to preserve the front side of the donated corneal tissue present beneath the native epithelium. The donor corneal tissue does not undergo rough treatment, such as lyophilization, freezing, or other chemical fixation. Nevertheless, it is sometimes desirable to use only a portion of the front of the provider lens, for example when the lens structure of the invention is annular in shape.
    [47] The ocular lens device of the present invention preferably comprises a Bowman's membrane, in which case the donor tissue retains the autologous structure of the human epithelium. Again, it is highly desirable to harvest from the donor source in such a way that the native front under the epithelium is preserved. These native structures have been found to have excellent ability to support and maintain the replaced epithelium discussed below, especially after the resurrection step discussed below. The sharpness of the tissue lens core of the present invention was generally handled in such a way as to be at least 85%, preferably 75% to 100%, most preferably at least 90% of the human corneal tissue sharpness of corresponding thickness.
    [48] The overall diameter of the lens of the present invention is functionally suitable for performing the desired correction, and is generally less than about 25 mm, more preferably 10 to 15 mm. Again, the thickness of the resulting lens is functionally suitable for performing the desired correction, for example generally less than 300 μm, more preferably 5 to 100 μm.
    [49] As shown in FIG. 3B, the myopia patient lens core 316 is generally formed in such a way that the central circular region 318 is flattened within its forward curvature, preferably using the procedure discussed below. In correcting aphagia, a lens such as that shown in FIG. 3C is formed with a relatively thicker center 322 and a thinner perimeter 324. In general, the shapes discussed herein are similar to those known in so-called "soft" contact lenses, and the instructions can be obtained from techniques related to the overall form of lenses selected for correcting specific eye diseases.
    [50] As shown in Figures 3D and 3E, the lens of the present invention can also be used to correct presbyopia. Especially for the treatment of presbyopia, the lens 330 is also provided with a generally opaque annular area 332 adjacent to the center of the device. The open center 334 preferably has planar-lens features, and the effective diameter is less than about 1.5 mm, preferably about 0.5 to 1.5 mm, most preferably 0.75 to 1.75 mm. The diameter of the open center 334 or center region or “pinhole” is generally formed and selected to be less than the pupil diameter of the host eye in daylight. This creates a "pinhole" effect, lengthening the overall effective focal length of the eye and minimizing the need for the eye to adapt to the environment. In addition, other bifocal lens designs may use concentric rings, segmented or scalloped annular regions or rings, or progressive diffraction.
    [51] 3E shows a side cross-sectional view of the lens 330 of the present invention shown in FIG. 3D, adjacent to the front face of the cornea 344, illustrating certain features of this modification. The outer diameter 336 of the opaque annular ring 332 is generally chosen to be smaller than the diameter of the pupil 340 in the iris 342 in low light. In this manner, the cornea and lens of the eye and the lens of the present invention allow incident light to pass through the center 334 of the opaque ring, more importantly near the opaque ring 332, to provide a corrected field of view during low light conditions. Cooperate in a way that allows it.
    [52] The annular ring 332 is arranged on the back surface by filtering a beam of light by disposing a suitable dye, ie by "tattooing", or by placing a substantially opaque biocompatible member such as, for example, a Dacron mesh. It can be located at. Other arrangements of the annular ring 332 can be envisioned, for example, on the front of the lens of the present invention. Preferably, the annular ring 332 itself is very opaque, for example passing less than about 80% of incident visible light, but less opaque, or by moving the incident color into the visible range by color refraction or the like. It may be selected in a manner to correct other diseases.
    [53] As shown in FIG. 3F (front view) and FIG. 3G (sectional view), another variation 346 of the lens device of the present invention includes the core lens 348 discussed above, which includes a periphery 350 of the lens core 348. It has an epithelial layer 352 extending beyond it. The method of creating a deformation 346 having an extra peripheral epithelial layer 352 is similar to that described elsewhere herein, provided that preferably the core 348 is generally fitted to the front of the provider core lens 348. It is placed in a shaped carrier (354 in FIG. 3H).
    [54] The carrier 354 shown in FIG. 3H preferably provides several functions. First, it provides a substrate for growing the epithelial layer 352 before the core lens 348 is placed on the epithelial layer 352. This extra surface past the periphery of the core lens 348 provides a support for another brittle epithelial layer 352. The carrier 354 may be placed in or formed of a container of a suitable shape, which in turn provides a support for the frangible carrier 354 during the growth phase of the epithelial layer 352.
    [55] 3H, whether the carrier 354, epithelial layer 352-epithelial layer 352 extends beyond the periphery of the core lens 348, for example, the epithelial layer 352 is only part of the core lens 348. Or a combination 356 of the core lens 348 placed on the epithelial layer 352, whether or not all over it, is another variation of the present invention. The composition 356 shown in FIG. 3H can be placed directly on the host eye by appropriately selecting a material for the carrier, thereby providing support for the epithelial layer 352 and the core lens 348, as well as optionally for the eye during initial placement. Provide drugs or other therapeutic substances.
    [56] When the carrier is used for placement in the eye, the carrier 354 preferably comprises a material that meets two related criteria. First, the material is preferably removed from the eye to be dissolved, corroded, or otherwise treated soon after the combination 356 of the carrier 354, epithelial layer 352, and donor lens 348 is introduced into the eye. will be. In addition, the carrier is preferably made of a material which serves as a substrate for the previously grown epithelial layer. Most preferably, carrier 354 satisfies both criteria. Carrier 354 may include materials such as collagen, gelatin, starch, glucoseamine, glucan, proteins, carbohydrates, polyanhydrides such as polylactide and polyglycolide, mixtures and copolymers thereof, polydiaxanone, and the like. have.
    [57] In addition, the carrier 354 may be infused with a drug or other therapeutic material, antiangiogenic material, and the like.
    [58] 3I and 3J show front and side cross-sectional views, respectively, of a lens 360 of the present invention having a central opening 362 through the lens body. Although this lens modification 360 is shown without an epithelial layer, it is also within the scope of the present invention to include an epithelial layer.
    [59] Lens molding process
    [60] Returning to FIG. 3A, preferably the provider core lens 300 is obtained after slicing corneal tissue from the donor with a microkeratotomy to form this lens core 300. The donor lens 300 has a structural surface that is the front of the lens core, which acts as the structural surface of the donor corneal tissue. Preferably, the lens core front face is taken to retain the Bowman's membrane (if the donor lens contains it) and the epithelium 302. The resulting backside 304 of the inventive lens is generally concave in shape, but need not be. The front face of the lens can be shaped by a forming step, preferably involving the use of a removable laser, such as an excimer laser, in order to obtain the necessary magnification of the lens. Another suitable forming step is high pressure waterjet cutting.
    [61] Sterilization, Deactivation, and Resurrection Steps
    [62] While the sequence of process steps outlined below is typical, it should be understood that such steps may vary as needed to produce the desired result.
    [63] In general, the lens will first be shaped into a suitable shape as discussed above. Next, the lens core may be sterilized, deactivated, and revived. Removal of epithelium (de-epithelialization) and corneal cells (acellularization) from the donor lens will be considered "deactivation". The addition of human epithelial and corneal cells will be considered "resurrection". One preferred method for achieving these steps is provided directly below. Other equivalent methods are known.
    [64] Phosphate buffered saline (PBS) with antibiotics, epithelial cell medium, and corneal cell medium are the solutions used during these procedures. A solution of "PBS with antibiotics" may contain:
    [65] PBS with antibiotics
    [66] 1.Amphotericin B (ICN Biomedicals) 0.625 µg / ml
    [67] 2. Penicillin (Gibco BRL) 100 IU / ml
    [68] 3. Streptomycin (Gibco BRL) 100 μg / ml
    [69] 4. Phosphate Buffered Saline (Gibco BRL)
    [70] The composition of epithelial cell medium may comprise:
    [71] Epithelial cell medium
    [72] 1.Dulbecco's Modified Eagle Badge / Hams F12 Badge (Gibco BRL)
    [73] 2. 10% Fetal Bovine Serum (Gibco BRL)
    [74] 3. Epithelial Growth Factor (ICN Biomedicals) 10ng / ml
    [75] 4. Hydrocortisone (Sigma-Aldrich) 0.4µg / ml
    [76] 5. Cholera Toxin (ICN Biomedicals) 10 -10 M
    [77] 6.Adenine (Sigma-Aldrich) 1.8x10 -4 M
    [78] 7. Insulin (ICN Biomedicals) 5㎍ / ml
    [79] 8. Transferrin (ICN Biomedicals) 5µg / ml
    [80] 9. Glutamine (Sigma-Aldrich) 2x10 -3 M
    [81] 10. Triyodothyronine (ICN Biomedicals) 2x10 -7 M
    [82] 11.Amphotericin B (ICN Biomedicals) 0.625㎍ / ml
    [83] 12. Penicillin (Gibco BRL) 100 IU / ml
    [84] 13. Streptomycin (Gibco BRL) 100 μg / ml
    [85] The composition of the corneal cell medium may comprise:
    [86] 1. DMEM
    [87] 2. 10% Newborn Calf Serum (Gibco BRL)
    [88] 3. Glutamine (Sigma-Aldrich) 2x10 -3 M
    [89] 4. Amphotericin B (ICN Biomedicals) 0.625µg / ml
    [90] Sterilization Step
    [91] After taking the lens core from the donor corneal tissue and after the shaping step, the lens can be sterilized, for example by immersing in 98% glycerol at room temperature. Three weeks of glycerol treatment inactivates intracellular viruses and any bacteria or fungi. Ethylene oxide gas sterilization can also be used, but tends to cause various damages to the parenchyma.
    [92] Deactivation stage
    [93] De-epithelialization
    [94] It is preferred to de-epithelialize the donor lens by leaving the lens in a 1 molar salt solution (preferably sodium chloride) at a temperature of 4-25 ° C. After 4-8 hours of incubation, the entire epithelial layer will generally be separated from the corneal parenchyma and can be easily removed. The lens can then be washed in PBS solution with antibiotics to remove salt and cellular material.
    [95] Another method of removing the epithelium is by the use of a vacuum. The epithelium can be separated from the parenchyma by suction (-100 mmHg to -450 mmHg). After 15 minutes to 1 hour, epithelium will typically separate from the parenchyma in the basal membrane layer. The lens can then be washed in PBS solution with antibiotics to remove salt and cellular material.
    [96] Finally, the donor lens can be de-epithelialized by leaving the lens in a sterile PCS solution with antibiotics for 4 hours and exchanging the solution several times. The lens core may then be immersed in PBS solution at 37 ° C. for 1 week, causing separation between epithelium and parenchyma. The epithelium can then be removed by physical scraping or washing with a liquid stream. A few lenses can peel the epithelium by gently scraping off with forceps.
    [97] Acellularization
    [98] The de-epithelialized lenses can then be immersed in detergent solution (eg, 0.025% to 15% sodium dodecyl sulfate) to wash away corneal cell material. The detergent will solubilize and wash away the keratinocyte material. This can happen for 1 to 8 hours. The cell material can then be washed in a buffered solution with antibiotics to remove detergent and cell material.
    [99] Alternatively, the de-epithelialized lens can be immersed in sterile PBS with antibiotics for a suitable period of time, eg, weeks, perhaps six weeks, to remove native corneal cells. The solution can be exchanged twice a week. In some cases, it may be unnecessary to remove corneal cells from the donor lens, for example when the donor tissue is obtained from a transgenic source and has minimal antigenicity.
    [100] Resurrection stage
    [101] Cell manufacturing
    [102] Human epithelial cells and corneal cells are used in the resurrection process. Epithelial cells can be obtained from tissue banks, but preferably from fetal or neonatal tissues. Fetal cells are most preferred because the nature of the fetal tissue minimizes scarring during any wound healing process.
    [103] In some cases, freshly isolated epithelial cells, obtained by trypsin treatment of corneal tissue, may be seeded onto precoated feed layers of lethal irradiated 3T3 fibroblasts (i.3T3) in epithelial cell medium. The cells are cultured and the medium is exchanged every 3 days for about 7-9 days until the cells are 80% confluent. Remaining i.3T3 is removed with 0.02% EDTA (Sigma-Aldrich) before epithelial cells are detached using trypsin (ICN Biomedicals). Another method of regenerating the epithelium involves culturing autologous epithelial cells on human amnion membranes, which Tsai et al. (2000) "Reconstructing damaged corneas by transplantation of autologous limb epithelial cells", New England Journal of Medicine 343: 86-93.
    [104] Corneal cells can be extracted from the remaining parenchymal tissue. The parenchyma is washed in PBS, finely chopped and placed in 0.5% collagenase A (ICN Biom-edicals) at 37 ° C. for 16 hours. Next, corneal cells obtained from this enzyme digestion are continuously cultured in corneal cell medium. Epithelial cells and corneal cells produced in the revival phase will be considered "replacement" epithelial cells and corneal cells.
    [105] Generation of Provider Lenses
    [106] The cell-free donor lens core may then be placed in a hydrophilic polyelectrolyte gel to complete the resurrection. Preferred polyelectrolytes are chondroitin sulfate, hyaluronic acid, and polyacrylamide. Most preferred is polyacrylic acid. The lens is immersed in corneal cell medium and incubated with approximately 3 × 10 5 corneal cells for 48 hours at 37 ° C. Next, approximately equal amounts of epithelial cells are added to the anterior parenchymal surface. Corneal cell medium is exchanged every 2 to 3 days. Once the epithelium is regenerated, the polyelectrolyte gel draws water from the lens at a pressure of about 20-30 mm Hg until the original lens dimensions are obtained.
    [107] The replaced epithelium covers at least a portion of the front face of this modified lens of the invention, and the replaced corneal cells redistribute the parenchyma of the lens core after resurrection.
    [108] As noted above, another variant of the lens of the present invention includes an epithelial layer (352 of FIG. 3G) extending from the periphery of the lens core 348. The same procedure as just outlined can be used to prepare the epithelial cell layer in the carrier 354 prior to placing the lens core 348 over the pre-fabricated epithelial cell layer.
    [109] In some cases it may also be beneficial to incorporate a therapeutic, growth factor, or immunosuppressant into the lens core to further reduce the risk of rejection or to treat a disease state.
    [110] Placement of the lens over the eye
    [111] One process of applying the lens of the present invention is depicted in FIGS. 4A and 4B. During the procedure, the donor lens 300 shown in FIG. 3A is placed over a portion of the de-epithelialized recipient cornea 308. The result is the arrangement and configuration 312 shown in FIG. 4B. The replaced epithelium and host epithelium of the lens finally grow to form a continuous waterproofing layer 310. It has been found that the lens of the present invention adheres or bonds to the recipient cornea without sutures or adhesives, but can also be removed without substantial difficulty.
    [112] Another batch process variant is shown in FIG. 5. In this variant, it is preferable to use only partially revived core lenses in that the corneal cells are replaced but the epithelial layer is not replaced. Of course, core lenses partially covered with the seed layer of epithelial cells are also acceptable. In some cases, step a of FIG. 5 shows the native eye 600 with epithelial layer 602 and corneal parenchyma 604. Step b in FIG. 5 shows the placement of the suction device 606 over the front face of the eye 600. The aspiration device 606 applies a small vacuum of about -100 mmHg to -450 mmHg, for example, to cause aspiration of the epithelial layer 602 as shown in step c. This blister 608 is typically filled with a physiological fluid. Clearly, the suction device 606 has a footprint on the corneal surface that is similar in size to the lens to be placed on the cornea. Step d shows the placement of the lens toward the open epithelial flap 608 and the corneal parenchymal margin 612 below the epithelial flap 608. Step c of FIG. 5 shows the finished placement of the lens 610 over the cornea below the native epithelial membrane. This process has many advantages, including being less traumatic to the surface of the eye than a simple removal of the epithelium.
    [113] It is also within the scope of the present invention to use the manufacturing process of the LASEK process in the present invention for the step of exposing the corneal surface for the application of the lens of the invention. The lASEK procedure is known and, unlike the LASIK procedure, does not involve the use of surgical tools to temporarily remove the anterior flap of corneal tissue, but rather uses ethanol washing and temporary withdrawal of the epithelial layer just for laser treatment. Such preliminary steps, rinsing with ethanol to disrupt the junction between the corneal parenchyma and the epithelium, are suitable for providing epithelial layers for ecliptic migration and insertion of the lens of the invention on the corneal surface.
    [114] The structural and physiological properties and benefits of this donor eye lens have been described. This way of describing the invention should not in any way limit the scope of the invention.
    [7] The present invention is a pre-fabricated lens made of donor corneal tissue obtained from a tissue source such as human or animal cornea. This lens is generally a corneal disc, preferably molded on the back side to conform to the front side of the eye. The lens of the present invention may be molded by a removable laser, such as an excimer laser or other suitable laser. Corneal lens nuclei are living tissues that have not been frozen, lyophilized, or chemically modified, such as glutaraldehyde, so that corneal tissue is not crosslinked. After the existing corneal cells are removed, they are replaced with human corneal cells to reduce antigenicity. After the epithelium is removed from the central area of the recipient cornea, the lens is placed over this area in the same way that the contact lens is placed over the eye.
    [8] Ocular lenses known in the prior art do not use native corneas, but are made using collagen hydrogels such as soluble collagen such as polyhydroxyethylmethacrylate, or other biocompatible materials. For example, US Patent No. 5,213,720 to Civerchia gels and crosslinks soluble collagen to produce an artificial lens. In addition to hydrogels, US Pat. No. 4,715,858 to Lindstrom discloses lenses made from various polymers, silicones, and cellulose acetate butyrates.
    [9] If the ocular lens uses corneal tissue, the lens is a corneal implant or requires a separate formulation for bonding the lens and corneal layer. US Pat. No. 5,171,318 to Gibson et al. And 5,919,185 to Peyman, relate to discs of corneal tissue that are partially or wholly embedded in the parenchyma. The ocular lens device disclosed in US Pat. No. 4,646,720 to Peyman et al. And 5,192,316 to Ting is suturely attached to the recipient cornea. The corneal inlay described in Kern US Pat. No. 4,676,790 is adhered to the recipient cornea using sutures, laser welding, or application of a liquid adhesive or crosslinking solution.
    [10] The ocular lens device of the present invention does not alter the anatomical structure of corneal tissue. US Pat. No. 4,346,482 to Tennant et al. Discloses a "living contact lens" consisting of an anterior curved donor cornea for vision correction. However, the lens is frozen on a shelf before reshaping, resulting in the death of parenchymal corneal cells. US Patent No. 4,793,344 to Cumming et al. Describes a donor corneal tissue lens modified by treatment with a glutaraldehyde fixative that preserves tissue and prevents lens swelling. This treatment alters the basic structure of the corneal lens nucleus by crosslinking the tissue.
    [11] Moreover, the cited documents do not indicate any lens making method of removing native corneal tissue cells and replacing them with cultured cells from human cornea. The device of the present invention deactivates autologous epithelium and corneal cells to make acellular corneal tissue and then revitalizes with human epithelial and corneal cells. Attempts to construct a so-called "corneal tissue equivalent" have been shown in US Pat. No. 5,374,515 to Parenteau et al. However, the collagen used in this "equivalent" is obtained from bovine tendon instead of the cornea. In addition, added corneal cells and epithelium are not from human sources. In addition, tissues using these cell culture processes are very brittle.
    [12] Excimer lasers are used to reshape the cornea by a "laser in situ corneal hypoplasia" (LASIK) procedure. In this technique, excimer lasers are used to perform the photolysis of the parenchyma of the corneal plate, or in-situ photo melting of the exposed parenchyma layer. Studies indicate that the inaccuracy of the calibration by this process can be as much as one diopter from the desired value. In contrast, the lenses (contacts and glasses) can be calibrated within 0.25 diopters of the desired value.
    [13] US Pat. No. 6,036,683 to Jean et al. Describes reshaping the cornea using a laser. However, lasers alter the native structure of the cornea by irregularly coagulating collagen. Post-laser relaxation of collagen is not possible with this treatment.
    [14] However, in some variations, the present invention relates to a pre-fabricated donor contact lens that bonds to the recipient cornea without closure. This lens preserves the anatomy of normal corneal tissue. The donor lens can be obtained from human and animal sources and deactivated autologous corneal cells and epithelium to make acellular tissue, and then optionally revived using at least one of human corneal cells and epithelial cells, thereby providing a lens viability Maintain and reduce antigenicity. The corneal overlay technique of the present invention can be completed under general anesthesia as well as local anesthesia, and the availability of precut lenses will greatly reduce process time, patient cost, and risk of surgical complications. In addition, the healing time will be reduced due to the transplantation of lenses that have already been redistributed into the corneal cells.
    [15] The cited documents present or suggest the invention as described herein.
    [16] Summary of the Invention
    [17] The present invention is a pre-fabricated ocular lens device having a lens core made of donor corneal tissue from a tissue source such as a human or animal cornea. The device can be used as a contact lens or an implanted lens and can generally have a convex front side and optionally a concave back side. The parenchymal part of the lens core can be redistributed into the replaced corneal cells, and the front face is preferably covered with replaced epithelium. The lens core is bonded to the recipient cornea without sutures or other bonding material.
    [18] Lens cores can be used in a variety of ways to correct astigmatism, myopia, ataxia, and presbyopia. The lens core may be made of transgenic or heterologous corneal tissue. Appropriately treated lenses of the invention may have at least 85% of human corneal tissue clarity of corresponding thickness. The lens core is not frozen, lyophilized or chemically treated with a fixative. However, variations of this device may contain therapeutic agents, growth factors, or immunosuppressants.
    [19] Another component of the invention is a method of manufacturing a lens device. After a sharp incision of the lens nucleus from the donor corneal tissue, the backside is shaped using a removable laser, such as an excimer laser or other suitable shaping laser. The native epithelial and corneal cells are removed and replaced with human epithelial and corneal cells if desired.
    [20] Another part of the invention is a corneal overlay method comprising de-epithelializing a portion of the front face of the recipient cornea and placing the ocular lens device of the invention over the front face. Another method involves temporarily separating epithelial tissue by aspiration or other procedure, and placing the lens of the invention under the epithelial tissue.
    权利要求:
    Claims (71)
    [1" claim-type="Currently amended] A lens core comprising a donor corneal tissue generally having a convex front and back surface, wherein the lens core comprises at least one of a) corneal cells replaced in the lens core and b) replaced epithelial cells covering at least a portion of the front surface. Eye lens device.
    [2" claim-type="Currently amended] 2. The eye lens device of claim 1, wherein the back surface is generally concave.
    [3" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises acellular corneal tissue.
    [4" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core consists essentially of acellular corneal tissue.
    [5" claim-type="Currently amended] The eye lens apparatus of claim 1, wherein the back surface is concave.
    [6" claim-type="Currently amended] The ocular lens apparatus according to claim 1, wherein a molding step is performed on the rear surface.
    [7" claim-type="Currently amended] 7. The eye lens apparatus according to claim 6, wherein the back side is molded by a removable laser.
    [8" claim-type="Currently amended] The ocular lens apparatus of claim 1, wherein the ocular lens has at least 85% of the clarity of human corneal tissue of a corresponding thickness.
    [9" claim-type="Currently amended] The ocular lens device of claim 1, wherein the ocular lens has about 75% to about 100% of the clarity of human corneal tissue of a corresponding thickness.
    [10" claim-type="Currently amended] 10. The apparatus of claim 9, wherein the lens core has at least 90% of the sharpness of human corneal tissue of a corresponding thickness.
    [11" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core consists essentially of donor corneal tissue.
    [12" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises human corneal tissue.
    [13" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises homologous corneal tissue.
    [14" claim-type="Currently amended] 12. The ocular lens device of claim 11, wherein the lens core comprises heterologous corneal tissue.
    [15" claim-type="Currently amended] 15. The ocular lens device of claim 14, wherein the heterogeneous lens core comprises corneal tissue selected from the group consisting of rabbit, cow, pig, and guinea pig corneal tissue.
    [16" claim-type="Currently amended] 12. The ocular lens device of claim 11, wherein the lens core comprises transgenic corneal tissue.
    [17" claim-type="Currently amended] 12. The ocular lens device of claim 11, wherein the donor corneal tissue has a structural surface and the front of the lens core is a structural surface of donor corneal tissue.
    [18" claim-type="Currently amended] 2. The ocular lens apparatus of claim 1, wherein the size and appearance are selected to correct at least one selected from the group consisting of astigmatism, myopia, ataxia, and presbyopia.
    [19" claim-type="Currently amended] 19. The apparatus of claim 18, wherein the size and shape are selected to correct myopia, and the device generally has a circular flat lens core center region.
    [20" claim-type="Currently amended] 19. The ophthalmic lens device of claim 18, wherein the size and appearance are selected to correct ataxia, the device having a generally flattened periphery.
    [21" claim-type="Currently amended] 19. The apparatus of claim 18, wherein said size and shape are selected to be bifocal.
    [22" claim-type="Currently amended] 19. The ocular lens apparatus of claim 18, wherein the size and shape are selected to correct presbyopia and generally have a circular lens core center region without correction.
    [23" claim-type="Currently amended] 23. The eye lens device of claim 22, wherein the lens core further comprises an opaque annular ring having a central open area and a peripheral diameter.
    [24" claim-type="Currently amended] 24. The device of claim 23, wherein the ring is formed by tattooing or placing an opaque material on the back side.
    [25" claim-type="Currently amended] 24. The ocular lens apparatus of claim 23, wherein the central open area has a diameter of less than about 1.5 mm.
    [26" claim-type="Currently amended] 26. The eye lens device of claim 25, wherein the central open area has a diameter of about 0.5 mm to about 1.5 mm.
    [27" claim-type="Currently amended] 26. The eye lens device of claim 25, wherein the central open area has a diameter of about 0.75 mm to about 1.25 mm.
    [28" claim-type="Currently amended] 25. The device of claim 24, wherein the ring comprises a Dacron mesh.
    [29" claim-type="Currently amended] 24. The ocular lens apparatus of claim 23, wherein the opaque annular ring perimeter diameter is 3 to 5 mm.
    [30" claim-type="Currently amended] 30. The ocular lens apparatus of claim 29, wherein the diameter around the ring is selected less than the pupil diameter of the selected recipient's eye in less light.
    [31" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core further contains a therapeutic agent, an immunosuppressive agent, or a growth factor.
    [32" claim-type="Currently amended] 2. The ocular lens apparatus of claim 1, wherein the lens core is not frozen, lyophilized, or chemically treated by a fixative.
    [33" claim-type="Currently amended] 12. The ocular lens device of claim 11, wherein the lens core is comprised of corneal tissue grown in vitro.
    [34" claim-type="Currently amended] The ocular lens device of claim 1, wherein the epithelial cells and corneal cells comprise human corneal cells.
    [35" claim-type="Currently amended] 35. The ocular lens device of claim 34, wherein the epithelial cells and corneal cells comprise neonatal, fetal, or tissue bank corneal cells.
    [36" claim-type="Currently amended] The eye lens apparatus of claim 1, wherein the lens core has a thickness, and the thickness is less than 300 μm.
    [37" claim-type="Currently amended] The ocular lens apparatus according to claim 36, wherein the lens core thickness is 5 to 100 µm.
    [38" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises replaced corneal cells.
    [39" claim-type="Currently amended] The eye lens device of claim 1, wherein the lens core comprises replaced epithelial cells covering at least a portion of the front face.
    [40" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core further comprises an epithelial cell layer having a periphery and extending beyond the periphery of the lens core.
    [41" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises a replaced epithelial cell covering at least a portion of the front face and further comprising a carrier supporting the replaced epithelial cell and the lens core.
    [42" claim-type="Currently amended] 42. The ocular lens device of claim 41, wherein the lens core further comprises an epithelial cell layer having a periphery and extending beyond the periphery of the lens core.
    [43" claim-type="Currently amended] 42. The device of claim 41, wherein the carrier comprises a material that is bioerodible or biodegradable.
    [44" claim-type="Currently amended] 44. The device of claim 43, wherein the carrier has a size and shape suitable for introduction over the eye.
    [45" claim-type="Currently amended] 44. The group of claim 43, wherein the carrier consists of collagen, gelatin, starch, glucoseamine, glucan, polymer anhydrides such as proteins, carbohydrates, polylactide and polyglycolide, mixtures and copolymers thereof, and polydiaxanone An ocular lens device, characterized in that it comprises a material selected from.
    [46" claim-type="Currently amended] The ocular lens apparatus according to claim 1, wherein the lens core is annular and has an opening between the front face and the back face.
    [47" claim-type="Currently amended] The ocular lens device of claim 1, wherein the lens core comprises corneal cells replaced with the lens core.
    [48" claim-type="Currently amended] 2. The ocular lens device of claim 1, wherein the lens core comprises replaced epithelial cells covering at least a portion of the front face.
    [49" claim-type="Currently amended] 50. The ocular lens apparatus of claim 49, wherein the lens core comprises replaced epithelial cells covering substantially all of the front face.
    [50" claim-type="Currently amended] a) preparing the front side of the cornea; And
    b) introducing the ocular device of any one of claims 1 to 49 onto the prepared front face.
    A method for correcting the vision of a human eye having a cornea having a front side comprising a.
    [51" claim-type="Currently amended] 51. The method of claim 50, wherein said preparing comprises removing a substantial portion of any epithelial cells present on the front side.
    [52" claim-type="Currently amended] 51. The method of claim 50, wherein said preparing comprises lifting the epithelial layer from the front side.
    [53" claim-type="Currently amended] 53. The method of claim 52, wherein said lifting comprises lifting the epithelial layer from the front side using a vacuum.
    [54" claim-type="Currently amended] 53. The method of claim 52, wherein the lifting step comprises applying ethanol to the epithelial layer to lift the epithelial layer from the front.
    [55" claim-type="Currently amended] a) harvesting a lens core comprising donor corneal tissue and generally having a convex front and back surface; And
    b) covering at least a portion of said generally convex front with replaced epithelium; And
    c) i) deactivating the lens core; And
    ii) resurrecting the lens core
    Redistributing the lens core to the replaced corneal cells, comprising:
    A manufacturing method of the eye lens device comprising a.
    [56" claim-type="Currently amended] 56. The method of claim 55, further comprising forming the back side.
    [57" claim-type="Currently amended] 59. The method of claim 56, wherein the forming step includes applying a removable laser to the back side.
    [58" claim-type="Currently amended] 59. The method of claim 57, wherein the forming step comprises applying an excimer laser or other suitable forming laser to the back side.
    [59" claim-type="Currently amended] 59. The method of claim 56, wherein forming comprises applying a waterjet cutter to the backside.
    [60" claim-type="Currently amended] 55. The method of claim 54, wherein said shaping comprises shaping said back surface to correct at least one selected from the group consisting of myopia, ataxia, presbyopia, and astigmatism.
    [61" claim-type="Currently amended] 56. The method of claim 55, further comprising harvesting the lens core.
    [62" claim-type="Currently amended] 62. The method of claim 61, wherein the lens core is harvested from human, rabbit, cow, pig, or guinea pig corneal tissue.
    [63" claim-type="Currently amended] 56. The method of claim 55, wherein said resurrection step comprises replacing with cultured cells from human corneal tissue.
    [64" claim-type="Currently amended] 64. The method of claim 63, wherein said cells are cultured from neonatal tissue, fetal tissue, or tissue bank tissue.
    [65" claim-type="Currently amended] 65. The method of claim 64, further comprising sterilizing the lens core after the molding step.
    [66" claim-type="Currently amended] 66. The method of claim 65, wherein said sterilizing comprises contacting said lens core with glycerol.
    [67" claim-type="Currently amended] 66. The method of claim 65, wherein said sterilizing comprises contacting said lens core with ethylene oxide gas.
    [68" claim-type="Currently amended] 56. The method of claim 55, wherein said deactivating comprises removing epithelium from said front side and corneal cells from said lens core.
    [69" claim-type="Currently amended] 56. The method of claim 55, wherein the resurrection step comprises adding epithelial cells to at least a portion of the front face and corneal cells to the lens core.
    [70" claim-type="Currently amended] 56. The method of claim 55, wherein the activating step comprises placing the lens core on a polyelectrolyte gel.
    [71" claim-type="Currently amended] 56. The method of claim 55, wherein the corneal tissue matrix of the lens core is unaltered.
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    同族专利:
    公开号 | 公开日
    EP1301223A2|2003-04-16|
    CN1458849A|2003-11-26|
    WO2002006883A2|2002-01-24|
    US20030105521A1|2003-06-05|
    CN1243573C|2006-03-01|
    AU7894701A|2002-01-30|
    US20050070942A1|2005-03-31|
    US6544286B1|2003-04-08|
    CA2418306A1|2002-01-24|
    AU2001278947B2|2006-03-30|
    US20030083743A1|2003-05-01|
    WO2002006883A3|2002-05-23|
    US6880558B2|2005-04-19|
    IL153969A|2006-12-10|
    MXPA03000511A|2004-09-10|
    IL153969D0|2003-07-31|
    JP2004504627A|2004-02-12|
    US20050124982A1|2005-06-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-07-18|Priority to US09/618,580
    2000-07-18|Priority to US09/618,580
    2001-07-18|Application filed by 에드워드 페레즈
    2001-07-18|Priority to PCT/US2001/022633
    2003-06-11|Publication of KR20030045779A
    优先权:
    申请号 | 申请日 | 专利标题
    US09/618,580|US6544286B1|2000-07-18|2000-07-18|Pre-fabricated corneal tissue lens method of corneal overlay to correct vision|
    US09/618,580|2000-07-18|
    PCT/US2001/022633|WO2002006883A2|2000-07-18|2001-07-18|Pre-fabricated corneal tissue lens and method of corneal overlay to correct vision |
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