USE OF CORNEAL HARDENING AGENTS IN ENZYME ORTHOKERATOLOGY

Abstract: An Enzyme Orthokeratology method is provided for correcting refractive errors in the eye of a subject mammal. Accelerating reshaping of the cornea is accomplished by administering a corneal hardening amount of a corneal hardening agent to the eye of the subject. Reformation is accomplished under the influence of a rigid contact lens or a series of lenses having a concave curvature that will correct a refractive error. The cornea rapidly reshapes its convex curvature to the concave curvature of the contact lens, rendering the eye emmetropic. The cornea is permitted to "harden" to retain the new emmetropic shape. After "hardening" has occurred, the lens rendering the eye emmetropic is removed.

Description: USE OF CORNEAL HARDENING AGENTS IN ENZYMEORTHOKERATOLOGY Field of the Invention The present invention relates to methods for accelerating non-surgical corneal reshaping involving the release of corneal hardening agents which facilitate reshaping of the cornea to correct refractive errors of the eye. Background of the Invention The cornea is the clear dome on the front of the eye. About eighty percent of the focus, or refracting, power of the eye is at the cornea. When the cornea is misshapen or the axial length of the eye is too long or too short, or when the lens of the eye is functioning abnormally, the refractive errors of myopia (nearsightedness), astigmatism (blurred vision) or hyperopia (farsightedness) can result. Throughout history, mankind has experimented with ways to improve vision. Although these ways have provided many people with a reasonable quality of life, they still have limitations. Glasses correct refractive errors of the eye by changing the angle at which the light enters the cornea by refracting the light with a lens before it reaches the cornea. But for many lifestyles, glasses are very inconvenient. And for some people, they do not give the quality of vision desired. When the glasses are taken off, the refractive error still exists. Contact lenses correct refractive errors of the eye by replacing the defective corneal curve with the front curve of a contact lens that is calculated to render the eye emmetropic, which is a state where no visual correction is necessary. But wearing contact lens also has a price. The wearer must spend considerable time and money both in the maintenance and the application of the contacts. There still remains a limitation as to the types of activities in which one can participate. And, lastly, long term lens wearers may develop an intolerance to wearing their lenses as well as long term damage. When the lens is removed, the refractive error still remains. Radial keratotomy ("RK") is a surgical operation to improve myopia by changing the curve of the cornea over the pupil. The surgeon makes several deep incisions in the cornea in a radial or spoke-like pattern. The incisions are intended to flatten out the central cornea to correct the patient's vision. However, RK can only be used to correct low amounts of myopia. It cannot address the problems of hyperopia. The main drawback is that the cornea is seriously weakened and frequently continues to change shape with time. A newer type of RK that involves making shorter incisions is replacing standard RK. But newer techniques using computerized assessment, precisely calculated cutting patterns, and lasers will probably result in the rapid decline of RK. Photorefractive keratectomγ ("PRK") is a surgical procedure similar to RK involving the use of an excimer laser, which is controlled by a computer that measures the shape of the eye and sets the power of the laser. With the PRK process, the excimer laser permits the ability to sculpt rather than cut the surface of the cornea. There are a combination of laser machines that with a combination of computer controls can reliably treat myopia, hyperopia, and astigmatism. -1- However, since PRK is a surgical procedure, it can result in complications. Infection is the most serious complication. Other possible problems include delayed surface healing, corneal haze or scarring, over or undercorrection, and the development of astigmatism. Some individuals can have a poor or excessive healing response. The complications must be treated with medications or further surgery. Laser in-situ keratomileusis ("LASIK") is a surgical procedure that is a variation on PRK involving an excimer laser and a precise cutting machine called a microkeratome. An ophthalmologist uses the microkeratome to form a circular flap on the cornea. The flap is flipped back, as if on a hinge, to expose the inner layers of the cornea. With the flap folded back, the doctor now makes the refractive correction on the inner layers of the cornea using the excimer laser. Finally, the flap is repositioned to complete the procedure. With a precision laser treatment and normal reattachment and healing of the flap, the refractive results can be rapid and superb. There is, however, a very significant list of potential complications and risks including failure of the microkeratome to leave a hinge on the corneal flap with the first incision, loss of the corneal flap during the operation, loss of the corneal flap after the operation, slipping of the flap and healing off center, first incision too deep or too shallow, invasion of the surface tissue into the central tissue of the cornea, infection of the cornea, loss of visual acuity from scarring or optical distortion due to the flap not being repositioned correctly, technical problems with complex and finicky automated cutting devices, and the procedure being much more dependent upon the surgeon's operating skills than the computerized precision of the procedure. Thermokeratoplasty is another corneal reshaping method. In ther okeratoplasty Heat is applied to the cornea to induce shrinkage. Corneal stromal collagen shrinks when heated to a temperature of 55°C to 58°C, without the destruction of the tissue. If the pattern of shrinkage is properly selected the resulting change in the stress field and mechanical properties caused by the shrunken collagen fibers can be used to reshape the cornea. A variety of methods are known with which to practice thermokeratoplasty. For example, U.S. Patent No. 4,881,543 discloses one method and apparatus for heating the central stroma of the cornea with microwave electromagnetic energy to the shrinking temperature of the collagen while circulating a cool fluid over the anterior surface of the cornea. In another example, U.S. Patent No. 5,779,696 describes the use of light energy to reshape the cornea in a process known as photothermokeratoplasty. All of these process suffer from a variety of short comings, including a common flaw in which corneas in the treated subjects are unstable after the thermokeratoplasty procedure is concluded. Orthokeratology is a non-surgical procedure designed to correct refractive errors by reshaping the cornea to the curvature required for emmetropia. This is accomplished by applying a series of progressive contact lens changes that retrain the eye to achieve a corneal curvature. However, once a desired corneal curvature has been produced, retainer contact lenses must be worn to stabilize the results or regression may occur. Enzyme Orthokeratology is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors by reshaping the cornea to the curvature required for emmetropia. The program is supplemented by chemically softening the cornea. By supplying drugs that soften the cornea, the cornea is chemically -2- reshaped by being molded to the concave surface of a contact lens having a predetermined curvature. The contact lens radius is selected to render the eye emmetropic. Retainer contact lenses will not be required for good visual acuity after removal of the contact lens from the cornea and regression will not be a problem. However, the length of program of treatment varies from weeks to months with progressive contact lens changes and periodic follow-up examinations. Notwithstanding the foregoing, there remains a need for non-surgical methods of correcting refractive errors of the eye which can correct various degrees of refractive error and produce relatively permanent results in a much shorter period of time. Summary of the Invention An Enzyme Orthokeratology method is provided for correcting refractive errors in the eye of a subject mammal. Accelerating reshaping of the cornea is accomplished by administering a corneal hardening amount of a corneal hardening agent to the eye of the subject. Reformation is accomplished under the influence of a rigid contact lens or a series of lenses having a concave curvature that will correct a refractive error. The cornea rapidly reshapes its convex curvature to the concave curvature of the contact lens, rendering the eye emmetropic. The cornea is permitted to "harden" to retain the new emmetropic shape. After "hardening" has occurred, the lens rendering the eye emmetropic is removed. A method for correcting refractive errors in an eye of a subject mammal, comprising the steps of selecting a pharmaceutically acceptable corneal hardening agent on the basis of its being able to harden the cornea in the eye of the subject without causing damage to the cornea, administering to the eye of the subject a corneal hardening amount of the agent so that the cornea can be reshaped from a first configuration to a desired second configuration, fitting the cornea with a rigid contact lens having a concave curvature of the desired second configuration, permitting the cornea to reshape to the desired second configuration under the influence of the lens, and removing the lens when the cornea is capable of maintaining the desired second configuration without the support of the lens. Preferably, the types of refractive errors are selected from the group consisting of myopia, hyperopia and astigmatism and the corneal hardening agent is a cross linker such as an aldehyde. This aldehyde may be selected from the group consisting of acetaldehyde, glγceraldehyde, phenγlacetaldehyde, valeraidehyde, 3,4- dihγdroxyphenylacetaidehγde, mutarotationai isomers of aldehydes, ascorbic acid and dehydroascorbic acid. The corneal hardening agent may also be an enzyme, where the enzyme mediates cross linking reactions. Examples of a suitable enzyme include lysyl oxidase or prolyl oxidase. In one embodiment, the corneal hardening agents may be administered by injection into the eye, by topical administration into the eye in the form of eye drops or by means of a contact lens. In another embodiment, the additional step of administering to the eye a corneal softening amount of a pharmaceutically acceptable corneal softening agent sufficient to soften the cornea of the eye so that the cornea can be reshaped is performed as part of the method to correct a refractive error. In this embodiment, the corneal softening agent is an enzyme that degrades proteoglycans in the cornea, such as hyaluronidase. Another embodiment of the present invention is a kit for performing refractive corrections in an eye of a subject mammal, comprising: a corneal hardening agent in unit dosage form and a rigid corrective lens having a desired concave structure. Still another embodiment of the present invention is a reaction mixture comprising: the eye of a subject mammal, a corneal hardening agent in unit dosage form; and a rigid corrective lens having a desired concave structure. Yet another embodiment is a method of rehabilitating corneal irregularity and correcting refractive error in an eye of a subject mammal with irregular corneal shape, comprising the steps of: identifying a subject with irregular corneal shape, selecting a pharmaceutically acceptable corneal hardening agent on the basis of its being able to harden the cornea in the eye of the subject without causing damage to the cornea, administering to the eye of the subject a corneal hardening amount of the agent so that the cornea can be reshaped from a first configuration to a desired second configuration, fitting the cornea with a rigid contact lens having a concave curvature of the desired second configuration, permitting the cornea to reshape to the desired second configuration under the influence of the lens, and removing the lens when the cornea is capable of maintaining the desired second configuration without the support of the lens. Subjects may be identified for this procedure by diagnosing them as having a condition selected from the group consisting of: keratoconus, contact lens induced corneal warpage, contact lens intolerance, corneal ulcers, corneal melting disorders, recurrent corneal erosions, pterygium, and irregular corneal shape or uncorrected refractive error due to corneal surgery. Another embodiment of the present invention is a method for improving the clinical success of surgery to the eye involving the manipulation of a cornea of a subject mammal, comprising the steps of: identifying a subject who has undergone a corneal manipulation, selecting a pharmaceutically acceptable corneal hardening agent on the basis of its being able to harden the cornea in the eye of the subject without causing damage to the cornea, administering to the eye of the subject a corneal hardening amount of the agent so that the cornea can be reshaped from a first configuration to a desired second configuration, fitting the cornea with a rigid contact lens having a concave curvature of the desired second configuration, permitting the cornea to reshape to the desired second configuration under the influence of the lens, and removing the lens when the cornea is capable of maintaining the desired second configuration without the support of the lens. In this embodiment, the typical corneal manipulations are selected from the group consisting of radial keratotomy, photorefractive keratectomy, LASIK, thermokeratoplasty, photothermokeratoplasty, corneal transplant surgery, cataract surgery, and corneal reshaping by laser. Brief Description of the Drawings Figure 1 shows a plan view of an Enzyme Orthokeratology rigid gas permeable lens for use in treating myopia. Detailed Description of the Preferred Embodiment Enzyme Orthokeratology includes the use of one or more enzymes and/or the use of other agents in conjunction with a Orthokeratology contact lens program. In a traditional Orthokeratology program, a misshapen cornea is treated with a corrective lens to alter its shape and eliminate a vision impairment. This procedure bends or compresses the misshapen cornea from a defective first position to a more optimum second position. This procedure produces a reshaped -4- cornea in which the visual defect has been eliminated. Unfortunately, these effects are not permanent. Since the underlying structural components of the cornea are unchanged, the corneal shape now in an optimized second position will eventually revert to the defective first position in the absence of the corrective lenses. In contrast to traditional Orthokeratology, the methods of Enzyme Orthokeratology according to the invention alter the shape of the cornea using a corrective lens and preserve the desired second position induced by the corrective lenses. This preservation is achieved by altering and hardening the structural components of the cornea. Corneal hardening is achieved by inducing cross links between the components of the cornea. Cross links are chemical bonds formed between corneal components. These cross links preserve a structural change induced in the cornea as a result of wearing corrective lenses. In this way, corneas treated with Enzyme Orthokeratology according to the invention may take on and hold a new shape that eliminates a vision impairment, preferably without any need for the continued use or support of contact lenses. In the methods of Enzyme Orthokeratology provided herein, enzymes and/or other agents alter and modify the structural corneal components. These enzymes or agents may be administered to harden the cornea into the desired second configuration induced by a corneal shape correcting methods such as Orthokeratology. The term "harden" is used herein to denote the modification or cross linking of corneal components. This hardening results in an increased ability of a treated cornea to preserve the desired second configuration after the active treatment regime has concluded. -5- I. STRUCTURE AND COMPONENTS OF THE CORNEA The cornea itself is composed of five layers. The outermost layer is the epithelium, which is 4-5 cells thick. Beneath the epithelium is the acellular Bowmans membrane. The middle layer is the stroma, which is composed of scattered corneal fibroblasts (keratocytes) among organized lamellae of collagen, proteoglycans and glycoproteins. Below the stroma is another acellular layer called Descemet's membrane. The innermost layer of the cornea, comprised of a single layer of flattened cells, is the endothelium. The stroma makes up the bulk of the cornea. It is composed of highly organized collagen, which accounts for the transparency of the structure. The acellular components of the stroma consist mainly of collagen, proteoglycans and glycoproteins. The collagen is organized into lamellae that are in turn made up of flattened, parallel bundles of collagen fibrils. The keratocytes secrete the stromal lamellae. Of the various types of collagen in existence, collagen of more than one type has been identified throughout the stroma. The corneal stroma is composed of 78% water, 1 % salts, and 21 % biological macromolecules, almost 75% of which is collagen fibrils. Collagen is a family of fibrous proteins of novel structure and function. It is the most abundant protein in mammals and serves, in part, to hold cells together. There are a number of types of collagen, classified by their amino acid structures. Structurally, a collagen fibril is composed of three protein chains coiled about each other in a triple helical conformation. Collagen has a very unusual amino acid sequence. Nearly every third amino acid residue is a glycine. In contrast, hemoglobin has a glycine content of only five (5) percent. Furthermore, collagen has an unusually high concentration of the proline and lysine derivatives 4-hydroxγproline and 5-hydroxγlysine. These amino acid derivatives play a crucial role in determining the structure of the collagen fibril since they are frequently modified and often form cross links. Lysine amino acids may be modified to alter the structure of the corneas. These residues may be cross linked through an aldol condensation. These cross links serve to strengthen the collagen fibers, presumably by reinforcing the collagen triple helix. The importance of these cross links is apparent when one considers the disease scurvy. Scurvy is caused by a deficiency of ascorbic acid. Ascorbic acid is a cofactor in the formation of hydroxypyridinium cross links between two hγdroxγlysine residues and one lysine residue. The degradation of connective tissue that is a hallmark of scurvy is due, in part, to a lack of collagen cross links. The modification of collagen proline residues may also effect the structure of the protein. The extent of proline hydroxylation has been shown to effect the thermal stability of collagen. Collagens from a variety of sources exhibiting varying degrees of hydroxylation were examined to determine their respective temperatures of melting, interestingly, collagen containing a higher percentage of hγdroxyproiine melted at a higher temperature than collagen with lower percentages of hydroxylation. The connective tissue of the cornea is also rich in proteoglycans. Proteoglycans are composed of a hyaluronate core, a protein core, and glycosaminoglycans, which are proteoglycan monomers with repeating disaccharide units. -6- Approximately 60% of the glycosaminoglycans of the cornea are made up of keratan sulfate, while the remaining 40% are mostly chondroitin sulfate. II. HARDENING AGENTS USED IN ENZYME ORTHOKERATOLOGY A number of enzymes and agents may be used to perform the corneal hardening function of Enzyme Orthokeratology according to the invention. Of particular interest are cross linking agents and corneal hardening enzymes. However, Enzyme Orthokeratology according to the invention is not limited to the use of these enzymes and agents, and includes chemicals that can be administered to harden a cornea through various different mechanisms of action. Federal law requires that the use of pharmaceuticals in the treatment of patients be approved by an agency of the Federal government, the Food and Drug Administration. Similar approval is required by most foreign countries. Only pharmaceutical-grade forms of enzymes and agents are to be used in the practice of the present invention in accordance with the laws of the forum state. Corneal hardening agents are to be selected on the basis of safety and efficacy. As in conventional Enzyme Orthokeratology, the present invention is related to traditional Orthokeratology in that it is defined primarily as a contact lens procedure of correcting refractive errors by reshaping the cornea to the curvature required for emmetropia. However, the program is supplemented by chemically hardening the cornea. By supplying drugs that harden the cornea, the cornea is chemically reshaped by being molded to the concave surface of a contact lens having a predetermined curvature. The contact lens radius is selected to render the eye emmetropic. Retainer contact lenses will not be required for good visual acuity after removal of the contact lens from the cornea and regression will not be a problem. The complications and risks of surgery will be prevented by virtue of following these non-surgical steps. A. Aldehydes Used In Enzyme Orthokeratology An aldehyde is a carbonγl group bonded to one carbon atom and one hydrogen atom. Formaldehyde, the simplest example of an aldehyde, is an exception to this rule since it has two hydrogen atoms bonded to the carboπyl group. A carbonyi group is a carbon-oxygen double bond with the carbon having two available sites to bond with other atoms. The chemical nature of the carbonyi group, namely the double bond and the ability of oxygen to orbit six free electrons, taking two from the double bond, makes this group extremely reactive. One chemical reaction in which aldehydes frequently engage is called the aldol condensation reaction. In one aspect of the present invention, aldehydes are reacted with each other to form cross links within corneal components using the aldol condensation reaction, in a typical aldol condensation reaction, the carbonyi group undergoes an enolization where an enolate anion is formed. An enoiate anion is formed when one pair of electrons is shifted to the carbon of the carbonγl group from a neighboring carbon atom. A proton acceptor may remove a proton from the neighboring carbon atom in the reaction, and if that acceptor is a hydroxyl then water is formed. As the electrons shift to the carbon of the carbonyi group a double bond is formed between it and the neighboring carbon atom. This shift in electrons causes a pair of electrons to shift from the carbonγl carbon to the carbonyi oxygen, creating a negative charge on that oxygen. The resulting carbon-carbon double bond of the enolate reaction is extremely reactive. -7- The electrons from the enolate anion's carbon-carbon double bond attack the carbonyi group of a neighboring aldehyde molecule resulting in a joining or condensation of the two molecules The resulting compound is an alkoxide that may then be protonated to yield a hγdroxγaldehγde. The aldol condensation reaction can be used bγ the present invention to cross link various corneal structural molecules, including iγsine residues located in corneal collagen proteins in a neutral pH without the addition of an additional catalγst, strong acid or base. Corneal collagen contains an unusually large number of Iγsine residues. The amine groups at the ends of the Iγsines side chains are used to cross link Iγsine- containing collagen proteins. In the positivelγ charged ammonium state, Iγsγl oxidase oxidizes the carbon to which the ammonium group is attached. The nitrogen group leaves resulting in the creation of an aldehγde derivative of lysine called allysine. The aldehγde groups of neighboring allγsines may engage in an aldol condensation. The reaction of the two side chains results in a cross link between the two amino acids. Lγsyi oxidase also plays a role in the formation of a three waγ lysine product known as a hydroxγpγridinium cross link. Four residues in each tropocollagen molecule maγ participate in this tγpe of cross link. These include a iγsine residue near the amino terminus, a Iγsine near the carboxγl terminus, and hγdroxγlγsines in the helical region near the ends of the collagen molecule. Typically hγdroxγpγridinium cross links are formed between residues of the amino terminus of one collagen molecule and the carboxγl terminus of a neighboring molecule, in a proposed reaction pathwaγ, hγdroxγiγsiπe is first converted to hγdroxγallγsine bγ Iγsyl oxidase. A mechanism of formation has been proposed where two divalent ketoamine cross links may interact to produce one trivalent 3-hγdroxγpγridinium cross link. The formation of hγdroxγpγridinium cross links maγ be an important mechanism in the functioning of the present invention. The present invention contemplates the use of a varietγ of different aidehγdes to cross link constituent corneal structures particularly collagens and proteogiγcans. Those aidehγdes include acetaldehγde, glγceraldehγde, pheπγlacetaldehγde, valeraldehγde, 3,4-dihγdroxγphenγlacetaldehγde, glγcoaldehγde (the aldehγde form of ethγlene glγcol), pγruvaldehγde, dihγdroxγ acetone, acetoi, glγoxal, and mutarotational isomers of aidehγdes including glucose, fructose, lactose, and other sugars. Other contemplated cross linking agents include additional aldehγde compounds and ascorbic acid and dehγdroascorbic acid. Aidehγdes that contain -hydrogen can be useful cross linking agents in that theγ can react with N-acetγl groups of glγcosaminoglγcan chains in corneal proteoglycans to produce long chain polymeric proteogiγcans. In one embodiment of the present invention, the primary aldehγde used to harden a cornea is glγceraldehγde. Commonlγ used scientific names for this aldehγde include: glγceraldehγde, 2,3-dihγdroxγpropional and ,β- dihγdroyxypropionaldehγde. Glγceraldehγde is the simplest aldose and a derivative of this molecule, glγceraldehγde 3- phosphate, is a metabolic intermediate product of carbohγdrate metabolism. The fact that a derivative of glγceraldehγde plaγs such an important role in cellular metabolism implicates the safetγ of this compound when used to reshape the cornea in an otherwise healthγ eγe. -8- Giγceraldehγde maγ be obtained from a varietγ of sources including SIGMA Chemical Companγ, Inc., St. Louis, Mo; Aldrich Chemical Companγ, Inc., Milwaukee, WI; Fluka Chemical Corp., Ronkonkoma, NY; Fisher Scientific, Pittsburgh, PA. Glγceraldehγde exists as a tasteless solid with a melting point of 145°C. It is a monosaccharide with the empirical formula (CH 2 0) 3 and a molecular weight of 90.08. Presentlγ puritγ maγ varγ among commerical suppliers of glγceraldehγde, ranging from approximatelγ 95% to 98%. The invention should onlγ be practiced with the purist form of this compound. In furthering the present invention, the glγceraldehγde ophthalmic solution was prepared under sterile conditions by dissolving glyceraidehγde into a volume of 0.9% sodium chloride solution, USP, (McGaw Pharmaceuticals, Irvine, CA) followed bγ subsequent sterile filtration. Other drugs such as proparacaine or tropicamide maγ be included to anesthetize the cornea. The optimum concentration of glyceraldehγde maγ varγ depending on the protocol, the nature of the deliverγ vehicle, and the number of administrations. In general, concentrations of glγceraldehγde will varγ within the range of about 0.01 % to 10% weight to volume (w/v). In one embodiment, the concentration range of the glγceraidehγde solution will varγ from 1 % to 5% (w/v). In still another embodiment, the concentration of 3% giγceraldehγde is used. It is further noted that aidehγdes other than giγceraldehγde are contemplated for use in the present invention. Such compounds include acetaldehγde, glγceraldehγde, phenγiacetaldehγde, valeraldehγde, 3,4- dihγdroxγphenγlacetaldehγde, glγcoaldehγde (the aldehγde form of ethγlene glγcoi), pγruvaldehγde, dihγdroxγ acetone, acetol, glγoxal, and mutarotationai isomers of aidehγdes including glucose, fructose, lactose, etc. Suitable alternative aidehγdes have biochemical characteristics similar to those of giγceraldehγde possessing α-hγdrogen, including biodegradabilitγ, low toxicity, and ready readsorption into the treated area. B. Enzymes Used In Enzyme Orthokeratology In one aspect of the present invention, enzymes are used as corneal hardening agents. These enzymes increase corneal rigidity bγ modification of corneal structural components. These structural modifications comprise covalent intra- and/or intermolecular cross links, hγdroxγlation, or other modifications. In one example, the formation of collagen cross links are exploited to increase corneal rigidity or hardness using the methods of the present invention. In one embodiment, lysγi oxidase is used as an enzγmatic corneal hardening agent. The enzyme lysγl oxidase plaγs a central role in the formation of collagen cross link formation. Lγsγl oxidase is a 30-kd metalloenzγme which converts the amine side chains of specific Iγsine and hγdroxγ-lγsine residues in collagen into aidehγdes. Once the enzγme has converted the collagen Iγsiπe residues to their aldehγde derivatives, neighboring Iγsine residues maγ form cross links bγ undergoing the aldol condensation reaction described above. The formation of collagen cross links serve to reduce the mobilitγ of individual collagen molecules within the matrix of the cornea, thus increasing the rigidity of the structure. In another embodiment enzymes which hγdroxγiate collagen residues maγ be used as corneal hardening agents. It is known in the art that certain iγsine and proline residues are hγdroxγlated bγ iγsγl hγroxγlase and prolγl hγdroxγlase respectivelγ in vivo. These modifications maγ also be exploited to induce corneal rigiditγ or hardness. -9- For example, the extent of proline hγdroxγlatioπ has been shown to effect the thermal stabilitγ of collagen. Thermal stabilitγ of a protein reflects the structural stabilitγ of the molecule and maγ denote the presence of stabilizing components within the protein. Collagen from a varietγ of sources exhibiting varγing degrees of hγdroxγlation was examined to determine their respective temperatures of melting. Interestinglγ, collagen containing a higher percentage of hγdroxγproiine melted at a higher temperature than collagen with lower percentages of hγdroxγiation. This correlation between the respective temperatures of melting and the extent of proline hγdroxγlatioπ implies that an increase in this modification maγ stabilize the collagen protein. Accordingiγ, hγdroxγlases maγ also be used to induce corneal hardness. In another embodiment, hγdroxγlation maγ be used as a preiiminarγ enzγmatic step preparing corneal collagen for glycosylation. Here, lysine or proline residues in collagen would be hydroxγlated with Iγsγl hγdroxγlase or prolγi hγdroxγlase respectivelγ. These residues could then be glycosylated through the action of an enzγme like galactosγl transferase and/or glucosγl transferase. These modifications would also result in the induction of corneal hardness and are therefore suitable for use in the present invention. in addition to these enzγmes, other enzγmes known in the art that alter and modifγ protein structure maγ be used with the methods of the present invention. For example, glucose oxidase, in conjunction with glucose, can be used to form oxidative cross-links, which are discussed more fullγ below. Suitable enzγmes induce protein modifications that increase corneal rigiditγ. C. Oxidative Hardening Agents Used In Enzyme Orthokeratology An additional group of reagents that are known in the art to induce protein cross-linking are the oxidative crosslinkiπg reagents. These reagents act by producing oxygen free radicals. In turn, oxygen free radicals interact with labile cites in the cornea resulting in the induction of inter- and intramolecular chemical bonds. One group of these reagents includes various sulphate compounds that are used to form cross-links. Examples of these compounds include copper sulfate (CuS0 4 ) and iron sulfate (FeS0 4 ). Ascorbic acid and CuS0 4 or Fe 2 (S0 4 ) 3 and other complexes of copper and iron act as oxidative cross- linking agents. Examples of these complexes includes cuproxoiine, caeluroplasmin, transferrin, lactoferrin, cupric gluconate, and others. Chromium sulfate Cr 2 (S0 4 ) 3 is another sulfate compound that is usable as an oxidative cross-linking agent. The use of ultraviolet light (UV) is also contemplated to induce oxidative cross links. The judicious use of UV alone or in combination with various photosensitizers is contemplated for use to induce oxidative cross links. Examples of photosensitizers include riboflavin, psoraien, Rose Bengal, methylene blue, and others. These oxidative cross-linking methods can be used alone to induce cross links in a subject, or maγ be used in combination with the aldehγde or eπzγmatic cross-linking methods when compatible. For example, UV and ascorbic acid maγ be used in conjunction to induce cross-linking. Conversely, CuS0 4 and lysγl oxidase maγ not be used simultaneously since, as is well known in the art, CuS0 4 inhibits Iγsγl oxidase activitγ. D. Determining Corneal Hardening Agents and Their Dosages -10- The corneal hardening chemicals, such as various agents and eπzγmes, used in the methods of the present invention, in addition to the proper dosages of such agents and enzγmes, can be determined bγ one of skill in the art through routine experimentation. Such experimentation can comprise testing a dose of an enzγme or agent on donor globes (eγes) mounted in plastic model sockets or testing such a dose on laboratory animals. Briefly, to determine an appropriate corneal hardening amount of a known hardening agent or enzyme, or an agent or enzγme to be tested for its abiiitγ to produce corneal hardening, a dose of the agent or enzγme is administered to a cornea in a donated eγe or a cornea of a test animal, and the hardening and toxic effect of the agent is thereafter determined. In order to determine whether an enzγme or agent is effective in hardening a cornea without producing toxicitγ, or, if it is a known hardening agent, whether a particular dosage will produce corneal hardening without causing toxicitγ, the eπzγme or agent is first mixed in a carrier vehicle that is pharmaceutically acceptable to a mammal. Preferably, the enzyme or agent is in lyophilized (drγ powder) form, and is dissolved in isotonic saline. However, one of ordinarγ skill in the art will understand that a varietγ of pharmacologically acceptable carriers which do not interfere with the functioning of an enzγme or agent can be used. A test dose of the enzγme or agent in solution is then administered to a test cornea in order to determine its corneal hardening and toxic effect. In one procedure for testing candidates, the test enzγme or agent is first administered to donor globes (eγes from a human donor) mounted in plastic sockets. This procedure is particularlγ preferred for determining the effect of an enzγme or agent on a human cornea because in this waγ a human cornea can be tested without subjecting a living person to experimentation. A donor globe used in this procedure is prepared for experimentation bγ injecting it with sufficient saline to maintain intraocular pressure of the globe at approximatelγ 20 mm Hg. The test dose of enzγme or agent is then administered to the donor cornea. Such administration can be, for example, bγ injection of the enzγme into the cornea. Normally, the lens will become opacified following this step due to the introduction of water into the eye and a change in the refractive index of the eγe. After a test period of time, the mounted globe is then examined to determine whether any corneal hardening or toxicitγ has occurred, and if so the extent of such hardening and toxicitγ. The examination of the cornea can be performed, for example, through slit-lamp examination to determine the claritγ of the cornea; pachγmetrγ to measure the thickness of the cornea; computer-assisted corneal topographγ to evaluate surface topographical changes; measurement of the tensile strength of the cornea; measurement of the distensibilitγ of the cornea; keratometrγ to measure central corneal curvature; and retinoscopγ to measure the refractive error of the cornea. The values determined from these tests are compared to values determined prior to the administration of the agent or eπzγme. In addition, a treated cornea in a mounted globe can be subjected to a number of other tests to determine the strength and viabiiitγ of the cornea following treatment. For example, light, scanning, x-raγ diffraction anaiγsis, and transmission electron microscopy can be used to examine the morphology of the cornea; tissue culture is prepared to -11- determine the viabiiitγ of the cells of the cornea following treatment; biochemical studies can be made of the collagens and other structural components of the cornea following treatment. The foregoing tests of donated globes and corneas can be used to verifγ that use of a particular enzγme or agent does not compromise the transparencγ of the cornea, decrease the viabiiitγ of the corneal cells, or damage the structural integrity of the cornea. Testing the use of an enzγme or agent on the cornea of a test animal, however, is also desirable in order to make sure that the candidate has no unexpected effect in living mammals that is not discovered during tests of donated eγes. In order to test the effect of a particular test enzγme or agent, a test dose in a pharmacologically acceptable carrier solution is administered to a test animal, in this case a mammal, so as to deliver that agent to the cornea of the animal. Following the administration of an agent to the cornea of the animal, the animal's cornea can be subjected to the following examinations: siit lap examination to determine the ciaritγ of the cornea, anterior chamber and iris; pachγmetrγ to measure corneal thickness; computer assisted corneal topographγ to evaluate the surface topographical change of the cornea; measurement of the elasticitγ of the cornea; toπometrγ to measure intraocular pressure; f undoscopic examination in order to evaluate the optic nerve and retina; keratometrγ to measure central corneal curvature; retinoscopγ to measure refractive error; staining with fluorescein or Rose Bengal to identifγ damage to the corneal epithelium; and indirect ophthalmoscopγ. The values determined through these tests can be compared to values determined prior to the administration of the enzγme or agent, as well as to values determined for the untreated eγe of the animal. In addition, a treated cornea of a test animal can be subjected to a number of other tests to determine the strength and viabiiitγ of the cornea following treatment. For example, light, scanning, and transmission electron microscopγ can be used to examine the morphologγ of the cornea; a tissue culture is prepared to determine the viabiiitγ of the cells of the cornea following treatment; and biochemical studies can be made of the collagens and other structural components of the cornea following treatment. Other corneal hardening eπzγmes and agents not disclosed herein and proper doses of such known and unknown enzγmes and agents can be determined as described hereinabove in relation to determining enzγmes and doses of enzγmes. In another embodiment of the invention, a corneal softening agent is first administered to a plurality of donor globes or to the corneas of an experimental animal, as described above. Corneal softening agents include various enzymes and agents, for example, proteases and proteoglγcan degrading eπzγmes, advantageouslγ, hyaluronidases. When using experimental animals, once the corneas have begun to soften, one cornea of the experimental animal is then treated with a test dose of the enzγme or agent to be tested for its hardening and toxic effect in order to determine whether the dose of the enzγme or agent can harden or toxifγ the cornea. The other cornea is left alone as a control. When using donor globes, a plurality of corneas can be tested, as long as one is left untreated as a control. The treated corneas can then be tested with a dose of test enzyme or agent. The control cornea and tested corneas should be treated for approximatelγ the same amount of time in order to be able to make a valid comparison of the effectiveness of the test eπzγmes and agents on the tested corneas. -12- After a period of time, the hardness or extent of hardening in a previouslγ softened cornea as well as toxicitγ is compared using the procedures described above with reference to determining the extent of corneal hardness and toxicitγ induced bγ an experimental enzγme or agent. If the treated cornea is harder than the control, the test dose of the candidate maγ be determined as being useful in inducing corneal hardening, and if the treated cornea is the same as the control then the test does of the candidate maγ be concluded to be safe as not causing damage to the cornea. An optimal dose maγ also be established using this method. The present invention further provides a kit for the preparation and use of the corneal hardening and softening agents from individual components. The kit will comprise a first container holding a hardening agent and a second container holding a softening agent. In addition, the kit will include instructions to prepare the agents for use bγ individualiγ combining them with a pharmaceutically acceptable carrier. The kit maγ include a varietγ of different reagents necessarγ to practice the method of the present invention. For example, the kit can contain corneal reshaping lenses for use bγ one of skill in the art to reshape the cornea of a subject. Additionaiiγ, the kit can contain various mean to administer the active agents of the present invention such as syringes and needles, eγe droppers, and other necessarγ equipment, such equipment being well known to those of skill in the art. III. Methods of Administering Corneal Hardening Agents The foregoing enzγmes and agents for hardening a cornea maγ be administered in anγ waγ known to the art. For example, in one embodiment, an enzγme or agent is injected directiγ into the eγe in a location proximal to the cornea. In this embodiment, the enzγme or agent should be mixed in a pharmacologically acceptable carrier which will not alter the effectiveness of the enzyme or agent contained therein. In another embodiment of the present invention, corneal hardening enzymes and agents are administered to the eγe of a subject bγ topical application in the form of eγe drops. A sufficient number of drops are applied so as to administer a desired concentration of enzγme or agent to the cornea of the subject. The eγe drop method of administration maγ be superior to injection based administration based on the less discomfort to the cornea of the subject resulting from an injection technique. In still another embodiment, alternative means of aiding diffusion across the eγe into the cornea maγ be used. Such means include, for example, the use of liposomes to deliver the active eπzγme or agent. The enzγme or agent is packaged into liposomes, which can pass across the lipid soluble membrane of the corneal epithelium and into the corneal stroma. Other means of aiding diffusion include the use of an electrical current to make the outer membrane of the eγe more permeable to the passage of enzγmes and agents, known as iontophoresis. Using this procedure, an electrical current traveling thorugh a salt solution causes the agents to pass into the eγe as charged particles. Compounds that enhance the abiiitγ of the active compounds of the present invention to penetrate the cornea are contemplated. A varietγ of compositions are envisioned for use as vehicles bγ which to administer the active agents of the present invention to the eγe of a subject mammal. A list of substances includes: acidifγing agent, aerosol propeliant , -13- air displacement, alcohol denaturant, alkalizing agent, anticaking agent, antifoaming agent, antimicrobial preservative, aπtioxidant, buffering agent, capsule lubricant, chelating agent, coating agent, color, complexing agent, dessiccant, emulsifγing and/or solubilizing agent, filtering aid, flavors and perfumes, giidaπt and/or anticaking agent, humectant, ointment base, plasticizer, polymer membrane, solvent, sorbent, sorbent, carbon dioxide, stiffening agent, suppository base, suspending and/or viscosity-increasing agent, sweetening agent, tablet binder, tablet and/or capsule diluent, tablet disintegrant, tablet and/or capsule lubricant, tonicity agent, vehicle, viscositγ increasing, water repelling agent, wetting and/or solubilizing agent. In one embodiment using glγcerol dehγde, the divalent cation cheiator ethγlenediaminetetracetic acid (EDTA) and a phosphate buffered saline solution at a pH of 8.0-8.5 was effective. In alternative embodiments, sustained release vehicles are used. Sustained release vehicles are compositions that act to hold the active ingredients of the present invention in functional association with the cornea. Compounds and compositions in the sustained release technologγ are well known in the art. (See, Controlled Drug Deliverγ, 2 nd ed., Joseph R. Robinson & Vincent H.L. Lee, Eds., Marcel Dekker, Inc., New York, 1987). Bγ holding the active ingredients in association with the cornea to be treated, a sustained release vehicle acts to increase the efficacγ of the active ingredients of the present invention. This increase in efficacγ can be attributed to the sustained release vehicle acting to raise the local concentration of the active ingredients of the present invention with respect to the treated cornea to levels higher than would be possible without the sustained release vehicle. Sustained release vehicles for use with the present invention hold or localize the active agents of the present invention in proximitγ to the cornea and have no deterimental effects on the cornea or the activitγ of the agents of the present invention. In a preferred embodiment, the sustained release vehicle is water soluble. Examples of suitable sustained release vehicles include: cellulose ethers such as methγl cellulose, methγlhγdroxγpropγl cellulose, methγlhγdroxγethγi cellulose, hγdroxγpropγl cellulose, hγdroxγethγl cellulose, and sodium carboxymethyl cellulose. Cellulose esters such as cellulose acetate phthalate and hγdroxγpropγl methγl cellulose phthalate; polymers derived from at least one acrylic acid, acrylic acid esters, methacrγlic acid and methγacrγlic acid esters such as methacrγlic acid-methyl methacrγlate polγmer and methacrγlic acid-ethγlacrγlate copolymers are also contemplated for use with the present invention. Additional polymers contemplated for use with the present invention include polymers derived from methγlvinγl ether and maleic acid anhγdride, polγvinγlpγrrolidone, polyvinγl alcohols, and the like, as well as mixtures of anγ of the compounds named above. Those of ordinarγ skill in the are would know at what concentrations to use these compounds. In one embodiment, polγmer concentrations range from about 0.001 % to about 5.0%. In another embodiment, the concentrations range from about 0.1 % to about 1.0%. An example of a sustained release formulation containing the corneal hardening agent glγceraldehγde would comprise glγceraldehγde at 3%, sodium carboxγmethγl cellulose at 0.5% and bring the total volume to 100 milliliters. In γet another embodiment of the present invention, corneal hardening enzγmes and agents are administered to the cornea through use of a contact lens. As will be discussed in more detail below, the methods of the present invention -14- involve the application of a rigid contact lens to a cornea in a suboptimal first conformation in order to reshape that cornea to a desired second conformation. In one embodiment of the present invention, the fitting of the contact lens and the administration of a corneal hardening enzγme or agent occurs simultaneously. In an alternative embodiment of the present invention, the fitting of the contact lens and the administration of a corneal hardening enzγme or agent occurs sequentiailγ. As an example of one embodiment of the present invention, a corneal hardening amount of a corneal hardening agent is loaded into a chamber inside a rigid contact lens, preferablγ one which is gas permeable. Alternatively, the enzγme or agent can be loaded or impregnated into a soft lens capable of taking up the enzγme or agent bγ soaking the soft lens in a solution containing the enzγme or agent. The enzγme or agent can also be loaded into a combination of a soft and a rigid lens. In all of the following embodiments of a contact lens for administering a cornea! hardening enzγme or agent, the enzγme or agent is administered as it diffuses out of (is released from) the chamber in the lens or the material of the lens (if the eπzγme or agent is soaked into a soft lens). Dosages for different refractive conditions and contact lens deliverγ vehicles can be optimized through routine experimentation bγ one of skill in the art. In accordance with one method of compound administration using the contact lenses of the present invention, corneal hardening enzγmes and agents can be applied to the eγe through the use of rigid contact lenses. These lenses can be made from known fluoro siiicone acrγlate lens materials, which are gas permeable. The lens is provided with an internal chamber for storing the corneal hardening enzγme or agent. The chamber preferablγ comprises a radially symmetrical space encircling the entire lens between the anterior surface and posterior surface of the lens. Rigid lenses for the present purpose can conveniently be made bγ lathe cutting, molding, or milling a posterior component and an anterior component from a contact lens button which, during fabrication, can be secured together to form a unitarγ lens using bonding techniques or adhesives known in the art. The chamber can be formed bγ lathe cutting an annular recess into the convex surface of the posterior component of the lens before the final lens fabrication. Anγ of a varietγ of dimensions can be used in accordance with the present invention, a preferred lens is provided with an annular chamber having a width of approximatelγ 1.0 mm to about 1.5 mm and a depth of from about 0.05 mm to about 0.10 mm. A plurality of microscopic holes are provided in the posterior portion of the lens to allow fluid communication between the chamber and the eγe, therebγ facilitating the timed release of the corneal hardening enzγme or agent into the cornea. These holes maγ be provided bγ mechanical or laser drilling, or bγ molding prior to assembling the anterior component and posterior component of the lens, in one embodiment the holes are drilled using a mechanical drill having a microcarbon drill bit. The pumping action of the eγelids combined with natural tearing assists the release of the corneal hardening enzγme or agent through the tiny holes. Preferably, the holes are produced by mechanical drilling with a microcarbon bit and will have a diameter of from about 0.002 mm to about 0.010 mm, and preferably about 0.005 mm. The number and diameter of the holes can be varied to affect the time release characteristics, as will be apparent to one of skill in the art. In general, however, for the diameter ranges specified above, from about 3 to about 10 holes are contemplated to be used. -15- In one embodiment of the lens, the posterior portion of the lens has a centerpoint thickness of approximatelγ 0.12 mm and an annular recess is lathed to a depth of about 0.075 mm. A number of holes, each having a diameter of about 0.005 mm, are drilled through the bottom of the chamber and spaced equidistantiγ apart around the peripherγ of the chamber to provide communication with the posterior surface of the lens. The number of holes in a lens will varγ, depending on the desired rate of administration of corneal hardening enzγme or agent from the chamber. The anterior portion of the lens, having a centerpoint thickness of about 0.12 mm is thereafter secured to the posterior portion to enclose the annular recess and form a chamber, therebγ forming a lens having an overall center thickness of about 0.24 mm. Bonding can be accomplished bγ applγing a small amount of a bonding agent such as Concise enamel bonding sγstem sold bγ 3M (St. Paul, Minnesota). Other means of joining the posterior and anterior portions of the contact lens will be apparent to those of skill in the art. Posterior radii of curvature of the lens are selected that will reshape the anterior corneal curvature to a shape required for rendering the eγe emmetropic (no unaided correction). The posterior and anterior configurations of the contact lens in accordance with the present invention are similar to those used in conventional Orthokeratologγ fitting procedures. In general, the convex anterior surface of the lens approximates a substantialiγ uniform radius of curvature along ail planes, and can varγ from an aspherical design, a tenticular design, a spherical design, or anγ other configuration necessarγ to accommodate the fitting needs of a patient. The concave posterior surface of the lens is divided into several discrete zones, each having a unique curvature. For example, a posterior central base curve maγ be radially symmetrically disposed about the centerpoint of the lens. An intermediate posterior curvature may be disposed annulariy about the radial outer peripherγ of the posterior central base curve. Adjacent to the radially outward side of the intermediate posterior curvature may be a third peripheral posterior curvature. Thus, the lens can be considered to comprise three distinct zones, a central optic zone, an intermediate zone, and a peripheral zone. Preferably, in accordance with the present invention, an annular chamber maγ be disposed within the intermediate zone. in another aspect of the present invention, a contact lens is provided which is composed of two laγers which are laminated together. In this advantageous design for a contact lens of the present invention, larger chambers for storing corneal hardening eπzγme or agent can be created. In this contact lens, an anterior portion of the contact lens maγ be manufactured having an anterior surface and a posterior surface. A posterior portion of the contact lens maγ also be manufactured with an anterior surface and a posterior surface. The outer perimeter of the posterior surface of the anterior portion maγ be designed to have the same radius of curvature as the outer perimeter of the anterior surface of the posterior portion. In this waγ, when the posterior surface of the anterior portion and the anterior surface of the posterior portion are laminated together, a seal maγ be formed between the outer perimeters of the anterior and posterior portions. However, in a central portion of the anterior portion, the posterior surface maγ have a steeper radius of curvature than the anterior surface of a central portion of the posterior portion. Because of this steeper radius of curvature, when the anterior portion and the posterior portion are laminated together, a chamber is formed between the -16- central portion of the anterior portion and central portion of the posterior portion of the contact lens. The volume of the chamber can be adjusted bγ changing the radii of curvature of the posterior surface of the central portion and of the anterior surface of the central portion, as will be apparent to one of skill in the art. Prior to manufacture, one or more holes may be made in the central portion of the posterior portion of the contact lens of this design. The holes may be produced bγ mechanical drilling with a microcarbon bit or bγ means of a laser such as an argon laser, and will have a diameter of from about 0.002 mm to about 0.010 mm, and preferablγ about 0.005 mm. The number and diameter of the holes can be varied to affect the time release characteristics, as will be apparent to one of skill in the art. Thus, the rate at which a dose of a corneal hardening enzγme or agent is dispensed from the chamber is largeiγ controlled bγ the size and number of holes present in the central portion of the posterior portion of the lens. In general, however, for the diameter ranges specified above, from about 3 to about 10 holes are contemplated to be used. These holes maγ be spaced around the central portion of the posterior portion of the contact lens in order to provide communication between the chamber and the surface of the eγe of a subject wearing the lens. In a preferred embodiment of this lens, the posterior portion of the lens maγ have a centerpoint thickness of approximatelγ .125 mm. The anterior portion of the lens maγ have a centerpoint thickness of about .125 mm. When the anterior portion and the posterior portion are joined, a lens is created having an overall center thickness of about 0.24 mm. If it is desired to change the shape of a cornea with increased rapiditγ, a lens of increased thickness can be used which exerts more pressure on the cornea to conform to the desired configuration. Bonding can be accomplished bγ appiγing a sufficient amount of a bonding agent such as the Concise enamel bonding sγstem sold bγ 3M (St. Paul, Minnesota). Other methods of bonding will also be apparent to one of skill in the art. As with other embodiments of the present invention, concave radii of curvature of the posterior surface of the posterior portion of the lens are selected that will reshape the anterior corneal curvature to a desired shape required for modifying corneal curvature and reducing refractive error. Thus, the posterior and anterior configurations of the contact lens of this aspect of the present invention are similar to those used in conventional Orthokeratologγ fitting procedures, as previousiγ described and as are known to those skilled in the art. A lens of this embodiment of the present invention maγ be made from known fluoro siiicone acrγlate lens materials. Such rigid lenses can be made bγ lathe cutting, molding, or milling a posterior component and an anterior component from a contact lens button. After the anterior and posterior components are manufactured, theγ can be secured together to form a unitarγ lens using bonding techniques, adhesives, or anγ other method of attachment known to the art. For example, an enamel bond sγstem can be used to join the anterior and posterior contact lens portions. An example of such a sγstem is the Concise enamel bond sγstem sold bγ 3M (St. Paul, Minnesota). In an alternate embodiment of a contact lens of this aspect of the present invention, a lens is provided which has a peripheral chamber rather than a chamber in the central portion of the lens. In this embodiment, the lens maγ be composed of an anterior portion and a posterior portion which are laminated together. In this embodiment, a chamber is provided in an intermediate portion of the lens. -17- In another embodiment, the chamber maγ be formed in the intermediate portion of the lens bγ providing an area of the posterior surface of the anterior portion of the lens, which has a steeper radius of curvature than that found in the remainder of the posterior surface of the anterior portion of the lens. As in the foregoing embodiment of a chambered contact lens, the volume of cornea! hardening enzγme or agent which can be contained in the lens and thus administered to a subject is largely determined by the radius of curvature of the posterior surface of the interior portion of the lens in the intermediate portion of the lens, as well as bγ the radius of curvature of the anterior surface of the posterior portion of the lens in the intermediate portion of the lens. The posterior portion of the lens is also provided with holes through the posterior portion of the lens in the intermediate portion of the lens. These holes serve to allow the transfer of the contents of the chamber from the chamber to the eγe of the subject. The number and size of the holes will largeiγ determine the rate at which a corneal hardening enzγme or agent is delivered to the eγe. Although the embodiments of a chambered contact lens have been described as being produced bγ laminating together an anterior portion and a posterior portion of the lens, one of skill in the art will recognize that other methods of forming the previouslγ described chambers are also possible. Daγ and/or night wear of these Enzγme Orthokeratologγ lenses maγ be used. The cornea can generally be reshaped in a matter of several hours to a few days. The reshaping progress can be monitored using conventional methods. The lens of the present invention can be utilized to correct myopia, astigmatism, and hyperopia. In accordance with a further deliverγ method of the present invention, a soft lens bandage or shield may be soaked or charged with a dose of the cornea! hardening enzyme or agent. The soft lens maγ then be properlγ fit to the cornea and worn for a matter of hours to release the enzγme or agent into the cornea. After the enzγme or agent sufficientlγ hardens the cornea, the soft lens either dissolves or is taken off. One tγpe of soft lens for use with this method is a collagen material which tends to uptake a reiativelγ high volume of solution containing enzγme or agent and release it relatively slowly. The material maγ be highlγ purified bovine collagen. The diameter ranges from about 13.5 mm to about 16 mm. Base curves preferablγ range from about 8.0 mm to about 9.5 mm. The DK (which is a measure of the oxγgen permeability of a material) should be about 50 and the H 2 0 hγdration percentage should be about 83%. One lens that maγ be found to be particularlγ well suited for the practice of this aspect of the present invention is the Medilens corneal shield available from Chiron Ophthalmics, Inc. of Irvine, California. The Medilens corneal shield is a clear, pliable thin film fabricated from bovine tissue. This tissue has a high percentage of collagen closely resembling the collagen molecules of the human eγe. The Medilens corneal shield is stated to provide protection and lubrication to the ocular surface, gradually dissolving within approximatelγ 24 hours. The drγ weight of the lens is approximatelγ 5.5 mg, and wet weight following loading with a solution containing an agent or enzγme is approximatelγ 34 mg. Loading is accomplished bγ soaking the -18- lens in a solution, as previouslγ described, for approximatelγ 60 minutes at room temperature. The uptake of the lens has been measured to be approximatelγ 28.5 mg, and the hγdration of the iens is approximatelγ 84%. In volume terms, the uptake of the iens is approximatelγ 200-300 L. Other types of soft lens materials tend to uptake less of a solution containing an enzγme or agent and also to release it more quicklγ. Examples of such materials are common hγdrophilic soft iens materials such as etafilcon A and phemfilcon A, available as Acucue™ from Johnson & Johnson Vision Products, Inc (New Brunswick, NJ) and Wesieγ Jessen (Des Plaines, IL). These lenses can be the disposable or long-term wear varietγ. Lens having an H 2 0 contesnt of between about 58% and about 70% maγ be found to be useful in the present method. Simuitaπeouslγ or sequentially with release bγ the soft lens or other deliverγ vehicle of the corneal hardening enzγme or agent into the cornea, a rigid contact lens is then fit to the cornea. The rigid contact lens rapidlγ reshapes the treated cornea. A contact lens is used which has a posterior radius that will reshape the anterior cornea to a curvature required for emmetropia. The reshaping process maγ take from several hours up to a few daγs. In one embodiment, the rigid contact lens maγ be fitted over the central portion of a soft contact iens which has been loaded with a corneal hardening enzγme or agent while that soft contact iens is on the eγe of a patient. Due to the intraocular pressure of the eγe, the treated cornea will tend to steepen in curvature. While this maγ be desirable in the case of hγperopia, this should be controlled in treating mγopia and other conditions. And even when treating hγperopia, the amount of deepening in corneal curvature should be controlled. Therefore, it maγ be desirable to place a rigid contact iens over a soft lens which is delivering enzγme or agent in order to control the change in shape of the cornea prior to the time that a rigid iens is fitted directiγ onto the eγe in order to reshape the cornea. In another embodiment, a rigid lens maγ be fused to the central portion of a soft contact lens which delivers corneal hardening enzγme or agent to the cornea. In this waγ, the chances of having errors due to an improper fitting of the rigid iens over the soft lens can be avoided. In accordance with a further embodiment of the present invention, a saturn-tγpe contact lens, such as the Softperm iens sold bγ Pilkington Barnes HindfSt. Helens, UK)maγ be utilized. This tγpe of lens comprises a lens with a rigid center and a soft lens peripheral skirt. The rigid, preferablγ gas permeable center contains no enzγme or agent whereas the soft lens peripheral skirt maγ be soaked in a solution containing the corneal enzyme or agent. The peripheral skirt of the saturn-type iens maγ be manufactured from sγnergicon A copolγmer available from Wesieγ Jessen (Des Plaines, IL). The rigid noπ -hydrophilic center maγ typically be from about 5.5 mm to 6.5 mm in diameter and has only about 0.2% H 2 0 absorption. The outer peripherγ is polγmerized into a soft hydrophilic skirt extending circumferentialiy about the outer peripherγ of the center and maγ have a width of from about 3.0 to 4.0 mm, and about 25% H 2 0 absorption. The base curve of this saturn-tγpe lens ranges from about 7.2 mm to 8.2 mm. As the saturn-tγpe lens is worn, the corneal hardening eπzγme or agent is released into the cornea from the soft peripheral skirt, modifγing the cornea in hours. The rigid center of the saturn-tγpe iens immediatelγ begins reshaping the cornea. The rigid center has a posterior radius of curvature that will reshape the anterior cornea to a curvature required -19- for emmetropia as has been discussed. The cornea is reshaped from several hours to a few daγs. The soft lens skirt gives added comfort and less edge sensation which helps the Orthokeratologγ process and encourages retainer lens wear. The corneal hardening enzγme or agent dissipates out of the cornea in a few daγs while the cornea assumes its new shape. The saturn-tγpe lens or another rigid retainer maγ preferabiγ worn for a few more daγs to stabilize the new corneal shape. The lens is then removed. A "fused soft lens" contact iens sγstem can also be used to release the corneal hardening enzγme or agent into the cornea and simultaneouslγ reshape it. In this embodiment of the present invention, an annular ring of soft lens tγpe material is fused to the inside intermediate curve and peripheral curve of a rigid gas permeable contact lens. The resulting fused (soft) lens is soaked in the enzγme or agent, and the chemical is retained in the soft lens portion. The chemical is then time released into the cornea, which modifies it. The rigid preferabiγ gas permeable center has a posterior central curvature that reshapes the anterior cornea's curvature to a shape which corrects refractive error, preferablγ a shape which renders the eγe emmetropic. The rigid contact lens center is preferably a fluoro-siiicone-acrylate material with a Ok of about 60-92. The diameters varγ from about 7.5 mm to 10.5 mm and the base curves of the rigid lens varγ from about 7.0 mm to 9.0 mm. The "fused on" soft lens portion is a hydrophilic soft lens material such as etafilcon A or phemfilcon A. Attachment of the annular ring to the rigid contact lens is accomplished by an adhesion process. The width of soft annular ring varies between about .75 and 1.5 mm each side. IV. The Procedure for Use of Hardening Agents in Enzγme Orthokeratologγ A. Procedure Generally The present invention contemplates the use of corneal hardening agents to alter the shape of a subject's cornea from a suboptimal first position to a desired, optimized second position. An Enzγme Orthokeratologγ contact iens must be properlγ fit to the surface of the cornea. When the corneal hardening agent is applied, the cornea hardens to lock the proper corneal shape in place. The Enzγme Orthokeratology method provided herein maγ include the use of a corneal softening agent. The corneal softening agent aids in altering the shape of a subject's cornea. An Enzγme Orthokeratologγ contact lens must be correctiγ fit. When a corneal hardening agent is applied, the cornea hardens to attain the proper corneal shape. Following hardening of the cornea, the corrective iens is removed and the subject's cornea retains the desired altered conformation. Unlike traditional Orthokeratologγ methods, the present invention does not require the use of retainer lenses to prevent or inhibit the complete regression of the cornea to the suboptimal original condition. Also, the time course of treatment of the present invention maγ be reduced compared to that of other Enzγme Orthokeratologγ methods. The time course of treatment using the present invention maγ be shorter since the use of a corneal hardening agent eliminates the need for one to wait for the corneal softening agent to act. Reduction of treatment time maγ provide increased success rates since the levels of subject participation are minimized. B. Rigid Contact Lens Design -20- One preferred embodiment of the rigid contact lenses designed for Enzγme Orthokeratologγ comprises a iens made of a fluoro-siiicone-acrylate material (methyl-methacrγlate difiuoroitaconate siloxanγl copolγmer) available from Paragon Optical Co., Inc. (Reading, PA). The high oxγgen permeabilitγ of this material DK60 - DK151 x 10-11, allows sleeping in the lens if necessarγ. The lens also has excellent wettabilitγ. In one preferred lens design, the preferred lens possesses a reverse geometrγ sculpture. The design constitutes a piuralitγ of curve planes comprising the geometrγ of the lens which is used to alter the shape of the cornea during the Enzγme Orthokeratologγ procedure. In one embodiment, the iens contains four curves which comprise the geometrγ of the lens. In another embodiment, the reverse geometrγ lenses have two curves steeper than the base curve. The shape and design of these lenses produce the desired results in reshaping a subject's cornea from a suboptimal first position to an optimal second position within hours to daγs of application. FIGURE 1 shows a plan view of an Eπzγme Orthokeratologγ rigid gas permeable lens 10 for use in treating mγopia. The shape of the lens is determined bγ the deformation of the cornea which is to be corrected. Accordiπglγ, the lenses of the present invention are shaped to correct various corneal irregularities. The lenses of the present invention use principles of hγdrodγπamics and a push-pull sγstem to alter the shape of a cornea to a desired conformation. In the embodiment shown in FIGURE 1, the flat base curve 12 pushes against and compresses the central cornea into a signif icantlγ reduced or longer radius. The central cornea is simultaneouslγ pulled or redistributed into the steep curvature zone 14. The centration curve zone 16 centers the lens and limits the flow of the cornea in response to the forces imposed bγ the flat base curve and the steep curve. The flat peripheral curve 18 allows for tear exchange and movement of the lens on the surface of the eγe. One preferred embodiment of the rigid contact lenses designed for Enzγme Orthokeratologγ comprises a iens made of a fluoro-siiicone-acrylate material (methyl-methacrγlate difiuoroitaconate siloxanγi copolγmer) available from Paragon optical. The high oxγgen permeabiiitγ of this material allows sleeping in the lens if necessarγ. The lens has excellent wettabilitγ with a low wetting angle. The flat base curve zone 12 (Fig. 1) corrects the refractive error of the eγe to improve unaided visual acuitγ. Generaliγ the flat base curve (optical zone) 12 diameter ranges from about 6.0 mm to 7.0 mm and is equal to the base curve in millimeters. The steep curve zone 14 lies outside of the flat base curve zone 12 and has a width range from about 0.6 mm to 0.8 mm. The steep curve zone 14 radius of curvature maγ be 5 to 10 diopters steeper than the lens base curve depending on the refractive error. Generaliγ, the ratio of the base curvature (BC) to the flattest central corneal curvature (K) in the first conformation (BC/K ratio) multiplied bγ a factor of 2 determines the steep zone radius of curvature. For example, the lens base curve is fit 4 diopters flatter than the central corneal curvature (BC/K ratio -4F). The steep zone radius -(BC/K)*2 or 8 diopters steeper than the lens BC. The centration curve zone 16 lies immediatelγ adjacent to the steep curve zone 14 and the range of this zone varies from about 0.8 to 1.0 mm. Generally, the curvature of the centration curve zone 16 will equal the curvature of the base curve zone 12 plus two to three diopters. The peripheral curve zone 18 -21- is flatter than the base curve 12 of the lens. The width of the peripheral curve zone 18 varies from 0.4 mm to 0.5 mm. The peripheral curve zone 18 allows for tear circulation and oxγgen exchange during blinking. The total diameter of the iens is determined bγ the base curve diameter plus the steep zone plus the centration zone to the peripheral curve. The lens diameter ranges from about 10 mm to 13 mm. The power of the lens is based on the refractive error of the patient and the lens base curve to central corneal curvature relationship. Generally the iens thickness is .24 mm for 0 power; .01 mm should be subtracted for each diopter of minus correction, and .02 mm should be added for each diopter of plus. The concave posterior curvature of the flat base curve zone 12 is preferably calculated to reshape the cornea from a suboptimal first conformation to an optimal second conformation, thus making the eye emmetropic when the cornea is molded to this curvature. The front curvature of the flat base curve zone 12 is of a radius calculated to give the subject no refractive error and 20/20 aided visual acuitγ while wearing the lens. All of the rigid contact lens parameters varγ depending upon the refractive error, corneal curvature and size, and fitting formula, as is known in the art. A further embodiment of a rigid contact lens designed specifically to be used in the treatment of hyperopia is contemplated. Such a contact lens should be rigid, such as the previouslγ described lenses made from a fluoro-silicone- acrγlate material. In this embodiment, the concave (posterior) portion of the lens maγ be a spheric or an aspheric base curve. A central portion of the lens is formed so that the concave surface of the central portion is shaped so as to produce emmetropia. This central portion has a base curve maγ be 1-5 diopters steeper than the central corneal curvature. The peripheral curves are much flatter than standard contact lenses and the diameters are larger. The steeper base curve of the lens is designed to steepen the central corneal curvature to reduce hγperopia and improve near and far unaided visual acuitγ. In an alternative lens design, the rigid contact lenses contemplated for Enzγme Orthokeratologγ comprises a lens made of a fluoro-siiicone-acrylate material (methyl-methacrγlate difiuoroitaconate siloxaπyi copolγmer) available from Paragon optical. The high oxγgen permeabiiitγ of this material DK60 - DK151 x 10-11, allows sleeping in the iens if necessarγ. The lens has excellent wettabilitγ with a low wetting angle. The base curve of the lens varies from 6.5 mm to 9.0 mm, depending upon the central corneal curvature. The total diameter of the lens is the base curve in millimeters from + 1.3 mm to 2.0 mm, and the range is about 7.5 mm to 15 mm. The central optic zone is transparent and corrects the refractive error of the eγe to produce excellent visual acuitγ. The optic zone diameter ranges from 6.5 mm to 9.0 mm. The intermediate zone contains a chamber for enzγme or agent to release the solution into the cornea. The width of the intermediate zone varies from .35 mm to 1.0 mm. The intermediate curve maγ be steeper or flatter than the base curve of the lens depending on the refractive error. The peripheral curve is flatter than the base curve of the lens. The width of the peripheral zone varies from .35 mm to 1.0 mm. The peripheral curves allow for tear circulation and oxγgeπ exchange during blinking. The power of the iens is based on the refractive error of the patient and the lens base curve to central corneal curvature relationship. The thickness is .24 mm for 0 power; .01 mm should be subtracted for each diopter of minus -22- correction, and .02 mm should be added for each diopter of plus. The concave posterior curvature of the optic zone (base curve) is preferablγ calculated to make the eγe emmetropic when the cornea is molded to this curvature. With mγopia the base curve is fit 1-3 diopters flatter than the central corneal curvature. This maγ be accomplished with one to three lenses. The front curvature of the optic zone is of a radius calculated to give the subject no refractive error and 20/20 aided visual acuitγ while wearing the iens. The final lens will have zero refractive power. All of the rigid contact lens parameters varγ depending upon the refractive error, cornea) curvature and size, and fitting formula, as is known in the art. This iens design maγ also be used unloaded to reshape the cornea. A further embodiment of the rigid contact lens design for use in the treatment of astigmatism. With astigmatism, the cornea exhibits an unequal curvature, ( ' .e v flatter curvature in one meredian and steeper curvature in the opposite meridian.) In one iens design, an aspheric base curve and peripheral curves are used to reshape the cornea to a more spherical shape. The lens has a uniform eccentricitγ change which reduces the curvature in the steeper meridan. This feature sphericaiizes the cornea, reduces the astigmatism, and imporves unaided visual acuitγ. A second design incorporates a toric base curve with base prism to orientate the steepr and flatter curves of the lens in the proper direction to correct the unequal curvature of the cornea. The lenses of this embodiment are constructed of similar materials as described above, however, 60-92 DK lenses are preferred. Yet another embodiment of a rigid contact iens is designed specifically to be used in the treatment of hγperopia. Such a contact lens should be rigid, such as the previouslγ described lenses made from a fluoro-siiicone-acrylate material. In this embodiment, the concave (posterior) portion of the lens is formed with a peripheral portion which has an aspheric base curve. A central portion of the lens is formed so that the concave surface of the central portion is shaped so as to produce emmetropia. This central portion has a base curve which is 1-5 diopters steeper than the base curve of the peripheral portion of the iens, and has a radius of curvature which is up to 1 mm steeper than the peripheral portion. The base curve of the central portion of the lens maγ also be designed to produce a desired radius of curvature of a cornea which does not render the cornea emmetropic, but which still steepens the base curve of the cornea. C. Myopia Enzyme Orthokeratology Procedure Myopia is a condition in which, typically, the shape of the eye is elongated, resulting in the focusing of parallel light rays in front of the retina. A corrective lens with a corrective curvature is used in this procedure that has a base curve flatter than that of the central corneal curvature up to the amount of the myopia in diopters. The inner radius of the intermediate zone may be up to 8 diopters steeper than the base curve. The steeper central corneal curvature is reshaped to a flatter curvature and the flatter paracentral curvature is reshaped to a steeper shape. The result is a spherical cornea from center to paracentral with a flatter central curvature. This eliminates myopia because the light is refracted farther back on the retina instead of in front of the retina and there is less spherical aberration. As will be apparent to one of skill in the art, a number of other lens designs can be used in treating myopia which have varγing diameter base curves and thicknesses. Included in such designs are contact lenses having aspheric base curves and peripheral curves and those having spherical base curves and aspheric peripheral curves. -23- The following example illustrates a method for correcting mγopia using Enzγme Orthokeratologγ of the present invention. In this example, a patient exhibits 20/300 uncorrected visual acuitγ (UVA) or 3 diopters mγopia; a flattest central curvature of 45 diopters or 7.5 mm; and a paracentral curvature of 40 diopters and the cornea is positivelγ shaped at +0.30. The patient is treated according to the methods of the present invention. Using the above-described methods, an appropriate concentration of glγceraldehγde was determined for use in the present invention. In one embodiment, a range of glγceraldehγde concentrations from about 0.1 % to 5.0% are contemplated for use in the present invention. In another embodiment, a range of concentrations from about 1 % to 4% are further contemplated. Finailγ, in still another embodiment, use of a glγceraldehγde solution of about 3% to induce corneal cross linking is contemplated bγ the present invention. A corneal -hardening amount of a corneal hardening agent is administered to the patient. One such agent is a 3% glγceraldehγde solution. The 3% glγceraldehγde solution is prepared under sterile conditions bγ dissolving 1.5 grams of glγceraldehγde into 50 mL of 0.9% sodium chloride USP. This solution is then sterile filtered and aiiquoted. The route of administration maγ include a sole intrastromal injection, or it maγ consist of topical applications to the corneas of the subject. In an embodiment where an intrastromal injection step is used, subjects receive a single corneal intrastromal injection of about 20 L of a 3% glγceraldehγde solution using an appropriate injection technique. For example, the subject is administered an optical anesthetic such as a 0.5% proparacaine solution (Bausch and Lo b, Tampa, FL). The eγe to be injected is gentlγ proptosed and the sγringe needle is geπtlγ introduced into the supertemporal quadrant into the corneal stroma. The hardening agent is then injected as a single bolus into the corneal stroma. Upon injection, the hardening agent cross links corneal components for a period of time, from minutes to daγs, as appropriate, hardening the cornea. Application of a 3% glγceraldehγde solution maγ alternatively be performed through eγe drops at one to four drops from one to four times dailγ. The 3% glγceraidehγde solution is applied in a dropwise fashion to the treated corneas, the procedure used entails gentlγ tilting the subject's head to allow the drop to fall on the cornea and not adjacent structures, holding the upper eγelid open, applγing a drop of the solution to the eγe of the subject, and allowing the subject to blink. The administration of the corneal hardening agent maγ occur hourlγ or dailγ from one to one hundred (100) daγs. Rigid gas permeable corrective contact lenses are fitted to the eγes of the subject to mediate corneal reshaping. The corrective lens provides a scaffold upon which the cornea maγ be reshaped into the desired second configuration. The dimensions of the corrective lenses used in the treatment are determined bγ the deformation of the subject's eγes as determined bγ standard diagnostic techniques known to one skilled in the art. The corrective lenses in this example have a base curve of 42 diopters or 8.0 mm (3 diopters flatter than central curvature). The optic zone width is 8.0 mm. The power of the lens is piano (0). The size of the lens is 9.6 mm (8.0 + 1.6 mm). Its thickness is 0.20 mm. The intermediate curve radius is 7.5 mm or 45 diopters (3 diopters steeper than the case curve) with a width of 0.50 mm. The peripheral curve has a radius of 10.0 mm, with a width of 0.30 mm. -24- In another embodiment of the present invention, the lens is loaded with a dose of corneal hardening agent. The contact lens is properlγ fitted to the cornea and the agent is released into the cornea over the course of from a few minutes to a few daγs, as appropriate. The enzγme penetrates into the stroma where it hardens the connective tissue laγer. The treated cornea reshapes its anterior central curvature (45 diopters) to the posterior base curve of the lens (42 diopters). The cornea's new anterior central curvature becomes 42 diopters (3 diopters flatter than its original 45 diopters). The paracentral anterior cornea (40 diopters) steepens to 42 diopters -8.0 mm. The cornea now has a spherical shape. The original three diopters of mγopia are now reduced to no correction (piano or emmetropic), and unaided (natural) visual acuitγ is improved to normal 20/20 from 20/300. Before, during, and after treatment, a patient's optical health maγ be monitored. Monitoring methods include standard phγsicai examinations performed bγ one skilled in the art. Additionally, slit lamp biomicroscopy maγ be used to assess a patient's optical health. A slit lamp such as a Nikon FS-2 Slit Lamp maγ be used for the subject's examination. Such an examination might include the steps of dilated the eγes of the subject bγ instilling one drop of 1.0% tropicamide (Bausch and Lomb, Tampa, FL) and 2.5% phenγlephrine (Bausch and Lomb, Tampa, FL). Following dilation the subject is then positioned in front of a slit lamp and examined for edema. The anterior chambers of the subject maγ then be examined for chamber depth, aqueous cell and flare, and fibrin. The iris of each subject maγ be examined for atrophγ, sγmmetrγ, or sγnechiae. The lenses maγ also be examined for the presence of cellular debris, capsule, or lens protein abnormalities. The vitreous humor of each maγ also be examined for the presence of cells or other abnormalities. Finally, Fluress (topical fiuorescein) (Akorπ Pharmaceuticals, Abita Springs, LA) maγ be instilled to examine the subjects for anγ epithelial defects that might be present. In this case, the application of the corneal hardening agent acts to cross link amino acid residues in the collagen of the stroma, which in turn results in an increase in corneal rigiditγ. Since corneal hardening takes place while the cornea is held in the desired second conformation bγ the iens, the hardened cornea hardens in the desired second configuration. As a result of application of the hardening agent, the treated corneas retain the proper shape upon removal of the corrective lenses. In an alternate embodiment of the Enzγme Orthokeratologγ procedure described above, a corneal softening amount of a corneal softening agent is administered prior to addition of a corneal hardening agent. For example, 500 international units (IU) of hγaluronidase is administered bγ intrastromal injection into a subject's eγes. The hγaluronidase is manufactured as a sterile Iγophilized product and packaged in vials, each containing 6,000 IU of a highly purified hyaluronidase (Biozγme, Blaenavon, UK). In addition to the enzγme, the product maγ include 1.22 mg potassium phosphate, monobasic; 1.92 mg potassium phosphate, dibasic; and 5 mg lactose. Within three hours of intended use, the vials are reconstituted with 0.24 mL of 0.9% sodium chloride USP and 20 L is drawn up into sγringes to deliver the desired 500 International Units (IU). A suitable syringe for use in this method is a 0.3 cc insulin syringe fitted with a half- inch 29-gauge needle (Becton-Dickinson, Franklin Lakes, NJ) or its equivalent. Upon injection, the corneal softening agent hγdroiγzes the carbohγdrate substrate for a period of time, from minutes to daγs, as appropriate, softening the cornea and -25- preparing it for reshaping. At this point, the corneal softening agent is allowed to dissipate or its activitγ is inhibited, and a corneal hardening procedure is followed to achieve a desired corneal shape. D. Astigmatism Enzyme Orthokeratology Procedure Astigmatism is a refractive error of the lens sγstem, caused usualiγ bγ an oblong shape of the cornea. In this condition, the central corneal curvature is uneven, resulting in a stretching of the image on the retina. The horizontal and vertical central meridians are of different curvatures. Corrective astigmatism contact lenses maγ use corrective toric and aspheric base curves, intermediate curves, and peripheral curves that maγ incorporate prism and/or truncation. The initially flatter central meridian of the eye is reshaped to take on a steeper curvature and the initial steeper curvature and the initial steeper central meridian is reshaped to take on a flatter curvature. This process reshapes the central corneal curvature to a spherical shape and eliminates astigmatism. To correct astigmatism using Enzγme Orthokeratologγ, the following procedure is used. In one embodiment of the present invention, the material for the lens is fluoro-siiicon-acrγlate. The base curves (6.0 mm-8.5 mm) may be back toric, front toric, or bitoric. The flattest central corneal curvature is aligned with a steeper base curvature. The steeper central corneal curvature is aligned with a flatter base curvature. Aspheric or spherical base curves and peripheral curves may also be used. The lens diameter is the base curve in millimeters + 1.3 to 1.8 mm. The range is from about 7.5 mm to about 11.5 mm. The optic zone diameter equals the base curve in mm and ranges from about 6.5 to about 9.5 mm. The intermediate curve radius ranges from about 1 diopter to about 2 diopters flatter than the base curve. The width is from about 0.35 to about 1.0 mm. The peripheral curves range from about 2 to about 4 diopters flatter than the base curve. The width is 0.35 to 1.0 mm. The intermediate and peripheral curves may be aspheric. Prism and/or truncation is used to keep the lens aligned in the proper position to reshape the astigmatic cornea. The thickness of the lens varies with lens power. If zero lens power = 0.20 mm, subtract 0.01 mm for each diopter of minus and add 0.02 mm for each diopter of plus power. The power of the lens is computed based on the patients refractive error and the base curve/corneal curvature relationship. The astigmatic lenses may be loaded with a corneal hardening agent or enzγme as a deiiverγ vehicle, or the lens design maγ be used unloaded to reshape the cornea. E. Hyperopia Enzyme Orthokeratology Procedure Hγperopia results from a suboptimaliγ short distance from the surface of the eγe to the retina. To correct hγperopia the central curvature of the cornea must be reshaped to a steeper curvature. The light entering such an eγe requires greater refraction since the image projected through the cornea is focused behind the retina and needs to be moved forward onto the retina. The lens base curve maγ be fitted steeper than the central corneal curvature with flatter aspheric intermediate and peripheral curves. A hole in the center of the lens maγ be used to encourage and give the space for the central cornea to steepen. Alternatively, a contact lens as described hereinabove may be used to correct hyperopia. To correct hγperopia using Enzγme Orthokeratology, the following procedure is used. In one embodiment of the invention, a fluoro-siiicone-acrylate material is used to form the corrective lens. A hole ranging from 2.5 mm to 4.5 mm diameter is provided in the center. The base curve of the lens is fit steeper than the central corneal curvature. The -26- corrective lens possesses a corrective curvature wherein the base curves varγ from 5.5 mm to 8.0 mm and the diameter is the base curve in millimeters + 1.0 mm to 1.5 mm (6.5 to 9.5 mm range). Smaller diameters are used because the curvature of the lenses is steeper than that of the central cornea. The intermediate and peripheral curves should be aspheric curves 1 to 3 diopters flatter than the base curve. The width of these curves is 0.35 mm to 1.0 mm. The optic zone is between 5.5 mm to 8.0 mm. The thickness of the lens is dependent upon the power necessary for correction. With hγperopia the lenses will be thicker. If the power is piano (0) the thickness -0.20 mm, then add 0.02 for each diopter of plus. The power of the lens is computed based on the patients refractive error adjusted for the base curve/corneal curvature relationship. The hγperoptic lenses maγ be loaded with a corneal hardening agent or enzγme as a deliverγ vehicle, or the lens design maγ be used unloaded to reshape the cornea. V. Other Therapeutic Uses of Enzyme Orthokeratology The present methods of reshaping a cornea can be used to effect therapeutic benefits other than correcting refractive errors. Additonal therapeutic benefits include improving corneal smoothness, improving or rehabilitating corneal irregularities and stabilization of corneal structures. One contemplated use of the present invention is to rehabilitate irregularities and improve refractive errors that result from various corneal surgeries including photorefractive keratectomγ (PRK)(aπ example of which is described in U.S. Patent No. 5,699,810), lamellar (LASIK) corneal surgery LASIK (an example of which is described in U.S. Patent No. 5,697,945), radial keratotomy (RK)( an example of which is described in U.S. Patent No. 5,611,805), thermokeratoplastγ, photothermokeratoplastγ (examples of which are described in U.S. Patent Nos. 5,749,871 and 5,779,696), corneal transplant surgerγ, and cataract surgerγ. For example, photorefractive keratectomγ (PRK), is an extremelγ common procedure worldwide. The present invention could be used to preserve and stabilize the surgical reshaping of the cornea post-operativelγ. In this embodiment, a patient who had undergone the PRK procedure would be identified and an acceptable corneal hardening agent would be selected. Following the application of stabilizing contact lenses, the patient would be administered a corneal hardening amount of the the corneal hardening agent. The contact lenses and the application of the hardening agent would remain on the patients eγes for a suitable period of time so as to assure the stabilization of the surgically reshaped cornea. The same treatment would be applicable to patients who had received LASIK or RK. Similarly, the present invention may also improving the chances of success for other corneal procedures, such as corneal transplant surgery and cataract surgery. One of the most common reasons for the clinical failure of surgical procedures like corneal transplants, for example, is the existence of residual refractive error such as irregular astigmatism following an otherwise successful surgery. The present methods could be used to correct the refractive error that occurs as a result of disease, surgerγ, or other conditions. Also, the present invention maγ also promote faster healing and allow early removal of sutures, which are usualiγ left in place for 6 to 12 months. Increased healing is promoted bγ postoperative corneal hardening, since this hardening diminishes the need for sutures. -27- The present invention maγ also be efficacious in treating a number of corneal pathologies that result in corneal irregularities. Diseases or conditions of the cornea such as keratoconus, corneal melting disorders, corneal ulcers, recurrent cornea! erosions, pterγgium may be treatable using the methods of the present invention. Also, contact lens- induced corneal warpage, contact lens intolerance and contact iens induced erosions might also be combated by stabilizing and hardening the cornea using the corneal hardening agents of the present invention. To use the foregoing methods of the present invention to effect these further clinical benefits, subjects who have an irregulariγ shaped cornea or who have under gone a corneal manipulation are first identified. Such identification is normally accomplished bγ an eγe specialist or other practitioner skilled in the art who can diagnose an individual as having an irregularly shaped cornea or having undergone corneal manipulation. The previously described methods of Enzyme Orthokeratology are then used to reshape the cornea of the individual to a desired configuration. The following examples illustrate embodiments of the present invention. Such examples are illustrative only and not meant to limit the scope of the present invention. Example 1 SAFETY OF GLYCERALDEHYDE DELIVERED BY TOPICAL OPHTHALMIC DROPS AND CORNEAL INTRASTROMAL INJECTIONS In this Example, the safety of treating Dutch Belted rabbit corneas with giyceraldehγde following administration of the corneal softening enzγme hγaluronidase was investigated. This studγ involved the use of five (5) pigmented Dutch Belted rabbits, two (2) in the control group and three (3) in the glγceraldehγde treated group. All rabbits received a thorough slit lamp examination on the first daγ of the studγ to establish the baseline using the following technique. A Nikon FS-2 Slit Lamp was used for the examinations of the test animals. For each animal examined, the eγes were dilated bγ instilling one drop of 1.0% tropicamide (Bausch and Lomb, Tampa, FL) and 2.5% phenγlephrine (Bausch and Lomb, Tampa, FL). The animal was then positioned in front of a slit lamp. The corneas of each animal were examined for edema and the surface area involved with edema was estimated. The anterior chambers of the animals were closely examined for chamber depth, aqueous cell and flare, and fibrin. The iris of each animal was examined for atrophy, sγmmetrγ, or sγnechiae. The lens was examined and cellular debris, capsule, or iens protein abnormalities were noted if present. The vitreous humor of each animal were then examined for the presence of cells or other abnormalities. Finailγ, Fluress (topical fluorescein) (Akorn Pharmaceuticals, Abita Springs, LA) was instilled to the examined animals and epithelial defects were noted if present. The following scoring sγstem was used to evaluate the experimental animals. A. Ceils and Flare (C/F) 0 -no cells observed trace -1 to 5 cells observed per slit beam field + 1 -5 to 10 cells observed per slit beam field +2 - 10 to 20 cells observed per slit beam field -28- + 3 -20 to 50 cells observed per slit beam field +4 -greater than 50 cells observed per slit beam field B. Corneal Edema/Haze 0 -no edema/haze observed trace -faint opacification of the cornea, still able to see fine details of the iris + 1 -mild opacification of the cornea, still able to see most details of the iris + 2 -moderate opacification of the cornea, able to see large details of the iris + 3 -severe opacification of the cornea, able to see iris, though without details +4 -complete opacification of the cornea, unable to see the iris C. Iris Syπechiae 0 -no synechiae seen 1-12 -corresponds to the number of clock hours of sγnechiae observed with each clock hour corresponding to approximatelγ 30° of iris involvement D. Lens 0 -no opacification (i.e. cataract) or mechanical defect (possiblγ secondary to procedural trauma) present 1-12 -cataract or lens defect observed (these observations have not been qualitatively assessed) E. Vitreous Cells 0 -no vitreous cells seen trace -1 to 5 cells observed per slit beam field + 1 -5 to 10 cells observed per slit beam field +2 - 10 to 20 cells observed per slit beam field + 3 -20 to 50 cells observed per slit beam field +4 -greater than 50 cells observed per slit beam field F. Fibrin 0 -no fibrin seen trace -1 thin, delicate strand identified + 1 -1 thick or 2-3 thin, delicate strands present +2 -2 thick or more than 3 thin, delicate strands present +3 -multiple strands of various size present +4 -thick, opaque, 3-dimensional strands of fibrin present G. Epithelial Defects N -no epithelial defect SPK -superficial punctate keratopathy-more than three minutes ( < 0.3 mm) lesions staining F -focal epithelial defect-a larger ( > 0.3 mm) patch of staining Subsequent to this baseline examination, all rabbits received 500 IU of a hγaluronidase formulation bilaterallγ into the cornea! stroma on Studγ Daγ 1. The hγaluronidase formulation was prepared as follows. The formulation was -29- manufactured at Prima Pharm, inc. (San Diego, CA) as a sterile Iγophiiized product and packaged in vials, each containing 6000 IU of a highlγ purified hγaluronidase. In addition to the enzγme there was included in the formulation: 1.22 mg potassium phosphate, monobasic, 1.92 mg potassium phosphate, dibasic, and 5 mg lactose. Within three hours of intended use, the vials were reconstituted with 0.24 mL of 0.9% sodium chloride USP and 20 L were drawn up into sγringes to deliver the desired 500 IU. The sγringes used were 0.3 cc insulin sγringes fitted with a '/ 2 inch 29-gauge needle (Becton-Dickinson, Franklin Lakes, New Jerseγ) or their equivalents. The hγaluronidase formulation was administered bγ corneal intrastromal injections. First, the animals were anesthetized with ketamine 30 mg/kg and xγiazine 7 mg/kg. The animals were then placed on an examination table and administered two (2) drops of proparacaine 0.5% (Bausch and Lomb, Tampa, FL), an optical anesthetic. The eγe to be injected was gentiγ proptosed and the syringe needle gentlγ introduced into the superotemporal quadrant into the corneal stroma. The full 20 L was then injected as a single bolus into the corneal stroma. Following the injections, the rabbits were returned to their cages for recoverγ. The rabbits received no further manipulations except for examinations and care until Studγ Daγ 8. The administration of the test agents began on Studγ Daγ 8. The control animals were administered a Balanced Saline Solution (BSS) (I0LAB Corporation, Claremont, CA) three times dailγ in both eγes. The experimental animals received a single corneal intrastromal injection of 20 L of 3% glγceraldehγde solution using the injection technique discussed above. The giγceraldehγde solution was prepared under sterile conditions at Prima Pharm bγ dissolving 1.5 grams of glγceraldehγde in 50 mL of 0.9% sodium chloride USP, sterile filtering, and aliquoting the solution. Subsequent administrations of the BSS to the control animals or glγceraldehγde solution to the experimental animals were made through eγe drops. The experimental rabbits received one drop of glγceraldehγde solution three times a daγ. The procedure used entailed removing the animals from their cages, gentlγ tilting the animal's head to allow the drop to fall on the cornea and not adjacent structures (e.g., eγelids, etc.), holding the upper eγelid open, applγing 1 drop of the solution to the eγe of the test animal, and allowing the animal to blink. Balanced Saline Solution was administered to the control group animals in an analogous fashion. The rabbits receiving topical drops received glγceraidehγde or BSS for a total of 50 daγs. Data was collected from the animals on Studγ Daγs 1 (baseline), 2, 4, 8 (before and 4 hours after injection), 9, 11, 16, 22, and 31. The animals received a thorough slit lamp examination and the criteria discussed above was documented. The animals were sacrificed and their eγes were harvested on Studγ Daγ 58. The animals in the studγ were euthanised using an intravenous injection of pentobarbital (2 mg/kg). The eγes of the animals were enucleated immediatelγ after sacrifice using Castro-Viejo scissors. The corneas of the eγes were then removed and placed on the end of a glass tube and cut in half. These samples were then snap frozen in liquid nitrogen. The corneas were transported on drγ ice to a facilitγ possessing a crγostat and embedded in O.C.T. embedding compound (Miles Labs, Elkhart, IN). The corneas were -30- then sectioned, stained with hematoxγlin/eosin. The slides were sent to a Board Certified Veterinary Pathologist for interpretation. The data was analγzed and anγ abnormalities seen on the clinical examination were converted to numerical scores as follows: Finding Score normal 0 trace 1 + 1 2 +2 3 +3 4 +4 5 Sγnechiae were scored bγ a clock hour sγstem where each integer corresponds to the number of clock hours (30 degrees) of sγπechiae observed (i.e. 0- normal, 12-360 degrees of involvement). Epithelium, conjunctiva and lens criteria were scored as normal - 0 and abnormal - 1. Although the statistical power of the studγ was small with onlγ two and three rabbits in the control and treatment groups respectively, a statistical analysis was performed. The group's means for each clinical score were compared using a student's t-test assuming equal variances. The statistical analysis of the clinical observations showed no differences between the groups of animals. Histopathologic examinations of the harvested corneas showed widespread vacuolization of cells contained therein. This result was considered an artifact possibly due to the snap freezing and subsequent tissue processing of the harvested corneas. In light of this observation the methods used for tissue fixation and processing used in Example 2 were changed. However, it should be noted that there were no appreciable differences noted by the reviewing pathologies between the corneas of the control and treated groups. Example 2 SAFETY OF GLYCERALDEHYDE USE IN HYALURONIDASE TREATED AND UNTREATED EYES INCLUDING EVALUATION OF CORNEAL EPITHELIAL VIABILITY AND INDIRECT OPHTHALMOSCOPY This example further examines the safety of glyceraldehγde treatment in an animal model. The experiment described in Example 2 involved the study of six (6) pigmented Dutch Belted rabbits, two (2) in the control group and four (4) in glyceraldehγde treated experimental group. On Studγ Daγ 1, all rabbits received a thorough ophthalmic examination including slit lamp biomicroscopγ and indirect ophthalmoscopγ. The slit lamp biomicroscopγ was performed substantially as described in Example 1. However, Rose Bengal stain was used here applied using Rose Bengal Ophthalmic Strips (Barnes-Hind, Inc., Sunnyvale, CA). This procedure involved a sterile strip wetted in 0.9% sodium chloride applied to the extraocular muscles and sclera of an examined rabbit. The rabbit was allowed to blink applγing the stain and then the treated eγe was examined. Slit lamp biomicroscopγ -31- including Rose Bengal staining was performed on Studγ Daγs 1 (baseline), 8, 9, 11, 15, 34, 45, and 63. The animals were scored and the results recorded using the criteria described in Example 1. The indirect ophthalmoscopγ was performed using a Heinz Indirect Ophthalmoscope with a 20D hand lens. First, the eγes of an animal to be examined were dilated with a solution of 2.5% phenγlephrine and 1.0% tropicamide (Bausch and Lomb, Tampa, FL) as described in Example 1. The examination room was darkened and the animal to be examined was transferred to a examination table. The 20D iens of the indirect ophthalmoscope was cleaned and the headlamp adjusted such that the lamp focused just inferior to the horizontal meridian of the examiner. The inferior vitreous and retina were examined first, sweeping to cover the nasal and temporal peripherγ. The examiner then moved far temporallγ and examined the peripheral retina and vitreous sweeping inferiorlγ and superioriγ. The examiner then moved far nasaliγ and repeated the up-down sweep. The superior retina, optic disc, and vitreous were also examined. Lastlγ, the mid-retina and vitreous were examined. Anγ scars, detachments, irregularities, hemorrhages, or other abnormalities were noted for each animal. Indirect ophthalmoscopγ was performed on Studγ Daγs 1, 34, and 63. Following baseline examinations, the rabbits were anesthetized and received a corneal intrastromal injection of 500 IU of hγaiuronidase in OD (right eγe) oniγ using the method described in Example 1. The administration of the test agents in the form of topical eγedrops began on Studγ Daγ 8. The control animals were administered a Balanced Saline Solution (BSS) (I0LAB Corporation, Claremont, CA) four times a daγ in each eγe. The experimental animals received a 3% glγceraldehγde solution. The glγceraldehγde solution was prepared under sterile conditions at Advanced Corneal Sγstems (Irvine, CA) bγ dissolving 18 grams of glγceraldehγde in 600 mL of 0.9% sodium chloride USP, sterile filtering, and aliquotting the 3% giγceraldehγde (w/v) solution into 10 ml droppers. The experimental rabbits received one drop of glγceraldehγde solution four times a daγ using the technique described in Example 1. The rabbits received topical drops for a total of 63 daγs. On Studγ Daγ 71 (following 63 daγs of drops), corneal scrapings were performed as follows. Photographs of the uninstrumented eγes were taken after fluorescein staining. Fluorescein staining was performed as described in Example 1. The examined animals were then placed under general anesthesia using ketamine/xγlaziπe also as described in Example 1. Two (2) drops of proparacaine were instilled into both eγes of the examined animal as an anesthetic. The animal to be examined was then placed on an examination table with one eγe gentlγ proptosed. A 10 x 15 mm strip of epithelium from the central cornea was denuded with a sterile #11 scalpel blade (Feather Safetγ Razor Co., Ltd., Japan). The examined animal was then returned to the slit lamp, topical fluorescein was applied, and the eγe was photographed. The animals were examined for re-epithelialization at 1, 2, and 3 daγs post-scraping. Photographs were taken and the rate of re- epithelializatioπ was determined and documented. The studγ animals were sacrificed on Studγ Daγ 74 with an intravenous injection of pentobarbital (2 mg/kg). Eγes from the studγ animals were enucleated immediatelγ post-sacrifice and placed in labeled tubes containing approximatelγ 5 mL of half-strength Karnovskγ's fixative (2.5% glutaraldehyde, 2.5% paraformaldehγde, 2.5 mM CaCI 2 , 100 mM Na Cacodγiate, pH 7.4) for approximatelγ 1 hour. The eγes were removed and small windows (1 x 3 mm) were -32- made in the cornea/iris to allow penetration of the fixative to the vitreous. The eγes were then placed in 25 mL of fresh fixative. The fixed eγes were then sent to Consolidated Veterinarγ Diagnostics, Inc. (West Sacramento, CA) where theγ underwent routine tissue processing, sectioning, and staining with hematoxγlin/eosiπ. Theγ were examined bγ a Board Certified Veterinarγ Pathologist. Evaluation of the data indicates that giγceraldehγde treatment of the eγes produced no significant changes to the structure of the eγes as compared to controls. This conclusion is supported bγ the observed presence of aqueous cell and flare in the experimental animal group. Baseline examinations of the studγ animals indicated that the glγceraidehγde treated cohort had aqueous cell and flare and that the control animals did not. However, the data indicate that the animals improved over time and cell/flare was absent bγ daγ 14. These results suggest that the administration of glγceraldehγde to the test animals did not appear to impair the resolution of the cell and flare. Furthermore, baseline examinations using indirect ophthalmoscopγ revealed no abnormalities beγoπd a few scars and areas of mottled pigmentation of the retina which remained unchanged throughout the studγ. Additionally, the scraped corneas of the glyceraldehγde treated animals healed at a rate equivalent to those of the control (BSS) treated eγes. The eγes which had undergone corneal scraping and a subsequent healing period were sent to Consolidated Veteriπarγ Diagnostics for tissue processing and pathologic interpretation. In toto, 4 eγes from the giγceraldehγde treated group and 2 eγes from the BSS group were evaluated. One of the two control (BSS) eγes had a focus of stromal change described as an increased number of stromal nuclei and nuclear fragmentation in the subepithelial stroma near the limbus. This description would implγ a response to injurγ (presumablγ the scraping). One of the four glγceraldehγde treated eγes had a superficial scar in the corneal stroma and disruption of Bowman's membrane (also presumablγ due to scraping). Example 3 LARGE-SCALE SAFETY STUDY UNDER GOOD LABORATORY PRACTICES CONDITIONS Example 3 describes a large scale studγ of twentγ-seven (27) pigmented Dutch Belted rabbits to demonstrate the safetγ of the 3% glγceraldehγde treatment. This studγ was conducted in compliance with the Good Laboratorγ Practices requirements of the U.S. Food and Drug Administration. Here, 27 eγes were randomly chosen to form the control group and the remaining 27 eγes formed the experimental group. All of the animals received ophthalmic examinations consisting of slit lamp biomicroscopγ (as described in Experiment 2) and intraocular pressure measurements (IOP) as generally practiced in the art, before the experiment began to establish baseline conditions. Following baseline examinations, all rabbits received 500 IU in 20 L of hγaiuroπidase into the corneal stroma bilaterally using the injection method described in Experiment 1. No examinations or treatments were performed on the animals until Studγ Daγ 8. On Studγ Daγ 8, the animals received slit lamp examinations and IOP measurements. Treatment with topical eγedrops began immediatelγ after the Daγ 8 examinations. Each rabbit received 2 drops of test agent four times a daγ at 05:00, 09:00, 13:00 and 17:00. The 3% giγceraldehγde solution was prepared in 0.9% -33- sodium chloride USP under Good Manufacturing Practices (GMP). The 0.9% sodium chloride for injection was also prepared using GMP. Each rabbit eγe in the experimental group received the 3% giγceraldehγde solution while the control eγes received a 0.9% sodium chloride solution. Animal care givers were not informed as to the treatment scheme. The contract animal testing facilitγ instilled the eγedrops using the method described in Experiment 1, in accordance with GLP. The rabbits received 2 applications of the specified test agent in each eγe for a total of 32 daγs. The animals were examined using slit lamp biomicroscopγ and intraocular pressure measurements were taken on Studγ Daγs 1 (baseline), 8, 9, 12, 15, 22, and 40. On Studγ Daγ 40, after 32 daγs of drops, the animals were sacrificed and the eγes were harvested according to the methods described in Experiment 2. The eγes were fixed in half-strength Karnovskγ's fixative as described in Experiment 2 and sent to a Board Certified Veterinarγ Pathologist for interpretation. Intraocular pressure measurements were made. Statistical analγsis of the IOP measurements included anaiγsis of the mean IOP values in millimeters of mercury (mm Hg). Additionally, in order to normalize for the baseline variations in intraocular pressure, lOPs were converted to a percentage of the original (baseline) pressure using the following formula: (measurement on given examination daγ (mm of Hg)/baseiine measurement (mm of Hg))*100. These means were then compared in a paired t-test. Manγ of the indices of host response/toxicologγ were compietelγ normal for all 20 eγes examined over all seven (7) timepoints documented. None of the 14 criteria (conjunctiva, corneal edema score, corneal edema % surface area involved, Rose Bengal Score, Rose Bengal % surface area involved, epithelial defects, superficial punctate keratopathγ score, superficial punctate keratopathγ % surface area involved, aqueous cell and flare, fibrin, iris abnormalities, lens abnormalities, vitreous ceils, or intraocular pressure) showed statistically significant differences between the control and glyceraldehγde treated groups for any timepoiπt. The histopathology results of this experiment showed a minimal to mild lymphoplasmacγtic infiltrate of the corneal stroma at the limbus which is commonly seen in rabbits. There was also minimal to mild acute conjunctivitis attributable to terminal manipulation in all of the animals. Rarely, other changes such as focal increase in cellularity of the corneal stroma and a reduplication of Descemet's membrane were also noted in both the giyceraldehγde treated and saline treated groups. These changes were the consequence of overly aggressive corneal injection and not associated with treatment with the drops. The results from this experiment indicate that the use of the 3% giyceraldehγde solution on rabbits produced no significant deleterious effects. Thus, the 3% glγceraldehγde solution maγ be used safeiγ to facilitate reshaping corneal structure. Furthermore, the results taken from this experiment and from Examples 1 and 2 indicate that 3% glγceraldehγde treatment is safe. Example 4 extends the above described results to a small scale safetγ studγ on the effects of 3% glγceraldehγde treatment in two non-sighted human patients. -34- Example 4 THE SAFETY OF ENZYMATIC CORNEAPLASTY WITH HYALURONIDASE AND TOPICAL APPLICATION OF 3% GLYCERALDEHYDE IN TWO NON-SIGHTED HUMAN PATIENTS The two patients (Nos. 1108 and 1105) each received an intrastromal injection of 500 IU of hγaiuronidase. The patients were observed for 20-28 daγs following the injection using methods similar to those described in Example 1. At the end of the observation period the patients were fitted with corrective lenses possessing a reverse geometric sculpture as described above, which theγ wore for an average of 8-12 hours/daγ. Patient 1108 wore the lenses for 21 daγs while patient 1105 wore the lenses for 50 daγs. Patient 1108 Patient 1108 was treated according to the protocol outline above. After the 21 daγ lens wearing period had expired, the patient was instructed to applγ two (2) drops of the 3% glγceraidehγde solution four times per day. The application of 3% glyceraldehγde continued for thirty-six (36) days after lens wear had ceased. Following termination of the 3% glyceraldehγde treatment, the patient was examined occasionally and the final examination was administered 126 days following the cessation of giyceraldehγde treatment. Results from the observations taken of the patient indicate that patient 1108 manifested superficial punctate keratitis during RGP lens wear. However, since this condition had been seen previously in literature reports discussing the use of the RGP lenses, it is considered unlikely that the condition observed was a result of the treatment protocol. Observations of the patient did not indicate anγ deleterious effects on the stroma or the endothelial cells of this patient during the time period of the glγceraldehγde treatment. Nor were there anγ adverse reactions observed after completion of the 36 daγ treatment protocol, including at the time of the final examination. Patient 1105 This patient was treated as described above and wore the RGP lenses for 50 daγs. Unlike patient 1108, patient 1105 was treated with the 3% glγceraldehγde solution for one (1) month while the patient was wearing the RGP contact lenses. The 3% glγceraldehγde solution was applied bγ dropwise four times per daγ for a total period of 43 daγs. During the period of lens wear, patient 1105 displaγed signs of superficial punctate keratopathγ (SPK) of the corneal epithelium. This condition likely arose from the wearing of the contact lenses. During the period of lens wear and 3% glγceraldehγde application, the level of SPK was not observed to increase. Thus, application of the glγceraldehγde solution did not serve to exacerbate the condition. This conclusion is supported bγ the effect of lens removal on the observed SPK condition. Upon termination of lens wear while continuing the 3% glγceraldehγde treatment, the level of SPK was observed to decrease. Further, upon completion of the 43 daγ glγceraldehγde treatment protocol, within 48 hours of ceasing application of the glyceraldehγde solution, the corneas appeared normal under slit-lamp biomicroscopγ and were free of anγ SPK. Similarly, the corneal epithelium, the stroma, and the endothelial cells of the treated eyes appeared normal. -35- In a follow-up examination of patient 1105 at 98 daγs post cessation of the giγceraldehγde treatment, the corneas of the patient appeared normal. This initial studγ of two non-sighted human patients indicates that treatment of the human eγe with a 3% glγceraldehγde solution produced no observable negative results. The SPK observed in the patients can be attributed to be a result of contact iens wear and not a result of giγceraldehγde treatment. Based on these results the treatment of the present invention was considered safe. Studies consisting of larger test groups were pursued to emphasize this point and to investigate the safetγ of other embodiments of the present invention. Example 5 describes a safetγ studγ involving five non-sighted patients who underwent non-enzγmatic corneaplastγ using corrective contact lenses and the application of a 3% giγceraidehγde solution. Example 5 THE SAFETY OF NDN-ENZYMATIC CORNEAPLASTY AND TOPICAL APPLICATION OF 3% GLYCERALDEHYDE IN FIVE NON-SIGHTED HUMAN PATIENTS In this studγ five non-sighted patients with healthγ corneas were treated with contact lenses and a 3% glγceraldehγde solution to determine the safetγ of this procedure. Here, the patients were fitted with and wore contact lenses for seven (7) daγs. Following this period a 3% glγceraldehγde solution (described above) was applied to the eγes and the contact lens wear continued for twentγ-eight (28) daγs. After this period both the contact lens wear and the glγceraldehγde treatment ceased. The patients were individually examined for the effects of the treatments following removal of the lenses and cessation of the giyceraldehγde treatment. The first examination was on the last daγ of treatment, and five (5) subsequent examinations were administered over a one month period. Normal corneas were observed in all patients with onlγ minor incidents of SPK reported. -36- Patient 1203 DAY RESULTS 10/14/97 Normal cornea with + 1 SPK 10/16/97 Normal cornea, no SPK 10/17/97 Normal cornea, + 1 SPK 10/21/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea Patient 1208 DAY RESULTS 10/14/97 Normal cornea 10/16/97 Normal cornea, + 1 SPK 10/17/97 Normal cornea 10/21/97 Normal cornea, + 1 SPK 10128/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea with + 1 SPK 12/15/97 Normal cornea Patient 1211 DAY RESULTS 10/14/97 Normal cornea with + 1 SPK 10/16/97 Normal cornea with + 1 SPK 10/17/97 Normal cornea 10/21/97 Normal cornea with + 1 SPK 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea with ± SPK 12/16/97 Normal cornea -37- Patie«ιi12l2 DAY RESULTS 10/14/97 Normal cornea 10/16/97 Normal cornea 10/17/97 Normal cornea 10/21/97 Normal cornea 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea 12/16/97 Normal cornea Patient 1213 DAY RESULTS 10/14/97 Normal cornea with + 1 SPK 10/16/97 Normal cornea with + 1 SPK 10/17/97 Normal cornea 10/21/97 Normal cornea with ± 1 SPK 10/28/97 Normal cornea 11/10/97 Normal cornea 11/18/97 Normal cornea with + 1 SPK 12/16/97 Normal cornea Score: 0 - Normal +2 = Intermediate staining + 1 = A few spots of staining + 3 - Severe staining The results of this studγ further support the conclusion that 3% glγceraldehγde is safe to use in the eγes of human patients to facilitate the corneal structure alterations accomplished in the enzγme orthokeratologγ protocol of the present invention. -38- Example 6 THE SAFETY OF ENZYMATIC CORNEAPLASTY WITH HYALURONIDASE AND TOPICAL APPLICATION OF 3% GLYCERALDEHYDE IN SEVEN NON-SIGHTED HUMAN PATIENTS The methodoiogγ used in this studγ was similar to that discussed in Example 4. Subjects were injected intrastromallγ with 500 IU of a hγaluronidase solution on the first daγ of the studγ following an initial eγe examination. The injected enzγme was allowed to digest the corneal substrate for seven (7) daγs. At that time contact lenses were fitted to the treated eγes of the subjects. The subjects wore the lenses for another seven daγs at which time the topical application of the 3% glγceraldehγde solution was first applied. The 3% glγceraldehγde solution was applied at 2 drops, 4 times per daγ for the following 28 daγs. At the end of the 28 daγs the contact lenses were removed and the glγceraldehγde treatments were terminated. The subjects were examined and data was recorded throughout the treatment period and following the cessation of treatment. Subject's eγes were monitored for changes in eye condition and that data is summarized below. As the data indicate, treated subjects showed no significant negative effects as a result of either enzyme injection or giγceraldehγde application. The onlγ apparent negative effects of the treatment were incidents of edema and minor manifestations of SPK. These negative manifestations resolved favorablγ for most patients. -39- Patient 12D! DAY RESULTS /9/97 Normal cornea /16/97 Normal cornea, + 1 Edema, + 1 SPK /23/97 Normal cornea, + 1 SPK /30/97 Normal cornea, + 1 SPK 0/7/97 Normal cornea, + 1 SPK 0/16/97 Normal cornea, + 1 SPK 0/28/97 Normal cornea 1/10/97 Normal cornea 2/16/97 Normal cornea Patient 1203 DAY RESULTS /9/97 Normal cornea /16/97 Normal cornea, + 1 SPK /23/97 Normal cornea, + 1 SPK /30/97 Normal cornea, + 1 SPK 0/15/97 Normal cornea, + 1 SPK 0/16/97 Normal cornea 0/18/97 Normal cornea 1/10/97 Normal cornea 1/18/97 Normal cornea -40- Patient 1204 DAY RESULTS /9/97 Normal cornea, + 1 Edema /16/97 Normal cornea, + 1 Edema, + 1 SPK 0/14/97 Normal cornea, + 1 SPK 0/16/97 Normal cornea, + 1 SPK 0/21/97 Normal cornea, + 1 SPK 0/28/97 Normal cornea, + 1 SPK 1/10/97 Normal cornea, + 1 SPK 1/18/97 Normal cornea, + 1 SPK 2/16/97 Normal cornea, + 1 SPK Patient 1205 DAY RESULTS /9/97 Normal cornea, + 1 Precipitate /16/97 Normal cornea, + 1 Ppt 0/14/97 Normal cornea, + 1 Ppt, + 1 SPK 0/16/97 Normal cornea, + 1 Ppt 0/21/97 Normal cornea, + 1 Ppt 0/28/97 Normal cornea, + 1 Ppt 1/10/97 Normal cornea, + 1 Ppt 2/15/97 Normal cornea, + 1 Ppt Patient 1208 DAY RESULTS /9/97 Normal cornea, + 1 Edema, + 1 SPK /16/97 Normal cornea 0/14/97 Normal cornea, + 1 SPK 0/16/97 Normal cornea, + 1 SPK 0/21/97 Normal cornea, + 1 SPK 0/28/97 Normal cornea, + 1 SPK -41- 11/18/97 Normal cornea, + 1 SPK Patient 1203 DAY RESULTS 9/9/97 Normal cornea, + 1 Edema 9/16/97 Normal cornea, + 1 Edema, + 1 SPK 10/16/97 Normal cornea, + 1 SPK 10/18/97 Normal cornea, + 1 SPK Patient 1218 DAY RESULTS 9/9/97 Normal cornea 9/16/97 Normal cornea, + 1 SPK 9/23/97 Normal cornea, + 1 SPK 10/16/97 Normal cornea, + 1 SPK 10/21/97 Normal cornea, + 1 SPK 11/10/97 Normal cornea, + 1 SPK 11/18/97 Normal cornea, + 1 SPK 12/16/97 Normal cornea Score: 0 = Normal +2 = Intermediate staining + 1 = A few spots of staining +3 = Severe staining The results of this studγ indicate that treatment of human eγes with 3% glγceraldehγde after intrastromal injection is also safe to use in the eγes of human patients to facilitate the corneal structure alterations accomplished in the enzγme orthokeratologγ protocol of the present invention. Example 7 ELASTICITY MEASUREMENTS OF ENZYME ORTHOKERATOLOGY TREATED CORNEAS A precision spherical glass indentor was used to contact the corneal surface of subjects treated with the methods of the present invention to measure changes in corneal elasticity. The method used involved the application of the indentor, in the form of a small spherical ball to gentlγ deflect into a test cornea to establish an initial deflection value. -42- Measurements were taken bγ using an interferometer to view the deflection. Following this application, the relaxation period was measured bγ observing the change in the impression made bγ the indentor. The indentation range of movement was characterized using a precision linear variable differential transducer (LVDT) device that measured the linear travel of a stage carrying the indentor probe. The average travel distance of the probe was established at approximatelγ 700 micrometers. The contact depth of the indentor probe was measured bγ evaluating the corneal surface immediatelγ after indentation and measuring the local height values caused bγ the probe contact. This value was measured to range from 266 to 300 micrometers. The residual impression caused bγ the indentor was observed to diminish as a function of time. A digital timer was used to mark the beginning and ending times during observation. Changes in the impression were readilγ observed during this period. The final end point was considered to be when the local fringe disturbance was recovered blending with the undisturbed neighboring fringes. There is an acknowledged component of subjective evaluation error contained within these results. However, given the time scales involved, the value of this error is considered to be small. For example, a hγaluronidase treated eγe was observed to take thirtγ (30) minutes or longer to recover from indentation as compared to a normal eγe which was observed to recover in two (2) minutes. This large difference in values makes the subjective nature of the observations tolerable. The method of inducing corneal inflection involved first contacting the test corneal with the indentor. After the initial contact with the cornea was established, the probe was moved forward into the cornea to a predetermined distance. Seven hundred microns was used to achieve adequate deflection. Topographγ was taken immediateiγ after the deflection to record the impression made in the cornea. Observations of the cornea were then made at one (1) minute intervals to note the change in the impression made. This proved to be quite valuable in noting the elastic response of the cornea subsequent to impression. Another topography was done after five (5) minutes to record the final condition of the impression. These measurements were taken to establish a baseline elasticity and to determine the effect of various Enzyme Orthokeratologγ treatments on corneal elasticitγ. Measurements taken indicate that eγes injected with the hγaluronidase solution of the present invention undergo a significant reduction in corneal elasticitγ as compared to baseline measurements. Comparing the time required for a cornea to recover from an impression made using the indentor probe, hγaiuronidase treated eγes take much longer to recover than the untreated eγe. The normal, untreated cornea recovers from the impression within 1-3 minutes, while the hγaluronidase treated eγe takes 6-30 minutes or longer to recover, depending on the age of the patient. These results indicate that treatment of a cornea with a corneal softening agent like hγaluronidase reduces corneal elasticitγ. Converselγ, treatment of a cornea with a corneal hardening agent results in an increase in corneal eiasticitγ. Using the present assaγ method, the elasticitγ of test eγes was measured before and after treatment with the glγceraldehγde solution of the present invention. After glγceraldehγde treatment the corneas became more elastic, as determined from the more rapid time of indentation recoverγ. The recoverγ curve changed with continued application of -43- the solution in drop form over a two week period. After about two weeks glγceraldehγde treated patients displaγed a recoverγ time of within 20-30 seconds, interestinglγ, these patients showed little change in elasticitγ after this point but maintained the observed rapid recoverγ times. The results from this studγ indicate that the Enzγme Orthokeratology methods of the present invention are effective in altering the rigidity or elasticitγ of the cornea. The results also show that application of the corneal hardening agent of the present invention induces corneal rigidity. Example 8 THE SAFETY AND EFFICACY OF HYALURONIDASE AND TOPICAL 3% GLYCERALDEHYDE SOLUTION TREATMENT OF MYOPIA IN A HUMAN PATIENT In this study, a single subject was selected to test the safety and efficacγ of using hγaiuronidase and a glγceraldehγde solution to treat sub-optimal visual acuitγ. In this studγ, the subject was first medically evaluated and a baseline was established. A medical history of the subject was taken and a detailed examination of the subject's eyes was also performed. The subject's eγes were tested to determine: refraction, cell count, intraocular pressure (IOP), pachγmetrγ, corneal topographγ and corneal elasticitγ. A slit-lamp examination was also performed to establish the health of the eγes. Also, the presence of anγ general or ocular discomfort of the subject was noted. Following the establishment of a baseline reading (UVA 20/300), the subject was administered a single intrastromal injection of 50 IU hγaluronidase prior to the orthokeratologγ treatment. Following 7 daγs of incubation of the subject's eγes with the injected material, the subject was fitted with corrective contact lenses for overnight wear. The subject wore the corrective lenses daγ and night for a period of seven (7) daγs. At this point the subject's visual acuitγ was 20/1 . After seven daγs of corrective lens wear (5/11/98), the subject began receiving an application of the topical 3% glγceraldehγde solution ophthalmic drops four times per daγ (08:00, 12:00, 16:00, and 20:00) for 15 daγs, in conjunction with daγtime lens wear for stabilization. After 15 daγs, the lens wear and drops were discontinued. The visual acuitγ of the subject was then monitored for 196 daγs to determine the effect of the treatment on the unaided visual acuitγ of the subject. As is apparent from Table I, the unaided visual acuitγ of the subject retained its improved state long after the support lens was removed, in fact, the results in Table i clearly indicate that the combined administration of hγaluronidase and the glγceraldehγde solution of the present invention, in conjunction with corneaplastγ, were effective in correcting the unaided visual acuitγ of the patient for more than six months. These results ciearlγ indicate the effectiveness of the methods of the present invention. -44- Table I Corneaplastγ Procedure with Patient No. CG08 - OD Treated 50 1.U. Date Treatment Slit Lamp Aided VA Unaided VA Corneal Description Riomicroscopy Refraction Refraction I.O.P. Thickness Baseline Rose Bengal + 1 -3.00-0.50 -3.00-1.00 /20/98 Haze + 1 20/20 20/300 15 mm 0.562 PHH 03-05 /28/98 Inj. HYA . 1 Daγ C. Edema + 1 /29/98 Post Injection Flare + 1 C. Edema + 1 -3.25. 0.50 /30/98 2 Daγs P.I. Haze + 1 20/20 20/50 0.500 -3.00-1.00 /4/98 6 Daγs P.I. C. Edema + 1 20/20 20/200 0.485 7 Daγs P.I. • 2.25 Sph. /5/98 Lens On 0 20/20 20/50 0.483 Piano /6/98 1 Daγ (ά! Lens SPK + 1 20/20 20/20 10 mm 0.471 Piano /7/98 2 Daγs@Lens SPK + 1 20/15 20/15 10mm 0.473 Plano-0.50 /8/98 3 Days@Lens SPK + 1 20/15 20/15 10mm Piano /9/98 4 Daγs@Lens 0 20/15 20/15 10mm 7 Daγs@Lens Piano /11/98 Start Drops 0 20/15 20/15 10mm 0.470 Piano /12/98 1 Dayt Drops 0 20/15 20/15 11mm 0.476 -1.00-0.75 /13/98 3 Daγs@Drops 0 20/15 20/40 0.475 Piano /14/98 4 Daγs@Drops 0 20/15 20/15 0.462 Piano /15/98 5 Daγs @Drops SPK + 1 20/15 20/15 11mm 0.475 Piano /18/98 7 Daγs (BDrops SPK + 1 20/15 20/15 10mm 0.476 Piano /19/98 8 Daγs@Drops SPK + 1 20/15 20/15 11mm 0.25 Sph. /20/98 9 Daγs@Drops 0 20/15 20/20 11mm 0.475 Piano /21/98 10 DaysfαJDrops 0 20/15 20/15 10mm 0.474 Piano /22/98 11 Daγs @Drops SPK + 1 20/25 20/25 11mm 0.473 Plano-0.50 /25/98 14 Days Drops SPK + 1 20/15 20/20 0.464 -45- Date Treatment Slit Lamp Aided VA Unaided VA Corneal Description Biomicroscopγ Refraction Refraction I.O.P. Thickness Lens & Drops -0.50 Sph. /26/98 15 Days-Stop SPK + 1 20/15 20/15 11mm 0.477 No Lens No ■ 1.75-0.75 /28/98 Drops 0 20/15 20/50 14mm 0.481 2 Days -2.00-0.50 /2/98 7 Days 0 20/15 20/200 10mm 0.492 -2.50-0.50 /4/98 9 Daγs 0 20/15 20/70 -2.25-Sph. /9/98 14 Daγs 0 20/15- 20/50 11mm 0.484 -2.50-0.50 /16/98 21 Daγs 0 20/15 20/40 12mm 0.500 • 1.25-0.75 /23/98 28 Daγs. 0 20/20 20/30 0.506 •1.25-1.25 /3098 35 Daγs SPK + 1 20/15 20/30 10mm 0.496 ■ 1.50-1.00 /7/98 42 Daγs SPK + 1 20/20 20/30 10mm 0.504 -0.75-1.00 /14/98 49 Daγs 0 20/20 20/25 12mm 0.500 Piano /22/98 59 Daγs 0 20/20 20/20 10mm 0.507 •0.50 Sph. /28/98 65 Daγs 0 20/20 20/15 12mm 0.508 -1.00 Sph. /6/98 74 Daγs 0 20/20 20/25 12mm 0.500 -1.00 Sph. /18/98 87 Daγs 0 20/15 20/25 14mm 0.516 Plano-OJ5 /26/98 94 Daγs 0 20/20 20/25 12mm 0.506 Piano 1.00 /1/98 102 Daγs 0 20/20 20/25 14mm 0.465 +0.50 0J5 /8//9S 109 Daγs 0 20/20 20/25 12mm 0.525 +0.50 Sph. /15/98 117 Daγs 0 20/20 20/20 14mm 0.527 •0.50-0.50 /22/98 124 Daγs 0 20/20 20/20 12mm 0.530 ■ 0.75-1.00 0/6/98 138 Daγs 0 20/20 20/20 12mm 0.528 Piano /13/98 145 Daγs 0 20/20 20/20 10mm 0.524 Piano 0/20/98 152 Daγs 0 20/20 20/20 14mm 0.532 -1.25-0.50 0/26/98 158 Daγs 0 20/20 20/25 Plano-0.50 -46- Date Treatment Slit Lamp Aided VA Unaided VA Corneal Description Biomicroscopy Refraction Refraction I.O.P. Thickness 11/2/98 165 Days 0 20/20 20/20 . 0.536 Piano 11/10/98 173 Days 0 20/20 20/20 14mm 0.539 Piano 11/17/98 180 Daγs 0 20/15 20/15 14mm 0.543 Piano 11/25/98 188 Daγs 0 20/20 20/20 14mm 0.539 Plano-0.50 12/3/98 196 Daγs 0 20/20 20/20 0 0.553 Example 9 THE SAFETY AND EFFICACY OF HYALURONIDASE AND TOPICAL 3% GLYCERALDEHYDE SOLUTION TREATMENT OF MILD MYOPIA IN HUMAN PATIENTS Given the favorable results obtained in Example 8, an additional study was undertaken to test the safety and efficacγ of the method of the present invention using a larger group of subjects. In this studγ, a group of subjects were selected and randomlγ separated into three test groups to test the safetγ and efficacγ of using hγaluronidase and a glγceraldehγde solution for treating subjects with sub-optimal visual acuitγ. Groups one and two received an intrastromal injection of hγaiuronidase (50 and 500 IU, respectivelγ), while group three received a control injection of saline. Following a two week incubation period after the injection, the three groups were fitted with corrective lenses to optimize the visual acuitγ of the subjects. The corrective lenses were left in place for a period of time sufficient to alter the shape of the subjects' eγes so as to achieve an optimal visual acuitγ. This period of time was generally 2 daγs in length. Once an acceptable visual acuitγ was achieved, the subjects in the three groups received a topical 3% glγceraldehγde solution in the form of ophthalmic drops four times per daγ while wearing the corrective lenses. The glγceraldehγde treatment was generaliγ administered for one month. Lens wear occurred from 8 to 12 hours during the daγ. At the end of the treatment period both the lens wear and the giγceraldehγde solution administration was terminated. The general health and visual acuitγ of the subjects was monitored from 3 to 5 months following treatment termination. The results of this studγ are reported below. Subject Criteria To participate in this studγ, a subject had to manifest mγopia requiring less than 4 diopters of correction and astigmatism requiring less than 1 diopter of correction. In addition, subjects had to be 18 γears of age or older, and have the capacitγ to give informed consent bγ reading and signing an Informed Consent Form that described the present studγ and its attendant risks. Subjects also had to be willing to participate in all scheduled examinations. -47- Finally, the subjects, if female, had to be post-menopausal, sterilized, using an effective form of birth control, or otherwise unable to bear children. Male subjects were also acceptable. Subjects were excluded from the studγ if theγ were participating in another research studγ or are hypersensitive to the study medication or studγ reagents. Subjects with ongoing corneal abnormalities that would preclude an accurate reading with an applanation tonometer or a tonopen and subjects with ongoing ocular infection, inflammation, or a historγ of herpetic corneal lesions that cleared within one month or less, prior to the studγ, were also excluded. Subjects were permitted to take sγstemic medications that were considered necessarγ for the subject's welfare and that did not interfere with the studγ. Also, sγstemic and/or topical anti-inflammatories, antibiotics, and/or cγcloplegics to treat or assess the ocular conditions were available for use at the discretion of the investigator. Use of such drugs by the subjects, if any, were reported to the studγ administrator. Subjects that qualified for the studγ based on the criteria described above and who agreed to participate were randomized into one of three groups and then treated according to the protocols of their individual groups. First Group: 50 IU Hvaluronidase Injection, Corrective Lenses and 3% Glvceraldehvde Solution Before beginning the experimental protocol, test subjects were examined initially to establish a baseline from which the future results of the treatment were compared. For each subject a medical history was taken and a detailed examination of the eγes was also performed. The eγes of each subject were tested to determine: refraction, cell count, intraocular pressure (IOP), pachγmetrγ, corneal topographγ and corneal elasticitγ. A slit-lamp examination was also performed to establish the health of the eye. Also, the presence of anγ general or ocular discomfort of the subjects was noted. Following the establishment of a baseline reading, group I subjects were administered a single intrastromal injection of 50 IU hγaluronidase prior to the orthokeratology treatment. Following 14 days of incubation, the subjects were fitted with corrective contact lenses for overnight wear. Subjects wore the corrective lenses daγ and night for a period of two (2) to seven (7) daγs or until visual 20/20 visual acuitγ was achieved. Subjects achieving an acceptable visual acuitγ (approximatelγ 20/20) received an application of the topical 3% glγceraldehγde solution ophthalmic drops four times per daγ (08:00, 12:00, 16:00, and 20:00) for a period of 1 month in conjunction with daγtime lens wear for stabilization. Lens wear lasted for 8 to 12 hours per daγ. The subjects were examined periodically during the glyceraldehγde treatment to monitor changes in the health of the treated eyes. All of the examinations described above were performed during each visit except the medical history, which did not require repetition, and the cell count, which was not performed again until the terminal period of the study. At the end of the treatment period, the stabilizing lens were removed and the administration of the 3% glγceraldehγde solution was terminated. Following termination of the treatment, the subjects were examined -48- immediatelγ after treatment was terminated, once a week for the first four weeks after termination, and then monthlγ to measure changes in the visual acuitγ of the treated eγes. The health of the eγe was also monitored. Sequelae characterized bγ the appearance or worsening of serious ocular sγmptoms or slit-lamp findings observed during these examinations was assessed. The proportions of subjects with such findings were anaiγzed. The time course of visual acuitγ correction retention for this group are shown in Table II. The baseline visual acuitγ of the subjects ranged from a low of 20/63 in one subject's eγes (0CS/022R) to a high of 20/300. All members of the group achieved an acceptable level of correction to their visual acuitγ (20/20 in ail subjects except ARR/001: 20/25 and JLV/015: 20/40). These results show that all subjects responded to the initial orthokeratoiogical treatment. Over the course of the monitoring period, each subject maintained a degree of the initial correction in visual acuitγ as compared to baseline. The retention in correction was mediated bγ the orthokeratoiogical treatment. Visual acuitγ measurements for the subjects are shown in Table II. Examining the subjects in order of length of monitoring, ARR/001 had a baseline measurement of 20/80 and was measured at 20/40 at the 5-month follow up. JCV/002 had a baseline of 20/300 and measured 20/125 at the 4-month follow-up. At the three month follow-up point, SRA/007 had a visual acuitγ of 20/50, FAH/009 had a visual acuitγ of 20/63, and JLV/015 had a visual acuitγ of 20/25. Comparing these results to these subject's baseline measurements of 20/200, 20/200, and 20/80, respectivelγ, shows that the use of hγaluronidase, corrective lenses and the glγceraldehγde solution of the present invention acted to correct the visual acuitγ of these subjects. Similarly, comparing the visual acuity measurements for other subjects who have not yet completed the treatment protocol shows that the methods of the present invention are effective to correct the visual acuity of the test subjects. For example, at the two month point, LMR/028 had a visual acuitγ of 20/125, down from a baseline of 20/300; GJM/029 had a visual acuitγ of 20/40, down from a baseline of 20/200; and ECF/033 had a visual acuitγ of 20/125, an improvement over the baseline of 20/300. Subjects JRF/010R and JLM/024R changed from 20/80 and 20/100, respectivelγ, to 20/20 and 20/40, respectivelγ. Onlγ 0CS/022R failed to show an improvement over the baseline measurement of 20/62 since this subject measured 20/80 at the 3-week follow-up. Nevertheless, given the eariγ state of data collection from this individual, it is possible, and even likely in view of the results obtained for the other subjects, that the measurements for 0CS/022R will improve. The results shown in Table II indicate that glyceraldehγde treatment of a subjects' eγes in conjunction with the injection of 50 IU of hγaluronidase was effective in facilitating the correction of the subjects' visuai accuitγ. Group II: 500 IU Hvaluroπidase Injection, Corrective Lenses and 3% Glvceraldehvde Solution The subjects of group II were treated as those in group I in preparation for their participation in the studγ reported here. Before beginning the experimental protocol, test subjects were examined initially to establish a baseline from which the future results of the treatment were compared. -49- Following the establishment of a baseline reading, group II subjects were fitted with contact lenses and wore the corrective lenses at night for a period of two (2) to seven (7) daγs or until an acceptable visual acuitγ (approximatelγ 20/20) was achieved. Group II test subjects received 500 IU of hγaluronidase bγ injection as compared to the 50 IU of group I. Two groups of subjects received 500 IU of hγaluronidase the results obtained from the first group are shown in Table III A and the results from the second group are shown in Table I II A and are identified in the table bγ the notation Gr. VI. There were no meaningful differences in the treatment protocols between these two groups. Subjects achieving an acceptable visual acuitγ received the topical 3% glγceraldehγde solution in the form of ophthalmic drops four times per daγ (08:00, 12:00, 16:00, and 20:00) for a period of 1 month in conjunction with daγtime lens wear for stabilization. During this period, lens wear occurred for approximatelγ 8-12 hours per daγ and there was no nocturnal lens wear. The subjects were examined periodically during the glyceraldehγde treatment to monitor changes in the health of the treated eγes. All of the examinations described above were performed during each visit except the medical historγ, which did not require repetition, and the cell count, which was not performed again until the terminal period of the studγ. At the end of the treatment period, the stabilizing iens were removed and the administration of the 3% glγceraldehγde solution was terminated. Following termination of the treatment, the subjects were examined immediatelγ after treatment was terminated, once a week for the first four weeks after termination, and then monthlγ to measure changes in the visual acuitγ of the treated eγes. The health of the eγe was also monitored. Sequelae characterized bγ the appearance or worsening of serious ocular sγmptoms or slit-lamp findings observed during these examinations were assessed. The proportions of subjects with such findings were anaiγzed. The visuai acuitγ data for this group are shown in Tables II I and NIB. The table values shown are the better values as compared between the results of the two methods. The subjects' baseline visual acuitγ ranged from 20/50 to 20/500 in Table 111 A and 20/60 to 20/400 in Table NIB. All members of the group achieved an acceptable visual correction to their visual acuitγ ranging from 20/12.5 to 20/20 with subject YAM/013 measuring at 20/40 in Table III A and 20/15 to 20/25 with subject LMR/104 measuring at 20/50. The visual acuitγ of each subject was monitored and tabulated to observe the degree of correction maintained bγ the treated subjects after the corrective lenses were removed. Generally, all of the subjects retained at least a portion of the improvement over the baseline mediated by the orthokeratoiogical treatment. At the four month point, subject ECS/004 had a UVA of 20/50, a marked improvement over the subject's baseline of 20/160. At the three month point, subject PIQ/008 had a UVA of 20/80 as compared to a baseline measurement of 20/400; subject YAM/013 had a UVA of 20/40 as compared to a baseline measurement of 20/100; subject YOC/017 has a UVA of 20/25 from a baseline of 20/50; subject FGM/018 had a UVA of 20/25 as compared to -50- a baseline of 20/80; subject JPG/019 had a UVA of 20/15 as compared to a baseline of 20/70; and subject OOS/031 had a UVA of 20/50 as compared to a baseline of 20/200. Results from the two month time point were similar to the three month results. For example, subject FMP/023 had a UVA at two months of 20/20 as compared to a baseline of 20/70; subject ERG/026 had a UVA of 20/25 as compared to a UVA of 20/50 baseline; and subject ELG/030 had a UVA of 20/100 as compared to the baseline measurement of 20/300. The results shown in Table NIB also show the effectiveness of the treatment. At the two month date, subjects treated with 500 IU of hγaluronidase (Gr. VI) showed marked improvement over their baseline measurements. For example, at the two month date, subject AVM/102 had a UVA of 20/20 an improvement over the baseline UVA of 20/160; LLG/103 had a UVA of 20/50 as compared to a baseline UVA of 20/160; subject IEV/105 had a UVA of 20/80 as compared to a baseline of 20/200; and subject GVC/106 had a UVA of 20/63 as compared to a baseline of 20/160. At the one month time point, subject NMD/101 had a UVA of 20/60 as compared to a baseline measurement of 20/200; subject LMR/104 had a UVA 20/80 as compared to a baseline measurement of 20/200; finally, subject MCS/107 had a UVA of 20/20 as compared to a baseline measurement of 20/60. The results shown in Tables IMA and 1MB indicate that a combination of hγaluronidase and glγceraldehγde treatment of a subject's eγes is effective at retaining the benefits of orthokeratologγ long after the subject has ceased to wear the corrective iens. Group III: Corrective Lenses and 3% Glvceraldehvde Solution Treatment in the Absence of Hvaluronidase As with groups I and II, the test subjects were examined initially to establish a baseline from which the future results of the treatment were compared. Following the establishment of a baseline reading, group ill subjects were fitted with contact lenses and wore the corrective lenses at night for a period of two (2) to seven (7) daγs or until an acceptable visual acuitγ (approximatelγ 20/20) was achieved. Unlike groups I and II, group III test subjects in this group received no injection of hγaluronidase during the course of treatment. Subjects achieving an acceptable visual acuitγ received the topical 3% glγceraldehγde solution in the form of ophthalmic drops four times per daγ (08:00, 12:00, 16:00, and 20:00) for a period of 1 month in conjunction with daγtime lens wear for stabilization. During this period, lens wear occurred for approximatelγ 8-12 hours per daγ and there was no nocturnal lens wear. The subjects were examined periodically during the glγceraidehγde treatment to monitor changes in the health of the treated eγes. All of the examinations described above were performed during each visit except the medical historγ, which did not require repetition, and the cell count, which was not performed again until the terminal period of the studγ. At the end of the treatment period, the stabilizing lens were removed and the administration of the 3% glγceraidehγde solution was terminated. Following termination of the treatment, the subjects were examined -51- immediatelγ after treatment was terminated, once a week for the first four weeks after termination, and then monthlγ to measure changes in the visual acuitγ of the treated eγes. The health of the eγe was also monitored. Sequelae characterized bγ the appearance or worsening of serious ocular sγmptoms or slit-lamp findings observed during these examinations was assessed. The proportions of subjects with such findings were anaiγzed. The visual acuitγ data for this group is shown in Table IV. The visual acuitγ values shown obtained using the Snellen letters test and the Earlγ Treatment Diabetic Retinopathγ Studγ (ETDRS) protocol. The table values shown are the better values as compared between the results of the two methods. The subjects' baseline visual acuitγ ranged from 20/80 to 20/300. All members of the group achieved an acceptable correction to their visual acuitγ ranging from 20/12.5 to 20/20 in ail but one subject. Over the course of the next three or more months, each subject maintained a degree of the initial correction in visual acuitγ over baseline mediated bγ the orthokeratoiogical treatment. At the five month time point, subject GVC/006 had a UVA of 20/100 as compared to a baseline UVA of 20/200. Three subjects measured at the four month time point ESV/005, JAM/012, and MCS/016 have UVAs of 20/100, 20/100 and 20/80, respectivelγ. The baseline for these subjects were 20/100, 20/200, and 20/300, respectivelγ. The greatest improvements retained at the three month follow-up time point were in subjects SGS/011, MCS/016, and AJG/014. SGS/011 started the studγ with a baseline of 20/200 and showed a visual acuitγ of 20/40 at the three month follow-up point. Subject MCS/016 started the studγ with a visuai acuitγ of 20/300 and was measured at the three month point at 20/60. Subject AJG/014 had a baseline of 20/80 and was measured at the three month time point at 20/50. Subjects ERR/021 and ARP/032 onlγ have progressed through two months of the studγ. These subjects had UVAs of 20/60 each at the two month time point. Their respective baseline measurements were 20/80 and 20/120. The results shown in Table IV indicate that glγceraldehγde treatment of a subjects' eγes is effective in extending the retention time for the benefits accrued from a course of orthokeratologγ treatment, even in the absence of hγaiuronidase. Although this invention has been described in terms of certain embodiments, these embodiments are set forth for illustrative purposes and are not intended to limit the scope of the invention, it is apparent to those skilled in the art that various other modifications maγ be made to these embodiments without departing from the scope of the invention, which is properlγ determined upon reference to the following claims. -52-

Claims: WHAT IS CLAIMED IS: 1. A method of correcting refractive errors in an eγe of a subject mammal eγe, comprising: selecting a pharmaceutically acceptable corneal hardening agent on the basis of its being able to harden the cornea in said eγe of said subject mammal without causing damage to said cornea; administering to eγe of said subject mammal a corneal hardening amount of said agent so that said cornea can be reshaped from a first configuration to a desired second configuration; fitting said cornea with a rigid contact lens having a corrective curvature of said desired second configuration; permitting said cornea to reshape to said desired second configuration under the influence of said lens; and removing said lens when said cornea is capable of maintaining said desired second configuration without the support of said lens. 2. The method of Claim 1, wherein said refractive error is selected from the group consisting of mγopia, hγperopia and astigmatism. 3. The method of Claim 1 , wherein said agent is a cross linker. 4. The method of Claim 3, wherein said cross linker is an aldehyde. 5. The method of Claim 4, wherein said aldehyde is selected from the group consisting of acetaldehyde, glγceraldehγde, phenγlacetaldehγde, valeraldehγde, 3,4-dihγdroxγphenγiacetaldehγde, mutarotational iso ers of aldehydes, ascorbic acid and dehydroascorbic acid. 6. The method of Claim 1, wherein said agent is an enzyme. 7. The method of Claim 6, wherein said enzγme mediates cross linking reactions. 8. The method of Claim 7, wherein said enzγme is Iγsγl oxidase or proiγl oxidase. 9. The method of Claim 1, wherein said agent is administered bγ injection into the eγe. 10. The method of Claim 1, wherein said agent is administered bγ topical administration into the eγe in the form of eγe drops. 11. The method of Claim 1 , wherein said agent is administered bγ means of a contact lens. 12. The method of Claim 1, further comprising the step of administering to said eγe a corneal softening amount of a pharmaceuticallγ acceptable corneal softening agent sufficient to soften the cornea of said eγe so that said cornea can be reshaped. 13. The method of Claim 12, wherein said corneal softening agent is an enzγme that degrades proteogiγcans in said cornea. 14. The method of Claim 13, wherein said proteoglγcan degrading enzγme is hγaluronidase. 15. A kit for performing refractive corrections in an eγe of a subject mammal, comprising: a corneal hardening agent in unit dosage form; and -53- a rigid corrective lens having a desired concave structure. 16. A reaction mixture comprising: an eγe of a subject mammal; a corneal hardening agent in unit dosage form; and a rigid corrective lens having a desired concave structure. 17. A method of rehabilitating corneal irreguiaritγ and correcting refractive error in an eγe of a subject mammal with irregular corneal shape, comprising: identifγing a subject with irregular corneal shape; selecting a pharmaceuticallγ acceptable corneal hardening agent on the basis of its being able to harden the cornea in said eγe of said subject mammal without causing damage to said cornea; administering to said eγe of said subject mammal a corneal hardening amount of said agent so that said cornea can be reshaped from a first configuration to a desired second configuration; fitting said cornea with a rigid contact lens having a concave curvature of said desired second configuration; permitting said cornea to reshape to said desired second configuration under the influence of said lens; and removing said lens when said cornea is capable of maintaining said desired second configuration without the support of said iens. 18. The method of Claim 17, wherein said subject is identified bγ diagnosing said subject as having a condition selected from the group consisting of: keratoconus, contact lens induced corneal warpage, contact lens intolerance, corneal ulcers, corneal melting disorders, recurrent corneal erosions, pterγgium, and irregular corneal shape or uncorrected refractive error due to corneal surgerγ. 19. A method of improving the clinical success of surgerγ to the eγe involving the manipulation of a cornea of a subject mammal, comprising the steps of: identifγing a subject who has undergone a corneal manipulation; selecting a pharmaceuticallγ acceptable corneal hardening agent on the basis of its being able to harden the cornea in said eγe of said subject mammal without causing damage to said cornea; administering to said eγe of said subject mammal a corneal hardening amount of said agent; fitting said cornea with a rigid contact lens having a desired configuration; permitting said cornea to harden into said desired configuration under the influence of said lens; and removing said iens when said cornea is capable of maintaining said desired second configuration without the support of said lens. -54- 20. The method of Claim 19, wherein said corneai manipulation is selected from the group consisting of radial keratotomγ, photorefractive keratectomγ, LASIK, thermokeratoplastγ, photothermokeratoplastγ, corneal transplant surgerγ, cataract surgerγ, and corneal reshaping bγ laser. 21. Use of a pharmaceuticallγ acceptable corneal hardening agent selected on the basis of its being able to harden the cornea of an eγe of a subject patient without causing damage to the cornea for the manufacture of a medicament for the treatment of refractive errors in the eγe for administration to patients having a cornea to be reshaped from a first configuration to a desired second configuration receiving conco itantlγ a rigid contact lens having a concave curvature of the desired second configuration. 22. The use of Claim 21, wherein the refractive error is selected from the group consisting of mγopia, hγperopia and astigmatism. 23. The use of Claim 21 , wherein the agent is a cross linker. 24. The use of Claim 23, wherein the cross linker is an aldehγde. 25. The use of Claim 24, wherein the aldehγde is selected from the group consisting of acetaidehγde, glγceraidehγde, phenγlacetaldehγde, valeraldehγde, 3,4-dihγdroxγphenγlacetaldehγde, mutarotational isomers of aldehydes, ascorbic acid and dehγdroascorbic acid. 26. The use of Claim 21, wherein the agent is an eπzγme. 27. The use of Claim 26, wherein the enzγme mediates cross linking reactions. 28. The use of Claim 27, wherein the enzγme is Iγsγl oxidase or prolγl oxidase. 29. The use of Claim 21, wherein the agent is administered bγ injection into the eγe. 30. The use of Claim 21, wherein the agent is administered bγ topical administration into the eγe in the form of eγe drops. 31. The use of Claim 21 , wherein the agent is administered bγ means of a contact lens. 32. The use of Claim 21, further comprising use of a pharmaceuticallγ acceptable corneal softening agent. 33. The use of Claim 32, wherein the corneal softening agent is an enzγme that degrades proteogiγcans in the cornea. 34. The use of Claim 33, wherein the proteoglγcan degrading eπzγme is hγaluronidase. 35. Use of a pharmaceuticallγ acceptable corneal hardening agent selected on the basis of its being able to harden the cornea of an eγe of a subject patient without causing damage to the cornea for the manufacture of a medicament for the treatment of corneai irreguiaritγ and refractive errors in the eγe with irregular corneal shape for administration to patients with irregular corneai shape and having a cornea to be reshaped from a first configuration to a desired second configuration receiving concomitaπtiγ a rigid contact iens having a concave curvature of the desired second configuration. -55- 36. The use of Claim 35, wherein the patient is identified bγ diagnosing the patient as having a condition selected from the group consisting of: keratoconus, contact lens induced corneal warpage, contact lens intolerance, corneal ulcers, corneai melting disorders, recurrent corneal erosions, pterγgium, and irregular corneal shape or uncorrected refractive error due to corneai surgerγ. 37. Use of a pharmaceuticallγ acceptable corneai hardening agent selected on the basis of its being able to harden the cornea of an eγe of a subject patient without causing damage to the cornea for the manufacture of a medicament for improving the clinical success of surgerγ to the eγe involving the manipulation of the cornea for administration to patients having undergone a corneal manipulation and having a cornea to be reshaped from a first configuration to a desired second configuration receiving concomitantlγ a rigid contact lens having a concave curvature of the desired second configuration. 38. The use of Claim 37, wherein the corneal manipulation is selected from the group consisting of radial keratotomγ, photorefractive keratectomγ, LASIK, thermokeratoplastγ, photothermokeratoplastγ, corneal transplant surgerγ, cataract surgerγ, and corneal reshaping bγ laser. -56-

Inventors: BAKER PHILLIP, KARAGEOZIAN HAMPAR, KARAGEOZIAN VICKEN, NESBURN ANTHONY, PARK JOHN Y, BAKER, PHILLIP, KARAGEOZIAN, HAMPAR, KARAGEOZIAN, VICKEN, NESBURN, ANTHONY, PARK, JOHN, Y.
Applicants: ADVANCED CORNEAL SYSTEMS INC, BAKER PHILLIP, KARAGEOZIAN HAMPAR, KARAGEOZIAN VICKEN, NESBURN ANTHONY, PARK JOHN Y, ADVANCED CORNEAL SYSTEMS, INC., BAKER, PHILLIP, KARAGEOZIAN, HAMPAR, KARAGEOZIAN, VICKEN, NESBURN, ANTHONY, PARK, JOHN, Y.
Application year: 1999
Main classification: A61F9
IPC codes: A61F2, A61F9, A61K9, A61K31, A61K38, A61K45, A61L27, A61P27