Method for treating eye disorders

Abstract

The present invention provides a method for treating an eye disorder and a composition used in the method. The method includes applying a crosslinkable liquid composition to the front surface of the cornea of the eye using a mold, crosslinking the crosslinkable liquid composition on the front surface of the cornea of the eye, obtaining a composition crosslinked on the front surface of the cornea of the eye by crosslinking, and correcting the curvature of the crosslinked composition.

Description

Technical Field

[0001] The present invention is widely applicable in the medical field, and more particularly relates to a method for treating eye disorders such as chronic or subacute corneal diseases accompanied by refractive anomalies or corneal irregularities.

Background Art

[0002] The cornea is a transparent tissue in the anterior eye segment. The cornea functions as the window of the eye and is responsible for two-thirds of the refraction of incoming light. On the other hand, the remaining refraction is performed by the crystalline lens. Appropriate refraction of incoming light is necessary for a sharp image to be projected onto the retina, where the light is converted into electrical signals that are transmitted via the optic nerve to the visual cortex of the brain. Refractive disorders such as myopia, hyperopia, astigmatism, and presbyopia blur the vision at various distances and are mostly caused by abnormal corneal curvature. To counteract the abnormal light path, a lens can be placed in front of the eye as a correction, and the lens can be in the form of either a contact lens or spectacles. If the refractive anomaly is not corrected, (severe) visual impairment, and secondarily, headaches, fatigue, and eye irritation can occur. This is why refractive anomalies are cited as the most common cause of reversible blindness worldwide.

[0003] Another solution to correct refractive disorders is to reshape the cornea by laser refractive surgery. Laser refractive surgery, also known as laser ablation or photoablation, encompasses different techniques including photorefractive keratectomy (PRK), laser in-situ keratomileusis (LASIK), and small incision lenticule extraction (SMILE). The common factor among these procedures is ablation, i.e., removing corneal tissue by laser pulses, with the aim of adjusting the curvature of the cornea. This act of tissue removal brings about a change in corneal curvature, and thus corrects the focusing power of the cornea to appropriately focus light on the retina. In the case of hyperopia, the central optical region is made relatively steeper by applying laser pulses around the central part of the cornea, while for myopia, the central part of the cornea is flattened to reduce the curvature.

[0004] Since all photoablation treatments for refractive abnormalities such as PRK, LASIK, and SMILE are basically subtractive, these treatments have limitations. The most obvious limitation is the extent of tissue removal required to achieve the effect, as tissue is removed from the cornea to make the curvature relatively steeper or flatter. Removing too much corneal tissue results in a thin cornea that is prone to corneal ectasia (thinning of the cornea) and corneal perforation. For hyperopia, photoablation laser surgery is actually safe and effective up to +2 diopters (dpt), but becomes less predictable for more severe cases. This is also the case for astigmatism up to 3 dpt. Second, for refractive surgery (for hyperopia or presbyopia), the effect wears off over time because epithelial cells grow and cover the grooves induced in the cornea, thereby returning to a state similar to the original abnormal curvature. Third, refractive surgery has risks associated with suboptimal performance of the procedure depending on the specific technique, such as the risk of corneal haze and a long period until vision recovery (PRK), flap-related problems (LASIK), or complications due to a highly difficult technique (SMILE).

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] There is still a need for new methods of treating these eye disorders such as refractive abnormalities.

MEANS FOR SOLVING THE PROBLEMS

[0006] The present invention is based, at least in part, on the inventors' innovative insights and experimental evaluations that chronic or subacute corneal diseases or disorders with refractive abnormalities or corneal irregularities can be treated by applying a cross-linkable composition as a liquid to the anterior surface of the cornea of the affected eye using a mold, and then cross-linking the composition in situ. If necessary, the curvature of the newly formed corneal annulus can then be corrected using techniques such as photoablation without reducing the corneal stromal volume of the cornea itself. The advantage of cross-linking the tissue in situ is that the polymerization of the hydrogel and the adhesion to the cornea due to chemical interactions occur simultaneously. Furthermore, since the non-cross-linked biomaterial is liquid, it fits perfectly to the shape of the patient's cornea compared to a prefabricated annulus.

[0007] The method of the present invention and the cross-linkable composition used in the method provide a long-term but reversible solution for treating eye disorders, such as chronic or subacute corneal diseases accompanied by refractive anomalies or corneal irregularities. Since it has no effect on corneal stromal tissue and does not damage corneal nerves, the risk of postoperative complications, such as dry eye disease or postoperative pain, is very limited. Furthermore, the method of the present invention and the cross-linkable composition used in the method can add a biomaterial to the corneal surface, and since the method is not affected by the thickness of the cornea itself, it provides a wider treatment area than subtractive laser refractive surgery. For example, for myopia and presbyopia, higher degrees of correction are possible, irregular corneas can be treated, and higher degrees of astigmatism correction can be achieved than when using only a laser. Furthermore, the method enables partial or complete repair / restoration of a cornea damaged due to chronic or acute corneal diseases.

[0008] Accordingly, the present invention provides a cross-linkable liquid composition for use in treating an eye disorder in a subject's eye, the treatment comprising applying the cross-linkable liquid composition to the anterior surface of the cornea of the eye including the eye disorder, and cross-linking the cross-linkable liquid composition on the anterior surface of the cornea of the eye, the step of cross-linking obtaining a cross-linked composition on the anterior surface of the cornea of the eye, and optionally, correcting the curvature of the cross-linked composition, and the method includes introducing the cross-linkable liquid composition into a mold positioned on the anterior surface of the cornea of the eye, and the eye disorder is a chronic or subacute corneal disease accompanied by a refractive anomaly or corneal irregularity.

[0009] Similarly, the present invention provides a method for treating an eye disorder in a target eye, the method comprising applying a crosslinkable liquid composition to the anterior corneal surface of the eye including the eye disorder, and crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eye, the crosslinking resulting in obtaining a composition crosslinked on the anterior corneal surface of the eye, and optionally, correcting the curvature of the crosslinked composition, wherein the eye disorder is a chronic or subacute corneal disease associated with refractive error or corneal irregularity, and the crosslinkable composition is applied to the anterior corneal surface of the eye using a mold. More specifically, the method includes introducing the crosslinkable liquid composition into the mold before positioning the mold on the anterior corneal surface of the eye, or positioning the mold on the anterior corneal surface of the eye and introducing the crosslinkable liquid composition into the mold.

[0010] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the mold is a corneal vacuum suction device, a corneal bath or a contact lens.

[0011] In certain embodiments, at least a part of the corneal epithelial cells is removed from the anterior corneal surface before or after positioning the mold on the corneal surface.

[0012] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the method includes removing the mold after crosslinking of the crosslinkable composition.

[0013] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the crosslinkable liquid composition is applied as a single layer. In certain embodiments, more specifically, when the crosslinkable liquid composition is applied to a lens and then placed on the surface of the eye, applying it as a single layer means applying the crosslinkable liquid composition as a single layer in a mold. In certain embodiments, more specifically, when the crosslinkable liquid composition is applied into an O-ring placed on the eye, applying it as a single layer means applying the crosslinkable liquid composition as a single layer to the anterior surface of the cornea of the eye.

[0014] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the crosslinkable liquid composition comprises a crosslinkable biomaterial and optionally one or more photoinitiators. More specifically, the crosslinkable biomaterial is selected from the group consisting of protein-based polymers, polysaccharide-based polymers, and synthetic polymers.

[0015] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, crosslinking is carried out by photocrosslinking, by exposure to O 2 or by one or more enzymes, preferably by photocrosslinking such as by UV irradiation.

[0016] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the crosslinked composition has a diameter ranging from 6.0 mm to 9.0 mm and a thickness ranging from 20.0 μm to 400.0 μm after crosslinking and before correcting the curvature of the crosslinked composition.

[0017] In certain embodiments of the crosslinkable liquid composition or method used in the present invention, the crosslinked composition has resistance to biodegradation over a period of at least 6 months, preferably at least 12 months.

[0018] In certain embodiments, the refractive anomaly is selected from the group consisting of myopia, hyperopia, astigmatism, and presbyopia.

[0019] In certain embodiments, the chronic or subacute corneal disease with corneal irregularity is selected from the group consisting of corneal ulcer, corneal erosion, corneal ectatic disorder, or corneal irregularity caused by trauma or epithelial basement membrane dystrophy.

[0020] These aspects and preferred embodiments of the present invention, as well as further aspects and preferred embodiments, are described in the following sections and the appended claims. The subject matter of the appended claims is hereby incorporated herein by reference in its entirety.

Brief Description of the Drawings

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[0022] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0023] The terms "comprising", "comprises", and "comprised of" are used herein synonymously with "including", "includes", or "containing", "contains", and these terms are inclusive or non-limiting and do not exclude additional recited members, elements, or method steps. These terms also encompass "consisting of" and "consisting essentially of", which enjoy well-established meanings in patent terminology.

[0024] A reference to a numerical range by endpoints includes all numbers and fractions within the respective range and the recited endpoints, whether the numerical range is recited with the expression “from... to...,” or “between... and...,” or some other expression. This applies regardless of the expression by which the numerical range is introduced.

[0025] As used herein, the terms “about” or “approximately,” when referring to a measurable value such as a parameter, quantity, time period, etc., mean a variation of the value from the specified value, e.g., within ±10% or less, preferably within ±5% or less, more preferably within ±1% or less, still more preferably within ±0.1% or less of the specified value, provided such variation is appropriate for practicing the disclosed invention. Of course, the value modified by the modifier “about” or “approximately” is itself specifically and preferably disclosed.

[0026] On the other hand, the terms “one or more” or “at least one,” e.g., one or more or at least one of a group of elements, are self - explanatory, and by way of further illustration, this term includes, inter alia, reference to any one of the foregoing elements, or to any two or more of the foregoing elements, e.g., any three or more, four or more, five or more, six or more, or seven or more of the foregoing elements, and reference to all of the foregoing elements. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7, or more.

[0027] The discussion of the background to the invention herein is included to explain the context of the invention. This is not an admission that any of the material referred to was publicly available, known, or part of common general knowledge in any country at the time of the priority date of any of the claims.

[0028] Throughout the present disclosure, various publications, patents, and published patent specifications are referenced as to identify the source. All documents cited herein are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents specifically referred to herein are hereby incorporated by reference in their entirety.

[0029] Unless otherwise defined, all terms used in the disclosure of the present invention, including technical and scientific terms, have the meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. As a further guidance, definitions of terms are included to better understand the teachings of the present invention. When a particular term is defined in relation to a particular aspect or a particular embodiment of the present invention, such relevance or meaning is meant to apply throughout this specification, i.e., in the context of other aspects or embodiments of the present invention, unless otherwise specifically defined.

[0030] In the following sections, different aspects or embodiments of the present invention are defined in more detail. Each aspect or embodiment so defined can be combined with any other aspect(s) or embodiment(s), unless the contrary description is apparent. In particular, any feature shown as being preferred or advantageous can be combined with any other single or multiple features shown as being preferred or advantageous.

[0031] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular property, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, although they may. Further, the particular properties, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as will be apparent to those skilled in the art from this disclosure. Additionally, some embodiments described herein include some properties included in other embodiments but not others, and combinations of features of different embodiments are meant to be within the scope of the invention and to form different embodiments understandable by those skilled in the art. For example, in the appended claims, any combination of the embodiments recited in the claims may be used.

[0032] The present invention is based, at least in part, on the innovative insights and experimental evaluations of the inventors that a composition capable of crosslinking on the anterior surface of the cornea of an affected eye can be applied as a liquid using a mold for holding the composition capable of crosslinking during application of the composition capable of crosslinking to the anterior surface of the cornea, and then the composition is crosslinked in situ, and optionally, the curvature of the newly formed corneal annulus is corrected, for example by photoablation, without reducing the corneal stroma of the cornea itself, so as to treat chronic or subacute corneal diseases with refractive anomalies or corneal irregularities. Accordingly, the method of the present invention is less invasive than subtractive laser refractive surgery such as PRK, LASIK, and SMILE.

[0033] The method of the present invention and the crosslinkable liquid composition used in the method provide an integrated, long-term but reversible solution for treating eye disorders, such as chronic or subacute corneal diseases with refractive anomalies or corneal irregularities, and have several advantages compared to known methods for treating such eye disorders.

[0034] For example, unlike glasses or contact lenses, the compositions and methods used in the present invention do not interfere with the subject during heavy work or contact sports, the cross-linked composition on the cornea obtained by the method of the present invention does not cause discomfort to the subject, and once applied, it provides a long-term treatment for eye disorders without the risk of severe eye bacterial infections due to lens unsanitary conditions.

[0035] Furthermore, compared to subtractive laser refractive surgeries such as PRK, LASIK, and SMILE, the method of the present invention does not affect the corneal stromal tissue and does not create an epithelial flap, so the risk of post-operative complications such as dry eye disease, post-operative pain, or flap-related problems is very limited. Additionally, the method of the present invention adds a biomaterial to the corneal surface, and since the method is not affected by the thickness of the cornea itself, it provides a wider treatment area than subtractive laser refractive surgeries. For example, for myopia and presbyopia, for instance, higher degrees of correction are possible, irregular corneas can be treated, and high-degree astigmatism correction can be achieved.

[0036] The methods and compositions of the present invention are specifically aimed at treating pre-existing eye disorders of the subject prior to treating the subject by the methods taught herein, and are not aimed at treating refractive abnormalities caused by the presence of the cross-linked material applied by the methods taught herein.

[0037] Accordingly, the present invention provides a crosslinkable liquid composition for use in the treatment of eye disorders, which is used in a specific manner, namely, a crosslinkable composition applied using a mold. More specifically, the present invention provides a crosslinkable liquid composition for use in a method of treating an eye disorder, the method comprising the steps of applying the crosslinkable liquid composition onto the anterior surface of the cornea of the eye, within a mold positioned on the eye; and crosslinking the crosslinkable liquid composition on the anterior surface of the cornea of the eye, thereby obtaining a composition crosslinked on the anterior surface of the cornea of the eye. Optionally, the method further comprises the step of correcting the curvature of the crosslinked composition.

[0038] Similarly, the present invention provides a method of treating an eye disorder in an eye of a subject in need of treatment, the method comprising applying a crosslinkable liquid composition to the anterior surface of the cornea of the eye, which includes the eye disorder, using a mold; crosslinking the crosslinkable liquid composition on the anterior surface of the cornea of the eye, thereby obtaining a composition crosslinked on the anterior surface of the cornea; and optionally, correcting the curvature of the crosslinked composition.

[0039] In certain embodiments, the compositions and methods of the present invention are contemplated for use in the treatment of eye disorders that are chronic or subacute corneal diseases, preferably corneal refractive abnormalities, with refractive errors or corneal irregularities.

[0040] References to "therapy" or "treatment" include curative treatments, and these terms refer in particular to the alleviation or measurable reduction of one or more symptoms or measurable markers of a pathological condition, such as a disease or disorder or dysfunction (e.g., as a result of trauma or surgery). Measurable reduction includes any statistically significant reduction in a measurable marker or symptom. Generally, these terms include both curative treatments and treatments aimed at reducing the symptoms of a disease and / or slowing the progression of the disease.

[0041] Thus, the term "ocular disorder" generally encompasses both conditions caused by disease and other factors that may affect the normal function of the eye, such as conditions caused by trauma or surgery.

[0042] The terms "subject", "individual", or "patient" are used interchangeably throughout this specification and generally preferably refer to a human, although references to non-human animals, preferably warm-blooded animals, and even more preferably non-human mammals may also be included. It is particularly preferred that the human subject includes both genders and all age categories. In other embodiments, the subject is an experimental animal or animal substitute as a disease model. This term does not refer to a specific age or gender.

[0043] The term "subject in need of treatment" or similar terms, as used herein, refers to a subject diagnosed with or having the disease or disorder described herein.

[0044] The term "refractive error" or "refraction error", as used herein, refers to an ocular disorder in which the shape of the eye and / or cornea prevents light from focusing correctly on the retinal fovea, thereby impairing vision. Non-limiting examples of refractive errors are myopia (nearsightedness), hyperopia (farsightedness), astigmatism and irregular astigmatism, and presbyopia. Symptoms caused by refractive errors include, but are not limited to, double vision, blurred vision, seeing glare or halos around bright lights, strabismus, headache, and eye strain. Refractive errors can be diagnosed by any means known in the art, for example, by using an autorefractor. In preferred embodiments, refractive errors are due to a primary cause (e.g., naturally occurring or non-surgically induced), or are due to a secondary cause, including, but not limited to, those surgically induced as a result of an infectious disease, genetic factor, degenerative eye disease, or trauma to the eye (e.g., corneal ectasia after LASIK).

[0045] In certain embodiments, the refractive anomaly is selected from the group consisting of myopia, hyperopia, astigmatism (e.g., regular or irregular astigmatism), and presbyopia.

[0046] The terms "myopia" or "nearsightedness," as used herein, have the meaning generally recognized in the art. In myopia or nearsightedness, light rays focus in front of the retina. This can be caused by the focusing power (refractive power) of the cornea and lens being very high and / or the eye being too long from front to back. For myopia, subtractive photorefractive ablation laser surgery is actually safe and effective up to -10 diopters (dpt), but becomes less predictable and shows a higher complication rate for more severe myopia. Thus, in certain embodiments, the refractive anomaly is myopia with a diopter greater than -10.0, e.g., from -10.5 to -20.0.

[0047] The terms "hyperopia" or "farsightedness," as used herein, have the meaning generally recognized in the art. With respect to hyperopia or farsightedness, light rays focus behind the retina. This can be caused by the focusing power of the cornea and lens being very low and / or the eye being too short from front to back. For hyperopia, subtractive photorefractive ablation laser surgery is actually safe and effective up to 3 diopters (dpt), but becomes less predictable for higher diopters. Thus, in certain embodiments, the refractive anomaly is hyperopia with a diopter greater than +3.0, e.g., from +3.5 to +10.0, from +3.5 to +8.0, preferably from +3.5 to +4.0, +3.5, or +4.0.

[0048] The term "presbyopia" or "age-related hyperopia", as used herein, has its generally recognized meaning in the art. Presbyopia is a physiological insufficiency of the eye's accommodation for near and far vision that gradually decreases the ability to clearly focus on nearby objects with age. Presbyopia is generally caused by age-related changes in the lens (decrease in elasticity and increase in hardness) and changes in the ciliary muscle of the eye, which cause the eye to focus light behind the retina rather than on the retina when looking at nearby objects.

[0049] The term "astigmatism", as used herein, has its generally recognized meaning in the art and includes regular astigmatism, irregular astigmatism, simple astigmatism, compound astigmatism, myopic astigmatism, hyperopic astigmatism, mixed astigmatism, lenticular astigmatism, and corneal astigmatism, etc. Astigmatism is a refractive error in the eye caused by rotational asymmetry of the refractive power of the eye. The underlying mechanism involves irregular curvature of the eye's cornea or abnormalities of the lens. In an eye without astigmatism, the cornea and lens have generally the same curvature in all directions. This allows light to focus on a single point on the retina. A person with astigmatism has a higher curvature in one direction or meridian than in another direction or meridian, and thus light cannot focus on a single point on the retina. As a result, the visual field is blurred at all distances. Subtractive photorefractive laser surgery is actually safe and effective up to about 3 diopters (dpt) for astigmatism, but becomes less predictable for higher diopters. Thus, in certain embodiments, the refractive error is astigmatism with a diopter greater than +3.0, for example, from +3.5 to +16.0, from +3.5 to +8.0, preferably from +3.5 to +5.0, for example +3.5, +4.0, +4.5, or +5.0. Corneal astigmatism may be induced by corneal surgery or corneal transplantation.

[0050] In certain embodiments, the ocular disorder is a chronic or subacute corneal disease associated with corneal irregularities. Non-limiting examples of chronic or subacute corneal diseases associated with corneal irregularities include corneal ulcers (e.g., those caused by trauma or inflammation), corneal erosions, corneal ectatic disorders (i.e., thinning of the cornea), such as keratoconus, keratoglobus or post-LASIK corneal ectasia, or corneal irregularities that induce ametropia, e.g., due to trauma or epithelial basement membrane dystrophy.

[0051] In certain embodiments, the chronic or subacute corneal disease associated with corneal irregularities is selected from the group consisting of corneal ulcers, corneal erosions, corneal ectatic disorders or corneal irregularities caused by trauma or epithelial basement membrane dystrophy. The corneal ectasia is preferably keratoconus.

[0052] As used herein, the term "corneal ectasia" or "corneal ectatic disorder" refers to a group of rare non-inflammatory ocular disorders characterized by thinning of the central, paracentral or peripheral cornea of both eyes.

[0053] In embodiments, the corneal ectasia can be selected from the group consisting of keratoconus, keratoglobus, pellucid marginal degeneration, posterior keratoconus, post-LASIK corneal ectasia, and Terrien's marginal degeneration.

[0054] The term "keratoconus" refers to a progressive, non-inflammatory, binocular, asymmetric disorder characterized by thinning and weakening of the paraxial corneal stroma that results in distortion of the corneal surface.

[0055] In embodiments of the uses or methods taught herein, the chronic or subacute corneal disease associated with corneal irregularities may be caused by an invasive procedure to correct an ocular disorder. Thus, in embodiments, the chronic or subacute corneal disease associated with corneal irregularities may be caused by a laser refractive surgery such as PRK, LASIK or SMILE.

[0056] In alternative embodiments, the chronic or subacute corneal disease is a disease not caused by an invasive procedure to correct an eye disorder. Thus, in certain embodiments, the chronic or subacute corneal disease with corneal irregularities is not caused by laser refractive surgery such as PRK, LASIK, or SMILE.

[0057] Similarly, in certain embodiments, the subject has not undergone any invasive procedure to correct an eye disorder, such as refractive error, on the eye prior to the application of the crosslinkable liquid composition. In a more detailed embodiment, the subject has not undergone laser refractive surgery such as PRK, LASIK, or SMILE prior to the application of the crosslinkable liquid composition to the anterior surface of the eye's cornea.

[0058] Particular attention is paid to subjects for whom existing techniques cannot treat the eye disorder, for example, subjects excluded from treatment by refractive correction laser therapy, such as subjects with very thin corneas, subjects with persistent dry eye, or subjects who engage in contact sports. Thus, in certain embodiments, the thickness of the subject's cornea is less than 480.0 μm, less than 450.0 μm, or less than 400.0 μm.

[0059] Crosslinking is the formation of chemical linkages between molecular chains to form a three-dimensional network structure of the connected molecules. Crosslinking can be formed by chemical reactions that occur spontaneously or initiated, for example, by one or more enzymes, heat, pressure, pH changes, or irradiation. These chemical reactions can also generally be initiated by the presence of one or more crosslinking agents containing multiple functional groups.

[0060] The crosslinkable liquid composition used in the method of the present invention can be crosslinked (either spontaneously or by induction such as by UV irradiation), does not dissolve at body temperature, for example, about 37°C, and can contain any type of biocompatible material (e.g., biomaterial) that can take up a substantial amount of water from the surroundings.

[0061] "Crosslinkable liquid" or "crosslinkable liquid composition", when referred to in this specification, includes crosslinkable biomaterials. The crosslinkable biomaterials may be synthetic, non-synthetic, or a combination thereof. The terms "liquid" or "liquid composition" in the context of the present invention encompass both fully liquid compositions and semi-liquid compositions, i.e., compositions having a viscosity between that of a solid and a liquid.

[0062] In certain embodiments, the crosslinkable biomaterial is selected from the group consisting of protein-based polymers, polysaccharide-based polymers, synthetic polymers, or combinations thereof.

[0063] The protein-based polymer may be, but should not be considered limited to, collagen, such as recombinant mammalian collagen or mammalian-derived collagen, gelatin, fibrinogen, silk fibroin, or a 3,4-dihydroxyphenyl-L-alanine (DOPA) polymer inspired by mussels. In certain embodiments, the collagen is selected from the group consisting of type I collagen, type III collagen, type IV collagen, type V collagen, type VII collagen, and combinations thereof.

[0064] Non-limiting examples of polysaccharide-based polymers include hyaluronic acid or alginic acid. Gelatin-based biomaterials may be those described in GelCORE, for example, Ehsan Shirzaei Sani et al., Sutureless repair of corneal injuries using naturally derived bioadhesive hydrogels, Science Advances, 2019, Vol. 5, no. 3 or methacrylated thermoresponsive COMatrix, for example, Ghasem Yazdanpanah et al., A light-curable and tunable extracellular matrix hydrogel for in situ suture-free corneal repair, Advanced Functional Materials, 2022.

[0065] Non-limiting examples of synthetic polymers include polyethylene glycol (PEG), poly(ε-caprolactone) (PCL), and poly(vinyl alcohol). Synthetic polymers may be those described in polyethylene glycol-collagen, for example, Yoon Hong Chun et al., In vivo biocompatibility evaluation of in situ-forming polyethylene glycol-collagen hydrogels in corneal defects, Scientific Reports, 2021.

[0066] In certain embodiments, the crosslinkable biomaterial is functionalized using methacrylate, diacrylate, diacrylamide, xxxx (etc.). Thus, in certain embodiments, the crosslinkable biomaterial consists essentially of or consists of one or more of 2-(hydroxyethyl) methacrylate (HEMA), 2-methacryloyl-oxyethyl phosphorylcholine (MPC), HEA, methyl methacrylate (MMA), methacrylic acid (MAA), polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, and polyethylene glycol diacrylamide.

[0067] In certain embodiments, the crosslinkable biomaterial, when crosslinked, does not have a transparency of less than 50% as measured across the visible spectrum (400 nm to 750 nm). In certain embodiments, the crosslinkable biomaterial is not dextran methacrylate.

[0068] The concentration of the crosslinkable biomaterial in the crosslinkable liquid composition can be varied, and likewise the degree of its substitution can be varied.

[0069] In certain embodiments, the crosslinkable liquid composition comprises at least 1.0% (weight / volume), at least 5.0% (weight / volume), at least 10.0% (weight / volume), at least 15.0% (weight / volume), or at least 20.0% (weight / volume) of the crosslinkable biomaterial. In certain embodiments, the crosslinkable liquid composition comprises from 1.0% (weight / volume) to 30.0% (weight / volume), for example, from 1.0% (weight / volume) to 20.0% (weight / volume) of the crosslinkable biomaterial. In certain embodiments, the crosslinkable liquid composition comprises 20.0% (weight / volume) of the crosslinkable biomaterial.

[0070] The crosslinkable liquid composition may further comprise one or more crosslinking agents and / or one or more photoinitiators involved in the crosslinking reaction.

[0071] A photoinitiator is a compound that, upon exposure to light, decomposes into reactive species that activate the polymerization of specific functional groups on a crosslinkable biomaterial. Thus, photoinitiators are generally used herein when a crosslinkable liquid composition is capable of crosslinking by photocrosslinking. The type and concentration of the photoinitiator in the crosslinkable liquid composition contemplated herein can vary. Specific photoinitiators are generally associated with an excitation wavelength spectrum, and the peak of that spectrum is the optimal wavelength for creating radicals upon excitation. Non-limiting examples of photoinitiators that can be used in the methods taught herein include riboflavin, indocyanine green, janus green, rose bengal, methylene blue, sodium persulfate, ruthenium, 2,4,6-trimethylbenzoyl)-phosphine oxide (TPO) (Diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide), Irgacure 2959, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), or combinations thereof.

[0072] In certain embodiments, the photoinitiator is a photoinitiator that can be excited using visible light. Non-limiting examples of photoinitiators that can be excited using visible light include 2,4,6-trimethylbenzoyl)-phosphine oxide (TPO) (Diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide), lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), riboflavin, rose bengal, or sodium persulfate.

[0073] The photoinitiator is preferably a photoinitiator that can be excited within the UV spectrum, which can also be referred to as "blue light", and thus at wavelengths from 250 nm to 450 nm. Non-limiting examples of photoinitiators that can be excited using UV irradiation are Irgacure 2959, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0074] In a preferred embodiment, the one or more photoinitiators are water-soluble photoinitiators. Non-limiting examples are ruthenium, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), 2,4,6-trimethylbenzoyl)-phosphine oxide (TPO) (Diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide), and other members of the Irgacure photoinitiator family.

[0075] In certain embodiments, the crosslinkable composition comprises from 0.1% (weight / volume) to 2.0% (weight / volume), for example from 1.0% (weight / volume) to 2.0% (weight / volume) of one or more photoinitiators.

[0076] In certain embodiments, the crosslinkable liquid composition can be crosslinked by photo-crosslinking such as UV irradiation, by exposure to O 2 or by one or more enzymes. In a preferred embodiment, the crosslinkable liquid composition can be crosslinked by photo-crosslinking or enzymatic crosslinking. Thus, the crosslinkable liquid composition has reactive functionality to form short oligomer / polymer chains between macromolecular chains. As described elsewhere herein, the reactive functional groups can be, but are not limited to, methacrylate, or thiol-ene click chemistry.

[0077] In certain embodiments, the crosslinkable liquid composition further comprises one or more therapeutic agents (e.g., analgesics, anti-inflammatory agents, antibiotics, growth factors for stimulating epithelialization, or steroids), and / or other agents such as colorants.

[0078] When the crosslinkable liquid composition is crosslinked, the crosslinked composition preferably does not interfere with the normal functionality of the eye and provides sufficient nutrients and gas exchange to maintain viable corneal epithelium and stroma. Thus, in certain embodiments, the crosslinked composition is permeable to water, nutrients, oxygen, therapeutic agents (e.g., analgesics, anti-inflammatory agents, antibiotics, growth factors to stimulate epithelialization, or steroids), and / or growth factors (e.g., exogenous or endogenous growth factors such as nerve growth factor (NGF)).

[0079] The crosslinked composition is preferably compatible with clinical imaging techniques, such as clinical corneal examinations using refractometers, optical coherence tomographs, Scheimpflug tomographs, Placido-based tomography devices or in vivo confocal imaging.

[0080] Thus, in certain embodiments, the crosslinkable liquid composition and / or the crosslinked composition, when crosslinked, have a transparency of at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% as measured using light having a representative wavelength spectrum (400 nm - 750 nm) of the visible spectrum. The transparency can be determined by any means in the art, for example, by a microplate reader or a spectrophotometer such as those described in Rizwan et al. Sequentially-crosslinked bioactive hydrogels as nano-patterned substrates with customizable stiffness and degradation for corneal tissue engineering applications or Van Hoorick et al. (Designer Descemet Membranes Containing PDLLA and Functionalized Gelatins as Corneal Endothelial Scaffold, Adv. Healthcare Materials, Vol. 9(6):2000760; (2020); https: / / doi.org / 10.1002 / adhm.202000760).

[0081] In certain embodiments, the crosslinkable liquid composition and / or the crosslinked composition have a refractive index similar to that of native corneal stroma. The refractive index can be measured by any means in the art, for example, by using a refractometer.

[0082] When the crosslinkable liquid composition crosslinks, the crosslinked composition retains water within the three-dimensional network structure of the polymer, and as a result, a hydrogel is formed. In certain embodiments, the crosslinked composition has a swelling ratio of 200% to 1000% when fully hydrated. The swelling ratio can be defined as the fractional increase in weight of the crosslinked composition due to water absorption. The swelling ratio can be affected by the type of biomaterial, the concentration of the biomaterial within the crosslinkable liquid composition, and the degree of functionalization.

[0083] One of the major advantages compared to existing techniques of the methods taught herein is to provide a long-term solution for treating chronic or subacute corneal diseases with refractive anomalies or corneal irregularities. Thus, in certain embodiments, the crosslinked composition is stable at body temperature, for example, at about 37°C, preferably for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 5 years, or at least 10 years.

[0084] The inventors have found that by applying the crosslinkable composition to the anterior surface of the eye's cornea using a mold, the crosslinkable composition and the final crosslinked composition can be accurately placed on the anterior surface of the eye's cornea, and it is possible to avoid the crosslinkable composition overflowing over the entire anterior surface of the eye and / or under the eyelid before crosslinking. Further, the mold provides a primary shape, diameter, and / or pre-curvature for the final corneal annulus formed by the crosslinked biomaterial. By creating the corneal annulus in situ, the corneal annulus fits perfectly to the shape of the patient's cornea compared to a separately created corneal annulus.

[0085] In certain embodiments, the mold is an O-ring shaped corneal bath (also referred to as an o-ring). In alternative embodiments, the mold is a contact lens, preferably a contact lens that does not adhere to the biomaterial, more preferably a scleral contact lens, whether or not the biomaterial is in a non-crosslinked or crosslinked state. In certain embodiments, the mold is a silicone hydrogel contact lens. A contact lens having a convergent meniscus shape allows the crosslinked composition (i.e., the biomaterial) to be shaped into a lens shape having a lens body (or lens (optical) region) and a lens edge (or peripheral region) around the lens body. Thus, such a contact lens is thinner towards the peripheral edge and thus generally has a thinner peripheral tip than when using a corneal bath and is used as a mold for the shaped crosslinked composition. As a result, less biomaterial needs to be removed when correcting the curvature of the crosslinked composition, thereby making the methods taught herein more efficient.

[0086] In certain embodiments, the mold is a corneal suction device. The suction device can be fixed on the cornea and works in the same way as an o-ring except that the diameter for applying an anesthetic varies. In fact, a suction device (either a dedicated suction ring or a suction device with a trephine removed) can be vacuum-fixed to the uppermost part of the eye, and then a crosslinkable composition can be added and irradiated. Then, the suction device is removed from the eye. The suction device is illustrated, for example, in FIG. 1B of Kim et al. (J. Vet Sci, 2015, 16, 349-356). When the mold is a suction device, the method may include the steps of removing the corneal epithelium, depressing a vacuum syringe (coupled with a vacuum ring) and placing the ring in the center of the cornea, gently releasing the vacuum syringe to adhere the vacuum ring to the eye, placing a crosslinkable fluid composition inside the ring, and crosslinking the crosslinkable fluid composition with light.

[0087] In certain embodiments, the mold is a standard contact lens, and the inventors have found that when used in the method of the present invention, only those with a peripheral portion thicker than the central portion are essentially produced.

[0088] In certain embodiments, the shape of the mold can be adapted according to the eye disorder to be treated. For example, for the treatment of farsightedness, the biomaterial can be added mainly to the central portion of the cornea, and for the treatment of nearsightedness, the biomaterial can be added mainly to the peripheral portion of the cornea.

[0089] Regarding the shape of the mold, the swelling of the crosslinkable liquid composition that may occur during crosslinking and the uptake of water by the biomaterial can be taken into account. For example, if it is known that a crosslinkable biomaterial swells to twice its size when crosslinked, and if the thickness of the crosslinked composition is desired to be about 50.0 μm (before curvature correction), the mold can be designed such that only a layer of the crosslinkable liquid composition with a thickness of about 25.0 μm is applicable. In certain embodiments, the radius of curvature of the central rear region of the contact lens is from 8.0 mm to 15.0 mm, from 8.0 mm to 14.0 mm, from 8.0 mm to 13.0 mm, from 8.0 mm to 12.0 mm, from 8.0 mm to 11.0 mm, from 8.0 mm to 10.0 mm.

[0090] The curvature of the contact lens enables a gap or a lens-shaped cavity to be formed between the front surface of the cornea of the subject to be treated and the rear surface of the central (optical) region of the contact lens, while the rear surface of the peripheral region preferably fits exactly along the peripheral region of the cornea or sclera. This gap or lens-shaped cavity can be filled with the crosslinkable composition as described elsewhere in this specification.

[0091] In certain embodiments, the shape of the mold is such that it can shape the crosslinked composition to have an average thickness before the step of correcting the curvature of the crosslinked composition that ranges from 20.0 μm to 400.0 μm, such as from 50.0 μm to 400.0 μm, from 100.0 μm to 400.0 μm, from 200.0 μm to 400.0 μm, or from 100.0 μm to 300.0 μm.

[0092] In certain embodiments, the mold covers at least 80%, at least 85%, at least 90%, or at least 95% of the anterior corneal surface of the eye, such as at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%. In certain embodiments, the mold completely covers the anterior corneal surface of the eye.

[0093] In certain embodiments, the shape of the mold enables shaping the crosslinked composition to have a diameter ranging from 6.0 mm to 9.0 mm, such as from 6.0 mm to 8.0 mm or from 7.0 mm to 9.0 mm. It has been found that a larger diameter can pose a risk of covering limbal epithelial cells that differentiate and migrate to become corneal epithelial cells. Thus, physically covering the limbus preferably forms a risk of internal growth of corneal epithelial cells or interferes with the differentiation of limbal stem cells, which should be avoided.

[0094] In certain embodiments, the overall diameter of the mold (including the diameter of the central region and the diameter of the peripheral region of the mold) for contact lenses or vacuum aspiration, etc., is from 5.0 mm to 30.0 mm, from 5.0 mm to 25.0 mm, from 10.0 mm to 25.0 mm, from 14.0 mm to 24.0 mm, from 5.0 mm to 10.0 mm, from 6.0 mm to 9.0 mm, or from 7.0 mm to 8.0 mm.

[0095] In certain embodiments, when crosslinking a liquid composition that can be crosslinked using UV irradiation or visible light, the mold is one that allows the UV or visible light to reach the crosslinkable liquid composition. For example, if the mold is a contact lens, the contact lens is one that allows the passage of UV or visible light.

[0096] In certain embodiments, after filling the mold with the crosslinkable liquid composition, the mold and the crosslinkable liquid composition are applied to the front surface of the cornea of the eye.

[0097] In certain embodiments, the crosslinkable liquid composition is applied to the front surface of the cornea of the eye in a volume ranging from 25.0 μl to 200.0 μl, from 25.0 μl to 100.0 μl, preferably from 50.0 μl to 100.0 μl, for example, about 50.0 μl. By using a combination of the mold and a limited volume amount, it is further possible to avoid the crosslinkable composition from overflowing across the entire front surface of the eye and / or under the eyelid before crosslinking.

[0098] In embodiments, the method may include applying the mold to the front surface of the cornea of the eye either before or after applying the crosslinkable liquid composition to the mold. In embodiments of the uses or methods taught herein, the mold may be a corneal vacuum suction device, a corneal bath, or a contact lens, and the method includes applying the mold to the front surface of the cornea of the eye before applying the crosslinkable liquid composition to the mold, crosslinking the composition, and removing the mold after crosslinking of the crosslinkable liquid composition.

[0099] In certain embodiments, the method includes maintaining the mold at a predetermined position on the front surface of the cornea of the eye throughout the period of crosslinking the crosslinkable liquid composition.

[0100] In certain embodiments, if the mold is a contact lens, place the center of the contact lens at the center of the front surface of the cornea.

[0101] In certain embodiments, the method includes removing the mold after crosslinking of the crosslinkable composition (and optionally, prior to correcting the curvature of the crosslinked composition if correction is contemplated).

[0102] In certain embodiments, the crosslinkable liquid composition is supplied as a single layer to the anterior surface of the eye's cornea. Correspondingly, in certain embodiments, the crosslinked composition on the anterior surface of the eye's cornea consists of a single layer of biomaterial. In certain embodiments, the single layer of biomaterial is uniform, i.e., composed of one and the same biomaterial.

[0103] In certain embodiments, prior to applying the mold and the crosslinkable liquid composition to the anterior surface of the eye's cornea, epithelial cells are removed from the anterior cornea to expose the corneal stroma for implanting a corneal ring segment into the corneal stroma. The corneal epithelial cells can be removed from at least a portion of the anterior cornea by any means known in the art, for example, by using alcohol delamination, a blunt knife, a diamond burr, a cotton swab, or an Amoils brush. Alternatively, the surgeon can choose to remove the epithelium after placing the mold (to remove only the epithelial cells within that area).

[0104] In certain embodiments, the methods taught herein do not include removing or damaging Bowman's membrane, the corneal stroma, or combinations thereof prior to applying the crosslinkable liquid composition to the anterior surface of the eye's cornea.

[0105] In certain embodiments, crosslinking is by photo-crosslinking, O 2It is carried out by exposure or by one or more enzymes such as transglutaminase, transferase, tyrosinase and peroxidase. In the case of enzymatic cross-linking, the enzyme and the polymer capable of cross-linking can be mixed in a so-called dual-barrel syringe adapted for direct mixing at a predetermined ratio at the time of application. In a preferred embodiment, the cross-linking is carried out by photocross-linking, for example, by using UV light or visible light, more preferably by UV irradiation.

[0106] The UV spectrum generally extends from 250 nm to 450 nm. The wavelength of the UV irradiation is preferably from 250 nm to 450 nm, from 300 nm to 450 nm or from 300 nm to 400 nm, for example about 365 nm.

[0107] In certain embodiments, the cross-linkable liquid composition is cross-linked until at least 80.0%, preferably at least 90.0%, for example 99.9% or 100.0% of the cross-linkable liquid composition is cross-linked. In certain embodiments, UV irradiation is used and the cross-linkable liquid composition is cross-linked for a period of at least 10 minutes, at least 20 minutes, at least 30 minutes, or at least 40 minutes, preferably at least 30 minutes.

[0108] In certain embodiments, the total dose of UV used during UV irradiation is at least 0.7 joules (J) / cm 2 、at least 0.8 joules (J) / cm 2 、at least 0.9 joules (J) / cm 2 、at least 1.0 joules (J) / cm 2 、at least 2.0 joules (J) / cm 2 、at least 3.0 joules (J) / cm 2 、at least 4.0 joules (J) / cm 2 or at least 5.0 joules (J) / cm 2 、preferably at least 1.0 joule / cm 2 or at least 5 joules / cm 2, for example, about 5.4 J / cm 2 is. The irradiation force or intensity is from 1 mW / cm 2 to 10 mW / cm 2 and this is inversely correlated with the irradiation time.

[0109] In the method of the present invention, the crosslinking is carried out in situ on the anterior surface of the eye's cornea. Thus, in certain embodiments, the crosslinking is carried out at body temperature, for example, at a temperature from 35.0 °C to 40.0 °C or from 36.0 °C to 38.0 °C.

[0110] The methods taught herein provide an easy-to-use long-term treatment for chronic or subacute corneal diseases with refractive anomalies or corneal irregularities. The crosslinked composition on the anterior surface of the eye's cornea has resistance to biodegradation, so the risk of complications after the procedure, such as dry eye disease, pain or regression of the applied correction, is low and there is no need for regular replacement.

[0111] In certain embodiments, the crosslinked composition has resistance to biodegradation over a period of at least 6 months, preferably at least 12 months. The resistance to biodegradation can be controlled by the monomer / oligomer type of the biomaterial, the concentration of the polymer in the crosslinkable liquid composition, the molecular weight of the monomer of the biomaterial and / or the degree of substitution of the monomer / oligomer of the biomaterial. The degree of crosslinking can also be controlled by crosslinking parameters such as UV crosslinking parameters like duration and light intensity. The resistance to biodegradation can also be adjusted by mixing different types of polymers. For example, hydrogels based on polyethylene glycol (PEG) generally have higher resistance to biodegradation than protein-based hydrogels and these can be mixed.

[0112] In certain embodiments, the crosslinkable liquid composition is resistant to degradation by matrix metalloproteinases (MMPs) of the corneal epithelium, such as MMP-1, MMP-2, MMP-3, MMP-9, or combinations thereof.

[0113] Crosslinking of the crosslinkable liquid composition on the anterior surface of the eye's cornea results in adhesion due to the formation of covalent bonds with the amino acids of corneal collagen between the crosslinked composition or corneal annulus and the anterior surface of the eye's cornea. In certain embodiments, the posterior surface of the crosslinked composition adheres to the Bowman's membrane of the eye with an adhesion strength of at least 10.0 kPa, preferably an adhesion strength from 10.0 kPa to 100.0 kPa. The adhesion strength can be determined by any method known in the art, for example, using a gelatin-coated glass slide in accordance with ASTM F2255 and a lap shear test using a general testing machine.

[0114] In certain embodiments, the posterior surface of the crosslinked composition contacts the Bowman's membrane of the eye.

[0115] In certain embodiments, the crosslinked composition is flexible. The flexibility of the crosslinked composition can be altered by changing the type of biomaterial used, the concentration of the biomaterial used in the crosslinkable liquid composition, the degree of substitution of the biomaterial used, or the molecular weight of the biomaterial used. The flexibility of the crosslinked composition is preferably similar to that of the native cornea.

[0116] In certain embodiments, it may be interesting to correct the curvature of the anulus after crosslinking a composition capable of crosslinking on the anterior surface of the eye's cornea. More particularly, the shape of the crosslinked composition can be adjusted for optimal treatment of eye disorders and / or patient-specific treatments, such as vision correction tailored to the patient. For example, the radius of curvature of the crosslinked composition can be corrected, for example, by using photoablation, to treat eye disorders. By adjusting the shape of the crosslinked composition, the refractive properties of the eye being treated can be varied in a desired manner to correct eye disorders, such as refractive anomalies.

[0117] It will be understood by those skilled in the art that the radius of curvature of the crosslinked composition can be corrected differently depending on the eye disorder being treated. For example, for the treatment of farsightedness, the biomaterial can be mainly maintained in the central part, and for the treatment of nearsightedness, the biomaterial can be mainly maintained in the peripheral part. The depth of ablation of the corneal anulus is correlated with the expected refractive correction and is calculated in the same way as current laser refractive surgery. An individualized treatment profile, also known as a nomograph, is created and transferred to the laser for treatment. Note that the method of refractive correction is different from current strategies due to the inherent properties of corneal anulus technology. In the case of myopia, in laser refractive surgery, the peripheral tissue is reduced, while with corneal anulus, myopia is corrected by adding peripheral tissue. The reverse is also true. In laser refractive surgery, hyperopia is corrected by removing tissue in the central-peripheral part, while with corneal anulus, hyperopia is corrected by adding tissue to the central part (Figure 10).

[0118] In certain embodiments, the crosslinked composition is photoablated to obtain refractive correction, preferably spherical refractive correction in the range from -20 diopters to +10 diopters. In certain embodiments, the crosslinked composition is photoablated such that the crosslinked composition has a central portion having a substantially uniform thickness extending from at least the lower surface to the upper surface of the crosslinked composition, and the crosslinked composition has an optical power in the range from -20 diopters to about +10 diopters, preferably from -10 diopters to about +5 diopters, along at least the inner portion of the crosslinked composition. In certain embodiments, the cornea of the eye is not photoablated.

[0119] In certain embodiments, when the eye disorder is astigmatism, the crosslinked composition is photoablated to obtain an aspherical shape.

[0120] In certain embodiments, the crosslinked composition is photoablated to obtain a lens shape, for example, where the thickness at the periphery of the outer portion of the crosslinked composition is from 10.0 μm to 50.0 μm and increases to from 30.0 μm to 100.0 μm towards the central portion of the crosslinked composition.

[0121] In certain embodiments, the upper surface of the crosslinked biomaterial is photoablated to shape the upper surface.

[0122] Furthermore, those skilled in the art will also understand that when determining the amount of the crosslinked composition to be removed from the eye to treat an eye disorder, the swelling of the crosslinked composition that may occur when the epithelial cells grow to cover the crosslinked composition should be taken into account.

[0123] Photoablation can be performed using a laser such as an excimer laser.

[0124] In certain embodiments, the correction of the curvature of the crosslinked composition does not include removing corneal tissue such as corneal stromal tissue, for example, by photoablation.

[0125] In certain embodiments, correction of the curvature of the crosslinked material is not necessary. This applies when the layer of material is very thin and / or when a mold can be used to ensure that the material after crosslinking is precisely the desired shape and thickness. In certain embodiments, when the treatment of chronic or subacute corneal diseases is the main purpose, photoablation of the corneal endothelium is not performed.

[0126] In certain embodiments, the methods taught herein are reversible, i.e., if necessary, the crosslinked composition can be completely removed from the anterior surface of the eye's cornea, for example, by photoablation, hydrodissection, microkeratome or manual scraping.

[0127] After correcting the curvature of the crosslinked composition, the corneal epithelium can spontaneously reorganize originating from the limbus, which is the transition region between the cornea and the sclera. The growth of the corneal epithelium to cover the crosslinked composition generally occurs within 1 to 2 weeks after correcting the curvature of the crosslinked composition. In certain embodiments, to improve the regrowth of the corneal epithelium, one or more therapeutic agents, such as NGF, are administered to the eye.

[0128] The subject may be treated postoperatively with a therapeutic agent, such as a corticosteroid, and / or an antibiotic, that reduces pain and / or inflammation.

[0129] Although the invention has been described in conjunction with specific embodiments, it is obvious that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, the invention is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and scope of the appended claims.

[0130] The aspects and embodiments of the present invention disclosed in this specification are further supported by the following non-limiting examples.

Example

[0131] Example 1. Crosslinking of Biomaterials to the Anterior Surface of the Cornea of Human Donor Eyes 1.1. Materials and Methods Research-grade cadaver human donor eyes were placed in a povidone iodine solution and disinfected for 1 minute. Subsequently, the donor eyes were washed three times for 5 minutes each in 1× phosphate buffered saline (PBS). Next, the cornea was excised from the donor eyes using a circular trephine to obtain a corneoscleral ring, which was maintained in PBS until further use. A photo-crosslinkable solution (also referred to as a polymer solution) was prepared from gelatin methacryloyl (GelMA; Advanced Biomatrix #5208). The polymer solution (10% (weight / volume)) was warmed at 37 °C and mixed with an appropriate concentration of a photoinitiator (GelMA 10% (weight / volume) and 2 mol% of irgacure 2595 (Merck 410896)). 50 μL of the polymer solution + photoinitiator was loaded onto a silicone hydrogel contact lens and placed on the top of the human donor cornea. The cornea with the polymer was placed in an AnalytikJena crosslinker (365 nm) and left for approximately 20 minutes with a cumulative irradiance of 5400 mJ / cm 2 The contact lens was removed and the eye was rehydrated. Forceps were used to investigate the adhesion of the polymerized material to the cornea. The cornea with the implant was imaged using optical coherence tomography (CASIA2 OCT device) while holding it with forceps. The corneal implant was measured using the built-in CASIA2 software.

[0132] 1.2. Results A corneal surgeon with expertise in corneal sealants and tissue adhesives determined that the methacrylated gelatin adhered firmly to the corneal surface (Figure 1). Subsequently, imaging using optical coherence tomography showed that the adhesion of the Anlay to the cornea was appropriate, with a central thickness of approximately 1000 μm and a thinning of the peripheral region (Figure 2). Based on corneal curvature measurements, an increase in corneal thickness resulted in a change in the refractive power of the cornea (data not shown).

[0133] Example 2. Gel fraction, water uptake and transparency of methacrylated gelatin 2.1 Materials and methods Gelatin methacrylate (GelMa) was used with phosphate buffered saline (1×) as the solvent at different concentrations (5 wt / vol%, 10 wt / vol% and 15 wt / vol%).

[0134] Different photoinitiators were added to the GelMa solution at different dosages and stored in amber vials to protect from light: Irgarcure 2595 (I2595): 0.5% (“Irga1”) and 1% (“Irga2”) Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP): 0.125% (“LAP1”) and 0.250% (“LAP2”)

[0135] One drop of the GelMa solution + photoinitiator was dropped onto a glass Petri dish.

[0136] The GelMa solution + photoinitiator was crosslinked at 365 nm with a total dose of 5.4 J / cm 2 as.

[0137] The gel fraction is defined as the weight ratio of the dry network polymer (crosslinked material) to the polymer before washing with the solvent. The weight was determined using a Sartorius BP211D microbalance.

[0138] The swelling ratio is defined as the rate of increase in the weight of the hydrogel due to water absorption. The weight increase was determined at predetermined intervals using a Sartorius BP211D microbalance.

[0139] The transparency (% light transmittance) was converted from the absorbance value using the following equation: %T = 10 (2-A) (%T = transparency; A = absorbance). The absorbance value was measured using a Tecan multimode microplate reader.

[0140] 2.2 Results Figure 3 shows that the gel fraction of GelMA increased with the polymer concentration due to the increase in the polymer density of the crosslinked bonds.

[0141] Figure 4 shows the water uptake when different photoinitiators were used for different concentrations of GelMA. The hydrogel with the lowest concentration of GelMA showed the highest water uptake, and vice versa, which can be explained by the increase in the gel fraction and thus the viscosity of the hydrogel with the increase in the polymer concentration. Equilibrium was reached after 4 hours for all concentrations.

[0142] Figure 5 shows that the transparency of GelMA was at least 75% as measured across the visible spectrum. No significant difference in transparency was observed for any polymer concentration or photoinitiator concentration.

[0143] Example 3. An exemplary method for treating refractive abnormalities of the eye, such as myopia, illustrated in Figure 6 1. Diagnose the patient's refractive abnormality according to established methods. 2. Remove the patient's corneal epithelium using diluted alcohol, a blunt knife, or an Amoils brush. 3. Apply the uncrosslinked polymer (dissolved photo-crosslinkable polymer and the final concentration of photoinitiator) to the uppermost part of the eye, where a mold, such as a contact lens or a vacuum suction device, is used throughout the crosslinking period. The volume of the solution is preferably 50 μL or less. 4. Irradiate the treated eye to completely crosslink and adhere the corneal annulus. The cumulative light dose of the UV light corresponds to or is less than the current UV irradiation protocol for the treatment of keratoconus (e.g., 5.4 J / cm 2 ). The irradiation time depends on the selected intensity. a. For example, when the photoinitiator used is Irgacure 2595: Ultraviolet light at 365 nm b. For example, when the photoinitiator used is LAP: Visible light in the range of 400 nm to 450 nm is also possible 5. During the crosslinking process, covalently bond the polymer to the extracellular matrix of the eye and rehydrate it (an isotonic eye drop can be administered). The equilibration period may be at least 4 hours. Before laser refractive surgery, remove the mold such as a contact lens or a vacuum suction device (before or after the equilibration period). 6. Subject the patient to laser refractive surgery and excise only the corneal annulus with an excimer laser, without excising the corneal tissue. 7. It is preferable to treat the patient with corticosteroids and antibiotics as used in refractive surgery. 8. The corneal epithelium grows spontaneously to cover the corneal annulus within 1 to 2 weeks after surgery.

[0144] Example 4. An exemplary method for treating refractive abnormalities of the eye such as farsightedness, illustrated in FIG. 7 1. Diagnose the refractive abnormality of the patient according to an established method. 2. Remove the patient's corneal epithelium using diluted alcohol, a blunt knife, or an Amoils brush. 3. Place an o-ring or a vacuum suction device on the upper part of the patient's cornea. 4. Apply the uncrosslinked polymer (dissolved photo-crosslinkable polymer and the final concentration of photoinitiator) into the o-ring or vacuum suction device. The volume of the solution is preferably 50 μL or less. 5. Irradiate the treated eye to fully crosslink and adhere the corneal onlay. The cumulative light dose of the UV light corresponds to or is less than the current UV irradiation protocol for the treatment of keratoconus (e.g., 5.4 J / cm 2 ). The irradiation time depends on the selected intensity. a. For example, when the photoinitiator used is Irgacure 2595: ultraviolet light at 365 nm b. For example, when the photoinitiator used is LAP: visible light between 400 nm and 450 nm is also possible 6. During the crosslinking process, covalently bond the polymer to the extracellular matrix of the eye and rehydrate it (isotonic eye drops can be administered). The equilibration period can be at least 4 hours. Remove the o-ring or vacuum suction device (usually before or during the equilibration period). 7. Subject the patient to laser refractive surgery and excise only the corneal onlay with an excimer laser, without excising the corneal tissue. 8. It is preferable to treat the patient with corticosteroids and antibiotics as administered after refractive surgery. 9. The corneal epithelium grows spontaneously to cover the corneal onlay within 1 to 2 weeks after surgery.

Explanation of Symbols

[0145] Drawing Translation Figure 2 Corneal onlay Cornea Figure 3 Gelfractie Y-axis Name Figure 4 Degree of swelling Time Figure 5 Trans Transparency Wavelength Figure 6 Uncorrected eye Uncorrected eye Fill mold with biopolymer and apply on eye Fill the mold with biopolymer and apply it to the eye Biopolymer crosslinking Biopolymer crosslinking UV light UV light Photoablation Photoablation Laser Laser Corrected eye Corrected eye Figure 7 Uncorrected eye Uncorrected eye Apply o-ring on cornea and fill with biopolymer Apply an o-ring to the cornea and fill it with biopolymer Biopolymer crosslinking Biopolymer crosslinking UV light UV light Photoablation Photoablation Laser Laser Corrected eye Corrected eye Figure 8 Cornea Cornea Corneal onlay Corneal onlay Figure 10 Photoablated cornea for refractive correction according to traditional methods Photoablated cornea for refractive correction according to traditional methods Corneal onlay for refractive correction Corneal onlay for refractive correction Myopia Myopia Hyperopia Hyperopia

Claims

1. A pharmaceutical product comprising a crosslinkable liquid composition for treating an eye disorder in the target eye, wherein the pharmaceutical product is Applying the crosslinkable liquid composition to the corneal surface of the eye, including the eye disorder, Optionally, corneal epithelial cells have been removed from the anterior surface of the cornea. The crosslinkable liquid composition is crosslinked on the anterior surface of the cornea of ​​the eye, and by this crosslinking, a crosslinked composition is obtained on the anterior surface of the cornea of ​​the eye. And optionally, The curvature of the cross-linked composition is corrected. Includes, The aforementioned eye disorder is a chronic or subacute corneal disease accompanied by refractive errors or corneal irregularities. A pharmaceutical product in which the crosslinkable liquid composition can be introduced into a mold positioned on the anterior surface of the cornea of ​​the eye.

2. The pharmaceutical product according to claim 1, wherein the crosslinkable liquid composition comprises a crosslinkable biomaterial and optionally one or more photoinitiators, and the crosslinkable biomaterial is functionalized with methacrylate, diacrylate, or diacrylamide.

3. The pharmaceutical product according to claim 1 or 2, wherein the mold is a corneal bath or a contact lens, and the pharmaceutical product comprises applying the mold to the surface of the cornea of ​​the eye either before or after applying the crosslinkable liquid composition to the mold.

4. The pharmaceutical according to claim 1 or 2, wherein the pharmaceutical comprises removing the mold after crosslinking the crosslinkable composition.

5. The pharmaceutical product according to claim 1 or 2, wherein the crosslinkable liquid composition is applied as a single layer.

6. The pharmaceutical product according to claim 1 or 2, wherein the crosslinkable liquid composition comprises a crosslinkable biomaterial and optionally one or more photoinitiators.

7. The pharmaceutical product according to claim 6, wherein the crosslinkable biomaterial is selected from the group consisting of protein-based polymers, polysaccharide-based polymers, and synthetic polymers.

8. The aforementioned crosslinking bond is formed by photocrosslinking, O 2 The pharmaceutical product according to claim 1 or 2, which is carried out by exposure to or by one or more enzymes, preferably by photocrosslinking such as UV irradiation.

9. The pharmaceutical product according to claim 1 or 2, wherein the crosslinked composition has a diameter of 6.0 mm to 9.0 mm and a thickness of 20.0 μm to 400.0 μm before the curvature of the crosslinked composition is corrected.

10. The pharmaceutical product according to claim 1 or 2, wherein the crosslinked composition is resistant to biodegradation for a period of at least 6 months, preferably at least 12 months.

11. The pharmaceutical product according to claim 1 or 2, wherein the refractive error is selected from the group consisting of myopia, hyperopia, astigmatism, and presbyopia.

12. The pharmaceutical product according to claim 1 or 2, wherein the chronic or subacute corneal disease accompanied by corneal irregularity is selected from the group consisting of corneal ulcer, corneal erosion, corneal diastolic disorder, or corneal irregularity caused by trauma or epithelial basement membrane dystrophy.

Images